Hereditary Nystagmus and Strabismus (including Congenital Cranial Dysinnervation Disorders and Okihiro Syndrome)

Class of congenital ocular motility disorders of genetic or mixed aetiology: idiopathic infantile nystagmus (the X-linked FRMD7 form and rare autosomal forms), the congenital cranial dysinnervation disorders (isolated and syndromic Duane syndrome, including Okihiro syndrome due to SALL4, congenital fibrosis of the extraocular muscles, horizontal gaze palsy with progressive scoliosis, the HOXA1 syndromes and Moebius sequence) and comitant strabismus of multifactorial inheritance.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope of the class

Nystagmus is an involuntary, repetitive oscillation of the eyes, which parents often describe as «shaking eyes»; it is a sign of disordered oculomotor control and not a diagnosis. In infancy, nystagmus may be the first manifestation of a bilateral visual deficit, whereas later-onset nystagmus more probably points to neurological disease [71]. Strabismus is the misalignment of the visual axes; it affects 4–5% of children according to the Oxford Desk Reference and 0.8–6.8% depending on the population according to the American Academy of Ophthalmology (AAO) guideline, with a much higher frequency in children with neurodevelopmental disorders [15, 41]. This article brings together the hereditary forms of both signs when they constitute the main manifestation: idiopathic infantile nystagmus, whose best-known molecular form is the X-linked form due to variants in FRMD7, and hereditary strabismus, which includes comitant strabismus of multifactorial basis and the congenital cranial dysinnervation disorders (CCDD), a group of incomitant strabismus disorders of neurodevelopmental origin [1, 3, 5].

The class also includes Okihiro syndrome (Duane-radial ray syndrome), which is covered here in full as a syndromic form of Duane syndrome, because the same gene, SALL4, causes apparently isolated Duane and multisystem presentations with malformations of the upper limbs, kidneys, heart and ear [5, 22]. Diseases in which nystagmus is secondary to a sensory disease are covered only in the differential diagnosis: oculocutaneous and ocular albinism, including GPR143, aniridia and the PAX6 spectrum, isolated foveal hypoplasia and FHONDA syndrome, Leber congenital amaurosis, cone dystrophies and achromatopsia, and congenital stationary night blindness.

1.2. Definition of each entity

Idiopathic infantile nystagmus (IIN) is nystagmus present at birth or arising in early infancy without an identifiable afferent ocular defect or brain disease, with a normal electroretinogram (ERG) and visual evoked potentials (VEP); when a pathogenic variant in FRMD7 is identified, the recommended designation is FRMD7-related infantile nystagmus (FIN) [1]. Infantile nystagmus syndrome (INS) is the generic term for forms of nystagmus with onset in infancy, with or without a sensory defect, characterised by slow phases of increasing velocity; the CEMAS classification (Classification of Eye Movement Abnormalities and Strabismus, National Eye Institute, 2001) distinguishes INS from fusion maldevelopment nystagmus syndrome (FMNS, formerly latent or manifest latent nystagmus) and from spasmus nutans [1, 16, 72]. FMNS is the most frequent non-INS form of nystagmus in infancy and is associated with early loss of binocularity [16].

Duane syndrome is a congenital, non-progressive strabismus with limitation of abduction, adduction or both, accompanied by retraction of the globe and narrowing of the palpebral fissure on attempted adduction; it results from absence or hypoplasia of the abducens nucleus and nerve (cranial nerve VI) with aberrant innervation of the lateral rectus by branches of the oculomotor nerve (cranial nerve III) [5]. Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital, non-progressive ophthalmoplegia, with or without ptosis, affecting part or all of the territory of cranial nerve III and sometimes of IV and VI; despite the name, the muscle fibrosis is secondary to abnormal development of the oculomotor neurons and their axons [6]. Horizontal gaze palsy with progressive scoliosis (HGPPS) combines congenital absence of conjugate horizontal movements, with preserved vertical gaze and convergence, with scoliosis beginning in childhood and failure of decussation of brainstem tracts [8]. The HOXA1-related syndromes (BSAS and ABDS) combine horizontal gaze palsy or Duane type III with deafness due to inner ear aplasia, carotid artery anomalies and, in ABDS, central hypoventilation [7]. Moebius sequence is defined, by the minimum criteria, as congenital, non-progressive facial palsy, abduction deficit and complete vertical motility [70]. Okihiro syndrome (DRRS) combines the Duane anomaly, unilateral or bilateral, with radial ray malformations; together with acro-renal-ocular syndrome (AROS) and SALL4-related Holt-Oram syndrome, it forms a single spectrum of disorders due to SALL4 haploinsufficiency [22].

1.3. Historical overview and milestones of molecular discovery

Duane syndrome owes its name to the ophthalmologist Alexander Duane (1858–1926). For decades it was attributed to a myogenic origin, through fibrosis of the lateral rectus or the medial rectus (Matteucci, 1946), until electromyography, autopsies and magnetic resonance imaging demonstrated its neurogenic nature: Scott and Wong (1972) recorded simultaneous activation of the medial and lateral recti, explaining globe retraction by co-contraction, and Hotchkiss and colleagues (1980) documented at autopsy the absence of abducens nucleus motor neurons and of the ipsilateral cranial nerve VI, with partial innervation of the lateral rectus by branches of cranial nerve III [5]. The description of Moebius sequence goes back to P. J. Moebius, who in 1888 described congenital bilateral abducens and facial palsy; Henderson reviewed 61 cases of congenital facial diplegia in 1939 [70]. The association between Duane and radial ray defects was described by Ferrell and colleagues in 1966, by Temtamy and colleagues in 1975 and by Okihiro and colleagues in 1977, in a three-generation family; Temtamy and McKusick called it Duane/radial dysplasia syndrome in 1978 and the designation «Okihiro syndrome» was first used by Hayes and colleagues in 1985 [22, 73].

The CCDD concept was proposed at the 110th International Workshop of the European Neuromuscular Centre (ENMC), in Naarden (Netherlands), in October 2002, to designate congenital disorders of the innervation of the cranial musculature [2, 5]. The following decade brought the identification of the main genes: heterozygous variants of KIF21A, a kinesin, were found in 44 of 45 probands with CFEOM1 (Yamada and colleagues, 2003) [74]; biallelic variants of PHOX2A (ARIX) were associated with CFEOM2 in 2001 [75]; in 2002, Okihiro syndrome was mapped to 20q13 and attributed to SALL4 variants [76, 77]; ROBO3 was identified as the cause of HGPPS in 2004 [78]; homozygous truncating HOXA1 variants in three isolated populations were described in 2005, constituting the first human Mendelian disease due to a HOX gene critical for the central nervous system [79]; in 2006, Tarpey and colleagues identified 22 FRMD7 variants in 26 families with X-linked idiopathic nystagmus, after the locus had been mapped to Xq26–q27 by Kerrison and colleagues in 1999 [80, 81]; in 2008, hyperactivating CHN1 variants were associated with familial Duane [82]; in 2010, eight TUBB3 missense variants defined the «TUBB3 syndromes» [52]; in 2016, MAFB loss of function was associated with Duane with or without inner ear defects [39].

Recent research has shifted classification from phenotyping to molecular subtyping: a 2026 review lists, in addition to the classic genes, EBF3 in Duane and COL25A1, ECEL1 and ACKR3 in atypical or syndromic CCDD [3]. Exome and genome sequencing in 467 probands with unsolved ocular CCDD showed a yield of 9.2% and great heterogeneity [83], and a cohort of 149 patients with Moebius syndrome defined by strict criteria found no unifying germline cause [11]. In nystagmus, genome sequencing in the UK 100,000 Genomes Project established positive genetic findings in 46% of 473 patients with infantile nystagmus or albinism [18].

1.4. Nomenclature and reclassifications

The expression «congenital motor nystagmus» is outdated and has been replaced by IIN; «INS» designates the broader group of infantile nystagmus with a characteristic waveform, with or without a sensory defect [1]. Hertle proposed in 2002 renaming Duane syndrome as «co-contractive retraction syndrome» types 1 to 3, without widespread adoption; the syndrome is also called Duane anomaly or Stilling-Türk-Duane syndrome [5, 41]. The numbering of the Duane loci lends itself to confusion: the «2» of DURS2 designates the CHN1 locus at 2q31 and not clinical type II of the Huber classification, and the «3» of DURS3 designates the MAFB locus [84]. The name «Athabascan brainstem dysgenesis» (ABDS) was proposed by Holve and colleagues in 2003, replacing «Navajo brainstem syndrome» [7, 85]. Holt-Oram syndrome has also been called «heart-hand syndrome», a non-specific designation that applies to several conditions [22]. Reference repositories contain inaccuracies worth knowing: the GeneGuidance database assigns to Duane with deafness (DURS3) the code ORPHA:2774, which corresponds to multicentric carpotarsal osteolysis, whereas the Orphanet code for Duane with congenital deafness is ORPHA:529574; and it assigns the same ORPHA:69737 to BSAS and ABDS, whereas ABDS is ORPHA:69739 [86–89]. The Orphanet record for Duane syndrome (ORPHA:233) includes OMIM 616219, which corresponds to COL25A1-related CFEOM5, whose spectrum includes Duane with synergistic divergence [59, 90]. The cytoband of GPR143 appears as Xp22.32 in the Oxford Desk Reference and as Xp22.2 in current OMIM-derived records; this article uses Xp22.2 [33, 71]. The OMIM entry for NYS6 confirms Xp22.2 in the gene–phenotype table, although the text of the NYS1 entry still gives Xp22.3 for GPR143 [9, 31].

The OMIM numbering of congenital nystagmus has some peculiarities. The NYS1 entry records «idiopathic infantile nystagmus» as a former designation and includes X-linked infantile periodic alternating nystagmus, which Huygen and colleagues called XLPAN in 1995 and Hertle and colleagues XIPAN in 2005 [9]. The symbol NYS1 was used by Cabot and colleagues in 1999 for the Xp11.4–p11.3 locus, but it is reserved for the Xq26–q27 locus described by Kerrison and colleagues, so Cabot's locus became NYS5 [30]. The former designation NYS4 was reclassified and removed from the series, and the series includes an autosomal recessive form, NYS8 (OMIM 257400), due to ROBO1 variants at 3p12.3 [9, 26]. Outside nystagmus, the acronym IVIC comes from the Instituto Venezolano de Investigaciones Científicas, where the syndrome was described in 1980; Neri and Sammito proposed in 1989 the name «oculo-oto-radial syndrome», but the symbol OORS now designates another disease in OMIM [44]. Brown syndrome was initially attributed to an anomaly of the superior oblique tendon sheath («superior oblique tendon sheath syndrome») and later to restricted gliding of the tendon through the trochlea [91]. Wildervanck syndrome is also called cervico-oculo-acoustic syndrome [92].

In the current version of OMIM (entries edited in August 2026), the designations CFEOM1, CFEOM2 and CFEOM3, created as clinical categories, are now defined by gene: CFEOM1 corresponds to KIF21A, CFEOM2 to PHOX2A and CFEOM3, previously assigned to any family in which at least one member did not have the classic picture (unilateral ptosis, facial weakness or developmental delay, for example), now corresponds to TUBB3 [45, 49]. The former CFEOM3B, used for patients with asymmetric or unilateral involvement and a KIF21A variant, was merged into CFEOM1, because most share the variant with relatives who have the classic phenotype [45]. Within TUBB3, OMIM separates non-syndromic CFEOM3A from two syndromic forms: CFEOM3A1 (OMIM 621655), due to the p.Glu410Lys variant, with anosmia and developmental delay, and CFEOM3A2 (OMIM 621666), due to the p.Arg262His variant, with joint contractures, developmental delay and peripheral neuropathy [49, 50]. CFEOM3C (OMIM 609384) designates a single family with the translocation t(2;13)(q37.3;q12.11), and CFEOM4, or Tukel syndrome (OMIM 609428), is mapped to 21qter; the locus symbols do not follow this numbering (FEOM1 at 12q12, FEOM2 at 11q13, FEOM3 at 16q24 and FEOM4 at 13q12), and the FEOM4 locus lies in the chromosomal region of CFEOM3C and not in that of Tukel syndrome [45, 49]. Three entities previously considered distinct, generalised fibrosis syndrome, vertical retraction syndrome and congenital fibrosis of the inferior rectus, coexisted in a single family from the Wessex region, which removed the basis for that subdivision [45]. In the series of complex cortical dysplasias, TUBA1A-related CDCBM16 (OMIM 611603) replaced the former designation lissencephaly 3, and TUBB2B-related CDCBM7 (OMIM 610031) has symmetric or asymmetric polymicrogyria as its alternative title [53, 55]. For Okihiro syndrome, OMIM uses the designation «Duane-radial ray syndrome» (DRRS), in which the hyphen indicates the sum of two manifestations and not a second syndrome described by Duane; Temtamy advocated the acronym «DR syndrome», with D for Duane and deafness and R for radial and renal, having described the association before Okihiro, and acro-renal-ocular syndrome corresponds to the same entity [42]. Moebius sequence was defined in 2007, at a research conference of the Moebius Syndrome Foundation, as congenital non-progressive facial weakness with limited abduction of one or both eyes, and OMIM considers it distinct from hereditary congenital facial paresis, restricted to the facial nerve [67]. DCC-related HGPPS2 has developmental split-brain syndrome as an alternative designation [62].

2. Molecular Genetics and Pathophysiology

2.1. General mechanisms

The genes of this class act at two distinct levels. In idiopathic infantile nystagmus, the defect lies in the circuits that stabilise gaze and generate the optokinetic and vestibulo-ocular reflexes, without damage to the retina or the afferent visual pathways; the waveform with a slow phase of increasing velocity is practically pathognomonic of INS, regardless of age and of the presence of a sensory deficit [1, 16]. In CCDD, the defect lies in the development of the cranial motor neurons: changes in neuronal differentiation or identity (MAFB, HOXA1, SALL4, PHOX2A) prevent the formation of a nucleus or nerve, and changes in axon guidance (CHN1, KIF21A, TUBB3, ROBO3) cause axons to fail to reach the target muscle or to cross the midline; when the proper nerve is missing, branches of another nerve innervate the orphaned muscle, which explains the characteristic paradoxical movements, such as globe retraction in Duane, synergistic convergence in CFEOM and the Marcus Gunn phenomenon [3, 6, 93]. In common comitant strabismus no major gene has been identified and the genetic contribution is polygenic, with an effect mainly on esodeviation [12, 94].

2.2. FRMD7 and X-linked infantile nystagmus (NYS1)

FRMD7 is located at Xq26.2, has 12 exons and encodes a 714-amino-acid protein with FERM domains (FERM_F1, FERM_B and FERM_C) and an FA domain encoded by exons 1 to 11; the MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript is NM_194277.3 (ENST00000298542.9; protein NP_919253.1), whereas the 2018 GeneReviews uses the previous version NM_194277.2 [1, 4, 95]. The protein is located in the neuronal cell body, the primary dendritic extensions and the tips of growth cones and promotes neurite outgrowth, probably by activating RAC1 [1, 96]. In the human embryo at about 37 days, expression is restricted to the midbrain and hindbrain, regions that control eye movements, and occurs in the developing optokinetic and vestibulo-ocular reflex arcs and in the neural retina [1, 80]. In the mouse retina, Frmd7 is expressed in starburst amacrine cells and is required to establish the asymmetric inhibitory inputs of these cells onto direction-selective ganglion cells; loss-of-function mice lack the horizontal optokinetic reflex and horizontal direction-selective retinal responses, which corresponds to the absent or reversed horizontal optokinetic response observed in patients, with a preserved vertical response [25, 97].

The mechanism is mainly loss of function. The frameshifts studied escape nonsense-mediated decay, but the truncated protein is degraded in the proteasome, which reduces the dose of functional protein; the C-terminally truncated protein has an abnormal nuclear localisation [1, 25]. Among four missense variants studied in vitro (NM_194277.3:c.812G>A p.(Cys271Tyr), c.685C>T p.(Arg229Cys) and, in the published designation, p.Gly24Glu and p.Ser340Leu), p.(Cys271Tyr) had the most severe cellular phenotype, through nuclear accumulation and inhibition of the neurite outgrowth mediated by the normal protein, a dominant-negative effect; the same line of work identified the FRMD7–CASK interaction [25, 98]. FRMD7 knockdown in Neuro-2A cells alters neurite outgrowth during retinoic acid-induced differentiation [1].

The variant spectrum is broad and scattered. A 2026 review collected 178 published variants in 390 families, from which two benign variants frequent in East Asia were excluded (NM_194277.3:c.1403G>A p.(Arg468His), with a frequency of 10.05%, and c.1961A>C p.(Glu654Ala)), leaving 176 variants in 389 families: 79 missense, 95 truncating and 2 in-frame deletions [4]. Thirty-four splicing variants have been published, 18 canonical and 16 non-canonical, including three deep intronic ones (NM_194277.3:c.284+63T>A, c.285-118C>T and c.383-1368A>G), and seven large deletions (1.8% of families); 78.9% of families had variants in the functional domains [4]. An intragenic deletion of exons 2 to 4 in a three-generation family, a deletion of exons 2 to 12 and a 1.29 Mb deletion encompassing FRMD7 in a patient with nystagmus and autism have been described [99–101]. In the Zhongshan Ophthalmic Center (Guangzhou) cohort, which included 10,530 families with genetic eye diseases sequenced by exome or extended panel, 56 pathogenic or likely pathogenic variants were found in 75 families with IIN, 33 of them novel: 31 missense, 1 in-frame deletion and 24 truncating (8 frameshift, 6 nonsense, 9 splicing and 1 synonymous with an effect on splicing); the most frequent were c.41_43del p.(Lys14del), c.1312del p.(Ser438GlnfsTer6) and c.910C>T p.(Arg304Ter), each in 4 of 75 families (5.3%), and c.811T>A p.(Cys271Ser) in 3 (4.0%) [4]. No FRMD7 copy number variation was detected in 149 families with IIN, and the variant NM_194277.3:c.742-3C>G caused, in a minigene assay, skipping of exon 9 or an AG insertion with frameshift [4]. The most frequent variant in the literature, c.875T>C p.(Leu292Pro), occurs in 6.9% of published families (27 of 389, 22 Korean and 5 from Japan, Europe or the USA) and was absent from the Chinese cohort, which suggests a Korean founder effect; in ClinVar it has conflicting classifications of pathogenicity [4, 102]. Truncating FRMD7 variants have an aggregate gnomAD frequency of 4.39×10⁻⁵ and the gene has a pLI of 0.73; exon 12 concentrates truncating variants (11.1% in the literature and 25.6% in the Chinese cohort), but missense variants in this exon have low scores and have almost never been observed in IIN [4].

To interpret FRMD7 missense variants, five in silico tools calibrated for the gene (REVEL, BayesDel_addAF, BayesDel_noAF, VEST4 and MetaRNN) had a sensitivity of 96.8% and specificities of 85.0% to 92.5%; the sum of the five reached a specificity of 97.5% and a Youden index of 0.94, against a specificity of 70.0% and Youden index of 0.67 for the set of 37 dbNSFP tools; SIFT, PolyPhen, CADD and AlphaMissense performed less well [4]. These thresholds derive from a single cohort and from published variants, and serve as supporting evidence, not as a stand-alone classification criterion.

Penetrance is complete or almost complete in hemizygous males (77 of 77 in the Chinese cohort) and incomplete in heterozygous females [1, 4]. GeneReviews estimates it at about 50% and the Leicester phenotypic study found 53% of obligate carriers clinically affected [1, 103]. In the Chinese cohort, 22 of 56 heterozygous females (39.3%) were affected: 12 of 23 with missense variants (52.2%), 9 of 27 with truncating variants (33.3%) and 1 of 6 with an in-frame deletion (16.7%), a difference without statistical significance in this sample (p=0.18) [4]. A 2026 multicentre study brought together 560 heterozygous females from 126 pedigrees (477 from 100 pedigrees in 40 publications and 83 from 26 pedigrees in two UK clinical cohorts) and found a clinical penetrance of 30.1% with truncating variants (74 of 246; 95% confidence interval, 95% CI, 24.7–36.1%) and 49.7% with non-truncating variants (156 of 314; 95% CI 44.2–55.2%), with an odds ratio of 2.12 (95% CI 1.32–3.40) in the generalised estimating equations model treating the pedigree as a cluster, robust to exclusion of each pedigree or publication and concordant between the literature and the institutional cohorts [25]. The authors stress the limitations: 100 of the 126 pedigrees come from the literature, with a bias towards symptomatic families; carriers with mild or subclinical manifestations may have been classified as unaffected, which underestimates absolute penetrance; and the binary classes group heterogeneous variants (loss of the start codon, exon deletions, non-canonical splicing) [25]. Eye movement recordings of clinically unaffected females may reveal subclinical nystagmus, and a subgroup has a subnormal optokinetic response [1, 103]. Estimates prior to identification of the gene came from linkage families: 54% penetrance in obligate carriers from three families (Kerrison and colleagues, 1999), 29% (6 of 21) when one of the pedigrees was extended (Kerrison and colleagues, 2001) and about 50% in three Korean families (Oh and colleagues, 2007), which explains the 30–54% range quoted for females [9]. Transmission was described as X-linked recessive in a Chinese family and as X-linked dominant in an English family with the same variant, and the classic literature already acknowledged that the same family may appear recessive in one branch and dominant in another [9].

The mechanism of incomplete penetrance in females is unresolved. Kaplan and colleagues described skewed X inactivation in a family with the missense variant NM_194277.3:c.685C>G p.(Arg229Gly) and proposed it as the explanation [104]; the GeneGuidance curation considers that skewed inactivation has not been demonstrated as a mechanism in this gene [96]; the 2026 study describes the evidence as conflicting and points out that inactivation assays in blood are of limited value for a gene that acts in the brainstem and retina [25]. The hypothesis that missense variants, through a dominant-negative effect, are more penetrant in carriers with skewed inactivation is speculative [4]. There is no male lethality and the disease is non-progressive, with normal life expectancy [96].

