Hereditary Congenital Cataracts

Non-syndromic congenital and childhood-onset cataract (isolated or limited to the eye), genetically heterogeneous, caused mainly by variants in genes encoding crystallins, connexins, lens membrane and cytoskeletal proteins and transcription factors; syndromic, metabolic and infectious forms appear as differential diagnoses.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

A cataract is an opacity of the lens [39]. Congenital cataract is a clinical sign and not a precise diagnosis: the same opacity may result from a variant in a structural lens gene, a treatable metabolic disease, a prenatal infection, an anterior segment malformation or trauma [45]. Cataracts may be isolated, associated with other ocular malformations (aniridia, congenital glaucoma, microphthalmia) or part of multisystem syndromes [39]. The clinical scope of this article is non-syndromic congenital or childhood-onset cataract, which Orphanet designates early-onset non-syndromic cataract (ORPHA:91492), including forms with ocular anomalies limited to the eye, such as microcornea, and forms with subtle metabolic defects without systemic disease, such as mild renal glucosuria or hyperferritinaemia [1, 2]. Syndromic, metabolic and infectious cataracts are treated as differential diagnoses.

Terminology by age distinguishes congenital cataract (present at birth), infantile (up to 2 years), juvenile (2 to 12 years), adolescent (12 to 21 years) and presenile (before 40 years); Mendelian cataract usually begins between birth and 40 years [2]. Hereditary cataracts are generally bilateral and relatively symmetrical, but morphology is so heterogeneous that there is no standardised classification system. The most widely used simplified classification groups the opacities into zonular (nuclear or central, lamellar and sutural), polar (anterior and posterior), total or mature and membranous (fusion of the capsules after resorption of the contents), qualifying them by shape (aculeiform, coralliform, discoid, polymorphic), density (pulverulent, punctate) and colour (cerulean or blue-dot) [2]. A totally opaque lens is the common end point of all types, and at that stage classification is no longer possible [39].

1.2. Historical overview

Reports of familial cataract in Europe date back to the end of the 19th century. A six-generation English pedigree with autosomal dominant zonular pulverulent cataract, documented in 1909, became the original pedigree of the CZP1 locus (also designated CAE1), and a nine-generation British pedigree with «Coppock-like» discoid cataract, described in 1910, was later linked to the γ-crystallin gene cluster on chromosome 2 [2]. In 1963, Renwick and Lawler described probable linkage between a congenital cataract locus and the Duffy blood group locus [49]; when the Duffy group was mapped to chromosome 1, in 1968, this cataract became the first monogenic disease assigned to a human autosome [2]. The crystallins had been discovered and named by Mörner about 125 years before the 2020 review by Berry and colleagues [50].

Gene identification began at the end of the 1990s. In 1997, Litt and colleagues associated an autosomal dominant cerulean cataract with a chain-termination variant in CRYBB2, in a family in which visual acuity was only slightly reduced until adulthood [51], and, in 1998, a dominant congenital cataract mapped to 21q22.3 with the R116C variant of CRYAA; the authors noted that at least one third of congenital cataracts are familial and that the dominant form appeared to be the most common in the Western world [52]. In the same year, Shiels and colleagues refined the CZP1 locus in the original eight-generation pedigree (maximum multipoint LOD score, the logarithm of the odds of linkage, of 5.22) and identified in GJA8, which encodes connexin 50, the P88S variant cosegregating with the disease [53]. In 1999 came the first GJA3 (connexin 46) variants at the CZP3 locus on chromosome 13 [54] and the clarification of the role of the γ-crystallins: the variant in the CRYGE pseudogene proposed as the cause of Coppock-like cataract proved to be a polymorphism present in 23% of controls, the original family in fact had a missense variant in CRYGC, and aculeiform cataract was attributed to a variant in CRYGD [2, 55]. In 2001, Berry and colleagues described the first CRYAB variant associated with isolated congenital cataract, a frameshift deletion in a four-generation English family with posterior polar cataract [56].

Next-generation sequencing (panels, exome and genome in families and trios) has replaced linkage analysis [2]. The Cat-Map database, maintained at Washington University, recorded in June 2024 more than 1850 entries, more than 900 publications from more than 50 countries and more than 450 human genes and loci associated with hereditary or age-related cataract, of which more than 300 are associated with syndromic forms [2, 57]. In 2020, about 50 genes were associated with isolated cataract [50], and 2025 reviews cite more than 100 genes associated with paediatric cataract [45].

The history of treatment is equally recent. In 1957 Costenbader advised against surgery for unilateral congenital cataract unless it was hypermature; from the 1970s onwards, small series with early surgery, contact lens and occlusion of the fellow eye showed that good acuity could be achieved, and pars plana vitrectomy, modern contact lenses, foldable intraocular lenses and the work of Hubel and Wiesel on the critical period of visual development changed practice [58]. Replacement of the lens by an intraocular lens was pioneered by Ridley in 1949–1950 [2], and the Infant Aphakia Treatment Study (IATS), begun in 2004, was the first randomised trial to compare an intraocular lens with aphakia and a contact lens in infants [59].

1.3. Nomenclature and entities within scope

OMIM numbers the non-syndromic Mendelian forms in a «Cataract» series (CTRCT1 to CTRCT47 and beyond), in which each number corresponds to a gene and inheritance may be dominant, recessive or both; Orphanet groups them under ORPHA:91492 with morphological subtypes, and some subtypes (cataract-microcornea, ORPHA:1377; juvenile cataract-microcornea-renal glucosuria, ORPHA:247794) are classified as malformation syndromes even though the disease is limited to the eye or to a benign laboratory trait [1, 24]. The morphological name does not identify the gene: the same variant may produce different morphologies in the same family, and the same morphology results from different genes [39, 60]. The historical names of variants (for example, P23T in CRYGD, numbered without the initial methionine, = NM_006891.4:c.70C>A p.(Pro24Thr), and Q215X in SLC16A12, = NM_213606.4:c.733C>T p.(Gln245Ter)) often differ from current HGVS (Human Genome Variation Society) nomenclature on the MANE (Matched Annotation from NCBI and EMBL-EBI) Select transcript, and the correspondence is standardised in section 2.11 [61, 62].

2. Molecular Genetics and Pathophysiology

2.1. The lens and the basis of transparency

The newborn lens measures about 6.5 mm by 4 mm, weighs about 65 mg and corresponds to the nucleus of the adult lens, because the fibres formed during embryonic and fetal life are never replaced [2]. The central fibres lose their nucleus and organelles during differentiation, and the proteins synthesised at that stage remain in the lens throughout life; for this reason, a misfolded or insoluble crystallin produces aggregates that scatter light without any measurable metabolic block [64, 65]. The α-, β- and γ-crystallins make up about 90% of lens proteins and determine the refractive index gradient; the α-crystallins (αA, encoded by CRYAA, and αB, encoded by CRYAB) belong to the small heat shock protein family and function as chaperones, whereas the β- and γ-crystallins are structural proteins organised in «Greek key» motifs [50, 64].

The lens is avascular and depends on an internal microcirculation of ions, water and small molecules maintained by gap junctions formed by connexins 46 and 50 and by aquaporin 0 [6–8]. The fibre-specific cytoskeleton includes the beaded filaments formed by filensin (BFSP1) and phakinin (BFSP2), which interact with αA-crystallin [2, 10]. Fibre differentiation also requires programmed denucleation and organelle elimination, controlled by HSF4 and by FYCO1-dependent autophagosome transport, and a transcriptional programme in the anterior epithelium involving PITX3, FOXE3 and PROX1 [12, 13, 17]. In galactosaemia, by contrast, the cataract is osmotic: galactose accumulated in the fibres is reduced to galactitol, an alcohol that does not cross the membrane and draws in water [30].

2.2. Genetic architecture

The most common inheritance of isolated familial cataract is autosomal dominant, usually through variants in structural proteins [39]. Crystallin variants account for almost half of non-syndromic hereditary congenital cataracts; in 2020, Berry and colleagues counted 308 variants in the 13 crystallin genes, about 23% of all hereditary cataract variants recorded in Cat-Map [50]. In 2024, Shiels counted more than 440 crystallin variants associated with hereditary or age-related cataract and more than 220 variants combined in the two connexins [2]. CRYAA, CRYGD and CRYBB2 account for more than half of crystallin variants, including the recurrent p.(Arg12Cys), p.(Arg21Trp), p.(Arg54Cys) and p.(Arg116Cys) of CRYAA (NM_000394.4), p.(Pro24Thr) of CRYGD (NM_006891.4) and p.(Gln155Ter) of CRYBB2 (NM_000496.3), with the c. notation in section 2.11 [2, 62].

Source: counts from Berry and colleagues [50]; evidence classes from Ing and colleagues [66]. AD, autosomal dominant; AR, autosomal recessive.

2.3. α-Crystallins: CRYAA and CRYAB

αA-crystallin is a small heat shock protein of the HSP20 family, very abundant in the lens, which keeps unstable proteins in soluble complexes and contributes, with filensin and phakinin, to the intermediate filaments of the fibres [4]. More than 75% of pathogenic CRYAA variants lie in the N-terminal domain (amino acids 1 to 63), mainly at arginines (R12C, R21W/L/Q, R49C, R54C, R65Q, R116C/H, R117H, R119H; published one-letter designations on NP_000385.1, NM_000394.4) [50]. R65Q corresponds to NM_000394.4:c.194G>A p.(Arg65Gln), classified in ClinVar as of uncertain significance; R117H and R119H have no ClinVar record and remain as published designations [62]. Dominant disease is the main form (CTRCT9, OMIM 604219), with variable opacities within the same family (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular) and, in some members, microcornea and corneal opacity [4]. The recessive forms result from null or missense alleles that abolish the protein: the homozygous nonsense variant NM_000394.4:c.27G>A p.(Trp9Ter) in a consanguineous Persian Jewish family and homozygosity for NM_000394.4:c.160C>T p.(Arg54Cys) in three Saudi siblings with total white congenital cataract and microcornea, whose heterozygous parents had punctate opacities visible only on careful slit-lamp examination [4, 67]. Two de novo variants that abolish the stop codon and extend the protein caused bilateral microphthalmia with severe anterior segment dysgenesis, including congenital aphakia, microcornea and iris hypoplasia [4].

CRYAB encodes αB-crystallin (HSPB5), also expressed in muscle, heart, kidney and brain, with lens-specific and heart-specific enhancers [50]. The gene is associated with four distinct entities: cataract 16 (CTRCT16, OMIM 613763), dominant or recessive, classically posterior polar (a discoid posterior subcapsular opacity that impairs vision out of proportion to its size) and also nuclear or lamellar; adult myofibrillar myopathy 2A (OMIM 608810), dominant, with proximal and distal weakness, respiratory failure, hypertrophic cardiomyopathy and cataract, whose founder variant is NM_001289808.2:c.358A>G p.(Arg120Gly); fatal infantile hypertonic myofibrillar myopathy (OMIM 613869), recessive, with progressive muscle rigidity in the first weeks and death usually before 3 years, described in Canadian Aboriginal infants; and dilated cardiomyopathy 1II (OMIM 615184), whose evidence is limited to one missense variant and which is not included in the March 2026 recuration of the ClinGen dilated cardiomyopathy panel [5]. In restrictive cardiomyopathy, a CRYAB variant was described in two German siblings diagnosed at 19 and 28 years, both also carrying a rare RBM20 variant, without the authors having considered a digenic or biallelic cause [68]. In the myofibrillar myopathies, the median age at onset is 55 years (range 7–77), creatine kinase is normal or slightly raised and cardiomyopathy is frequent, with hypertrophic cardiomyopathy in childhood associated with αB-crystallin [69]. The common mechanism is loss or corruption of chaperone function: in muscle, the mutant protein aggregates with desmin; in the lens, protein aggregation destroys transparency [5]. A CRYAB cataract may occur without myopathy, but cataract is also part of myofibrillar myopathy 2A; when a CRYAB variant is found, a muscular, respiratory and cardiac history is mandatory [5].

2.4. β-Crystallins

CRYBA1 (CTRCT10, OMIM 600881) causes bilateral dominant cataract of variable morphology: the first described was zonular with Y-sutural opacities, and there are nuclear, lamellar, pulverulent and posterior polar forms [70]. Two classes of variants predominate: splicing variants at the first base of intron 3 (c.215+1G>A and variants at the same nucleotide) and the recurrent in-frame deletion p.Gly91del, described in at least 14 families of various origins, mainly with nuclear or lamellar cataract, which disrupts the «tyrosine corner» and reduces folding and solubility [50, 62, 70]. Misfolded βA3/A1 protein destabilises the β-heteromers, and the splicing variants activate the unfolded protein response and apoptosis in differentiating fibres [70].

CRYBA4 (CTRCT23, OMIM 610425) was established in a large Indian family with zonular cataract and NM_001886.3:c.281T>C p.(Phe94Ser); families with cataract-microcornea (NM_001886.3:c.190G>T p.(Gly64Trp)) and a five-generation family with p.(Gly24Val) (published designation, no ClinVar record) have been described, and a partial CRYBB1-CRYBA4 duplication segregated with dominant cataract, with the effect attributed to the truncated copy of CRYBB1 [71]. CRYBB1 (CTRCT17, OMIM 611544) causes pulverulent or nuclear cataract, sometimes lamellar and with microcornea, with dominant inheritance (NM_001887.4:c.658G>T p.(Gly220Ter), which produces a much less soluble truncated protein; p.(Ser129Arg), a published protein designation that in ClinVar corresponds to c.387C>G or c.387C>A, which destabilises the βB1/βA3 heteromer) or recessive inheritance (homozygous frameshift in consanguineous Bedouin families; homozygous initiation codon variant) [72]. N-terminal CRYBB1 variants tend towards recessive inheritance and C-terminal variants towards dominant inheritance, possibly because of nonsense-mediated mRNA decay (NMD) in the former [50]. The variant NM_001887.4:c.171del p.(Asn58ThrfsTer107) occurs in the homozygous state in several unrelated Saudi patients, with variable phenotypes (anterior polar, nuclear, lamellar pulverulent, sutural, with or without strabismus and glaucoma) [28, 62].

