Congenital Eye Anomalies of Genetic Cause – Diagnostic Approach

Approach by ocular finding to congenital malformations and dysfunctions of the eye and adnexa — microphthalmia, anophthalmia and coloboma, anterior segment dysgenesis, corneal opacification, cataract and ectopia lentis, developmental glaucoma, retinal dysplasia and leukocoria, optic nerve anomalies, infantile nystagmus and eyelid anomalies —, with the syndromic, metabolic and environmental differential diagnosis, the genetic testing strategy and the rare entities covered in detail (NDP-related retinopathies, ectopia lentis due to ADAMTSL4, congenital endothelial dystrophy due to SLC4A11, X-linked megalocornea, Peters plus, Fraser, MIDAS, cat eye and Hallermann-Streiff syndromes).

Literature and regulatory information update: 29 October 2026.

0. Initial Reference Table

0.1. Overview of the article

0.2. Rare entities covered in detail in this article

OMIM, Orphanet and ICD-10 codes follow the Orphanet nomenclature and the OMIM entries consulted [27, 28].

0.3. Entities to consider by presenting ocular finding

1. Introduction

1.1. Scope and logic of an approach article

After the brain, the eye is the organ most sensitive to developmental disturbances, and its morphogenesis depends on the orderly interaction of tissues of different embryonic origins, under the control of many developmental genes and with great vulnerability to teratogens [2]. The result is a set of congenital anomalies that, in clinical practice, reach the genetics clinic through a finding rather than a diagnosis: a small eye, a keyhole pupil, a cloudy cornea, leukocoria, nystagmus in an infant, ptosis or an abnormal palpebral fissure. The same finding may result from dozens of genes, a chromosomal anomaly, a congenital infection, drug exposure or a treatable metabolic disease; conversely, a single gene, such as PAX6, can produce aniridia, Peters anomaly, coloboma, foveal hypoplasia or optic nerve hypoplasia [1, 6]. Structural eye diseases account for about 10% of visual impairment in children, and the microphthalmia/anophthalmia/coloboma spectrum contributes up to 15% of childhood blindness and severe visual impairment worldwide [3, 4].

The aim of the article is to guide reasoning from the ocular finding: deciding whether the anomaly is isolated or part of a syndrome, identifying the causes that require immediate action (retinoblastoma, congenital glaucoma, pituitary insufficiency, Wilms tumour, treatable vascular or metabolic disease), choosing the genetic test most likely to yield a diagnosis and counselling the family even when the test is negative. The more frequent entities are only mentioned in the differential diagnosis (section 0.3); the rare entities are covered in greater detail: NDP-related retinopathies (Norrie disease and allelic forms), familial exudative vitreoretinopathy, persistent fetal vasculature, ectopia lentis due to ADAMTSL4, congenital hereditary endothelial dystrophy and Harboyan syndrome, X-linked megalocornea, and Peters plus, Fraser, MIDAS, cat eye and Hallermann-Streiff syndromes.

1.2. Historical overview

The description of developmental eye anomalies long preceded their molecular basis. Hallermann-Streiff syndrome was outlined by Audry in 1893 and delineated by Hallermann in 1948 and by Streiff in 1950 [58]. In 1962 Fraser described two sibships with cryptophthalmos and associated anomalies, and more than 250 patients have now been published [51]. In 1956 De Morsier recognised the association between absence of the septum pellucidum and optic nerve hypoplasia, which he called septo-optic dysplasia, and in 1970 Hoyt and colleagues added hypopituitarism [59]. In 1988 Al-Gazali and colleagues described the first two women with microphthalmia and linear skin defects (MIDAS syndrome) [52]. Anterior segment terminology evolved from separate entities (Axenfeld anomaly, Rieger anomaly, Rieger syndrome) to the Axenfeld-Rieger spectrum, after it was recognised that named phenotypes do not necessarily correspond to distinct genetic entities [1].

The molecular era brought the successive identification of the main genes, cited here according to the review sources that mention them: NDP in Norrie disease (Meindl and colleagues, 1992), HESX1 in septo-optic dysplasia (Dattani and colleagues, 1998), FOXC1 in the congenital glaucoma and Axenfeld-Rieger spectrum (Nishimura and colleagues, 1998), de novo truncating SOX2 variants in anophthalmia (Fantes and colleagues, 2003), CHD7 in CHARGE syndrome (Vissers and colleagues, 2004), B3GALTL (now B3GLCT) in Peters plus syndrome (Lesnik Oberstein and colleagues, 2006), STRA6 and RARB of the retinoic acid pathway in PDAC syndrome (Casey and colleagues, 2011; Srour and colleagues, 2013), CHRDL1 in X-linked megalocornea (Webb and colleagues, 2012) and ITPR1 in Gillespie syndrome (McEntagart and colleagues, 2016) [1, 2, 14, 59–61]. From 2012 onwards, panel sequencing became routine in retinal dystrophies and later in structural anomalies; the United Kingdom introduced clinical genome sequencing with the 100,000 Genomes Project and France with the France Genomic Medicine Plan 2025 [3, 4, 62].

1.3. Nomenclature and reclassifications

Several gene designations used in clinical reference texts have been replaced by the current nomenclature of the HUGO Gene Nomenclature Committee (HGNC): B3GALTL became B3GLCT, CHX10 became VSX2, FKHL7 became FOXC1, BIGH3 became TGFBI, OA1 became GPR143, PABP2 became PABPN1, COH1 became VPS13B, FRAS2 became FREM2, and the neuronal ceroid lipofuscinosis genes are designated CLN1 to CLN3 (the reference text prints “CLCN”) [1, 5, 6, 12, 42, 62, 63]. Persistent hyperplastic primary vitreous is now called persistent fetal vasculature (PFV) [20]. In congenital hereditary endothelial dystrophy, the so-called dominant form (“CHED1”) was removed from the second edition of the corneal dystrophy classification of the International Committee for Classification of Corneal Dystrophies (IC3D), in 2015, because review of the five published families suggested that many, or all, had posterior polymorphous corneal dystrophy (PPCD1, OMIM 122000); the recessive form due to SLC4A11 (formerly CHED2, OMIM 217700) was then renamed simply CHED [39, 41]. PPCD1 results from heterozygous variants in the OVOL2 promoter (20p11.23) and is diagnosed mainly in the second or third decade [64]. The GeneReviews chapter on the MAC spectrum was retired on 7 November 2019 as out of date and is used only as a historical reference for definitions [19].

1.4. Definitions of the entities within the scope

Microphthalmia is an eyeball with a total axial length (TAL) at or below 2 standard deviations (SD) below the mean for age; in adults, the lower 2.5% limit of TAL is about 21.0 mm, and the mean TAL is 17 mm in the newborn and 23.8 mm in the adult [19]. The British reference text uses a practical criterion of axial length below 18.5 mm at 2 years of age, when the normal mean is 22.5 mm [2]. Severe microphthalmia corresponds to a corneal diameter below 4 mm and a TAL below 10 mm at birth or below 12 mm after the first year; the globe may not be apparent on inspection, although computed tomography (CT) or magnetic resonance imaging (MRI) show ocular remnants, optic nerve and extraocular muscles (“clinical anophthalmia”) [19]. Anophthalmia is the complete absence of the globe with adnexa present (eyelids, conjunctiva and lacrimal apparatus) [19]. Coloboma results from defective closure of the optic fissure in the sixth week post-conception and is located in the inferonasal sector, from the disc, retina and choroid to the ciliary body, zonules and iris, where it produces the keyhole pupil at the 6 o'clock position [19, 60]. Nanophthalmos is a small eye without structural anomaly, with proportionally thick sclera and a normal-sized lens, which narrows the anterior chamber and predisposes to glaucoma [2].

Cryptophthalmos is complete fusion of the eyelid margin without eyelashes, with continuous skin from the forehead to the face over a globe with a malformed cornea, usually bilateral and part of Fraser syndrome [19]. Congenital cystic eye is a cyst of neuroglial tissue without normal ocular structures, which at birth may mimic anophthalmia and is distinguished from the cyst associated with colobomatous microphthalmia [19, 65]. In the anterior segment, megalocornea is defined by a corneal diameter of 13 mm or more at birth with a clear cornea, microcornea by a diameter below 9–10 mm, and sclerocornea by non-progressive congenital corneal opacification with vascularisation, resembling the sclera [1]. Peters anomaly is a congenital central corneal opacity due to absence of the central endothelium and Descemet membrane, with iridocorneal or lenticulocorneal adhesions [1]. Retinal dysplasia is a bilateral congenital structural anomaly of the retina, with retinal folds and detachment present at birth, frequently associated with central nervous system (CNS) malformations [61]. Optic nerve hypoplasia (ONH) is a non-progressive congenital anomaly, unilateral or bilateral, with a small pale disc, sometimes surrounded by a ring of peripapillary pigmentation [66]. Ectopia lentis is displacement of the lens due to loss of zonular fibres without trauma [13]. Ptosis is impaired eyelid elevation due to poor function of the levator palpebrae superioris muscle, and blepharophimosis is reduction of the horizontal length of the palpebral fissure [5]. Nystagmus is an involuntary, continuous oscillation of eye movement that, in infants, often signals bilateral visual impairment [12].

2. Molecular Genetics and Pathophysiology

2.1. Ocular embryology and tissue origin

The lens derives from the surface ectoderm, the retina and pigment epithelium from the neuroectoderm, the extraocular muscles from the mesoderm, and the cornea, iris and connective tissue of the extraocular muscles from neural crest cells [2]. This multiple origin explains two clinical principles. The first is the interdependence of the anterior segment: cornea, iris and trabecular meshwork develop together, and alteration of one structure can disturb the others even when the gene is expressed in a single tissue, which makes the combination of corneal anomaly, iris hypoplasia and glaucoma common [1]. The second is the link between the eye and the cerebral midline or pituitary, shared by forebrain transcription factors (HESX1, SOX2, SOX3, OTX2), which justifies endocrine assessment in the presence of ONH or syndromic microphthalmia [41, 59]. The optic fissure, which forms on the inferior and medial aspect of the optic cup, closes in the sixth week; defective closure gives rise to typical colobomas and, in a Scottish study, all familial recurrences of MAC occurred in the closure-defect group [2, 60]. Growth of the eye continues after birth, mainly in the first three years and, within these, in the first: the posterior segment accounts for 60% of the prenatal increase and more than 90% of the postnatal increase in TAL, and the microphthalmic eye may grow to a variable extent [19].

2.2. Genetic heterogeneity and pleiotropy

About 150 genes are associated with structural eye disease, and more than 90 with the MAC spectrum, with all modes of inheritance [3, 4]. The R36 “Structural eye disease” panel of Genomics England PanelApp (version 5.10, of 23 October 2026) has 148 green, 55 amber and 298 red genes, and two green CNV regions: the 22q11.1 gain of cat eye syndrome and the 15q24 loss [6]. In the 15q24 region, SIN3A causes Witteveen-Kolk syndrome (AD; microcephaly, short stature, mild intellectual disability and facial dysmorphism with hypertelorism, downslanting palpebral fissures and strabismus), and some patients with a similar picture have deletions or duplications of contiguous genes that include SIN3A [67]. The subpanels overlap: the anophthalmia/microphthalmia subpanel has 37 green genes, ocular coloboma 29, developmental glaucoma 18 and corneal anomalies 32 [6]. Many genes cause several ocular and extraocular phenotypes, which hampers genotype-phenotype correlation and justifies cross-phenotype panels [3]. In non-syndromic anophthalmia and microphthalmia, about 30 genes are repeatedly implicated in families and many others in isolated cases, each responsible for a small percentage, so they should be tested together (panel, exome or genome); more than half of patients remain undiagnosed, especially in unilateral and mild forms [68]. PAX6 is the example of pleiotropy: in PanelApp it is associated with aniridia, Peters anomaly, ocular and optic nerve coloboma, foveal hypoplasia, ONH, keratitis and morning glory anomaly [6]. There is allelic heterogeneity (truncating PAX6 variants cause aniridia, whereas some missense variants in the paired box domain cause Peters anomaly) and genetic heterogeneity (Peters anomaly can result from PAX6, MAF, PITX2, CYP1B1 and PITX3) [1, 69].

2.3. Biological pathways involved

Congenital eye anomalies cluster into a few functional pathways, which helps to anticipate extraocular manifestations.

2.4. Variant types and disease mechanisms

Heterozygous loss of function dominates in dominant transcription factor genes; in SOX2, variants are often de novo nonsense, and de novo truncating variants were found in 4 of 35 patients with anophthalmia (11%) in an early study, with all carriers bilaterally affected [2]. In severe bilateral microphthalmia or anophthalmia, an identifiable cause is found in up to 80%, mainly through loss of function of SOX2 or OTX2 and biallelic STRA6 variants, whereas in asymmetric cases, especially isolated unilateral ones, the yield is below 10% [4]. Structural variants carry relevant weight: in the French AURAGEN cohort, 5 of the 18 genome diagnoses were structural variants (3 CNVs and 2 balanced inversions); the inversion inv(11)(p11.2p13), with a breakpoint about 10 kb downstream (3') of PAX6, caused bilateral aniridia, and the de novo inversion inv(6)(p25.1p25.3), about 100 kb upstream (5') of FOXC1, caused bilateral sclerocornea and microphthalmia, because both separate the gene from its cis-regulatory elements [3]. In the same cohort, a 649 bp intragenic deletion in CRYBB1 removed only 11 bases of exon 6 [3]. In aniridia, about 15% of PAX6 variants are intronic, most at the intron-exon junction [4]. In Norrie disease, sequencing detects about 80% of variants and deletion/duplication analysis about 20%, and a variant in the untranslated region (UTR) has been described [20]. In the MIDAS spectrum, most patients have a terminal Xp deletion including HCCS, with interstitial deletions and intragenic variants being less frequent [52].