Genotype–phenotype correlation is weak: intra- and interfamilial variability is extensive, but periodic alternating nystagmus is predominantly associated with missense variants [1, 105]. Visual acuity did not differ between truncating and missense variants in the Chinese cohort (0.34 versus 0.36 logMAR; p=0.75) [4]. In the original series of Tarpey and colleagues, the 22 variants from 26 families included premature termination codons (NM_194277.3:c.601C>T p.(Gln201Ter) and c.1003C>T p.(Arg335Ter), which would preserve 28% and 47% of the protein), five splicing variants, four of them at the +1 and +2 nucleotides of the donor site, six missense variants at residues invariant across species and one synonymous variant (p.Val84Val, historical notation) that creates a new acceptor site in exon 4; none was present in 300 control X chromosomes [9]. In six unrelated Chinese families, He and colleagues identified the same 2 bp deletion (1274delTG, historical notation) on a common haplotype, a founder effect, and estimated from the literature that FRMD7 accounts for about 47% of X-linked nystagmus in Chinese patients [9]. In a four-generation family, nystagmus and deuteranomaly cosegregated because FRMD7 and the red–green opsin cluster lie about 11 cM apart on the same chromosome; recombinations separated the two traits in some relatives, which shows physical linkage and not a pleiotropic effect of FRMD7 [9]. In the series of Tarpey and colleagues, 15 of the 16 families linked to Xq26–q27 had an FRMD7 variant, but the yield was lower outside that context: 8 of 14 families with two or more affected individuals (57%) and 3 of 42 isolated cases of idiopathic congenital nystagmus (7%; 28 males and 14 females) [24]. In a three-generation family, two brothers with isolated infantile nystagmus were hemizygous for the intronic variant 1050+5G>A (historical notation), predicted to include 345 nucleotides of intron 11 and truncate the protein; the sister, mother and maternal grandmother, asymptomatic carriers, had prolonged pursuit with late corrective saccades on optokinetic drum testing, and a maternal aunt with nystagmus and CFEOM was not a carrier, so her presentation was attributed to another disease [24].

2.3. Other loci and genes of infantile nystagmus

Five IIN loci have been described: three autosomal dominant, NYS2 (OMIM 164100, 6p12), NYS3 (OMIM 608345, 7p11.2) and NYS7 (OMIM 614826, 1q31.3–q32.1), and two X-linked, NYS1 (OMIM 310700, Xq26.2, FRMD7) and NYS5 (OMIM 300589, Xp11.4); in NYS7, the defect identified is non-coding structural variants [4]. Autosomal dominant inheritance of IIN has been described in rare families [1]. The NYS6 form (OMIM 300814) is allelic to X-linked ocular albinism: variants of GPR143 (Xp22.2), the G protein-coupled receptor of the melanosome membrane, can cause nystagmus with mildly reduced acuity, strabismus and astigmatism without evident albinism, the mild end of a spectrum whose complete form is ocular albinism (OA1) [33]. The distinction has practical relevance: in a cohort from south-east China, GPR143 accounted for 11 of 98 families with INS (11.2%), all with foveal hypoplasia, and for 45.8% (11 of 24) of families with X-linked INS [106]. OMIM classifies NYS6 as X-linked recessive: in the three Chinese families that defined it, only males had nystagmus; in one of them, spanning six generations, with the GPR143 missense variant NM_000273.3:c.266C>T p.(Ser89Phe), four of the eight affected males also had foveal hypoplasia and reduced acuity, and three males and one female carrier had mottled retinal pigmentation, whereas in the other two, with a 37 bp deletion and a 14 bp duplication, there were no signs of ocular albinism [31].

In addition to the five loci usually listed, OMIM records an autosomal recessive form, NYS8 (OMIM 257400), due to ROBO1 variants at 3p12.3 [9]. This form rests on a single consanguineous Turkish family: three siblings aged 29 to 42 years with isolated bilateral horizontal nystagmus, normal neurological development, higher education and normal brain MRI in the two studied; the homozygous missense variant c.4565C>T p.(Ser1522Leu) (NM_002941.4 in ClinVar, with conflicting classifications of pathogenicity), identified by exome sequencing, exists in the heterozygous state in gnomAD with a frequency of 0.058% and in the homozygous state in one individual of African origin, which allows for incomplete penetrance or a mild phenotype that goes unnoticed [26, 102]. In Drosophila, the variant behaved as a partial loss-of-function allele, and OMIM keeps the gene–phenotype relationship as provisional [26]. The entries for the autosomal dominant loci and NYS5 document the evidence base of each. NYS2 (6p12) was mapped in a large African American family in which 21 of 54 living relatives had nystagmus, with a maximum lod score of 10.15; among those examined, binocular acuity ranged from 20/30 to 20/100 (mode 20/50), strabismus was present and the waveforms included asymmetric pendular and unidirectional jerk forms [27]. NYS3 (7p11.2) rests only on a haplotype shared by three affected members of one family and on a balanced translocation t(7;15)(p11.2;q11.2) present in a father and son with nystagmus and absent in unaffected relatives [28]. NYS5 (Xp11.4–p11.3) was defined in a four-generation French family with 12 affected individuals (7 females and 5 males), with X-linked dominant inheritance with incomplete penetrance and exclusion of linkage to the FRMD7 locus; the 18.6 cM interval contains genes for other X-linked eye diseases, such as complete congenital stationary night blindness [30]. In NYS7, two Chinese families with horizontal pendular nystagmus and normal anterior segment, retina and fovea, one spanning four generations with male-to-male transmission, had overlapping heterozygous deletions of 914 kb and 795 kb at 1q32 (GRCh37 coordinates) without coding genes, whose common region spans the boundary between two topologically associating domains (TAD) containing PTPRC and NR5A2; the proposed mechanism is three-dimensional genome reorganisation, and these deletions were only detected by short- and long-read genome sequencing and by array comparative genomic hybridisation, after the exome had been negative [29]. NYS2 was also observed as a probably dominant trait in the Old Order Amish community of Holmes County (Ohio) [27].

Heterozygous variants of MANBA, the lysosomal beta-mannosidase gene (4q24), were associated with autosomal dominant infantile nystagmus in a four-generation family: an obligate carrier in the first generation, her son and his two children (a boy and a girl) had the variant NM_005908.4:c.1913G>A p.(Arg638His), published as c.2013G>A in the numbering of the original article, with 50 to 65% of normal enzyme activity and no other signs of beta-mannosidosis; a second variant, NM_005908.4:c.2246T>A p.(Leu749His) (c.2346T>A in the article), was found in a man from a cohort with sporadic nystagmus whose parents were not studied [102, 107, 108]. Both variants reduced beta-mannosidase activity in the patients and in transfected HEK293T cells, the gene is expressed in the pretectal nucleus of the developing midbrain, a structure involved in optokinetic nystagmus, and the authors identified nystagmus in at least 24 lysosomal diseases with brain involvement [107]. The evidence is limited: OMIM records the association as pending confirmation and without its own phenotype number; p.(Leu749His) appeared in 248 of 121,234 ExAC alleles, with three homozygotes, all East Asian, and ClinVar classifies it as benign or likely benign for beta-mannosidosis, whereas p.(Arg638His), observed in 10 of 121,270 alleles and without homozygotes, has conflicting classifications [102, 108]. Biallelic beta-mannosidosis and the other glycoproteinoses are part of the differential.

A 1.44 Mb deletion at Xq26.1–q26.2 (NC_000023.11:g.130756102_132199443del, GRCh38), described in 2026 in a Bedouin family from southern Israel, completely removes FRMD7, IGSF1, ARHGAP36, OR13H1 and STK26 and the 5′ end of ENOX2 (about 147 kb, including 3 of the 15 coding exons) [34]. This contiguous deletion adds to nystagmus the endocrine risk of IGSF1 deficiency, an anterior pituitary glycoprotein: central hypothyroidism with low free thyroxine (FT4) and low or inappropriately normal thyroid-stimulating hormone (TSH), which may escape TSH-based newborn screening, hypoprolactinaemia, delayed pubertal rise in testosterone with normal or early testicular growth, macroorchidism in adulthood, transient growth hormone deficiency and increased adiposity; in a series quoted by the authors, female carriers had a milder biochemical phenotype (18% with low FT4, 60% low-normal and 22% with mild prolactin deficiency) [34]. The association between congenital nystagmus and central hypothyroidism was described by Schulman and Crawford in 1969, and cases with similar deletions include a newborn with a deletion of about 1.29 Mb, nystagmus and central hypothyroidism, and two brothers with an IGSF1 deletion without FRMD7, with mild congenital hypothyroidism and no nystagmus [34].

In 2026 an autosomal recessive form due to CACNB3, which encodes the β3 subunit of voltage-gated calcium channels, was proposed: in a family studied by groups from Germany and the United Kingdom, linkage analysis and exome sequencing identified the homozygous variant c.316G>C p.(Gly106Arg) in the SH3 domain, with reduced membrane localisation and increased calcium release mediated by the IP3 receptors of the endoplasmic reticulum [10]. This is evidence from a single family, with no ClinVar record; the notation refers to the MANE transcript NM_000725.4 according to the article and the gene should be regarded as a candidate [10, 95].

2.4. Duane syndrome: CHN1 and MAFB

CHN1 (2q31.1) encodes α2-chimaerin (N-chimaerin), a Rac-specific GTPase-activating protein (RacGAP) with an N-terminal SH2 domain, a central C1 domain similar to that of protein kinase C, which binds phorbol esters and diacylglycerol, and a C-terminal RhoGAP domain; the longest isoform (NP_001813.1) has 459 amino acids and acts as a direct effector of EphA4 in axon guidance [5, 84]. All pathogenic variants are gain-of-function missense variants: they increase RacGAP activity, translocation to the membrane or self-association, and none lies in the SH2 domain; deletions and loss of function are not expected as a cause [5, 82, 84]. In the chick embryo, chimaerin hyperactivity causes oculomotor axons to stall before the target; in Chn1 p.Leu20Phe knock-in mice, abducens axons stall, retract and degenerate and the lateral rectus becomes innervated by cranial nerve III axons, with globe retraction, whereas knockout mice show only initial defasciculation with partially correct innervation, which confirms gain of function [82, 109]. The reduced volume of the superior oblique on MRI of patients with CHN1 indicates hypoplasia of cranial nerve IV and defines CHN1-related Duane as a CCDD with guidance errors of cranial nerves VI, IV and III [110]. Penetrance may be reduced [5]. CHN1 variants also cause vertical strabismus and supraduction deficits without Duane, and there are isolated reports of a Moebius-like presentation or of more extensive cranial involvement [84, 110]. In zebrafish, two novel variants from families with Duane disrupted the development of the oculomotor nerves [84]. The DURS2 locus was mapped to 2q31 in a four-generation Mexican family with 25 living affected individuals (maximum lod score of 11.73), confirmed in a four-generation British family and in two North American families, one Hispanic and the other Caucasian, and analysis of the recombinations reduced the critical region from 9.9 to 4.6 Mb before CHN1 was identified [35]. In the Mexican family, 24 of the 25 patients had bilateral Duane type 1 or 3, 76% had manifest strabismus and 48% amblyopia, three had unilateral cranial nerve IV palsy, and congenital ptosis, unilateral deafness, nystagmus and seizures occurred in one patient each; in the British family, 8 of the 9 affected individuals had esotropia in primary position and 8 had an A or V pattern [35]. Multipositional orbital MRI of 8 patients from two families showed small orbital motor nerves, an often undetectable abducens nerve, structurally abnormal lateral recti in 7, signs of innervation of the lateral rectus by cranial nerve III branches destined for the vertical recti, and hypoplasia of the superior oblique, superior rectus or levator; only the medial and inferior recti and the inferior oblique were spared, which characterises DURS2 as a diffuse CCDD and not one limited to cranial nerve VI [35]. The nine missense variants recorded in OMIM (seven from 2008 and two from 2011, the latter at residues that stabilise the closed, inactive conformation of the protein) cosegregated with the disease and were absent from 788 control chromosomes; the families were of Mexican, North American Caucasian, British and Italian origin [36].

MAFB (20q12) encodes a 323-amino-acid transcription factor of the bZIP family, with an extended homology region, a basic DNA-binding region and a leucine zipper for dimerisation [5]. The murine allelic series shows that tissues differ in their sensitivity to loss of function: homozygous knockout causes Duane and inner ear defects, with perinatal lethality; 50% loss (null heterozygosity) causes Duane without hearing deficit; kreisler alleles with less than 50% function cause Duane and a common-cavity inner ear malformation; above 50% there is no phenotype [5]. In the absence of Mafb the abducens nucleus does not form and the lateral rectus is innervated by cranial nerve III, an aberrant innervation secondary to the lack of cranial nerve VI [39, 93]. In humans, three loss-of-function variants caused Duane and a dominant-negative variant (NM_005461.5:c.803del) caused Duane with sensorineural deafness in three of four affected relatives over three generations [5, 39]. The association between Duane and inner ear anomalies points, as with HOXA1, to an early disturbance of hindbrain development [5]. MAFB has two allelic diseases: multicentric carpotarsal osteolysis (OMIM 166300), due to missense variants clustered in a 51 bp region of the transactivation domain, with renal involvement in 70% of a European series of 54 patients, and non-coding variants associated with cleft lip and palate [5, 86]. Multicentric osteolysis usually begins in early childhood with episodes resembling juvenile idiopathic arthritis of the wrists and ankles, progresses to destruction of the carpal and tarsal bones and is frequently associated with nephropathy with hypertension and renal failure, which appears years after the osteolysis; in the series of Zankl and colleagues (2012), MAFB missense variants were found in all 11 isolated cases and in two families, and in these families nephropathy was absent, which shows that renal disease is not obligatory [111]. Penetrance of MAFB-related Duane showed no reduction in the limited number of families studied [5]. In the family that defined DURS3 with deafness, the mother and a son had Duane and right-sided deafness, with type 1 in the mother and type 3 in the son, and a granddaughter with bilateral Duane type 3 and deafness had a common-cavity malformation on CT of the petrous bone; on screening of 400 probands with Duane and 10 with Duane and deafness, the three additional families (two with 1 bp deletions and one with a deletion of about 600 kb encompassing only MAFB, with six affected individuals over two generations) did not have deafness, which supports the threshold model between 50% loss and more than 50% loss of function [37, 38]. In the heterozygous mouse embryo, the hypoplastic abducens nerve reaches the lateral rectus, but aberrant branches of cranial nerve III form towards the lateral rectus and the retractor bulbi; in the homozygote, the abducens nerve is absent and a branch of cranial nerve III follows the course it would have taken [38].

The DURS1 locus (8q13; OMIM 126800) was defined by chromosomal rearrangements, and microduplication or duplication of 8q12, the 8q13–q21.2 deletion and a de novo translocation t(6;8)(q26;q13) are associated with Duane with other cranial nerve deficits, dysmorphism, intellectual disability and heart disease; three reports suggest that abnormal CHD7 dosage explains the 8q12 phenotype [5]. The first localisation came from a de novo 8q12.2–q21.2 deletion with branchio-oto-renal syndrome, Duane, hydrocephalus and trapezius aplasia (Vincent and colleagues, 1994); comparison with other rearrangements narrowed the critical region to about 1 cM near EYA1 (Rickard and colleagues, 2001); and the translocation t(6;8)(q26;q13) disrupted CPA6, but 18 patients with sporadic Duane had only polymorphic variants of that gene [40]. In a study of 101 probands with isolated Duane and 30 with Duane and other findings, none had a HOXA1 variant, and the authors recommended looking for asymptomatic vascular anomalies, after a patient with apparently isolated Duane had revealed carotid hypoplasia [40]. The 2026 review adds HOXA1, SALL4 and EBF3 to the list of Duane genes, but most cases remain without a genetic diagnosis [3].

2.5. SALL4 and Okihiro syndrome

SALL4 (20q13.2) encodes a C2H2-type zinc finger transcription factor of the spalt family, essential for the maintenance of embryonic stem cells and for development of the limb bud, kidney, heart, ear and abducens motor neurons; the protein interacts with Nanog and is not expressed in adult somatic tissues, although it is re-expressed in some tumours, such as hepatocellular carcinoma [22, 112]. SALL4-related disorders result from haploinsufficiency: almost all variants associated with malformation syndromes are truncating and subject to nonsense-mediated decay, and whole-gene deletions produce the same phenotype [22]. Sequencing detects 85–90% of pathogenic variants and targeted deletion and duplication analysis the remaining 10–15% [22]. Most variants are private or have been observed in at most three independent families [22]. The first variants were found in 2002, in five families studied because of their clinical similarity to SALL1-related Townes-Brocks syndrome and, in the same year, in three families by mapping, including the original Okihiro family; in 2004, in six families without a point variant, loss of heterozygosity of intragenic SNPs and quantitative PCR revealed SALL4 deletions (of the whole gene, of exons 1 to 3, of exon 4 or of 8.9 kb including exon 1), de novo in the two sporadic cases, which established haploinsufficiency as the mechanism, in contrast to the probable dominant-negative effect of SALL1 variants [43]. By 2005, 22 variants had been described, all with a premature termination codon [43]. In the mouse, Tbx5 regulates Sall4 expression in the forelimb and heart, and the two factors interact in a circuit of positive and negative regulation, which provides a common basis for the TBX5- and SALL4-related heart-hand syndromes [43].

Two exceptions are informative. The variant p.Arg905Ter (c.2713C>T) is predicted to escape mRNA decay and generates a protein with a non-functional zinc finger, associated with great clinical variability and severe hemifacial microsomia in one family member; the missense variant c.2663A>G p.(His888Arg) replaces an amino acid essential for zinc coordination, is predicted to increase DNA binding and is associated with midline defects (single central incisor, pituitary hypoplasia, hypertelorism) with mild Okihiro features (both on NM_020436.5) [22]. In the opposite direction, three missense variants that increase SALL4 expression and POU5F1 activation (c.541G>A p.(Val181Met), c.1790A>G p.(Lys597Arg) and c.2279C>T p.(Thr760Ile)) behave as gain of function and cause only premature ovarian insufficiency, without malformations, whereas carriers of loss-of-function variants do not have reduced fertility; the direction of the effect determines the phenotype, so a missense variant cannot be equated with a truncating one [22]. Patients with DRRS and developmental delay probably have a larger deletion including neighbouring genes (20q13.13–q13.2 microdeletion), since development and cognition are normal in the intragenic forms [22, 73]. In a family with a frameshift variant, some members had mild thrombocytopenia and leucocytosis, a finding that underlies the designation IVIC syndrome (OMIM 147750); two missense variants have been associated with isolated ventricular septal defect, without the causal relationship being established [22]. IVIC syndrome was described in 1980 by Arias and colleagues in 19 living descendants of a Venezuelan family of Canary Islands origin, over six generations and with complete penetrance: radial ray defects of highly variable expression (from an almost normal thumb to a severely malformed upper limb), constant involvement of the radial carpal bones, strabismus due to extraocular muscle involvement in most, bilateral non-progressive congenital mixed hearing loss, mild thrombocytopenia and leucocytosis, and, in some, imperforate anus and renal malrotation; in 2007 a heterozygous SALL4 variant, present in 14 affected individuals, was identified in this family [43, 44]. Subsequently an Italian family with father-to-son transmission, a family with an affected mother and son and a Turkish family with discordant monozygotic twins (one with hand anomalies and hearing loss, the other with strabismus only) were described, which points to epigenetic or environmental modification of expression; as only one family has molecular confirmation, OMIM keeps the relationship with SALL4 as provisional and considers DRRS an allelic disease with a similar phenotype [44].

Penetrance is about 95%: in 2004, only one of 69 known carriers (1.4%) was clinically unaffected, and in one of the families with non-penetrance all carriers had a mild phenotype, with thenar hypoplasia and Duane [22]. The cases of apparently isolated Duane with a SALL4 variant described had relatives with DRRS (isolated Duane in 1 of 8 and in 1 of 4 affected individuals from two families), and 25 patients with non-familial isolated Duane had no SALL4 variants [5]. In the Chinese series of 42 patients with Duane, a de novo SALL4 splicing variant (c.1432-2A>T, published designation; the position does not correspond to an intron–exon boundary in NM_020436.5) was found in a patient with Duane type 1 [113].

2.6. Congenital fibrosis of the extraocular muscles

KIF21A (12q12) encodes a kinesin; heterozygous missense variants cluster at hotspots in the stalk domain and account for about 55% of all CFEOM, predominantly CFEOM1 [6, 74]. The recurrent variant c.2860C>T p.(Arg954Trp) (NM_001173464.2; alternative nomenclatures p.Arg941Trp and p.Arg918Trp in other transcripts) is pathogenic in ClinVar, without conflict [102]. There is no correlation between variant and phenotype in CFEOM1, despite detailed examinations and high-resolution orbital MRI [6]. Very rare KIF21A variants cause syndromic phenotypes similar to those of TUBB3, and the variant c.1991T>C p.(Leu664Pro), de novo in the second coiled-coil domain, caused progressive peripheral neuropathy with hypoplasia of the corpus callosum and comitant strabismus without CFEOM, through reduced binding to TUBB3, and, in a second case, early-onset distal motor neuropathy with normal brain MRI; it constitutes an allelic disease of KIF21A [6, 114, 115]. In the series that identified the gene, 31 familial probands and 13 sporadic cases with CFEOM1 had six different heterozygous variants; the recurrence of p.Arg954Trp and p.Arg954Gln is explained by the codon containing a CpG dinucleotide methylated in blood and sperm, a mutational hotspot, and identification of the variant in a sporadic case changes the estimated recurrence risk [45]. In OMIM, the same allele (608283.0001) appears as R954W and as R943W, depending on the isoform used in each report [45]. KIF21A variants are a rare cause of the CFEOM3 phenotype: none was found in 11 families and 10 sporadic cases with CFEOM3, and the families with CFEOM3 and a KIF21A variant (Turkish, Taiwanese and Chinese) had members with the classic phenotype, which brings them closer to a CFEOM1 of variable expression [45]. Orbital MRI of 19 patients from 6 families showed atrophy of the levator and superior rectus, small or absent orbital motor nerves, with cranial nerve III most hypoplastic but cranial nerve VI also affected, an A pattern with aberrant innervation of the lateral rectus by a branch of cranial nerve III and subclinical reduction in optic nerve calibre (p<0.001), with no differences between variants, which indicates primary neuronal disease with secondary myopathy [45]. A Japanese family with dominant CFEOM and a shared haplotype at the FEOM1 locus, without a KIF21A variant, had slowly progressive gait ataxia from adolescence in the two middle-aged patients, cerebellar atrophy on MRI in all, mild hearing loss and learning difficulties [45].