CRYBB2 (CTRCT3, OMIM 601547) causes dominant cataract of variable morphology within the same family: cerulean, with bluish and white dots in concentric layers and little reduction of vision until adulthood, sutural, pulverulent, nuclear, coronary and progressive membranous [51, 73]. The classic variant NM_000496.3:c.463C>T p.(Gln155Ter) results from gene conversion from the neighbouring pseudogene CRYBB2P1, which shares more than 97% homology; this mechanism explains the independent recurrence of the same variant in different families and as a de novo variant [62, 73]. Recessive inheritance has been described in a consanguineous family with a homozygous deletion that creates a CRYBB2-CRYBB2P1 fusion and in a Swiss patient homozygous for NM_000496.3:c.526G>A p.(Asp176Asn), with heterozygous parents without opacities; up to October 2020, the 32 published CRYBB2 variants were all dominant [29, 73]. CRYBB3 (CTRCT22, OMIM 609741) is mainly recessive: the homozygous founder variant NM_004076.5:c.493G>C p.(Gly165Arg) occurs in consanguineous Pakistani families, and in a Pakistani cohort of 116 families with recessive cataract CRYBB3 was the second most frequent gene (5.2% of families); dominant variants at Gly156 are associated with paediatric cataract with microphthalmia [74]. CRYBA2 has the weakest relationship: NM_057093.2:c.148G>A p.(Val50Met) cosegregated with dominant cataract in a four-generation family with incomplete penetrance, and p.(Tyr153His) (published designation, no ClinVar record) in a Chinese family with presenile cataract (onset between 24 and 30 years) [23].

2.5. γ-Crystallins

The γ-crystallins are symmetrical monomers synthesised in the developing lens and retained throughout life; the defect is physical (aggregation), with no biochemical assay [64]. CRYGA, CRYGB, CRYGC and CRYGD form a cluster at 2q33.3, alongside the pseudogenes CRYGEP1 and CRYGFP, whereas CRYGS is at 3q27.3; the similarity between paralogues requires the gene assignment to be checked in variants and citations [75]. CRYGC (CTRCT2, OMIM 604307) is the historical prototype of Coppock-like cataract, a pulverulent discoid opacity of the embryonal nucleus with multiple white dots in the lamellar zone; it is frequently associated with microcornea or microphthalmia, which changes the surgical plan and the refractive target [64, 76].

CRYGD (CTRCT4, OMIM 115700) causes aculeiform cataract (needle-like crystals traversing the axial zone), cerulean, coralliform, polymorphic non-nuclear, nuclear and lamellar cataract, sometimes with microcornea [65]. Truncating variants in exon 3 (about one third of pathogenic CRYGD variants) remove the third and fourth Greek key motifs; in mouse models, the truncated protein forms amyloid fibres and aggregates in the fibre nuclei, displaces phakinin to the nucleus and prevents the accumulation of Prox1, with nuclear cataract [50]. The variant c.70C>A p.(Pro24Thr), historically P23T, accounts for about one third of causal CRYGD variants and gives mainly a coralliform phenotype in families from several continents; the mutant protein has reduced solubility and aggregates through a non-amyloid mechanism, with near-native folding and abnormal surface interactions [50, 60]. Different haplotypes in Chinese carrier families indicate a mutational hotspot rather than a founder effect [60].

CRYGS (CTRCT20, OMIM 116100) causes progressive polymorphic cortical opacities, pulverulent cataract with the recurrent variant NM_017541.4:c.169G>T p.(Gly57Trp) and lamellar cortical cataract, with onset ranging from congenital to late progressive [75]. In the Swiss cohort, a sibling carrying CRYGS NM_017541.4:c.224G>A p.(Gly75Asp) had a normal examination at 20 years, documenting incomplete penetrance [29].

2.6. Connexins: GJA8 and GJA3

Connexins 46 (GJA3) and 50 (GJA8) are the most abundant connexins of the lens and form gap junctions and hemichannels that ensure the circulation of ions and small molecules essential for transparency and fibre maturation [2, 6]. GJA8 (CTRCT1, OMIM 116200) causes, mainly in dominant fashion, zonular pulverulent, progressive nuclear or nuclear pulverulent cataract, and also total and posterior subcapsular cataract; it is frequently associated with microcornea, microphthalmia and nystagmus, and screening of 426 individuals with anophthalmia, microphthalmia or coloboma identified GJA8 variants, so anterior segment dysgenesis, sclerocornea and secondary glaucoma belong to the spectrum [2, 6]. The variants do not act uniformly: NM_005267.5:c.137G>T p.(Gly46Val) increases hemichannel activity, NM_005267.5:c.827C>T p.(Ser276Phe) and NM_005267.5:c.131T>C p.(Val44Ala) decrease it, and most missense variants have a dominant negative or gain-of-function effect; a single consanguineous family with a homozygous frameshift at codon 203 establishes a rare recessive form, in which the null allele causes disease only in the homozygous state [6]. The recurrent 1q21.1 deletion includes GJA8 and is associated with congenital cataracts in some carriers [35].

GJA3 (CTRCT14, OMIM 601885) causes dominant zonular pulverulent, nuclear, posterior polar, perinuclear and Coppock-like cataract [7]. The mechanisms are varied: NM_021954.4:c.227G>A p.(Arg76His) and c.226C>G p.(Arg76Gly) form hemichannels but reduce junctional plaques and coupling; p.(His224Arg) (published designation, no ClinVar record) forms junctions but increases dye uptake by hemichannels; NM_021954.4:c.427G>A p.(Gly143Arg) binds calmodulin to an increased extent and in a calcium-insensitive manner [7]. GJA3 variants are frequently associated with high myopia, and the first two transmembrane domains, which form the pore of the hemichannel (connexon), concentrate variants [76, 77].

2.7. Membrane and cytoskeletal proteins

MIP encodes aquaporin 0, which transports water and mediates adhesion between fibres (CTRCT15, OMIM 615274, dominant). Morphologies include polymorphic, progressive punctate lamellar, cortical, anterior and posterior polar, embryonal nuclear and pulverulent cortical; in a four-generation family, the distribution of the opacities appeared to follow that of the protein in the lens [8]. A review of 29 causal variants showed clustering in helices H4 to H6, the C-terminal domain and loop C, with no clear correlation with morphology. The recurrent variant NM_012064.4:c.97C>T p.(Arg33Cys) traffics normally and has water permeability equal to that of the wild type, but reduces cell adhesion and gap junction coupling [8].

LIM2 (CTRCT19, OMIM 615277), of the PMP22/claudin superfamily, has recessive forms with severe congenital cataract or early-childhood nuclear cataract (NM_001161748.2:c.461G>A p.(Gly154Glu); p.(Gly78Asp), a published designation with no ClinVar record) and a dominant form with the recurrent variant NM_001161748.2:c.388C>T p.(Arg130Cys) in British, Czech, Chinese and Japanese families, with pulverulent, nuclear, membranous or sutural cataract; in four Chinese families, p.(Arg130Cys) was associated with increased axial length and myopic fundus changes [9]. BFSP1 (CTRCT33, OMIM 611391) follows the variant class: biallelic multi-exon intragenic deletions cause recessive juvenile cortical cataract with unaffected carriers (a 3343 bp deletion including exon 6 in an Indian family; a 15.4 kb deletion of exons 3 to 5 in a Pakistani family), and specific missense variants such as NM_001195.5:c.1042G>A p.(Asp348Asn) cause dominant congenital nuclear cataract [10]. BFSP2 (CTRCT12, OMIM 611597) causes dominant congenital or progressive juvenile cataract (sutural, pulverulent, lamellar, cortical, stellate, nuclear); a consanguineous family with a homozygous probably null allele and healthy heterozygotes shows that the dominant alleles act through a dominant negative effect on filament assembly and not through haploinsufficiency [11]. This distinction prevents a heterozygous truncating variant in BFSP1 or BFSP2 from being automatically interpreted as a cause of dominant disease [10, 11].

VIM (CTRCT30, OMIM 116300) rests on a single substitution, NM_003380.5:c.451G>A p.(Glu151Lys), in one proband among 90 screened, with congenital pulverulent cataract and abnormal filament assembly [25]. CHMP4B (CTRCT31, OMIM 605387), a subunit of the ESCRT-III complex, was identified by linkage in a white family with progressive childhood posterior subcapsular cataract (NM_176812.5:c.386A>T p.(Asp129Val); LOD 5.50) and in a Japanese family with posterior polar cataract; in the mouse, the heterozygous knock-in equivalent to p.(Asp129Val) does not reproduce the cataract, so the human mechanism has not been established [26].

2.8. Transcription factors

HSF4 (CTRCT5, OMIM 116800) encodes a heat shock transcription factor that controls the lens heat shock proteins and fibre denucleation [2, 12]. Missense variants in the DNA-binding domain cause dominant lamellar cataract, described in three Chinese families and in the Marner cataract of a large Danish family (described in 1949, stellate zonular and anterior polar); null variants outside this domain, such as NM_001374675.1:c.1213C>T p.(Arg405Ter) in Pakistani families, cause recessive disease [2, 12].

PITX3 (CTRCT11, OMIM 610623; anterior segment dysgenesis 1, OMIM 107250) causes a dominant spectrum ranging from isolated progressive posterior polar cataract to cataract with anterior segment mesenchymal dysgenesis; in three unrelated families all affected individuals had progressive bilateral posterior polar cataract, and dysgenesis appeared only in a minority (1 of 10 and 4 of 11 affected individuals in two of them) [13]. The recurrent variant is the 17 bp duplication in exon 4, c.640_656dup p.(Gly220ProfsTer95), identified in four Belgian families; a second variant, c.573del p.(Ser192AlafsTer117), was described in a Belgian-Romanian family, and both retain nuclear localisation but reduce DNA binding and transactivation [78]. Downstream, regulation of FOXE3 and PROX1 in the anterior epithelium fails, and a severe recessive form combines microphthalmia and neurological dysfunction because of the role of the gene in dopaminergic neurons [13].

MAF has two dominant phenotypes separated by the domain affected. Variants that abolish DNA binding in the basic region of the bZIP domain (for example, NM_005360.5:c.863G>C p.(Arg288Pro)) cause isolated cerulean or pulverulent cataract (CTRCT21, OMIM 610202), sometimes with microcornea, anterior segment dysgenesis and iris coloboma. De novo missense variants in the glycogen synthase kinase 3 (GSK3) phosphorylation motifs of the transactivation domain stabilise the protein and cause Aymé-Gripp syndrome (OMIM 601088), with cataract, sensorineural hearing loss, characteristic facies and developmental delay [14, 36]. A variant in the bZIP region and a variant in the GSK3 motifs are not equivalent in laboratory interpretation [14].

FOXE3 (CTRCT34, OMIM 612968; anterior segment dysgenesis 2, OMIM 610256) takes part in closure of the lens vesicle and proliferation of the anterior epithelium [2, 15]. Inheritance tracks severity: biallelic truncating variants or variants in the forkhead domain cause primary congenital aphakia (the lens never forms), as a rule with severe corneal opacity, sclerocornea and microphthalmia (in the largest series, 90% of recessive families with severe corneal opacity, 83% with aphakia and 80% with microphthalmia), whereas dominant forkhead domain extension variants give cataract in 99% of carriers with normal eye size in 96% [15]. In a multicentre series of 14 children (27 eyes) with primary aphakia, 9 of the 11 tested had FOXE3 variants; the cornea was silvery and vascularised in 96% of eyes, and glaucoma developed in 81% [15]. The dominant variant NM_012186.3:c.457G>C p.(Asp153His), with conflicting classifications in ClinVar, has been associated with susceptibility to thoracic aneurysm (OMIM 617349) with moderate evidence, which does not justify aortic surveillance on the basis of a FOXE3 variant alone [15]. PAX6, the main aniridia gene, can cause apparently isolated cataract, as in a patient with bilateral cataract and glaucoma due to a frameshift variant [2, 77].

2.9. Other genes associated with isolated cataract

EPHA2 (CTRCT6, OMIM 116600) encodes an ephrin receptor with expression increasing from the equator towards the cortical fibres; it causes dominant posterior polar, nuclear, total, posterior subcapsular or cortical cataract, recessive forms that are mainly nuclear in consanguineous families and, in the homozygous state, syndromic microphthalmia; common variants are reproducibly associated with age-related cortical cataract [2, 16]. There is no curated tumour predisposition relationship for EPHA2, so a germline finding in this gene has no oncological implication [16].

FYCO1 (CTRCT18, OMIM 610019), an adaptor that links Rab7, PI(3)P and LC3 to autophagosome transport, causes recessive nuclear or total congenital cataract; it was identified in 12 Pakistani families and one Israeli Arab family (9 variants, mainly nonsense or frameshift) and is one of the most common causes of recessive cataract in Pakistan [17]. Among the Yakut of Eastern Siberia, the variant NM_024513.4:c.1621C>T p.(Gln541Ter) was homozygous in 25 of 29 families with congenital cataract (86%), with a carrier frequency of 7.9% and a founder haplotype dated to about 260 ± 65 years [17]. TDRD7 (CTRCT36, OMIM 613887), a component of the lens RNA granules, causes recessive congenital cataract; in two consanguineous families, the men also had non-obstructive azoospermia, and the glaucoma described in the mouse has weak human evidence [18].

