Nanophthalmos and Posterior Microphthalmos

The class of the small but structurally organised eye: nanophthalmos 1 to 4 (MYRF, MFRP, the NNO3 locus, TMEM98) and posterior microphthalmos 5 and 6 (MFRP, PRSS56), with the syndromic forms due to MFRP and MYRF (cardiac-urogenital syndrome spectrum), BEST1-related vitreoretinochoroidopathy, CRB1-related nanophthalmos with retinopathy and Mackay-Shek-Carr syndrome; the microphthalmia–anophthalmia–coloboma spectrum enters the differential diagnosis.

Literature and regulatory information update: 28 October 2026.

0. Initial Reference Table

Table 0.1 identifies the entities of the class and Table 0.2 summarises the clinical and management data. The OMIM numbers of the entities NNO1 to NNO4, MCOP5 and MCOP6, the cytoband, the inheritance pattern and the number of the gene associated with each were confirmed in the OMIM entries of the phenotypes and in the entry of the PRSS56 gene; the numbers of ADVIRC, ARB, Mackay-Shek-Carr and MYRF-CUGS and those of the genes MYRF, MFRP, TMEM98, BEST1 and CRB1 were confirmed in the respective OMIM entries and cross-checked with Orphanet, the review by Carricondo and colleagues and the gene curation of GeneGuidance [1–19].

Table 0.1. Entities, genes and identifiers

Note: in Orphanet, ORPHA:35612 has as its preferred term "Isolated complete colobomatous microphthalmia", but the synonyms ("Nanophthalmos", "Nanophthalmia") and the definition describe nanophthalmos, with a short eye, severe hyperopia, a high lens/eye ratio and a high incidence of angle-closure glaucoma; the inconsistency is internal to the database and the code is used according to the definition [17]. The MANE Select transcript of BEST1 does not appear in the sources of this edition; NM_004183.3 is the one used by GeneReviews [28].

Table 0.2. Clinical and management data

1. Introduction

1.1. Definition and scope

Nanophthalmos is a small eye with preserved organisation and function, in which the short axial length results from reduction of the anterior and posterior segments, with a thickened choroid and sclera and a lens of normal volume [18, 29]. The Oxford Desk Reference also calls it simple microphthalmia and links the proportionally thicker sclera and the normal-sized lens to the shallow anterior chamber and to glaucoma [45, 46]. Posterior microphthalmos is shortening of the eye at the expense of the posterior segment, with an anterior chamber of normal or near-normal dimensions [18]. The two conditions share genes, high hyperopia and complications, and the literature uses them sometimes as synonyms and sometimes as distinct points on the same spectrum [18, 38]. The class covered in this article includes the isolated forms due to PRSS56, MFRP, MYRF and TMEM98, the NNO3 locus, the ocular syndromic forms due to MFRP (pigmentary retinopathy, foveoschisis, optic disc drusen), nanophthalmos as part of the systemic spectrum of MYRF, nanophthalmos associated with BEST1 and CRB1 and Mackay-Shek-Carr syndrome [18, 26, 47]. Microphthalmia with structural malformation (coloboma, retinal dysplasia, persistent fetal vasculature) and anophthalmia belong to the microphthalmia–anophthalmia–coloboma (MAC) spectrum; BEST1-related bestrophinopathy, Leber congenital amaurosis and congenital glaucoma appear here in respect of the short eye.

1.2. Classification of the small-eye phenotype

Carricondo and colleagues organised the small-eye spectrum into six categories, reproduced in Table 1.1 in the present authors' own words, and cross-tabulated axial length with the dimensions of the anterior segment (white-to-white corneal diameter, WTW, and anterior chamber depth, ACD) in a grid of phenotypes (Table 1.2) [18].

Table 1.1. Clinical spectrum of the small eye

Source: Carricondo et al., Table 1 [18].

Table 1.2. Phenotypes according to axial length and anterior segment

Source: Carricondo et al., Table 2 [18].

In the grid, nanophthalmos occupies the cell of the short eye with a small anterior segment and posterior microphthalmos that of the short eye with a medium anterior segment. Relhan and colleagues, in a series of 38 patients with a spherical equivalent above +7.00 D and an axial length equal to or below 20.5 mm, called nanophthalmos those eyes with a corneal diameter below 11.0 mm and posterior microphthalmos those with a diameter equal to or above that value; the nanophthalmic eyes had a shallower anterior chamber, a thicker lens, a steeper cornea and angle-closure glaucoma in 69.23%, against 0% in posterior microphthalmos, which in turn had macular folds in 24% (data cited by Carricondo and colleagues) [18]. Other groups consider the two forms synonymous, because the corneal diameter follows the shortening and the genes are the same [18]. Jung and colleagues additionally separated relative anterior microphthalmos, with a corneal diameter equal to or below 11 mm, an ACD equal to or below 2.2 mm and an axial length equal to or above 20.5 mm [48].

1.3. Reference biometry

Normal total axial length is about 17 mm in the newborn (anterior segment 6.8 mm; posterior segment 10.2 mm) and 23.8 mm in the adult (7.3 mm and 16.5 mm), according to the historical GeneReviews chapter on the MAC spectrum, which cites Weiss and colleagues [30, 49]. Microphthalmia is defined by an axial length at least 2 standard deviations below the mean for age; in adults, the 2.5th percentile corresponds to about 21.0 mm, and in children age-specific normative curves are used [30]. In the simple microphthalmic eyes studied by Weiss, the anterior segment was within or below the normal range and the posterior segment was uniformly at least 2 standard deviations below the mean [30, 49]. Postnatal growth of the eye is concentrated in the first three years, especially the first, and the posterior segment accounts for more than 90% of that growth [30]. A Brazilian review proposes, for microphthalmia, lengths below 16 mm at birth, 19 mm at 12 months and 21 mm in adults, and describes nanophthalmos with an axial length of 16 to 18 mm and hyperopia of +15 to +20 D [50]. The Oxford Desk Reference gives a mean normal axial length of 22.5 mm at 2 years, against values usually below 18.5 mm in microphthalmia [45]. The French microphthalmia–anophthalmia PNDS (French National Diagnosis and Care Protocol) gives, for the normal eye, about 17 mm at birth, 18.5 mm at 6 months, 20 mm at 1 year and 22 to 23 mm at around 4 years; the microphthalmic eye also grows, without reaching normal dimensions, and therefore the refraction changes with age and has to be measured again [44].

1.4. History

The term "posterior microphthalmos" was introduced by Franceschetti and Gernet in 1965 for small eyes with an anterior segment of normal dimensions; other authors called the same eyes nanophthalmic, and Warburg preferred, in 1993, the designation "partial microphthalmia" [5]. Brockhurst described in 1974–1975 the association of nanophthalmos with uveal effusion as a clinical entity in five patients with an apparent familial basis: glaucoma appeared between the fourth and sixth decades, antiglaucoma surgery precipitated choroidal and retinal detachment, conventional detachment surgery was ineffective and the choroidal elevation could be mistaken for a tumour and lead to unnecessary enucleation [51]. In 1979, Kimbrough, Trempe, Brockhurst and Simmons treated angle closure in nanophthalmic eyes with laser (iridotomy and contraction of the iris stroma), a procedure that appeared to open the angle even without iridotomy [52]. In 1987, MacKay and colleagues described a recessive syndrome with retinal degeneration, nanophthalmos, cystic macular degeneration and angle-closure glaucoma, now recorded as Mackay-Shek-Carr syndrome [26, 53]. The dominant retinal strand of the class has a parallel history: Hermann reported in 1958 a French family with microphthalmia in 13 members over four generations, some of them with pigmentary retinopathy, cataract and glaucoma; Kaufman and colleagues created in 1982 the designation autosomal dominant vitreoretinochoroidopathy (ADVIRC) for a circumferential peripheral fundus dystrophy; and François and colleagues re-examined Hermann's family in 1993 and showed the dominant segregation of microcornea, vitreoretinochoroidopathy, glaucoma and cataract [8]. Weiss and colleagues characterised simple microphthalmia by segmental biometry in 1989 [49].

The molecular era began in 1998, when Othman and colleagues mapped the first locus, NNO1, to chromosome 11, in a large North American family with autosomal dominant inheritance (31 affected individuals over five generations, 22 of whom were examined), with hyperopia of +7.25 to +13.00 D (mean +9.88 D), an axial length of 17.55 to 19.28 mm (mean 18.13 mm) and 12 affected individuals with angle-closure glaucoma or an occludable angle (multipoint LOD 6.31) [1, 54]. The linked markers lay on the short arm (11p); in 2019, reconstruction of the haplotypes with more markers shifted the interval to a 3.5 Mb non-recombinant region on 11q, containing 135 genes, among them BEST1, already excluded in that family [1]. In 2004, Yardley and colleagues identified BEST1 as the cause of ADVIRC and of MRCS syndrome, and in 2008 Burgess and colleagues delineated autosomal recessive bestrophinopathy [8, 9, 37]. In 2005, Sundin and colleagues identified null mutations in MFRP (11q23.3) in recessive nanophthalmos, with hyperopia of +8.00 to +25.00 D [34]. The family studied was the Amish-Mennonite group in which Cross and Yoder had described, in 1976, three sisters with nanophthalmos; a LOD of 5.95 placed the locus at 11q23.3, four affected individuals were homozygous for a frameshift variant of MFRP, a fifth affected individual had only one allele detected, without a second variant in the exons of MFRP or of C1QTNF5, and in the screening of 26 unrelated families only two more had MFRP variants [2]. In 2006, Ayala-Ramirez and colleagues described, in four Mexican siblings, the posterior microphthalmos–retinitis pigmentosa–foveoschisis–optic disc drusen syndrome due to MFRP [35]. In 2008, Li and colleagues mapped the NNO3 locus to 2q11-q14 in a six-generation Chinese family [4]. Fuchs and colleagues had described in 2005 two families from the Faroe Islands with posterior microphthalmos and considered a founder effect with pseudodominant transmission, and Hmani-Aifa and colleagues mapped in 2009 the MCOP6 locus to 2q37.1 in six consanguineous Tunisian families (LOD 8.85) [5]. In 2011, three groups linked PRSS56 (2q37.1) to recessive posterior microphthalmos: Gal and colleagues in families from the Faroe Islands and Tunisia, Orr and colleagues in families from eastern Canada and Mexico, and Nair and colleagues with a murine model of angle-closure glaucoma [55–57]. In 2014, Awadalla and colleagues associated TMEM98 with dominant nanophthalmos in an Australian family of European ancestry; the association was questioned in a letter in 2015 and replicated in the same year by Khorram and colleagues [58–61]. In 2018, the review by Carricondo listed five genes (MFRP, TMEM98, PRSS56, BEST1, CRB1) and two loci (NNO1 and NNO3) [18].

In 2018, Pinz and colleagues reported de novo variants in MYRF in two boys with scimitar syndrome and urogenital anomalies, the basis of the cardiac-urogenital syndrome [62]. In 2019, Rossetti and colleagues identified, in a clinical database of 12,000 exomes, three boys with splicing or frameshift variants of MYRF, de novo in all cases with parental DNA available, and noted the overlap with PAGOD syndrome (pulmonary artery and lung hypoplasia, agonadism, omphalocele and diaphragmatic defect) [63]. As high hyperopia and nanophthalmos are among the most frequent traits, the GeneReviews authors propose the designation MYRF-related ocular-cardiac-urogenital syndrome (MYRF-OCUGS) [29]. In 2019, Garnai and colleagues showed that the NNO1 gene is MYRF, and Xiao and Siggs with their respective colleagues described carboxy-terminal truncating variants of MYRF in dominant high hyperopia and nanophthalmos [64–66]. In 2020, Cross and colleagues demonstrated that the TMEM98 protein inhibits the autocleavage of MYRF and is necessary for the specification of eye size, unifying the two dominant forms on a common molecular axis [67]. In 2026, Rozumek and colleagues showed that the MYRF variants that cause isolated nanophthalmos are hypomorphic, which explains the separation between the ocular and the syndromic form [68].

1.5. Operational criteria

There is no consensus diagnostic criterion; Areiter and colleagues state that there are no generally accepted criteria [69]. Studies use different thresholds (Table 1.3), which prevents direct comparison of complication frequencies between series.

Table 1.3. Operational definitions of nanophthalmos in the literature

The French PNDS (French National Diagnosis and Care Protocol) places nanophthalmos and posterior microphthalmos in the group of simple microphthalmia, alongside colobomatous microphthalmia, complex microphthalmia and anophthalmia or extreme microphthalmia, and adopts Relhan's criteria to separate them: in nanophthalmos, the corneal diameter and the ACD are reduced and the lens is thicker, and in posterior microphthalmos the reverse is usually observed [44]. The threshold of 14 mm at birth is lower than the 16 mm proposed for microphthalmia in the Brazilian review, and the refractive threshold of +7.00 D is stricter than the +5.50 D of the Prasov cohort [44, 47, 50].

2. Molecular Genetics and Pathophysiology

2.1. Axial growth, sclera and the mechanism of complications

Nanophthalmos results from arrest of eye growth at early stages and has a marked genetic basis, with dominant and recessive familial cases and sporadic cases attributed to new variants, somatic mutations or environmental factors [18]. The genes of the class are expressed in the retinal pigment epithelium (RPE), the ciliary body, the retina and the sclera, and take part in emmetropisation, the process by which postnatal axial growth compensates for the refractive power of the cornea and lens during the first years of life [18]. In the nanophthalmic sclera, the collagen fibrils are abnormal in all three layers, which explains the thickness and inelasticity of the wall; that rigidity hampers venous drainage through the vortex veins and the transscleral flow of proteins, and from this follow uveal effusion, exudative retinal detachment and angle closure [18]. It has not been established whether the scleral abnormality is primary or secondary to a signal emitted by the retina and the RPE, where most of the genes are expressed [18]. Chen and colleagues examined sclera collected during an acute attack with intraocular pressure (IOP) above 60 mmHg and found disorganised collagen, irregular bundles and loose connective tissue, in contrast to the dense lamellar sclera of controls [77]. Yamani and colleagues described, in sclera resected from a nanophthalmic eye, frayed and split collagen fibrils, with poorly stained centres, especially in the inner sclera (lamina fusca), and glycogen-like deposits, to which they attributed the scleral inelasticity [1]. In the Chinese family of Yu and colleagues, linked to the TMEM98 region, the full-thickness sclera had swollen, twisted or frayed fibres among normal fibres, and the two globes that progressed to atrophy had sclera three times the normal thickness, coiled amorphous material, proliferation of pigmented cells and formation of bone-like tissue [7]. The combination of a normal-volume lens with a small anterior segment reduces the anterior chamber and increases the lens thickness/axial length ratio, which favours pupillary block and the lens-related and retrolenticular mechanisms of angle closure [18, 40].