TUBB3 (16q24.3) encodes neuronal β-tubulin III; heterozygous missense variants alter the dynamic instability of microtubules and, in some cases, the interaction with kinesins, with axon guidance defects without altered cortical migration in the knock-in model [52, 116]. They account for about 35% of CFEOM; all cause CFEOM3, and some add intellectual or social disability, facial palsy, late-onset axonal sensorimotor polyneuropathy, Kallmann syndrome, vocal cord paralysis, congenital contractures and cyclical vomiting [6, 52]. The E410K syndrome, due to c.1228G>A p.(Glu410Lys), combines CFEOM, facial palsy, neuropathy and a spectrum of endocrine anomalies, and Orphanet records an overlapping entity, Moebius–axonal neuropathy–hypogonadotropic hypogonadism syndrome (ORPHA:2560) [6, 102, 117]. Other TUBB3 variants cause cortical tubulinopathies without CFEOM (complex cortical dysplasia 1, OMIM 614039) [56, 116]. In the series that defined this form (9 patients from 7 families), most had strabismus with nystagmus, but none had external ophthalmoplegia; there was mild to severe intellectual disability, axial hypotonia, spasticity in 3, and on MRI dysmorphic basal ganglia with fusion of the putamen and caudate (8 of 9), vermis dysplasia (9 of 9), a hypoplastic brainstem (8 of 9) and a hypoplastic corpus callosum (8 of 9); three families had dominant inheritance, four cases were de novo, and in one family a girl with a severe phenotype was homozygous for the missense variant that her mother and affected siblings carried in the heterozygous state [51]. The variants of this form mainly compromise tubulin heterodimerisation or microtubule stability, whereas CFEOM3 variants disrupt microtubule dynamics and the interaction with kinesins, which helps to explain the separation between the two phenotypes [51, 52]. In OMIM, the series of complex cortical dysplasias also includes TUBB2B (CDCBM7, OMIM 610031) and TUBA1A (CDCBM16, OMIM 611603), two genes with occasional CFEOM [6, 51, 53, 55]. GeneReviews summarises the correlations suggested for TUBB3 in a table published only in PDF format, which was not among the sources of this review; the correlations described in the text rest on few individuals [6]. The series that associated TUBB3 with CFEOM3A comprised 18 families: p.Arg262Cys in 11, with the mildest phenotype, p.Ala302Thr (c.904G>A on NM_006086.4) in 3, p.Arg62Gln in one and p.Asp417Asn in 4, the latter with peripheral neuropathy; all formed microtubules, but reduced heterodimer formation to a variable degree and altered microtubule dynamics and stability [49, 50, 102]. p.Asp417Asn (c.1249G>A) shows variable expressivity within a family: among eight carriers there was CFEOM with neuropathy, neuropathy with developmental delay without CFEOM, CFEOM with learning difficulties and isolated neuropathy, and in another family a carrier brother was asymptomatic; p.Asp417His (c.1249G>C), in a mother and two children, added facial palsy and contractures of the wrists and fingers [49, 102]. The same codon can give rise to different phenotypes: p.Arg262Cys causes CFEOM3A, whereas p.Arg262His (c.785G>A, pathogenic or likely pathogenic in ClinVar) causes CFEOM3A2, with facial palsy, Kallmann syndrome, basal ganglia anomalies, contractures and neuropathy, de novo in 14 patients from 13 families and, in a pair of monozygotic twins, probably due to gonadal mosaicism; likewise, p.Ala302Thr causes CFEOM3A and p.Ala302Val complex cortical dysplasia without CFEOM [50, 102]. p.Glu410Lys defines CFEOM3A1, with anosmia, hypogonadotropic hypogonadism, facial palsy, developmental delay and hypoplasia of the corpus callosum, almost always de novo; the first documented dominant transmission was from a mother, herself with the variant de novo, to her three children [50]. In a Chinese cohort of 122 individuals from 96 families with CCDD studied by exome, 11 had a TUBB3 variant (p.Arg262Cys in 6, p.Glu410Lys in 2 and p.Arg380Cys, p.Arg262His and p.Ser78Thr in one each); p.Glu410Lys, p.Arg262His and p.Arg380Cys were associated with craniocerebral and systemic malformations, p.Arg262Cys and p.Ser78Thr with milder phenotypes, and absence of the facial nerve and dysplasia of the olfactory bulbs with p.Arg262His and p.Glu410Lys [50]. The heterozygous p.Arg262Cys mouse is normal, which is consistent with the non-penetrance observed in humans, and the homozygote dies hours after birth from respiratory failure, with guidance defects of commissural axons and cranial nerves [50].

PHOX2A (11q13.4) encodes a homeodomain transcription factor required for formation of the nuclei of cranial nerves III and IV; biallelic variants cause CFEOM2 (about 10% of CFEOM), described mainly in consanguineous Middle Eastern families, with absence of cranial nerves III and IV on MRI, poorly reactive pupils and retinal dysfunction with visual field and ERG changes in 18 patients from 4 families [6, 48, 75]. CFEOM2 was delineated in three consanguineous Saudi families with 18 affected individuals, linked to 11q13 (combined lod score of 12.2), two of them with the same haplotype, suggestive of a founder effect; unlike CFEOM1, the picture pointed to involvement of the superior and inferior divisions of cranial nerve III, and MRI shows hypoplasia or absence of cranial nerves III and IV [45, 47]. TUBB2B (6p25.2) and TUBA1A (12q13.12) each account for less than 1% of CFEOM, in association with perisylvian polymicrogyria, basal ganglia asymmetry and other malformations; in the tubulinopathy series, CFEOM was observed in one family with TUBB2B [6, 56, 118]. That family, a mother and two daughters, had the TUBB2B missense variant c.1261G>A p.(Glu421Lys) (NM_178012.5, pathogenic in ClinVar): the daughters had ptosis and limited eye movements from birth, moderate intellectual disability and, on MRI, polymicrogyria, dilatation of the left lateral ventricle, fusion of the caudate head with the putamen and thin extraocular muscles, and the mother had low intellectual functioning and limited eye movements [53, 102]. Beyond these cases, the spectrum of TUBB2B-related CDCBM7 ranges from fetal microlissencephaly to asymmetric polymicrogyria with hemiparesis and epilepsy, and that of TUBA1A-related CDCBM16 includes lissencephaly, pachygyria, hypoplasia of the corpus callosum, vermis and brainstem and, in the most severe prenatal forms, fetal akinesia sequence and arthrogryposis [53, 55]. In a series of 128 children with polymicrogyria, 3 (2.3%) had a TUBB2B variant [54]. COL25A1 (4q25) causes autosomal recessive CFEOM5 (OMIM 616219), with small extraocular muscles and aberrant movements such as Duane or synergistic divergence; the original families had isolated congenital ptosis or exotropic Duane with synergistic divergence, and the spectrum has expanded to arthrogryposis multiplex congenita with or without cranial dysinnervation and to lethal fetal phenotypes with akinesia, contractures and hydrops [6, 59]. The family that defined CFEOM5 was Saudi and consanguineous: three siblings homozygous for a missense variant in a Gly-X-Y collagen sequence (p.Gly382Arg, historical notation), two with congenital ptosis due to levator dysinnervation and one with bilateral Duane, exotropic in one eye and esotropic in the other, without systemic defects; among 41 other patients with CFEOM, only one had COL25A1 variants, null variants in compound heterozygosity [57, 58]. Tukel syndrome, CFEOM3 with postaxial oligodactyly or oligosyndactyly of the hands, has an unknown genetic cause and presumably recessive inheritance [6]. In OMIM it corresponds to CFEOM4 (OMIM 609428), with a locus at 21qter [45].

Table source: GeneReviews CFEOM, with additions from GeneGuidance [6, 48, 59]. AD, autosomal dominant; AR, autosomal recessive.

In a Chinese series of 37 patients with CFEOM, the 25 with KIF21A had bilateral ptosis in 95% and synergistic convergence in 40%, against 70% and 20% in the 12 with TUBB3; the diameter of cranial nerve III and the optic nerve area were smaller in patients than in 20 controls, and cranial nerve VI was thinner in the KIF21A group; patients with KIF21A were mostly isolated cases with a more severe ocular phenotype, and those with TUBB3 more often had syndromic CFEOM with brain malformations [119].

2.7. ROBO3 and horizontal gaze palsy with progressive scoliosis

ROBO3 (11q24.2) encodes a receptor of the Roundabout family required for hindbrain axons to cross the midline; in HGPPS (OMIM 607313), biallelic loss of function prevents decussation of the corticospinal and lemniscal tracts in the medulla, so that motor control and proprioception become ipsilateral and a unilateral supratentorial lesion can cause ipsilateral hemiparesis [8, 78]. Diffusion tractography shows uncrossed corticospinal tracts and absent decussation of the superior cerebellar peduncles, with normal callosal connectivity; somatosensory evoked potentials are predominantly ipsilateral, motor evoked potentials uncrossed and brainstem auditory evoked potentials without crossing at the trapezoid body [8, 120]. Over 20 years, more than 60 pathogenic or likely pathogenic variants have been described in almost 100 patients [63]. Examples are p.(Glu319Lys) (c.955G>A on NM_022370.4, likely pathogenic in ClinVar), in two homozygotes with normal cognitive testing, and, in a 2026 series, compound heterozygosity for p.(Arg703Pro) with c.2073+4A>G and homozygosity for p.(Arg245Trp) [8, 64, 102]. Cognition is variable, with mild to moderate psychomotor delay in two compound heterozygous siblings [8]; the OMIM description, based on the series of Bosley and colleagues (2005), considers cognitive function normal, a discrepancy that reflects the subsequent expansion of the spectrum [60]. In the initial series, the 10 index families were consanguineous and homozygous (1 nonsense, 1 splicing, 2 frameshift and 6 missense); in 2006 two sporadic children of non-consanguineous parents with compound heterozygosity were described, and the heterozygous mother of one of them had mild scoliosis that did not require treatment [60]. Nine of the ten variants in the initial series lay in the extracellular domains of the receptor [61]. Before the gene was identified, the association of scoliosis and ophthalmoplegia led to consideration of a mitochondrial cytopathy similar to Kearns-Sayre syndrome, a hypothesis ruled out by the autosomal recessive inheritance [60]. There is a second genetic form, HGPPS2 (OMIM 617542), due to biallelic DCC variants at 18q21.2 [60, 62]. It was described in 2017 in two siblings of consanguineous Mexican parents and in a girl of consanguineous Saudi parents, with homozygous intragenic DCC deletions producing null alleles, one detected by homozygosity mapping with CNV analysis and the other by targeted sequencing; in addition to horizontal gaze palsy and progressive scoliosis beginning in childhood, the patients had global developmental delay, intellectual disability, agenesis of the corpus callosum, absent anterior and hippocampal commissures, hypoplasia of the pons and midbrain and a midline cleft along the entire brainstem, and the two boys had hypotonia and mirror movements [62]. Tractography of the girl showed absent commissural tracts, Probst bundles along the lateral ventricles, lack of decussation of the superior cerebellar peduncles and absent transverse pontine fibres [62]. Heterozygous DCC variants cause mirror movements and agenesis of the corpus callosum, and the parents assessed did not have mirror movements, which suggests incomplete penetrance or variable expressivity [62]. Unlike HGPPS1, with normal callosal connectivity, HGPPS2 combines midline crossing defects in the forebrain and brainstem with intellectual disability [8, 62].

2.8. HOXA1 and the BSAS and ABDS syndromes

HOX genes are organised in four clusters (A to D) on different chromosomes and specify the anteroposterior pattern of the embryo; HOXA1 (7p15.2), one of the most 3′ and earliest expressed, is required for hindbrain development, and homozygous null mice have defects of that region [7]. Most biallelic variants eliminate all functional domains (loss of function); one Indian patient had preservation of the PBX-binding domain [7, 121]. By 2024, 34 individuals with biallelic variants had been described [7]. Two founder variants define the highest-risk populations: c.76C>T p.(Arg26Ter) among the Navajo and Apache, with ABDS, and c.175dup in the populations of Saudi Arabia and Turkey, with BSAS; BSAS has also been described in India [7, 79, 121]. Sequencing detects all known variants and no deletions or duplications have been described [7]. The ClinGen curation classifies the association of HOXA1 with autosomal recessive syndromic intellectual disability as definitive [87]. Linkage in BSAS was established in the largest Saudi family, with an 8.5 Mb homozygous region reduced to about 300 kb at 7p15.2, shared by the Saudi patients (combined lod score of 7.7); the Saudi families were homozygous for the insertion c.175dup (175_176insG in the original notation), on a founder haplotype, the Turkish patient for the nonsense variant NM_005522.5:c.84C>G p.(Tyr28Ter) (pathogenic in ClinVar) and the five patients with ABDS analysed for c.76C>T p.(Arg26Ter), absent from 344 control chromosomes [65, 66, 102]. A third BSAS variant, the 1 bp deletion 185delG (historical notation), was described in a Saudi patient with Duane, horizontal gaze restriction and deafness, with normal cognition [66]. None of these variants has been studied functionally or in patient cells, and loss of function is inferred from the predicted truncation [66].

2.9. Moebius sequence: non-Mendelian causes and proposed genes

Moebius sequence is a phenotype produced by several mechanisms: autopsies show hypoplasia or absence of the central nuclei, destructive degeneration of the nuclei (the most common type), peripheral nerve involvement or myopathy [70]. The predominant hypothesis is vascular: a disruption sequence of the supply from the primitive subclavian artery or the primitive trigeminal arteries before the vertebral arteries adequately perfuse the brainstem, shared with Poland anomaly and Klippel-Feil sequence, triggered by transient ischaemic or hypoxic insults during pregnancy [70, 122]. Prenatal exposure to misoprostol is the best-documented example; in Brazil, in a case–control study of 96 infants with Moebius and 96 with neural tube defects diagnosed between 1990 and 1996, 49% of case mothers and 3% of control mothers had used misoprostol in the first trimester (odds ratio of 29.7; 95% CI 11.6–76.0), generally in a failed attempt to terminate the pregnancy [123]. The Brazilian textbook of genetic syndromes adds thalidomide, alcohol, cocaine, benzodiazepines and infection as environmental factors [69]. A Brazilian prospective cohort of 86 pregnant women exposed to misoprostol and 86 unexposed found no increase in major defects (2 of 67 versus 2 of 81), but showed more miscarriages (17.1% versus 5.8%; relative risk of 2.97; 95% CI 1.12–7.88), with limited statistical power; the absolute risk of Moebius per exposure is therefore low, despite the high odds ratio in the case–control study [124].

Monogenic causes have been described mainly in atypical cases: TUBB3 (CFEOM3 with vertical gaze deficit), KIF21A, HOXB1 (hereditary congenital facial paresis 3, OMIM 614744, with esotropia, in families that do not always meet the minimum criteria) and de novo variants in PLXND1 and REV3L in sporadic cases [6, 70, 125]. Hereditary congenital facial paresis 3 (HOXB1, 17q21.32, autosomal recessive) shows the risk of classifying a Mendelian CCDD as Moebius: the first four patients, two pairs of siblings from conservative German American families («Pennsylvania Dutch») with a previous diagnosis of Moebius, were homozygous for the missense variant NM_002144.4:c.619C>T p.(Arg207Cys), on a shared haplotype rare in Europe (0.787%) indicating a founder effect; they had facial diplegia with absence of the facial nerve on MRI, high-frequency sensorineural hearing loss and partially accommodative esotropia with high hypermetropia, but full abduction, so they did not meet the Moebius criteria [126]. Subsequently, homozygous c.620G>A p.(Arg207His) was described in a Turkish girl and homozygous c.66C>G p.(Tyr22Ter) in a consanguineous Moroccan family with full ocular motility, facial dysmorphism (midface retrusion, smooth philtrum, lagophthalmos) and pinna malformations; the Hoxb1-null mouse does not form the somatic motor component of the facial nerve [126]. A 2025 cohort of 149 patients with Moebius syndrome defined by strict criteria, all sporadic, sequenced 67 affected individuals and 117 relatives and found 173 variants in 113 genes, with 7 de novo and 5 biallelic candidate genes, without a convincing recurrent gene and without convincing variants in PLXND1 or REV3L; the authors conclude that there is no unifying germline aetiology and allow for environmental exposures, somatic variants or complex inheritance [11]. In 2026, an infant with Moebius and additional malformations, with a non-diagnostic genome, had a methylation episignature moderately positive for the «recurrent constellation of embryonic malformations» (RCEM), which suggests that some cases belong to a broader malformation spectrum [127]. Genes of atypical syndromic CCDD also include ECEL1 and ACKR3 [3].

Neuropathology and electrophysiology support heterogeneity of mechanisms. A neuropathological classification of 15 cases (Towfighi and colleagues, 1979) distinguished four groups: hypoplasia of the cranial nerve nuclei due to rhombomeric malformation; neuronal loss and degeneration secondary to a defect of the peripheral facial nerve; focal necrosis, gliosis and calcifications of the brainstem nuclei, attributed to vascular insufficiency or infection; and primary myopathic changes without damage to the nuclei or nerves [67]. In a newborn who died at 11 days, the brainstem was asymmetric and hypoplastic, with dysplastic inferior olivary nuclei, pyramidal tracts without decussation and neuronal loss with gliosis and microcalcifications in the nuclei of cranial nerves VI, VII and XII, unlike three cases of hereditary congenital facial paresis, with isolated loss of the facial nuclei [67]. In 24 sporadic patients, electromyography separated a group with increased distal motor latency after facial nerve stimulation, compatible with a rhombencephalic malformation with small motor neurons, from another with a chronic neuropathic pattern and enlarged motor units, compatible with axonal or neuronal loss acquired in the prenatal period [67]. MRI of six Dutch patients aged 12 to 23 years did not identify the facial nerve on either side in five and showed an anteroposterior diameter of the pons smaller than that of 20 controls (19.7 versus 22.5 mm), and review of the radiological literature found brainstem hypoplasia in 32% of cases [67]. Isolated chromosomal rearrangements, such as a reciprocal translocation t(1;13)(p34;q13) that cosegregated with facial diplegia and flexion contractures of the fingers in seven members of three generations and a 13q12.2 deletion in a child, underpin the provisional locus at 13q12.2–q13; other translocations with a breakpoint at 1p22 have been described in similar presentations, and OMIM keeps the associations with REV3L and PLXND1 variants as pending confirmation [67]. Patients with Moebius and hypogonadotropic hypogonadism have also been described, one of them with peripheral neuropathy, a picture that overlaps with that of the TUBB3 p.Glu410Lys variant [50, 67].

2.10. Comitant strabismus: genetic contribution

The AAO guideline recognises family history as a risk factor for strabismus and states that a Mendelian pattern is observed in some families [15]. The classic twin study from Australia and the United Kingdom (1462 pairs) found a prevalence of esodeviation (esophoria and esotropia) of 8.6% and of exodeviation of 20.7%; for esodeviation, the polychoric correlation was 0.65 in monozygotic and 0.33 in dizygotic twins, with a heritability of 0.64 (95% CI 0.50–0.75), whereas for exodeviation the correlations were similar (0.55 and 0.53) and there was no significant genetic component; the additive genetic correlation with refractive error was 0.13, with less than 1% shared variance [12]. A genome-wide association study in the All of Us programme (USA), in adults with genome sequencing and cases defined by clinical codes, identified a locus in PLA2R1 in participants of African ancestry (365 cases, 53,577 controls) and signals in RIMBP2 and an intergenic region in those of Latin American ancestry (235 cases, 40,602 controls), with no signal in those of European ancestry (1579 cases, 121,490 controls); rare variant analysis pointed to 33 genes with increased burden, differing between ancestries, in exploratory results not yet replicated [94]. A 2025 review identified strabismus described in 255 genetic syndromes, with highly variable penetrance: CCDD cause paralytic strabismus and comitant strabismus occurs mainly in syndromes with intellectual disability; the authors allow that non-syndromic strabismus may result from changes in the expression or regulation of the same genes [128]. The question of whether Duane syndrome and infantile esotropia are allelic was raised on the basis of families with both phenotypes [129].

2.11. Sequencing cohorts and new genes in ocular CCDD

The ocular CCDD phenotyping consortium (Boston) sequenced by exome or genome 467 undiagnosed probands (550 affected and 1108 individuals): it found pathogenic or likely pathogenic variants in 43 (9.2%) and prioritised variants of uncertain significance in a further 70 (15.0%), in known CCDD genes, in genes of syndromes that sometimes include CCDD (MYH10, KIF21B, TGFBR2, TUBB6), in genes compatible with the syndromic component (CDK13, TGFB2), in genes without previous association (TUBA4A, KIF5C, CTNNA1, KLB, FGF21) and in phenocopies that had led to erroneous diagnoses [83]. A CRISPR/Cas9 zebrafish screen of 43 human genes proposed SEMA3F, OLIG2 and FRMD4B as candidates and showed, on protein-binding microarrays, reduced or abolished DNA binding of the variants of uncertain significance PHOX2A p.(Trp137Cys), MAFB p.(Glu223Lys) and OLIG2 p.(Arg156Leu) (published designations); these data are functional and preclinical and do not by themselves reclassify the variants [130].

2.12. Normalised variants

Normalisation, in Human Genome Variation Society (HGVS) nomenclature, used the NCBI MANE Select transcripts and the ClinVar entries; VariantValidator was unavailable during the review, so the frameshift extensions that appear only in GeneReviews are presented with attribution to the source [95, 102].

3. Clinical Spectrum and Manifestations by System

3.1. FRMD7-related infantile nystagmus

GeneReviews does not define formal clinical criteria; the suggestive findings are onset by 6 months, horizontal conjugate oscillations, visual acuity usually better than 0.3 logMAR (Snellen 6/12), good binocular vision, normal colour vision, a family history compatible with X-linked inheritance and, in some patients, dampening on convergence; less frequent are anomalous head posture (AHP, about 15%) and strabismus (about 8%) [1]. The mean age at onset is 2 months [1]; in the Chinese cohort, all 76 patients with a documented age at onset had started by 6 months [4].

The waveform evolves over the first months. In a case followed longitudinally from 5 weeks, because the child was part of a study of normal visual development, there was no nystagmus at 5 weeks, square wave jerks appeared at 7, small pendular nystagmus at 8, large-amplitude jerk nystagmus at 10, small pendular nystagmus at 14 and conjugate pendular nystagmus between 7 and 12 months [1, 131]. Initially, large-amplitude, low-frequency horizontal movements («triangular movements») are seen, followed by pendular or jerk forms of smaller amplitude and the development of foveation periods; in another series, the predominant form in the first 6 months was asymmetric pendular and jerk with extended foveation [1, 132].

Source: single case with serial recordings [1, 131].

The waveform may be pendular, jerk (with a slow phase of increasing velocity) or bidirectional; amplitude depends on the direction of gaze, being smallest in primary position, and the amplitude and direction of the fast phase may vary over time in periodic alternating nystagmus [1]. Comparison of 90 patients with FRMD7 and 48 with IIN without a variant in the gene showed a median acuity of 0.2 logMAR (6/9) in both groups, good stereopsis in most and strabismus in 7.8% and 10%, respectively; AHP was more frequent in the group without FRMD7 (p<0.0001), amplitude depended more on gaze direction in the FRMD7 group (p<0.0001) and pendular forms were more frequent with FRMD7 (p=0.003) [103]. The oscillations worsen with attention, anxiety, attempted fixation and deviation of gaze away from the null zone [1]. Acuity is relatively good because the waveform is interrupted by foveation periods and because, unlike other infantile nystagmus, there is no sensory defect such as foveal hypoplasia [1]. AHP arises when the null zone is eccentric; some patients have head titubation, without limb or trunk tremor or balance disturbance [1]. Oscillopsia is very rare, partly because of the foveation periods, and may occur in gaze positions with more intense nystagmus or with fatigue [1]. The optokinetic response is abnormal, with low gain or a reversed pattern, and is absent in periodic alternating nystagmus with an FRMD7 variant [1, 103].