SLC16A12 encodes monocarboxylate transporter 12 (MCT12), which transports creatine and guanidinoacetate; the nonsense variant described as Q215X in a large Swiss family causes dominant juvenile cataract with microcornea (CTRCT47, OMIM 612018) [24, 63]. The mild renal glucosuria in that family was later explained by heterozygosity for an SLC5A2 (SGLT2) allele, so mutated MCT12 accounts only for the ocular manifestations [63]. LSS (lanosterol synthase) causes extensive recessive congenital cataract (CTRCT44, OMIM 616509) in two families homozygous for W581R and G588S (= NM_002340.6:c.1741T>C p.(Trp581Arg) and c.1762G>A p.(Gly588Ser)), and also hypotrichosis, alopecia with intellectual disability and palmoplantar keratoderma with early cataract, generally with normal plasma cholesterol [19, 79].

AGK (acylglycerol kinase, a subunit of the TIM22 complex) causes, in the homozygous or compound heterozygous state, Sengers syndrome (OMIM 212350), with cataract in 98%, hypertrophic cardiomyopathy in 88%, lactic acidosis and myopathy; at the mild end, one family had isolated cataract (CTRCT38, OMIM 614691), and a 7.6 kb deletion was initially diagnosed as isolated cataract [20]. Heterozygous WFS1 causes isolated dominant congenital nuclear cataract (CTRCT41, OMIM 116400; 11 affected individuals in an Irish family), without predicting diabetes insipidus or neurodegeneration; the biallelic form corresponds to Wolfram syndrome [21]. NHS causes Nance-Horan syndrome and X-linked cataract 40 (OMIM 302200), the latter through rearrangements with aberrant transcription of the gene, with dense nuclear cataract in males and mild sutural cataract in females [22].

The more than 30 broadly expressed («extralenticular») genes associated with isolated cataract also include GCNT2 (recessive cataract in Japanese patients, through differential splicing between erythrocyte and lens), TMEM114 (dominant lamellar cataract due to a translocation), RNLS, LONP1 (recessive nuclear cataract, with or without CODAS syndrome), LEMD2 (recessive juvenile cataract of the Hutterites, associated with sudden cardiac death), UNC45B (dominant Danish family), SIPA1L3, PANK4 (intronic variant in a Chinese family) and DNMBP (biallelic loss of function in three Pakistani families) [2]. Variants in the IRE (iron-responsive element) sequence of the 5′ region of FTL cause dominant cataract with hyperferritinaemia without iron overload, and galactokinase deficiency (GALK1) causes recessive galactitol cataract, which can improve on a lactose-free diet [2].

2.10. Validity of the gene–disease association

In September 2026, ClinGen (Clinical Genome Resource) had no formal validity assertions for most crystallin genes [5, 70]. In 2026, Ing and colleagues applied the ClinGen protocols to 13 crystallin genes in dominant paediatric cataract: CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYGC and CRYGD obtained definitive evidence; CRYGA and CRYGS moderate; CRYBA2, CRYBA4, CRYBB3 and CRYGB limited [66]. Experimental evidence raised CRYAB from limited to definitive, CRYAA from moderate to definitive, CRYGA and CRYGS from limited to moderate and CRYGB from no known relationship to limited [66]. This published analysis diverges from some GenCC (Gene Curation Coalition) classifications, in which CRYBA4 received a definitive classification (G2P) and CRYGS definitive (G2P) and strong (Ambry, Labcorp) [71, 75]. The divergence is explained in part by the inheritance assessed: Ing's curation refers only to the dominant form, and CRYBB3, limited as dominant, has definitive evidence for the recessive form in G2P [66, 74]. In practice, a heterozygous variant in a gene with limited evidence requires familial cosegregation or functional evidence before it is considered causal [23, 74].

2.11. Standardisation of historical variants

The following variants were standardised in VariantValidator on the MANE Select transcript (GRCh38) and cross-checked against ClinVar in October 2026 [61, 62]. The MANE transcripts sometimes differ from those cited in the curation sources (for example, CRYAB NM_001289808.2 instead of NM_001289807, and HSF4 NM_001374675.1), and some articles use old versions (CRYBB2 NM_000496.2, CRYGS NM_017541.2) [29, 61].

AD, autosomal dominant; AR, autosomal recessive; P/LP, pathogenic/likely pathogenic; VUS, variant of uncertain significance. The historical variant Q215X of SLC16A12 corresponds in ClinVar to p.(Gln245Ter), with a difference of 30 codons in transcript numbering [62]. The GJA3 variant p.His224Arg had no ClinVar record and was not standardised; the CRYGD variant p.(Tyr56Ter) of the Brazilian family has two possible nucleotide changes (NM_006891.4:c.168C>G and c.168C>A), and ClinVar returns the first [62, 80].

2.12. Genotype–phenotype correlations

Morphology suggests but does not identify the gene, because there is overlap between crystallins and connexins and because the same variant produces different morphologies [23, 64]. Useful correlations nevertheless exist. In a Chinese series of 392 families with congenital cataract, coralliform cataract occurred in 12 families (3.1%), and 10 of them (83.3%) had CRYGD p.(Pro24Thr) [60]. Guo and colleagues, in an analysis of 39 genes, of their own cohort of 150 families and of exomes from 10,530 families with eye diseases, found correlations mainly for BFSP2, MIP, GJA3, PITX3 and CRYGD: GJA3 variants are frequently accompanied by high myopia, those of CRYGC by microcornea or microphthalmia, and arginine-to-cysteine substitutions predominate in CRYAA, LIM2 and MIP and proline-to-threonine in CRYGD [76]. Posterior polar cataract with or without anterior segment dysgenesis is sufficiently characteristic to point towards PITX3, but does not confirm it [13]. Most CRYGC and CRYGD variants give nuclear and coralliform cataract [50].

2.13. Penetrance, expressivity and variant-dependent inheritance

Morphology is not always the same within a family, expression is variable and many carriers are asymptomatic because of mild involvement [39]. In family 3 of Verdin and colleagues, with the PITX3 duplication, the proband had bilateral congenital cataract with anterior segment dysgenesis, whereas the carrier mother had only congenital cataract, extracted at 6 years [78]. Incomplete penetrance is documented for CRYBA2 p.(Val50Met) and CRYGS p.(Gly75Asp) [23, 29]. In several genes inheritance is decided by the variant and not by the gene: CRYAA, CRYAB, CRYBB1, CRYBB3, LIM2, BFSP1, BFSP2, HSF4, EPHA2, FOXE3 and GJA8 have dominant and recessive alleles [12, 72, 74]. The Swiss authors recommend considering recessive inheritance even in classically dominant genes, such as CRYBB2 [29].

2.14. Allelic disorders and susceptibility variants

The genes within scope have allelic disorders that change surveillance. CRYAB is associated with myofibrillar myopathy and cardiomyopathy [5]; MAF with Aymé-Gripp syndrome [14]; AGK with Sengers syndrome [20]; WFS1 with Wolfram syndrome when biallelic and with a dominant form with neonatal diabetes, profound deafness and cataract due to de novo variants [21]; LSS with hypotrichosis and alopecia [19]; TDRD7 with azoospermia [18]; PITX3 and FOXE3 with anterior segment dysgenesis [13, 15]; NHS with Nance-Horan syndrome [22]. Distinct from these are the common, non-Mendelian associations: EPHA2 and CRYAA/CRYAB variants with age-related cataract [2, 16], a CRYBA4 polymorphism with high myopia in southern China [71], variation in the 5′ untranslated region of SLC16A12 with age-related cataract [24] and rare FYCO1 missense variants with sporadic inclusion body myositis (11.3% of patients versus 2.6% of controls) [17]. A galactokinase deficiency variant (the «Osaka» variant) is associated with age-related cortical cataract in Japanese people, but not in Europeans [2].

3. Clinical Spectrum and Manifestations by System

3.1. Morphology and most frequent phenotype

In the British cohort studied by Berry and colleagues, the most common phenotype was nuclear cataract, followed by posterior polar, total, lamellar, cerulean, coralliform, anterior polar, pulverulent, cortical, complete and polymorphic [50]. In the meta-analysis by Wu and colleagues, congenital cataract tended to be bilateral, isolated, hereditary and of total or nuclear morphology [38]. In the United Kingdom, among 243 children with newly diagnosed congenital or infantile cataract in one year of active national surveillance, 66% had bilateral disease; isolated cataract was more common in the bilateral than in the unilateral form (61% versus 47%), associated ocular anomalies were more common in the unilateral form (47% versus 14%) and associated systemic disease occurred in 25% of bilateral and 6% of unilateral cases [40]. Unilateral cataract is generally sporadic and frequently associated with persistent fetal vasculature, whereas most bilateral cataracts in developed countries have a genetic cause [45].

3.2. Natural history of the visual system

The functional consequence depends on the density, position and age at appearance of the opacity. A dense central opacity that obscures the red reflex deprives the retina of a focused image during the critical period of visual development and causes deprivation amblyopia, the least common but usually the most severe and difficult to treat form; the loss is greater with unilateral than with bilateral obstruction of similar degree, because of interocular competition [41]. Untreated deprivation in the first 3 months of life produces a profound and permanent reduction in acuity, typically to 20/200 or worse; if deprivation begins after 3 months, the reduction is less profound, but even brief deprivation in infancy can cause amblyopia [41]. Early deprivation is strongly associated with sensory nystagmus (in the bilateral form) and strabismus (in both forms) [41]. In infants there is a latent period of 4 to 8 weeks, with mainly subcortical vision, followed by the critical period; in the Hubel and Wiesel model, eyelid suture of one eye of the cat for 3 months permanently altered the striate cortex, which then responded almost exclusively to the non-occluded eye [45]. In dense bilateral cataract, Birch and colleagues found no latent period: in the first 14 weeks, final acuity fell on average by one line for every 3 weeks of delay in surgery [81].

Polar cataracts, which allow retinoscopy around the opacity, and lamellar cataracts, which allow a reasonable view of the fundus, typically cause mild to moderate or no amblyopia, and many partial cataracts are accompanied by a refractive error that must be corrected [41]. Posterior polar cataract impairs vision out of proportion to its size [5], and the more posterior and dense an opacity, the greater its visual effect [11]. Cerulean cataract reduces vision little until adulthood, when it is usually extracted [51], and the coralliform cataract associated with CRYGD p.(Pro24Thr) is bilateral, present at birth and non-progressive, with corrected acuity between 20/200 and 20/25 [60]. Several forms progress during childhood or youth (BFSP2, PITX3 posterior polar, CRYGS, MIP punctate lamellar, CHMP4B posterior subcapsular), and in these the surgical decision is guided by visual function [8, 11, 13, 26, 75]. Even with early detection, infants with bilateral cataracts may be left with significant visual impairment [39].

3.3. Associated ocular anomalies

Microcornea (corneal diameter less than 10 mm in an otherwise normal eye) accompanies variants of CRYAA, CRYBA4, CRYBB1, CRYBB2, CRYGC, CRYGD, GJA8, MAF, SLC16A12 and NHS [1, 22, 24]. Microphthalmia and anterior segment dysgenesis occur with GJA8, PITX3, FOXE3, MAF, recessive EPHA2, CRYBB3 (Gly156), CRYBA4 and the CRYAA variants that abolish the stop codon [4, 6, 13, 15, 74]. In the Myanmar cohort, 36% of children had microphthalmia [77]. Microcornea, microphthalmia and anterior segment dysgenesis alter the surgical plan, the intraocular lens calculation and the risk of glaucoma (sections 7 and 11) [64, 82]. Families with LIM2 p.Arg130Cys may have increased axial length and myopic changes, and some families with CRYBA2 have glaucoma or myopia [9, 23].

3.4. Extraocular manifestations in the «isolated» forms

Some forms classified as isolated have extraocular manifestations that should be sought. CRYAB cataract may be the first manifestation of myofibrillar myopathy, with muscle weakness, respiratory failure and cardiomyopathy [5]. Men with biallelic TDRD7 variants have non-obstructive azoospermia [18]. LSS is associated with hypotrichosis, alopecia and palmoplantar keratoderma [19]. Dominant FTL cataract is accompanied by hyperferritinaemia without iron overload [2]. AGK may present as apparently isolated cataract before hypertrophic cardiomyopathy and lactic acidosis [20]. In Nance-Horan syndrome, cataract is often the first sign, and in the Swiss cohort syndromic forms (NHS, BCOR, COL4A1) were diagnosed in patients initially referred as isolated cataract [29]. In the British cohort of Berry and colleagues, 4 of 13 patients classified as isolated bilateral cataract revealed non-ocular phenotypes after recontact [83].

3.5. Treated and untreated disease

The natural history of unoperated dense cataract is irreversible amblyopia with sensory nystagmus and strabismus [45]. Treated disease has a different profile: final acuity depends mainly on age at surgery, optical correction and adherence to occlusion, and complications specific to surgery arise, above all glaucoma, visual axis opacification and myopic shift with growth of the eye [45, 58]. In the IATS, at 10.5 years, 25% of treated eyes reached an acuity of 20/40 or better and 44% were left with 20/200 or worse, regardless of the optical strategy [84]. In the IoLunder2 cohort (United Kingdom and Ireland), median acuity at 5 years was 0.34 logMAR in bilateral cataracts and 0.70 logMAR in the operated eye of unilateral cases [85]. Patients with isolated hereditary congenital cataract have better visual and surgical outcomes than those with associated ocular or systemic anomalies [39].

