congenital cataract

Microphthalmia, Isolated, with Cataract

Clinical Characteristics
Ocular Features: 

Isolated microphthalmia with cataract is clinically and genetically heterogeneous and remains to be fully delineated.  The cataracts occur congenitally.  Nystagmus was an additional feature in several individuals with MCOPCT2.  The basis for a third type of microphthalmia with cataract (MCOPCT3) is even less certain but microcornea was also present in several members of a single family.  Globe dimensions have not been reported, however, and the criterion for the diagnosis of microphthalmia in reported families is unknown.

Systemic Features: 

Several patients with MCOPCT1 have had mental retardation.

Genetics

Based on genetic data at least three entities may exist but they are discussed in this database as a group because so few families have been reported.  MCOPCT1 follows an autosomal dominant pattern and segregates with a single unknown mutation at 16p13.3.  Another family with a reciprocal translocation t(2;16)(p22.3;p13.3)  involving a breakpoint in the 16p13.3 region seems to support the idea that an altered gene in this location is responsible for the phenotype.  MCOPCT2 also usually follows an autosomal dominant pattern and seems to be caused by mutations in the SIX6 gene (14q23.1).  The mode of inheritance in MCOPCT3 is uncertain since the transmission pattern in one family suggested X-linked dominance while in another family only males were affected.  No mutation or locus has been identified.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery may be beneficial when vision is significantly compromised.

References
Article Title: 

Cataracts, Congenital Sutural with Punctate and Cerulean Opacities

Clinical Characteristics
Ocular Features: 

The anterior and posterior Y sutures have prominent, dense white opacities.  The embryonal and fetal nuclei are clear but the cortex contains gray-bluish, sharply defined and elongated as well as punctate opacities.  These are denser near the posterior pole and the posterior Y suture is also more heavily involved.  The cortical opacities may be arranged in concentric lamellae.  Considerable variation in density of opacities has been noted among patients.

Systemic Features: 

None reported.

Genetics

A large Indian family consisting of 5 generations containing 33 affected individuals has been described.  This is an autosomal dominant disorder in which a mutation has been found in exon 6 of the CRYBB2 gene (22q11.2-q12/22q11.23).  This region contains four crystallin genes as well as the CRYBP1 pseudogene.  It has been suggested that gene conversion between exon 6 of the CRYBB2 gene and CRYBR1 may be responsible for the phenotype.  Three additional families with identical mutations in the same CRYBB2 exon have been reported and, since each family seems to have a unique phenotype, it is likely that more than a simple bp mutation is responsible for the cataracts.  

Some Coppock-like cataracts (604307) also result from mutations in CRYBB2 at the same location but others have  mutations in the CRYGC gene.  Type 2 congenital cerulean cataracts (601547) have also been associated with mutations in the CRYBB2 gene. 

Another autosomal dominant congenital cataract with sutural opacities (600881) has a slightly different phenotype and results from a mutation on chromosome 17.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may need to be removed.

References
Article Title: 

Cataracts, Congenital, Autosomal Recessive 3

Clinical Characteristics
Ocular Features: 

This type of congenital cataract has been reported in two unrelated Pakistani families.  The phenotype was dissimilar in the two families.  In one, only posterior subcapsular opacification was present.  In the other the cataract was membranous and accompanied by a corneal opacity, microcornea, and nystagmus.  Nothing is known about the course of the opacification.

Systemic Features: 

No systemic disease is apparently present.

Genetics

Consanguinity was reported for both families.  Fine mapping identified a locus at 1p34.3-p32.2 that cosegregates with the lens opacities but the mutation is unknown.  This region is distinct from the locus containing the mutation(s) causing Volkmann (115665) and posterior polar (116600) autosomal dominant cataracts.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Visually significant lens opacities could be removed.

References
Article Title: 

Cataracts, Congenital, Volkmann Type

Clinical Characteristics
Ocular Features: 

The nature of lens opacities is highly variable, ranging from dense opacification to barely detectable opacities.  The opacities may be located in the embryonic, fetal and juvenile nuclei as well as around the Y sutures.  They are congenital in origin and progressive.   Minimal opacities can be asymptomatic early but all eventually require removal, usually by the first or second decades of life.  Most cases have been reported from Denmark. 

Systemic Features: 

No systemic disease is present. 