2.2. MFRP (NNO2 and MCOP5)

MFRP (membrane frizzled-related protein; 11q23.3; MANE transcript NM_031433.4, protein NP_113621.1) encodes an apical transmembrane glycoprotein of the RPE and the ciliary body, with domains homologous to the Tolloid proteases and a Wnt-binding domain; expression outside the eye is residual (brain), which explains the phenotype restricted to the eye [18, 19, 34]. The gene is transcribed into a bicistronic RNA that also encodes C1QTNF5; the bicistronic transcript NM_001278431.2 is the MANE Select of C1QTNF5 and not of MFRP, which matters when interpreting reports [19]. The protein is necessary for axial growth along the visual axis and for maintenance of the photoreceptors [19]. Sundin and colleagues found that patients without functional MFRP protein could have good corrected acuity, a clinically normal electroretinogram (ERG) and modest changes in dark adaptation, which led to the proposal of a function dedicated to axial length; later series showed progressive pigmentary retinopathy in some patients [34, 35, 38]. The rd6 and rdx (Mfrp 174delG) mice have a flecked retina and photoreceptor degeneration without the full nanophthalmic phenotype, and the zebrafish better reproduces the short eye [18]. Inheritance is autosomal recessive and the mechanism is loss of function [19]. Wasmann and colleagues counted, in 2014, 14 MFRP variants (two amino acid substitutions at conserved positions and 12 truncating ones), according to Carricondo [18]. Almoallem and colleagues described the first genomic rearrangement of the gene, a deletion of the 5' untranslated region with part of exon 1, which makes it necessary to include copy-number analysis in the study of MFRP [38]. Among 15 obligate carriers of MFRP variants studied by Mukhopadhyay and colleagues, only one was hyperopic, which indicates that haploinsufficiency of the gene does not contribute appreciably to physiological hyperopia [3].

2.3. PRSS56 (MCOP6)

PRSS56 (serine protease 56; 2q37.1; MANE NM_001195129.2) encodes a secreted serine protease of 603 amino acids, with an N-terminal signal peptide, a central chymotrypsin-like serine protease domain (catalytic triad His145, Asp191 and Ser286) and a C-terminal domain conserved in vertebrates; the gene has 13 coding exons and is expressed in the neural retina, the cornea, the sclera and the optic nerve of the adult and, in the mouse, from embryonic day 17 [6, 55]. The substrates and the signalling pathway are not defined and there is no established extraocular function or clinical biochemical assay [19]. In the mouse, alteration of Prss56 reduces axial length and produces a phenotype resembling angle closure; the size differences appear after birth and increase progressively, and the genetic background modifies the magnitude of the effect [18, 57]. Nair's mouse, obtained by chemical mutagenesis (a variant in the splice donor site of exon 11), had elevated IOP, a narrow temporal angle with the iris apposed to the trabecular meshwork and a reduced axial length with a lens of normal diameter, that is, an increased lens/eye ratio [6]. Paylakhi and colleagues showed that Prss56 is expressed from embryonic day 16.5 in late retinal progenitors and thereafter only in a subset of Müller cells; inactivation of the gene, global or restricted to Müller glia, reduces ocular length and thickens the retina, inactivation at different stages before and after eye opening shows that axial growth requires sustained protease activity, and in the double mutant the loss of Prss56 abolishes the myopic axial elongation caused by Egr1 deficiency [6]. PRSS56 and MFRP appear to act in a common emmetropisation pathway (data from Soundararajan cited by Carricondo) [18]. Inheritance is autosomal recessive through loss of function [19, 55].

2.4. MYRF (NNO1 and MYRF-CUGS)

MYRF (myelin regulatory factor; 11q12.2; MANE NM_001127392.3) encodes a transcription factor anchored in the endoplasmic reticulum (ER) membrane, which undergoes autocleavage: the C-terminal fragment remains in the ER and the N-terminal fragment, with the DNA-binding domain, migrates to the nucleus [29]. The nuclear fragment binds the CTGGYAC sequence and activates oligodendrocyte myelination genes (MBP, MOG, MAG, PLP1, DUSP15); the gene is also expressed in the heart, lung, diaphragm, eye and coelomic epithelium of the fetal gonads [19, 29]. In human ocular tissues, expression is highest in the RPE–choroid complex and the optic nerve, and in the mouse it is about a hundred times higher in the RPE than in the neural retina [12]. The gene, with 26 exons, was cloned during the mapping of the BEST1 region and lies about 160 kb from it in GRCh38 coordinates, which explains why the linkage of the MRCS family and of the Belgian family with ADVIRC overlapped the NNO1 interval before the two genes were identified [8, 12]. The cardiac-urogenital syndrome results from haploinsufficiency [19, 78]. In the eye, Garnai and colleagues showed that the original NNO1 family segregates the canonical splicing variant c.3376-1G>A, upstream of the last exon, which generates a stable transcript with a frameshift at the carboxy terminus (p.Gly1126Valfs*31), and that mice with conditional inactivation of Myrf have RPE depigmentation, retinal degeneration and reduced expression of Tmem98 [64]. In that model, segmental loss of RPE pigment was visible at embryonic day 15.5, photoreceptor loss mainly affected the cones and, at 10 months, heterozygotes had minor fundus lesions, without histological, electroretinographic or OCT changes; in HEK293T cells, TMEM98 bound preferentially to the uncleaved form of MYRF and stabilised it in a dose-dependent manner, and the interaction region lies downstream of the cleavage site, between amino acids 586 and 846 [12]. Outside the eye, Luna and colleagues showed in 2026, in the mouse, that inactivation of Myrf at the start of lung development produces left congenital diaphragmatic hernia with complete penetrance and hypoplastic lungs, that the gene is required in the mesothelium of the diaphragm and not in diaphragmatic fibroblasts or lung epithelium, and that it restricts the differentiation of mesothelial progenitors into mesenchymal cells, which provides a mechanistic basis for the diaphragmatic hernia and pulmonary hypoplasia of MYRF-CUGS [12]. Siggs and colleagues found, by chromatin immunoprecipitation in rat oligodendrocytes, that MYRF binds immediately upstream of the transcription start of Tmem98, and that the C-terminal variants escape nonsense-mediated RNA decay [66]. Rozumek and colleagues demonstrated in 2026 that the variant c.3376-1G>A is hypomorphic: in human RPE cells it reduces the expression of target genes and the C-terminal cleavage product, without altering cleavage or localisation; the homozygous humanised mouse dies before embryonic day 18.5; and two additional splicing variants in families with isolated nanophthalmos generate non-functional isoforms [68]. The authors propose a tissue-specific threshold model, in which alleles with partial loss of function affect only the RPE and cause isolated nanophthalmos, whereas more complete loss of function causes the syndromic disease [68]. Garnai and colleagues found no causal MYRF variants in 60 independent cases of high hyperopia and nanophthalmos, and three participants of the ClinSeq cohort with MYRF variants predicted to be deleterious had neither high hyperopia nor nanophthalmos [1]. Guo and colleagues identified, in 11 Chinese trios, two de novo frameshift variants at the same nucleotide (789delC and 789dupC, rs769274302; in ClinVar, NM_001127392.3:c.789del and c.789dup, both p.(Ser264fs)) and, in a replication series of 3 trios and 10 sporadic cases, p.Arg478Pro (c.1433G>C in OMIM nomenclature) and c.2956C>T p.(Arg986Ter), in patients aged 16 to 35 years; these variants lie outside the carboxy terminus and were described in patients with nanophthalmos without any description of systemic features [1, 12, 79].

2.5. TMEM98 (NNO4) and the TMEM98–MYRF axis

TMEM98 (17q11.2; MANE NM_015544.3) encodes a membrane protein of the ER and the cell surface, also secreted, expressed in all ocular tissues tested, including the sclera and the optic nerve head [19, 58]. The gene has two transcripts that differ only in the 5' untranslated region and encode the same 226-amino-acid protein, acidic and leucine-rich, detected in the nucleus and cytoplasm and also expressed in the 16 non-ocular tissues analysed [14]. TMEM98 binds MYRF in the ER and blocks its autocleavage, keeping the N-terminal fragment out of the nucleus; in the RPE, this interaction takes part in setting eye size [19, 67]. The mechanism proposed for the dominant variants is loss of that restraint, with ectopic cleavage and activation of MYRF [19]. The three amino acid substitutions described (p.Ala193Pro, p.His196Pro, p.Arg201Pro) introduce a proline into the charged C-terminal α8 helix (residues 183–210), which indicates that the stability of that helix is necessary for function [80]. In Awadalla's family, p.Ala193Pro was present in all 16 affected individuals and absent in the 19 unaffected relatives and in 285 Australian controls of European ancestry [14]. Khorram and colleagues also described, in a four-generation family of Micronesian ancestry from the Mariana Islands, a heterozygous 34 bp deletion that removes the last 28 nucleotides of exon 4 and the first 6 of intron 4, eliminates the splice donor site and truncates the protein; the original nomenclature (c.694_721delAGAATGAAGACTGGATCGAAGATGCCTCgtaagg) and that of OMIM (c.694_712del, inconsistent with the 34 bp size) do not use the MANE transcript, and ClinVar records the variant as NM_015544.3:c.236_263+6del (VCV000224332) [14, 18, 61, 79]. In the mouse with the p.Ala193Pro variant edited by CRISPR, inheritance was recessive: homozygotes had normal axial length, IOP and scleral collagen, but white retinal spots with retinal folds on histology, a finding also present in human heterozygotes [81]. ClinGen classified the validity of the TMEM98–nanophthalmos 4 relationship as "limited" (glaucoma and neuro-ophthalmology panel, 22 April 2025), whereas submissions to GenCC range from "moderate" to "strong"; interpretation of TMEM98 variants therefore requires caution [19]. Awadalla and colleagues found no new TMEM98 variants in seven other Caucasian families with dominant nanophthalmos, and in the Chinese family of Yu and colleagues, linked to the same 17p12-q12 region (LOD 4.97), sequencing of 14 candidate genes revealed no pathogenic variant [7].

2.6. BEST1, CRB1 and the NNO3 locus

BEST1 (11q12.3) encodes bestrophin 1, a chloride channel of the basolateral membrane of the RPE [18, 28]. The variants that alter splicing cause ADVIRC, with nanophthalmos, microcornea, hyperopia and a narrow angle, according to Yardley and colleagues [28, 37]. The variants identified by Yardley (NM_004183.4:c.256G>A p.(Val86Met) and c.707A>G p.(Tyr236Cys) in ADVIRC, c.715G>A p.(Val239Met) in the MRCS family) are amino acid substitutions that, in in vitro assays, cause exon skipping, unlike neighbouring variants causing Best disease; Burgess and colleagues added c.704T>C p.(Val235Ala), which generates a product with an additional copy of exon 6, and showed that p.Val235Ala and p.Tyr236Cys weaken or abolish an exonic splicing enhancer element, whereas the Best disease variant at the same position (p.(Val235Leu), a designation published at the protein level, which may result from c.703G>C or from c.703G>T) strengthens it [8, 15]. Sequencing of BEST1 in 18 patients with microphthalmia or coloboma and in 50 with anterior segment dysgenesis revealed no pathogenic variants [15]. Autosomal recessive bestrophinopathy runs with hyperopia, a shallow anterior chamber and a propensity to angle closure; heterozygous carriers do not have the disease [28]. Burgess and colleagues found variants in all ten alleles of five families (six amino acid substitutions and one nonsense variant); two of the mutant isoforms reduced the chloride current without impairing the normal channel when coexpressed, which led to the interpretation of ARB as the null phenotype of bestrophin 1 [9, 15]. CRB1 (1q31.3) encodes a 1406-amino-acid transmembrane protein of the photoreceptor inner segments, which controls cell polarity; besides Leber congenital amaurosis type 8, retinitis pigmentosa and pigmented paravenous chorioretinal atrophy, it has been associated with nanophthalmos with retinitis pigmentosa in reports predating 2018 [18]. The OMIM entry for the gene does not assign a phenotype number to nanophthalmos and lists Leber congenital amaurosis 8, pigmented paravenous chorioretinal atrophy (autosomal dominant) and retinitis pigmentosa 12 [16]. The relationship between CRB1 and the short eye rests on two observations: in a Middle Eastern family, high to extreme hyperopia and Leber congenital amaurosis cosegregated with p.(Gly1103Arg) in homozygosity, without dependence on unlinked modifiers; and in the cohort of Henderson and colleagues (306 patients with early-onset recessive retinal dystrophies, of whom 41 from 32 families had CRB1 variants), hyperopia was a common feature, alongside nummular pigmentation at the level of the RPE and a thickened retina on OCT [16]. Jacobson and colleagues interpreted the thickened, unlayered retina of these patients as resembling the immature retina [16]. The NNO3 locus (OMIM 611897) lies at 2q11-q14 and was defined by Li and colleagues in a six-generation Chinese family with dominant inheritance (12 affected and 16 unaffected individuals genotyped; LOD 3.29 at D2S2265; a 15 cM interval between D2S1890 and D2S347); the affected individuals had small globes with enophthalmos, narrow palpebral fissures, mild ptosis, a shallow anterior chamber, small corneas, normal pupils and hyperopia of +6.00 to +11.25 D (mean +8.25 D), without other ocular or systemic anomalies; the gene was not identified [4, 18].

2.7. Genetic architecture in cohorts

Table 2.1 summarises the cohorts with a molecular diagnosis. The proportions measure the contribution of each gene in patients selected by ophthalmology clinics and not the population frequency.

Table 2.1. Diagnostic yield and distribution by gene

GeneGuidance attributed to the study by Li and colleagues sometimes 63 and sometimes 67 patients; the abstract clarifies that these are 67 patients from 63 families and that the percentages by gene refer to the families [19, 33]. In the European recessive cohorts, MFRP and PRSS56 explain most cases; in the Chinese cohorts, PRSS56 is the most frequent gene, followed by MFRP, and the dominant genes account for about a quarter [33, 38, 86]. The low yield of the North American cohort, which included high hyperopia without nanophthalmos, indicates that a broad fraction of cases lies outside the coding sequences of the known genes [47].

2.8. Variants, nomenclature and founder populations

The variants in Table 2.2 were normalised in ClinVar against the MANE transcripts; VariantValidator did not respond and no numbering conversions were made by hand [79].

Table 2.2. Reference variants

The protein notation of Amaral and colleagues for c.498del (p.Asn267Thrfs*25) is incompatible with the nucleotide position, which corresponds to codons 166–167; ClinVar assigns p.(Asn167fs) and that is the form used here [36, 79]. The variants c.1124+1G>T and c.1124+1G>A affect the same donor position but substitute different nucleotides and should not be confused [31, 79, 92]. The variant c.1486G>A, the most frequent in the Chinese series of Tao, has conflicting classifications in ClinVar and is not presented as established pathogenic [79, 85]. Several "pathogenic" classifications rest on submissions without assertion criteria, of low level in the ClinVar star system [79]. The MYRF GeneReviews writes "PRDD56" in the differential table, a typographical error for PRSS56 [29]. The PRSS56 variant p.Pro599Ala, attributed by Nair and colleagues to a Tunisian family and listed as an allele in OMIM, is classified as benign in ClinVar by multiple submitters with criteria, and p.Val302Phe, detected in heterozygosity in an individual from the 1000 Genomes project, is of uncertain significance; neither serves, on its own, as diagnostic proof [6, 79]. The duplication c.1066dup appears in the literature as 1066insC or 1066dupC, designations of the same variant [6]. The MFRP variant published as R518W corresponds in ClinVar, on the MANE transcript, to c.1549C>T p.(Arg517Trp), with a difference of one codon in the numbering [3, 79]. The deletion published by Sundin as 492delC and the one designated 498delC by Crespi are the same variant: the deleted base belongs to a run of seven cytosines starting at c.492, and the 3'-end alignment rule fixes the position at c.498; the insertion 499insC of Ayala-Ramirez, in the same run, corresponds to c.498dup, and Kannabiran and colleagues interpreted this repeat as a mutational hotspot of MFRP [13, 79]. Crespi and colleagues predicted for c.498del a termination codon 25 codons downstream, which is compatible with the "*25" of Amaral's notation and places the discrepancy in the codon number [13, 36]. The 1143insC variant of the Amish-Mennonite family corresponds in ClinVar to c.1150dup p.(His384fs) [13, 79]. In MYRF, c.2336+1G>A, listed in OMIM as an allele of MYRF-CUGS, and p.(Arg695His) are of uncertain significance in ClinVar, and in BEST1 p.Tyr236Cys, an ADVIRC allele in OMIM with a demonstrated effect on splicing, is likewise of uncertain significance as assigned by one submitter; in these cases, the classification depends on segregation and functional data [12, 15, 79]. The BEST1 variants of Table 2.2 are described in ClinVar on NM_004183.4, a version later than the one used by GeneReviews [28, 79]. The variant of Garnai's boy was published as c.769dupC with p.Ser264GlnfsTer74, and the ClinVar record that holds it has no HGVS nomenclature, so the original notation is retained [12, 79].