In the Chinese cohort of 133 confirmed carriers (99 patients, 77 hemizygous males and 22 heterozygous females, and 34 asymptomatic female carriers), the acuity of 63 patients ranged from −0.10 to 0.82 logMAR (mean 0.35±0.21), with 49.2% at 0.30 logMAR or better and 92.1% at 0.52 logMAR or better; affected females had better acuity than males (0.22±0.18 versus 0.38±0.20; p=8.78×10⁻³), and asymptomatic carriers had a median acuity of −0.08 logMAR [4]. The 5 hemizygous males under 6 years with acuity worse than 0.52 logMAR all had uncorrected refractive error; 3 of the 4 followed reached 0.52 or better with correction after 6 years of age, and the fourth, with anisometropia and high myopia (−8.75 and −4.25 D), remained at 0.70 [4]. The anterior segment was normal in 65 of 68 patients (3 with mild hypoplasia of the iris collarette); 6 children had temporal disc pallor or a tessellated fundus; autofluorescence was normal; OCT showed a normal fovea in 28 of 30, and the ERG, in 15 patients, was normal or mildly abnormal [4]. GeneReviews allows for grade 1 foveal hypoplasia in some patients and abnormal optic nerve morphology, findings not confirmed in the Chinese cohort [1, 4, 133, 134]. Iris transillumination, fundoscopy, brain MRI, ERG and VEP are normal in FIN [1]. Affected females report slightly better acuity, with no differences in amplitude, frequency or waveform compared with males [1, 103].

3.2. Idiopathic infantile nystagmus without an FRMD7 variant and periodic alternating nystagmus

IIN without an identified molecular cause shares infantile onset, normal sensory function (normal colour vision, slit-lamp examination, ERG and VEP) and horizontal conjugate oscillations with a slow phase of increasing velocity; it differs from FIN by more frequent AHP with an eccentric null zone, by amplitude less dependent on gaze and by a lower frequency of pendular forms; strabismus occurs in about 10% and a family history is rare [1, 103]. Periodic alternating nystagmus reverses direction every few minutes and requires observation for at least 5 minutes in primary position; in a child with INS it suggests albinism, it has no sinister significance, but it may contraindicate standard AHP surgery, because the null zone shifts spontaneously [16, 135]. The FRMD7-related X-linked form (XIPAN) was characterised in a three-generation family in which the three affected males had jerk and pendular nystagmus with a latent component, strabismus and significant refractive error, and the female had only myopic astigmatism, with periodic nystagmus visible only on eye movement recording, a probable marker of carrier status [9]. In a later series of 10 families with an FRMD7 variant, periodicity had never been diagnosed clinically and appeared only on prolonged fixation recordings; within the same family, only some carriers had it, and no patient with periodic alternating nystagmus had a horizontal optokinetic reflex, which led the authors to propose an instability of the optokinetic and vestibular systems [9]. In a family with a woman whose periodic alternating nystagmus was noticed at 18 years, the mother had fixed congenital nystagmus, and the authors considered that the daughter's had been present since birth without being recognised [9].

3.3. Xq26.2 deletion with FRMD7 and IGSF1

In the Bedouin family with the 1.44 Mb deletion, nystagmus was the most penetrant trait (9 of 10 relatives examined; absent only in one confirmed female carrier), horizontal and jerk, more marked on lateral gaze, with acuity of 6/6 to 6/21, AHP in 2, head shaking in 1, esotropia in 2, amblyopia in 1, mild to moderate hypermetropia and mild to high astigmatism; fundus, OCT, ERG, VEP and brain MRI were normal in those examined [34]. Endocrine manifestations were less frequent and variable: one female carrier with nystagmus had low prolactin (2 ng/mL; reference 3–29), the 6-year-old hemizygous boy had low-normal FT4 (0.9 ng/dL; reference 0.8–1.5) with normal TSH and a history of neonatal jaundice, and the only relative with overt central hypothyroidism, diagnosed at 8 years with developmental delay, was not genotyped; three relatives were obese [34]. The spectrum thus ranges from the asymptomatic female carrier to isolated nystagmus and to the combination of ocular and endocrine manifestations [34].

3.4. Nystagmus associated with strabismus

Nystagmus associated with strabismus may be manifest, latent or manifest-latent and is more frequent in early-onset strabismus [15]. Latent nystagmus appears on occlusion of one eye and is conjugate, horizontal jerk, with slow nasal drift of the fixing eye; it is the only form that reverses direction when fixation changes eye [15]. Manifest-latent nystagmus, equivalent to FMNS, has the same waveform, is visible binocularly, increases with occlusion and leads the patient to turn the head to keep the fixing eye in adduction [15, 16]. In nystagmus blockage syndrome, the patient overconverges to dampen the nystagmus, and the esotropia appears to increase with prism neutralisation [15]. The prevalence of strabismus in children with infantile nystagmus ranges from 16% to 52%, with lower risk in IIN, intermediate in retinal dystrophies and albinism and high in bilateral optic nerve hypoplasia [16].

3.5. Duane syndrome

Duane is congenital and non-progressive: the horizontal limitation results from lack of innervation of the lateral rectus by cranial nerve VI and the retraction from innervation of that muscle by cranial nerve III; the limitation may not be recognised in early infancy [5]. The left eye is most often affected (70% of unilateral cases in the GeneReviews authors' cohort) and the syndrome is more frequent in females, especially in unilateral and sporadic cases (56% and 51%, respectively, in the same cohort) [5, 136]. The Oxford Desk Reference gives bilaterality in 20% [41]; findings are bilateral more often in familial cases and in those with a variant in a known gene [5, 137]. The 20% figure goes back to Duane's original description (1905), which brought together 54 cases; in a series of 25 sporadic cases, 64% were female, only 12% were bilateral and the left eye was involved in 72%, and up to 10% of cases are familial, with autosomal dominant inheritance [40]. On MRI, the abducens nerve on the affected side was not visualised in 18 of 18 eyes with Duane type 1 and in 3 of 5 with type 3, but was visualised in 2 of 2 eyes with type 2, in 2 of 5 with type 3 and in all 60 control eyes, which makes types 1 and 2 homogeneous and type 3 heterogeneous with respect to presence of the nerve [40]. Associations of Duane with upper limb anomalies, with a heart-hand syndrome probably Holt-Oram with dominant inheritance (1966) and, in one case, with blepharophimosis, ptosis and epicanthus inversus due to a FOXL2 variant have been described [40].

Source: GeneReviews Duane, table 1 [5]. An alternative classification describes the deviation in primary position (esotropic or exotropic Duane) and the limited movement (adduction, abduction or both).

In a tertiary centre in southern India, almost a third of patients had exotropia [5]. The compensatory head turn aligns the eyes, avoids diplopia and preserves binocular vision. Amblyopia occurs in about 10%, mainly in patients without binocular vision, and responds to standard treatment if detected early; acuity is good in the remainder [5]. Other dysinnervation phenomena include infraduction of the affected eye on attempted abduction, present in most esotropic Duane, the Marcus Gunn phenomenon, an exaggerated oculo-auricular phenomenon (contraction of the auricular muscles on lateral gaze) and crocodile tears (lacrimation on chewing, due to aberrant salivary fibres of the facial nerve directed to the lacrimal gland) [5, 41]. MRI shows, in most patients with CHN1, non-visualisation of the abducens nerve, sometimes abnormal lateral recti and a small cranial nerve III and optic nerve; in sporadic cases without a variant, absence or severe hypoplasia of the abducens nerve with a normal-appearing lateral rectus [138, 139]. In the Chinese series of 42 patients (17 type 1, 4 type 2 and 21 type 3), the abducens nerve was absent in 12 of 14 type 1 patients and in 9 of 17 type 3 and hypoplastic in the 4 type 2 patients, and tractography showed no internuclear fibres in the medial longitudinal fasciculus in patients without an abducens nerve [113].

Most patients have isolated Duane. Estimates of systemic findings range from less than 10% in a series of 441 cases to just over 50% in another series; in the GeneReviews authors' cohort, about 30% of patients with Duane have non-ocular findings, 25% when the SALL4 spectrum is excluded, and 26.7% of those without a variant in a known gene have findings ranging from preauricular tags to Hirschsprung disease [5, 136, 140]. With CHN1, Duane is more often bilateral, with vertical anomalies in addition to the deviation on adduction and more family history; with MAFB, it is more often bilateral and may be accompanied by mild to severe sensorineural hearing loss; with SALL4, it tends to be bilateral [5].

3.6. Okihiro syndrome and other SALL4-related disorders

In a series of 69 affected individuals from 23 families with a pathogenic SALL4 variant, 13% had the original Okihiro triad (Duane, radial ray malformation and sensorineural hearing loss), 45% Duane with radial defects and 21% radial defects only [22]. The frequencies of the main features, in an unpublished series by the GeneReviews author, are as follows.

Source: GeneReviews SALL4 [22].

In addition to Duane, colobomas of the iris, retina and choroid, cataract, optic disc hypoplasia and microphthalmia may occur, and Smith's Recognizable Patterns adds nystagmus, ptosis, choroidal atrophy, microcornea and conjunctival lipodermoid [22, 73]. In the upper limbs, shortening of the ulna, syndactyly, radial club hand, carpal anomalies (small scaphoid, navicular and trapezium), short humeri and hypoplasia of the deltoids are also described; in the lower limbs, club foot, tibial hemimelia and syndactyly of the toes; and also fused cervical vertebrae with a short neck and spina bifida occulta [22, 73]. Ear anomalies include abnormal pinnae, slit-like ear canals and small ears; gastrointestinal anomalies include anal stenosis and imperforate anus; some people have epicanthic folds, hypertelorism, a depressed nasal bridge and hemifacial microsomia [22]. Neural tube defects have been observed (myelomeningocele in two patients) [22]. Growth and cognition are normal in the intragenic forms, upper limb function is usually good, and arterial hypertension and recurrent urinary tract infections are frequent, in relation to the renal anomalies [22, 73]. AROS is characterised by radial malformations, renal anomalies and ocular coloboma with Duane; rare SALL4-related Holt-Oram syndrome by upper limb malformations and congenital heart disease without other findings [22]. Many patients with severe limb malformations were considered to have Holt-Oram syndrome until Duane was found in a relative, and at least two were diagnosed as thalidomide embryopathy [73].

The families that delineated DRRS show the breadth of expression. In the family described by Okihiro and colleagues in 1977, five people from three generations had Duane and hypoplasia of the thenar eminence, one of them with Hirschsprung disease and another with congenital deafness; in a three-generation French-Canadian family with seven affected individuals, the defects ranged from mild hypoplasia of the distal phalanx of the thumb to severe hypoplasia with preaxial polydactyly, and from mild renal malrotation to crossed ectopia without fusion, with vesicoureteric reflux, bladder diverticula, complete or optic nerve coloboma, ptosis and Duane [42]. Renal anomalies are probably underestimated in reports predating routine renal ultrasound [42]. Kohlhase and colleagues described slit-like openings of the external auditory canal, flat feet with a wide gap between the first and second toes, hypertelorism and epicanthus, and proposed the slit-like ear canal as a clue to distinguish DRRS from Holt-Oram syndrome when Duane is absent; the diagnosis is often missed because Duane goes unnoticed alongside limb malformations suggestive of Holt-Oram syndrome [42]. In a patient with a previous diagnosis of Holt-Oram and a SALL4 variant, reassessment by the attending physician revealed ophthalmoplegia, and the mother had pelvic kidneys; in another family, a father diagnosed in childhood with thalidomide embryopathy (bilateral thumb aplasia and hypoplastic radii, with possible exposure in pregnancy) had a daughter with radial defects and both had a SALL4 variant [42, 43]. In the OMIM description, the severe heart defects typical of Holt-Oram syndrome are not part of DRRS [42].

3.7. Congenital fibrosis of the extraocular muscles

The diagnosis of CFEOM rests on the ocular findings: congenital, non-progressive ophthalmoplegia, with or without ptosis, affecting part or all of the oculomotor nucleus and nerve and the muscles it innervates (superior, medial and inferior recti, inferior oblique and levator palpebrae) and sometimes cranial nerves IV and VI [6]. Limitation of vertical gaze, usually upwards, is severe and that of horizontal gaze is variable; patients compensate with chin elevation and with head rather than eye movements, to «see under» the ptotic lids [6]. Binocular vision is typically absent, refractive errors are common and amblyopia, due to strabismus, refractive error or ptosis, causes permanent visual loss if untreated [6]. The strabismus is incomitant, with hypotropic and exotropic positions more frequent than hypertropic and esotropic ones; intrafamilial variability is notable in CFEOM3, whereas in CFEOM1 the vertical strabismus is uniform and the horizontal variable [6]. In classic CFEOM1, the eyes are fixed 20 to 30 degrees below the horizontal, which forces extension of the head; the classic description of the familial form is by Heuck (1879), who documented at autopsy fibrotic muscles with abnormal insertion, and the modern neuropathological study of one patient showed absence of the superior division of cranial nerve III and of the corresponding subnuclei [45]. In a Canadian family with CFEOM3 due to TUBB3, severe patients had ptosis and eyes fixed in hypotropia and exotropia, moderate ones asymmetric involvement and mild ones only limitation of vertical gaze with globes in normal position; in another family, all affected individuals had an absent Bell phenomenon and superficial keratopathy, many with corneal scarring [49]. An infant with classic CFEOM elevated the right eye above the midline when the teeth or maxillary gums on that side were touched, a sign of aberrant innervation between the nerve to the superior rectus and the trigeminal nerve, distinct from the Marcus Gunn phenomenon because it does not depend on jaw movements [45].

Source: GeneReviews CFEOM, table 1 [6].

The oculomotor nerves are typically hypoplastic on MRI [6]. In a subgroup of CFEOM3, mainly with tubulin variants, there are central nervous system malformations: agenesis or hypoplasia of the corpus callosum and anterior commissure, pachygyria, polymicrogyria, schizencephaly, dysgenesis of the olfactory bulbs and sulci, ventriculomegaly, deficient falx, paucity of white matter, dysmorphic basal ganglia, malformations of the thalamus and hippocampus, cerebellar or brainstem hypoplasia, absent cerebral peduncle, arachnoid cysts and, rarely, encephalocele or hydranencephaly, sometimes with microcephaly and intellectual disability [6]. The same subgroup may have facial palsy and dysmorphism, vocal cord paralysis, intellectual or social disability, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), progressive axonal sensorimotor polyneuropathy, congenital contractures, gait abnormalities, cyclical vomiting and epilepsy [6, 52]. The Marcus Gunn phenomenon, often noticed during feeding as momentary elevation of the ptotic lid with jaw movements, results from innervation of the levator by axons destined for the motor branch of the trigeminal nerve and reinforces the neurogenic origin [6]. In PHOX2A-related CFEOM2, 18 patients from 4 families had corrected acuity reduced beyond what amblyopia would explain, with visual field and ERG changes, which makes retinal dysfunction part of the phenotype [48]. In cortical tubulinopathies in general, facial diplegia and strabismus suggestive of pseudobulbar palsy are frequent in central pachygyria and dysgyria [56].

3.8. Horizontal gaze palsy with progressive scoliosis

Patients have congenital absence of conjugate horizontal movements, with preserved elevation, depression and convergence; they compensate by turning the head and may be mistaken for bilateral cranial nerve VI palsy or infantile esotropia, with normal vision, visual fields and pupils [8, 120]. In a series of 5 patients, abduction and adduction were limited, 2 had synergistic convergence and 1 underwent surgery for esotropia [141]. Scoliosis is progressive and disabling in childhood and adolescence, as shown by 13 patients from 6 consanguineous Tunisian families, but it is not obligatory: two siblings aged 5 and 2 years did not have it, and in one series only 2 of 5 patients had it [8, 141]. MRI shows brainstem hypoplasia with a midline cleft of the pons («split pons») and a butterfly-shaped medulla, a uniform imaging signature despite variable clinical severity [64, 120, 142]. In the series of 11 patients from 5 families with genetic confirmation, none had horizontal smooth pursuit, saccades, optokinetic nystagmus or vestibulo-ocular response; vertical versions were normal (saccadic pursuit in 5), convergence was present in all, 8 had small- to moderate-amplitude pendular nystagmus, and all had come to medical attention because of severe thoracolumbar scoliosis beginning in childhood, although the gaze palsy had been present since birth [60]. On high-resolution MRI of 8 patients, the abducens nerves were visible in the extra-axial space and the extraocular muscles and intraorbital nerves had a normal configuration, which indicates hypoplasia rather than absence of the abducens nuclei and distinguishes HGPPS from CCDD with absent nerves and hypoplastic muscles [60]. In a Chinese Hakka family described in the 1970s, one of the siblings developed bilateral facial myokymia and continuous contracture of the facial muscles in his early twenties [60].

3.9. HOXA1 syndromes

Source: GeneReviews HOXA1, table 2; denominator = individuals assessed for the feature [7].

The motility disorder, unilateral or bilateral and apparent from early infancy, results from anomalies of the abducens nucleus and nerve and may be accompanied by refractive errors, nystagmus, vertical involvement, esotropia and ptosis; without treatment, it causes amblyopia [7]. Profound congenital sensorineural deafness, in 32 of 34 patients, is due to complete absence of the labyrinth, a common-cavity deformity or a rudimentary or absent cochlea [7]. The vascular anomalies (carotid aplasia or hypoplasia, early branching of the common carotid, aplasia of the anterior cerebral artery, vertebral duplication with compensatory enlargement of the vertebrobasilar system) are mostly silent, but there was a vertebral stroke in one patient with ABDS and a stroke after cardiac surgery in one with BSAS [7, 85]. Central hypoventilation is the distinguishing feature of ABDS: it is identified in most before 6 months, worsens during sleep, required supplemental oxygen (mechanical ventilation or nasal cannula) and aminophylline in all and allowed weaning in survivors after the first year; no patient with BSAS had it [7]. The heart defects of ABDS mainly affect the outflow tract (tetralogy of Fallot, coarctation, double aortic arch, hypoplastic arch, aortic stenosis, aberrant subclavian artery, ductus arteriosus, bicuspid aortic valve, ventricular septal defect, total anomalous pulmonary venous drainage); in BSAS, double outlet left ventricle, tetralogy of Fallot and ventricular septal defect have been described, and one patient had heart disease without ocular or hearing disorder [7]. In ABDS, vocal cord paresis (2 of 10) and dysphagia (6 of 10) lead to recurrent aspiration and gastrostomy [7, 85]. Cognitive dysfunction affects all patients with ABDS and has been attributed to chronic cerebral hypoxia from the combination of hypoventilation, vascular anomalies and the altitude of the Athabascan communities; two patients who grew up at lower altitude had mild impairment; in BSAS, the spectrum ranges from isolated motor delay to global delay and autism spectrum disorder, with normal neurological function in 7 of 20 [7, 143]. On imaging, BSAS combines carotid malformations, inner ear anomalies, variable absence of cranial nerves VI to XII and small petrous bones without a carotid canal, and ABDS generalised cerebral atrophy with a normal-appearing brainstem [7]. There is no known genotype–phenotype correlation, and high altitude is suspected as a contributing factor to hypoventilation [7]. The horizontal palsy of ABDS is not a cranial nerve VI palsy: on attempted lateral gaze, neither does the ipsilateral eye abduct nor the contralateral eye adduct, but adduction is present on convergence, and vertical movements are preserved [65]. In the first descriptions, brainstem auditory evoked potentials (6 patients) and caloric testing (5) elicited no response, facial expression was poor without the facial palsy pattern of Moebius, and deafness, very rare in Moebius, was constant, which led to abandonment of the initial diagnosis of «Moebius variant»; in one family, the death of a sibling attributed to sudden infant death syndrome was interpreted as a probable consequence of central hypoventilation [65]. In BSAS, CT of the skull base showed unilateral or bilateral absence of the carotid canal, and MR angiography malformations of the internal carotid, from unilateral hypoplasia to bilateral agenesis [65]. The boundary between BSAS and ABDS blurred when patients with ABDS with mild cognitive changes and two homozygous siblings without gaze restriction or deafness were described, which led the authors to allow that isolated bilateral Duane or isolated congenital heart disease may be the only manifestation of homozygosity [65]. The differences between the two syndromes may be due, in part, to genetic modifiers in these isolated populations, and the ABDS phenotype is closer to the Hoxa1-null mouse, which dies of perinatal respiratory failure [65].

3.10. Moebius sequence

The cohort of 149 patients with Moebius syndrome defined by strict criteria (congenital non-progressive facial palsy and limited abduction) showed tongue hypoplasia in 81.9%, micrognathia in 66.4%, congenital club foot in 42.3%, major limb anomalies in 31.5%, intellectual disability in 30.9%, sleep disorder in 22.8% and Poland anomaly in 14.1% [11]. Smith's Recognizable Patterns describes an expressionless mask-like face, micrognathia due to early neuromuscular deficit of jaw movement, U-shaped cleft palate or bifid uvula in about a third (Robin sequence), ptosis, prominent pinnae, a small or poorly mobile tongue and possible involvement of cranial nerves III, IV, V, IX, X and XII; in the eyes, refractive errors (42%), voluntary Bell phenomenon (43%), intorsion with fixation (42%), almost normal convergence and dysinnervation (41%) manifested by lacrimation on eating or on attempted lateral gaze; and also club foot (41%), Poland anomaly (20%), scoliosis (14%), hypodontia, limb reduction defects, syndactyly, Klippel-Feil sequence and, occasionally, hip dysplasia and arthrogryposis [70]. A Swedish multidisciplinary survey of 25 patients found limb malformations in 10, Poland anomaly in 2, hypodontia in 7, microglossia in 6, cleft palate in 4 and hearing loss in 5, impaired facial expression in 16, speech in 13 and feeding or swallowing in 12, and 6 patients with autistic disorder, all with intellectual disability [122, 144]. Intellectual disability is estimated at 10–15% by Smith's and autism, previously estimated at 25%, is probably less frequent; the expressionless face and speech difficulties create problems of social acceptance, but self-perception studies document resilience [70]. The differences between these estimates reflect different inclusion criteria, assessment methods and sample sizes. The Brazilian textbook of genetic syndromes also describes convergent strabismus, ptosis, microphthalmia, myopia and hypermetropia, chest deformities, absence or hypoplasia of the pectoralis, adactyly, hearing loss, speech delay and learning and sleep difficulties [69].

In the Dutch series of 37 patients (6 months to 53 years) with the minimum criteria of congenital facial weakness and limited abduction, 92% had bilateral facial weakness, 34% Duane and 3 CFEOM; 86% had feeding difficulties at birth, 77% tongue hypoplasia, 76% nasal dysarthria, 55% language delay, 86% malformations of the extremities, 11% Poland anomaly and 88% motor incoordination, and 4 patients had sensory loss of the face and cornea due to a partial defect of the trigeminal sensory root [67]. Seven had neonatal respiratory difficulty, two died in the neonatal period, 2 were autistic and 12 attended special education [67]. In a survey of 13 carers of preschool children, the frequency of behavioural problems (16.7%) was similar to that of children without the syndrome, but carers reported more stress than controls [67].