Mosaicism operates at three levels. Somatic mosaicism may explain unilateral forms, as in unilateral microphthalmia of uncertain aetiology [2]; the GJA8 variant NM_005267.5:c.137G>A p.(Gly46Glu), de novo and present in 20% of cells, caused microphthalmia with congenital cataract, anterior persistent fetal vasculature and pendular nystagmus [3]. Germline mosaicism explains recurrences with healthy parents: two siblings with bilateral anophthalmia shared the SOX2 variant c.58_80del p.(Gly20fs) (notation from the abstract, without transcript), absent from the blood of both parents [8]. Maternal mosaicism has been described in a carrier of an NDP variant with Coats disease whose sons had Norrie disease [20].

2.5. Inheritance, penetrance and expressivity

All forms of Mendelian inheritance have been described in developmental eye anomalies [2]. Among the 106 simplex cases with a molecular diagnosis in a Manchester cohort of children up to 5 years of age, inheritance was AR in 73 (69%), AD in 24 (23%) and X-linked in 9 (8%), and six had a de novo variant; without a molecular diagnosis, the mode of inheritance of a simplex case remains undetermined [7]. Incomplete penetrance and variable expressivity are the rule in dominant developmental genes: phenotypically normal parents carrying SOX2 or OTX2 loss of function have been described, and in OTX2 the spectrum ranges from bilateral anophthalmia to isolated early retinal dystrophy with normal globes [41, 65]. Germline variants may have asymmetric effects between the two eyes, and hereditary microphthalmia is often unilateral [2]. In MYOC glaucoma, the phenotype varies within the same family from normal through ocular hypertension to severe primary open-angle glaucoma [14]. In X-linked diseases, carriers may have subtle signs of diagnostic value: punctate opacities in Lowe syndrome, posterior sutural opacities in Nance-Horan syndrome, mosaic retinal pigmentation and patchy iris transillumination in X-linked ocular albinism [12, 63]. Occasionally severity in a carrier exceeds the usual: a woman heterozygous for a familial partial NHS deletion had bilateral complex microphthalmia, cataract and glaucoma [3].

2.6. Founder variants and nomenclature standardisation

Ectopia lentis due to ADAMTSL4 is the clearest example of a founder effect among the entities in this article. Variants were standardised in VariantValidator (GRCh38) on the MANE Select transcript NM_019032.6 (NP_061905.2) [74]. The European variant NM_019032.6:c.767_786del p.(Gln256ProfsTer38) (NC_000001.11:g.150553758_150553777del) was found in 3 of 190 heterozygous donors in western Norway, corresponding to a homozygote frequency of about 1/16,000 with a wide confidence interval, and in 2 of 360 individuals in Germany [13, 74]. In New Zealand Māori, the variant NM_019032.6:c.2237G>A p.(Arg746His) has a carrier frequency of 1/132 [13, 74]. In Bukharan Jews (Kazakhstan and Tajikistan), the variant NM_019032.6:c.2594G>A p.(Arg865His), originally published as c.2663G>A p.Arg888His on the long isoform NM_001288608.2, has a carrier frequency of 1/48, predicting about 1/9000 homozygotes [13, 74]. The historical notation cannot be applied to the MANE transcript, where c.2663G>A would correspond to a different change, p.(Gly888Glu) [74]. For NDP, the historical nomenclature of the disease includes Anderson-Warburg syndrome, atrophia bulborum hereditaria, Episkopi blindness, Norrie-Warburg syndrome and pseudoglioma congenita [20].

2.7. Genotype-phenotype correlations and allelic diseases

3. Clinical Spectrum and Manifestations by System

3.1. Distribution of phenotypes in current cohorts

Referral cohorts give a picture of the clinical composition. In the French AURAGEN cohort (100 probands referred for genome sequencing, 2026), there were 54 patients with microphthalmia or anophthalmia (half with ASD), 20 with isolated ASD, 16 with coloboma, 6 with cataract and 4 with foveal hypoplasia; 55 had systemic signs (neurodevelopmental disorder in 19, abnormal brain MRI in 7, genitourinary anomalies in 6) and 18 had an affected relative [3]. In the consecutive clinic at Moorfields Eye Hospital (London, 2017–2018; 72 patients from 62 families, mean age 4.9 years), MAC accounted for 24.2% of families, ASD 17.7%, congenital cataract 16.1%, infantile nystagmus 21.0%, albinism 14.5% and complex strabismus 6.5% [4]. In the Paris population registry (2010–2020), 44.3% of congenital eye anomalies were bilateral, 20.9% had a genetic anomaly and 53.0% had at least one extraocular anomaly [9]. In the United Kingdom, 60% of children with MAC have systemic associations [4].

3.2. Microphthalmia/anophthalmia/coloboma spectrum

The MAC spectrum can combine in any way between the two eyes (coloboma in one eye and microphthalmia or anophthalmia in the other), and even in unilateral microphthalmia the “normal” fellow eye often has mild changes [2, 19]. In the prospective British SEA-UK study (135 children newly diagnosed between 2006 and 2008), typical coloboma was the most common phenotype, anophthalmia was rare (7 cases) and 55.5% were bilateral [11]. Coloboma may be limited to the iris or involve the ciliary body, retina and optic nerve; retinal involvement produces a visual field defect and optic nerve involvement produces reduced acuity [60]. Sclerocornea, cataract and retinal dysplasia are frequently associated [19]. The main monogenic forms (SOX2, OTX2, RAX, VSX2, STRA6, ALDH1A3, MAB21L2, PRSS56, MFRP) have their own management; the rare syndromes presenting with MAC are described here.

Fraser syndrome, AR, has cryptophthalmos in 85–93% of patients, usually bilateral, with frontal hair extending to the eyebrow, hypoplastic notched nares, ear anomalies, short dental roots, partial cutaneous syndactyly, incompletely developed genitalia, renal agenesis or hypoplasia and laryngeal stenosis or atresia [51]. Most cases are diagnosed prenatally, with bilateral renal agenesis in 50% and unilateral in 17%; congenital high airway obstruction (CHAOS) with oligohydramnios suggests the diagnosis; 8–25% are stillborn and postnatal mortality is high owing to renal and laryngeal causes; in survivors cognition is frequently normal, hearing usually normal and useful vision unlikely, and no affected person has reproduced [51]. An earlier clinical series recorded cutaneous syndactyly in 50–60%, malformed ears with conductive hearing loss in 40–60%, renal agenesis in 40%, laryngeal stenosis in 25% and abnormal genitalia in 20%, with a birth incidence of about 1/250,000 [5]. The diagnostic criteria of Thomas and colleagues (1986) were revised by van Haelst and colleagues (2007), who added airway and urinary anomalies to the major criteria and removed intellectual disability and clefts: major criteria are syndactyly, the cryptophthalmos spectrum, urinary tract anomalies, ambiguous genitalia, laryngeal and tracheal anomalies and a positive family history; minor criteria are anorectal anomalies, dysplastic ears, skull ossification defects, umbilical anomalies and nasal anomalies; the diagnosis is accepted with 3 major criteria, 2 major and 2 minor, or 1 major and 3 minor [50]. Because cryptophthalmos is not obligatory, the syndrome should be considered when acrofacial and urogenital malformations are associated even without an eyelid anomaly, and fetal ultrasound allowed diagnosis at 18 weeks on the basis of obstructive uropathy, microphthalmia, syndactyly and oligohydramnios [50]. OMIM distinguishes three genetic forms, Fraser 1 (FRAS1), Fraser 2 (FREM2) and Fraser 3 (GRIP1), and an isolated cryptophthalmos, unilateral or bilateral, also due to biallelic FREM2 variants; cryptophthalmos may be complete (continuous skin from forehead to face, the most common form), incomplete (medial eyelid fusion with preserved lateral structures) or of the symblepharon type (fusion of the upper eyelid to the globe) [48–50, 94].

MIDAS syndrome occurs almost exclusively in females, because it is X-linked and lethal in males; it combines microphthalmia and sclerocornea with areas of dermal aplasia without fat herniation on the face, scalp and neck, which heal leaving hyperpigmented areas; intellectual disability occurs in 24%, and there is structural heart disease, conduction defects, hypertrophic and oncocytic cardiomyopathy, with two deaths in the first year presumably due to arrhythmia [52]. The three known genes (HCCS, COX7B, NDUFB1) are essential to the mitochondrial respiratory chain, and COX7B causes the form without microphthalmia; XX males with Y material through an X/Y translocation may also be affected [52].

Cat eye syndrome has inferior coloboma of the iris, choroid or retina, anal atresia with rectovestibular fistula, preauricular pits or tags, heart disease in more than one third (total anomalous pulmonary venous drainage, persistent left superior vena cava, ventricular and atrial septal defects) and renal anomalies; only 9% of the more than 100 cases described have all the major features, intellectual disability is usually mild (severe in 7%) and growth is normal in most [55]. In one series, only 41% had the triad of iris coloboma, anal anomaly and preauricular anomaly, and 32% had mild to moderate intellectual disability, more frequent in males [60]. The cause is a supernumerary inv dup(22)(pter→q11) chromosome with tetrasomy of the segment, or an interstitial 22q11 duplication with trisomy; it may be an unbalanced product of the reciprocal translocation t(11;22)(q23;q11) [55, 60].

Hallermann-Streiff syndrome combines bilateral microphthalmia (80%), cataracts (94%, which may resorb spontaneously), corneal stromal opacities, nystagmus and strabismus with brachycephaly with a thin calvaria, micrognathia, a thin pointed nose, neonatal teeth, hypotrichosis and cutaneous atrophy of the nose [58]. One third are born preterm or with low birth weight, mean final height is 152 cm in women and 155–157 cm in men, intellectual disability occurs in 15%, and the narrow upper airway causes severe pulmonary infections, obstructive sleep apnoea and difficult intubation; the ocular deficit is the main handicap and usually culminates in blindness despite surgery; all cases described are sporadic [58]. OMIM keeps the entry without an established gene or mode of inheritance and records discordant reports: two siblings of consanguineous parents, concordant and discordant monozygotic twins and a family with five affected members in three generations, with father-to-son transmission, alongside Cohen's review (1991), which considered all cases sporadic; familial recurrence is therefore rare but not zero [57].

Other rare syndromes with MAC: PDAC or Matthew-Wood syndrome (pulmonary hypoplasia, diaphragmatic eventration or hernia, anophthalmia/microphthalmia and heart disease, due to biallelic STRA6 or biallelic or de novo heterozygous RARB; early lethality in some patients and severe delay in survivors); ophthalmo-acromelic syndrome or Waardenburg anophthalmia (anophthalmia with limb defects from syndactyly to ectrodactyly, biallelic SMOC1); anophthalmia-oesophageal-genital syndrome (oesophageal atresia and genital anomalies with heterozygous SOX2); Goltz focal dermal hypoplasia (XLD, PORCN, asymmetric chorioretinal or iris colobomas); branchio-oculo-facial syndrome (AD, coloboma, haemangiomatous cervical branchial clefts); and Fryns “anophthalmia plus” (facial cleft, nasal deformity, neural tube defects) [2, 60]. The 14q22 deletion with SIX6 hemizygosity is associated with panhypopituitarism and early renal failure [2].

OMIM numbers the monogenic forms as isolated microphthalmia (MCOP), microphthalmia/coloboma (MCOPCB) and syndromic microphthalmia (MCOPS), and notes that true or primary anophthalmia, with arrest of the primary optic vesicle, is rarely compatible with life, is accompanied by major brain defects and can only be confirmed histologically; in most published cases, “anophthalmia” in fact designates extreme microphthalmia or clinical anophthalmia [95, 96]. The table shows the entries corresponding to the forms mentioned in the article, with the features that guide testing.

3.3. Anterior segment and cornea

In ASD (Peters anomaly, Axenfeld-Rieger spectrum, aniridia, sclerocornea), the risk of glaucoma is about 50% [14]. Peters anomaly is bilateral in 80%, often asymmetric, with frequent lens anomalies and microphthalmia and associated glaucoma [1]. Aniridia has a frequency of 1/60,000–100,000, is familial (AD) in 65% and is associated with foveal hypoplasia in 100%, cataract, corneal opacity, ONH and glaucoma; foveal hypoplasia is a more frequent and reliable sign than absence of the iris [1, 24]. Iris hypoplasia ranges from almost total absence of the iris to a large irregular pupil mimicking coloboma or small slit-like defects visible only on transillumination [77]. WAGR syndrome is a contiguous gene syndrome due to a microscopic or submicroscopic 11p13 deletion including WT1 and PAX6; obesity is associated with BDNF haploinsufficiency when the deletion includes it [105]. Congenital mydriasis, with fixed dilated pupils, is the constant ocular sign of smooth muscle dysfunction syndrome due to heterozygous variants at codon 179 (arginine) of ACTA2 (10q23.31), which combines patent ductus arteriosus, pulmonary hypertension, aneurysms, moyamoya-type cerebrovascular disease, intestinal hypoperistalsis and hypotonic bladder [106].

Peters plus syndrome (Krause-Kivlin), AR due to B3GLCT, has an anterior segment anomaly in almost all patients, typically bilateral Peters with central opacity and posterior corneal excavation (von Hippel posterior ulcer) visible on anterior segment optical coherence tomography (OCT) or ultrasound biomicroscopy (UBM); associated features are microphthalmia, cataract, glaucoma, rhizomelic short stature, broad hands and feet with brachydactyly, mild to moderate intellectual disability, prominent forehead, short palpebral fissures, hypertelorism, long philtrum, cleft lip or palate and heart disease [41]. According to the OMIM synopsis, growth retardation, short stature and brachydactyly appear to be present in all patients and developmental delay is frequent, whereas pinna anomalies, clefts and cardiac and genitourinary malformations are less common [46]. SHORT syndrome (AD, PIK3R1, 5q13.1) combines short stature, joint hyperextensibility or inguinal hernia, deep-set eyes, Rieger anomaly and teething delay, with a triangular face, near-constant partial lipodystrophy, insulin resistance, nephrocalcinosis and hearing loss, and with normal development and cognition [1, 107]; Gillespie syndrome combines partial aniridia, cerebellar ataxia and intellectual disability, due to a restricted repertoire of dominant ITPR1 variants [1].