The geographical distribution of the variants includes founder effects and hotspots. In the Faroe Islands, where recessive posterior microphthalmos is frequent, the PRSS56 variant p.Trp309Ser appears in homozygosity or combined with p.Arg176Gly [55]. Among 27 Faroese patients from 25 families, 20 were homozygous for p.Trp309Ser, 6 were compound heterozygous with p.Arg176Gly and one had no PRSS56 variant; 3 of 94 Faroese controls were heterozygous for p.Trp309Ser (3.2%, in a small sample), none of 100 German controls was, and genealogy linked the parents of all carriers to a 17th-century couple [6]. The PRSS56 duplication c.1066dup, described in a consanguineous Tunisian family, was found on different haplotypes in Australia and is present in more than half of the families with PRSS56 published up to 2020, which indicates a mutational hotspot and not only a founder [55, 82]. In Tunisia, the variant occurred in homozygosity in five of six families, four of them with the same haplotype, which points to a local founder, and it was also found in homozygosity in five Saudi families [6]. In a Czech Roma family, the PRSS56 variant NM_001195129.2:c.1509G>C p.(Met503Ile) in homozygosity in the father and the daughter produced pseudodominant inheritance through consanguinity; two of 118 Roma controls were heterozygous and the shared chromosomal segment suggests a founder effect [90]. In Brazil, MFRP c.498del was found in 8 of 10 patients from four centres [36]. The same variant (498delC in the former nomenclature) was described in homozygosity in a Spanish family and in a family from southern India, both consanguineous, and in compound heterozygosity in a Mexican family, which makes it recurrent in populations with no known relationship [3]. The MFRP variant c.1124+1G>T has a frequency of 0.0002352 in non-Finnish Europeans in gnomAD v3.1.2 [31]. In the Amish-Mennonite family, MFRP c.1150dup was absent from 750 controls [13]. The BEST1 variant NM_004183.4:c.418C>G p.(Leu140Val) occurred in homozygosity in a Pakistani family, initially diagnosed as retinitis pigmentosa and reclassified as ARB, and in four further South Asian probands in the Oxford cohort, which points to a recurrent allele in this region [9, 15]. The MYRF variant p.(Gln403Arg) of the mild encephalopathy shares the haplotype in the two Japanese families described, suggestive of a founder effect [95].

2.9. Genotype–phenotype correlations

The recessive forms are, on average, more extreme. In the Chinese cohorts, PRSS56 and MFRP are associated with a shorter axial length, a shorter vitreous chamber, a lower vitreous/axial length ratio, a steeper cornea and severe foveal hypoplasia, whereas MYRF and TMEM98 are associated with earlier-onset glaucoma and with multiple ciliary body cysts [33, 87]. In the cohort with secondary glaucoma of Yu and colleagues, patients with a dominant form had earlier glaucoma, a longer axial length, a lower spherical equivalent and more severe field defects than those with recessive forms, which leads the authors to recommend earlier intervention in the dominant forms [86]. Uveal effusion is more frequent with PRSS56 in Li's series; in Tao's series, the null alleles of MFRP are associated with more uveal effusion and those of PRSS56 with more angle-closure glaucoma [33, 85]. MYRF is associated with a thinner nerve fibre layer [33]. Pigmentary retinopathy is practically exclusive to MFRP: Lang and colleagues observed retinal dystrophy only with MFRP variants, Almoallem found retinitis pigmentosa in 5 of 10 patients in the MFRP group and Prasov described more retinal degeneration in the MFRP families and more choroidal folds in the PRSS56 families [38, 47, 83]. Papillomacular folds occurred in 12 of 19 (63.2%) patients with posterior microphthalmos and 3 of 6 (50%) with nanophthalmos in Almoallem's series, without a clear genotype–phenotype correlation [38]. Patients with a genetic diagnosis have a shorter axial length and higher hyperopia than those without a diagnosis [82, 86]. In Saudi families with PRSS56, truncating variants were associated with greater axial shortening than amino acid substitutions, and corneal curvature increased in proportion to the shortening [5]. In Tunisia, with the same variant c.1066dup, one family had microcornea and the others corneas of normal diameter, and the Faroese patients had corneas at the lower limit of normal, data that led Gal and Nowilaty with their respective colleagues to see posterior microphthalmos and nanophthalmos as a continuum [5].

In PRSS56 and MFRP, Xu and colleagues observed that biallelic carriers have more extreme parameters and more complications than monoallelic ones, and Lang recommends screening for high hyperopia in heterozygotes [83, 87]. In MYRF, the variants that truncate or alter the carboxy terminus (splicing of the last intron, single-base deletions) give mainly high hyperopia and nanophthalmos, but members of large families with the same variant may have systemic features: in the NNO1 family, four affected and no unaffected individuals had dextrocardia, and one of them also had hypoplasia of the right lung and pulmonary artery stenosis, and in a family of five affected individuals the proband had only nanophthalmos, the father nanophthalmos and cryptorchidism and the other three the classic syndrome [1, 29, 64, 96]. The GeneReviews authors conclude that these cases belong to the MYRF-CUGS spectrum, with reduced penetrance and severity, and not to a separate disease [29]. Siggs's patient, with a C-terminal variant, had a short axial length, high hyperopia and dextrocardia [66].

2.10. Allelic diseases, co-inheritance and modifiers

MYRF has one allelic disease, mild encephalopathy with reversible myelin vacuolisation (OMIM 618113), described in nine individuals from two families with p.(Gln403Arg), without reported overlap with the cardiac-urogenital syndrome; GenCC classifies the association as "limited" [19, 29, 94]. The disease manifests as acute episodes of encephalopathy in childhood, often triggered by fever, with altered consciousness, delirious behaviour or seizures and reversible white matter lesions, especially in the splenium of the corpus callosum; the acute phase is treated with corticosteroids and neurological recovery between episodes is usually complete [95]. In the two Japanese families, four patients had confirmatory imaging and five relatives a suggestive history; the variant reduced transcriptional activity in vitro, psychomotor development was normal even after repeated episodes and sequencing of MYRF in 33 sporadic cases was negative, which suggests an allele with sufficient function under basal conditions and insufficient function under physiological stress, such as infection [12, 95]. BEST1 also causes Best vitelliform macular dystrophy, adult-onset vitelliform dystrophy and MRCS syndrome [22, 28]. The OMIM entry for the gene also lists retinitis pigmentosa 50 (613194) and includes MRCS2, known in a single family, in the vitreoretinochoroidopathy entry [8, 15, 97]. CRB1 causes Leber congenital amaurosis and retinitis pigmentosa [18]. FAM111A causes Kenny-Caffey syndrome type 2 and gracile bone dysplasia, both with nanophthalmos or microphthalmia [19, 29]. Two families illustrate co-inheritance: in the Swiss series, one patient had MFRP-related nanophthalmos and ADAR-related Aicardi-Goutières syndrome, and in the Roma family with PRSS56 another member was homozygous for the CTDP1 variant NM_004715.5:c.863+389C>T of congenital cataract–facial dysmorphism–neuropathy syndrome [83, 90]. The genetic background modulates the effect of Prss56 in the mouse, but there are no established human modifiers in the sources consulted [18].

3. Clinical Spectrum and Manifestations by System

3.1. Common ocular phenotype

The nanophthalmic eye is small, hyperopic and set in a deep orbit, which may make the palpebral fissures appear narrow [18, 19]. Hyperopia is constant and ranges from +8.00 to +25.00 D or more; in the Brazilian MFRP series it was +4.25 to +17.50 D, in the NNO1 family +7.25 to +13.00 D and in the Australian family with TMEM98 it averaged +11.8 D [18, 36, 54, 58]. The cornea is steeper, with topographic steepening and irregular astigmatism; the anterior chamber is shallow and the lens is thick relative to the eye [18, 19]. In the fundus there are a "crowded" optic disc, tortuous and engorged vessels, an absent or rudimentary foveal avascular zone, chorioretinal and papillomacular folds, retinal cysts, optic disc drusen, retinoschisis and foveoschisis, and the subfoveal choroid is thicker [18, 50]. Central retinal vein occlusion has been described [18]. Walsh and Goldberg, in eight patients, attributed the visual limitation to a small and rudimentary foveal avascular zone [1]. Corrected acuity may be normal in childhood, and the prognosis depends on the complications over the course of life [50].

3.2. Natural history by age

In childhood, uncorrected axial hyperopia produces bilateral or anisometropic refractive amblyopia and esotropia, and amblyopia becomes irreversible if correction is not early [18, 29, 41]. In simple microphthalmia, amblyopia is mainly functional, unilateral or bilateral, and results from hyperopia of +7.00 D or more and from strabismus; the anatomical complications add an organic component to it [44]. Sener and colleagues found strabismus in most of their patients with nanophthalmos and, in 15 assessed, monocular amblyopia in 3 and binocular amblyopia in 12 [1]. In an Indian hospital series of 144 consecutive patients (2010–2018), amblyopia affected 30.0% and legal blindness 16.7% at presentation [32]. In adulthood, angle closure and uveal effusion predominate. Brockhurst placed glaucoma between the fourth and sixth decades, and in the Indian series the mean age at presentation was 48.76 ± 15.99 years (5–74), with 55.6% women [32, 51]. Cataract surgery, frequent in the sixth and seventh decades, exposes the eye to its own complications (section 7). In the recessive forms due to PRSS56, corrected acuity remained stable over 2 to 16 years of follow-up (median 10 years) in a Saudi series, with limited improvement after the age of 5 [89]. In MFRP-related retinopathy, nyctalopia may appear in the fourth decade and loss of acuity in the seventh [31].

3.3. Angle closure and glaucoma

Angle-closure glaucoma is the complication that defines the prognosis. Frequencies vary with patient selection and the definition of nanophthalmos, and the values from hospital series are upper limits and not population risks (Table 3.1).

Table 3.1. Frequency of angle closure and glaucoma in nanophthalmos

The absence of glaucoma in the Saudi series of posterior microphthalmos is not equivalent to zero lifetime risk, because the ages and the duration of follow-up are not given in the description; in Yu's Chinese family, glaucoma recurred after repeated trabeculectomies and two eyes progressed to phthisis of the globe [5, 7]. In the meta-analysis, higher IOP at presentation and shorter axial length were associated with more glaucoma, and acute angle-closure attack was the complication most often observed [98]. In the Indian series, peripheral anterior synechiae were associated with glaucoma (odds ratio 3.66; 95% CI 1.71–7.84) [32]. The mechanism combines pupillary block, lens-related and retrolenticular factors, supraciliary effusion that rotates the ciliary body forwards, and aqueous misdirection [40, 99]. In the dominant forms (MYRF, TMEM98), glaucoma begins earlier, and in the Austrian family with TMEM98 p.Arg201Pro the late-onset glaucoma was accompanied by early loss of acuity [33, 80, 86]. In the paediatric case with a MYRF variant described in section 10, IOP rose to 53–60 mmHg at 3–4 years of age [93].

3.4. Uveal effusion

Uveal effusion is the accumulation of fluid in the suprachoroidal and supraciliary space, with choroidal detachment and, in extensive forms, exudative retinal detachment with shifting subretinal fluid [51, 91]. It may be spontaneous or arise after intraocular surgery, especially antiglaucoma surgery [29, 51]. The mechanism is increased choroidal venous pressure through compression of the vortex veins in the thickened sclera, and the EGS (European Glaucoma Society) includes nanophthalmos in that aetiological category [18, 40]. Effusion was a late complication in 10 of 20 eyes (50%) after trabeculectomy with sclerotomy in a Turkish series and was present in 32 of 41 eyes (78%) in a Saudi surgical cohort, not yet peer-reviewed [76, 100]. Supraciliary effusion may be asymmetrical and present as unilateral angle closure in a patient with bilateral nanophthalmos; the difference in anterior chamber depth between the eyes is a clue [99]. Choroidal elevation may simulate a tumour [51].

3.5. Retina and macula

Papillomacular folds, foveoschisis and foveal hypoplasia are findings of posterior microphthalmos and of the recessive forms [19, 38]. In the Saudi series with PRSS56, all patients had papillomacular folds, foveoschisis and disruption of the ellipsoid zone, with a full-field ERG that varied with age, preserved colour vision and mild field depression in some [89]. The cystic changes associated with the folds have been mistaken for cystoid macular oedema after cataract surgery and for macular oedema due to RPE dysfunction [101, 102]. Pigmentary retinopathy is characteristic of MFRP (section 3.6). Human heterozygotes for TMEM98 p.Ala193Pro have discrete white retinal spots with retinal folds [81].

The French PNDS (French National Diagnosis and Care Protocol) orders the posterior segment complications of simple microphthalmia by form. More frequent in nanophthalmos are choroido-scleral thickening, whose reduced permeability leads to uveal effusion with choroidal detachment and non-rhegmatogenous serous retinal detachment, and retinal pigmentary changes, which may be secondary to chronic effusion or correspond to a true pigmentary retinal dystrophy. More frequent in posterior microphthalmos is the interpapillomacular retinal fold. Occurring in both forms are foveal hypoplasia with a flat fovea, extramacular chorioretinal folds, a pseudopapilloedema appearance, macular hole, fine retinal striae, foveoschisis and reduction of the central avascular zone [44]. The distinction between secondary pigmentary change and dystrophy has genetic consequences, because dystrophy points to the forms with retinopathy (MFRP, CRB1, Mackay-Shek-Carr) and justifies the ERG (section 5.3) [19, 31].