3.11. Comitant strabismus

Constant infantile esotropia with onset before 6 months rarely resolves, whereas intermittent or variable esotropia, or esotropia with an angle under 40 prism dioptres (PD), may resolve by the first year; intermittent esotropia in the first 3 months does not predict constant strabismus [15]. Acquired esotropia is more frequent than infantile esotropia and arises between 1 and 4 years, and accommodative esotropia may begin at 2 months [15]. Infantile esotropia is later accompanied by cross-fixation, latent or manifest-latent nystagmus, dissociated vertical deviation, oblique muscle dysfunction, A or V patterns and optokinetic nystagmus asymmetry [15]. Exotropia affects about 1% of the population, the intermittent form being the most frequent, twice as common in girls in a US population cohort; half of exotropias with infantile onset are accompanied by ocular or systemic anomalies in clinical series [15].

3.12. Natural history and treated disease

Infantile nystagmus is non-progressive and tends to attenuate: on telephone follow-up of 31 patients with FIN (1 to 15 years), 11 (35.5%) reported a gradual reduction in intensity with age, whereas near vision and attention worsened it in 6; 16 had involuntary head oscillations and 13 AHP, and the 4 who underwent surgery improved [4]. In a longitudinal study without intervention in IIN, acuity improved by 0.16 logMAR per 10 years, with follow-up to 18 years of age [72]. In 10 children with FIN followed between 0.8 and 5.9 years, acuity went from 0.59±0.70 to 0.25±0.26 logMAR (p=3.46×10⁻³), 8 of them wearing glasses regularly, which shows the weight of refractive correction in the observed course [4]. Duane syndrome and CFEOM are congenital and non-progressive; the evolutionary risk is amblyopia in the first years and, in CFEOM, corneal exposure [5, 6]. In HGPPS, scoliosis is the progressive manifestation [8]. In the syndromic forms, prognosis depends on the associated malformations (hypoventilation and heart disease in ABDS, kidney and heart in SALL4) [7, 22].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In the infant, nystagmus is usually noticed between 4 and 6 months, although the actual onset, when sought in at-risk children, is on average at 1.9 months [16]. The history immediately points to aetiological groups: pregnancy, maternal drug exposure and prematurity are associated with nystagmus; photophobia points to cone dysfunction or albinism, especially with high-frequency, low-amplitude nystagmus; nyctalopia points to rod disease; a chin-down posture with vertical oscillation suggests downbeat nystagmus; the habit of pressing or rubbing the eyes (oculo-digital sign) suggests blindness of retinal cause; the absence of oscillopsia in an older child favours early onset; and pigmentation different from that of relatives suggests albinism [16, 71]. A three-generation pedigree, or more if X-linked inheritance is suspected, and examination of the parents are part of the first visit; iris transillumination in a parent may provide the clue to albinism, and a pattern of maternal transmission with variably affected females is typical of FIN [16, 71]. Later-onset nystagmus without eye disease is more probably neurological [71].

In strabismus, the risk factors are anisometropia and hypermetropia (the risk of esotropia increases with the degree of hypermetropia), neurodevelopmental disorder, prematurity and low birth weight (below 2000 g the risk increases greatly), a low Apgar score, craniofacial and chromosomal anomalies, prenatal exposure to tobacco or alcohol and family history [15]. Strabismus with limitation of movement, ptosis, globe retraction, paradoxical movements or facial palsy suggests a CCDD rather than comitant strabismus [5, 6]. Horizontal limitation with globe retraction and fissure narrowing on adduction is the indispensable sign of Duane; bilateral ptosis with infraducted eyes and chin elevation is the typical presentation of CFEOM1; complete absence of horizontal movements with preserved convergence suggests HGPPS or a HOXA1 syndrome; and an expressionless face with abduction deficit and normal vertical motility defines Moebius sequence [5–8, 70].

4.2. Clues to a syndromic form

In a patient with Duane, the targeted examination looks for ear tags and pinna malformations, a short neck (Klippel-Feil, Wildervanck), thumb and radial ray anomalies (Okihiro), heart murmurs, hearing loss (Wildervanck, Okihiro, MAFB, HOXA1), developmental delay (chromosomal anomalies) and other signs of aberrant innervation, such as crocodile tears [41]. The association of Duane with thenar hypoplasia, a triphalangeal or duplicated thumb, a short forearm, renal anomalies, coloboma, choanal atresia or anal stenosis should prompt study of SALL4, even if only one relative has limb malformations [22, 73]. A child with radial and renal malformations, or with renal position anomalies, without Duane, is more likely to have a SALL4 disorder than TBX5-related Holt-Oram syndrome [22]. In a patient with CFEOM, perinatal distress, developmental delay, slow growth, facial weakness, dysfunction of other cranial nerves, peripheral neuropathy, micropenis, cryptorchidism or contractures suggest specific TUBB3 variants [6]. In an infant with unexplained infantile nystagmus, especially a boy, with developmental concerns, prolonged neonatal jaundice, abnormal growth or puberty or other pituitary signs, an Xq26.2 deletion with IGSF1 should be suspected and FT4 and TSH measured, because TSH alone does not detect central hypothyroidism [34]. An infant with horizontal gaze palsy and profound deafness, especially of Navajo, Apache, Saudi or Turkish ancestry, should be assessed for central hypoventilation and carotid and cardiac anomalies [7].

4.3. Warning signs and urgent situations

Warning signs in infantile nystagmus are late onset without signs of eye disease, constant oscillopsia in an older child, dissociated (disconjugate), gaze-evoked, see-saw or convergence-retraction nystagmus, horizontal nystagmus that becomes vertical on vertical gaze, vertical or torsional nystagmus without retinal disease to explain it and the presence of neurological signs or systemic disease; in these cases systemic investigation and neuroimaging are required, with assessment by a paediatrician or paediatric neurologist [16]. The Oxford Desk Reference recommends brain MRI in all children with acquired nystagmus with onset after 6 months, to exclude chiasmal disease [71]. In a series of 140 children with optic pathway glioma at a Toronto centre, 30 presented primarily with nystagmus and all 27 with complete records had chiasmal involvement; the most consistent sign was onset of nystagmus at 3 months or later, followed by asymmetry or predominance in one eye, disconjugate or multiplanar nystagmus and change in pattern over time, so the authors recommend early neuroimaging when onset is after 3 months, especially with these atypical features [145]. Bilateral optic nerve hypoplasia, which frequently presents with nystagmus, requires assessment by a paediatric endocrinologist because of the association with septo-optic dysplasia and pituitary deficiencies [146].

The concise practice points of the Royal College of Ophthalmologists (RCOphth), prepared in 2022 by the NUKE development group and published in April 2023, organise these data into red flags, which point to causes requiring urgent investigation, treatment or referral, and green flags, which point to less urgent causes; none is pathognomonic of a cause, and together they serve to prioritise the urgency of investigation [147]. The document recommends that all children with nystagmus be referred to hospital ophthalmology services and that the presence of any red flag should lead to consideration of urgent referral, typically on the same day [147].

Source: RCOphth 2023, table 1, adapting Self 2020, Casteels 1992 and Osborne 2018 [147].

Emergencies specific to the class are the central hypoventilation of ABDS, with hypoxaemia mainly during sleep, stroke in patients with carotid anomalies, particularly in the perioperative period, and recurrent aspiration due to dysphagia [7]. In HGPPS, an acute hemispheric lesion may cause an ipsilateral rather than contralateral motor deficit, which matters in interpreting the emergency neurological examination [8]. Severe corneal exposure in CFEOM with operated ptosis or lagophthalmos requires early treatment [6].

4.4. Newborn screening

There is no newborn screening for any of the entities of the class. TSH-based newborn screening for hypothyroidism does not detect the central hypothyroidism of IGSF1 deficiency [34]. Relatives at risk of Duane should have an eye examination in the first year of life [5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles and clinical criteria

None of the entities of the class has formal diagnostic criteria validated by international consensus. FIN is defined by suggestive findings (onset by 6 months, horizontal conjugate oscillations, acuity usually better than 6/12, normal binocular and colour vision, a family history compatible with X-linked inheritance) and is confirmed by a hemizygous pathogenic or likely pathogenic variant in a male or a heterozygous one in a female; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. Duane syndrome is a clinical diagnosis made by the ophthalmologist, based on limitation of abduction, adduction or both with globe retraction on adduction, a sign considered indispensable [5]. CFEOM is diagnosed by the ocular findings described in section 3 [6]. The minimum criteria for Moebius sequence are congenital non-progressive facial palsy, abduction deficit and complete vertical motility; normal vertical motility and absence of ptosis distinguish it from CFEOM [70, 148]. A SALL4 disorder should be suspected in patients with features of DRRS, AROS or Holt-Oram syndrome and is confirmed by a heterozygous pathogenic variant [22]. HGPPS is suggested by MRI and confirmed by ROBO3 sequencing [8]. The HOXA1 syndromes are confirmed by biallelic pathogenic or likely pathogenic variants [7].

5.2. Clinical and orthoptic examination of nystagmus

Nystagmus is examined in the nine positions of gaze, describing the axis (horizontal, vertical, torsional, circumrotatory), conjugacy, form (pendular or jerk, with the direction of the fast phase), frequency and amplitude; in INS, the nystagmus is typically horizontal, remains horizontal on elevation and depression and has a null zone outside which it intensifies [16]. FMNS is conjugate and horizontal, beats towards the side of the fixing eye, reverses with alternate occlusion, intensifies on abduction and dampens on adduction of the fixing eye, and is best identified with alternate occlusion in extreme lateral gaze [16]. Gaze-evoked nystagmus, the most frequent acquired form, beats towards the side of gaze, does not change with monocular occlusion and is accompanied by saccadic smooth pursuit; downbeat, upbeat or asymmetric forms require consideration of a neurological cause, without excluding INS [16]. The orthoptic examination records the AHP for near and distance, with and without correction, head shaking (frequent after the first year and which the child can voluntarily stop when asked), binocular and monocular acuity with and without AHP, the cover test and the change in nystagmus with occlusion, binocular vision and stereoacuity, ductions and versions, the vestibulo-ocular reflex, optokinetic nystagmus (normal, absent or reversed), smooth pursuit, convergence and measurement of the deviation with prisms [16, 149]. Monocular acuity in patients with nystagmus, especially latent nystagmus, is measured by fogging the fellow eye with a high plus lens or a translucent occluder, instead of an opaque occluder, and binocular acuity should also be recorded [150]. A positive angle kappa is associated with albinism in children with INS and is usually absent in IIN [16, 151]. To detect the periodic alternating component, the child should be observed for 5 to 7 minutes with central fixation [135].

5.3. Optical coherence tomography

Handheld spectral-domain OCT allows the fovea to be studied in infants without sedation; in Leicester, in 50 children with nystagmus and 50 controls (mean age 3.2 years), it was successful in 94% and classified patients into typical foveal hypoplasia (21 with albinism and 2 with PAX6), atypical hypoplasia (5 with achromatopsia), other changes (6 with retinal dystrophies) and normal fovea (12 with idiopathic nystagmus and 4 with manifest-latent nystagmus), with sensitivity and specificity of 92.8% and 91.4% for typical hypoplasia, 86.7% and 94.8% for atypical, 41.1% and 97.7% for other changes and 88.4% and 95.1% for normal fovea [152]. Foveal hypoplasia is graded by the Leicester classification: grade 1, shallow foveal pit with widening of the outer nuclear layer and lengthening of the outer segments; grade 2, no foveal pit; grade 3, no widening of the outer segments; grade 4, no widening of the outer nuclear layer; the atypical form, with disruption of the ellipsoid zone, occurs in achromatopsia [135, 153]. Only grades 3 and 4 are associated with reduced acuity, and the grade allows future acuity to be predicted in preverbal children [135, 154]. In practice, the macular cube should include the optic nerve and at least five uninterrupted scans on each side of the central fovea [16]. OCT and electrophysiology discriminate GPR143 from FRMD7: in a Chinese series of 20 patients with GPR143 and 21 with FRMD7, foveal hypoplasia, multifocal ERG with flat topography and VEP asymmetry occurred only in the GPR143 group, whereas the amplitude and frequency of nystagmus did not differ [155].

5.4. Electrodiagnosis

Paediatric ERG and VEP are performed without anaesthesia, sedation or mydriasis, in 30–40 minutes, with a modified paediatric protocol; in adults the International Society for Clinical Electrophysiology of Vision (ISCEV) standards are followed [16]. In Leber congenital amaurosis all ERGs are attenuated; in achromatopsia the cone ERG is attenuated and the rod ERG normal; the negative ERG (a-wave more preserved than b-wave) occurs in X-linked congenital stationary night blindness and X-linked retinoschisis [16]. Because acuity is difficult to measure in the infant, the ERG is the test of choice to distinguish FIN from Leber congenital amaurosis and replaces assessment of colour vision in young children [1]. A normal ERG with degraded VEPs requires exclusion of a post-retinal cause (optic nerve hypoplasia, glioma, craniopharyngioma, achiasmia); crossed VEP asymmetry, which reverses with the eye stimulated, indicates a chiasmal anomaly as in albinism, more evident with flash VEPs in the infant, and uncrossed asymmetry indicates hemispheric dysfunction [16]. Children with genetically confirmed albinism, especially with hypomorphic phenotypes, may not have crossed asymmetry [16]. Because vertical, torsional or asymmetric nystagmus, associated with neurological disease, also occurs in retinal dystrophies, congenital stationary night blindness, albinism and IIN, electrodiagnosis is indicated in all [16].

5.5. Eye movement recording

A slow phase of increasing velocity is practically pathognomonic of INS, whereas FMNS and acquired gaze-evoked nystagmus have decreasing slow phases [16]. About 1 in 20 people can voluntarily induce a high-frequency, low-amplitude oscillation (psychogenic «flutter»), composed of saccades without a slow phase, which is not nystagmus [16]. Recording measures conjugacy, plane, pattern, direction, frequency, amplitude, foveation dynamics and the width of the null zone; intensity (amplitude × frequency) correlates less with visual function than foveation, which can be quantified by the eXtended Nystagmus Acuity Function (NAFX) [1]. Measuring these parameters before and after treatment provides an objective measure of response, and recording helps to plan surgery (periodic component, position of the null zone) [1, 16]. NAFX has limitations in albinism [72]. The British consensus illustrates the usefulness of recording with a 6-year-old boy referred for apparently recent-onset gaze-evoked nystagmus, with a normal urgent MRI, in whom recording showed accelerating slow phases and fine nystagmus in primary position: this was INS present since infancy and undetected because of a wide null zone, and the MRI would have been avoidable [16].

5.6. Infantile nystagmus algorithm

The consensus of the specialist UK centres (Nystagmus UK Eye research group, NUKE) organises children with nystagmus into seven clinical groups that define the investigation [16].

Source: Self and colleagues, table 4 [16].

The flowchart in the RCOphth practice points, adapted from the NUKE consensus and presented as the basis of practice in the United Kingdom, considers the minimum initial clinical work-up to be the history (ophthalmic, general medical, prenatal and perinatal, family), orthoptic examination, examination of the nystagmus itself, examination of the anterior and posterior segments and cycloplegic refraction; subsequent tests depend on these findings and on clinical priority, and local availability may change the order, but does not justify an incomplete investigation [147]. The sequence of decisions is as follows: classic skin and hair features of oculocutaneous albinism type 1 lead directly to the albinism and nystagmus panel; physiological end-point nystagmus generally requires no further tests, and pathological movements that are not nystagmus, such as opsoclonus, require urgent investigation with neuroimaging; a picture compatible with a known familial disease directs targeted genetic testing; aniridia directs to the anterior segment dysgenesis panel together with array comparative genomic hybridisation (array CGH); typical FMNS, without signs of another cause, does not require urgent investigation; acquired or neurological nystagmus and optic nerve hypoplasia lead to investigation with neuroimaging; in the remaining cases, retinal OCT directs to the retinal dystrophy panel when the findings are those of retinal dystrophy and to the albinism and nystagmus panel when there is classic foveal hypoplasia, and, if OCT is not available or is normal for age, paediatric electroretinography and visual evoked potentials confirm or exclude retinal disease before the panel is chosen [147]. When there is a clear history of prenatal exposure to medicines or drugs, neuroimaging may not be necessary in atypical nystagmus, but full phenotyping remains and all children should be seen by a general paediatrician; if the history is less clear, the exposure does not preclude investigation according to the flowchart [147]. The document assigns electrodiagnosis a central role in diagnosis and visual prognosis, states that eye movement recording helps but is not used routinely in most centres, and indicates the Leicester classification of foveal hypoplasia to estimate future vision in infants, as well as the «Albinism or congenital nystagmus» panel (R39) of the National Genomic Test Directory for England [147].

According to the RCOphth, criteria for referral from hospital paediatric ophthalmology services to a specialist nystagmus service are the local lack of an appropriate investigation pathway (OCT, electroretinography and visual evoked potentials, genetics), in which case referral may be only for those tests according to local networks, the need for specialist tests such as eye movement recording, a request for a second opinion and local unavailability of optical, pharmacological or surgical options [147].

The approach of the Oxford Desk Reference is concordant and adds, according to the presentation, genomic analysis (microarray, panel, exome or genome) if there is dysmorphism or significant unexplained delay, metabolic and endocrine screening if there are signs of progressive disease, audiology (peroxisomal diseases), renal ultrasound (Leber amaurosis, Joubert) and echocardiography (Alström), and DNA storage when the specific test is not available [71]. In a tertiary hospital in Israel, among 147 infants with nystagmus in the first year of life, the most frequent causes were albinism and inherited retinal dystrophies, the most useful tests were clinical examination, genetic testing and ERG, and a neurological cause was rare at this age; vertical nystagmus occurred in 8 infants, half with retinal dystrophy [156]. The 2026 British genome sequencing study quotes, from a reference that was not among the sources of this review, an estimate of about 30% of infantile nystagmus having an underlying neurological cause, which justifies not dispensing with neuroimaging when the findings do not fit groups 1 to 4 [18].

5.7. Genetic testing in infantile nystagmus

Clinical phenotyping is a prerequisite for choosing the panel (retinal or albinism and nystagmus) and for interpreting the result with clinical genetics [16]. In current practice, the multigene nystagmus and albinism panel, or genome sequencing, has replaced single-gene testing, which GeneReviews reserves for typical FIN phenotypes (FRMD7 sequencing followed, if negative, by targeted deletion and duplication testing); in atypical phenotypes it recommends exome or genome [1]. In Southampton, 81 unrelated patients with nystagmus and basic phenotyping had a probable genetic cause in 43.2% with a small panel, with similar yield regardless of prior phenotyping, which reduces invasive tests [157]. In a US registry (Akron, 2010–2024), 205 children with INS studied by panels had a molecular diagnosis in 41.5% (85 of 205), with 83 variants in 30 genes; albinism (32%), Leber congenital amaurosis (14%) and achromatopsia (14%) were the most frequent diagnoses, and seven genes (TYR, CNGB3, RPGR, GPR143, ABCA4, OCA2 and FRMD7) accounted for 65% of solved cases [17]. In the 100,000 Genomes Project, 473 affected individuals from 388 families, recruited through albinism or infantile nystagmus codes, had positive findings in 46% and a definitive diagnosis in 37%; the English National Health Service (NHS) R39 panel («Albinism or congenital nystagmus») identified variants in 16 of its 38 genes, mainly TYR (56 families) and OCA2 (21), with FRMD7 in 9 families and GPR143 in 10, and a further 36 genes outside the panel accounted for 45 families, including Waardenburg syndromes (SOX10, MITF, PAX3), CNGA3 and neurodevelopmental genes, and 4 dual diagnoses in 3 families [18]. In this study, refractive errors and diagnoses linked to foveal hypoplasia were enriched (odds ratio of about 2.8 for refractive errors) and strabismus and neurodevelopmental features overrepresented; the yield published in the literature ranges from 35% to 60% [18].

Source: GeneReviews FRMD7, table 1; the values are proportions of detectable variants in published series and not clinical sensitivity [1].

5.8. Limitations of testing in nystagmus

A negative panel does not exclude a genetic cause. Panels and exome sequencing assess poorly structural variants, copy number changes, deep intronic variants and non-coding variants; the British genome study acknowledges that these classes were not systematically assessed and that the R39 panel does not capture syndromic aetiologies or dual diagnoses [18]. The Xq26.2 deletion in the Bedouin family escaped karyotyping and the targeted panel, was suggested by the microarray (loss at Xq26.2, more evident in the hemizygous boy), was not identified as a variant on the exome, where only the absence of reads in FRMD7 betrayed it, and was only delimited by genome sequencing, with confirmation by junction PCR and Sanger sequencing; the authors recommend structural variant analysis in unexplained IIN or IIN with endocrine anomalies [34]. In NYS7, the exome did not find the cause in a family with established linkage, and only short- and long-read genome sequencing, with array comparative genomic hybridisation, revealed non-coding deletions of about 0.8–0.9 Mb [29]. Deep intronic and non-canonical splicing variants have been published in FRMD7, whose interpretation may require RNA or minigene studies [4]. In a female, absence of nystagmus does not exclude carrier status, given the penetrance of 30–50% [25]. FRMD7 missense variants benefit from in silico tools calibrated for the gene, and exon 12 missense variants are rarely causal [4].

5.9. Duane syndrome

More than 98% of patients with isolated Duane and no family history have no identified genetic aetiology [5]. Molecular testing of CHN1, MAFB and SALL4 is most appropriate when there is a family history of isolated Duane, bilateral Duane, or types I, III or combined; type II has not been observed in families or with variants in the known genes, which suggests another aetiology [5]. Miyake and colleagues found CHN1 in 7 of 20 families with Duane and no variant in 140 patients without a family history [82, 158]; in 401 patients, MAFB accounted for 4 probands, 3 with a family history and 1 de novo [39].

Source: GeneReviews Duane, table 2 [5].

Testing may be simultaneous (sequencing of the three genes and, if negative, deletions and duplications of MAFB and SALL4) or sequential in isolated Duane: CHN1, then MAFB (sequencing and deletions/duplications) and then SALL4; if there is hearing loss, MAFB moves to first place [5]. A multigene panel with these genes and those of the differential, or exome and genome sequencing, are alternatives; if the exome is not diagnostic, an exon-targeted microarray detects deletions and duplications; Duane with significant congenital anomalies should be studied by chromosomal microarray [5]. After diagnosis, the eye examination records the deviation in primary position, the AHP, horizontal and vertical restrictions, aberrant movements, refraction and amblyopia, with optional forced duction and force generation testing and photographic documentation; if surgery is planned, brain and orbital MRI should be considered; general physical examination, hearing assessment and genetics clinic referral are added [5]. When there is a short neck, a cervical spine radiograph is performed; abdominal ultrasound looks for renal anomalies (8q13 deletion, cat eye syndrome, Wildervanck, Klippel-Feil) and echocardiography, audiography and, if there is hearing loss, inner ear imaging complete the assessment [41].