X-linked megalocornea, due to CHRDL1, presents at birth with bilaterally enlarged corneas (>13 mm) without raised intraocular pressure (IOP), a deep anterior chamber, astigmatism, iris stromal atrophy, miosis and iridodonesis, sometimes with lens subluxation; mosaic corneal degeneration, arcus juvenilis and presenile cataract appear later; central corneal thickness is reduced and most patients retain normal ocular function [41]. The main clinical risk is confusion with congenital glaucoma, in which the cornea is cloudy [1, 41]. The male predominance of megalocornea reflects X-linked inheritance, the most common form; there is an AR form (OMIM 249300), and megalocornea may be part of Marfan syndrome; complications include cataract and glaucoma after lens dislocation or subluxation [44]. Megalocornea with developmental delay, cerebellar anomalies and short stature defines Neuhauser syndrome, AR [1]. In a review of 35 patients, primary megalocornea and psychomotor delay were present in all, and more than half had hypotonia, growth retardation, an abnormal electroencephalogram or seizures, micro- or macrocephaly, brain malformations (atrophy, hypoplasia of the corpus callosum), craniofacial dysmorphism, heart disease and refractive errors; the authors proposed the diagnosis in the presence of intellectual disability with megalocornea without raised IOP, and AR inheritance rests on the original family [108].

Congenital corneal opacification has three groups of causes: structural malformations (Peters, sclerocornea, MAC, congenital aphakia due to FOXE3); congenital corneal dystrophies; and metabolic diseases, many progressive [1, 42]. CHED, AR due to SLC4A11, causes bilateral corneal oedema and opacification at birth or in the neonatal period, with thickened corneas, blurred vision and nystagmus; untreated it leads to deprivation amblyopia and is an important cause of paediatric corneal transplantation, especially in consanguineous populations [41]. In the recessive form, opacification is present at birth or in the neonatal period, nystagmus is frequent and there is neither photophobia nor tearing, which helps to distinguish it from congenital glaucoma; vision is often better than the degree of opacification would predict, and in a series of 23 patients penetrating keratoplasty had a relatively good surgical prognosis, with visual gain even when performed late [39]. The disease is characterised by corneal thickening and opacification, altered endothelial morphology and an abnormal collagenous layer in Descemet membrane [39]. Harboyan syndrome, allelic, combines the same corneal disease with progressive postlingual sensorineural hearing loss, usually recognised between 10 and 25 years of age, although audiometry detects significant loss at 4 years; by 2008, 62 variants had been described in 98 families (92 with CHED and 6 with Harboyan), more than half consanguineous [41]. Congenital stromal corneal dystrophy due to DCN (12q22) is another rare congenital cause [42]. Sclerocornea may be peripheral, with regular superficial scleral vascular arcades, or total, with the whole cornea opaque and vascularised; the AD form (OMIM 181700, no gene identified) is mild and peripheral, associated with cornea plana, whereas the AR form is severe and associated with cornea plana 2 [109]. Cornea plana 2 (AR, KERA, 12q21.33) reduces corneal curvature, with hypermetropia, a hazy limbus and early arcus lipoides, and is often accompanied by other ocular anomalies [110]. In childhood, corneal opacification suggests mucopolysaccharidoses (I, II, IV, VI and VII), mucolipidoses (which may be associated with a cherry-red spot), cystinosis, Fabry disease, Winchester syndrome and skeletal dysplasias [42]. Adult corneal dystrophies, almost all AD, rarely reach the genetics clinic and may recur after transplantation [42].

3.4. Lens: cataract and ectopia

Congenital cataract has a birth incidence of 1–15/10,000; 22–27% are hereditary, a higher proportion in bilateral cases [63]. The isolated familial form is mainly AD, due to variants in crystallins, connexins, EPHA2, PITX3, MAF, HSF4 and MIP, with morphology sometimes differing within the same family [63]. In an otherwise healthy child with normal development and stature, the probability of a syndromic cause is much lower than in the newborn [63]. Cataract is part of diseases with therapeutic or vital consequences: classic galactosaemia and galactokinase deficiency, Lowe syndrome, cerebrotendinous xanthomatosis (CTX), peroxisomal diseases, Cockayne syndrome, COFS syndrome (cerebro-oculo-facio-skeletal, AR, with rapid neurodegeneration), Wiedemann-Rautenstrauch neonatal progeria and Nance-Horan syndrome (XL semidominant, NHS; severe cataract from birth in boys, screwdriver-shaped incisors, mild to moderate intellectual disability in about 80% of boys; carriers with sutural cataract and about 5% without ocular signs) [63]. In the OMIM classification, Lowe syndrome is XLR (OCRL, Xq26.1), with the triad of congenital cataract, severe intellectual disability and renal tubular dysfunction with slowly progressive renal failure, and Nance-Horan syndrome is XLD (NHS, Xp22.2-p22.13), with obligate carriers whose lens ranges from total opacity to transparency, almost always with bilateral opacities, and sometimes with microcornea [91, 92]. Trisomy 21 is associated with cataract in 60% of affected children [63]. The hidden syndromes detected by genetic testing include COL4A1 disease, which accounted for 4 of the 9 unsuspected syndromes in a series of bilateral cataracts, and Sengers syndrome (section 10) [7, 72]. Brain small vessel disease 1 with or without ocular anomalies (BSVD1; AD, COL4A1, 13q34) results from fragility of the vascular basement membranes, with possible haemorrhage from intrauterine life or with birth trauma and a lifelong risk, porencephaly, seizures, hemiplegia and retinal and renal involvement; penetrance and expressivity are variable [111].

Ectopia lentis due to ADAMTSL4 manifests as dislocation in any direction, sometimes with spherophakia, lens coloboma and iridodonesis; in ectopia lentis et pupillae, the pupil is usually displaced in the direction opposite to the lens, with enlarged iris processes, a deep anterior chamber, a thin cryptless iris, transillumination, peripupillary fibrosis with poor mydriasis and a pupillary membrane [13]. The diagnosis is usually made in early childhood, at birth in cases with severe pupillary ectopia and only in adulthood in mild forms, and it is more severe than in other non-syndromic ectopias [13]. Refractive errors range from hypermetropia of +5 to +15 dioptres (functional aphakia) to myopia of −5 to more than −15 dioptres, with astigmatism; the risk of amblyopia is greatest when the lens edge lies 0.3–2.3 mm from the pupillary centre [13]. Cataract appears early (all patients over 45 years of age had undergone surgery in one series), IOP is raised in up to 20–25%, with an acute rise in anterior subluxation, and central corneal thickness is increased (median 589 μm, range 528–630), which may explain a moderately raised IOP with little glaucomatous damage; retinal detachment is more frequent, partly after surgery, and acuity ranges from light perception to 20/20 [13]. Skeletal features are rare (craniosynostosis, flat feet, pectus carinatum, scoliosis, laxity) [13]. In the dominant differential, isolated ectopia lentis due to FBN1 (ECTOL1, 15q21.1) was termed “ectopia lentis syndrome” by Loeys and colleagues (2010) when there is no aortic involvement, to emphasise that the condition is systemic and requires extraocular assessment [112]. MSPKA syndrome (microspherophakia and/or megalocornea with ectopia lentis, with or without secondary glaucoma; AR, LTBP2, 14q24.3) has small spherical lenses with increased anteroposterior thickness, high myopia and accommodation deficit due to dislocation or subluxation [113].

3.5. Developmental glaucoma

Primary congenital glaucoma (buphthalmos) presents with corneal opacification and photophobia, has a birth incidence of about 3/100,000 in Spain and possible AR inheritance, with CYP1B1 as the main gene [14]. OMIM describes it as the most common type of childhood glaucoma, AR, with an incidence varying between 1/30,000 and 1/1250 depending on the population, onset between birth and 3 years of age and signs of raised IOP, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal oedema and optic disc cupping [87]. FOXC1 produces a spectrum ranging from congenital glaucoma to Axenfeld and Rieger anomalies and iris hypoplasia [14]. Juvenile glaucoma is AD with many loci; MYOC explains about 6–8% of families with primary open-angle glaucoma and juvenile glaucoma [14]. Secondary glaucoma in childhood accompanies ASD, NF1 with an extensive ipsilateral plexiform neurofibroma, Sturge-Weber syndrome, Lowe syndrome (sometimes after cataract surgery), lens dislocation in Marfan syndrome and homocystinuria, nanophthalmos and Norrie disease [14, 63].

3.6. Retina: retinal dysplasia, leukocoria and NDP-related retinopathies

Retinal dysplasia results from failure of retinal and vitreous development, with bilateral detachment present at birth, predominates in males and has Norrie disease as its most common cause [61]. NDP-related retinopathies form a continuum [20]. In Norrie disease there are greyish-yellow fibrovascular retrolental masses of immature retinal cells (pseudogliomas) and bilateral total detachments in the first 3 months; between 3 months and 8–10 years cataract, synechiae, iris atrophy, a shallow anterior chamber, corneal opacification, band keratopathy and phthisis develop; most lose all light perception in the first year; all have retinal dysplasia and incomplete foveal development; the globe may be normal, microphthalmic or buphthalmic, and secondary glaucoma due to pupillary block is frequent [20, 61]. Ultrasound shows bilateral detachment without intraocular calcification, which helps to distinguish it from retinoblastoma [61].

The extraocular manifestations of Norrie disease define the overall prognosis. In a series of 56 patients, there was developmental delay or intellectual disability in 14 of 51 boys, autism spectrum disorder in one third, emotional lability in up to one quarter, seizures in 16 of 56 (with spontaneous resolution in half) and hearing loss in 42 of 56 by the end of adolescence, reaching 80–90% by the end of the third decade; almost all report depression coinciding with the onset of deafness; speech discrimination is relatively preserved [20]. In adults, varicose veins of the lower limbs with stasis ulcers appear in almost half of patients over 16 years of age and erectile dysfunction in 14 of 20, and life expectancy may be reduced by trauma, epilepsy and peripheral vascular disease [20]. The phenotype in female carriers is rare [61].

NDP also causes allelic forms that are confused with non-genetic diseases [20]. NDP-associated PFV has a white fibrotic stalk with hyaloid remnants from the disc to the posterior capsule, unilateral or bilateral, with cataract, restricted globe growth, traction, exudation, detachment and secondary glaucoma; the British reference text describes PFV as always unilateral, which does not apply to the genetic forms, in which bilateral cases have been described [20, 61]. OMIM describes PFV as usually unilateral and associated with microphthalmia, cataract, glaucoma and congenital non-attachment of the retina, with phenotypic overlap with Norrie disease; the AR form results from biallelic ATOH7 variants or homozygous deletion of its regulatory region (10q21.3), and an AD form was described in an Egyptian family without an identified gene [33, 34]. X-linked FEVR presents with peripheral retinal avascularity with or without congenital falciform folds, temporal dragging of the macula and a fibrovascular scar at the ora serrata, with ischaemia, neovascularisation and tractional or exudative detachment up to 20 years of age; stage 5 is indistinguishable from Norrie disease, but without extraocular manifestations [20]. NDP-associated advanced retinopathy of prematurity (ROP) was found in 4 of 16 preterm infants with advanced ROP resembling Norrie disease and in 3 of 9 with atypical ROP, the others having variants in other FEVR genes [20]. In a 3-year prospective study in a paediatric retina clinic, 11 of 109 patients with vitreoretinopathies had NDP variants (5 Norrie, 1 bilateral PFV, 4 FEVR and 1 advanced ROP) [20]. In FEVR, expression varies greatly within the same family: severely affected patients become blind in early childhood, whereas mildly affected ones may have a peripheral avascular area so small that only fluorescein angiography reveals it; peripheral avascularity is considered the primary anomaly, and hyperpermeability, neovascularisation, traction, folds and detachments are secondary to it [30, 32]. OMIM classifies X-linked FEVR as XLR and XLD [30, 31].

Coats disease (retinal telangiectasia), described by Coats in 1908, is a defect of retinal vascular development with subretinal exudation and detachment; in a review including 150 of the authors' own cases, mean onset was at 5 years, 95% were unilateral and 75% male, with slowly progressive course [114]. Black and colleagues (1999) described a woman with a unilateral Coats variant and a son with Norrie disease, both carrying the same NDP variant (p.Cys96Trp, in OMIM notation), and found the same variant in somatic mosaic form, limited to the retina, in 1 of 9 enucleated eyes of boys with Coats, suggesting that some cases result from local norrin deficiency [114]. Coats-like retinal telangiectasia is also an extramuscular manifestation of facioscapulohumeral dystrophy, usually asymptomatic and detected on screening, although it may precede the muscle disease [114].

In microcephaly with or without chorioretinopathy, lymphoedema or intellectual disability (KIF11, AD), chorioretinopathy is the most common ocular anomaly, but retinal folds, microphthalmia and astigmatism are also described, and some carriers have no evident ocular phenotype [115]. In osteoporosis-pseudoglioma, juvenile osteoporosis manifests as long bone and vertebral fractures, kyphoscoliosis, limb deformity and short stature, and the visual disturbance, congenital or early, results from retinal detachment and microphthalmia [83]. Neovascular inflammatory vitreoretinopathy (AD, CAPN5, 11q13.5) combines marked ocular inflammation, vascular loss, large patches of hyperpigmentation and retinal neovascularisation, vitreous haemorrhage and detachment, and resembles retinitis pigmentosa, uveitis and proliferative diabetic retinopathy [116]. Aicardi syndrome, almost exclusively in females, is defined by the triad of agenesis of the corpus callosum, infantile spasms and chorioretinal lacunae; XLD inheritance with male lethality and de novo mutations is assumed, the case of a 47,XXY man is compatible with this hypothesis, but that of a boy described in 1980 contradicts it, and the gene remains to be identified [117].