3.6. Phenotypes by gene

MFRP. The common core is the short eye with marked hyperopia despite a cornea and lens of normal dimensions, to which progressive retinal disease is added [19]. In the Brazilian series of 10 patients (10–65 years), all were hyperopic (+4.25 to +17.50 D), axial length ranged from 14.4 to 18 mm, there were disc drusen in 5/10, foveoschisis in 5/10 and retinal pigmentary changes in 8/10, and acuity ranged from 0.05 to no light perception; macular atrophy, serous retinal detachment and chorioretinal folds occurred in isolated patients [36]. In a consanguineous Portuguese family, three siblings homozygous for c.1124+1G>A had nyctalopia, reduced acuity, field constriction, bilateral shortening of the posterior segment with a normal anterior segment, an ERG compatible with retinitis pigmentosa and, on OCT (optical coherence tomography), outer retinal schisis, foveal hypoplasia and retinal and choroidal folds [92]. In the Mexican family of the original description, the ERG and fluorescein angiography showed progressive retinal dystrophy, ultrasound showed a short axial length and disc drusen and OCT showed macular retinoschisis [35]. The proband of that family, the daughter of second cousins, noticed nyctalopia and loss of acuity at around 24 years of age and, at 49, had corrected acuity of 20/200 and 20/100, corneas of normal diameter, thickened sclera, disc drusen, an abolished rod response and an almost undetectable cone response on ERG and, on OCT, outer retinal schisis without a foveal depression; the three affected siblings, aged 39 to 45, had the same picture, which had begun in the third decade, without somatic anomalies, intellectual disability or deafness [3]. Crespi and colleagues described three Spanish siblings, children of first cousins, aged 40 to 60 years, with shortening of the posterior segment and a normal anterior segment, acuity of 20/60 to 20/200, advanced rod–cone dystrophy and foveoschisis, more severe in the older ones (one eye without light perception); two had angle-closure glaucoma, which led the authors to prefer the term nanophthalmos despite the normal corneas [3]. Zenteno and colleagues described compound heterozygosity for a novel and a recurrent MFRP variant in a family with the nanophthalmos–retinitis pigmentosa complex, without systemic features [29, 103]. In those two Mexican brothers, aged 16 and 18, nyctalopia and loss of acuity dated from childhood, axial length was below 15 mm in all eyes, the Arden ratio of the electro-oculogram was reduced and OCT showed macular cystic lesions with separation of the inner layers [3]. In seven patients from four families, Mukhopadhyay and colleagues recorded high hyperopia in all, nyctalopia in five, a rod–cone pattern ERG, disc drusen in only one, loss of central vision at 42 years from progressive bilateral serous detachments in one patient and, in another followed for 30 years, stable acuity and hyperopia [3]. Three siblings from a consanguineous family in southern India, homozygous for c.498del, had nyctalopia from the first decade, atypical retinitis pigmentosa and, in the two younger ones, hyperopia of +11 and +13 D [3]. Not all patients with MFRP have retinopathy: two South African brothers of Indian ancestry with p.(Arg517Trp) and a 10-year-old Saudi boy with a homozygous frameshift variant (axial length 15.65 mm, +15.75 D) had posterior microphthalmos with a papillomacular fold, without nyctalopia or signs of retinal degeneration [3]. In Sundin's Amish-Mennonite family, a 30-year-old woman had angle-closure glaucoma and extensive retinal detachment in one eye, whereas four affected relatives had neither glaucoma nor detachment [2]. In an Irish national study of more than 1000 patients with retinal dystrophies, 4 (about 0.4%) had an MFRP genotype [31].

PRSS56. The eye is short, without systemic malformation, with an anterior segment of nearly normal dimensions, extreme hyperopia, a steep cornea, a shallow anterior chamber, a thick lens and a thick sclera; foveal hypoplasia and papillomacular folds are characteristic [19]. In the Saudi series, hyperopia ranged from +12.00 to +17.75 D and axial length from 12.2 to 16.4 mm [89]. Uveal effusion is more frequent with this gene [33]. In the Roma family, the cornea was steeper, there were retinal folds, buried disc drusen and constricted fields, without retinal dystrophy [90]. In the synthesis of Gal and colleagues, the adult has hyperopia of +7.5 to +21 D, axial length of 14 to 20 mm, deep-set eyes that narrow the palpebral fissures, mildly to moderately reduced acuity, frequent anisometropic or strabismic amblyopia, crowded optic discs, tortuous vessels and an abnormal foveal avascular zone [5]. In the Faroe Islands, median hyperopia was +16.5 D (+7.75 to +22 D), with angle-closure glaucoma, uveal effusion, strabismus and amblyopia among the complications [5]. In the six Tunisian families of Hmani-Aifa (25 patients), the phenotype was uniform within and between families, with a papillomacular fold in most, two cases of uveal effusion and two of age-related cataract; Gal's Tunisian family had choroidal neovascularisation in one eye and central vein occlusion secondary to glaucoma in the other [5]. In the two eastern Canadian families of Orr and colleagues, the first (axial length of about 15 to 16 mm) had narrow but not occludable angles, normal IOP, large lenses, small optic nerves without cupping, a thickened choroid and a macula without a foveal depression, and in the second (17 mm) both siblings had glaucoma; in the Mexican family, the proband had chronic angle closure, vascular tortuosity and asteroid hyalosis [5]. In the Saudi series of Nowilaty and colleagues (25 patients from 13 families, with PRSS56 or MFRP), all had hyperopia of at least +8 D, a normal-looking anterior segment and papillomacular folds, without glaucoma, nyctalopia, retinal degeneration or systemic disease [5].

TMEM98. The eyes are small and structurally normal, with an axial length of 15.9 to 18.4 mm in Khorram's families, a mean length of 17.6 mm and a mean hyperopia of +11.8 D in the Australian family, where 16 of 35 members examined (46%) were affected [58, 61]. Angle-closure glaucoma begins earlier than in the recessive forms, ciliary body cysts are more frequent and more disc drusen have been reported [18, 33, 87]. In Awadalla's family, resident in Australia and the United Kingdom, corrected acuity ranged from no light perception to 20/20, six affected individuals had angle-closure glaucoma, the sclera was thick with prominent scleral vessels, there were disc drusen and vascular tortuosity, and intraocular surgery tended to be complicated by aqueous misdirection, macular oedema and choroidal effusion, with poor outcomes [7]. In Khorram's families, one of German ancestry in the USA and the other Micronesian from the Mariana Islands, the spherical equivalent was +13.0 ± 0.89 D and +3.93 ± 1.57 D, respectively, which shows the variation in hyperopia between families with the same gene [7]. In the Chinese family of Yu and colleagues, linked to 17p12-q12 without an identified variant, nine affected individuals aged 6 to 66 years had an axial length of 18.22 to 20.26 mm and hyperopia of +4.50 to +11.50 D [7].

MYRF — ocular form. High hyperopia and nanophthalmos are among the most frequent features of the spectrum: of 19 individuals with ocular morphology assessed in depth, 16 had high hyperopia, a figure possibly overestimated because some were recruited from nanophthalmos cohorts [29]. Amblyopia, esotropia, angle-closure glaucoma, spontaneous and postoperative choroidal effusions, foveal hypoplasia and peripheral chorioretinal scars with mild RPE mottling are described, the latter perhaps specific to MYRF and not a sequel of nanophthalmos [29, 64, 93]. In Xiao's Chinese family, dominant high hyperopia was accompanied by angle-closure glaucoma in two patients from two families [65]. In the original NNO1 family, a 31-year-old woman examined before bilateral cataract surgery for narrow angles had marked hyperopia, crowded optic discs with small cupping, vascular tortuosity, choroidal folds on OCT and an ERG with slightly reduced amplitudes and normal implicit times; after surgery, IOP was normal, but shallow peripheral angles with peripheral anterior synechiae persisted on ultrasound biomicroscopy [1]. Among the Chinese patients of Guo and colleagues, a girl with amblyopia diagnosed at 7 years had elevated IOP at 15, and a 30-year-old woman with blurred vision since childhood rapidly lost acuity in one eye; both had angle-closure glaucoma [1].

MYRF — cardiac-urogenital syndrome. The frequency of the features depends on the mode of ascertainment: cases identified prenatally have more severe malformations, such as congenital diaphragmatic hernia (CDH), than those diagnosed later [29, 104]. Table 3.2 summarises the frequencies from GeneReviews.

Table 3.2. Frequency of the features in MYRF-CUGS

Source: GeneReviews, Table 2 [29].

In 46,XY individuals, the genital spectrum ranges from isolated unilateral cryptorchidism to female-appearing genitalia, with micropenis, hypospadias, chordee, small testes, bifid scrotum and persistent urachus; Müllerian structures may be present, usually hypoplastic, and testicular dysgenesis reduces fertility [29]. One 46,XY individual had a premalignant germ cell neoplasia at orchidopexy before 2 years of age and the risk of gonadoblastoma is uncertain because of the sparse data [29]. Only six 46,XX individuals have been reported, three with atypical internal genitalia (absence of uterus, tubes or vagina, small or absent ovaries) [29]. The heart defects range from isolated dextrocardia to hypoplastic left heart, with scimitar syndrome, atrial and ventricular septal defects, coarctation, bicuspid aortic valve, aortic and mitral atresia and tetralogy of Fallot [29, 62]. About half of the individuals phenotyped in depth have CDH, predominantly left-sided, or pulmonary hypoplasia without CDH [29]. Of the 15 with developmental delay or intellectual disability, 3 had only speech delay and 8 global or severe delay, 7 of whom had cardiopulmonary disease and extensive hospitalisations; without cardiopulmonary malformation, only one had a developmental disorder (autism spectrum disorder) [29]. Other isolated findings include changes in hepatic lobation, hepatotesticular and splenotesticular fusion, appendico-umbilical fistula, microcephaly, hypotonia, posterior fossa cyst, delayed myelination, thymic involution, hypothyroidism and a growth hormone-secreting pituitary tumour; most have no dysmorphic features [29, 62].

The founding reports show the severity of the form ascertained in the neonatal or prenatal period. Of Pinz's two boys, one had mesocardia on prenatal ultrasound, obstructive left cor triatriatum, drainage of the right pulmonary veins into the inferior vena cava, right pulmonary hypoplasia, distal tracheal narrowing, bronchomalacia, hypospadias with micropenis and unilateral cryptorchidism; the other had near-interruption of the aortic arch, a ventricular septal defect, right CDH with hepatopulmonary fusion and intestinal malrotation, and died on the 10th day of life [11]. Chitayat's fetus, of Ashkenazi Jewish ancestry, had hypoplastic left heart, total anomalous pulmonary venous connection, ambiguous genitalia and hepatotesticular and splenotesticular fusion [11]. Qi and colleagues, analysing exomes or genomes of 271 trios from a CDH cohort, found MYRF variants in seven patients from six families, all with heart disease and, among the four examined, all with urogenital anomalies; a pair of monozygotic twin girls was discordant for CDH, which indicates that this manifestation depends on other genetic, environmental or stochastic factors [11]. Garnai and colleagues described an 8-year-old boy with nanophthalmos, mitral valve prolapse, unilateral cryptorchidism and micropenis, whose mother, asymptomatic and with a normal eye examination, carried the variant in mosaic form [11, 12]. In the cases of Pinz, Chitayat and Qi, the variants arose de novo [11].

BEST1 — ADVIRC and ARB. ADVIRC begins in the first decade with circumferential hyperpigmentation of the peripheral retina bounded by a sharp demarcation line in the mid-periphery, punctate white preretinal opacities, vitreous cells and fibrillar vitreous condensation, cystoid macular degeneration and, at times, preretinal neovascularisation; acuity is maintained until late stages [18, 28]. It is associated with nanophthalmos, microcornea, hyperopia and a narrow angle with angle-closure glaucoma [28, 37]. ARB presents with white or yellowish subretinal deposits at the macula and mid-periphery that evolve into scars, subretinal fluid, cystoid macular oedema and, rarely, choroidal neovascularisation, with acuity from 20/20 to less than 20/200; patients are hyperopic, with a shallow anterior chamber and prone to angle closure [28]. In Lafaut's Belgian family (12 affected individuals), all had the annular peripheral pigmentary changes, six had early cataract, four had microcornea and a shallow anterior chamber without microphthalmia (measured axial lengths of 21.0 to 21.9 mm), two had acute angle-closure glaucoma at 45 and 64 years of age and one subacute glaucoma at 35; the electro-oculogram was abnormal in the 10 affected individuals tested, and the ERG ranged from normal, in the youngest, to severely reduced in the two patients with extensive chorioretinal atrophy [8]. In the family of Traboulsi and Payne (13 affected individuals over five generations), acuity was 20/25 or better in almost all and six had cataract in the early fifth decade [8]. In Reddy's English family, designated MRCS, there was nyctalopia in the second decade, cataract operated in the second or third decade, moderate myopia in the youngest, chronic angle-closure glaucoma in the two oldest and posterior staphyloma in 9 of 12 eyes, with normal axial length except in the three eyes without staphyloma (16.4 to 18.7 mm) [8]. In ARB, Burgess's original series included three patients from two families with angle-closure glaucoma; in the Oxford cohort (18 patients from nine families), loss of central vision began from the second decade, with difficulty with night vision or photophobia, preserved peripheral fields, a hyperautofluorescent band around a hypoautofluorescent area, schitic and cystoid changes of the fovea on OCT and, on widefield imaging, a beaten-metal appearance from the mid to the extreme periphery in 8 of 11 patients; the electro-oculogram was reduced or abolished in all those tested [9].

CRB1. Nanophthalmos is associated with retinitis pigmentosa; on OCT, the retina may be thickened with loss of lamination, and there are forms with exudative vasculopathy resembling Coats disease [18, 19]. In Henderson's cohort, a minority developed peripheral retinal telangiectasia, which in some patients led to pupillary seclusion and angle-closure glaucoma [16].

Mackay-Shek-Carr syndrome. Described in seven members of one family, it combines progressive pigmentary retinal degeneration with nyctalopia and field restriction, cystic macular degeneration, hyperopia, nanophthalmos and angle-closure glaucoma, with recessive inheritance [26, 53]. In the original description, all had hyperopia and diffuse sclerochoroidal thickening on ultrasound; the younger patients had slit-like angles, cystic macular degeneration and an ERG without a rod response, with a cone response of normal shape but greatly prolonged b-wave implicit times; the older ones had macular atrophy of non-specific appearance, a greatly reduced or abolished ERG and progressive synechial angle closure leading to glaucoma [10]. Four siblings were affected, and one of them, married to a first cousin, had three affected children out of four, including identical twins [10].

3.7. Natural history and treated disease

The data from surgical series describe treated disease selected by severity, and the figures for legal blindness or glaucoma do not transfer to patients identified by family or genetic screening [32, 98]. The stability of acuity in the paediatric series with PRSS56 reflects patients with refractive correction and treatment of amblyopia [89]. The natural history without treatment is known mainly from the older descriptions, in which glaucoma in the fourth to sixth decade and surgery led to choroidal detachment and loss of the eye [51].

3.8. MYRF-related cardiourogenital syndrome: fetal series, coronary arteries, sex differentiation and recent reports

Favier and colleagues brought together, in an international collaborative study with centres in France, Israel, Canada, the USA, Germany and the Netherlands, 12 new prenatal cases and 5 previously published fetuses, a total of 17 fetuses or newborns with a pathogenic MYRF variant; at that date, 36 individuals with MYRF-CUGS had been published, almost all diagnosed after birth [104]. On ultrasound, the manifestations accessible were congenital heart disease in 13 of 17 (76%), CDH in 10 of 17 (59%) and differences of sex development in 7 of 14 46,XY fetuses (50%) [104]. Adding the prenatal, autopsy and postnatal data, heart disease affected 15 of 17 (88%); among the 15, there was hypoplastic left heart syndrome (HLHS) in 14 (93%), coarctation or hypoplasia of the aortic arch in 8 (53%), anomalous pulmonary venous return or scimitar syndrome in 8 (53%), cardiac situs anomaly in 7 (47%), atrial or ventricular septal defect in 6 (40%), valvular dysplasia in 5 (33%), persistent left superior vena cava in 4 (27%), coronary ectasia in 2 (13%), anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) in 1 (7%) and tetralogy of Fallot in 1 (7%) [104]. Internal or external genital anomalies were present in 11 of 17 (65%) and in 11 of 14 46,XY fetuses or newborns (79%), and autopsy or postnatal examination added seven cases of pulmonary hypoplasia not seen on ultrasound, four of genital anomalies, mostly internal, two of CDH and two of heart disease [104].

Termination of pregnancy was requested in 7 of the 17 pregnancies (41%); of the 10 born, 5 were preterm at 32 to 36 weeks, and 6 died between 1 hour and 7 days of life, all with CDH and most with associated HLHS (4 or 5 of the 6, depending on the section of the article) [104]. None of the four children alive at inclusion had HLHS, which the authors identify as the main determinant of poor prognosis, and three of them had developmental delay or intellectual disability, from mild speech delay to severe deficit [104]. Ocular axial length was measured retrospectively by fetal or postnatal magnetic resonance imaging in five cases and was reduced in two; in a fetus at 32 weeks, the anteroposterior and transverse diameters of the eye were 13 × 13.5 mm, below the 5th percentile [104]. The authors consider that the reproducibility of prenatal nanophthalmos has not been demonstrated [104]. These figures describe a series ascertained by severity in the prenatal period and do not transfer to patients diagnosed later, in whom genital and ocular anomalies predominate [29, 104].