4. Clinical Recognition and Warning Signs

4.1. Neonatal and infant screening

Red reflex examination is the basis of screening in most developed countries [45]. The 2008 joint statement of the American Academy of Pediatrics (AAP), the American Association for Pediatric Ophthalmology and Strabismus (AAPOS), the American Academy of Ophthalmology (AAO) and the American Association of Certified Orthoptists (AACO) recommends that all newborns, infants and children have a red reflex examination by a trained primary care clinician before discharge from the maternity unit and at all subsequent health supervision visits [86]. The AAO preferred practice pattern for paediatric eye evaluations (approved in 2022, published in 2023) recommends in newborns and infants under 6 months the red reflex test, external inspection, pupil examination and assessment of fixation and following, with referral to an ophthalmologist for abnormal findings [87]. In England, the NIPE (Newborn and Infant Physical Examination) programme performs the examination within the first 72 hours and at 6–8 weeks; the main ocular objective of the newborn examination is to detect congenital cataract through the red reflex [88].

The Brückner technique is performed in a darkened room, with the direct ophthalmoscope set at 0 dioptres, illuminating both eyes simultaneously from about 45–75 cm, before mydriasis [86, 87]. The reflex is normal when both eyes, viewed separately and together, have equivalent reflexes in colour, intensity and clarity, without opacities or white spots; colour varies with retinal pigmentation and ethnicity, so symmetry is the main criterion [86, 87]. Dark spots, a markedly diminished reflex, a white or dull reflex and asymmetry require referral, except for a mobile mucus opacity that disappears on blinking [86].

The NIPE handbook sets the 2-week time frame from the newborn examination, whereas the review by Self and colleagues describes it as «by 2 weeks of age»; the same authors point out the discrepancy between the pragmatic 11-week time frame for the infant screen and the better outcome obtained with surgery by 8 weeks [44, 88]. The NIPE handbook also states that surgery for severe cataract is usually performed between 6 and 10 weeks of age [88].

4.2. Screening performance

Red reflex screening misses a substantial proportion of cases. In the 1995–1996 British national cross-sectional study, with complete data on 235 children, 35% of cataracts were detected at the newborn examination, 12% at the 6–8-week examination and 82 children presented with symptoms; 57% were seen by an ophthalmologist by 3 months, but 33% only after 1 year, and in 91 cases the carers had suspected an eye problem before diagnosis [89]. In the IoLunder2 cohort (186 children operated on by 2 years of age in 2009–2010), neonatal detection occurred in 34% and late detection, after 8 weeks, also in 34%; moderate or late prematurity was independently associated with late detection (adjusted odds ratio, OR, 3.0; 95% confidence interval, CI, 1.1–8.5), which led the authors to conclude that routine screening does not effectively detect congenital cataract in this group, which is not eligible for retinopathy of prematurity screening [90]. In a Cambridge study, fewer than half of 33 children operated on before 3 years of age had been referred before 9 weeks, and only 10 after an abnormal NIPE examination [44].

4.3. New screening technologies

The DIvO study (Digital Imaging versus Ophthalmoscopy; NCT05282147) was designed to compare, in about 140,000 newborns from at least 13 English maternity units, the standard red reflex examination with infrared reflex imaging obtained by digital camera, using as reference linkage to hospital records of cataract diagnosis and treatment; the protocol cites a frequency of congenital cataract of 1 in 3000 babies in the United Kingdom, 60% bilateral [91]. In October 2026 the ClinicalTrials.gov record had “unknown” status, with estimated completion in December 2025, and no published results were found [91, 92]. In Italy, a feasibility study in primary care with 189 infants aged 1 to 6 months (April 2024 to March 2025) combined the digital infrared reflex test, the standard red reflex and asynchronous teleconsultation with an ophthalmologist: teleconsultation was feasible in 84%, the digital test was inconclusive in 5.3% and agreement with the red reflex was AC1 = 0.994 (95% CI 0.983–1.000), without specialist reference assessment for all infants [93].

4.4. Warning signs and urgency

Absence or asymmetry of the red reflex, leukocoria reported by the parents, poor visual contact after 8 weeks, nystagmus and strabismus in an infant warrant ophthalmological assessment [86–88]. A white reflex in an infant requires exclusion of retinoblastoma, which B-mode ultrasound distinguishes from a cataract with persistent fetal vasculature [45]. Dense infantile cataract is a surgical emergency, whereas partial, lamellar or developmental cataracts can be managed conservatively with surveillance [45]. In older children with less dense cataracts, the surgical indication is suggested by a change in visual behaviour, a fall in acuity, sensory strabismus or nystagmus, progression, poorer visualisation of the retina, loss of contrast sensitivity or glare [45].

4.5. Risk groups

A family history of congenital or infantile cataract, prematurity, trisomy 21 and other genetic syndromes and maternal exposure to rubella or cytomegalovirus should be recorded, especially in communities with low vaccination coverage [44, 45]. The NIPE handbook adds congenital eye disease in a first-degree relative (aniridia, coloboma, retinoblastoma), an extensive port-wine stain on the eyelids, neurodevelopmental disorders, sensorineural deafness and treatment with CFTR (cystic fibrosis transmembrane conductance regulator) modulators in the baby or the mother; a first-degree relative with bilateral congenital or hereditary cataract may justify early specialist opinion even with a normal examination [88]. The AAP recommends a complete ophthalmological examination, regardless of the red reflex, in relatives of patients with infantile or juvenile cataracts, retinoblastoma, retinal dysplasia or glaucoma [86], and the AAO preferred practice pattern for amblyopia includes a family history of childhood cataract among the risk factors that justify at least one complete ophthalmological examination [41].

4.6. Clues to a non-isolated form

Age at appearance is a guide: cataract with onset later in childhood suggests metabolic disease or a structural defect such as posterior lenticonus [44, 45]. In the history and examination, deafness suggests Cockayne, NF2 or Stickler; neonatal jaundice, galactosaemia or cerebrotendinous xanthomatosis (CTX); photosensitivity and deep-set eyes, Cockayne; faltering growth, metabolic disease, COFS (cerebro-oculo-facio-skeletal syndrome) or Cockayne; short stature, Stickler, Kniest or chondrodysplasia punctata; a wide fontanelle and lipoatrophy, Wiedemann-Rautenstrauch; hypotrichosis and a beaked nose, Hallermann-Streiff; coarse features and macroglossia, alpha-mannosidosis; cleft palate, Stickler or Kniest; «screwdriver» incisors, Nance-Horan; blisters, incontinentia pigmenti; poikiloderma, Rothmund-Thomson; ichthyosis or limb asymmetry in a girl, X-linked chondrodysplasia punctata; xanthomas, CTX; clubfoot, hypotonia or myotonia, myotonic dystrophy [39]. Cataract with granulomatous uveitis in an infant suggests Spiroplasma ixodetis infection and not hereditary cataract [94].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and ophthalmological examination

There are no formal diagnostic criteria for isolated hereditary congenital cataract; diagnosis rests on demonstration of the opacity, exclusion of syndromic, metabolic, infectious and traumatic causes and molecular identification [39, 45]. The examination includes dilated biomicroscopy, dilated fundoscopy (or B-mode ultrasound if the fundus is not visible), measurement of corneal diameter and axial length to detect microcornea and microphthalmia, tonometry to measure intraocular pressure (IOP) and age-appropriate acuity, with anterior segment photography to document morphology [6, 39, 87]. Biometry and B-mode ultrasound are also needed for intraocular lens calculation [12]. Parents and siblings should be examined at the slit lamp: this examination may reveal subtle opacities that establish the mode of inheritance, such as the punctate opacities of heterozygotes for recessive CRYAA alleles, the radial cortical opacities of female carriers of Lowe syndrome and the posterior sutural opacities of female NHS carriers [39, 45, 67].

The history should include a three-generation pedigree covering cataract, visual impairment, retinal detachment, deafness, neurological, joint, renal or gastrointestinal disease and consanguinity, the age at detection, congenital anomalies and non-genetic factors (infections in pregnancy, congenital or acquired infections, corticosteroids, radiation, diabetes) [39]. The general examination includes growth and head circumference [39].

5.2. Traditional aetiological investigation

The Oxford clinical genetics reference book proposes, in an otherwise normal child, TORCH serology (toxoplasmosis, rubella, cytomegalovirus, herpes simplex and others), testing for urinary reducing substances, urinary amino acids and organic acids and examination of parents and siblings, adding other tests according to the systemic findings [39]. This approach has a low yield: in a British study, traditional investigation gave the diagnosis in 1 of 27 consecutive referrals for bilateral cataract (3.4%) [44]. Current reviews recommend that biochemical, microbiological and immunological tests be guided by the clinical picture and requested together with genetic testing, because indiscriminate use has low utility [45]. TORCH serology remains indicated in congenital cataracts or those with onset in the 1st year [39]. Testing for reducing substances and galactose-1-phosphate uridyltransferase (GALT) activity identifies galactosaemia, which is treatable and whose cataract may regress with diet [6, 30].

5.3. Genetic testing: modalities and yield

Genetic testing is now the key investigation and has replaced the traditional pathway in the major UK centres, where the next-generation sequencing panel is used by all the authors of the review by Self and colleagues [27, 44]. The English R31 panel (PanelApp 230, version 8.15, September 2026) contains 119 green genes for diagnostic use, covering isolated, syndromic and metabolic forms simultaneously [42]. The non-syndromic green genes include CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD, CRYGS, GJA3, GJA8, MIP, LIM2, BFSP1, BFSP2, HSF4, EPHA2, MAF, PITX3, FOXE3, TDRD7, FYCO1, CHMP4B, VIM, SLC16A12, MIR184, WFS1, DNMBP, GCNT2, NHS, PAX6, VSX2, MYH9, COL4A1, FTL and NF2 [42].

Yield varies with cohort selection: reviews report 70–85% in isolated cataract and 63% in syndromic cataract with panels [44], 50–90% in bilateral cases with a targeted panel [27] and 50–70% in cohorts of European ancestry, compared with up to 20% in some reports from non-European populations [77]. Monogenic variants would explain about two thirds of congenital cataracts, whereas previously one third was estimated [76]. In the study by Lloyd and colleagues, the crude yield of genome sequencing (48.8%, 21 of 43) was higher than that of exome with a virtual panel (38.2%, 29 of 76), but the difference was not statistically significant (OR 1.54; 95% CI 0.68–3.52; P = 0.334); the variants that exome may miss include copy number variants (CNV), such as a multi-exon deletion of CRYBB1 and a 2.3 Mb deletion at 11p13 that included PAX6 and WT1, and non-canonical intronic variants, such as CRYBA1 NM_005208.5:c.32-3C>G and CTDP1 NM_004715.5:c.863+389C>T, the latter found in two unrelated probands [43]. In the same cohort, 84.3% of diagnoses in patients classified as non-syndromic were in isolated cataract genes, but 15.6% were in genes with a systemic spectrum (GALK1, NHS, OPA3, PAX6 deletion), and crystallins accounted for 24% of diagnostic variants and connexins for 12%; inheritance was dominant in 66% of diagnoses, recessive in 20% and X-linked in 14% [43]. Trio genome sequencing better identifies de novo variants and improves counselling and targeted screening of siblings [45]. The panel reduced the time to diagnosis from years to weeks, and in a study of 50 patients more than 15% had variants in genes for inborn errors of metabolism, 5 of 6 of them treatable (for example, cryohydrocytosis with stomatin deficiency caused by SLC2A1, treated with a ketogenic diet, and CTX due to CYP27A1, treated with chenodeoxycholic acid and statins) [44]. The Swiss authors recommend exome sequencing as the first-line test and trio exome in isolated cases from non-consanguineous families [29].

5.4. Practical algorithm

Dense cataract does not wait for the genetic result: surgery follows the timetable in section 7, and genetic testing proceeds in parallel [45]. The flowchart proposed by Lloyd and colleagues for the child with bilateral congenital cataract places genetic testing as the routine diagnostic pathway, with multidisciplinary interpretation of variants [45].

5.5. Limitations of the tests

A negative result does not exclude a genetic cause. The main technical limitations are as follows. The pseudogene CRYBB2P1 shares more than 97% homology with CRYBB2; short reads may be mapped to the pseudogene and lost, and non-specific PCR amplification has already produced false «mutations», so specific primers or review of the alignment are required [73]. The γ-crystallin paralogues (CRYGA to CRYGD at 2q33.3, the pseudogenes CRYGEP1 and CRYGFP, and CRYGS at 3q27.3) create the same risk of misassignment [75]. Recessive BFSP1 alleles are multi-exon deletions, which require exon-level CNV detection; deletions are a significant proportion of NHS variants; a 7.6 kb deletion in AGK was missed by sequencing [10, 20, 39]. A female with a full Nance-Horan phenotype may have an X-autosome translocation with skewed X inactivation, which requires karyotype or FISH if NHS sequencing is negative [22]. FOXE3 and MAF have known coverage problems in the exome [77]. The exome misses deep intronic and structural variants, its coverage varies between laboratories and CNV annotation from exome data is not standardised, whereas the genome is more comprehensive [98]. Deep intronic variants such as CTDP1 c.863+389C>T, the cause of CCFDN, escape most exon panels [33, 62]. Low-level somatic mosaicism in the parents and regulatory variants are not quantified in the sources consulted for these genes.