The other genetic causes of retinal dysplasia or exudative vitreoretinopathy include autosomal FEVR (FZD4, LRP5, TSPAN12, ZNF408, CTNNB1), osteoporosis-pseudoglioma (AR, LRP5; severe juvenile osteoporosis with fractures and congenital or early blindness), microcephaly with lymphoedema and chorioretinopathy (AD, KIF11), Coats plus syndrome (biallelic CTC1; retinal telangiectasias and exudates, intracranial calcifications with leukoencephalopathy and cysts, osteopenia with fractures, potentially fatal gastrointestinal haemorrhage), Walker-Warburg syndrome, incontinentia pigmenti and X-linked retinoschisis [20, 61]. Non-genetic ROP, vasoproliferative in very preterm infants, regresses spontaneously in most; severe cicatricial disease occurs almost exclusively below 1000 g at birth and high inspired oxygen is a risk factor [61].

Isolated and syndromic inherited retinal dystrophies (more than 200 genes; night blindness and peripheral field loss in rod dysfunction; reduced central vision, photophobia and dyschromatopsia in cone dysfunction) enter the differential diagnosis [62]. Of interest here are mainly the treatable syndromic forms or those with systemic risk, discussed in sections 6 and 7.

3.7. Optic nerve

ONH presents with nystagmus when bilateral and with strabismus when unilateral; visual function ranges from near normal to blindness and is difficult to predict in infancy [66]. The most important association is the hypothalamic-pituitary dysfunction of septo-optic dysplasia (SOD), defined by at least two elements of the triad of ONH, cerebral midline defects and hypopituitarism [59]. In a series of 80 patients with SOD, 55% had hypothalamic-pituitary dysfunction, diagnosed by 2 years of age in 86% of these; central hypothyroidism and growth hormone (GH) deficiency were the most common, followed by adrenal insufficiency and diabetes insipidus; presentation was ophthalmological (nystagmus in 36%, strabismus in 14%) or metabolic (neonatal hypoglycaemia) [41]. HESX1 explains less than 1% of cases [41]. In the OMIM synopsis, about 30% of patients with SOD have the complete triad, 62% hypopituitarism and 60% absence of the septum pellucidum; the reported incidence is 1/10,000 live births, with no sex difference and higher frequency in children of young mothers [88]. HESX1 variants (3p14.3) may be heterozygous, homozygous or compound heterozygous, and also cause combined pituitary hormone deficiency without ONH or midline defect, including adenohypophyseal aplasia with neonatal hypoglycaemia and shock [88, 89]. Papillorenal syndrome (AD, PAX2, 10q24.31; allelic with focal segmental glomerulosclerosis 7) combines disc dysplasia, optic nerve coloboma or morning glory anomaly with small kidneys that may progress to chronic kidney disease, vesicoureteral reflux, high-frequency hearing loss and CNS or genital anomalies; mild forms (pit or subtle disc dysplasia) are underdiagnosed, whereas extensive colobomas or the morning glory anomaly reduce acuity [60, 66, 118]. Tubulinopathies combine ONH with severe neuronal migration disorders [66].

3.8. Infantile nystagmus and albinism

Nystagmus in infancy often indicates bilateral visual impairment (ONH, achromatopsia, blue cone monochromatism, congenital stationary night blindness, Leber congenital amaurosis, albinism), whereas late-onset nystagmus is more likely to be secondary to neurological disease [12]. Photophobia points to achromatopsia, aniridia or albinism, and eye pressing with the fingers (oculo-digital sign) to retinal disease [12]. X-linked ocular albinism (Nettleship-Falls, GPR143) affects about 1/50,000 males, with iris and retinal hypopigmentation, nystagmus, strabismus, foveal hypoplasia and abnormal decussation of optic nerve fibres [12]. It is the most common form of ocular albinism; carriers usually have punctate iris transillumination and mosaic fundus pigmentation, and in patients of African or Japanese ancestry the iris may be brown, with little or no transillumination and a minimally depigmented fundus (“non-albinotic fundus”), which hampers clinical diagnosis [93]. Foveal hypoplasia is defined by absence of the foveal pit with continuity of all layers of the neurosensory retina in the presumed foveal area, and all cases described are accompanied by reduced acuity and nystagmus; besides the heterozygous form due to PAX6 (foveal hypoplasia 1), foveal hypoplasia 2 (AR, SLC38A8, 16q23.3) may be associated with abnormal optic nerve decussation and anterior segment dysgenesis [80, 119]. Two diseases with oculocutaneous albinism require systemic assessment: Chediak-Higashi syndrome (AR, LYST, 1q42.3), with severe immunodeficiency, neutropenia, giant inclusions in granulocytes and, in most, a lymphohistiocytic accelerated phase; and Hermansky-Pudlak syndrome, whose type 5 (AR, HPS5, 11p15.1) has a bleeding diathesis due to absence of platelet dense granules, but without pulmonary fibrosis, granulomatous colitis or neutropenia [120, 121]. Congenital oculomotor apraxia, formerly considered benign, is associated with structural brain anomaly, especially cerebellar, and with neurodevelopmental delay in more than half of cases, often due to ciliopathies [12].

3.9. Eyelids and periocular region

Simple congenital ptosis, due to levator muscle dysplasia, is the most common cause in children: sporadic, unilateral and non-progressive [5]. The Marcus Gunn phenomenon (unilateral ptosis that decreases or overcorrects on chewing or sucking) is associated in 6% of ptoses [5]. Ptosis causes amblyopia only when it obstructs the visual axis, and amblyopia due to strabismus or refractive error is corrected before the ptosis [5]. Genetic forms include mitochondrial diseases with progressive external ophthalmoplegia, myotonic dystrophy, oculopharyngeal muscular dystrophy, congenital fibrosis of the extraocular muscles (CFEOM) and dysmorphic syndromes (Aarskog, Baraitser-Winter, Noonan, Saethre-Chotzen, Smith-Lemli-Opitz, Kabuki, Wiedemann-Steiner) [5]. Blepharophimosis defines BPES and the Ohdo (neonatal hypotonia, severe feeding problems, small teeth, heart disease; sporadic KAT6B variants) and Dubowitz syndromes [5]. Baraitser-Winter syndrome (AD, ACTB or ACTG1) combines bilateral ptosis, coloboma, hypertelorism and neuronal migration disorder; a recurrent de novo ACTG1 variant was found in isolated coloboma [60]. OMIM separates type 1 (ACTB, 7p22.1, sometimes due to a 7p22 contiguous gene deletion) and type 2 (ACTG1, 17q25) and adds a broad nose with a large tip, a prominent metopic suture, arched eyebrows, sensorineural hearing loss, shoulder girdle muscle bulk with progressive joint stiffness and anteroposterior gradient pachygyria, present in almost all patients with ACTG1 and in about 60% of patients with ACTB [122]. Hypertelorism, which is distinguished from telecanthus (lateral displacement of the inner canthi, as in Waardenburg syndrome type 1), is usually syndromic (frontonasal dysplasia, craniofrontonasal syndrome due to EFNB1, Opitz G/BBB, Greig, Robinow, frontonasal dysplasias due to ALX1, ALX3 and ALX4, FREM1, acromelic frontonasal dysplasia due to ZSWIM6) [71].

3.10. Extraocular manifestations that change management

The value of the aetiological diagnosis is measured by the extraocular manifestations it requires to be monitored or treated. In a Manchester cohort, testing initiated extraocular surveillance in 9% of children (12% in cataracts and 25% in ectopia lentis) [7]. The most important examples are COL4A1 cerebral small vessel disease in cataracts, Wilms tumour in aniridia with an 11p13 deletion (WAGR syndrome) and ACTA2 multisystemic smooth muscle dysfunction, which together account for about 10% of aniridias, aortic root dilatation in FBN1 ectopia, platelet dysfunction in Hermansky-Pudlak syndrome presenting as albinism, rhabdoid tumour predisposition due to SMARCA4 in patients with microphthalmia or coloboma, hypertrophic cardiomyopathy and lactic acidosis in Sengers syndrome, adrenal insufficiency in SOD and progressive deafness and venous disease in Norrie disease [7, 20, 59, 72, 73].

4. Clinical Recognition and Warning Signs

4.1. Newborn and childhood screening: the red reflex

The 2008 joint statement of the AAP, the American Association for Pediatric Ophthalmology and Strabismus (AAPOS), the AAO and the American Association of Certified Orthoptists (AACO) considered the red reflex test an essential component of the examination of the newborn, infant and child [15]. This statement was replaced in 2016 by the policy statement “Visual System Assessment in Infants, Children, and Young Adults by Pediatricians” and its accompanying clinical report, “Procedures for the Evaluation of the Visual System by Pediatricians”, from the same bodies, which are now the current AAP reference for the red reflex [16, 123]. The 2016 statement from the same bodies establishes that eye examination begins in the nursery and continues at all well-child visits: inspection and red reflex in the newborn to detect cataract, corneal opacity and ptosis; instrument-based screening between 12 months and 3 years of age and annually until acuity can be measured; acuity with age-appropriate optotypes from 4 years of age; referral to a paediatric ophthalmologist of any child with an eye anomaly or who fails the assessment [16]. The same statement requires referral for specialist ophthalmological examination, regardless of the reflex, of newborns with a family history of congenital cataract, retinoblastoma or metabolic disease and those in whom systemic disease with severe ocular anomalies is suspected; a white or bright yellow reflex, or a dull or absent reflex, requires assessment by a paediatric ophthalmology specialist [16]. The clinical report describes the technique: darkened room, without mydriatic drops, direct ophthalmoscope set at 0 and simultaneous observation of both pupils at arm's length while the child looks at the light (Brückner test), then moving closer to observe each eye; the normal reflex is light yellowish-orange in lightly pigmented eyes and dark red in brown eyes, and both reflexes should be identical in colour, brightness and size [123]. The test detects opacities of the visual axis (cataract, corneal change) and posterior segment anomalies (retinoblastoma, retinal detachment), and asymmetry between the eyes may reveal strabismus or refractive error; frequent assessment at all visits helps the clinician to distinguish normal variation from an abnormal reflex [123]. The report adds as referral criteria poor binocular fixation and following after 3 months, constant strabismus after 4 months and nystagmus at any age [123]. A 2024 Portuguese review systematises the diseases detectable with the direct ophthalmoscope: in the retina, retinoblastoma, Coats disease, ROP, FEVR, myelinated fibres, ocular toxocariasis and toxoplasmosis, retinochoroidal coloboma and hamartomas; in the vitreous, persistent fetal vasculature; in the lens, cataract; in the anterior chamber and cornea, ASD, congenital glaucoma and birth trauma; leukocoria requires immediate ophthalmological assessment [124].

The red reflex is a test with high specificity and low sensitivity. A meta-analysis of 11 newborn screening studies estimated a pooled sensitivity of 23% (95% confidence interval [CI] 21–24%), a specificity of 98% (98–98%), a positive likelihood ratio of 32.5 and a negative one of 0.69 [17]. The authors describe the test as sensitive, which the figures do not support: a normal reflex does not exclude an anomaly, and clinical suspicion or family history justify ophthalmological examination even with a normal reflex [17]. In heavily pigmented fundi the normal reflex is not red, which led to the proposal of anatomical rather than chromatic terminology [125].

4.2. When to suspect, by age and context

Referral time is a practical problem: in the SEA-UK study, 41.5% of children with MAC had not been seen by an ophthalmologist by 3 months [11]. Bilateral involvement may only be detected after careful examination of the apparently normal eye [1]. An uneventful pregnancy, without infection or exposure to alcohol or drugs, increases the probability of a genetic basis [4].

4.3. Warning and emergency signs

4.4. Biochemical newborn screening

Newborn screening for structural eye anomalies relies on clinical examination and the red reflex. The sources consulted do not describe population-based biochemical or genetic screening programmes directed at these anomalies, except for screening for metabolic diseases that manifest with cataract, such as galactosaemia.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. General principles

There are no formal diagnostic criteria for congenital eye anomalies as a whole; diagnosis rests on rigorous ocular phenotyping, a systemic assessment and a genetic test chosen according to the complete phenotype. Before genetic counselling, a detailed ophthalmological examination and report should be obtained, with measurement and photography of the eye and adjacent structures and screening for glaucoma [1, 2]. The aim of the first genetics clinic visit is to decide whether the condition is purely ocular or whether there are non-ocular features suggesting a syndrome [1]. Ophthalmological examination of the parents, even in apparently sporadic cases, is part of the investigation, because small retinal colobomas, minor signs of ASD, subtle cataracts and carrier signs are easily missed by a non-specialist [14, 60, 63]. In an infant without an identified syndrome, reassessment 3–4 years later is useful, because many syndromes only become evident with age; for undiagnosed MAC, GeneReviews proposed reassessment within 2 years [19, 65].

5.2. History and examination common to all findings

The history includes a pedigree of at least three generations with questions directed at all visual difficulties (affected individuals may have minimal expression), consanguinity, exposure to teratogens, alcohol and infections in pregnancy, maternal diabetes, maternal phenylketonuria, growth, development allowing for the visual deficit, hearing loss, seizures and renal disease [1, 2, 66]. The examination includes biometry with head circumference, dysmorphological assessment and a targeted search for signs of discriminating value: orofacial clefts (trisomy 13, Peters plus, colobomatous microphthalmia), abnormal dentition (Rieger, Lenz, Nance-Horan), redundant periumbilical skin and hypospadias (Rieger), ear anomalies (CHARGE, cat eye, oculo-auriculo-vertebral spectrum), anal anomalies (CHARGE, cat eye), polydactyly (trisomy 13, Bardet-Biedl, Joubert), limb defects (ophthalmo-acromelic syndrome), linear or patchy skin lesions (Goltz, MIDAS), nail hypoplasia (Fryns), eyelid fusion (Fraser), thin nose and hypotrichosis (Hallermann-Streiff), micropenis and short stature (hypopituitarism) [1, 2, 60, 66].