ALCAPA, absent from the GeneReviews table of heart defects, was described in three patients with MYRF-CUGS followed in Cincinnati, presented as the first known cases, and in a fourth, Chinese case [29, 105, 106]. In the latter, a 5-month-old infant registered as female, with atypical external genitalia, a 46,XY karyotype and a de novo splicing variant in MYRF, had tachypnoea since birth without targeted treatment; the electrocardiogram showed pathological Q waves in I, aVL and V4–V6, and echocardiography showed ALCAPA with left ventricular dilatation (end-diastolic diameter of 35.2 mm), mild to moderate mitral regurgitation and an ejection fraction of 54% [106]. Angiography confirmed the origin of the left coronary artery from the pulmonary trunk, and the child recovered well from surgical correction [106]. The authors propose periodic electrocardiography and echocardiography targeted at the coronary arteries in all carriers of MYRF variants, especially with heart failure, ventricular dilatation or a borderline ejection fraction, and coronary angiography when there is suspicion; this is the proposal of a case report, without a defined interval and without a counterpart in GeneReviews [29, 106].

In sex differentiation, Zhang and colleagues described three 46,XY patients from Beijing with heterozygous loss-of-function variants of MYRF, one of them the recurrent variant c.789dup p.(Ser264fs), the same one described by Guo in nanophthalmos without reported systemic features, with underdeveloped testicular tissue, insufficient masculinisation and persistence of the Müllerian ducts [79, 88, 107]. In the same authors' review of the literature, among 31 46,XY patients and 2 46,XX patients with atypical sex differentiation and a MYRF variant, 11 had isolated testicular dysgenesis and 20 severe cardiopulmonary disease, most with CDH; the 26 distinct variants were 10 amino acid substitutions, 8 frameshift, 5 nonsense and 3 splicing, without a clear genotype–phenotype correlation [107]. In Philadelphia, two 46,XY patients identified through critical prenatal heart disease illustrate the extremes of the spectrum: one had female-appearing external genitalia, Müllerian structures on imaging and biochemical gonadal insufficiency; the other had perineal hypospadias, severe chordee, bifid scrotum and bilateral cryptorchidism, with normal testicular function during minipuberty [108]. Hormonal assessment during minipuberty therefore separates patients with functioning gonads from those with dysgenesis and gonadal failure [108].

In girls, the severe form without external genital anomaly may go undiagnosed until autopsy. Two Czech sisters of non-consanguineous, unaffected parents, with a third healthy sister, shared a MYRF splicing variant absent in the parents [109]. The first had dextroposition of the heart, anomalous drainage of the right pulmonary veins into the inferior vena cava (infantile-type scimitar syndrome), systemic collaterals to the right lung, rhabdomyomatous dysplasia of the lung and Meckel's diverticulum, without urogenital malformation; she died of heart failure at 12 weeks, with pulmonary hypertension that contraindicated more extensive cardiac surgery [109]. The second was born at 38 weeks, in a pregnancy monitored for coarctation and a small left ventricle, had a hypoplastic mitral valve and left ventricle considered inoperable and died at 10 days in palliative care; autopsy showed hepatopulmonary fusion, uterus didelphys with a double vagina, splenogonadal fusion and an accessory spleen [109]. In 2026, Sher and colleagues described a term newborn girl with a likely pathogenic splicing variant inherited from her mother, who had no known cardiac, diaphragmatic, pulmonary, ophthalmological or genitourinary history; the child had scimitar syndrome, a ventricular septal defect, arch hypoplasia, right CDH with hepatopulmonary fusion, pulmonary hypoplasia and uterus didelphys, and died in the neonatal period from severe pulmonary hypertension, refractory hypoxaemia and necrotising enterocolitis [110]. The authors present uterus didelphys as a Müllerian anomaly not previously described in MYRF-CUGS, but uterus didelphys already appeared in the autopsy of the second Czech sister and in the history of the symptomatic mother of a fetus in Favier's series [104, 109, 110].

4. Clinical Recognition and Warning Signs

4.1. Infant and child

Suspicion arises with bilateral high hyperopia, esotropia or amblyopia in a child with deep-set eyes and apparently narrow palpebral fissures [18, 19]. The instrument-based screening of the AAPOS (American Association for Pediatric Ophthalmology and Strabismus) regards as amblyogenic risk factors hyperopia above +4.00 D at any age, anisometropia above 1.25 D, astigmatism above 3.00 D before 4 years of age or above 1.75 D thereafter, and manifest strabismus above 8 prism dioptres; an inconclusive screening is repeated in 6 months and, if it remains inconclusive, a complete ophthalmological examination follows [111]. Hyperopia of +4.00 D or more is not synonymous with nanophthalmos: in a set of four population studies (USA, Singapore and Australia) with 15,051 children aged 6 to 72 months under cycloplegia, the prevalence was 3.2% (95% CI 2.9–3.5%) [112]. What separates nanophthalmos is the combination of very high hyperopia with a short axial length on biometry. A child with a parent or sibling with nanophthalmos should be examined even without complaints, because the parents may be only mildly affected and be identified only after the birth of a second child [45]. In a child with a genital anomaly, heart disease (especially scimitar syndrome or hypoplastic left heart), CDH or pulmonary hypoplasia, high hyperopia suggests MYRF-CUGS [29]. The French PNDS (French National Diagnosis and Care Protocol) distinguishes two modes of discovery. In nanophthalmos, the small eye with a reduced corneal diameter may be noticed by the paediatrician at the examination in the maternity unit, or later by the parents or another doctor, especially when the reduction is asymmetrical. In posterior microphthalmos, without a visible difference in globe size, the diagnosis is later and starts from low acuity with hyperopia above +7.00 D at an examination in early childhood, confirmed afterwards by full biometry [44].

4.2. Adult

In adults, suspicion arises with a shallow anterior chamber with high hyperopia, angle closure at a younger age than usual, spontaneous uveal effusion, papillomacular folds or pigmentary retinopathy with a short eye [18, 40]. The EGS recommends not ignoring axial length in patients with angle closure, because short eyes have their own surgical risk and require planning [40]. Ultrasound with measurement of retino-choroido-scleral thickness confirmed nanophthalmos in four of eight patients without a previous diagnosis in a North American series, and the authors recommend measuring it in hyperopic eyes at risk of a narrow angle [39]. Cystic macular lesions in a short eye should prompt consideration of the papillomacular folds of posterior microphthalmos before diagnosing postoperative macular oedema [101, 102].

4.3. Emergency signs

Emergencies are acute angle-closure attack (ocular pain, headache, nausea, vomiting, blurred vision, very high IOP), uveal effusion with exudative retinal detachment, aqueous misdirection after surgery (a uniformly shallow anterior chamber with high IOP and a patent iridotomy) and intraoperative suprachoroidal haemorrhage [40, 77, 91]. In a child, frontal headache, ocular pain and vomiting may correspond to intermittent angle closure, as in the case in section 10 [93]. The introduction of drugs that precipitate angle closure (topiramate, systemic sulfonamides, anticholinergics, sympathomimetics, antidepressants) in a patient with a short eye requires vigilance [40].

4.4. Newborn screening

There is no newborn screening for nanophthalmos. The second-trimester ultrasound visualises the eye and the lens, but it may fail to detect recurrence of microphthalmia [45].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus criteria (Table 1.3) [69]. In practice, nanophthalmos is diagnosed by the combination of a short axial length (usually <20–21 mm in adults, or ≥2 standard deviations below the mean for age in children), high hyperopia, a small anterior segment with a shallow anterior chamber, a lens of normal volume, increased retino-choroido-scleral thickness and absence of structural malformation [18, 30, 39]. Posterior microphthalmos allows a normal corneal diameter (≥11 mm) with a short posterior segment [18]. For MYRF-CUGS there are no published clinical criteria, and the diagnosis requires a heterozygous pathogenic or likely pathogenic variant in MYRF with suggestive findings [29].

5.2. Biometry and imaging

Biometry is the central diagnostic test and defines the phenotype, but not the gene [19]. It includes axial length by A-scan ultrasound or optical biometry, keratometry, anterior chamber depth, lens thickness and the lens thickness/axial length ratio [19, 86]. B-scan ultrasound measures retino-choroido-scleral thickness (mean of 2.41 mm in eight North American patients; about 2.0 mm in nanophthalmos against 1.5 mm in primary angle-closure disease in an Indian series) and detects uveal effusion and disc drusen [39, 113]. In the comparison by Rajendrababu and colleagues (58 eyes with nanophthalmos, 26 with primary angle closure and 60 with primary angle-closure glaucoma, before laser or surgery), nanophthalmos had a shorter axial length, a shallower anterior chamber, a median angle of 20.5° against 26°, greater lens vault and axial lens factor and a median IOP of 14 mmHg, without a difference in lens thickness or central corneal thickness; in the series of 144 patients, retino-choroido-scleral thickness (1.99 ± 0.25 mm) correlated inversely with axial length (17.64 ± 1.74 mm; r = −0.28) [32, 113]. Ultrasound biomicroscopy shows supraciliary effusion and ciliary body cysts [87, 99]. Gonioscopy and anterior segment imaging assess the angle; tonometry, the optic disc, OCT of the nerve fibre layer and visual fields stage the glaucoma [19]. Macular OCT documents foveal hypoplasia, papillomacular folds and foveoschisis, and fundus photography, autofluorescence and angiography complete the retinal assessment [19, 89]. Computed tomography and magnetic resonance imaging show short eyes with a thick sclera, hyperdense on tomography and hypointense on T2 [93]. In a child with a small eye, ultrasound also excludes retinal detachment or dysplasia, and brain and orbital magnetic resonance imaging is reserved for clinical anophthalmia or severe microphthalmia [45].

The French PNDS (French National Diagnosis and Care Protocol) describes the full initial assessment, adapted to age. The history includes the obstetric history, the medical and surgical ophthalmological history and the family history of ocular developmental anomaly. The functional examination comprises binocular and monocular acuity (or visual behaviour in the preverbal child), an orthoptic assessment with at least a stereopsis test, cover test (or corneal reflexes) and motility, objective refraction under cycloplegia and keratometry. Biomicroscopy, with a fixed or portable slit lamp, measures the horizontal corneal diameter (with callipers in infants), estimates anterior chamber depth by the Van Herick sign, includes gonioscopy when cooperation permits (adults and older children), examines the cornea, iris and lens before and after dilatation and examines the fundus by indirect ophthalmoscopy, with dilatation only if the angle permits. IOP is measured with an air-puff or applanation tonometer in adults and older children and with a rebound tonometer in infants, and the examination includes inspection of the facial structure and of eyelid anatomy, static and dynamic. The complementary examinations are A- or B-scan ultrasound for axial length, ultrasound biomicroscopy for corneal thickness, ACD, lens thickness and anterior segment morphology, optical biometry or anterior segment OCT for ACD, and fundus photographs of the posterior pole and widefield images with OCT of the macula, the optic disc and the peripheral lesions. In infants and in children in whom examination is difficult, for example with multiple disabilities, examination under general anaesthesia is often indispensable for a complete diagnosis [44]; general anaesthesia is, however, among the factors that may precipitate angle closure in an eye with a narrow angle (section 7.16) [40]. The PNDS also recommends examining the parents and siblings, referring the child to the genetics clinic and, in the face of any sign of a syndromic form, completing the work-up with an ear, nose and throat assessment with hearing testing, echocardiography, renal ultrasound and brain and orbital imaging [44].

5.3. Electrophysiology

The full-field ERG identifies the rod–cone dystrophy of the MFRP-related form, with unrecordable responses in the advanced stages, and is variable with age in the PRSS56-related forms [19, 31, 89]. In ADVIRC, the electro-oculogram is abnormal and the ERG normal or reduced; the normal Arden ratio is above 1.8, and in Best disease it is below 1.5 (generally 1.0–1.3) [19, 28].

5.4. Genetic testing

The first-line test is a multigene panel that includes at least PRSS56, MFRP, MYRF and TMEM98, and also BEST1 and CRB1; Lang's panel additionally included GJA1, C1QTNF5 and FAM111A [47, 83]. Almoallem and colleagues recommend sequence and copy-number analysis of MFRP and PRSS56 [38]. When the form is syndromic or the panel is negative, exome or genome sequencing with copy-number analysis is the next option [29, 85]. Panels for differences of sex development, congenital heart disease or CDH frequently do not include MYRF, as it is a recently described gene [29].

The yield ranges from 18.8% in a North American cohort with high hyperopia to 90.5% in selected recessive families (Table 2.1) [38, 47]. The statement that sequencing detects more than 99% of the known pathogenic variants of MYRF or of BEST1 refers to the proportion of variants detectable by the method and not to the clinical sensitivity of the test in the face of a short eye [28, 29]. A negative result does not exclude a genetic cause: there are genes not yet identified (NNO3, Mackay-Shek-Carr), deep intronic variants, MFRP rearrangements that escape sequencing and parental mosaicism in MYRF [18, 29, 38]. Families without a variant in PRSS56 or MFRP (one Faroese patient, one Turkish patient, a Mexican family and three Saudi families) and the Chinese family linked to 17p12-q12 without a variant in the candidate genes indicate additional genetic heterogeneity, and the search for MYRF in 60 cases of high hyperopia and nanophthalmos was negative [1, 5, 7]. Detection of a single allele in a recessive gene, as in Prasov's four families with monoallelic MFRP or PRSS56, does not establish the diagnosis and makes it necessary to search for the second allele by copy-number analysis, RNA studies or genome sequencing [47]. TMEM98 variants require caution because of the limited gene–disease validity in ClinGen [19].

The report should state the gene, the transcript and its version (NM_001195129.2 for PRSS56, NM_031433.4 for MFRP, NM_001127392.3 for MYRF, NM_015544.3 for TMEM98), the variant in HGVS nomenclature, the zygosity, the phase of the variants in a recessive gene and the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) class [19, 79]. A variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis; family segregation and, in splicing variants, RNA studies help to reclassify it [29, 68]. Hagedorn's case illustrates the limitation of a single amino acid substitution, without segregation and with discordant predictions [93].

5.5. Assessment of the syndromic form due to MYRF

In the presence of a MYRF variant, the recommended initial assessment includes growth, genital examination, pelvic, renal and abdominal (spleen) ultrasound, endocrine assessment, TSH and free T4 if there is poor growth or delay, ophthalmological assessment with refraction, developmental assessment, echocardiography, respiratory assessment with radiography, nutritional assessment with an upper gastrointestinal series if malrotation is suspected, and genetic counselling [29]. Müllerian structures are difficult to visualise in individuals not exposed to oestrogens, and their non-visualisation does not exclude them; examination under anaesthesia or laparoscopy may be necessary [29].