5.6. Interpretation, variants of uncertain significance and reporting

Variants of uncertain significance in congenital cataract genes are present in up to 56.0% of the general population, which makes interpretation of pathogenicity the main challenge [76]. Genes with a limited relationship require cosegregation or functional evidence [66, 74]. Exome sequencing in patients with isolated cataract may reveal heterozygous variants in genes for systemic recessive diseases (for example, GALT c.584T>C p.(Leu195Pro) in a British cohort), which correspond to carrier status and not to a diagnosis; the same cohort found variants in 11 systemic disease genes and 4 patients with non-ocular phenotypes after recontact [83]. The PITX3 variant p.(Gly220ProfsTer95) and the CRYBB2 variant p.(Gln155Ter) are recurrent and well established, but a novel variant in a gene of limited strength should remain classified as uncertain until segregation is available [73, 78]. The review by Rechsteiner and colleagues classified pathogenic, likely pathogenic and uncertain significance variants according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), and confirmed segregation by Sanger sequencing [29]. The report should state the gene, the transcript with version (for example, NM_006891.4 for CRYGD), the HGVS nomenclature at DNA and protein level, zygosity, the ACMG/AMP class and, where applicable, the historical name, to avoid confusion such as P23T/p.Pro24Thr [61, 62].

5.7. Genetic testing in minors

The joint guideline of the Sociedade Portuguesa de Oftalmologia and the Sociedade Portuguesa de Genética Humana, written for inherited retinal dystrophies but applicable as Portuguese context, states that Portuguese law permits genetic testing in minors only for the direct benefit of the child, with the consent of the parents or guardians and, ideally, of the minor, and restricts predictive testing for diseases with onset up to adulthood, unless early detection allows effective prevention or treatment [98]. The same guideline cites the European Society of Human Genetics (ESHG) recommendation of an initial targeted approach (panel) to minimise unsolicited findings, reserving broader genomic analysis for after a negative panel, and recommends at least one genetic counselling session [98]. In congenital cataract, diagnostic testing in the affected child has direct benefit (exclusion of treatable systemic disease, targeted surveillance, counselling); predictive testing of asymptomatic siblings is as a rule unnecessary, because slit-lamp examination detects the cataract [39, 96].

5.8. Prenatal diagnosis

The second-trimester anomaly scan visualises the eye and the lens, but probably lacks sufficient sensitivity to detect recurrence [99]. In a four-centre Chinese series (2004–2019), congenital cataract was diagnosed in 41 fetuses among 788,751 pregnant women undergoing an anomaly scan; the signs were a dense echogenic structure (39.0%), a hyperechogenic focus (36.6%) and the «double ring» sign (24.4%); 41.5% were isolated and 58.5% had other anomalies, mainly microphthalmia, cardiac and central nervous system anomalies; 6 had a family history, 4 confirmed congenital rubella and 2 aneuploidy [100]. In another Chinese series of 29 fetuses (2018–2023), genetic testing in 8 was abnormal in 5 (OCRL in two fetuses of the same woman, trisomy 13, RAB3GAP1 and NHS) [101]. In an Israeli series of 8 fetuses, 6 had extraocular anomalies and the only survivor had cataract secondary to maternal corticosteroid therapy, without visual impairment at 2 years [102]. Molecular prenatal diagnosis is technically possible when the familial variant has been identified [39].

6. Differential Diagnosis

6.1. Approach by age and context

The differential diagnosis is organised by age at appearance [39]. In congenital or early-childhood cataract, classic galactosaemia, galactokinase deficiency, Lowe syndrome, peroxisomal disorders (rhizomelic chondrodysplasia punctata, Zellweger spectrum), COFS syndrome, Hallermann-Streiff and Wiedemann-Rautenstrauch syndromes and Nance-Horan syndrome are considered; in childhood, Stickler syndrome, the chondrodysplasias punctata, CTX and the premature ageing or DNA repair disorders (Cockayne syndrome); in youth, NF2; in adults, myotonic dystrophy [39]. Among the autosomal recessive cutis laxa disorders, De Barsy syndrome due to ALDH18A1 (cutis laxa type IIIA) includes cataract, corneal opacity, strabismus, myopia and salt-and-pepper retinopathy, with thin translucent skin and developmental delay [103]. About 15% of children with infantile cataract have systemic signs and, in some metabolic diseases, cataract is the presenting sign, which justifies rapid diagnosis when treatment exists [27]. The R31 panel includes as green genes those of many of these entities (GALT, GALK1, CYP27A1, DHCR7, OCRL, NDP, BCOR, PEX genes, GNPAT, AGPS, FAR1, ERCC2, ERCC3, ERCC6, ERCC8, WRN, RAB3GAP1, RAB3GAP2, SIL1, COL2A1, COL11A1, COL18A1, MAN2B1, AGK, ABHD12, POLG, FAM126A), so the first-line test covers the isolated form and the genetic differential simultaneously [42].

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; XLD, X-linked dominant; XLR, X-linked recessive; CK, creatine kinase; MRI, magnetic resonance imaging.

6.2. Treatable metabolic diseases

Classic galactosaemia is the most important metabolic differential in the infant. In GeneReviews, 30% of 314 individuals with classic galactosaemia had cataracts, almost half described as mild, transient or neonatal and resolved with diet; only 8 underwent surgery, and diet was started on average at 77 days in those with cataract versus 20 days in those without [30]. It is very unusual for galactosaemia to present with cataract after early infancy, because cataract requires significant milk intake [30]. Galactokinase deficiency gives cataract in an otherwise healthy infant, with raised plasma galactose and urinary galactitol and normal erythrocyte GALT, and galactose mutarotase deficiency (GALM) gives cataract with raised galactose and a negative Beutler test [30]. Fanconi-Bickel syndrome (SLC2A2) may present with bilateral nuclear cataracts as the first neonatal sign and be detected on newborn screening for galactosaemia [63].

In CTX (CYP27A1), cataracts are the first finding in about 75% of patients, often in the first decade, and in 25% only after 40 years; the opacities are irregular cortical, anterior polar or dense posterior subcapsular, and chronic diarrhoea since childhood is a clue; in groups with juvenile cataract, CTX was diagnosed in 1.8% in the USA and in 1.55% in Turkey [32]. Chenodeoxycholic acid normalises cholestanol [32]. In the USA, the FDA approved on 21 February 2025 Ctexli® (chenodiol, 250 mg tablets) for CTX in adults, at a dose of 250 mg orally three times a day, with baseline measurement of aminotransferases (ALT and AST) and total bilirubin; in the European Union, Chenodeoxycholic acid Leadiant® has been authorised since 10 April 2017 for CTX in infants from 1 month of age, children, adolescents and adults [108, 109]. The difference in age between the two jurisdictions is relevant because juvenile cataract may be the sign that leads to diagnosis in childhood. A child with congenital cataract and biallelic variants in CYP51A1, a cholesterol biosynthesis gene, illustrates other emerging metabolic causes, confirmed by functional studies in lymphoblasts [110]. Peroxisomal disorders, the chondrodysplasias punctata, Smith-Lemli-Opitz syndrome and alpha-mannosidosis complete the metabolic differential [39, 42].

6.3. Lowe syndrome and Nance-Horan syndrome

In Lowe syndrome, all boys have dense congenital cataracts, which may go unnoticed in the first weeks; about 50% develop infantile glaucoma, and corrected acuity is rarely better than 20/100 [31]. About 95% of postpubertal heterozygous females have irregular punctate cortical opacities in radial bands, sparing the nucleus, and about 10% a dense white posterior polar cataract; the absence of these opacities before puberty does not exclude carrier status [31]. Aminoaciduria may be negative very early, so the test should be repeated [39]. An intraocular lens should be used with extreme caution because of the risk of glaucoma, contact lenses are avoided because of the risk of corneal keloid and cataract extraction may be complicated by bleeding due to a platelet defect [31].

In Nance-Horan syndrome, males have severe cataract from birth, usually nuclear and with microcornea, dental anomalies (screwdriver incisors, supernumerary teeth, bud-shaped molars) and a long face with a prominent chin [22, 39]. Female carriers have posterior Y-sutural opacities, mild but diagnostic, and about 5% have no ocular signs [22, 39]. The frequency of intellectual disability differs between sources: the Oxford book reports mild to moderate disability in about 80% of males, based on a 1997 series, whereas OMIM describes intellectual disability «in some cases» and cites the estimate by Walpole and colleagues (1990) of intellectual disability or developmental delay in more than one fifth of affected males, and the most recent curation reports a minority, up to about 30% [3, 22, 39]. In the London cohort, the three boys with Nance-Horan had cataract, mild developmental delay and abnormal dentition [43]. X-linked cataract 40 (NHS) and the presentation of female carriers with apparently isolated cataract place the syndrome at the boundary of the scope [2, 22].

6.4. Other syndromic and malformative forms

Oculofaciocardiodental syndrome (BCOR, Xp11.4) affects females only, with congenital cataract, microphthalmia, microcornea, secondary glaucoma, canine radiculomegaly, cardiac septal defects and mild intellectual disability in 15–20% [104]. Aymé-Gripp syndrome has early bilateral cataract, often congenital sensorineural hearing loss, characteristic facies and developmental delay in all patients, and is classified as ultra-rare (18 cases) [14]. CCFDN has bilateral congenital cataract as its invariable first manifestation, with microcornea and demyelinating neuropathy, and an exaggerated inflammatory response to contact lenses and intraocular lenses [33]. Hypomyelination with congenital cataract (HYCC1) gives bilateral cataracts requiring extraction in the first months and slow neurodegeneration after the 1st year [34]. The recurrent 1q21.1 deletion has ophthalmological involvement in about one third of carriers [35].

In trisomy 21, about 60% of children develop cataract [39]. Myotonic dystrophy should be considered in asymptomatic adults with cataracts and a family history [39]. NF2 causes embryonal, posterior subcapsular and juvenile cortical opacities with retinal hamartomas [39]. Stickler syndrome combines cataract with a high risk of retinal detachment, which may justify prophylactic cryotherapy or laser before or during surgery [45]. Aniridia combines cataract, foveal hypoplasia and glaucoma, and about 40% of 77 patients had chromosomal rearrangements, with Wilms tumour surveillance if the deletion includes WT1 [99]. Peters anomaly (central corneal opacity, bilateral in 80%, with frequent lens anomalies and glaucoma) and FOXE3 primary aphakia are part of the differential of the infant with an opaque cornea [99, 107]. Sengers syndrome belongs to the mitochondrial DNA depletion disorders [20].

6.5. Non-genetic causes

Persistent fetal vasculature is a frequent cause of unilateral congenital cataract, typically sporadic in healthy term infants; it is associated with microphthalmia, microcornea, elongated ciliary processes, a retrolental fibrovascular plaque, posterior polar cataract, posterior lenticonus and membranous cataract, and may mimic retinoblastoma [45]. In the IoLunder2 cohort, it was present in 46% of children with unilateral cataract and in 8% of those with bilateral cataract operated on by 2 years of age [106]. Infantile cataract due to Spiroplasma ixodetis was reviewed in 18 infants (28 eyes) from 8 European countries: 55.6% bilateral, 46.4% progressive, granulomatous anterior uveitis in all, 16S PCR positive in 89.3% of eyes tested; 17 of 18 received systemic antimicrobial treatment, mainly a macrolide, and the authors propose adding the agent to the TORCH acronym [94]. Congenital rubella is still present in prenatal diagnosis series [100]. Traumatic cataracts account for about 30% of childhood cataracts and are the main cause of avoidable visual disability in children [45]. Maternal corticosteroid therapy may cause fetal cataract [102].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no approved pharmacological treatment for isolated congenital cataract; treatment is lens extraction when the opacity is visually significant, followed by optical correction, amblyopia treatment and lifelong surveillance for complications [44, 45]. An opacity that obscures the red reflex in a preverbal child is an absolute indication for lens aspiration, usually with posterior capsulotomy and anterior vitrectomy in young children [22, 72]. Partial, lamellar or developmental cataracts can be managed conservatively with surveillance, to preserve accommodation [45], and partial cataracts that are not visually significant may benefit from mydriatics to increase light entry [27]. Treatment requires a multidisciplinary team with paediatric ophthalmic surgeons, orthoptists, contact lens optometrists, paediatricians, geneticists, genetic counsellors and school and visual impairment support services [27, 44].

7.2. Timing of surgery

Age at surgery is the strongest determinant of visual outcome in dense congenital cataracts, and the best results are obtained with surgery in the first 3 months; early surgery reduces strabismus and nystagmus [45]. In the IoLunder2 cohort, each additional month of age at surgery within the first 3 months was associated with a worse visual outcome [45]. Conversely, the risk of secondary glaucoma increases the earlier the operation: in the IATS and the Toddler Aphakia and Pseudophakia Treatment Study (TAPS), each additional month of age at surgery reduced this risk [45]; surgery before 4 weeks quadruples the risk of glaucoma, and each additional week reduces the risk by about 2% [44]. Birch and colleagues, in 37 infants with dense bilateral cataract operated on by 31 weeks, found a critical age of 14 weeks: before it, acuity fell by one line for every 3 weeks of delay; between 14 and 31 weeks, acuity no longer depended on age (mean 20/80); surgery after 4 weeks was associated with more strabismus and nystagmus, and surgery in the first 4 weeks with more secondary membranes and glaucoma [81].

The recommendations diverge by weeks because they balance two opposing risks, amblyopia and glaucoma, and because none derives from a randomised trial of surgical timing; Self and colleagues discuss cut-off points of 3–4 weeks, 6 weeks and 7–8 weeks, or no cut-off point [44]. In unilateral cataract, Birch and Stager observed a marked decline in acuity when surgery was performed after 6 weeks, and in a Swedish study of 54 children more of the children operated on before 6 weeks of corrected age reached an acuity of 1.0 logMAR or better [45]. Delaying bilateral surgery beyond 10 weeks frequently results in nystagmus [45]. Surgery should be postponed when systemic disease needs to be stabilised before anaesthesia; when glaucoma and cataract coexist (aniridia, Lowe syndrome), the glaucoma is operated on first; when the risk of retinal detachment is high (Stickler syndrome), prophylactic cryotherapy or laser is added [45].