Genetics

This type of cataract is inherited in an autosomal dominant pattern.  The causative mutation is unknown but a presumed locus has been identified at 1pter-p36.13.  This type of cataract may be allelic to congenital posterior polar cataract (116600).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Coppock-like (604307), and lamellar (116800), cataracts. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may require removal. 

References
Article Title: 

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Cataracts, Congenital, Posterior Polar

Clinical Characteristics
Ocular Features: 

Posterior polar cataracts are likely to occur congenitally but there is often a delay in detection until childhood or even adolescence.  Many patients with a late diagnosis develop nystagmus and strabismus.  Opacification usually begins bilaterally as disc-shaped plaques of opacification in the posterior polar region and progresses relatively rapidly to complete opacification.  Some patients require lens surgery in the first year of life while others not until they are young adults.

Systemic Features: 

This type of congenital cataract is not associated with systemic symptoms.

Genetics

Autosomal dominant posterior polar cataracts may result from mutations in the EPHA2 gene located at 1pter-p36.1.  Interestingly, an area with a likely locus adjacent to but outside the coding region of this gene has been associated with age-related cataracts.

This type of lens opacity may be allelic to Volkmann cataract (115665).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Coppock-like (604307), and lamellar (116800) cataracts. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serial monitoring and timely surgery are important for the prevention of amblyopia, strabismus, and nystagmus.

References
Article Title: 

Cataracts, Congenital Cerulean

Clinical Characteristics
Ocular Features: 

Tiny lens opacities of blue or white color generally appear from birth through 18 and 24 months of age but may not be diagnosed until adulthood.  They first appear at the outer edge of the fetal lens nucleus or in more superficial cortical layers depending on the type.  Infants may be visually impaired from birth and develop nystagmus and amblyopia.  The opacities are usually bilateral and progressive.  Lens removal may be required in early infancy but often not until the 2nd to 4th decades.

Systemic Features: 

No systemic abnormalities are associated with cerulean cataracts.

Genetics

Lens opacities can, of course, be associated with chromosomal aberrations, developmental conditions, intrauterine infections, and metabolic errors as well as single gene mutations.   About 23% are familial but even among these there is considerable genetic and clinical heterogeneity that confounds the nosology despite notable recent progress in genotyping.  Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Cerulean cataracts of congenital or childhood onset can be due to mutations in genes that encode various lens crystallins.  Type 1 (CCA1; 115660) or 'blue dot' cerulean cataracts result from mutations in a gene located at 17q24 but its identity is as yet unknown. Intriguingly, it is located in the same chromosomal vicinity as the galactokinase deficiency gene (GALK1).  The lens opacities follow an autosomal dominant pattern of transmission. The mutation, however, does not appear to involve a gene that codes for any of the major structural proteins of the lens.

Type 2 (CCA2; 601547) results from mutations in the CRYBB2 gene (22q11.2-q12.2) encoding the beta-B2-crystallin protein.  Inheritance is autosomal dominant.

Type 3 (CCA3; 608983) is caused by mutations in CRYGD (2q33-q35) coding gamma-D-crystallin.  It has been reported in a single family in which it seemed to appear earlier and progress more rapidly than other types.  The pedigree pattern was consistent with autosomal dominant inheritance.  Mutations in the same gene also cause an allelic disorder designated nonnuclear polymorphic congenital cataracts or PCC (601286), which may simply be clinical heterogeneity of the same condition.

Type 4 (CCA4; 610202) is due to mutations in the MAF gene (16q22-q23) and is also inherited in an autosomal dominant pattern.  Lens opacities have a later, more juvenile onset and the lens opacities are located in a lamellar distribution in superficial cortical layers.  These are progressive and often result in posterior subcapsular opacification that requires lens extraction in adults.

Type 5 (CCA5; 614422) is the result of a mutation in a locus at 12q24 and is dominantly inherited.  The opacities are located throughout the lens but are most numerous in the cortex.   They are most commonly diagnosed in the second decade of life and lens extractions are required a decade or so later.

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include Volkmann type (115665), Coppock-like (604307), lamellar (116800), and congenital posterior polar (116600) cataracts. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known to prevent the opacities but serial evaluations and cataract surgery are required to prevent amblyopia as the opacities progress.

References
Article Title: 

Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state

Plotnikova OV, Kondrashov FA, Vlasov PK, Grigorenko AP, Ginter EK, Rogaev EI. Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am J Hum Genet. 2007 Jul;81(1):32-43.

PubMed ID: 
17564961
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