GeneReviews does not define formal clinical criteria; suspicion rests on atypical genitalia, micropenis, hypospadias or cryptorchidism in 46,XY individuals and Müllerian anomalies in 46,XX individuals, high hyperopia or nanophthalmos, congenital heart disease (especially HLHS or scimitar syndrome), CDH and pulmonary hypoplasia even without a diaphragmatic defect, and, on imaging, hypoplasia or aplasia of the ovaries or Müllerian structures in 46,XX, Müllerian structures in 46,XY and intestinal malrotation [29]. Scimitar syndrome is defined by anomalous pulmonary venous return, partial or total, from the right lung to the inferior vena cava, with dextroposition of the heart, hypoplasia of the right lung and right pulmonary artery and anomalous systemic blood supply to the lung [29]. The diagnosis is established by a heterozygous pathogenic or likely pathogenic MYRF variant; sequence analysis detects more than 99% of the known pathogenic variants and intragenic deletions or duplications are rare, a proportion that refers to known variants and not to clinical sensitivity [29, 78]. The approach is single-gene testing or a panel for differences of sex development, congenital heart disease or CDH that includes MYRF, and exome or genome sequencing when the features are atypical or subtle [29]. In Favier's fetal series, the molecular diagnosis was postnatal in 8 of the 12 new cases, and prenatal exome sequencing identified the inherited variant in three families, two with a symptomatic undiagnosed parent and one with an asymptomatic mosaic mother; three inherited variants were classified as of uncertain significance by the ACMG/AMP criteria, although the relatives' phenotype was compatible [104].

5.6. Algorithm

The diagnostic pathway is organised in four steps. First, cycloplegic refraction and biometry confirm a short eye and high hyperopia and exclude malformation (coloboma, retinal dysplasia, persistent fetal vasculature), which points to the MAC spectrum. Second, gonioscopy, ultrasound biomicroscopy and B-scan ultrasound stage the angle and the ocular wall, and macular OCT and the ERG classify the retina. Third, examination of first-degree relatives and the search for systemic features (genitalia, heart, diaphragm, lung, calcium, skeleton, development) point to an isolated or a syndromic form. Fourth, a panel with copy-number analysis, followed by exome or genome sequencing if negative [18, 29, 38, 45].

5.7. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis by molecular testing and preimplantation genetic diagnosis are possible [29, 45]. In MYRF-CUGS, CDH and heart disease are the most frequent ultrasound findings and prompt fetal diagnosis [104]. Morphological ultrasound has no demonstrated sensitivity for the isolated short eye [45].

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of nanophthalmos and posterior microphthalmos

6.2. Morphological differential diagnosis

Faced with an eye that appears small, the French PNDS (French National Diagnosis and Care Protocol) recommends first distinguishing an abnormality of globe position (enophthalmos, or marked ptosis simulating it) from a true size abnormality, which only biometry confirms [44]. The next distinction is between an organised short eye and a malformed eye. Complex microphthalmia is accompanied by coloboma, retinal dysplasia or persistent fetal vasculature and belongs to the MAC spectrum, in which the recurrence and the genes are different [18, 45]. Relative anterior microphthalmos has a small anterior segment with normal or near-normal axial length [48]. High hyperopia without nanophthalmos occupies the extreme of the population distribution of axial length, without thickening of the wall; in Prasov's cohort, which included hyperopes from +5.50 D, the genetic yield was low [47]. The distinction between nanophthalmos and posterior microphthalmos is of practical interest because nanophthalmos concentrates angle-closure glaucoma and posterior microphthalmos macular folds [18].

6.3. Primary angle closure and uveal effusion

In an adult with angle closure, biometry separates nanophthalmos from primary angle-closure disease: shorter axial length, shallower anterior chamber, narrower angle and retino-choroido-scleral thickness of about 2.0 mm, against 1.5 mm [113]. The distinction changes management, because the EGS excludes nanophthalmos from the general recommendations on primary angle closure (section 7) [40]. Idiopathic uveal effusion syndrome (ORPHA:209956) is dealt with in the same surgical reviews, but it occurs in eyes without nanophthalmos; effusion secondary to inflammation, tumour, drugs or procedures has an identifiable cause [40, 114, 115]. Topiramate and sulfonamides cause acute angle closure through peripheral uveal effusion, a picture that can mimic the effusion of nanophthalmos in an eye of normal length [40]. Choroidal elevation should not be mistaken for melanoma [51].

6.4. Retinopathies with a short eye

Pigmentary retinopathy with a short eye points to MFRP, CRB1, Mackay-Shek-Carr or ADVIRC [18, 19, 26, 28]. ADVIRC is distinguished by the peripheral demarcation line and the abnormal electro-oculogram, and ARB by the vitelliform deposits [28]. Leber congenital amaurosis runs with hyperopia, but with nystagmus and an undetectable ERG from the first year of life [116]. Attenuated mucopolysaccharidosis II was associated in one case with retinitis pigmentosa with nanophthalmos, and the suspicion points to a mucopolysaccharidosis work-up [120].

6.5. Syndromic forms

A child with a short eye and genital anomalies, heart disease, CDH or pulmonary hypoplasia has MYRF-CUGS as the first hypothesis; the systemic differential includes GATA4 (without CDH, eye or lung involvement), NR2F2 (46,XX, eyelid anomalies, without hyperopia), PIGL (coloboma, vermis hypoplasia, cleft palate), RLIM (hypertelorism, long face, micrognathia), SPECC1L (hypertelorism, rare CDH), WT1 (Meacham syndrome; one patient with that clinical diagnosis had MYRF-CUGS), Fryns syndrome and PAGOD syndrome, of unknown molecular basis and overlapping with MYRF-CUGS [29]. Rossetti and colleagues recommend searching for MYRF variants in patients with a clinical diagnosis of PAGOD [63]. Kenny-Caffey syndrome type 2 combines nanophthalmos with short stature, hypocalcaemia and bone thickening; in a 13-year-old girl it was complicated by exudative retinal detachment from uveal effusion [117, 124]. The reports of nanophthalmos in Gabriele-de Vries and Tietz/Waardenburg 2A syndromes, in the GLIS3 deletion and in the complex with ocular cystinosis are isolated cases, known in this edition only from the title or the abstract [118, 119, 121, 122].

7. Treatments and Risk Management Strategies

7.1. Principles and guidelines

There is no treatment that corrects the genetic defect and no guideline dedicated to nanophthalmos, and no medicine has an approved indication for it; management addresses hyperopia, amblyopia, angle closure, uveal effusion and macular lesions, and the evidence is at the level of nanophthalmos and not of genotype [19, 40]. The EGS, in the 6th edition of its guidelines (2025), expressly excludes nanophthalmos, eyes with cataract and eyes after an acute attack from the graded recommendation on intervention in primary angle-closure disease; therefore, the recommendations on iridotomy and lens extraction for primary angle closure do not transfer directly to the nanophthalmic eye [40]. The EGS includes nanophthalmos among the glaucomas associated with non-acquired ocular anomalies, notes that genetic testing helps to distinguish the syndromes and gives guidance applicable to short eyes: measure axial length in all patients with angle closure, plan surgery according to it, be cautious with filtering surgery and use cyclophotocoagulation as an option [40]. The North American guideline on primary angle-closure disease from the AAO (American Academy of Ophthalmology), published in 2025–2026, replaces that of 2020, but the full text was not accessible for this edition; the 2020 guideline and a letter commenting on the new version were identified [125–127]. The 2025 consensus of the APGS (Asia-Pacific Glaucoma Society) and the AAPPO on acute primary angle closure, known from the abstract, accepts argon laser peripheral iridoplasty, anterior chamber paracentesis and laser pupilloplasty to lower IOP rapidly and favours earlier phacoemulsification; it applies to primary angle closure and not to nanophthalmos [128]. For children, the AAO guidelines on paediatric eye evaluations and amblyopia (2022) set the thresholds for refractive correction and the treatment of amblyopia [41, 111].

The French microphthalmia–anophthalmia PNDS (HAS, 2022) is the national guideline that covers nanophthalmos and posterior microphthalmos, within the group of simple microphthalmia; it does not specify medicines or doses for the short eye and gives guidance on optical correction, amblyopia, cataract in children, the timing of iridotomy and the rhythm of follow-up [44]. It diverges from the other sources on three points: in the diagnostic criterion (hyperopia of +7.00 D or more and axial length below 14 mm at birth and below 21 mm in adults, against the thresholds of Table 1.3); in laser iridotomy, which the PNDS postpones to the end of adolescence or to adulthood, whereas the EGS recommends it in suspects of angle closure at high risk, including high hyperopia, and the cohorts of the dominant forms call for earlier intervention; and in occlusion of the unilateral form, more intensive than the 2- to 6-hour daily regimens of the AAO (section 7.2) [33, 40, 41, 44, 86].

7.2. Refractive correction and amblyopia

Full correction of hyperopia and active treatment of anisometropic or strabismic amblyopia in childhood are the basis of treatment in the recessive forms, in which hyperopia is extreme [19]. The AAO paediatric guideline proposes, by panel consensus, the prescribing thresholds of Table 7.1; the hyperopia typical of nanophthalmos, above +8 D, exceeds them from the first year of life [18, 111]. In non-accommodative esotropia with a surgical indication, Sener and colleagues did not need to reduce the dosage of strabismus surgery because of the short axial length [1].

Table 7.1. Thresholds for refractive correction by age (dioptres)

Source: AAO, Pediatric Eye Evaluations Preferred Practice Pattern, Table 2 [111].

Bilateral refractive amblyopia from high hyperopia is treated, first of all, with spectacles: in the PEDIG (Pediatric Eye Disease Investigator Group) ATS7 trial, 113 children aged 3 to under 10 years with bilateral refractive amblyopia treated with spectacles alone gained 3.9 lines of binocular acuity in one year (95% CI 3.5–4.2), and 74% reached 20/25 or better [41]. In anisometropic amblyopia, 18 weeks of spectacles improve acuity by at least two lines in more than two thirds of children aged 3 to 7 years and in about a quarter of those aged 7 to 17 years [41]. When amblyopia persists after correction, the guideline allows occlusion or penalisation with 1% atropine in the dominant eye; atropine on two consecutive days per week for 4 months was as effective as daily instillation in moderate amblyopia (20/40 to 20/80), and in severe amblyopia from 3 to 12 years of age the twice-weekly regimen gave a gain of 4.5 lines (95% CI 3.2–5.8) [41]. The adverse effects reported were photosensitivity (18%), conjunctival irritation (4%) and, rarely, systemic effects (dry mouth and skin, fever, delirium, tachycardia); compression of the lacrimal sac reduces absorption, and the regimen has not been studied in trials below 3 years of age [41]. The US label for 1% atropine allows up to two instillations per day from 3 years of age and one drop per eye per day between 3 months and 3 years; the guideline's twice-weekly regimen falls below that maximum [41, 129]. The sources consulted do not assess penalisation with atropine in nanophthalmic eyes with a narrow angle; diagnostic mydriasis is considered generally safe by the EGS, especially with a patent iridotomy, and atropine is, on the other hand, a treatment for aqueous misdirection [40]. Reassessment after starting treatment of amblyopia is generally carried out 2 to 3 months later, adjusted to the intensity of treatment and to age [41].

The French PNDS adds details of execution. Correction is with spectacles, renewed after each new objective refraction under cycloplegia, because the refraction changes as the eye grows; moderate microphthalmia may have, besides hyperopia, astigmatism and, at times, myopia. Rigid contact lenses, or scleral lenses, fitted by an ophthalmologist specialising in contact lenses, may alternate with spectacles. In unilateral hyperopia, the thick convex lens increases the apparent size of the eye and attenuates the asymmetry, at the cost of a heavy lens, and the fitting may require custom-made frames [44]. In the unilateral form, the affected eye accumulates organic, strabismic and anisometropic amblyopia: besides optical correction, the PNDS proposes occluding the sound eye for at least half of the waking hours from the preverbal age to 3 years and maintaining treatment until 6 to 8 years of age. The acuity of the small eye often stabilises between 1/10 and 5/10, but the aim is to give it useful vision in case of future loss of the sound eye, and without treatment it would probably remain below 1/20, the legal blindness threshold [44]. The AAO amblyopia guideline uses shorter regimens in functional amblyopia: 2 hours of daily occlusion have an effect similar to 6 hours in moderate amblyopia (20/40 to 20/80), and 6 hours daily have an effect similar to occlusion for all waking hours but one in severe amblyopia (20/100 to 20/400) below 7 years of age; the same guideline recognises a treatable amblyopic component in eyes with a structural anomaly [41]. The sources consulted include no occlusion trials in nanophthalmic eyes, and the PNDS regimen rests on expert consensus. The apparent ptosis of these patients results from the enophthalmos, with normal levator muscle function, and eyelid surgery, performed as a day case, may be discussed for cosmetic reasons [44].

7.3. Prevention and treatment of angle closure

Surveillance of the angle begins in childhood and is lifelong (section 11) [19]. For the primary angle-closure suspect, the EGS recommends laser peripheral iridotomy in high-risk individuals, including those with high hyperopia (low evidence, weak recommendation), and, in primary angle closure and primary angle-closure glaucoma below 50 years of age, iridotomy (low evidence, strong recommendation); above 50 years, lens extraction or iridotomy (moderate evidence, EAGLE trial, strong recommendation) [40]. These recommendations do not include nanophthalmos and serve as an indirect reference [40]. In the nanophthalmic eye, laser has been used since 1979: Kimbrough and colleagues treated angle closure with iridotomy and with contraction of the peripheral iris stroma (iridoplasty), which appeared to open the angle even without iridotomy [52]. Clear lens extraction to control angle closure requires weighing the risk of closure against the surgical risk, greater in eyes with an axial length equal to or below 20 mm (aqueous misdirection, posterior capsule rupture), the lifetime risk of retinal detachment after lens extraction in young people and the loss of accommodation [40]. After the angle has been opened, prostaglandin analogues are, for the EGS, the most effective medication in primary angle-closure glaucoma (low evidence, strong recommendation) [40]. In the dominant forms (MYRF, TMEM98), the Chinese cohorts recommend earlier intervention, because of the younger onset of glaucoma [33, 86].

The French PNDS considers the risk of angle closure in childhood to be very small: closure worsens with age, because thickening of the lens pushes the iris forwards and reduces the anterior chamber. Therefore, surgical iridectomy is rarely indicated and laser iridotomy may wait until the end of adolescence or adulthood; the risk does not exist in posterior microphthalmos with a normal anterior segment, which the PNDS defines by a corneal diameter above 11 mm [44]. This guidance, written for simple microphthalmia in general, contrasts with the earlier glaucoma of the dominant forms due to MYRF and TMEM98 and with the paediatric case with a MYRF variant and IOP of 53–60 mmHg at 3–4 years of age (section 10) [33, 86, 93]. The PNDS itself calls for gonioscopy at every follow-up visit, especially in nanophthalmos, because of the risk of acute glaucoma (Table 11.1) [44].

7.4. Acute angle-closure attack

The EGS recommends not assuming that an acute attack always results from pupillary block: pupillary block is treated with pilocarpine, but the lens-related and retrolenticular mechanisms, frequent in the short eye, are treated with cycloplegia (atropine, tropicamide or cyclopentolate) and may worsen with pilocarpine; plateau iris and aqueous misdirection must be excluded [40]. IOP is lowered with topical and systemic aqueous suppressants and with hyperosmotic agents [40]. Intraocular surgery with very high IOP exposes the eye to suprachoroidal haemorrhage from sudden decompression, and phacoemulsification after an acute attack has more aqueous misdirection, refractive surprise and corneal decompensation; the EGS recommends biometry (axial length, ACD) after the attack [40]. In a 63-year-old man with a refractory attack (IOP above 60 mmHg on maximal medical therapy, axial length of 16.3 mm), lamellar sclerectomy with full-thickness sclerostomy, phacoemulsification, intraocular lens and posterior capsulotomy lowered IOP to 17 mmHg on the first day and kept it between 15 and 18 mmHg without medication at 8 months [77].