7.3. Surgical technique

Primary posterior capsulotomy with anterior vitrectomy is standard practice below 5 years; between 5 and 8 years, posterior capsulotomy may be performed without vitrectomy, with posterior optic capture of the lens; above 8 years it is acceptable to leave the posterior capsule intact, unless there is a dense capsular plaque, a capsular defect, anticipated poor cooperation with in-office Nd:YAG laser, unavailability of YAG under anaesthesia or uncertain follow-up [45]. Leaving the posterior capsule intact in an infant leads to significant visual axis opacification in almost all cases [45]. Posterior polar cataract is associated with an increased risk of posterior capsule rupture during surgery, which requires an adapted technique and makes morphology relevant information for the surgeon [5]. Microcornea and a small anterior segment alter the surgical plan, the refractive target and the lens calculation [64]. The diameter of the capsular bag is about 7 mm in the newborn, 9 mm at 2 years, 10 mm at 5 years and 10.5 mm in the adult [44].

Immediately sequential bilateral cataract surgery (ISBCS) reduces total anaesthesia time; there are no published cases of bilateral endophthalmitis in children, 4 cases have been described in adults, and the international panel considers the evidence sufficient to use it in selected paediatric cases, treating each eye as a separate procedure (new preparation, drapes, instruments and separate batches) [45]. ISBCS is common in infants who are left aphakic, whereas delayed sequential surgery remains the standard when an intraocular lens is implanted; the estimated saving was more than 2300 US dollars per patient in the USA and 2200 Canadian dollars to the health system in Canada [45]. The impact of repeated general anaesthesia on neurodevelopment is uncertain [44].

7.4. Intraocular lens or aphakia

The IATS randomised 114 infants with unilateral congenital cataract, operated on between 1 and 6 months (median age 1.8 months), to a primary intraocular lens (undercorrected by 6–8 dioptres, with spectacles for the residual error) or aphakia corrected with a contact lens, in 12 US centres [58, 59]. At 10.5 years, median acuity in the treated eye was similar in the two arms (0.89 logMAR with an intraocular lens versus 0.86 with aphakia; P = 0.82), with 25% of eyes at 20/40 or better and 44% at 20/200 or worse [84]. In the first 5 years, the intraocular lens arm had more intraoperative complications (28% versus 11%), more patients with adverse events (81% versus 56%) and many more additional intraocular operations (72% versus 16%), mainly for lens material proliferation into the visual axis, pupillary membranes and corectopia [111]. The IATS principal investigator recommends leaving the eye of infants under 7 months with unilateral cataract aphakic, focused with a contact lens, reserving a primary intraocular lens for when the cost and handling of the contact lens are so burdensome that they would lead to significant periods of uncorrected aphakia [58]. Costs at 5 years were lower with aphakia and a contact lens, and pseudophakia was associated with a temporary increase in parental stress in the 1st year [44, 58].

The IoLunder2 cohort (31 centres in the United Kingdom and Ireland; surgery by 2 years of age in 2009–2010) analysed 158 children without significant ocular comorbidity, 56% with a primary intraocular lens: the lens did not improve acuity or reduce glaucoma, but it increased the risk of reoperation for visual axis opacity under general anaesthesia (OR 5.94 in bilateral and 20.15 in unilateral cases), and the authors concluded that routine implantation in this age group cannot be recommended [85]. UK practice defers implantation until after 2 years and corrects aphakia with contact lenses or spectacles [44]. The 2025 international panel states that most children undergoing surgery now receive a primary intraocular lens, but does not recommend it below 6 months when paediatric contact lenses are available; if these are unavailable or impractical, a primary lens may be considered with full informed consent [45]. Relative contraindications to an intraocular lens include severe lens subluxation, juvenile idiopathic arthritis uveitis, aniridia, Peters anomaly and severe ocular comorbidities without capsular support [45]. The paediatric Delphi cited by Brémond-Gignac and colleagues reached consensus or near-consensus on 79% of management questions, and the lens implantation strategy was one of the controversial topics [112].

Sources for the table: [27, 44, 45, 58, 85].

When a lens is implanted, the single-piece hydrophobic acrylic lens in the capsular bag is the most widely used; the three-piece lens is intended for the sulcus, and the single-piece lens should not be placed in the sulcus (inflammation, haemorrhage, pigment dispersion, ocular hypertension) [45]. The bag-in-the-lens technique, with 5 mm anterior and posterior capsulorhexis, reduces reoperations but is not widely used [44, 45]. Toric lenses are reserved for cooperative children with regular corneal astigmatism of at least 1.5 dioptres, generally not before 5 years, and multifocal and extended depth of focus lenses are generally not recommended, because the eye continues to grow until at least 20 years [45]. A secondary intraocular lens may be placed when spectacles or contact lenses fail, or at the parents' choice when ocular growth slows after 4 years, preferably in the reopened capsular bag [45]. In the IATS, of the 51 children left aphakic up to 4.5 years, 22 (43%; 95% CI 29–58%) received a secondary lens by 10.5 years, at a median of 64.5 months, with both good and poor acuity, and with wide variation between centres [113].

7.5. Intraocular lens power

The aim is good vision and emmetropia in adulthood, but there are no data to recommend an optimal power; ocular growth is semilogarithmic, formula prediction errors are greater in children and no modern formula is consistently superior [45]. Published median absolute prediction errors range from 0.53 to 2.1 dioptres depending on formula and series (SRK-T 0.67–1.3; Hoffer Q 0.56–2.1; Holladay 1 0.58–1.2; Holladay 2 0.53–1.4; Haigis 0.74; Barrett Universal II 0.89), with greater dispersion below 3 years, and biometry and calculation errors explain only 12% of the variation in refraction at 10 years [45]. Most authors prefer moderate initial hypermetropia in young children [45].

Source: values for typical eyes, with large individual variance [45]. D, dioptres.

7.6. Optical correction

Contact lenses are an excellent option for aphakia, especially in infants, because they correct anisometropia and avoid aniseikonia; in the IATS, children who wore the lens for a greater proportion of waking hours tended to have better acuity at 4.5 years, even after adjusting for adherence to occlusion [45]. UK practice prefers daily-wear silicone hydrogel lenses, replaced every 4–6 weeks (3 to 4 pairs are supplied), slightly flatter than the flattest keratometry reading and about 1 mm larger than the corneal diameter; the cornea of the newborn up to 6 months has a mean radius of about 7.10 mm (47.59 D), the first lens is left in for one week before the parents complete their training, and review (fit, over-refraction, examination, refraction and intraocular pressure) is repeated every 3 months [44]. The international panel recommends assessing infants with contact lenses every 3 months, because the cornea flattens rapidly (mean curvature of about 48 D at term and 44 D at 18 months), and every 4–6 months from 18 months; corneal diameter reaches adult size (about 11.7 mm) at 2–3 years [45]. Microbial keratitis is the most serious adverse effect of contact lenses, rare in children [45]. Contact lenses require a specialist optometrist, insertion and removal by the parents and access to clean water [44].

Source: 2025 international panel [45].

Back-up spectacles are essential even with a contact lens. Temporary +20 D spectacles may be supplied on the day of surgery; in aphakic infants an overcorrection of +2.0 D is given for near vision and, after 2 years, bifocals with a +3 D addition are used [45]. The hypermetropia of an aphakic eye may reach +30.00 D, and high-power self-adhesive lenses are an immediate solution [44]. Aphakic spectacles magnify the image; children with bilateral aphakia and corrected acuity of 20/60 or worse often adapt better to spectacles at school, whereas in unilateral aphakia aniseikonia prevents binocularity [45]. In pseudophakic children, spectacles are prescribed until the 1-month visit if hypermetropia exceeds 1 D, myopia 3 D or astigmatism 1.5 D; retinoscopy is the reference standard for refraction [45].

7.7. Amblyopia treatment and occlusion

Amblyopia is the most common adverse event after paediatric cataract surgery, more severe in unilateral and dense disease [45]. The AAO preferred practice pattern for amblyopia classifies occlusion as first-line treatment of deprivation amblyopia (grade I-, moderate quality, discretionary recommendation), with correction of the deprivation and the refractive error and penalisation of the fellow eye by occlusion, atropine, Bangerter filters or dichoptic therapy; most patients with unilateral cataract retain a significant deficit [41]. In a randomised trial, acuity in the fellow eye fell by two or more lines in 1% of children with occlusion of at least 6 hours a day and in 9% of those treated with daily atropine, almost always reversibly [41].

Sources for the table: [44, 45, 58].

Adherence explained only 15% of the variance in acuity at 4.5 years in the IATS, and the hours of occlusion in the 1st year and in the following 3 years explained about 10% each; occlusion of at least 4 hours a day in the first 4 years gave a better result than less than 2 hours [44, 58]. Occlusion should be gradual in the first 6 months, because of the risk to binocularity and stereopsis, and consistent occlusion at the same time of day is associated with a better outcome; in one study, occlusion was abandoned before 4 years in 31% of children [44, 45]. Children with good acuity and stereopsis in the IATS had occluded for a mean of 3.4 hours a day in the 1st year, less than those with good acuity without stereopsis, which suggests an individual occlusion threshold [58]. Acuity at 4 years accurately predicts acuity at 10 years in dense amblyopia (20/200 or worse), regardless of occlusion after 4 years [45]. In nystagmus due to poor development of fusion, more hours a day are occluded on fewer days a week [44]. Quantitative measurement of monocular acuity should begin as early as possible (forced preferential looking in the preverbal phase, crowded optotypes as soon as possible) and nystagmus is recorded at every visit [44].

7.8. Perioperative drugs

Postoperative inflammation is more vigorous in infants, with pupillary membranes, synechiae, pupillary block and deposits on or decentration of the lens [44]. The following regimens derive from the practice of five British centres and not from drug labels; none of these eye drops has a specific indication for congenital cataract, and some are not licensed for all paediatric ages [44].

Oral corticosteroids are generally unnecessary [44]. In a study of 26 infants operated on before 2 years, two thirds had adrenal suppression with topical glucocorticoids, associated with the cumulative dose; there were 2 cases of Cushing syndrome and one adrenal crisis under general anaesthesia, and a child on prolonged topical corticosteroids should be referred to paediatric endocrinology [44]. Preservative-free preparations are used in preservative allergy and in aphakic children with contact lenses, and the regimen is adjusted in uveitis, trauma, after iris hooks or with previous glaucoma surgery [44]. Endophthalmitis prophylaxis uses povidone-iodine before the incision and an intracameral antibiotic [44].

For mydriasis at examination, the 2008 AAP statement considers in-office dilation safe in infants older than 2 weeks, with lower concentrations in preterm infants: below 9 months, one drop of the combination of cyclopentolate 0.25% with phenylephrine 2.5% about 15 minutes before the examination, avoiding atropine; above 9 months, tropicamide 1% and phenylephrine 2.5%, one drop of either or both, or the combination of cyclopentolate 0.2% with phenylephrine 1% [86]. The statement cites two different concentrations for the same commercial combination, and hypertension, tachycardia, urticaria, arrhythmias, contact dermatitis, bradycardia and respiratory depression have been described with mydriatics [86].

The combination of phenylephrine with ketorolac (Omidria®), added to the ocular irrigation solution (4 ml diluted in 500 ml; stable for up to 4 hours at room temperature or 24 hours refrigerated; one patient per vial), maintains intraoperative mydriasis and reduces postoperative pain [114]. The FDA authorised it on 30 May 2014 and the current label establishes safety and efficacy from birth to 17 years, based on studies in adults and on an active-controlled paediatric safety study in children up to 3 years (NCT02132312; 78 children undergoing unilateral cataract surgery) [114]. In the European Union, Omidria has been authorised since 28 July 2015 in adults only, so paediatric use in the EU is outside the approved indication [115].

7.9. Treatment of glaucoma following cataract surgery

The first line for glaucoma following cataract surgery is topical (beta-blockers, carbonic anhydrase inhibitors, prostaglandin analogues); systemic carbonic anhydrase inhibitors require monitoring of electrolytes and blood gases with prolonged use [45]. In the United Kingdom, almost all ocular hypotensive drugs except latanoprost are unlicensed for paediatric glaucoma, which should be explained to the parents [44]. About half of children respond to latanoprost (iris darkening, eyelash lengthening); beta-blockers have similar mean efficacy and are relatively contraindicated in asthma (chronic cough may be a sign of toxicity); systemic acetazolamide is useful for short periods and may cause anorexia, lethargy and acute crystal-induced kidney injury, which requires discontinuation if anuria occurs [44]. Alpha agonists may cause central nervous system depression, apnoea and unconsciousness, with greater risk in younger and lighter children: brimonidine is contraindicated below 2 years and should be used with caution below 6 years or 20 kg, and apraclonidine, which crosses the blood–brain barrier less, may be safe above 6 months [45]; UK practice prefers apraclonidine and, below 24 months, uses it only with caution, documented consent and a first dose supervised in hospital [44].

The escalation suggested in the United Kingdom is: latanoprost or timolol 0.25% as monotherapy; then the dorzolamide/timolol combination; then dorzolamide/timolol with latanoprost; finally cycloablation or surgery [44]. Half of glaucomas following cataract surgery require laser or surgery, often with a drainage device, and 360° trabeculotomy with an illuminated microcatheter is an option in open angles [44, 45]. In FOXE3 primary aphakia, glaucoma is frequently refractory, the threshold for a drainage device or cyclophotocoagulation is low and penetrating keratoplasty has very poor results, so low-vision support begins at diagnosis [15].