5.3. Algorithm by ocular finding

5.4. Ocular measurements and imaging

Normal corneal diameter is 9.0–10.5 mm in the newborn and 10.5–12.0 mm in the adult [19, 65]. A-mode ultrasound measures TAL and the anterior and posterior segments; B-mode assesses internal structures; CT or MRI of the brain and orbits assesses globe size and structure, the optic nerve, extraocular muscles and brain anatomy [19]. In anophthalmia, imaging shows amorphous tissue, variably present optic pathways and extraocular muscles and reduced orbital volume [65]. In microphthalmia, the anterior segment is normal or reduced and the posterior segment is uniformly at least 2 SD below the mean [19]. Electrophysiology is useful in microphthalmia when the retina has developed, and VEPs detect abnormal crossing of the optic pathways in albinism, although they may be inconclusive in young infants [4, 65]. The Portuguese recommendation for inherited retinal dystrophies suggests, in children, handheld OCT as an alternative and performing the ERG immediately after anaesthetic induction when sedation is required [23].

5.5. Genetic testing strategy

Genetic testing should be offered when the findings suggest a Mendelian disease with a known causal gene, with counselling by a physician experienced in hereditary diseases or by a genetic counsellor [22]. The request to the laboratory should describe all ocular and extraocular findings, preferably using Human Phenotype Ontology (HPO) terms, because a patient with a mixed phenotype (for example, ASD with cataract or coloboma) tested only on a subpanel may remain undiagnosed [4, 23].

Chromosomal microarray is the first analysis when there are extraocular signs, developmental delay or sporadic aniridia, because it detects deletions such as 11p13 (WAGR), 3q26 (with SOX2) and 14q22, 22q11 duplications and aneuploidies; it does not detect balanced rearrangements [2, 19, 24]. The most frequent chromosomal anomalies in MAC include trisomy 13, trisomy 18, mosaic trisomy 9, triploidy, deletions of 4p, 7p15.1-p21.1, 13q (including ring 13), 14q22.1-q23.2, 18q and 3q26, and duplications of 3q, 4p and 10q [19]. The proportion of chromosomal anomalies in MAC varies with the denominator: 16% of children with microphthalmia or anophthalmia in EUROCAT data and about 25–30% in a 2007 review [2, 19].

Next-generation sequencing (NGS) has replaced gene-by-gene testing. In a German cohort of 40 patients with congenital eye malformations (92% bilateral), the tiered strategy gave 6 diagnoses in 40 (15%) with phenotype-directed testing, a further 10 in 34 (29%) with a multigene panel of 186 ocular genes and a further 1 in 24 (4%) with the exome, a total of 17 in 40 (43%), or 48% counting two variants of uncertain significance (VUS) considered causal; the cross-phenotype panel increased the yield 2.5-fold compared with directed testing, and the authors recommend starting with a broad panel followed by exome [18]. In the French AURAGEN cohort, second-line genome sequencing (67 of 100 patients with prior negative NGS) gave 18% conclusive diagnoses; at least 10 of the 18 would have escaped a 187-gene panel and the exome would have detected about 16, missing the two inversions; the authors propose standardising genome sequencing in ocular malformation [3]. In the French programme, the overall genome yield was 29.1% in trios and 20.7% in singletons [3]. The gene panel should include CNV analysis; deletions suggested by NGS are confirmed by multiplex ligation-dependent probe amplification (MLPA) [18, 126].

5.6. Diagnostic yield by phenotype and technique

A review of 24 published cohorts summarises yields of 16–61% in microphthalmia/anophthalmia, 13–54% in ASD (excluding aniridia) and 37–77% in congenital cataracts; less than half of patients with an ocular malformation receive a molecular diagnosis [3]. In aniridia, an Italian cohort reached 89.9% with exome and targeted PAX6 analysis [3]. A Brazilian cohort of 17 patients with microphthalmia/anophthalmia and orofacial clefts had 35.3% diagnoses with microarray and exome [3]. In populations with high consanguinity the yield is higher (61% in microphthalmia/anophthalmia and 82% in posterior microphthalmia in Saudi Arabia) [3]. In severe bilateral anophthalmia or microphthalmia, the yield reaches 80% [4, 19].

The factors predicting yield are consistent across cohorts. In AURAGEN, a diagnosis was obtained in 23% of bilateral versus 7% of unilateral cases, in 22% of cases with microphthalmia and ASD versus 13% in isolated microphthalmia, in 6% of isolated colobomas and in 33% of patients with a family history versus 16% without [3]. In the German cohort, the yield was 46% in bilateral versus 0% in unilateral cases, 78% in complex versus 32% in simple ocular phenotypes, and 70% with a positive family history [18]. In Manchester, family history raised the yield to 74% and extraocular signs to 39% [7]. The cohorts differ in classification criteria (pathogenic and likely pathogenic variants versus inclusion of candidates), prior testing, consanguinity and phenotypic composition, and therefore cannot be compared directly; the Iranian yield of 70%, for example, includes single heterozygous findings in recessive genes [3, 128].

5.7. Limitations of testing

A negative test does not exclude a genetic cause. Panels directed at one subphenotype miss genes from other subpanels: MAB21L2 was missed by the initial subpanels in the German cohort and KERA, a cause of unilateral microphthalmia with cornea plana, was not on the British MAC panel [4, 18]. Panels of the period did not include genes described later, such as SLC38A8 in albinism and nystagmus forms [4]. Exome and panel do not detect balanced inversions that separate genes from their regulatory elements (PAX6, FOXC1) and have difficulty with small intragenic deletions [3]. In the 100,000 Genomes Project, non-coding analysis was limited to splicing regions and only 8 of 93 variants (8.6%) were non-coding [4]. Short-read genome sequencing resolves repetitive, pericentromeric and subtelomeric regions and complex structural variants poorly, and interpretation of non-coding variants (UTRs, promoters, enhancers) depends on databases that are still limited; long-read sequencing resolved a complex rearrangement in one case, but its added value is not established [3]. Low-level mosaicism escapes pipelines with high calling thresholds [3]. CNV analysis of exome data may reveal the second allele of a recessive gene when only one has been found [72]. In retinal dystrophies, the Portuguese recommendation emphasises the frequency of CNVs and the need to search for them, and the limited usefulness of blood RNA was confirmed in a large genome study [23, 127]. The absence of a diagnosis in unilateral cases suggests a greater weight of non-genetic factors or undetectable mosaicism [18]. Published yields are minimum values and justify periodic reanalysis [3, 18].

5.8. Report, variants of uncertain significance and partial results

The report should identify the gene, the reference transcript and its version, the variant in Human Genome Variation Society (HGVS) nomenclature, zygosity, classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and correspondence with the phenotype; it should be issued by an accredited laboratory and given to the patient [22, 23]. A VUS neither confirms nor excludes the diagnosis; in AURAGEN there were VUS in 9 patients (CRYGC, GJA3, PORCN, SOX2, TDRD7, an inversion near PITX3, a de novo intronic ARHGEF12 variant and two CNVs) [3, 20]. VUS compatible with the phenotype require family studies and review by a geneticist, and variants should not be excluded merely because a sign is missing or an unusual sign is present, because manifestations may appear over time (reverse phenotyping) [23]. Four AURAGEN patients had a single pathogenic or likely pathogenic allele in a recessive gene (FAT1, FOXE3, HPS3, OCA2), of uncertain significance without the second allele [3]. In six patients, the variant explained the systemic signs but not the eye (DYM, MAP4K4, MECP2, MED13L, PTEN, TLK2), and one patient had a dual molecular diagnosis (PTEN and ARHGAP35) [3]. Actionable secondary findings from the ACMG list appeared in 5 of 100 genomes (BRCA2 in 2, BRCA1, PALB2 and RYR1 in 1 each), which requires their disclosure to be discussed at consent [3, 23]. A variant found in an isolated cataract gene may be an incidental finding unrelated to the picture, such as the CRYBA2 VUS inherited from a healthy father in the case in section 10 [72].

5.9. Guidelines and recommendations

The sources consulted do not include a specific guideline on the genetic diagnosis of structural eye malformations; the ERN-EYE consensus page lists only the consensus on Bardet-Biedl syndrome [26]. The Portuguese recommendation provides the closest national reference, and its rules on counselling, consent and reanalysis apply by analogy to structural anomalies [23]. The European Society of Human Genetics (ESHG), cited in that recommendation, proposes starting with targeted sequencing in children and reserving broad genomic analysis for when that fails, which contrasts with the French proposal of standardised genome sequencing [3, 23].

5.10. Prenatal and preimplantation diagnosis

With the familial variant known, prenatal diagnosis is made by chorionic villus sampling (10–12 weeks) or amniocentesis (after 14 weeks), and preimplantation genetic testing (PGT) is possible [19, 65]. Without a known cause, imaging is the only option: transvaginal ultrasound identifies the eyes from 12 weeks, but in most reports ocular malformations are only detected after 22 weeks, and the sensitivity of ultrasound for microphthalmia or anophthalmia is unknown; fetal MRI is an adjunct in anophthalmia [19, 65]. In the Paris registry, 23.5% of congenital eye anomalies had a prenatal diagnosis: 29.2% of those associated with a genetic anomaly, 26.2% of those associated with another malformation and 13.3% of isolated ones [9]. When MAC is detected in a fetus without prior risk, microarray and sequencing with SOX2 deletion/duplication analysis or a panel are recommended [19]. In Norrie disease, fetal ultrasound is usually normal in the first two trimesters and detachment may appear late in the third (detected at 34 weeks in one case and at 36+5 weeks in another with normal ultrasound at 31+4) [20]. Counselling aspects are in section 8.

6. Differential Diagnosis

6.1. Comparative table of the main entities

6.2. Non-genetic causes

Congenital infections have the strongest evidence among the environmental causes of anophthalmia and microphthalmia: rubella, toxoplasmosis, varicella and cytomegalovirus, as well as other herpesviruses, parvovirus B19, influenza and coxsackie A9 [2, 65]. Congenital Zika virus infection has its own ocular pattern. In Salvador (Bahia, Brazil), in December 2015, 10 of 29 infants with microcephaly and presumed infection (34.5%; 17 of 58 eyes) had ocular anomalies, bilateral in 7: focal pigmentary changes and chorioretinal atrophy in 11 of 17 eyes (64.7%), optic nerve anomalies in 8 (47.1%), bilateral iris coloboma in one infant and lens subluxation in one eye [134]. In a systematic review of 479 postnatal cases, pigmentary changes (47.8%), macular chorioretinal atrophy (45%), increased optic disc cupping (39.6%), optic atrophy (37.8%) and ONH (19.4%) predominated, with microphthalmia in 2.7% and anterior segment lesions in 4.6%; the lesions did not improve and some worsened during follow-up [135].

Teratogens include alcohol, thalidomide, warfarin, phenytoin, valproate, retinoids, thiamazole/carbimazole (iris colobomas), maternal diabetes (diabetic embryofetopathy; ONH) and maternal phenylketonuria [2, 65, 66, 136]. Mycophenolate mofetil causes malformations in 23–27% of exposed live births according to pregnancy registries, including ocular, external ear and other facial anomalies, and first-trimester loss in 45–49% of exposed pregnancies; the US label carries a boxed warning for embryofetal toxicity [137]. Maternal vitamin A deficiency, maternal fever, radiation and solvent abuse have also been proposed, and clusters attributed to the pesticide benomyl have been described without a demonstrated causal link [65]. ROP, birth trauma and, in SOD, vascular disruption suggested by young maternal age, primiparity and first-trimester bleeding complete the non-genetic differential [59, 61, 124]. ONH is also associated with maternal smoking and prematurity [66].

6.3. Metabolic differential by ocular finding

The differential diagnosis lists of dysmorphology texts omit metabolic diseases without dysmorphism and isolated retinal dystrophies, which are completed with the metabolic lists [133, 136]. The table brings together the metabolic diseases that the appendix of the Atlas of Inherited Metabolic Diseases associates with each ocular finding and the indications of the British reference text.

6.4. Malformative differential by ocular finding

The table reproduces, in translation, the lists of malformation syndromes associated with each ocular finding in the appendix of Smith's Recognizable Patterns of Human Malformation (8th edition), separated into frequent and occasional association [136].

Some syndromes in the table have frequencies of ocular involvement described in the reference monographs. In Walker-Warburg syndrome there is anterior chamber malformation in 91% (cataract, corneal opacification usually due to Peters anomaly, narrow iridocorneal angle with or without glaucoma), retinal malformations in 100% (retrolental masses due to persistent hyperplastic primary vitreous, detachment due to retinal dysplasia), coloboma in 24% and microphthalmia in 53%, with congenital muscular dystrophy in all patients [138]. In Fanconi anaemia, 41% have ocular anomalies (ptosis, strabismus, nystagmus, microphthalmia), alongside radial ray defects in 49% [139]. In Mowat-Wilson syndrome, strabismus occurs in 55% and structural ocular anomalies in 10% (irregular iris pigment patches, heterochromia, microphthalmia, Axenfeld anomaly, retinal aplasia, coloboma of the iris, retina or optic disc), with Hirschsprung disease in 30.6% [140]. In ciliopathies, ophthalmological examination looks for abnormal eye movements, visual field defects, photophobia, colobomas and retinal pigmentation, with ERG when possible; in Joubert syndrome ocular anomalies include retinal dysplasia, colobomas, nystagmus, strabismus, ptosis and oculomotor apraxia [141]. Among skeletal and connective tissue dysplasias, B4GALT7 deficiency (spondylodysplastic Ehlers-Danlos syndrome, Larsen of Reunion Island variant) is associated with cataract and hypermetropia in some patients [142]; Carpenter syndrome may have corneal opacity, microcornea and an ill-defined optic disc [143]; and autosomal recessive forms of cutis laxa, including De Barsy syndrome, present with congenital cataract, corneal opacity, strabismus and myopia [144].