The US label for pilocarpine includes the treatment of acute angle-closure glaucoma (one drop of 1% or 2% up to three times within 30 minutes, after lowering IOP below 50 mmHg with suppressants and hyperosmotic agents) [130]. The EGS, which is the reference, contraindicates miotics in aqueous misdirection and warns that pilocarpine may worsen lens-related and retrolenticular closure, mechanisms typical of nanophthalmos; it also advises against pilocarpine to reverse diagnostic mydriasis [40]. In nanophthalmos, pilocarpine has a place only when the mechanism is documented pupillary block, and use according to the label falls outside what the guideline allows for the retrolenticular mechanisms.

7.5. Aqueous misdirection (malignant glaucoma)

The risk factors for aqueous misdirection are a short eye (axial length below 21 mm), hyperopia above +6 D and angle-closure glaucoma [40]. Medical treatment combines parasympatholytics (atropine or cyclopentolate), oral and/or topical aqueous suppressants and hyperosmotic agents, and miotics are contraindicated [40]. Surgical treatment requires a patent iridotomy (laser iridotomy if there is none); in the phakic eye, pars plana vitrectomy with or without lens extraction is performed, in the pseudophakic eye Nd:YAG laser vitreolysis or capsulotomy, and zonulo-hyaloido-vitrectomy may be performed by the anterior route through a peripheral iridectomy; diode laser cyclophotocoagulation may be used at any time [40]. Malignant glaucoma occurred in 9 of 92 operated eyes in the modular series of Gao and colleagues, being more frequent in younger patients [131].

7.6. Cataract surgery

Cataract surgery in the nanophthalmic eye has higher complication rates than in the eye of normal dimensions; Carricondo and colleagues cite intraoperative complications of about 40% to 60% in earlier series [18]. Table 7.2 summarises the series with quantitative data.

Table 7.2. Series of cataract surgery in nanophthalmic or short eyes

In Day's series, the risk of complication was multiplied by about 4 with an axial length below 20.5 mm, by 15 below 20.0 mm and by 21 below 19.0 mm, and elevated IOP or IOP on treatment was the other predictor [72]. In Rajendrababu's trial, manual small-incision surgery increased complications compared with phacoemulsification (odds ratio 5.95; 95% CI 1.49–23.73), as did high IOP (4.54) and lens thickness (3.38) [132]. The most accurate intraocular lens calculation formula varied between series: Holladay 1 in Jung, SRK/T and Kane in Yosar, Barrett Universal II and Hoffer Q in Claudel; the series are small and differ in axial length and in population [48, 73, 75]. O'Connell summarises data according to which up to 67% of nanophthalmic eyes end within ±1.00 D of target and 75% of eyes with isolated nanophthalmos gain up to 3 Snellen lines [31]. The EGS advises planning surgery according to axial length, because of the risk of aqueous misdirection and capsular rupture below 20 mm [40]. Prevention of uveal effusion rests on prophylactic sclerostomy (section 7.8) and on control of IOP fluctuations during surgery; prophylaxis with corticosteroids or acetazolamide appears ineffective according to the review cited by Tirlis and colleagues [132, 134].

In the child with microphthalmia, the French PNDS recommends regular monitoring of lens transparency. In the face of cataract with loss of vision, with or without posterior luxation (more frequent in the extreme forms), the lens is extracted, as a rule without an implant: intraocular lenses are of standard dimensions, with an optic usually of 6 mm, and there is no implant adapted to smaller eyes. Implantation is only technically possible with an axial length above 18–19 mm, and aphakia aggravates hyperopia [44].

7.7. Glaucoma surgery

Filtering surgery has been associated since Brockhurst's description with choroidal and retinal detachment, and the EGS recommends caution with bleb-forming procedures in short eyes and considers cyclophotocoagulation useful; if filtering surgery is contemplated after phacoemulsification, axial length should guide the risk assessment [40, 51]. In the Indian series of 144 patients, all 11 who underwent glaucoma surgery had intraoperative or postoperative complications [32]. Table 7.3 summarises the surgical series.

Table 7.3. Series of glaucoma surgery in nanophthalmos

Zhu and colleagues propose a therapeutic ladder: medical treatment and laser, then cyclophotocoagulation and, in refractory cases, pars plana vitrectomy, with maximum caution below 16 mm [74]. Schargel's study has not yet been peer-reviewed and its figures are provisional [76].

7.8. Uveal effusion

The EGS recommends treating the underlying mechanism, using topical and systemic anti-inflammatory and hypotensive agents as required and, in nanophthalmos, resorting to sclerectomy [40]. Brockhurst observed that conventional retinal detachment surgery is ineffective in uveal effusion [51]. Yamani and colleagues reported a patient treated with full-thickness sclerectomies in the four quadrants, with deepening of the anterior chamber, resolution of the choroidal detachment and improvement of acuity [1]. A Portuguese systematic review of 28 articles on sclerectomies in nanophthalmos and in idiopathic uveal effusion syndrome found the most reported technique to be sclerectomy, with or without sclerostomies or sclerotomies, followed by isolated sclerostomies or sclerotomies and, less frequently, decompression of the vortex veins; the results were positive in the resolution of effusion and detachment and in prevention, with improvement of acuity except when the retinal detachment had been prolonged; mitomycin C and intravitreal anti-VEGF were adjuncts in three studies and complications (phthisis, retinal and suprachoroidal haemorrhage, incision of a vortex vein) occurred in ten articles; the evidence is weak and there are no comparative studies against conservative treatment [115].

Table 7.4. Surgical and medical treatment of uveal effusion in nanophthalmos

Tirlis's regimen was: topical dexamethasone every 2 hours, reduced to every 4 hours for a week and four times a day in the following week, and oral acetazolamide 250 mg three times a day, both tapered over a month [134]. The acetazolamide dose is within the label range (250 mg to 1 g per 24 hours), but its use in uveal effusion is off-label [141]. The abstracts of Romano and Gujarathi do not state doses; the US label for prednisone provides for initial doses of 5 to 60 mg/day depending on the disease, without an indication for uveal effusion [99, 124, 142]. Song's abstract mentions "0.5 ml" of ranibizumab, which probably corresponds to a unit error, because the labelled dose is 0.5 mg in 0.05 ml [140, 143]. Cases of bilateral medical treatment and of resolution of exudative detachment after sclerectomy with a topical non-steroidal anti-inflammatory drug have also been published, known in this edition only from the title [144, 145]. These cases have a very low level of evidence. The EGS lists sulfonamides as a cause of angle closure through peripheral uveal effusion, an effect described for systemic drugs, and acetazolamide, also a sulfonamide, is used as a treatment for effusion in the cases cited; the sources do not resolve this tension [40, 134].

7.9. Cystic macular lesions

The cystic macular lesions of posterior microphthalmos and of MFRP-related retinopathy have been treated with topical carbonic anhydrase inhibitors, off-label. In a 52-year-old woman with MFRP-related syndrome, topical dorzolamide progressively reduced macular thickness and the cysts over 2 months, with acuity improving from 20/100 to 20/50, stable at 6 months [42]. In a series of 4 patients with posterior microphthalmos, topical 1% brinzolamide reduced central foveal thickness and the cystic area in both eyes of 3 patients and increased them in one, with stable acuity in 5 eyes and better acuity in 3 [146]. In the first Irish patient with MFRP, dorzolamide three times a day had a limited or absent response [31]. Durmaz Engin's abstract does not state the frequency of instillation; the labels and their divergence are in Tables 7.5 and 7.6. The European SmPC for brinzolamide does not recommend it in narrow-angle glaucoma because it has not been studied in that setting, which carries weight in a nanophthalmic eye [147].

7.10. Drugs: dosing, divergences and adverse effects

The drugs in Table 7.5 are used in the complications of nanophthalmos. The guidelines indicate classes of drugs without doses; the doses come from the official labels (FDA and EMA) and, when there is a published regimen in the setting of nanophthalmos or amblyopia, that regimen is the reference and the label serves for comparison [40, 41]. The Portuguese SmPCs and Brazilian labels were not consulted in this edition; the trade names given are those of the US and European labels cited.

Table 7.5. Drugs used in the complications of nanophthalmos

7.11. Regulatory status

Table 7.6. Regulatory status of the drugs used in the complications

No regulatory application, opinion, authorisation, suspension or withdrawal related to nanophthalmos was identified in the sources consulted, which does not prove that none exists.

7.12. Trials and comparative studies

Table 7.7. Comparative studies and trials relevant to management

The only randomised trial in nanophthalmos had 60 patients and missed significance on the overall primary outcome (p = 0.065), although it reduced uveal effusion; the odds ratio for sclerostomy comes from a multivariable model, and the wide confidence interval reflects the sample size [132]. The amblyopia studies included children with high hyperopia, but not specifically with nanophthalmos [41]. The surgical series are not comparable with one another, because they differ in the definition of nanophthalmos, in axial length, in technique and in follow-up, and the relative reductions in IOP or in complications should be read together with the absolute rates and the size of each series [72, 74, 131]. There are no published negative trials or suspensions, because no pharmacological therapeutic trials are registered for nanophthalmos [157].

7.13. Systemic management of MYRF-CUGS

GeneReviews recommends multidisciplinary care (cardiology, endocrinology, genetics, gastroenterology, gynaecology, ophthalmology, respiratory medicine, psychology and urology) [29]. In 46,XY individuals with undervirilisation or atypical genitalia, management follows the differences of sex development team, with hormone therapy, psychosocial support, assessment of gender identity and surgery (orchidopexy, hypospadias repair), and removal of dysgenetic gonads if there is concern about gonadoblastoma, especially when the person is raised female and the gonads have no hormonal function [29]. With low or absent serum testosterone, replacement may be started after 14 years of age with intramuscular testosterone enantate, 100 mg every 3 to 4 weeks, increasing by 50 mg every 6 months up to 200–400 mg; in adults, the dose typically stabilises between 50 and 400 mg every 2 to 4 weeks; with short stature eligible for growth hormone, testosterone is postponed or reduced [29]. Testosterone concentrations below 200 ng/dl or above 500 ng/dl may require adjustment of the dose or the frequency [29]. The effects include injection pain and wide variations in testosterone between injections, with mood swings [29]. Ovarian hypoplasia prompts referral to gynaecology or reproductive endocrinology, hypothyroidism is treated with levothyroxine and the cardiac, diaphragmatic, pulmonary, intestinal, splenic and renal malformations follow the standard treatment of each specialty [29]. The ALCAPA described in MYRF-CUGS was corrected surgically, with good recovery, in an infant with mitral regurgitation and mild ventricular dysfunction [106]. In the fetal series, HLHS was the main determinant of early death, and the decision between surgical palliation and palliative care depends on overall cardiopulmonary severity, including the CDH and the pulmonary hypoplasia [104, 109]. Hormone therapy in hormone-sensitive cancers and long-term oral androgens (methyltestosterone, fluoxymesterone) are avoided, because of hepatotoxicity [29].

7.14. Management of the bestrophinopathies with nanophthalmos

In ADVIRC and ARB, treatment is supportive, with low-vision aids; choroidal neovascularisation has been treated with intravitreal anti-VEGF (bevacizumab, ranibizumab), laser photocoagulation and photodynamic therapy with verteporfin, in reports without trials, and there are no published clinical guidelines for the bestrophinopathies [28]. The narrow angle of ARB and ADVIRC follows the principles of section 7.3 [28].

7.15. Developments of the last 12 months and research

The search of ClinicalTrials.gov found no pharmacological therapeutic or gene therapy trials for nanophthalmos or posterior microphthalmos; the active records are observational and genetic studies (NCT02077894, exome and genome sequencing of inherited eye diseases, National Eye Institute, 2000 participants; NCT01778543, pathogenesis and genetics of the MAC spectrum, 600; NCT06293560, genetic epidemiology of MAC in children, Baylor College of Medicine, 3000; NCT05954403, French national cohort of congenital eye defects, INSERM, 800; NCT06408701, optic vesicle organoids derived from induced pluripotent stem cells, CHU de Toulouse, 20) [157]. Table 7.8 classifies the publications of the window from October 2025 to October 2026 by level of evidence.

Table 7.8. Developments from October 2025 to October 2026

Gene therapy is at the preclinical stage: Velez and colleagues rescued, with a vector delivered by subretinal injection, photoreceptor death and normalised function and ocular length in adult Mfrp rd6/rd6 mice (data cited by Carricondo), and an induced pluripotent stem cell line was created from a patient with MFRP-related syndrome [18, 160]. Almoallem and colleagues point to genetic diagnosis as a prerequisite for future gene therapies in MFRP-related disease [38].

7.16. Agents to avoid, pregnancy, perioperative care and transition

The EGS lists the systemic drugs that may precipitate angle closure: nebulised bronchodilators (ipratropium, salbutamol), selective serotonin reuptake inhibitors, tricyclic antidepressants, muscle relaxants, illicit stimulants, parasympatholytics, sympathomimetics, topiramate and sulfonamides (the latter through peripheral uveal effusion) and general anaesthesia [40]. In a patient with an untreated narrow angle, these drugs require prior ophthalmological assessment; a patent iridotomy reduces the risk of diagnostic mydriasis [40]. In MYRF-CUGS, long-term oral androgens are avoided [29].

In pregnancy, the sources do not describe the course of nanophthalmos. The labels state that acetazolamide is teratogenic in animals and should only be used if the benefit justifies the risk, that dorzolamide caused vertebral malformations in rabbits at high oral doses, that brinzolamide has no adequate studies in pregnant women, that mannitol crosses the placenta and may cause fetal fluid shifts, that topical atropine undergoes systemic absorption and that prednisolone was teratogenic in mice [129, 141, 149, 151, 153, 155]. Timolol is detected in breast milk [152].

Perioperatively, biometry, IOP controlled before surgery, phacoemulsification in preference to manual small-incision surgery, prophylactic sclerostomy or sclerectomy in at-risk eyes and prevention of abrupt IOP fluctuations are the elements supported by the sources [32, 40, 132, 134]. General anaesthesia is among the factors that may precipitate angle closure [40]. In MYRF-CUGS, anaesthesia adds the cardiopulmonary risk of the malformations [29].

In the transition from paediatric to adult care, the focus shifts from amblyopia to the angle: refractive correction is maintained, and surveillance of the angle, the IOP and effusion should continue without interruption, especially in the dominant forms with early glaucoma [33, 86]. Patients with MYRF-CUGS move from the paediatric differences of sex development team to adult endocrinology and cardiology, with hormone replacement and surveillance for gonadoblastoma [29].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by gene

Table 8.1. Inheritance and recurrence risk

In the MYRF-related form, many cases are de novo, but transmission from a heterozygous parent is described, and the expression varies so much within a family that the parent may be asymptomatic or have only hyperopia or cryptorchidism [29, 96]. If the variant is not found in the parents, this is explained by a de novo variant or by germline mosaicism, or by somatic and germline mosaicism; Garnai and colleagues described a parent with somatic and germline mosaicism who was asymptomatic or had minimal manifestations [29, 64]; in that case, the mother of a boy with nanophthalmos and urogenital signs had a normal eye examination, so a normal ophthalmological examination does not exclude parental mosaicism [11]. When clinically unaffected parents have not been tested, the siblings remain at increased risk [29]. In ADVIRC, most affected individuals have an affected parent and fundus examination of the parents may not be reliable for classifying them [28].

In MYRF-CUGS published up to 2024, the variant was de novo in 29 of 36 individuals (80.5%) [104]. In the fetal series, the variant was de novo in 7 of 17 cases and inherited in 9 of 17, from three families, with unknown origin in one case; one of the transmitting mothers had an atrial septal defect, omphalocele and uterus didelphys, and the maternal grandmother a uterine anomaly [104]. Two affected Czech sisters, with the same splicing variant absent in the blood of both parents, indicate gonadal mosaicism, which can simulate recessive inheritance [109]. In Sher's newborn girl, the variant was inherited from a mother without known malformations, which reinforces the variable expressivity and the need to test the parents even when they are clinically healthy [29, 110].