7.10. Special situations

In persistent fetal vasculature, the decision depends on the rehabilitation prognosis and the risk of angle-closure glaucoma; mild off-axis cases may not need surgery, severe anterior traction with a flat anterior chamber requires urgent lensectomy, peripheral iridotomy prevents pupillary block in aphakic eyes and an intraocular lens is often impossible [45]. In Lowe syndrome, contact lenses are avoided and an intraocular lens is used with extreme caution [31]. In CCFDN, the inflammatory reaction to contact lenses and intraocular lenses is exaggerated [33]. In children with cataract and microcornea operated on in the 1st year, a Japanese series (43 eyes, follow-up of 13.7 years) obtained an acuity of 20/40 or better in 39% of bilateral aphakic and in 88% of bilateral pseudophakic children, with more visual axis opacification in the pseudophakic children (54.5% versus 12.5%) [116]. In infantile cataract due to Spiroplasma, the authors recommend systemic antimicrobial treatment as soon as infection is suspected and anti-inflammatory treatment according to the inflammation; the source does not give doses [94]. In uncomplicated traumatic cataracts, surgery is ideally performed 3–4 weeks after the injury [45].

7.11. Comparative regulatory status

The sources consulted do not describe national access data (INFARMED or ANVISA) for these products in the context of paediatric cataract.

7.12. Main trials and studies

The only randomised trial of optical strategy (IATS) included only unilateral cataracts operated on between 1 and 6 months, and its results cannot be transposed directly to bilateral cataract or to older children [58, 59]. IoLunder2 is observational, with possible confounding by indication, and the meta-analyses that suggested a protective effect of the intraocular lens against glaucoma have selection bias and confounding by age at surgery [44, 45]. Indirect comparison between the IATS (USA) and IoLunder2 (United Kingdom and Ireland) is limited by differences in population, age and outcome definitions; adverse events expressed as a percentage of patients should be read alongside the absolute rates in each arm. The suspended and withdrawn registrations and the negative genetic study of lanosterol are part of the available evidence.

7.13. Developments in the last 12 months and research

In the 12 months before October 2026, no drug or device specific to congenital cataract was approved by the FDA or the EMA; the search performed was negative, which does not prove non-existence [92]. The new data are clinical and observational. In 2026, Lloyd and colleagues published the comparison between exome with a virtual panel and genome in 119 probands from the North Thames Genomic Laboratory Hub (retrospective study), with a yield of 48.8% versus 38.2%, a non-significant difference in this sample; the abstract presents it as an increase of about 10% [43]. In 2026, Ing and colleagues published the ClinGen curation of 13 crystallin genes (published analysis, not an official ClinGen assertion) [66]. In October 2026, the IATS published the incidence of secondary intraocular lens implantation (43% of the children aphakic at 4.5 years had received a lens by 10.5 years) [113] and, in 2025, stereopsis at 10.5 years (6 of 109 children, 5.5%; 22.2% of those with acuity of 20/40 or better) [118]. Japanese and German series from 2025–2026 described the myopic shift at 15 years, the results in microcornea and long-term acuity [116, 119, 120]. The 2025 meta-analysis on retinal detachment and the European review on Spiroplasma ixodetis are the other relevant publications of the period [47, 94]. Two Chinese studies are registered (bifocal spectacles with peripheral defocus to control axial growth after surgery, NCT07778797, recruiting since August 2025; augmented reality training for amblyopia, NCT07693790, not yet recruiting) [92].

Non-surgical therapies remain at the preclinical stage. Lanosterol reduced crystallin aggregates in vitro, in rabbit lenses and in dogs [79], but did not dissolve aggregates or restore transparency in human lenses with age-related nuclear cataract or in rat chemical cataracts, and the UK Biobank genetic study does not support a protective role [2, 117]. Human lanosterol synthase mRNA in lipid nanoparticles, injected into the anterior chamber, increased expression in the lens and improved cataract in two rat models, without a human study [121]. Activation of the unfolded protein response, 25-hydroxycholesterol (partial restoration of transparency in CRYAA and CRYAB mice), rapamycin in Cx50-deficient zebrafish and CRISPR-Cas9 editing of the zygote or of spermatogonial stem cells in a mouse model of CRYGC cataract have been studied in animal models [2]. Basigin (CD147) as a chaperone improved creatine transport by missense MCT12 variants in cells [63]. «Lens regeneration» surgery from the epithelial cells left after extraction has controversial human efficacy and, in hereditary cataract, regeneration without genetic correction would lead to recurrence [2]. None of these approaches had a registered human study in the sources consulted [2, 92].

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

Brimonidine is contraindicated below 2 years [45]; atropine is avoided for mydriasis in young infants [86]; contact lenses are avoided in Lowe syndrome [31]; a single-piece intraocular lens is not placed in the sulcus [45]; prolonged topical corticosteroids require surveillance of intraocular pressure and of the adrenal axis [44]. In Sengers syndrome and mitochondrial disorders, anaesthetic and pharmacological safety follows the recommendations of the Mitochondrial Medicine Society [20]. In CRYAB myofibrillar myopathy, cardiac and respiratory assessment precedes anaesthesia [5]. The sources consulted do not describe specific data on pregnancy and lactation in isolated congenital cataract; the disease has no systemic manifestations that affect pregnancy, and the relevant question is reproductive counselling (section 8). Maternal corticosteroid therapy has been associated with fetal cataract in one case [102]. In transition to adulthood, glaucoma surveillance, correction of myopic shift and anisometropia continue and, in partial or progressive cataracts, the surgical decision follows adult criteria, for which there is the AAO preferred practice pattern «Cataract in the Adult Eye» [44, 75].

7.15. Guidelines and divergences between sources

There is no European (ERN-EYE) or Royal College of Ophthalmologists guideline specific to congenital cataract; the closest British synthesis is the review by Self and colleagues, which brings together two Royal College study days and the practice of five centres, without grades of recommendation [44]. The AAO has no preferred practice pattern specific to paediatric cataract; the patterns for paediatric eye evaluation and for amblyopia apply [41, 87]. The AAP statement on the red reflex dates from 2008 [86].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mode of inheritance

Once syndromic and environmental causes have been carefully excluded, ophthalmological examination of first-degree relatives can detect cataracts and determine the mode of inheritance [39]. Dominant inheritance is the most common in European and North American families, whereas recessive inheritance predominates in populations with high consanguinity; X-linked inheritance has been described, and consanguinity suggests recessive inheritance and metabolic disease [28, 39]. In the Swiss cohort, among the 20 solved families, 11 had dominant inheritance, 1 recessive and 4 X-linked, and there were de novo variants in 8 families (40%) [29].

8.2. De novo variants, penetrance and expressivity

Isolated cataract in a child of unaffected parents may result from a de novo dominant variant, which justifies trio testing [29, 45]. The recurrent gene conversion variants in CRYBB2 arise de novo in independent families [73], and Aymé-Gripp syndrome is almost always de novo [14]. Incomplete penetrance (CRYBA2 p.(Val50Met); CRYGS p.(Gly75Asp) in a sibling with a normal examination at 20 years) and variable expressivity (PITX3, with isolated cataract in a parent and cataract with anterior segment dysgenesis in the child; CRYGD p.(Pro24Thr), with different morphologies) make examination of apparently healthy relatives essential [23, 29, 60, 78]. «Dominant» genes may have recessive forms, such as homozygous CRYBB2 with healthy parents, CRYAA p.(Arg54Cys) and CRYBB1 c.171del, which changes the recurrence risk to 25% [28, 29, 67].

8.3. Cascade testing and examination of relatives

Carrier detection is by slit-lamp examination, by testing for the familial variant when known and, in some metabolic diseases, by biochemistry [39]. In the X-linked forms, the mother and at-risk women should be examined at the slit lamp: posterior Y-sutural opacities in NHS carriers and radial cortical opacities in about 95% of postpubertal Lowe carriers, whose absence before puberty does not exclude carrier status [22, 31]. An affected woman with the full phenotype may have skewed X inactivation [22]. In the Swiss cohort, a carrier of the NHS variant NM_001291867.2:c.719-2A>G had bilateral sutural cataract and her sister, also a carrier, had no opacities on dilated examination [29]. In a London family with Lowe syndrome due to an OCRL variant that extends the protein, the carrier mothers had no lens opacities, and the authors accept that this type of variant may be associated with a milder phenotype [43]. Genetic testing informs counselling and reproductive options, and the result changed management in half of the probands with cataract in a Manchester series, mainly by avoiding further investigations and guiding surveillance [9, 96].

8.4. Prenatal and preimplantation diagnosis

Prenatal diagnosis is technically possible with molecular or biochemical confirmation [39]. With the familial variant identified, the same molecular basis allows preimplantation genetic testing; the sources consulted do not describe series of molecular prenatal or preimplantation diagnosis specific to isolated cataract. The second-trimester scan detects some fetal cataracts, but is probably not sensitive for recurrence [99]. In the Chinese and Israeli ultrasound series, most fetuses with cataract had other anomalies, and termination rates were 75.6%, 72.4% and 7 of 8 cases; in isolated fetal cataract, the Israeli authors suggest detailed in utero ophthalmological examination for counselling [100–102]. For isolated cataract, a treatable disease with a variable visual prognosis, the reproductive decision should weigh the severity observed in the family, intrafamilial variability and the outcome of early surgery [39, 78].

8.5. Minors and content of counselling

In Portugal, genetic tests in minors are performed only for the direct benefit of the child, and predictive testing for diseases with onset up to adulthood is restricted unless there is a preventive or therapeutic benefit [98]. In cataract, clinical examination of siblings as a rule replaces predictive testing, because it detects the disease and guides treatment [39]. Counselling should explain the mode of inheritance, the variability of morphology and severity within the same family, the possibility of extraocular manifestations associated with some genes (CRYAB, AGK, WFS1, TDRD7), the need for lifelong follow-up and the availability of educational and visual support, and is provided by a team with paediatric ophthalmic surgeons, orthoptists, paediatricians, geneticists and genetic counsellors [9, 27].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Incidence and prevalence: what each figure measures

The figures are not interchangeable: incidence in the 1st year measures new diagnoses in one year, cumulative incidence adds up diagnoses to a given age, and prevalence counts existing cases in a sample of children; British active surveillance gave higher estimates than passive congenital anomaly registers [37]. The NIPE programme informs families that about 2 to 3 in every 10,000 babies have eye problems that require treatment [123]. Differences between countries reflect the effectiveness of screening, rubella vaccination and population genetics [45]. All these values refer to congenital and infantile cataract of all causes; the frequency of the isolated hereditary form is obtained by applying the hereditary fraction, which varies with the denominator.

9.2. Hereditary fraction

The hereditary proportion differs between sources because the denominators differ. The Oxford book cites 22–27% of congenital cataracts as hereditary, more in bilateral cases [39]; Shiels attributes about 22% of all congenital cataract to hereditary causes [2]; Reis and colleagues, in 2013, attributed 10–25% of paediatric cataracts to genetic causes [23]; in the United Kingdom, hereditary disease explained 56% of bilateral and 6% of unilateral cases, and no cause was identified in 92% of unilateral and 38% of bilateral cases [40]. Self and colleagues estimate that at least 50% of congenital cataracts have a genetic cause, probably an underestimate [44], and Guo and colleagues estimate that monogenic variants explain about two thirds [76]. The increase over time mainly reflects next-generation sequencing, which identifies genetic causes in cases previously classified as idiopathic. Dominant inheritance accounts for about 44% of cases [27], and almost half of hereditary cataracts are dominant, followed by recessive and X-linked forms [50].

9.3. Founder and consanguineous populations

Recessive forms predominate in populations with high consanguinity. In Saudi Arabia (cohort from two Riyadh centres, 2000–2019, 28 confirmed cases), homozygous recessive inheritance predominated, with the recurrent variant CRYBB1 c.171del in several unrelated patients, in contrast to the dominant predominance in North American and European cohorts [28]. In Pakistan, FYCO1 is one of the most common causes of recessive cataract, and CRYBB3 p.(Gly165Arg) is a founder variant, in 5.2% of 116 families [17, 74]. Among the Yakut of Eastern Siberia, FYCO1 p.(Gln541Ter) explains 86% of families with congenital cataract, with a carrier frequency of 7.9% [17]. Among the Romani, the CCFDN variant CTDP1 c.863+389C>T has a carrier frequency of about 7% among the Rudari and 1.4% in the general Romani population [33]. Among the Hutterites, LEMD2 causes a recessive juvenile cataract associated with sudden cardiac death [2]. European families contributed to the discovery of several genes and recurrent variants: CRYBA1 p.(Gly91del) in British families, LIM2 p.(Arg130Cys) in British and Czech families, HSF4 in the Danish Marner family, PITX3 in Belgian families, SLC16A12 in a Swiss family and WFS1 in an Irish family [9, 12, 21, 63, 70, 78]. In China, CRYGD p.(Pro24Thr) dominates coralliform cataract, as a mutational hotspot and not as a founder effect [60].

9.4. Data from Brazil and Portugal

In 11 Brazilian families from São Paulo with dominant nuclear and lamellar congenital cataract, sequencing of CRYAA, CRYGC and CRYGD identified the novel variant CRYGD p.(Tyr56Ter) in one family and CRYAA p.(Arg12Cys) in another, both with nuclear cataract, and excluded variants in these genes in the remaining 9 families [80]. A 2011 Brazilian review estimated the prevalence at 1–6 cases per 10,000 live births, with about 50% of genetic cause and a predominance of dominant transmission [124]. The sources consulted do not include epidemiological or molecular data from Portugal on congenital cataract; the 2025 Portuguese joint guideline on genetic testing refers to retinal dystrophies [98].