6.5. Specific differentials by finding

Leukocoria and pseudoglioma. Retinoblastoma is the first diagnosis to exclude, especially when the pseudoglioma is unilateral, by fundoscopy by a retina or ocular oncology specialist and by ultrasound and CT, which show hyperechoic or calcified foci in retinoblastoma and not in Norrie disease [20, 61]. Norrie disease is bilateral, present at birth and accompanied later by hearing loss; FEVR is usually milder, without extraocular manifestations and with avascular peripheral retina; osteoporosis-pseudoglioma is distinguished by fractures and low bone density; PFV is unilateral or bilateral, with restricted globe growth; Coats disease is unilateral, with telangiectasias and exudation; ROP occurs in preterm infants, and bilateral advanced ROP with or without hearing loss should raise suspicion of a genetic component [20]. Walker-Warburg syndrome is distinguished by hydrocephalus, agyria, encephalocele and raised CK [61].

Ectopia lentis. The FBN1 form is the most frequent and may be isolated; in Manchester, 2 of 8 children with apparently isolated ectopia had an FBN1 variant and were placed under aortic root surveillance, and 4 of 8 had isolated recessive forms (ADAMTSL4, LTBP2) [7, 13]. Homocystinuria, sulfite oxidase and molybdenum cofactor deficiencies, Weill-Marchesani syndrome and MSPKA syndrome complete the systemic differential; aniridia, the Axenfeld-Rieger spectrum, iridocorneal endothelial syndrome (acquired and rare in children), iris coloboma and posterior polymorphous dystrophy (COL8A2, OVOL2, ZEB1) enter the differential of pupillary displacement and iris anomalies [13].

Large, small or cloudy cornea. Megalocornea with a clear cornea and normal IOP is distinguished from buphthalmos, in which the cornea is cloudy and IOP raised [1, 41]. Microphthalmia is distinguished from mild microcornea with a normal-sized globe by biometry [19]. In corneal opacification, the first question is whether there is glaucoma, the second whether there is a structural malformation (Peters, sclerocornea, aphakia) and the third whether there is progressive metabolic disease [1, 42].

Apparent absence of the eye. Anophthalmia is distinguished from severe microphthalmia (ocular remnants on imaging), cryptophthalmos (fused eyelids without eyelashes) and congenital cystic eye (postnatal expansion with retropalpebral bulging, cyst with inserted extraocular muscles but no optic nerve) [19, 65].

Abnormal optic disc. ONH (small disc) is distinguished from optic atrophy (normal-sized pale disc) and from the “crowded” disc of hypermetropia; optic nerve coloboma and morning glory anomaly suggest PAX2 or PAX6 [66].

Nystagmus in infancy. The ERG distinguishes retinal dystrophies (Leber congenital amaurosis with a severely subnormal or unrecordable ERG, achromatopsia, congenital stationary night blindness) from albinism (VEP with abnormal crossing) and ONH (normal ERG, abnormal VEP); so-called idiopathic or motor nystagmus is accepted only after this assessment and counselled with caution [12, 66].

Hypertelorism and telecanthus. Measurement of the inner and outer intercanthal distances and the interpupillary distance, related to head circumference, separates true hypertelorism from telecanthus and epicanthic folds [71].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no authorised pharmacological therapy directed at structural eye malformations; treatment is surgical, optical, prosthetic and visual habilitation, adjusted to each finding, and includes prevention of amblyopia, control of glaucoma and surveillance of the extraocular manifestations identified by the aetiological diagnosis [13, 19–21]. Specific treatments for the more frequent entities (congenital cataract surgery, glaucoma surgery, conformers in anophthalmia, retinal gene therapy, hormone replacement in SOD) follow the recommendations for each entity. Molecular diagnosis changes management in a measurable proportion of patients: in Manchester, it changed management in 33% of children, avoiding unnecessary investigations in 21% (50% in cataracts, because it dispenses with conventional biochemical and infectious screening), initiating extraocular surveillance in 9%, reducing prognostic uncertainty in 7% (25% in retinal dystrophies) and giving access to gene therapy trials in 1% [7].

7.2. Treatable diseases presenting with an ocular sign

The first therapeutic aim of the approach is to recognise the diseases in which treatment changes the course, even when the presenting sign is ocular.

In SOD, cortisol deficiency is what kills: in a study of 88 patients followed for up to 36.8 years (median 12.4), there were 5 deaths, 3 from adrenal crisis and 2 from neurological problems; adrenocorticotropic hormone (ACTH) deficiency may be silent until an intercurrent illness, and pituitary deficiencies evolve, so a normal assessment at diagnosis does not exclude later deficiency [41, 59].

7.3. Microphthalmia and anophthalmia: orbit, prosthesis and residual vision

Retinal function may exist in microphthalmia, especially in SOX2 forms, which justifies refraction and amblyopia treatment; in unilateral cases, the healthy eye is protected [19, 65]. Globe volume triples between birth and adolescence and orbital growth follows it; therefore, in severe microphthalmia and anophthalmia, the ocularist begins shortly after birth to expand the palpebral fissures, conjunctival fornix and orbit with conformers of progressive size, which may not expand horizontally and produce an hourglass deformity [19, 65]. Oculoplastic surgery decides on surgery after 6 months, when orbital growth is assessed, and before orbital dimensions become fixed, because afterwards extensive reconstruction is required; options include fixed-size orbital implants, expandable implants (silicone balloon, hydrophilic polymers) and dermis-fat grafts, which grow after surgery [19]. Enucleation reduces orbital volume [65]. Extensive chorioretinal colobomas carry a risk of rhegmatogenous retinal detachment, and lens colobomas are associated with giant retinal tears [60].

7.4. NDP-related retinopathies and vitreoretinopathies

GeneReviews identifies no published clinical guidelines for NDP-related retinopathies; management is individualised by paediatric ophthalmology and paediatric vitreoretinal surgery, and early intervention may save vision [20]. In Norrie disease, most boys have total detachment at birth; surgery may not preserve vision, but some patients undergo surgery to maintain globe size and appearance or light perception [20]. When detachment is not yet total, prophylactic photocoagulation of the avascular retina has published results in isolated cases: in a 2-day-old newborn, after planned delivery at 34 weeks with detachment excluded by fetal ultrasound at 28 and 33 weeks, the retinas were attached at 10 months; in another, treated at birth at 37 weeks, Teller acuity was 20/100 at 23 months [20]. In a 1988–2008 review, 7 of 14 infants with the Norrie phenotype who underwent vitrectomy by 12 months of age (median 4.5 months) retained light perception in at least one eye, and early simultaneous bilateral intervention proved feasible [20]. These data support discussion with the family of prenatal testing and treatment immediately after birth, without constituting comparative evidence [20]. Enucleation is rare and reserved for the blind painful eye with phthisis [20]. IOP is lowered with topical or systemic drugs, and glaucoma due to pupillary block of the shallow anterior chamber is surgical [20, 61].

In PFV, the stalk is transected, distinguishing it from a retinal fold [20]. In X-linked FEVR and NDP-associated advanced ROP, prophylactic photocoagulation of the avascular peripheral retina is performed at diagnosis, to reduce vascular endothelial growth factor (VEGF), neovascularisation and traction, and early surgical dissection when necessary; treated preterm infants have more refractive errors, especially myopia after laser [20]. In Coats disease, laser is directed at telangiectasias, microaneurysms and avascular areas when there is macular exudation, and anti-VEGF agents, such as bevacizumab, are increasingly used, off-label [20].

Intravitreal anti-VEGF: reference dose by analogy. The sources consulted give no anti-VEGF dose for Coats disease, FEVR or NDP-associated ROP. As an analogous-condition reference (VEGF-dependent paediatric proliferative vitreoretinopathy), the European label of ranibizumab (Lucentis®) includes ROP in preterm infants with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or aggressive posterior ROP disease: 0.2 mg by intravitreal injection (0.02 mL), one injection per eye, which may be bilateral on the same day, up to three injections per eye in the six months after initiation if there are signs of activity, with a minimum interval of four weeks between injections in the same eye; in the RAINBOW trial, 78% of patients received a single injection per eye [145]. The most frequent ocular adverse reactions in preterm infants were retinal and conjunctival haemorrhage, and the non-ocular ones nasopharyngitis, anaemia, cough, urinary tract infection and allergic reactions; no new safety signals emerged up to 5 years of age [145]. Applying this dosing to genetic vitreoretinopathies is an off-label extrapolation, to be decided by the paediatric vitreoretinal surgeon; bevacizumab, cited by GeneReviews in Coats disease, is used off-label, and the sources consulted assign it no dose for this indication [20, 145].

Extraocular management of Norrie disease is multidisciplinary: early low-vision intervention at school and, in adults, a low-vision clinic and mobility training; standard antiepileptic drugs (none shown to be specific); psychiatric and behavioural assessment with an empirical trial of psychotropic drugs, without specific data; sleep medicine, because the absence of light perception disturbs circadian rhythm, with strict schedules and drugs such as melatonin; treatment of hearing loss according to degree and age, with cochlear implantation (which improved quality of life in 3 patients); peripheral vascular disease and erectile dysfunction by specialists; deafblind services [20].

7.5. Ectopia lentis due to ADAMTSL4

Assessment includes acuity, refraction, IOP, slit lamp, dilated fundus, orthoptics, axial length, anterior segment OCT or UBM, topography with central corneal thickness and gonioscopy [13]. Amblyopia is prevented with early refractive correction and occlusion [13]. Surgery is indicated in the presence of cataract, risk of complications (endothelial contact, pupillary block), ineffective occlusion, a lens edge in the middle of the pupil or uncorrectable astigmatism; it is rarely necessary in children, and most patients undergo surgery in adolescence or early adulthood, with visual improvement even after 7 years of age [13]. The technique has evolved from lensectomy with anterior vitrectomy and contact lens or secondary intraocular lens (IOL) to capsule-preserving surgery (bag-in-the-lens IOL with capsular rings or loop suture); if this fails, a three-piece IOL by the Yamane technique is used from 4–5 years of age [13]. Loss of accommodation, secondary glaucoma and detachment are weighed; before 2 years of age there is a myopic shift with growth; in small and highly displaced pupils sphincterotomy may be performed; IOP is usually controlled with topical antiglaucoma drugs [13].

7.6. Cornea, lens, glaucoma and eyelids

In corneal opacification, ophthalmological or medical follow-up is prolonged and corneal transplantation may be possible; in CHED, lack of treatment leads to deprivation amblyopia [41, 42]. In congenital cataracts, the isolated hereditary form has a better visual and surgical outcome than that associated with other ocular and systemic anomalies [63]. In Lowe syndrome, glaucoma may appear after cataract surgery [63]. In severe ptosis, regular ophthalmological review ensures that the eyelid does not obstruct the visual axis, and surgery for cosmetic reasons is performed in older children [5].

7.7. Low vision and habilitation

The 2026 ERN-EYE consensus recommends assessing the primary visual functions of the child with low vision (acuity, contrast sensitivity, visual field and colour vision) with instruments validated for each developmental stage, including infants and children with syndromes or neurodevelopmental disorders, with involvement of caregivers, adaptation to associated deficits and early assessment for timely habilitation [25]. Early intervention covers psychomotor, educational, autonomy and mobility areas [19]. Children with progressive dystrophies may need psychological and educational support from a multidisciplinary team [62].

7.8. Regulatory status

Authorised gene therapies for retinal dystrophies include voretigene neparvovec in biallelic RPE65 dystrophies, also administered in Portugal [23].

7.9. Ongoing trials and studies

The ataluren trial was negative on the primary outcome, with very small analysed groups and a confidence interval including both relevant benefit and harm; it does not allow conclusions about termination codon readthrough in other ocular anomalies [21]. The RAINBOW trial did not reach, on the primary outcome, the pre-specified significance threshold (one-sided p 0.0254 versus 0.025), despite the numerical difference of 13.8 percentage points and the lower rate of unfavourable structural outcome (1.4% versus 10.1%); it concerns ROP in preterm infants and not genetic vitreoretinopathies [145]. A search of the ClinicalTrials.gov registry for microphthalmia, anophthalmia and ocular coloboma found no trials of targeted pharmacological intervention, and the registered trials in congenital cataract and glaucoma are surgical or optical and not genotype-specific; absence from one registry does not prove the non-existence of trials in other registries [146, 147].

7.10. Developments in the last 12 months

No new regulatory authorisations for structural congenital eye anomalies were found in the last 12 months; the search was not exhaustive.

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

In Norrie disease, avoidance of loud noise, use of hearing protection and limited use of earphones are recommended [20]. In ectopia lentis due to ADAMTSL4, ocular trauma is avoided, with care in contact sports and abstention from boxing and martial arts [13]. In Hallermann-Streiff syndrome, the narrow upper airway implies difficult intubation and anaesthetic complications, sometimes tracheostomy [58]. In SOD and in ONH without an assessed hypothalamic-pituitary-adrenal axis, any anaesthesia or intercurrent illness requires cover for the risk of adrenal insufficiency [41]. In women of childbearing age, prevention of embryopathies involves preconception review of teratogenic drugs (mycophenolate, valproate, retinoids, warfarin), control of maternal diabetes and phenylketonuria and abstention from alcohol [2, 65, 137]. In women heterozygous for NDP, fluorescein angiography may identify changes treatable by prophylactic photocoagulation [20]. Transition to adult care should maintain prolonged ophthalmological follow-up (glaucoma, cataract, retinal detachment) and transfer the extraocular surveillance specific to each diagnosis (hearing and vascular disease in Norrie disease, aorta in FBN1 ectopia, renal function in papillorenal syndrome) [7, 20, 60].