5.10. SALL4-related disorders

In the typical phenotype, SALL4 sequencing is performed first and, if negative, targeted deletion and duplication analysis (exons or whole gene, by quantitative polymerase chain reaction (PCR), long-range PCR, multiplex ligation-dependent probe amplification (MLPA) or targeted microarray); as this detects 10–15% of variants, negative sequencing does not exclude the diagnosis [22]. In phenotypes outside the typical spectrum, a multigene panel with SALL4 and the genes of the differential (TBX5, SALL1, RBM8A, Fanconi anaemia genes) is recommended [22]. When a larger deletion is found or there is developmental delay, the microarray defines whether the deletion includes neighbouring genes [22]. An immunohistochemical SALL4 result in a tumour reflects somatic re-expression of the protein and bears no relation to the germline disease [112]. The initial assessment includes an eye examination with attention to eye movements and structural malformations; limb assessment with radiographs and orthopaedics as needed; renal ultrasound with electrolytes, urea and creatinine; cardiological assessment with echocardiography and electrocardiography, extended if a conduction defect is suspected; hearing assessment; surgical assessment of anal anomalies; assessment of growth, growth hormone and signs of pituitary hypoplasia; full blood count for thrombocytopenia or leucocytosis; and genetics clinic referral [22].

5.11. Congenital fibrosis of the extraocular muscles

GeneReviews recommends a multigene panel with the CFEOM genes or exome/genome sequencing [6]. The presentation guides interpretation: bilateral CFEOM with ptosis and restricted upgaze, without other findings, points to KIF21A or TUBB3; unilateral CFEOM or CFEOM without ptosis points more often to TUBB3; CFEOM3 with facial weakness, other cranial nerve deficits, peripheral neuropathy, micropenis, cryptorchidism or contractures strongly suggests specific TUBB3 variants [6]. The prenatal and perinatal history, development, growth, complete physical examination (including extremities and genitalia), neurological examination and three-generation pedigree complete the assessment [6]. The eye examination records the resting position of the eyes and head, restrictions, aberrant movements (synergistic convergence and divergence, retraction, Marcus Gunn), the palpebral fissure and levator function, corneal exposure, cycloplegic refraction and photographic documentation [6]. If surgery is planned, brain and brainstem MRI (size and course of cranial nerves III and IV) and high-resolution orbital MRI with 1–3 mm slices (size, insertion and course of the muscles and atrophy of the superior rectus–levator complex) are strongly recommended [6].

5.12. HGPPS, HOXA1 syndromes and Moebius sequence

In HGPPS, MRI with a split pons and butterfly medulla suggests the diagnosis, which ROBO3 sequencing confirms; tractography and evoked potentials document the absence of decussation, and a whole-spine radiograph assesses the scoliosis [8, 64, 142]. In the HOXA1 syndromes, the gene is sequenced and, if 0 or 1 variants are found, deletions and duplications are sought; in patients of Saudi or Navajo and Apache ancestry the respective founder variant is tested first; a CCDD panel or exome/genome sequencing serve atypical phenotypes; the absence of consanguinity or of affected siblings does not exclude the diagnosis [7]. The initial assessment includes neuro-ophthalmological and orthoptic examination with binocular vision testing, brainstem auditory evoked potentials, time-of-flight MR angiography of the neck and brain, neurological examination, brain MRI, electroencephalography if there are seizures, developmental assessment and, after 12 months, screening for autism spectrum disorder, awake oximetry, polysomnography and blood gases, electrocardiography and echocardiography, bronchoscopy and swallowing assessment, genetic counselling and family support [7]. Moebius sequence is a clinical diagnosis, with no specific laboratory test [69]; sequencing has a low yield when the strict criteria are met, but is useful in atypical cases (vertical deficit or ptosis, suggestive of CFEOM due to TUBB3 or KIF21A, or familial cases), and a methylation episignature may, in selected cases, suggest a broader malformation constellation [11, 70, 127].

5.13. Interpretation, reporting and general limitations

The molecular report should identify the gene, the versioned reference transcript (MANE Select), the variant in HGVS nomenclature, the zygosity (hemizygosity, heterozygosity, homozygosity or compound heterozygosity) and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). GeneReviews uses earlier versions of some transcripts (for example NM_194277.2 for FRMD7, NM_001822.5 for CHN1 and NM_005461.4 for MAFB) and the variants in its tables have not been verified by the editorial team, so comparison with current reports should be made by genomic position [1, 5, 95]. In diseases with incomplete penetrance (FRMD7 in females, CHN1, SALL4) and variable expressivity, family segregation of a VUS requires clinical examination of relatives and, in FIN, eye movement recording and optokinetic response in females without apparent nystagmus [1, 5, 22]. Identification of a variant explains the phenotype only when the two are compatible; in unsolved CCDD, some diagnoses are phenocopies with a cause in other systems [83]. Parental somatic mosaicism may escape study of leucocyte DNA [6, 22]. Sporadic isolated CCDD, most Duane and Moebius sequence have a low genetic yield, and a negative result is the rule in these groups [5, 11, 83].

5.14. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal testing and preimplantation genetic testing are possible in all entities with a known molecular cause [1, 5–7, 22]. In SALL4 disorders, testing does not predict which manifestations will occur or their severity, and high-resolution ultrasound is recommended to assess the fetus; the variant may be discovered for the first time when a routine ultrasound shows radial malformations, and in that case, if it is a larger deletion, the microarray defines the genes included [22]. Views on the use of prenatal testing in diseases with a good visual prognosis, such as FIN, differ between professionals and families [1].

6. Differential Diagnosis

6.1. Differential diagnosis of infantile nystagmus

The differential diagnosis of IIN is, in practice, that of INS with a sensory deficit and that of neurological causes. The associated sensory diseases are summarised in the table and, in the text, only in what distinguishes each from idiopathic nystagmus.

Albinism is the main genetic cause of infantile nystagmus in sequenced cohorts: 32% of diagnoses in the Akron registry and TYR and OCA2 as the most frequent genes in the 100,000 Genomes Project [17, 18]. The nystagmus of albinism is similar to that of IIN, but AHP is more severe and more frequent than in FIN, periodic alternating nystagmus is more common, fundus hypopigmentation is present in more than 94% and nystagmus is absent in up to 7.7% of patients, so its absence does not exclude albinism [135, 159, 164]. GPR143 deserves particular attention because it causes both typical ocular albinism and atypical forms with nystagmus and apparently normal pigmentation; foveal hypoplasia and the electrophysiological changes distinguish it from FIN [33, 106, 155]. Carriers of X-linked ocular albinism may have iris transillumination and a fundus with mosaic pigmentation («mud-splattered»), which distinguishes them from FIN carriers [135]. FHONDA (foveal hypoplasia, optic nerve decussation defect and anterior segment dysgenesis, due to SLC38A8) reproduces the visual phenotype of albinism without hypopigmentation: in a series of 511 patients with nystagmus studied by panel, 90% of cases with SLC38A8 had initially been classified as PAX6 or ocular albinism [160]. In the largest series (28 patients from the Netherlands, Israel, France and the USA), all had nystagmus, the median acuity was 0.7 logMAR, foveal hypoplasia was grade 4 in all 17 studied by OCT and abnormal crossing was present in the 9 tested [161, 162]. GeneGuidance also states that SLC38A8 accounted for 6.8% of typical foveal hypoplasia in 907 patients with a molecular diagnosis from 12 centres in 9 countries, the third cause after albinism and PAX6; this is a proportion within a clinical group, whose primary publication was not identified [162].

Spasmus nutans is the main benign differential diagnosis of nystagmus with onset in the first year. In Boston, between 2000 and 2020, 32 patients (41% girls; 19% with trisomy 21; 25% premature) were diagnosed at a mean of 16 months and resolution occurred at a mean of 48 months; all had nystagmus, 97% head nodding and 50% torticollis; at a mean follow-up of 66 months, amblyogenic refractive error appeared in 85% of the 20 with more than one examination, stereopsis was measurable in 12, strabismus persisted in 8 and 8 required amblyopia treatment, which justifies ophthalmological follow-up until the end of the amblyogenic age [163]. The diagnosis is one of exclusion: cases of «spasmus nutans» have been described that were in fact albinism with torsional nystagmus, Alström syndrome (a Portuguese case with a novel ALMS1 variant) or another monogenic cause identified by early exome sequencing [165–167]. In children with achromatopsia and INS, the waveform typically has a dual jerk and the AHP is often vertical [168].

6.2. Differential diagnosis of congenital incomitant strabismus

Duane is distinguished from other causes of horizontal limitation by globe retraction; cranial nerve VI palsy, acquired in most cases, has no retraction or fissure narrowing, and esotropia with cross-fixation reveals full abduction when the fellow eye is occluded [5]. CFEOM is distinguished from Duane by ptosis and restricted upgaze and from Moebius sequence by vertical motility [5, 6]. In HGPPS retraction is absent and scoliosis guides the diagnosis, although it may not yet be present in young children [8]. In ABDS, the differential diagnosis of central hypoventilation includes PHOX2B-related congenital central hypoventilation and other causes of early hypoventilation (primary neuromuscular, pulmonary or cardiac disease, brainstem lesion, hypoxic-ischaemic encephalopathy, infection, extreme prematurity) [7]. Moebius sequence has its own differential diagnosis, which includes basilar artery thrombosis, brainstem gliomas, congenital muscular dystrophy (proximal weakness without oral cavity malformation) and toxic neuropathies [69], and Carey-Fineman-Ziter congenital myopathy (MYMK, autosomal recessive), with facial weakness and Pierre Robin sequence [6]. Hereditary congenital facial paresis 3 is distinguished from Moebius by preserved abduction, the criterion that led to revision of the diagnosis in the German American patients initially classified as Moebius [126]. Craniofacial microsomia 2 shares with the HOXA1 syndromes the association between auricular and internal carotid anomalies, but the predominant phenotype is isolated microtia [7, 169]. In Brown syndrome, diplopia may be noticed only in adolescence or adulthood and appear to worsen rapidly, because of greater attention to the symptom, and there are forms acquired in adolescence: three Italian siblings developed unilateral Brown at 12–13 years, with tenderness on palpation of the trochlea in one of them, and the condition remained stable for about a decade [91].

6.3. Differential diagnosis of Okihiro syndrome

The most important differential diagnosis is TBX5-related Holt-Oram syndrome, which accounts for 70% of patients with the Holt-Oram phenotype [22]. Preaxial polydactyly is associated almost exclusively with SALL4; in TBX5-related Holt-Oram syndrome atrial septal defect is more frequent than ventricular septal defect, whereas in SALL4 disorders the reverse may be seen, and conduction defects are less frequent with SALL4 [22]. The presence of Duane, in a patient or a relative, and of renal or urogenital anomalies (especially of renal position) favours SALL4 [22]. Fanconi anaemia should be excluded in the presence of bilateral thumb or radial defects, consanguinity, café-au-lait spots or microcephaly, because of its progressive bone marrow failure and cancer predisposition [22, 172]. The VACTERL association usually presents with three to four components, is sporadic and has normal cognitive development; the diagnosis presupposes exclusion of the monogenic syndromes with radial defects [172]. In any radial defect, the Oxford Desk Reference recommends a full blood count, limb radiographs and, according to the presentation, spine and chest radiographs, echocardiography and electrocardiography, renal ultrasound and, if Fanconi anaemia is suspected, the chromosome breakage test [172].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of the recommendations

There is no treatment directed at the genetic cause of any of the entities of the class. The aims are to maximise visual acuity and binocular vision during the sensitive period of visual development, to prevent and treat amblyopia, to correct the AHP and misalignment when they have a functional or cosmetic impact, and to treat the extraocular manifestations of the syndromic forms [5, 6, 16]. The evidence base is heterogeneous. For comitant strabismus there is a formal graded guideline, the AAO Preferred Practice Pattern «Esotropia and Exotropia» of 2023 [15]. For infantile nystagmus, the reference is the practice consensus of the five specialist UK centres (NUKE), published in 2020 as a literature review and description of practice, without formal grading of evidence [16]; a 2025 systematic review identified 52 studies of symptomatic treatment, of which only 7 were randomised trials (1 surgical, 1 pharmacological, 1 optical and 4 of perceptual training), with outcomes so heterogeneous that they precluded meta-analysis [72]. The RCOphth concise practice points «Managing Nystagmus in Childhood» (April 2023, with review scheduled for April 2025 in the version consulted) condense the same consensus into a reference for the clinician, without grading of evidence, and define as cause-independent aims the optimisation of visual function, treatment of the neck strain of marked AHP and improvement of ocular alignment and appearance, with optical, pharmacological and surgical options that can be combined [147]. For Duane syndrome, CFEOM, the HOXA1 syndromes and SALL4 disorders, the recommendations are those of the authors of the GeneReviews chapters, who state that there are no published guidelines [5–7, 22].

7.2. Optical correction, amblyopia and low vision

Refractive correction is the first priority: more than half of patients with nystagmus (57%) have significant refractive error, and early correction can appreciably improve acuity [1, 16, 72]. In the Chinese FIN cohort, all children with acuity worse than 0.52 logMAR had uncorrected refractive error, and the authors recommend proactive correction [4]. Contact lenses offer optimal correction in a moving eye and have been proposed to have a dampening effect via proprioception of the ophthalmic branch of the trigeminal nerve; they correct high errors and astigmatism (up to 15.00 cylindrical dioptres with soft lenses) and are traditionally rigid gas-permeable (RGP) in INS [1, 16]. Randomised trials have not confirmed a clear advantage: in a crossover trial of 24 participants (12 with IIN and 12 with albinism) comparing spectacles, soft lenses and RGP lenses, there was no difference in intensity or nystagmus parameters, and near vision worsened with both lens types [16, 173]; in a parallel pilot trial at Moorfields in 38 adults with IIN, plano lenses and corrective lenses both improved binocular acuity at 2 weeks (0.07 logMAR; 95% CI 0.03–0.11, and 0.06 logMAR; 95% CI 0.02–0.10), with tolerability of 89% among the 27 who completed, but the trial was not powered to compare arms [174]. Uncontrolled series describe improved acuity in 79% of 112 patients with rigid lenses and, in 16 hypermetropes with INS, improved acuity, contrast sensitivity and motor indices at 3 months with RGP lenses [16, 72]. Contact lenses are considered mainly in older children with high refractive errors, weighing the risk of infection [16].

In albinism and in forms with foveal hypoplasia, if amblyopia persists after a refractive adaptation period of 16 to 18 weeks, occlusion is started; a discrepancy between measured acuity and that expected from the grade of foveal hypoplasia requires a search for another cause [135]. Amblyopia is treated as in any child, without modification because of the nystagmus [16]. Low vision aids (telescopes, magnifiers) are used after full refractive correction, and early referral to paediatric low vision services, a written report for the school and educational support are part of treatment; in the United Kingdom, the certificate of visual impairment facilitates school, transport and employment support [16, 135]. The RCOphth adds filter lenses in cases with photophobia, recommends considering registration of visual impairment in all children with nystagmus, because most, even with good acuity, have visual limitation in real-world tasks, and recommends referring families, as soon as they are ready, to the local sensory team (with the qualified teacher of children with visual impairment, who assesses special educational needs) and to the eye clinic liaison officer, who provides information on support groups, habilitation, mobility training and registration [147].

Prisms are useful in patients with binocular vision whose nystagmus dampens with convergence (base-out prisms) or who have a small AHP, either as a preoperative test or as long-term treatment [1, 16]. In a retrospective Toronto series, 31 children (19 with IIN, 6 with albinism and 6 with secondary nystagmus) treated with low-power conjugate prisms (mean 3.9±1.25 prism dioptres) reduced the distance AHP from 16.9°±9.9° to 4.6°±5.8° and had a small improvement in binocular acuity (0.44 to 0.41 logMAR; p=0.001) [175]. Triple yoked prisms resolved residual postoperative AHP (below 5°) in 18 of 27 children [16]. A Southampton series (2018–2025) recorded 7 successes and 12 failures with conjugate and artificial divergence prisms, mainly due to intolerance of optical aberrations in patients with poor binocular function [176]. In patients with nystagmus, refractive treatment of ametropia and anisometropia follows the general rules (spectacles for hypermetropia of +1.00 dioptre or more in a child with recent esotropia) [15].

7.3. Pharmacological treatment of infantile nystagmus

All drugs used in infantile nystagmus are prescribed off-label, and no label mentions nystagmus [72, 96]. The largest randomised, placebo-controlled, double-blind trial (Leicester, McLean and colleagues, 2007) included 48 patients with congenital nystagmus for 56 days: memantine (16), gabapentin (16) and placebo (15, plus 1 withdrawal); logMAR acuity improved with both drugs (F=6.2; p=0.004), as did intensity (F=7.7; p=0.001) and foveation (F=8.7; p=0.0007), subjective improvement was more frequent with active drug (p=0.03) and there was no difference in the visual function (VF-14) and social questionnaires; the acuity benefit was smaller in patients with an afferent visual deficit [19]. The figures of «16 participants» quoted in some sources correspond to each active arm, not to the total [19, 135]. In the subgroup with secondary nystagmus (for example, albinism), the change in acuity was not significant, although intensity and foveation improved [135]. According to a review cited in the 2025 systematic review, gabapentin had no effect in IIN, whereas memantine improved acuity by 0.15 logMAR [72]. Pharmacological treatment is typically reserved for adults and adolescents with troublesome visual symptoms, such as oscillopsia, which are rare in early-onset nystagmus; most treatments have been used above 16 years of age, it is not known who responds best or at what age, and there are no studies of long-term effect [16, 72].

The memantine dose in the British consensus (up to 40 mg/day, in adults) is the reference for nystagmus, as it derives from the randomised trial, but it lies outside the label conditions (maximum of 20 mg/day in adults in the EMA and FDA labels, for Alzheimer disease), and the gabapentin dose (up to 2400 mg/day) lies within the doses studied in epilepsy; both drugs are usually well tolerated when the dose is increased slowly [16, 177, 180]. The daily dose of memantine and gabapentin and the need for reduction because of systemic effects have been pointed out as limitations of treatment [20]. The RCOphth practice points indicate gabapentin up to 2400 mg/day in 3 to 4 doses and memantine 20 to 40 mg/day in 2 to 3 doses, specify that these doses apply only to adults, describe efficacy on nystagmus intensity and visual function in some adult patients, mention baclofen in congenital periodic alternating nystagmus and note that these drugs are rarely prescribed in children [147].

Topical brinzolamide has gained popularity with limited evidence [16]. In a double-blind crossover trial of 5 adults with INS (Akron), one drop three times daily improved the waveform in the null zone and the mean NAFX [181]. In a placebo-controlled crossover trial in New Delhi (2016–2017), 29 patients with idiopathic INS, aged 10 years or over, completed 3 months of brinzolamide and 3 months of placebo with a 7-day interval: median acuity went from 0.34 to 0.27 logMAR and from 0.4 to 0.34 logMAR in the two sequence groups (placebo without relevant change), with a significant effect on acuity and NAFX (p<0.001), 59% of patients gained 3 or more letters on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart and 14% one line or more; intraocular pressure fell by about 1 mmHg; there was no effect on AHP or stereopsis and there were no adverse effects over 3 months [20]. The authors note that treatment would be lifelong and that long-term and functional impact studies are lacking [20]. In a non-randomised prospective study from Cairo, in 40 children up to 14 years treated with brinzolamide 1%, mean nystagmus amplitude fell from 8.39° to 5.95° after 1 month and 5.27° at 6 months, but remained at 4.18° one month after discontinuation, and intensity increased in 32.5% of patients in the first month, which, without a control group, does not allow the drug effect to be separated from natural evolution [185]. Oral acetazolamide has been described in a single case report [72].

7.4. Nystagmus surgery

Anderson-Kestenbaum surgery moves the eccentric null zone to the primary position and corrects the AHP, which it causes; in practice, it also broadens the null zone and reduces the nystagmus outside it [1]. The Kestenbaum operation recesses the yoke muscles on the side opposite the AHP and resects or plicates the antagonists; the Anderson operation performs only bilateral recessions; there are «high-dose» and augmented variants [72]. The British consensus recommends increasing the classic amounts by 40% for AHP up to 30° and by 60% for AHP above 45°, or performing large symmetrical surgery; with these modifications, 72–100% of patients achieve an AHP of 15° or less [16]. Up to 43% of patients gain corrected acuity and some studies describe up to 60% reduction in recognition times, but up to 40% need further surgery, on average 6 years later, for undercorrection [16]. In the systematic review, 15 of 19 surgical studies that measured acuity had positive results, 8 with significant improvement of 0.037 to 0.21 logMAR, and only 3 of 22 measured quality of life [72].

Source: NUKE consensus, table 6, simplified guide [16]. In FMNS or with heterotropia, the fixing eye is operated on; bilateral inferior rectus recession may induce an A pattern, correctable by nasal transposition [16].

The preoperative assessment measures the AHP with and without spectacles, for near and distance, monocularly and binocularly and with maximum visual effort, using objective methods (goniometer, torticollometer, applications) over several visits, and looks for periodic alternating nystagmus (observation for at least 5 minutes, repeated orthoptic assessment and oculomotor recording if in doubt), FMNS and coexisting strabismus [16]. The British consensus accepts AHP surgery at preschool age when the head turn exceeds 20°, measured robustly and consistently, and the albinism GeneReviews places Anderson-Kestenbaum surgery, in general, after 2 years of age [16, 135]. The 2025 systematic review records divergence: one author advises avoiding surgery before 5 years because of the difficulty of preoperative assessment, whereas another reports good results before 2 years [72]. Direct scleral suturing or anchored hang-back recession is recommended [16]. The RCOphth indicates extraocular muscle surgery for significant AHP (above 20°), for the benefit to visual function and the associated head turn, considers that performing it as early as possible may maximise visual development, requires a search for periodic alternating nystagmus before proposing it and allows it to be combined with strabismus correction or artificial divergence surgery when there is a convergence null zone; in FMNS, AHP surgery is performed on the fixing eye and that of residual heterotropia on the non-fixing eye [147]. The complications described include partial regression of the effect, exophoria, strabismus, over- or undercorrection of the AHP, residual oscillopsia, conjunctival cyst and lack of improvement in distance acuity [72].

Tenotomy of the four horizontal recti with reattachment improved the waveform and visual function in a study of 10 adults with congenital nystagmus [1, 186]; the augmented version added no benefit and four-muscle myectomy with pulley fixation has been described [72]. In nystagmus with convergence blockage, bimedial recession with tenotomy improved frequency and acuity, with no difference compared with prisms [72]. In a prospective Akron series of 17 children with achromatopsia and INS operated on between 19 months and 12 years, with at least two recti in each eye, AHP, deviation, acuity, contrast sensitivity and NAFX improved, without complications and with 12% reoperation, and blepharospasm and photophobia also improved [168]. An Egyptian trial comparing the graded Anderson technique with the Kestenbaum technique in 28 patients with IIN (NCT05947331) had no published results in the registry at the time of the review [187].