8.2. Pseudodominance and consanguinity

In the Czech Roma family, the father and daughter homozygous for PRSS56 p.Met503Ile simulated dominant inheritance, because consanguinity and the carrier frequency in the community made the union of an affected individual with a carrier likely [90]. In the Saudi, Tunisian, Faroese and Portuguese families described, consanguinity or isolation explains the homozygosity [55, 89, 92]. Fuchs and colleagues predicted that the apparent dominant transmission in the Faroese families was pseudodominance, which the heterozygote frequency of 3.2% for p.Trp309Ser in local controls makes plausible [5, 6]. Counselling of a family with nanophthalmos in two generations should therefore consider recessive inheritance with pseudodominance before assuming a dominant gene.

8.3. Cascade testing and carriers

When the familial variant is known, testing of relatives at risk is possible, and detection is also carried out by ophthalmological examination [45]. The parents and siblings of an affected child should be examined with biometry and assessment of the angle, because the parents may be only mildly affected [29, 45]. Lang and colleagues recommend screening for high hyperopia in heterozygotes for MFRP and PRSS56, and Xu and colleagues observed altered, less extreme biometric parameters in monoallelic carriers [83, 87]. Other data do not support a phenotype in heterozygotes: only 1 of 15 obligate MFRP carriers was hyperopic, and Orr and colleagues observed no carrier phenotype in the families with PRSS56; examination of heterozygotes is thus an authors' recommendation, with divergent data [3, 5]. The Oxford Desk Reference recommends ophthalmological surveillance for glaucoma in first-degree relatives [46].

8.4. Prenatal and preimplantation diagnosis

Once the variant is known, prenatal diagnosis by molecular testing and preimplantation genetic diagnosis are possible [29, 45]. In MYRF-CUGS, fetuses ascertained prenatally have more severe malformations (especially CDH) than those diagnosed after birth, and the intrafamilial variability, which extends to discordance for CDH between monozygotic twins, makes it impossible to predict severity from the parent [11, 29, 104]. In isolated nanophthalmos, fetal ultrasound has no demonstrated sensitivity for the short eye [45].

8.5. Counselling of minors

Genetic testing of children at risk has direct clinical utility, because refractive correction and treatment of amblyopia depend on early diagnosis and surveillance of the angle is lifelong [18, 41]. Ophthalmological examination with cycloplegic refraction is, in any case, indicated in children from affected families, regardless of molecular testing [45]. In MYRF-CUGS, diagnosis of the child guides the cardiac, genital and pulmonary assessment [29].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no validated population estimate of the prevalence of nanophthalmos. The figure of 0.0009% to 0.017% in Western countries is cited by O'Connell and colleagues from another source, not read in this edition [31]. Orphanet classifies the microphthalmia–retinitis pigmentosa–foveoschisis–disc drusen syndrome (ORPHA:251279) with a prevalence below 1/1,000,000 and 9 reported cases, which is a number of reports and not a prevalence [19]. MYRF-CUGS has more than 60 identified individuals [29]. Mackay-Shek-Carr syndrome was described in a single family [26]. In the Faroe Islands, 3 of 94 controls were heterozygous for PRSS56 p.Trp309Ser (3.2%), an estimate of carrier frequency in a small sample and not of disease prevalence; the high prevalence of posterior microphthalmos in the archipelago is described without a figure in the sources consulted [6, 55]. The proportions of glaucoma (51.88% in the meta-analysis, 35.7% to 79.1% in the cohorts) measure the frequency among patients of ophthalmology clinics [32, 33, 98]. The frequencies of hyperopia in children (3.2% with +4.00 D or more between 6 and 72 months in studies from the USA, Singapore and Australia; 4–9% with +3.0 D or more between 5 and 17 years) are the denominator of screening and not estimates of nanophthalmos [111, 112]. In Ireland, 4 of more than 1000 patients with retinal dystrophies (about 0.4%) had an MFRP genotype [31]. The combined incidence of the MAC spectrum of 0.0119% in the United Kingdom, also cited by O'Connell, refers to another group of diseases [31].

9.2. Geography, ancestry and founder effect

Table 9.1. Data by region

The distribution of the genes differs between populations: in the European recessive cohorts, MFRP and PRSS56 carry similar weight; in the Chinese cohorts, PRSS56 predominates; in Brazil, the published series is of MFRP, with a recurrent variant [33, 36, 38]. The PRSS56 variant c.1066dup, recurrent in several populations, should be sought whatever the ancestry [82]. In populations with high consanguinity, such as the Saudi population, the genetic yield is higher [84]. The absence of data from other countries in the sources consulted does not demonstrate the absence of cases.

9.3. Special populations

In children, the aim is to prevent amblyopia, and the assessment should include the search for systemic features [29, 41]. In older people, cataract and angle-closure glaucoma coincide, and the surgical series have median ages of 71 to 72 years [71, 73]. Monocular patients require the most conservative approach possible, as in Tirlis's case [134]. In younger operated patients, malignant glaucoma and uveal effusion are more frequent [131].

9.4. Reference networks and patient organisations

The relevant European reference network is ERN-EYE, dedicated to rare eye diseases, including ocular developmental anomalies [43]. The National Eye Institute (USA) maintains genetic studies of congenital eye diseases with active recruitment [157]. Patient organisations include MACS (Micro and Anophthalmic Children's Society, United Kingdom), Retina International, for retinal dystrophies such as the MFRP-related form, and Retina Portugal [161–163]. For MYRF-CUGS, GeneReviews lists the Accord Alliance, CDH International, InterConnect, the National Eye Institute low-vision programme and the Children's Heart Foundation [29]. In France, simple microphthalmia is followed by the CARGO reference centre (Centre de référence des affections rares en génétique ophtalmologique), of the SENSGENE health network. There is no specific ALD (affection de longue durée): most patients are admitted under ALD 31 ("hors liste"), and the child with low vision, blindness or associated disability is recognised by the MDPH (Maison départementale des personnes handicapées), with periodic ophthalmological certificates. The PNDS lists as patient organisations the ANPEA (Association nationale de parents d'enfants aveugles), the APEDV (Association des parents d'enfants déficients visuels), Retina France and the Fédération des Aveugles de France [44].

10. Illustrative Clinical Case

10.1. Nanophthalmos with intermittent glaucoma in a 3-year-old child with a MYRF variant

Hagedorn and colleagues, from the University of Iowa, described a 3-year-old boy taken to the emergency department with frontal headache, ocular pain, vomiting and lethargy [93]. The neurological examination showed no focal deficits; brain computed tomography and magnetic resonance imaging revealed increased fluid in the posterior fossa (posterior fossa cyst) and the lumbar puncture had a normal opening pressure. The eye examination, limited by agitation, showed bilateral geographic peripheral chorioretinal scars, and toxoplasmosis serology was negative [93].

After the symptoms resolved, acuity with Teller cards was 2.4 cycles/cm in the right eye (equivalent to 20/260) and 6.5 cycles/cm in the left (20/94); IOP was 7 and 8 mmHg and cycloplegic refraction +7.00 +0.50 × 90 in both eyes [93]. Under anaesthesia, pachymetry was 640 and 616 µm, the white-to-white diameter 10.5 mm, gonioscopy showed an angle open to the scleral spur in the right eye and two clock hours of closure in the left, and the optic nerves had mild pallor with cup-to-disc ratios of 0.4 and 0.3 [93]. A-scan ultrasound measured axial lengths of 18.1 and 18.3 mm, sclera of about 2.0 mm, lens of 4.3 and 4.1 mm and anterior chamber of 2.2 and 2.4 mm; there were no signs of primary congenital glaucoma (buphthalmos, Haab striae, corneal oedema) [93]. Computed tomography and magnetic resonance imaging showed short eyes with a thick sclera, hyperdense on tomography and hypointense on T2 (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC7528587/figure/Fig2/), and the fundus photographs documented the posterior pole and the peripheral scars (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC7528587/figure/Fig1/) [93].

Over the following year, the patient had unilateral episodes of elevated IOP (up to 53 mmHg in the right eye and three episodes of 42 to 60 mmHg in the left), controlled for 9 months with the timolol–dorzolamide combination and with latanoprost; the diagnosis was nanophthalmos, microcornea and probable intermittent angle-closure glaucoma, and the patient was lost to follow-up [93]. Sanger sequencing of TMEM98 and MYRF and the study of MFRP in a commercial laboratory found no variants in TMEM98 or MFRP; in MYRF the heterozygous variant NM_001127392.3:c.1553C>T p.(Thr518Met) (rs562652459) was found, with a synonymous variant published as p.Pro263Pro, without a nucleotide position [93]. The variant was absent in 362 local controls, had a frequency of 0.000024 in non-Finnish Europeans in gnomAD, lay at a conserved residue of the DNA-binding domain and, in structural modelling, disrupted a hydrogen bond between Thr518 and Gln509; three of four algorithms predicted a deleterious effect (PolyPhen 0.677; CADD 21.5; Blosum62 −1), and SIFT predicted tolerance [93]. The parents were not tested and there was no family history [93].

The authors acknowledge that this is a single patient, without segregation, and that the variant may be a rare benign variant; the elevated IOP also allows a differential diagnosis with Posner-Schlossman syndrome and with juvenile open-angle glaucoma, and early-onset glaucoma may be characteristic of MYRF-related disease [93]. The variant was not found in ClinVar, and without segregation, functional study or recurrence in other patients the published evidence is not enough to consider it causal [79, 93]. The case shows three points: angle-closure glaucoma can arise at preschool age and present with headache and vomiting; the extraocular findings (posterior fossa cyst) and the peripheral chorioretinal scars are compatible with the MYRF spectrum; and prolonged medical treatment without iridotomy or study of the mechanism of closure, described in the report, does not correspond to a recommendation, because the EGS requires characterisation of the mechanism and measurement of axial length before deciding [29, 40].

10.2. MFRP-related retinopathy in two Irish adults

O'Connell and colleagues described two adults referred with diagnoses of retinitis pigmentosa and of choroideremia [31]. The first patient, aged 58, without consanguinity or family history, had nyctalopia, acuity of 0.78 and 1.0 logMAR, field constriction, dyschromatopsia, nuclear cataracts, bone spicules, arteriolar attenuation and drusen of the left disc; refraction was +15.50 and +16.75 D, axial length 16.33 and 16.40 mm, anterior chamber 2.62 and 2.69 mm and white-to-white diameter 12.1 and 12.0 mm (posterior microphthalmos phenotype); OCT showed cystic macular lesions (subfoveal thickness of 395 and 407 µm) that responded little or not at all to topical dorzolamide three times a day, and the full-field ERG was unrecordable; she was homozygous for MFRP c.1124+1G>T [31]. The second patient, aged 76, with a maternal uncle with retinitis pigmentosa, had worn spectacles for high hyperopia since the first decade, had nyctalopia and field constriction in the fourth decade and loss of acuity in the seventh; he had had an angle-closure attack in the right eye with residual glaucoma, was pseudophakic with peripheral iridectomies, had advanced chorioretinal degeneration, axial length of 16.41 and 16.45 mm and was compound heterozygous for c.1124+1G>T and c.642-2A>G [31]. The multimodal imaging figures are at https://pmc.ncbi.nlm.nih.gov/articles/PMC9808125/figure/F1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC9808125/figure/F2/ [31]. The figures of the two cases were consulted through their legends; the images were not inspected.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The visual prognosis depends on early correction of hyperopia and on the complications over the course of life [18, 50]. In the Indian series of 144 non-genotyped patients, with a mean age of 48.8 years, median corrected acuity was 0.78 logMAR (6/36), 30.0% had amblyopia, 16.7% legal blindness, 67.7% angle-closure disease and 35.7% angle-closure glaucoma [32]. In the meta-analysis, glaucoma affected 51.88% of eyes [98]. In the recessive forms due to PRSS56 with refractive correction, acuity remained stable for 2 to 16 years [89]. The MFRP-related form adds progressive retinal degeneration, with acuity from 0.05 to no light perception in the Brazilian series and an unrecordable ERG in the sixth decade in one of the Irish cases [31, 36]. The success of trabeculectomy with sclerotomy fell from 85% in the first year to 47% in the fifth [100]. The Japanese patient with PRSS56 and uveal effusion, stable for 15 years after the first operation, ended with an unrecordable ERG and constricted fields after a recurrence following cataract surgery [91]. In MYRF-CUGS, the prognosis is determined by the cardiopulmonary disease, which is associated with severe developmental delay; without cardiopulmonary malformation, development is usually normal [29]. In ADVIRC, acuity is maintained until late stages [28].

11.2. Surveillance

The glaucoma guidelines do not define intervals specific to nanophthalmos, and the French PNDS sets the rhythm of ophthalmology and orthoptics appointments by age; the intervals in Table 11.1 come from the sources indicated, and those without a published interval are individualised by the ophthalmologist.

Table 11.1. Surveillance

The EGS recommends measuring axial length in all patients with angle closure and repeating biometry after an acute attack [40]. Rajendrababu's meta-analysis recommends early biometric screening and close surveillance, and the Chinese cohorts recommend starting earlier in the dominant forms [33, 86, 98]. Patients should be informed of the symptoms of an acute attack and of the list of drugs that precipitate angle closure (section 7.16) [40].

12. Summary and Final Considerations

Nanophthalmos and posterior microphthalmos form a class of short, organised eyes, with high hyperopia, a thick sclera of abnormal collagen and a lens of normal volume in a small anterior segment. Four genes explain most of the solved cases: PRSS56 and MFRP, recessive, with more extreme phenotypes, foveal hypoplasia, papillomacular folds and, in the case of MFRP, progressive pigmentary retinopathy; and MYRF and TMEM98, dominant, linked in a molecular axis in which TMEM98 restrains the autocleavage of MYRF and with earlier glaucoma. The hypomorphic C-terminal variants of MYRF cause isolated nanophthalmos, and more complete loss of function the cardiac-urogenital syndrome, which requires genital, cardiac, diaphragmatic and pulmonary assessment; in the fetal series, HLHS and CDH determined early death, and the ALCAPA described in four patients justifies identifying the coronary origins on echocardiography. BEST1, CRB1, the NNO3 locus and Mackay-Shek-Carr syndrome complete the class. The yield of genetic testing ranges from about 19% to 90% depending on selection, and a negative result does not exclude a genetic cause, especially without copy-number analysis of MFRP and PRSS56.

Treatment does not correct the defect. In children, full correction of hyperopia and treatment of amblyopia according to the paediatric guidelines define the future vision. The French PNDS adds intensive occlusion in the unilateral form, lens extraction without an implant below 18–19 mm, iridotomy deferred to the end of adolescence and appointments every 3 to 6 months up to 18 years of age. In adults, surveillance of the angle, biometry and characterisation of the mechanism of closure guide the decision between laser, lens extraction and surgery, and the EGS expressly excludes nanophthalmos from the general recommendations on primary angle closure, contraindicates miotics in aqueous misdirection and advises caution with filtering surgery. Cataract surgery has complications in 15% to 28% of eyes in the series, with increasing risk below 20 mm; phacoemulsification is preferable to manual surgery and prophylactic sclerostomy reduced uveal effusion in the only randomised trial. Uveal effusion is treated with sclerectomy and, in selected cases, with corticosteroids and carbonic anhydrase inhibitors, with low-level evidence. There are no therapeutic trials or gene therapies in human study. Counselling distinguishes the recessive recurrence of 25%, the dominant recurrence of 50% with variable expressivity and mosaicism in MYRF, and pseudodominance in consanguineous families, and ophthalmological examination of relatives is indicated in all forms.

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