8. Reproductive Options and Family Counselling

8.1. Principles

Counselling depends on the aetiological diagnosis; without it, the mode of inheritance of a simplex case is undetermined, and among the simplex cases solved in Manchester AR inheritance predominated (69%) [7]. Careful ophthalmological examination of the parents is essential before accepting a case as sporadic, because variability is the rule and parents may have subtle signs, sometimes only recognised after the birth of a second affected child [1, 2, 60]. The Portuguese recommendation for inherited retinal dystrophies provides for two genetic counselling visits, before and after the result, and considers that counselling of the index case and other affected relatives may be done by an appropriately trained ophthalmologist, whereas that of healthy relatives should be done by a medical geneticist; under Portuguese law, testing of healthy persons can only be performed by a medical geneticist [23]. The AAO recommends counselling by a professional experienced in hereditary diseases for all those tested, because of the risks to reproductive plans, anxiety or guilt and family relationships [22, 129].

8.2. Recurrence risks by scenario

The SEA-UK study estimated a sibling risk ratio of 210 (95% CI 25–722) for MAC, which reflects the genetic weight of the spectrum [11]. In simplex cases of Norrie disease, most mothers are carriers even without a family history, de novo variants in the affected boy are rare, and a variant absent from maternal leucocytes suggests germline mosaicism; the mother of more than one affected son is an obligate heterozygote, and maternal aunts and female cousins are at risk [20, 61]. Heterozygous girls are rarely symptomatic, which may occur through unfavourable X inactivation [20].

8.3. Carrier testing and cascade testing

Cascade testing of first-degree relatives, after identification of the variant in the index case, is the most efficient way to define risks; in the absence of prior testing, an available affected relative should be tested first and, in X-linked diseases, preferably a male [23]. Carrier status can also be determined by ophthalmological examination (early cataract, punctate opacities of Lowe syndrome, sutural opacities of Nance-Horan syndrome, minor signs of ASD, mosaic pigmentation of X-linked ocular albinism, corneal dystrophy), by electrophysiology in relatives of boys with X-linked dystrophies and by biochemical or enzyme assays in metabolic diseases [1, 12, 42, 62, 63]. In ADAMTSL4 ectopia, complete ophthalmological examination of siblings is recommended, and molecular testing is more useful than examination because of variability [13]. In MYOC glaucoma, predictive testing serves to guide surveillance, and ophthalmological surveillance is offered to first-degree relatives [14].

8.4. Prenatal and preimplantation diagnosis

With an identified variant or rearrangement, prenatal diagnosis is made by chorionic villus sampling or amniocentesis, and PGT is possible [13, 19, 20, 60]. Second-trimester ultrasound visualises the eye and lens, but may not detect recurrence of microphthalmia; anophthalmia is detectable with specialist ultrasound [1, 2]. Prenatal ultrasound only detects very marked hypertelorism [71]. In Norrie disease, because detachment may occur late in the third trimester, preterm induction for prophylactic surgery may be considered, and without testing ultrasound looks for associated signs such as hydrocephalus [20, 61]. In congenital glaucoma, whose visual outcomes may be poor despite treatment, prenatal diagnosis is only possible with known variants [14]. In Portugal, according to the SPO/SPGH recommendation, prenatal diagnosis is regulated by Law no. 16/2007, which allows termination of pregnancy up to 24 weeks when there are sound grounds to predict a severe and incurable disease or congenital malformation, with a decision by an institutional technical committee, and PGT by Law no. 32/2006, under the supervision of the National Council for Medically Assisted Procreation (CNPMA) [23].

8.5. Counselling of minors

The AAO advises against testing asymptomatic minors for untreatable diseases, except in exceptional circumstances with formal counselling and written agreement of the parents [22]. Portuguese law allows genetic testing in minors only for the direct benefit of the child, with consent of the parents or guardians and, ideally, of the minor, and restricts predictive testing for adult-onset diseases, unless there is evidence that early detection allows effective prevention or treatment [23]. In developmental eye anomalies, testing of the affected child is diagnostic rather than predictive; testing of asymptomatic siblings is justified when it changes surveillance, as in Norrie disease (early retinal examination), ADAMTSL4 ectopia and MYOC glaucoma [13, 14, 20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Population studies and what they measure

The measures are not interchangeable: birth registries measure birth prevalence, including terminations and stillbirths, whereas ophthalmological surveillance measures cumulative incidence in childhood and captures later diagnoses, such as typical colobomas [9, 11]. The British reference text gives a frequency of 71/10,000 for uveoretinal colobomas, a value much higher than that of population registries (0.7/10,000 in Strasbourg) and not confirmed in the sources consulted; it should not be used as an estimate [10, 60]. For primary congenital aphakia, Orphanet gives an unvalidated prevalence class of 1–5/10,000, implausible for a disease with few families described [28]. GeneGuidance assigns Norrie disease a prevalence of 1–5/10,000, which contradicts Orphanet (<1/1,000,000) and probably results from a mapping error [28, 41]. There are no prevalence data for FEVR, PFV, CHED, isolated megalocornea or isolated sclerocornea [28]. The chromosomal proportion in MAC differs between EUROCAT data (16%) and a 2007 review (25–30%) owing to differences in denominator [2, 19].

9.2. Population determinants

Consanguinity increases the proportion of recessive forms and the diagnostic yield: ocular malformations were associated with parental consanguinity in Strasbourg, the exome yield in microphthalmia/anophthalmia reached 61% in Saudi Arabia, and CHED is an important cause of paediatric corneal transplantation in consanguineous populations [3, 10, 41]. In the United Kingdom, children of Pakistani ethnicity had a 3.7-fold higher risk of MAC than white children (95% CI 1.9–7.5), with a trend towards higher incidence in socioeconomically deprived settings [11]. Severe visual impairment in childhood is more frequent in ethnic minorities and in children with low birth weight [149]. ROP depends on the survival of very preterm infants, and high inspired oxygen is a risk factor [61].

9.3. Founder populations and groups with their own data

Founder variants of ADAMTSL4 explain the variation in the proportion of this aetiology in non-syndromic ectopia lentis, from 0% in a Chinese group to 50% in several European groups: c.767_786del in western Norway and Germany, c.2237G>A in Māori and c.2594G>A in Bukharan Jews (section 2.6) [13]. In Fraser syndrome, FRAS1 variants have been described in Pakistani and Lebanese patients and FREM2 variants in two Spanish Roma families [5]. Norrie disease has been described in northern and central Europeans, Americans of European origin, African Americans, French Canadians, Hispanics, Chinese, Iranians, Indians and Japanese [20]. Oculopharyngeal muscular dystrophy, a cause of late-onset ptosis, has its highest prevalence in French Canadians [5].

9.4. Portugal and Brazil

In Portugal, the Unidade Local de Saúde de Coimbra is a member of ERN-EYE [26]. In 2025 the SPO and SPGH published joint recommendations for genetic testing in inherited retinal dystrophies, drawn up by ophthalmologists and geneticists from Coimbra, Porto, Aveiro and Lisbon [23]. A 2024 Portuguese review systematises the red reflex test and leukocoria in childhood [124]. The sources consulted do not include Portuguese prevalence data for congenital eye anomalies. In Brazil, the 2015 Zika epidemic produced a series of infants with ocular anomalies in Bahia, and a Brazilian cohort of 17 patients with microphthalmia/anophthalmia and orofacial clefts had a genetic diagnosis in 35.3% [3, 134]. A Brazilian study on congenital cataract is cited by the British reference text [63]. The absence of data in these sources does not demonstrate the absence of published studies.

9.5. Special populations

Children with intellectual disability or neurodevelopmental disorders require adapted visual assessment instruments [25]. Patients with severe visual impairment need alternative methods of informed consent (audio recordings, braille, large-print and high-contrast documents, impartial witnesses, assistive technologies) [23]. Preterm infants with atypical bilateral advanced ROP constitute a group in which a genetic component should be sought [20].

9.6. Reference networks and patient organisations

ERN-EYE covers more than 900 rare eye diseases, with 52 full members and 8 affiliated partners in 24 of the 27 Member States, and coordinates the European REDgistry registry, fed in France by the national BaMaRa registry and the FREDD data warehouse of the SENSGENE network [26, 148]. ERN ITHACA, for syndromes with intellectual disability, supported the Manchester study together with ERN-EYE [7]. Patient organisations and resources cited in the sources include MACS (Microphthalmia, Anophthalmia and Coloboma Support, United Kingdom), ICAN (International Children's Anophthalmia and Microphthalmia Network), FOCUS Families (ONH and SOD), Nystagmus Network, the Albinism Fellowship, the Lowe Syndrome Association, RNIB, the Macular Society, RP Fighting Blindness UK, Fight for Sight, SENSE, Contact a Family, NORD, the National Federation of the Blind and the eyeGENE registry of the National Eye Institute [1, 12, 19, 60–63, 66]. The sources consulted do not identify Portuguese or Brazilian organisations specific to these anomalies.

10. Illustrative Clinical Case

10.1. “Isolated” congenital cataract that was Sengers syndrome

In 2026 Gong and colleagues published the case of a Chinese female infant, the second child of non-consanguineous parents, with a brother who died shortly after birth without an established cause [72]. The bilateral cataracts were diagnosed at birth, and the child was referred to ophthalmology, where surgery was discussed [72]. At 3 months feeding difficulties, lethargy and poor weight gain appeared; at 4 months, in a tertiary centre, she had reduced visual response, cardiomegaly and generalised hypotonia [72]. Ocular ultrasound showed hyperechoic signs in the lens, the echocardiogram marked hypertrophic cardiomyopathy of the interventricular septum and left ventricular wall with an ejection fraction of 45%, the electrocardiogram ventricular pre-excitation, supraventricular extrasystoles and non-specific ST-segment and T-wave changes, and lactate was 9.8 mmol/L [72]. The pedigree, ocular ultrasound, echocardiogram and electrocardiogram are brought together in figure 2 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12903264/figure/F2/).

The initial exome identified two heterozygous variants: AGK NM_018238.4:c.409C>T p.(Arg137Ter), inherited from the mother and classified as pathogenic, and CRYBA2 NM_057093.2:c.457T>C p.(Tyr153His), inherited from the healthy father and classified as a VUS [72, 74]. The result was considered inconclusive, because Sengers syndrome is AR and there was only one pathogenic AGK allele, and because the variant in an isolated cataract gene was present in a father without disease [72]. Reanalysis of the exome data for exon-level CNVs (EXCAVATOR2 algorithm, minimum coverage of 30× and log2 threshold of ±0.8) revealed a paternal heterozygous 7.6 kb deletion (chr7:141297542–141305156, GRCh37) including exon 5 of AGK, confirmed by breakpoint PCR (wild-type allele of 8827 bp and deleted allele of 1212 bp) and by Sanger; the breakpoints had no homology or Alu repeats [72]. The diagnosis of Sengers syndrome due to compound heterozygosity (congenital cataract, hypertrophic cardiomyopathy and lactic acidosis) was established at 6–7 months [72].

Progression of the cardiac disease prevented cataract surgery, the child was moved to home palliative care with progressive deterioration, and the parents received genetic counselling with a recurrence risk of 25% [72]. The authors record that, by July 2025, 34 unique pathogenic or likely pathogenic AGK variants had been described in ClinVar and LOVD, and that large rearrangements are under-reported owing to lack of CNV analysis [72].

10.2. Lessons for the approach

The case brings together four points of the approach. First, a congenital cataract accompanied by systemic signs (poor weight gain, hypotonia, cardiomegaly) should prompt a search for a multisystem disease before it is classified as isolated, and the metabolic differential lists include respiratory chain diseases among the causes of cataract [63, 133]. Second, a single pathogenic allele in a recessive gene compatible with the phenotype requires a search for the second, and CNV analysis of exome data may find it without a new test [3, 72]. Third, a variant in an isolated cataract gene may be an incidental finding, and family segregation is part of the interpretation [23, 72]. Fourth, the aetiological diagnosis changed management (cataract surgery not performed, palliative care) and reproductive counselling [72]. The therapeutic decisions in the report resulted from this patient's cardiac severity and do not constitute a rule for congenital cataracts, whose surgery follows its own indications.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Visual prognosis depends on the finding and its severity, and overall prognosis depends on the extraocular manifestations. In the British Childhood Visual Impairment Study, 77% of children with severe visual impairment or blindness had associated non-ophthalmic disorders, 10% died in the year after diagnosis, and at least 75% had diseases that were neither preventable nor treatable with the knowledge of 2000 [149]. In MAC, the classification of Hornby and colleagues helps to predict visual prognosis in colobomas, and the vision of a future affected child may range from normal to blindness [2]. In ONH, the disorder is non-progressive but visual function is difficult to predict in infancy; in SOD without other CNS defects the intellectual prognosis is good, and intellectual disability (30%) is associated mainly with associated CNS defects [59, 66]. In congenital cataract, the isolated hereditary form has a better visual and surgical outcome, and even with early detection infants with bilateral cataract may be left with significant visual impairment [63]. Untreated glaucoma leads to irreversible constriction of the visual fields, and most is treatable with surveillance and early detection [14]. In retinal dystrophies, visual loss is usually progressive and treatable co-pathologies (macular oedema, cataract) arise [62]. In Norrie disease, most lose light perception in the first year, hearing loss reaches 80–90% by the end of the third decade and life expectancy may be reduced [20]. In ADAMTSL4 ectopia, final acuity ranges from light perception to 20/20, and highly displaced pupils may coexist with normal acuity [13]. In Fraser syndrome, perinatal mortality is high and useful vision unlikely; in Hallermann-Streiff syndrome, the ocular deficit usually culminates in blindness [51, 58].