7.5. Perceptual training and biofeedback

Perceptual training improves visual function without dampening the nystagmus. In a single-blind randomised trial from Israel (3:1), 26 patients aged 9 to 55 years underwent visual stimulation with Gabor patterns in a computer programme, about 30 minutes 3 to 4 times a week for 4 months, and 10 remained untreated: 46% of those treated versus 10% of controls reached driving acuity (20/40), distance acuity improved by 0.11±0.07 logMAR (about one line) versus 0.013±0.06, and near acuity and stereopsis also improved [188]. In children, training improved acuity, reading acuity and critical print size (36 children) and, in a prolonged home-based regimen (37 children), isolated and crowded acuity, stereopsis, the extent of crowding and reading speed; biofeedback had positive results in one study and an effect limited to fixation in another [72]. A trial of biofeedback versus a sham procedure in IIN (NCT04142307, Toronto, 34 participants) was recruiting, with completion expected in December 2027 [187].

7.6. Comitant strabismus: recommendations of the AAO guideline

The treatment options for esotropia are refractive correction, bifocal lenses, prisms, surgery, botulinum toxin and other drugs [15]. Spectacles are generally prescribed for children with recent-onset esotropia and hypermetropia of +1.00 dioptre or more, with full cycloplegic correction [15]. Bifocals are indicated when the accommodative convergence/accommodation (AC/A) ratio is high, that is, when the near deviation exceeds the distance deviation by 10 PD or more with full correction, with an empirical addition of +2.50 to +3.00 dioptres and the segment bisecting the pupil in preschool children [15]. Prisms are rarely useful in infantile esotropia; in the Prism Adaptation Study, success (deviation of 8 PD or less) was 90% in patients who responded to prisms and were operated on for the adapted angle [15]. Amblyopia is treated before surgery, because moderate to severe amblyopia reduces success [15]. Surgery is indicated when spectacles and amblyopia treatment are insufficient; deviations of less than 12 PD are generally not operated on, except symptomatic acquired ones [15]. Alignment to 10 PD or less before 2 years of age increases the likelihood of binocular vision and may reduce dissociated vertical deviation, but there is no evidence of a better motor outcome with early surgery [15]. Bimedial recession is the usual initial surgery; deviations above 60 PD often require further surgery; adjustable sutures are of no proven use in children; the risk of consecutive exotropia persists for at least 10 years and recurrence is most likely in the first year, with accommodative recurrence in 50%, correlated with hypermetropia; amblyopia and nystagmus are associated with a higher reoperation rate [15]. When there is nystagmus with a null point and compensatory face turn, operating on both eyes is preferred [15]. In exotropia, about 80% of patients have good alignment 6 months after bilateral lateral rectus recession, but long-term recurrence is frequent [15].

7.7. Botulinum toxin in strabismus

OnabotulinumtoxinA (BOTOX®, Allergan) produces temporary chemodenervation of the injected muscle and, in the USA, is approved for the treatment of strabismus and blepharospasm associated with dystonia from the age of 12 years; safety and efficacy below 12 years have not been established for these indications [21]. The AAO guideline considers it an alternative in selected patients (evidence I+, moderate quality, discretionary recommendation), with a better prognosis when there is good vision in each eye, no restriction, a small to moderate angle and binocular potential; its value in infantile esotropia has not been established, repeat injections are frequent and, in the infant, the delay in realignment may be a disadvantage [15]. In exotropia, in a trial of 30 adults (20 with exotropia), the toxin was less effective than surgery with adjustable sutures (29% versus 77%), and the evidence is insufficient to recommend it [15]. Injectable bupivacaine has been used, in combination, for muscle strengthening [15].

Source: FDA label for BOTOX®, section 2.11 [21]. Injection is into the extraocular muscles under electromyographic guidance of the needle tip or with surgical exposure, in a volume of 0.05–0.15 mL per muscle, after local anaesthetic and decongestant drops; paralysis begins 1–2 days later, increases over the first week, lasts 2–6 weeks and resolves over a similar period; about half of patients need subsequent doses, and reassessment takes place 7–14 days after each injection [21].

Adverse effects in strabismus derive from diffusion to neighbouring muscles: vertical deviation in 17% of 2058 adults who received 3650 injections for horizontal strabismus, and ptosis in 1% after injection of the inferior rectus, 16% of the horizontal recti and 38% of the superior rectus; retrobulbar haemorrhage occurred in 0.3% of 5587 injections and may compromise the retinal circulation, so means of orbital decompression should be available [21]. The AAO guideline adds globe perforation and tonic pupil [15]. The label includes a warning about distant spread of toxin effect (dysphagia, respiratory failure, death) and about the non-interchangeability of units between botulinum toxin preparations [21]. In CCDD, the toxin is used to weaken the medial rectus in esotropic Duane, for residual misalignment in CFEOM and for the gaze palsy of the HOXA1 syndromes; in young children with CFEOM, this use is outside the age range approved in the USA [5–7, 116]. In the EU, botulinum toxins for strabismus are authorised through national procedures, and the Portuguese summary of product characteristics was not among the sources of this review.

7.8. Duane syndrome

Non-surgical treatment corrects refractive errors with spectacles or contact lenses, treats amblyopia by occlusion or penalisation of the better eye and uses prisms to improve the compensatory head posture in mild cases, better tolerated by older patients; correction of hypermetropia in a child may reduce the angle of strabismus and the head turn [5]. Surgery is indicated when the compensatory posture is symptomatic, when the deviation in primary position is sufficient to cause diplopia or amblyopia, or when the vertical deviation on adduction is disfiguring [5]. Surgery generally does not improve abduction of the affected eye (transpositions may give partial improvement), tightness of the medial rectus makes it technically difficult, and overcorrection on lateral gaze is frequent and may create new diplopia [5].

In esotropic Duane, medial rectus recession or lateral transposition of one or both vertical recti is performed, with or without simultaneous weakening of the medial rectus by recession or botulinum toxin, and the transposition may be augmented by resection of the transposed muscles or by posterior fixation sutures; in mild retraction, medial rectus recession and modest lateral rectus resection; in severe, disfiguring retraction, recession of both medial and lateral recti; in large deviations, contralateral medial rectus recession is added [5, 189, 190]. Y-splitting of the lateral rectus reduces vertical deviations on adduction without altering alignment in primary position [5]. In exotropic Duane, ipsilateral lateral rectus recession in most and, in severe cases, large lateral rectus recession with transposition of one or both vertical recti [5]. In the Chinese series, the 35 patients operated on gained binocular vision and cosmetic improvement [113]. The preventive aim is to treat amblyopia of the non-preferred eye, to preserve binocular vision in patients who abandon the compensatory posture and to avoid cervical muscle problems with large postures [5].

7.9. Congenital fibrosis of the extraocular muscles

Treatment corrects refractive errors and treats amblyopia early, protects the ocular surface with lubrication and, in severe exposure, with PROSE-type scleral lenses (prosthetic replacement of the ocular surface ecosystem), which have had significant benefit [6]. Surgery corrects ptosis and, on the extraocular muscles, corrects or improves the compensatory head posture and alignment in primary position, and may improve gait and gross motor development in young children [6]. The surgical principles are prior orbital imaging, because muscles may insert at unexpected sites; combining resections or plications to provide traction against large recessions during healing; recessions larger than those in standard tables, sometimes much larger, especially of the inferior rectus; attention to underlying exotropia, which the dysinnervation esotropia on upgaze may mask until the inferior rectus is weakened; potentiation of inferior rectus weakening by weakening the superior oblique, whose tendon frequently has an abnormal insertion, a tight muscle or a thin tendon; and deep weakening procedures (suturing the muscle to the orbital rim, myectomy) when necessary; botulinum toxin may help with residual misalignment [6]. Patients with specific TUBB3 variants need endocrine surveillance, surveillance of facial and vocal cord weakness and intervention for developmental delay [6]. In tubulinopathies, the individualised plan includes vision therapy for oculomotor deficits and strabismus from diagnosis [56].

7.10. Horizontal gaze palsy with progressive scoliosis

There is no disease-modifying treatment; orthopaedic surveillance of the scoliosis is the priority, and ophthalmological follow-up treats strabismus and amblyopia, bearing in mind that surgery corrects the deviation but does not restore horizontal gaze [8, 64]. The sources describe no evidence supporting a bracing protocol, a surgical threshold or a surveillance interval specific to this disease [8].

7.11. HOXA1 syndromes

GeneReviews states that there are no guidelines and bases its recommendations on the authors' experience [7]. The motility disorder is treated with orthoptic exercises, botulinum toxin and surgery in severe cases; deafness with hearing aids, cochlear implants, speech therapy and early educational support; carotid anomalies with the cardiovascular specialist (antiplatelet therapy, anticoagulation, angioplasty, stent or revascularisation as appropriate) and with control of hypertension and dyslipidaemia; heart disease with drugs, surgery and rehabilitation; facial paresis or spasms with anticonvulsants, muscle relaxants, botulinum toxin and physiotherapy; and vocal cord paresis, dysphagia and aspiration with tracheostomy, gastrostomy and treatment of reflux, which generally improve after infancy and allow removal of the gastrostomy and closure of the tracheostomy [7]. In developmental delay the usual measures are followed (early intervention, school support, physiotherapy and, for spasticity, baclofen, tizanidine or botulinum toxin) [7].

The central hypoventilation of ABDS requires mechanical ventilation (for example, positive pressure) with aminophylline, continuous monitoring and, in some patients, prolonged respiratory support [7]. GeneReviews does not give an aminophylline dose; the FDA label, for another indication (acute exacerbation of asthma and chronic lung disease), individualises the dose by serum theophylline concentration, with a target of 10–20 mcg/mL, and recommends, in a patient without theophylline in the previous 24 hours, a loading dose of 5.7 mg/kg of aminophylline (4.6 mg/kg of theophylline) calculated on ideal body weight and given over 30 minutes, which produces a mean concentration of 10 mcg/mL (6–16); each mg/kg of theophylline raises the concentration by a mean of 2 mcg/mL [191]. Application of this regimen to the central hypoventilation of ABDS is an extrapolation of indication, and maintenance depends on serum measurements [7, 191].

7.12. Okihiro syndrome and other SALL4 disorders

There are no published guidelines; treatment is directed at each organ [22]. Severe strabismus in Duane may require surgery, according to the principles of section 7.8; severe forearm malformations may require surgery, including pollicisation to construct a functional thumb when it is absent; renal anomalies are followed by nephrology or urology; surgery for congenital heart disease follows the usual rules, with cardiological decisions on antiarrhythmics, a pacemaker in severe block, anticoagulation and antibiotic prophylaxis of endocarditis; hearing loss is treated with hearing aids; growth hormone deficiency justifies considering growth hormone treatment, and pituitary hypoplasia is followed by endocrinology; anal anomalies are referred to surgery [22]. The children of patients without unequivocal clinical signs should be tested for the familial variant, because carriers need hearing, renal, ocular and cardiac assessment [22].

7.13. Moebius sequence

Treatment is multidisciplinary and rests on surgery for the malformations (strabismus, cleft palate, club foot, limbs), early rehabilitation (physiotherapy, speech and feeding therapy) and psychosocial support; prognosis depends on the associated anomalies and the timeliness of intervention [69, 70]. Facial reanimation procedures, including smile reconstruction, deserve consideration, with long-term results published [70]. Patients with syndromic CFEOM3 with facial weakness have benefited from the support of the Moebius Syndrome Foundation, although they do not have Moebius [6].

7.14. Regulatory status

No medicine is authorised, in the USA or the EU, for infantile nystagmus, CCDD or SALL4 disorders [96, 112]. The situation in Brazil (registrations of the Agência Nacional de Vigilância Sanitária, ANVISA) was not among the sources of this review.

7.15. Clinical trials

The trials are small, of short duration and with heterogeneous outcomes (acuity, NAFX, amplitude, intensity), which precludes indirect comparisons between drugs or between modalities [72]. The improvements in acuity described (0.06–0.11 logMAR, one line or less) are small in magnitude and their functional impact has not been measured consistently; quality of life has rarely been assessed [20, 72]. Crossover trials with periods of 56 days to 3 months provide no information on the long-term efficacy and safety of treatments that would be of indefinite duration [20, 72]. The neramexane programme in nystagmus has no public results and the reason for terminating the extension was not established [187]. Boston Children's Hospital maintains genetic studies of strabismus, nystagmus and CCDD (NCT03059420, since 2004, target of 20,000 participants; NCT04770519, 400 participants; both until 2030), and the National Human Genome Research Institute study of Moebius and congenital facial weakness (NCT02055248; 207 participants) gave rise to the 2025 cohort [11, 187]. A ClinicalTrials.gov search by condition identified no active gene therapy or pharmacological trials specific to FRMD7, IIN or CCDD in 2025–2026, which does not prove that none exist [187].

7.16. Developments in the last 12 months

Between November 2025 and October 2026, advances were concentrated in diagnosis and counselling. In terms of observational evidence, the multicentre cohort of 560 female carriers showed that non-truncating FRMD7 variants are more penetrant than truncating ones (49.7% versus 30.1%), which allows the risk to be estimated for each carrier identified by cascade testing [25]; the Chinese cohort and the review of 176 variants established the FRMD7 spectrum, the Korean founder effect and a set of in silico tools calibrated for the gene [4]; the 100,000 Genomes Project showed the yield of genome sequencing in infantile nystagmus and albinism [18]; the Xq26.2 deletion with IGSF1 added endocrine surveillance to unexplained nystagmus [34]; CACNB3 was proposed as a recessive IIN gene on the basis of one family [10]; and the Toronto series of optic pathway glioma defined onset at 3 months or later as a warning sign [145]. In CCDD, the 2026 review summarised the shift to molecular subtyping [3], the Chinese series compared KIF21A and TUBB3 clinically and on MRI [119] and two publications consolidated the imaging triad of HGPPS [64, 142]. In treatment, there was a randomised trial of perceptual training with benefit on acuity [188], a non-randomised study of brinzolamide in children [185], series of conjugate prisms [175, 176] and a surgical series in achromatopsia with INS [168]. At the preclinical level, in a mouse model of congenital stationary night blindness (Nyx nob), nystagmus originated from synchronised oscillations of retinal ganglion cells, generated in AII amacrine cells and transmitted to the accessory optic system, which pharmacological activation of dopaminergic D1 receptors completely suppressed; there is no human study [192]. Future therapies may target the underlying disease or a final common pathway of nystagmus, and the British authors advocate a set of specific treatments rather than a single solution [193]. No new regulatory opinions or authorisations for these indications were identified.

7.17. Agents and circumstances to avoid

In the HOXA1 syndromes it seems prudent to avoid high altitude, especially in ABDS, although the recommendation rests on few cases and is difficult to apply; lifestyle and pharmacological stroke risk factors should be avoided [7]. In SALL4 disorders, nephrotoxic drugs should be avoided when renal function is reduced, ototoxic drugs when there is hearing loss and drugs contraindicated by each patient's arrhythmia [22]. Brinzolamide is contraindicated in severe renal impairment and hyperchloraemic acidosis [183]; memantine requires caution with urinary alkalinisation [178]; baclofen should not be stopped abruptly [184]. In the prevention of Moebius sequence, exposure to misoprostol, thalidomide, alcohol, cocaine and benzodiazepines before conception and during pregnancy is avoided [69].

7.18. Pregnancy and lactation

Infantile nystagmus and CCDD do not in themselves alter obstetric management, but drugs used off-label should be reassessed in pregnancy. According to the European label, memantine should not be used in pregnancy unless clearly necessary and women taking it should not breastfeed [177]; brinzolamide is not recommended in pregnancy or in women of childbearing potential without contraception, and the risk to the breastfed infant cannot be excluded [183]; for gabapentin there is a North American pregnancy exposure registry and cohort data show no clear increase in major malformations, with limitations [180]; for baclofen there are only animal data, and use in pregnancy requires that the benefit justify the risk [184]. Patients with a HOXA1 syndrome and carotid anomalies or heart disease, and patients with SALL4 disorders and heart disease, arrhythmia or renal disease, need obstetric planning with the respective specialties [7, 22].

7.19. Perioperative period and anaesthesia

The AAO guideline recommends non-opioid analgesia and antiemetics (ondansetron) in strabismus surgery, allows topical antibiotic–corticosteroid combinations in the first week, of unproven benefit, and asks that parents be informed about orbital cellulitis and slipped or lost muscle [15]. In the HOXA1 syndromes, carotid anomalies increase the risk of perioperative stroke, as in the patient with a stroke after cardiac surgery, and the central hypoventilation of ABDS requires respiratory monitoring [7]. In HGPPS, the ipsilateral lateralisation of motor deficits should be known to the team assessing postoperative neurological complications [8]. In CFEOM, surgery requires prior orbital MRI and adapted techniques [6]. In SALL4 disorders with conduction defects, cardiological assessment precedes anaesthesia [22].

7.20. Transition to adulthood

The British consensus recommends a discharge report describing the nystagmus and the AHP, the diagnosis, the genetic and electrophysiological results, the treatments, the refraction and the acuity; the certificate of visual impairment may be revoked, for example, when the young person obtains a driving licence at 17 years [16]. Patients describe difficulties with the null zone, crowding, motion, being «slow to see» and variability of vision, as well as cosmetic and psychosocial impact (isolation, low self-esteem, depression) [16]. In adulthood, symptoms such as oscillopsia are the main reason to consider pharmacological treatment [72]. In HGPPS, adolescent scoliosis requires transition to adult orthopaedics [8]; in SALL4 disorders, renal, cardiac and hearing surveillance continues; in the HOXA1 syndromes, respiratory, cardiological and vascular support is lifelong when indicated [7, 22]. In Duane syndrome, adult surveillance is limited to general eye health recommendations [5]. According to the RCOphth, discharge from the specialist centre to the local hospital service is possible when the investigation or treatment pathway is complete in the infant or young child, according to the agreements of the local networks, and discharge to community care when it is complete in a cooperative child over 8 years or in an adult and there is an agreed long-term support plan; in both cases, patients and carers should have access to detailed information on nystagmus management to ensure the transition [147].

7.21. Agreements and disagreements between sources

The sources agree on the priority of refractive correction and early treatment of amblyopia, on Kestenbaum–Anderson surgery as the standard treatment of AHP and on the off-label nature of all drugs [1, 16, 72, 135]. They disagree on the maximum dose of memantine (40 mg/day in the British consensus, 20 mg/day in the labels) and on the dosing of brinzolamide (three times daily in the trials and in the FDA label, two to three times in the European label, which does not recommend it under 18 years) [16, 177, 182, 183]. They disagree on the age for nystagmus surgery: after 2 years (albinism GeneReviews), at preschool age if the head turn exceeds 20° (British consensus), or after 5 years (recommendation cited in the systematic review), with favourable results described before 2 years [16, 72, 135]. Botulinum toxin in strabismus is discretionary in the AAO guideline and the FDA label restricts it to 12 years or older, whereas the GeneReviews chapters on CCDD also propose it in children [6, 15, 21]. On contact lenses, the British consensus allows a theoretical advantage and the trials have not demonstrated it [16, 173, 174]. The 2023 RCOphth practice points coincide with the NUKE consensus on the doses of gabapentin and memantine, which they limit to adults, and advocate AHP surgery above 20° as early as possible, which departs from the recommendation to defer surgery until after 5 years [72, 147].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by entity

Sources: GeneReviews FRMD7, Duane, CFEOM, HOXA1 and SALL4, Hunt 2026, Poleg 2026, GeneGuidance ROBO3, Brazilian textbook of genetic syndromes, Webb 2025, Sanfilippo 2012 [1, 5–8, 11, 12, 22, 25, 34, 69].

8.2. X-linked infantile nystagmus

The father of an affected boy is neither affected nor a carrier and does not need assessment [1]. In a family with more than one affected individual, the mother of an affected boy is an obligate heterozygote; if the mother has more than one affected son without other affected relatives and the variant is not detected in her leucocyte DNA, germline mosaicism is most likely [1]. In a boy with no family history, the mother may be heterozygous or the variant may have arisen de novo; up to 7% of affected males are isolated cases, a figure derived from the founding study, in which 3 of 42 isolated cases had a variant [1, 80]. An affected girl may have inherited the variant from her mother or father, or have it de novo; a carrier father transmits it to all his daughters and none of his sons [1]. The penetrance estimate by variant class improves counselling of carriers identified by cascade testing: about one in two will manifest nystagmus if the variant is non-truncating and about one in three if it is truncating, cohort averages that do not predict the individual phenotype [25]. Carriers without apparent nystagmus may have subclinical manifestations on oculomotor recording or a subnormal optokinetic response, and their status should be defined by molecular testing, which is most informative when the proband's variant is known; in the absence of an affected male to test, sequencing is performed and, if negative, deletion and duplication analysis [1, 103]. The Oxford Desk Reference points out that, when no other disease is identified and the nystagmus is isolated, the diagnosis of idiopathic nystagmus should be communicated with caution, remaining alert to the possibility of coexisting or evolving neurological disease, and that eye examination with fundoscopy and electrophysiology of relatives may help, especially in the X-linked forms [71]. In families with an Xq26.2 deletion including IGSF1, counselling adds the endocrine risk for boys and the mild biochemical phenotype of female carriers [34]. One family with IIN and the homozygous CACNB3 variant suggests autosomal recessive inheritance, without sufficient data for counselling outside that family [10].

8.3. Duane syndrome

Most patients are the only affected member of the family and have no known molecular cause; about 10% of isolated Duane is familial, with autosomal dominant inheritance [5, 41]. Most patients with a variant in CHN1, MAFB or SALL4 inherited it from an affected parent and de novo variants are rare [5]. An apparently negative family history is confirmed only by eye examination or testing of the parents, because the phenotype may go unnoticed, be mild or be non-penetrant (CHN1) [5]. If the variant is not detected in the parents, the risk for siblings is estimated at about 1%, because of theoretical germline mosaicism, never described in this disease [5]. Intrafamilial variability includes unilateral and bilateral forms [5]. In probands without a molecular diagnosis, DNA storage is recommended [5]. At-risk relatives should have an eye examination in the first year of life and molecular testing when the familial variant is known [5]. In Duane syndrome with systemic anomalies, counselling depends on the underlying syndrome or chromosomal anomaly [41].

8.4. Okihiro syndrome and other SALL4 disorders

Inheritance is autosomal dominant and 40–50% of cases result from a de novo variant [22]. The parents of an apparently isolated case should be assessed by molecular testing and by physical, ophthalmological (malformations and eye movements), forearm radiographic, cardiac and renal ultrasound examination, because reduced penetrance and variable expressivity may conceal a carrier parent [22]. If the variant is not detected in the blood of either parent, the risk for siblings is estimated at 1% because of theoretical germline mosaicism; if the parents are not tested but are clinically unaffected, the risk remains increased [22]. Each child of a patient has a 50% probability of inheriting the variant, and penetrance is about 95% [22]. The children of patients without unequivocal clinical signs should be tested, because carriers need hearing, renal, ocular and cardiac surveillance [22]. Prenatal testing detects the variant but does not predict the manifestations or their severity, and high-resolution ultrasound assesses the fetal phenotype [22].