9.5. Low-income countries and access

Between 20,000 and 40,000 children with congenital or childhood cataract are born worldwide each year [27]. In low-income countries, cataract and corneal diseases are frequent causes of childhood blindness, whereas in high-income countries diseases of the optic nerve and visual pathways predominate [87]. In low-income economies, the recorded prevalence was 0.42–2.05 per 10,000, compared with 0.63–13.6 in high-income economies, a difference that mainly reflects ascertainment [122]. The yield of genetic testing is lower in some non-European populations (up to 20%), partly because of under-representation in databases [77]. Pseudophakia is attractive where contact lenses are difficult to maintain, but it does not resolve amblyopia or glaucoma [44]. In the IATS, private health insurance, used as a socioeconomic indicator, was the factor most associated with visual outcome [58], and in IoLunder2 inflammatory visual axis opacification was associated with socioeconomic deprivation (OR 5.39) [125].

9.6. Special populations

Preterm infants are diagnosed later and escape retinopathy of prematurity screening [90]. In children with intellectual disability, the risk of retinal detachment after surgery was 11.0% in the 2025 meta-analysis [47]. Children with trisomy 21 have a high risk of cataract and are among the screening risk groups [39, 44]. The children of mothers treated with CFTR modulators and babies treated with these drugs have been added to the risk factors of the NIPE programme [88].

9.7. European network and patient associations

ERN-EYE (European Reference Network for rare eye diseases), coordinated from Strasbourg, has no working group dedicated to the lens; the relevant groups are WG3, paediatric ophthalmology (Paris and Madrid), and WG4, anterior segment (Freiburg and Prague); the network runs a distance-learning programme on paediatric rare eye diseases and has patient representatives (ePAG) [48]. Patient associations include the Pediatric Glaucoma & Cataract Family Association, in the USA, and the Childhood Cataract Network, in the United Kingdom [126]. For the syndromic forms, the Oxford book lists the Lowe Syndrome Association, Climb (inherited metabolic diseases), Contact a Family and NORD [39, 99].

10. Illustrative Clinical Case

Wang and colleagues, from Beijing Tongren Hospital, reviewed the 392 families with congenital cataract seen between 2011 and 2021 and identified 12 (3.1%) with coralliform cataract [60]. All had autosomal dominant inheritance and bilateral, symmetrical cataracts diagnosed at birth, without progression and without systemic anomalies in the probands. The examination included visual acuity, intraocular pressure, biomicroscopy, A- and B-mode ultrasound and fundus photography. Corrected acuity in the probands ranged from 20/200 to 20/25: proband CC21 had 20/25 in both eyes and proband CC47 had 20/200 in both; patients who underwent surgery were operated on between 1 and 17 years, and several were not operated on. Slit-lamp photographs of nine probands (CC02, CC07, CC21, CC47, CC165, CC198, CC281, CC345 and CC382) show a white coral-shaped central opacity (Figure 1 of Wang et al., 2023) [60].

Sanger sequencing of CRYGD (NM_006891.4) identified the heterozygous variant c.70C>A p.(Pro24Thr) in 10 of the 12 families (83.3%), cosegregating with all affected individuals, absent in unaffected individuals and in 110 controls, and with a frequency of 0.003338% in the South Asian population of gnomAD v3.1.2; two families had no CRYGD variant [60]. The authors' literature review found the same variant in more than 20 families of Indian, Moroccan, Australian, Saudi, Caucasian, American, British, Turkish and Chinese origin, with coralliform, lamellar, cerulean, nuclear, aculeiform, fasciculiform and total phenotypes; the different haplotypes in the Chinese families indicate a mutational hotspot [60]. The mutant protein has reduced solubility and aggregates through a non-amyloid mechanism [60].

The case illustrates four clinical points. Coralliform morphology points strongly to one gene and one variant, unlike most morphologies. The relatively preserved acuity of many coralliform cataracts allows observation with refractive correction, and the age at surgery in this series (1 to 17 years, with several patients not operated on) shows that the decision did not follow the timetable for dense infantile cataract [60, 65]. The same variant produces different phenotypes in other families, so counselling should anticipate variability. The historical nomenclature P23T corresponds to the current p.(Pro24Thr), and searching for either form in ClinVar returns the same record (VCV 16940) [62].

A complementary European case shows the boundary of the scope. In family 3 of Verdin and colleagues, carrying the PITX3 duplication c.640_656dup, the proband had bilateral congenital cataract with anterior segment dysgenesis, with an optical iridectomy for central corneal opacity, light perception in the right eye and an acuity of 0.4 to 0.7 in the left eye operated on at 8 years, whereas the carrier mother had only bilateral congenital cataract, extracted at 6 years [78]. In the same series, one family had cataracts developing in childhood with 9 mm microcornea, glaucoma, nystagmus and retinal detachments [78]. Intrafamilial variability between isolated cataract and cataract with anterior segment dysgenesis is the rule in this gene.

11. Prognosis and Long-Term Follow-up

11.1. Visual outcome

Visual prognosis depends on the density and laterality of the cataract, age at surgery, optical correction, adherence to occlusion and ocular comorbidities [45]. In the IATS (unilateral cataract), 25% of treated eyes had an acuity of 20/40 or better and 44% of 20/200 or worse at 10.5 years; earlier surgery was associated with a better outcome (logMAR 0.5 versus 1.1), and spectacle wear for at least 80% of waking hours was associated with an acuity of 20/40 or better [58, 84]. In the IoLunder2 cohort, median acuity at 5 years was 0.34 logMAR in bilateral cases and 0.70 logMAR in the operated eye of unilateral cases [85]. In a German cohort of 116 patients operated on between 2000 and 2018 and followed for at least 6 years, mean acuity at 6 years was 1.0 logMAR (20/200) in unilateral and 0.4 logMAR (20/50) in bilateral cases [120]. In persistent fetal vasculature, only 20% (bilateral) and 24% (unilateral) had normal vision for age 1 year after surgery [106]. In FOXE3 primary aphakia, acuity at presentation was no better than fixing and following light in any patient [15]. Isolated hereditary cataract has a better outcome than cataract with ocular or systemic anomalies [39]. Late surgery is associated with a deficit in face recognition greater than expected from acuity [45].

Binocularity is limited in unilateral cataract. In the IATS, about half of patients with an acuity of 20/40 or better at 4.5 years had at least gross stereopsis; at 10.5 years, 6 of 109 children (5.5%) had stereopsis, 22.2% of those with an acuity of 20/40 or better, and almost 90% had strabismus [58, 118]. An adolescent operated on at 6 weeks for unilateral cataract with persistent fetal vasculature, with a contact lens and graded occlusion, reached 20/20 in both eyes, orthotropia and stereopsis of 40 seconds of arc, which shows the outcome possible with early treatment and high adherence [45].

11.2. Glaucoma following cataract surgery

Glaucoma following cataract surgery has an incidence of 6.0–58.7% across studies, may arise months or decades later, and in the IATS the risk continued to increase with the duration of follow-up [45]. Most series report 10–25% [44]. In the IATS, the Kaplan-Meier risk of glaucoma was 9% at 1 year, 17% at 5 years and 22% at 10 years, and that of glaucoma or glaucoma suspect 12%, 31% and 40%, with no difference between intraocular lens and aphakia; eyes with glaucoma grew more but had similar nerve fibre layer and acuity at 10 years [46]. The odds of glaucoma were 1.6 times higher for each month earlier than 6 months in age at surgery, and a smaller corneal diameter increased the risk [58]. In the IoLunder2 cohort, glaucoma developed by 5 years in 20% of children with bilateral and 12% with unilateral cataract, and glaucoma-related events in 24% and 36%; the independent predictors were younger age at surgery (adjusted OR 1.1 per week younger), ocular comorbidity and shorter axial length [82]. Risk factors also include aphakia, posterior capsulotomy, complications and reinterventions, and microcornea, persistent fetal vasculature and microphthalmia [44, 45]. Rebound tonometry underestimates pressure in the presence of corneal oedema, so an apparently normal pressure does not exclude glaucoma [44].

Diagnosis uses the IATS criteria (pressure above 21 mmHg with at least one anatomical sign: corneal enlargement, asymmetrical progressive myopic shift with increased corneal diameter or axial length, increase in cupping of at least 0.2, or surgery for pressure control) or those of the CGRN (Childhood Glaucoma Research Network), which allows diagnosis without raised pressure on the basis of corneal changes (Haab striae; diameter above 11 mm in the newborn, 12 mm before 1 year and 13 mm thereafter), optic nerve changes (progressive cupping, asymmetry of at least 0.2, focal rim thinning), progressive myopia with excessive ocular growth or a reproducible visual field defect [45].

11.3. Other complications

Visual axis opacification is common with or without an intraocular lens; with a lens implanted before 2 years, opacification requiring secondary surgery reaches about 40%, more than double that with aphakia [45]. In IoLunder2, opacification required surgery in 45% of the 162 eyes with a primary lens before 2 years, mainly in the 1st year; a three-piece lens and older age at surgery were protective [125]. In the North American IRIS registry (7680 children operated on between 2013 and 2020, median age 11 years, median follow-up 19.7 months), the cumulative incidence of a diagnosis of opacification was 36.8% in pseudophakic and 7.7% in aphakic children, with a median of 4.2 months to diagnosis; a history of trauma, uveitis or retinopathy of prematurity was associated with higher risk, and children under 3 years were under-represented [127]. Treatment is Nd:YAG laser or surgical revision with anterior vitrectomy [45]. Eyes operated on in infancy undergo myopic shift: in the IATS, pseudophakic eyes had a mean shift of 0.35 D per month up to 1.5 years and of 0.97 D per year up to 5 years, with a median anisometropia of −5.40 D at 10 years, and aphakic eyes went from +19.01 D after surgery to +10.38 D at 10 years [58]. In a Japanese series with a mean follow-up of 15 years, the median myopic shift in those operated on by 2 years was −8.2 D in bilateral aphakia and −11.2 D in bilateral pseudophakia [119]. Rhegmatogenous retinal detachment after paediatric cataract surgery occurred in 2.4% (95% CI 0.7–5.0%) in a meta-analysis of 5922 eyes with a mean follow-up of 4 years, and in 11.0% of children with intellectual disability [47].

11.4. Extraocular prognosis of genes with allelic disease

In carriers of CRYAB variants, the prognosis is determined by the heart and respiration when myofibrillar myopathy is present, and the recessive infantile form is fatal before 3 years [5]. In Sengers syndrome, survival depends on the cardiomyopathy, and homozygous nonsense variants are associated with higher infant mortality [20]. Saudubray's book distinguishes four forms (late-onset, with hypertrophic cardiomyopathy, congenital cataract, myopathy, exercise intolerance, hyperlactataemia and normal development, with survival up to the 4th or 5th decade and death mainly cardiac; fatal neonatal encephalomyopathy; fatal neonatal liver dysfunction; and isolated cataract); in a review of 29 patients, 17 died (59%), 15 of them between 2 days and 11 months, and tachydyspnoea and raised lactate were associated with risk of death; urinary 3-methylglutaconic acid was raised in 70%, and there is no treatment directed at the mechanism, cataract surgery and heart transplantation being useful [128]. The non-classic form of WFS1 with neonatal diabetes requires metabolic surveillance [21].

11.5. Surveillance

No guideline consulted sets a formal long-term surveillance schedule; the table brings together the intervals described in the reviews and in the sources for each gene.

12. Summary and Concluding Remarks

A genetic cause explains most bilateral congenital cataracts in developed countries, and isolated hereditary cataract is a genetically heterogeneous disease, with more than 100 genes associated with paediatric cataract, among which the crystallin genes account for almost half of non-syndromic cases [45, 50]. Inheritance is mainly dominant in European and North American populations and recessive in consanguineous populations, de novo variants are frequent and several genes have dominant and recessive alleles, so inheritance is decided by the variant and by examination of relatives [28, 29]. Morphology guides but rarely identifies the gene, with exceptions such as the coralliform cataract associated with CRYGD p.(Pro24Thr) [60].

Recognition depends on red reflex examination in the newborn and at subsequent visits, whose performance is imperfect: about one third of cataracts are detected late, especially in preterm infants [89, 90]. For a dense cataract, surgery is urgent, between 6 and 8 weeks in unilateral and between 6 and 10 weeks in bilateral cases, with immediate optical correction and prolonged occlusion; a primary intraocular lens does not improve acuity or reduce glaucoma in infants and increases reoperations [44, 84, 85]. Genetic testing by extended panel, exome or genome, preferably as a trio, is now the central investigation, because it identifies treatable systemic causes, avoids unnecessary investigations and guides counselling; a negative result does not exclude a genetic cause, and variants of uncertain significance require segregation [43, 76, 96]. Genes with extraocular allelic disease (CRYAB, AGK, WFS1, MAF, TDRD7) change surveillance [5, 20].

Glaucoma, which affects about 40% of eyes operated on in infancy after 10 years when suspected cases are included, visual axis opacification and myopic shift make follow-up lifelong [45, 46]. There is no approved pharmacological treatment, and approaches with lanosterol, lanosterol synthase mRNA or gene editing remain preclinical [2, 117, 121]. A specific European guideline, randomised trials on the timing of surgery and on bilateral cataract, and epidemiological and molecular data from Portugal are lacking [44, 48].

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