11.2. Surveillance table

11.3. Long-term follow-up

Ophthalmological follow-up of anterior segment anomalies is prolonged, centred on glaucoma screening, and that of cataracts includes surgery when indicated and surveillance for amblyopia and glaucoma [1, 63]. Nystagmus requires prolonged follow-up by ophthalmology or neurology according to the diagnosis [12]. In retinal dystrophies, regular reviews detect co-pathologies and allow the diagnosis to be revisited [62]. In undiagnosed cases, periodic reanalysis of genomic data and clinical reassessment with reverse phenotyping are part of follow-up, because published yields are minimum values and the number of known genes continues to grow [3, 18, 23]. Findings that require extraocular surveillance (aorta, kidney, pituitary, brain, heart, hearing, blood, tumours) should be transferred explicitly to the follow-up plan, because it is through them that the molecular diagnosis changes the prognosis [7, 73].

12. Summary and Final Considerations

Congenital eye anomalies of genetic cause are a heterogeneous group of malformations and dysfunctions of the eye and adnexa, with a birth prevalence of the order of 4–7.5/10,000, which account for about 10% of visual impairment in children and result from about 150 genes, chromosomal anomalies, mosaicism and, in a fraction, environmental causes such as congenital infections and teratogenic drugs [3, 9, 10, 65]. The approach starts from the presenting ocular finding, requires rigorous phenotyping of both eyes and of the parents, and looks first for extraocular signs and urgent situations: leukocoria and retinoblastoma, cloudy cornea and congenital glaucoma, ONH and cortisol deficiency, aniridia and Wilms tumour, ectopia lentis and the aorta or thrombosis, cataract with systemic disease and galactosaemia or mitochondrial disease [14, 24, 63, 66, 72, 124].

Microarray remains the first analysis when there are extraocular signs, delay or aniridia, and sequencing should use cross-phenotype ocular panels, with CNV analysis, or exome and genome; yields range from less than 10% in isolated coloboma and unilateral forms to 80% in severe bilateral anophthalmia or microphthalmia, and increase with bilaterality, phenotypic complexity and family history [3, 4, 18]. A negative test does not exclude a genetic cause, because regulatory inversions, non-coding variants, mosaicism and still unknown genes escape current techniques; periodic reanalysis is part of follow-up [3, 23]. Molecular diagnosis changed management in one third of children in a large paediatric series, mainly by avoiding unnecessary investigations and by initiating surveillance of extraocular manifestations [7].

There is no authorised pharmacological treatment for structural malformations; treatment is surgical, optical, prosthetic and habilitative, with early intervention in NDP-related retinopathies (prophylactic photocoagulation, vitreoretinal surgery) and individualised surgical management in ectopia lentis due to ADAMTSL4 [13, 20]. Counselling is based on the aetiological diagnosis and, in its absence, on empirical risks (about 5–13% in MAC and colobomas, depending on the scenario and the parents' examination), bearing in mind the possibility of germline mosaicism and minimal expression in the parents [2, 8, 60]. ERN-EYE, with a member in Coimbra, and the 2025 SPO/SPGH recommendation provide the European and Portuguese framework for genetic testing and follow-up [23, 26].

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81. OMIM® Online Mendelian Inheritance in Man. #165550 OPTIC NERVE HYPOPLASIA, BILATERAL. Johns Hopkins University; last edited 23/08/2016. https://omim.org/entry/165550. Accessed 29 October 2026.
82. OMIM® Online Mendelian Inheritance in Man. #120430 COLOBOMA OF OPTIC NERVE. Johns Hopkins University; last edited 18/08/2014. https://omim.org/entry/120430. Accessed 29 October 2026.
83. OMIM® Online Mendelian Inheritance in Man. #259770 OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME; OPPG. Johns Hopkins University; last edited 04/10/2024. https://omim.org/entry/259770. Accessed 29 October 2026.
84. OMIM® Online Mendelian Inheritance in Man. #601631 ANTERIOR SEGMENT DYSGENESIS 3; ASGD3. Johns Hopkins University; last edited 20/10/2023. https://omim.org/entry/601631. Accessed 29 October 2026.
85. OMIM® Online Mendelian Inheritance in Man. #602482 AXENFELD-RIEGER SYNDROME, TYPE 3; RIEG3. Johns Hopkins University; last edited 23/04/2025. https://omim.org/entry/602482. Accessed 29 October 2026.
86. OMIM® Online Mendelian Inheritance in Man. #180500 AXENFELD-RIEGER SYNDROME, TYPE 1; RIEG1. Johns Hopkins University; last edited 25/02/2026. https://omim.org/entry/180500. Accessed 29 October 2026.
87. OMIM® Online Mendelian Inheritance in Man. #231300 GLAUCOMA 3, PRIMARY CONGENITAL, A; GLC3A. Johns Hopkins University; last edited 01/06/2021. https://omim.org/entry/231300. Accessed 29 October 2026.
88. OMIM® Online Mendelian Inheritance in Man. #182230 SEPTOOPTIC DYSPLASIA. Johns Hopkins University; last edited 09/11/2021. https://omim.org/entry/182230. Accessed 29 October 2026.
89. OMIM® Online Mendelian Inheritance in Man. *601802 HESX HOMEOBOX 1; HESX1. Johns Hopkins University; last edited 21/01/2025. https://omim.org/entry/601802. Accessed 29 October 2026.
90. OMIM® Online Mendelian Inheritance in Man. #214800 CHARGE SYNDROME. Johns Hopkins University; last edited 30/06/2025. https://omim.org/entry/214800. Accessed 29 October 2026.
91. OMIM® Online Mendelian Inheritance in Man. #302350 NANCE-HORAN SYNDROME; NHS. Johns Hopkins University; last edited 22/10/2025. https://omim.org/entry/302350. Accessed 29 October 2026.
92. OMIM® Online Mendelian Inheritance in Man. #309000 LOWE OCULOCEREBRORENAL SYNDROME; OCRL. Johns Hopkins University; last edited 12/08/2021. https://omim.org/entry/309000. Accessed 29 October 2026.
93. OMIM® Online Mendelian Inheritance in Man. #300500 ALBINISM, OCULAR, TYPE I; OA1. Johns Hopkins University; last edited 13/12/2022. https://omim.org/entry/300500. Accessed 29 October 2026.
94. OMIM® Online Mendelian Inheritance in Man. #123570 CRYPTOPHTHALMOS, UNILATERAL OR BILATERAL, ISOLATED; CRYPTOP. Johns Hopkins University; last edited 11/04/2025. https://omim.org/entry/123570. Accessed 29 October 2026.
95. OMIM® Online Mendelian Inheritance in Man. #610125 MICROPHTHALMIA, SYNDROMIC 5; MCOPS5. Johns Hopkins University; last edited 09/11/2022. https://omim.org/entry/610125. Accessed 29 October 2026.
96. OMIM® Online Mendelian Inheritance in Man. #300166 MICROPHTHALMIA, SYNDROMIC 2; MCOPS2. Johns Hopkins University; last edited 08/05/2025. https://omim.org/entry/300166. Accessed 29 October 2026.
97. OMIM® Online Mendelian Inheritance in Man. #309800 MICROPHTHALMIA, SYNDROMIC 1; MCOPS1. Johns Hopkins University; last edited 09/11/2022. https://omim.org/entry/309800. Accessed 29 October 2026.
98. OMIM® Online Mendelian Inheritance in Man. #206900 MICROPHTHALMIA, SYNDROMIC 3; MCOPS3. Johns Hopkins University; last edited 10/12/2024. https://omim.org/entry/206900. Accessed 29 October 2026.
99. OMIM® Online Mendelian Inheritance in Man. *184429 SRY-BOX 2; SOX2. Johns Hopkins University; last edited 21/04/2026. https://omim.org/entry/184429. Accessed 29 October 2026.
100. OMIM® Online Mendelian Inheritance in Man. *600037 ORTHODENTICLE HOMEOBOX 2; OTX2. Johns Hopkins University; last edited 04/02/2020. https://omim.org/entry/600037. Accessed 29 October 2026.
101. OMIM® Online Mendelian Inheritance in Man. #601186 MICROPHTHALMIA, SYNDROMIC 9; MCOPS9. Johns Hopkins University; last edited 21/02/2024. https://omim.org/entry/601186. Accessed 29 October 2026.
102. OMIM® Online Mendelian Inheritance in Man. #206920 MICROPHTHALMIA WITH LIMB ANOMALIES; MLA. Johns Hopkins University; last edited 03/05/2024. https://omim.org/entry/206920. Accessed 29 October 2026.
103. OMIM® Online Mendelian Inheritance in Man. #613517 MICROPHTHALMIA, ISOLATED 6; MCOP6. Johns Hopkins University; last edited 04/03/2024. https://omim.org/entry/613517. Accessed 29 October 2026.
104. OMIM® Online Mendelian Inheritance in Man. #615113 MICROPHTHALMIA, ISOLATED 8; MCOP8. Johns Hopkins University; last edited 14/06/2022. https://omim.org/entry/615113. Accessed 29 October 2026.
105. OMIM® Online Mendelian Inheritance in Man. #194072 WILMS TUMOR, ANIRIDIA, GENITOURINARY ANOMALIES, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; WAGR. Johns Hopkins University; last edited 22/12/2022. https://omim.org/entry/194072. Accessed 29 October 2026.
106. OMIM® Online Mendelian Inheritance in Man. #613834 SMOOTH MUSCLE DYSFUNCTION SYNDROME; SMDYS. Johns Hopkins University; last edited 16/02/2026. https://omim.org/entry/613834. Accessed 29 October 2026.
107. OMIM® Online Mendelian Inheritance in Man. #269880 SHORT SYNDROME. Johns Hopkins University; last edited 22/04/2025. https://omim.org/entry/269880. Accessed 29 October 2026.
108. OMIM® Online Mendelian Inheritance in Man. %249310 NEUHAUSER SYNDROME. Johns Hopkins University; last edited 27/03/2024. https://omim.org/entry/249310. Accessed 29 October 2026.
109. OMIM® Online Mendelian Inheritance in Man. 181700 SCLEROCORNEA, AUTOSOMAL DOMINANT. Johns Hopkins University; last edited 13/08/2012. https://omim.org/entry/181700. Accessed 29 October 2026.
110. OMIM® Online Mendelian Inheritance in Man. #217300 CORNEA PLANA 2, AUTOSOMAL RECESSIVE; CNA2. Johns Hopkins University; last edited 21/04/2016. https://omim.org/entry/217300. Accessed 29 October 2026.
111. OMIM® Online Mendelian Inheritance in Man. #175780 BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES; BSVD1. Johns Hopkins University; last edited 20/11/2025. https://omim.org/entry/175780. Accessed 29 October 2026.
112. OMIM® Online Mendelian Inheritance in Man. #129600 ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT; ECTOL1. Johns Hopkins University; last edited 15/12/2025. https://omim.org/entry/129600. Accessed 29 October 2026.
113. OMIM® Online Mendelian Inheritance in Man. #251750 MICROSPHEROPHAKIA AND/OR MEGALOCORNEA, WITH ECTOPIA LENTIS AND WITH OR WITHOUT SECONDARY GLAUCOMA; MSPKA. Johns Hopkins University; last edited 21/07/2021. https://omim.org/entry/251750. Accessed 29 October 2026.
114. OMIM® Online Mendelian Inheritance in Man. 300216 COATS DISEASE. Johns Hopkins University; last edited 16/05/2013. https://omim.org/entry/300216. Accessed 29 October 2026.
115. OMIM® Online Mendelian Inheritance in Man. #152950 MICROCEPHALY WITH OR WITHOUT CHORIORETINOPATHY, LYMPHEDEMA, OR IMPAIRED INTELLECTUAL DEVELOPMENT; MCLMR. Johns Hopkins University; last edited 05/09/2024. https://omim.org/entry/152950. Accessed 29 October 2026.
116. OMIM® Online Mendelian Inheritance in Man. #193235 VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY; VRNI. Johns Hopkins University; last edited 28/09/2023. https://omim.org/entry/193235. Accessed 29 October 2026.
117. OMIM® Online Mendelian Inheritance in Man. %304050 AICARDI SYNDROME; AIC. Johns Hopkins University; last edited 11/09/2012. https://omim.org/entry/304050. Accessed 29 October 2026.
118. OMIM® Online Mendelian Inheritance in Man. *167409 PAIRED BOX GENE 2; PAX2. Johns Hopkins University; last edited 14/06/2022. https://omim.org/entry/167409. Accessed 29 October 2026.
119. OMIM® Online Mendelian Inheritance in Man. #609218 FOVEAL HYPOPLASIA 2; FVH2. Johns Hopkins University; last edited 15/09/2016. https://omim.org/entry/609218. Accessed 29 October 2026.
120. OMIM® Online Mendelian Inheritance in Man. #214500 CHEDIAK-HIGASHI SYNDROME; CHS. Johns Hopkins University; last edited 07/08/2023. https://omim.org/entry/214500. Accessed 29 October 2026.
121. OMIM® Online Mendelian Inheritance in Man. #614074 HERMANSKY-PUDLAK SYNDROME 5; HPS5. Johns Hopkins University; last edited 10/04/2024. https://omim.org/entry/614074. Accessed 29 October 2026.
122. OMIM® Online Mendelian Inheritance in Man. #243310 BARAITSER-WINTER SYNDROME 1; BRWS1. Johns Hopkins University; last edited 06/09/2023. https://omim.org/entry/243310. Accessed 29 October 2026.
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