8.5. Congenital fibrosis of the extraocular muscles

KIF21A, TUBA1A, TUBB2B and TUBB3 follow autosomal dominant inheritance and PHOX2A and COL25A1 recessive inheritance; Tukel syndrome has an unknown cause and presumably recessive inheritance [6]. De novo variants have been described in KIF21A, TUBA1A and TUBB2B, in an unknown proportion; with TUBB3, the variant was de novo in 25% of pedigrees with isolated CFEOM (4 of 16) and in 85% of pedigrees with additional neurological deficits (17 of 20) [6]. Parental germline mosaicism has been presumed with KIF21A and TUBB3, including a KIF21A variant that mimicked recessive inheritance and maternal germline mosaicism in a Chinese family [6]. In CFEOM2, two consanguineous families showed pseudodominance (one homozygous affected parent and the other a carrier) [6]. In the recessive forms, if only one parent is a carrier, a de novo variant, parental mosaicism or uniparental disomy must be considered [6]. Carrier testing requires the familial variant and is impossible in Tukel syndrome [6]. Cortical tubulinopathies are de novo in more than 95% of cases, and only rarely is a parent affected, usually with TUBB3 or TUBB2B [56].

8.6. HOXA1 syndromes, HGPPS and Moebius sequence

In the HOXA1 syndromes, the parents are presumed heterozygotes and should be tested; if only one is a carrier, a de novo variant or parental mosaicism is considered, and apparent homozygosity may correspond to an undetected deletion or uniparental isodisomy [7]. Testing of partners should be considered, especially with consanguinity or the same ancestry, taking into account the Navajo and Apache and Saudi founder variants, and the genetic status of asymptomatic at-risk siblings should be clarified [7]. In HGPPS, the recurrence risk for siblings is 25% [8]. Moebius sequence is sporadic in almost all cases; the Brazilian textbook considers the recurrence risk negligible when there is no exposure to the teratogen, there being no safe minimum dose of misoprostol, and the cohort of 149 patients recorded no intra- or intergenerational recurrence [11, 69]. The Oxford Desk Reference refers to some reports of dominant transmission and Orphanet records autosomal dominant inheritance, which corresponds to the rare families with a Moebius phenotype, sometimes atypical, and not to the classic sequence [68, 70, 122]. Families with HOXB1-related facial palsy follow recessive inheritance [6]. In the classic series, the empirical risk of familial recurrence was estimated at no more than 1 in 50 after excluding myopathies and at about 2% in a 1991 review, which found no recurrence in 31 cases with cranial nerve palsies, oral anomalies and limb defects; absence of skeletal defects, isolated facial palsy, deafness, ophthalmoplegia and digital contractures were identified as features of the index case associated with a higher risk [67]. Families with transmission over three generations, a consanguineous family compatible with recessive inheritance and a family with two affected brothers and an affected cousin, son of a maternal aunt, suggestive of X-linked inheritance, have been described [67].

8.7. Comitant strabismus

A family history of strabismus is a recognised risk factor, and the hereditary component is specific to esodeviation (heritability of 0.64) and independent of refractive error; no significant genetic component has been demonstrated for exodeviation [12, 15]. A Mendelian pattern is observed in some families [15]. There is no useful genetic test for isolated comitant strabismus, and counselling consists of recommending early eye examination of siblings and children of affected people, especially if there is hypermetropia [15].

8.8. Testing of minors, prenatal and preimplantation diagnosis

In the entities in which early diagnosis changes management (FIN, familial Duane, CFEOM, SALL4 disorders, HOXA1), testing of at-risk minors is justified by the benefit of eye examination during the amblyogenic age and, in the syndromic forms, by renal, cardiac, hearing, respiratory or endocrine surveillance [5–7, 22, 34]. Prenatal testing and preimplantation genetic testing are possible once the familial variant has been identified; the ideal time to discuss risk and reproductive options is before pregnancy, and counselling should be offered to affected or at-risk young adults [1, 22]. Use of prenatal testing in a condition with a good visual prognosis such as FIN is a personal decision on which views differ [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Infantile nystagmus

Frequency estimates measure different things. In the Capital Region of Denmark, review of the medical and birth records of children born between 2010 and 2017 identified 103 children with infantile nystagmus, a prevalence of 6.1 per 10,000 live births, about six times higher in preterm infants (28.4 versus 4.4 per 10,000 in those born at term); eye disease, mainly albinism and ocular malformations, was the most frequent cause, and a third remained without an identified cause [13]. In Leicestershire and Rutland (United Kingdom), a capture–recapture study with three sources (hospital, visual impairment services and education) estimated the prevalence of nystagmus of all forms and ages at 24.0 per 10,000 (±5.3), with 6.8 per 10,000 of neurological cause, 4.2 associated with low vision (for example, congenital cataract) and 3.4 associated with retinal disease, and with a higher frequency in white Europeans than in Asians (p=0.004) [14]. On the basis of this survey, GeneReviews estimates IIN at about 2 per 10,000 and FIN, a fraction of it, at less than 2 per 10,000 [1]. Orphanet classifies IIN as «not rare in Europe» and has no epidemiological data of its own [194, 195]. The quoted values of 6.1 to 14 per 10,000 live births refer to infantile nystagmus of all causes and not to IIN [25]. In an English cohort followed from birth to 5 years, Stayte and colleagues (1993) found nystagmus in 1 per 1000 children, also of all causes [9].

The aetiological distribution depends on the population and the recruitment method. In the Akron paediatric registry (USA), albinism, Leber congenital amaurosis and achromatopsia were the most frequent diagnoses [17]; in the 100,000 Genomes Project, with participants of diverse ethnicities but mostly white European, TYR and OCA2 predominated, FRMD7 accounted for 9 of 388 families and the TYR haplotype NM_000372.5:c.[575C>A;1205G>A] p.[(Ser192Tyr;Arg402Gln)] was the most frequent finding; the variants TYR NM_000372.5:c.1255G>A p.(Gly419Arg) and SLC38A8 NM_001080442.3:c.264C>G p.(Tyr88Ter) occurred only in South Asian families [18]. In the Zhongshan Ophthalmic Center cohort, FRMD7 accounted for 75 families with IIN out of 10,530 families with genetic eye disease, and the Korean variant c.875T>C was absent, which reinforces its regional founder character [4]. In south-east China, GPR143 accounted for 11.2% of families with INS [106]. The Xq26.2 deletion was described in a consanguineous Bedouin family from southern Israel [34]. In six Chinese families, the 2 bp FRMD7 deletion 1274delTG was on a common haplotype, a founder effect [9]. Among the rare autosomal forms, NYS2 was mapped in an African American family and observed among the Old Order Amish of Ohio, and NYS7 in two Chinese families [27, 29].

9.2. Strabismus

The prevalence of strabismus ranges from 0.8% to 6.8% depending on the population [15]. In the USA, esotropia and exotropia have similar prevalences; in Ireland esotropia is five times more frequent than exotropia and in Australia twice as frequent; in Hong Kong, Singapore, Japan and China exotropia is more frequent [15]. Exotropia affects about 1% of the population [15]. In the twin study from Australia and the United Kingdom, the prevalence of esodeviation was 8.6% and that of exodeviation 20.7%, values that include phorias and are not comparable with the prevalence of manifest strabismus [12]. In the All of Us programme, the genetic signals differed between participants of European, African and Latin American ancestry [94].

9.3. Congenital cranial dysinnervation disorders

Duane syndrome has an estimated prevalence of 1 in 1000 to 1 in 10,000 and accounts for 1–5% of strabismus according to GeneReviews, whereas the Oxford Desk Reference gives 1% of strabismus; Orphanet records 1–5 per 10,000 in Europe, based on an unvalidated textbook source [5, 41, 195]. OMIM quotes a prevalence of about 0.1% in the general population and 5% of strabismus, figures taken from a 1999 review and not from a population study of its own [40]. Brown syndrome accounts for about 2% of strabismus [91]. The syndrome has been described worldwide; in a series of 441 cases, the frequency of systemic findings was less than 10%, and in a centre in southern India almost a third of patients had exotropia [5, 136]. The prevalence of CFEOM (all causes) is 0.43 per 100,000 in the United Kingdom, an estimate validated by Orphanet from a 1998 study [46, 196]. The figure corresponds to the minimum prevalence of 1 in 230,000 estimated in the Wessex region (England) from four families, in an attempt at complete ascertainment [45]. CFEOM2 has been described mainly in consanguineous Middle Eastern families [6]. HGPPS has an unknown prevalence, with almost 100 patients described over 20 years, including 13 patients from 6 consanguineous Tunisian families and 14 families in a 2026 series [8, 63, 197].

The HOXA1 syndromes illustrate the founder effect: the c.76C>T variant gives a predicted incidence of 0.5 to 1 per 1000 live births on the White River Apache reservation and 1 per 3000 live births in the Navajo population, and c.175dup concentrates BSAS cases in Saudi Arabia and Turkey; patients have also been described in India [7, 121, 198]. The Athabascan peoples, who include the Navajo and Apache, are thought to have reached North America via the Bering Strait about 4000 years ago; of the patients with ABDS reviewed in 1999, 7 were Navajo, 2 Apache and 1 of Apache and Pima ancestry [65]. Orphanet records 13 cases of ABDS and 16 of BSAS [195]. Other founder populations or families of defined origin include the conservative German American families («Pennsylvania Dutch») with the HOXB1 p.Arg207Cys variant in hereditary congenital facial paresis 3, the Venezuelan family of Canary Islands origin with IVIC syndrome and the consanguineous Saudi family that defined CFEOM5 [44, 57, 126]. To these are added the Mexican families that allowed DURS2 to be mapped, the three consanguineous Saudi CFEOM2 families, with a shared haplotype, the consanguineous Mexican and Saudi HGPPS2 families and the consanguineous Turkish NYS8 family [26, 35, 47, 62]. According to OMIM, Wildervanck syndrome, almost limited to females, could account for at least 1% of deafness in women, an old estimate without a recent population study in the sources consulted [92]. The prevalence of SALL4 disorders is unknown, partly because in many countries they are not distinguished from TBX5-related Holt-Oram syndrome or other heart-hand syndromes; more than 100 patients have been identified [22].

9.4. Moebius sequence and data from Brazil

Frequency estimates for Moebius sequence diverge. Orphanet records a worldwide prevalence of 0.3 per 100,000, a birth prevalence of 2.12 per 100,000 in the Netherlands and, in Italy, a prevalence of 0.27 per 100,000 and a birth prevalence of 0.06 per 100,000 [68]. The Dutch figure corresponds to the incidence estimated by Verzijl and colleagues for births in 1996 in the Netherlands, 4 cases in 189,000 births (0.002%); the abstract of the article, which describes 37 patients, does not give the figure, but OMIM attributes it to that study, and a numerator of four cases limits the precision of the estimate [67, 68, 199]. The Brazilian textbook of genetic syndromes gives 1 in 250,000 live births (0.4 per 100,000), equal in both sexes, without indicating the primary source [69]. These differences reflect different definitions (classic sequence or expanded phenotype), sources of ascertainment and periods, and none should be taken as the national prevalence of another country.

Brazil has relevant data of its own: the case–control study of seven Brazilian hospitals (1990–1996) established the association between misoprostol, then used as an abortifacient, and Moebius sequence (odds ratio of 29.7), and the Brazilian prospective cohort of exposed women showed that the absolute risk per exposure is low [123, 124]. The mean age at diagnosis of Moebius in that study was 16 months (0.5–78) [123]. The Brazilian textbook of genetic syndromes cites a Brazilian case report published in 2001 [69, 200].

9.5. Portugal

The sources consulted contain no Portuguese epidemiological studies on these entities. Portuguese authors described a child with Alström syndrome and a novel ALMS1 variant whose initial presentation mimicked spasmus nutans [166]. The Portuguese member of ERN-EYE is the Unidade Local de Saúde de Coimbra [23].

9.6. Special populations

Preterm infants have an increased risk of infantile nystagmus (about sixfold) and of strabismus, especially below 2000 g birth weight [13, 15]. Children with neurodevelopmental disorders have a much higher frequency of strabismus than the general population, and comitant strabismus occurs mainly in syndromes with intellectual disability [41, 128]. Trisomy 21 was present in 19% of children with spasmus nutans in a Boston series, and Down syndrome is among the causes of nystagmus in the infant [1, 163]. Children with albinism and those with secondary nystagmus respond less to pharmacological treatment than those with IIN [19, 135]. In Athabascan communities, high altitude is a suspected aggravating factor for hypoventilation and cognitive function in ABDS [7].

9.7. European Reference Network and patient organisations

ERN-EYE is the European Reference Network for rare eye diseases; it includes neuro-ophthalmology and paediatric ophthalmology centres, runs an online training programme on rare paediatric eye diseases and publishes consensus statements, with no specific statement on infantile nystagmus or CCDD on the page consulted [23]. Patient organisations with information for families include the Nystagmus Network (United Kingdom; https://nystagmusnetwork.org/), the American Nystagmus Network (https://nystagmus.org/), the Moebius Syndrome Foundation (USA; https://moebiussyndrome.org/), the Albinism Fellowship (United Kingdom and Ireland), the Aniridia Network (United Kingdom and Ireland), the national visual impairment organisations RNIB and Guide Dogs (United Kingdom) and Contact a Family (United Kingdom), and the eyeGENE (National Eye Institute) and HOXA1 (Human Disease Gene Website Series) registries [1, 6, 7, 16, 41, 71, 147]. In 2015, the Nystagmus Network received 1186 contacts, mainly requests for general support, information on research and treatment and education [16]. The sources consulted did not identify Portuguese or Brazilian patient organisations specific to these entities. The NHS R39 panel is accessible in Genomics England PanelApp (https://panelapp.genomicsengland.co.uk/panels/) [18].

10. Illustrative Clinical Case

10.1. Familial infantile nystagmus due to a contiguous Xq26.2 deletion with FRMD7 and IGSF1

Poleg and colleagues described in 2026 a consanguineous Bedouin family from southern Israel, followed at Soroka Medical Center, with nystagmus over three generations [34]. The pedigree (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13512101/figure/genes-17-00962-f001/) included ten relatives, seven females and three males, aged 6 to 64 years, marking nystagmus, endocrine anomalies and consanguinity [34].

The molecular proband was a 6-year-old boy (III-3) with horizontal jerk nystagmus, head turn to the left with chin down, acuity of 6/15 in the right eye and 6/21 in the left, esotropia with amblyopia of the left eye and hypermetropia of +4.50 dioptres with astigmatism of −1.25 dioptres in both eyes; the lens and fundus were normal and the full-field ERG and flash VEP were normal [34]. He had a history of neonatal jaundice, ventricular septal defect, pulmonary stenosis and mild attention difficulties; FT4 was 0.9 ng/dL (reference 0.8–1.5), low-normal, with normal TSH (0.773 µIU/mL), without criteria for overt central hypothyroidism [34]. Among the relatives, a 7-year-old carrier girl (III-2) had nystagmus, esotropia, hypermetropia with astigmatism, acuity of 6/7.5 and normal brain MRI, ERG and VEP; a 36-year-old female carrier (II-2) had nystagmus, acuity of 6/9 and 6/7.5, TSH of 0.26 µIU/mL (reference 0.55–4) with normal FT4 and prolactin of 2 ng/mL (reference 3–29); a 46-year-old carrier (II-9) had no nystagmus, with acuity of 6/6 in both eyes; and a 29-year-old relative (III-7), not genotyped, had central hypothyroidism diagnosed at 8 years and intellectual disability [34].

Karyotype and a targeted panel were negative. Chromosomal microarray showed a loss at Xq26.2 in three relatives, more marked in the hemizygous boy; the exome identified no pathogenic variant, but visualisation of the reads showed absence of coverage in FRMD7; genome sequencing delimited, from discordant and split reads, a deletion of 1,443,342 bp (NC_000023.11:g.130756102_132199443del) with loss of FRMD7, IGSF1, ARHGAP36, OR13H1, STK26 and the 5′ end of ENOX2, confirmed by junction PCR and Sanger sequencing in six relatives (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13512101/figure/genes-17-00962-f002/) [34]. The deletion was submitted to ClinVar [34].

10.2. Interpretation and lessons

The case shows the spectrum of a contiguous deletion, from the asymptomatic female carrier to isolated nystagmus and the oculo-endocrine association [34]. Nystagmus was the most penetrant feature (9 of 10 relatives), with the X-linked inheritance pattern with variably affected females typical of FIN [16, 34]. The endocrine changes were mild or not demonstrated in confirmed carriers, and the only patient with overt central hypothyroidism was not genotyped, so cosegregation with the deletion was not established [34]. The diagnostic pathway illustrates the limitations of panels and exomes for structural variants and the complementary value of microarray, genome sequencing and junction PCR [18, 34]. The management the authors propose (measuring FT4 and TSH, and not just TSH, in children with unexplained IIN and pituitary signs, and monitoring thyroid function, growth, prolactin and puberty in boys with the deletion) is an authors' recommendation based on one family, with no guideline to support it [34]. Refractive correction and amblyopia treatment of the proband follow the general rules of section 7 [16, 135].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

FIN is non-progressive and compatible with normal life expectancy [96]. Acuity is as a rule better than 6/12 (0.3 logMAR): in the Chinese cohort, 92.1% of patients had 0.52 logMAR or better and 49.2% 0.30 or better, and affected females had better acuity than males [1, 4]. Acuity improves during childhood, especially with refractive correction (from 0.59 to 0.25 logMAR in 10 children followed), and in untreated IIN an improvement of 0.16 logMAR per decade up to 18 years has been estimated; about a third of patients report attenuation of the nystagmus with age [4, 72]. The visual prognosis of other forms of INS depends on the underlying sensory disease, and in albinism and foveal hypoplasias the grade of hypoplasia predicts future acuity [135, 154]. Nystagmus has an impact on quality of life through the AHP (neck pain, headaches, cosmesis), being slow to see, crowding and psychosocial consequences, and the ability to drive depends on the acuity attained [16, 135, 188].

In Duane syndrome, acuity is good except in the 10% with amblyopia, which is reversible only if treated early; surgery improves posture and alignment in primary position but does not restore abduction [5]. In CFEOM, binocular vision is usually absent and amblyopia and corneal exposure are the main threats to vision; the overall prognosis of the syndromic TUBB3 forms depends on the brain malformations, neuropathy and endocrine changes [6]. In HGPPS, prognosis is determined by the scoliosis [8]. In the HOXA1 syndromes, central hypoventilation, heart disease, carotid anomalies and dysphagia determine morbidity, and most patients with BSAS achieve independent walking [7]. In SALL4 disorders, growth and cognition are normal and prognosis depends on the renal, cardiac and limb anomalies; hypertension and urinary tract infections are frequent complications [22, 73]. In Moebius sequence, most patients have normal cognition, and prognosis depends on the associated anomalies and the timeliness of rehabilitation [69, 70].

11.2. Surveillance table

11.3. Comments on surveillance

The intervals in the table derive from authors' opinion (GeneReviews chapters) or from general strabismus guidelines, and not from studies comparing surveillance strategies [5–7, 15, 22]. Full blood count surveillance in SALL4 disorders is preventive, because data on the natural history of the thrombocytopenia are scarce [22]. In HGPPS, GeneGuidance found no evidence for a scoliosis surveillance protocol, a surgical threshold or a specific interval [8]. In Duane syndrome, there is no specific surveillance in adulthood beyond general eye health recommendations [5]. In all entities, re-referral is indicated if warning signs appear (section 4.3), because nystagmus initially classified as idiopathic may reveal an associated neurological or sensory disease [16, 71]. The discharge report, the RCOphth discharge criteria (cooperative child over 8 years and an agreed support plan) and the transition to adult ophthalmology are described in section 7.20 [16, 147].

12. Summary and Final Considerations

Infantile nystagmus and hereditary strabismus are signs with very diverse causes, and the first clinical step is to separate the motor and developmental forms, with a good prognosis, from the sensory and neurological forms. In nystagmus with onset in the first 6 months, the history, pedigree, examination of the nine positions of gaze, OCT and electrodiagnosis group most children without the need for MRI, which is reserved for warning signs, in particular onset at 3 months or later with asymmetry, dissociation or a vertical or torsional component [16, 71, 145]. The nystagmus and albinism panel or genome sequencing clarify the cause in about 40–46% of patients, with albinism as the main genetic cause and FRMD7 as the cause of X-linked idiopathic infantile nystagmus [17, 18, 157].

FIN has a normal fovea and electrophysiology, acuity usually better than 6/12 and a stable or favourable course, especially with early refractive correction [1, 4]. Penetrance in female carriers is about 30% with truncating variants and 50% with non-truncating variants, a finding that changes cascade counselling [25]. The Xq26.2 deletion including IGSF1 adds to nystagmus a risk of central hypothyroidism that TSH alone does not detect [34]. Treatment of nystagmus is symptomatic: optical correction, amblyopia treatment, prisms, Kestenbaum–Anderson surgery for the AHP, perceptual training and, in symptomatic adolescents and adults, off-label memantine, gabapentin or brinzolamide, with small benefits demonstrated in short trials; the reference memantine dose in nystagmus (up to 40 mg/day) exceeds the label maximum [16, 19, 20, 177, 188].

The congenital cranial dysinnervation disorders result from developmental defects of the ocular motor neurons, and not from primary muscle disease [3, 93]. Duane syndrome, the most frequent, is in the great majority sporadic and without an identified cause; testing of CHN1, MAFB and SALL4 has a yield in familial and bilateral cases [5]. Okihiro syndrome and the other SALL4 disorders require a search for anomalies of the upper limbs, kidneys, heart, ear and pituitary, distinction from TBX5-related Holt-Oram syndrome, Fanconi anaemia and the VACTERL association, and surveillance of renal function, cardiac conduction and hearing [22, 172]. CFEOM depends mainly on KIF21A and TUBB3, and TUBB3 variants may be accompanied by brain malformations, neuropathy and endocrine changes [6, 52]. ROBO3-related HGPPS combines absent horizontal gaze with progressive scoliosis and a brainstem imaging signature [8, 64]. The HOXA1 syndromes, with founder variants in the Navajo, Apache and Saudi populations, require respiratory, cardiac, vascular and hearing assessment [7]. Moebius sequence has no unifying germline cause, has a very low recurrence risk and is associated, in Brazil, with prenatal exposure to misoprostol [11, 69, 123].

Across the class, early detection and treatment of amblyopia and refractive errors during the sensitive period of visual development are the intervention with the greatest impact on final vision, and surgery for strabismus and head posture follows principles specific to each entity [5, 6, 15, 16]. The main gaps are the absence of formal guidelines for infantile nystagmus and for CCDD, the scarcity of long-term trials and the low rate of molecular diagnosis in sporadic cases [72, 83].

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