congenital cataracts

Cataracts, Congenital, with Brain Hemorrhage and Subependymal Calcification

Clinical Characteristics
Ocular Features: 

Bilateral neonatal leukocoria secondary to dense congenital cataracts (not further characterized) is evident at birth. Microphthalmia and pale optic discs have each been reported in a single patient.

Systemic Features: 

Newborns have catastrophic intracranial hemorrhages with massive cystic destruction of white matter and basal ganglia.  Subependymal calcification can be seen on CT scans.  Most individuals do not live beyond the neonatal period or early infancy.  Hyperreflexia, seizures, and spasticity are frequent clinical features.  Some patients have hepatomegaly and mild renal anomalies in size and location.  The forehead may be prominent and sloping.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the JAM3 (junctional adhesion molecule 3) gene (11q25).  The gene product is one of a family of proteins that contributes to intercellular tight junctions between epithelial cells, among others, and is postulated to be important to vascular permeability as well as lens development.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts

Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Sanchez MM, Gamundi MJ, Mochida GH, Walsh CA, Ali BR, Al-Gazali L. Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts. Hum Mutat. 2012 Dec 15.[Epub ahead of print]

PubMed ID: 
23255084

A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts

Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, Rakiec D, Tan WH, Akawi N, Al-Saffar M, Partlow JN, Tinschert S, Barkovich AJ, Ali B, Al-Gazali L, Walsh CA. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010 Dec 10;87(6):882-9.

PubMed ID: 
21109224

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

Cataracts, Congenital, Autosomal Recessive 5

Clinical Characteristics
Ocular Features: 

This type of autosomal recessive congenital cataract has been identified in a single consanguineous family.  The lens opacities (not further characterized) are the only ocular abnormalities found in two boys and 1 girl belonging to a single sibship born to parent who were second cousins.  Extensive systemic evaluations found no evidence of clinical disease as found in Sengers syndrome (212350).

Systemic Features: 

There are no systemic abnormalities.

Genetics

This type of cataract results from homozygous mutations in AGK (7q33-q36.1), a lipid metabolism gene.  Sengers syndrome (212350) is also caused by mutations in the same gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery may be indicated if the opacities are visually significant..

References
Article Title: 

Cataracts, Congenital, and Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Bilateral cataracts may be present at birth or later in the first decade of life.  The ERG and flash VEPs are normal.

Systemic Features: 

Psychomotor development is initially normal but signs of delay are usually present during the first year of life.  Patients may be able to walk but only with support.  Pyramidal and cerebellar dysfunction, muscle weakness and wasting, dysarthria, truncal hypotonia, intention tremor, and spasticity are evident during the first decade.  Some have seizures.  Cognitive impairment ranges from mild to moderate.  Most patients become wheelchair-bound late in the first decade of life and some do not survive beyond childhood.

Hypomyelination and mild axonal loss may be seen in peripheral nerve biopsies while neuroimaging shows evidence of diffuse and progressive cerebral white matter atrophy.

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in FAM126A (7p15.3) leading to a deficiency of the neuronal protein hyccin.  The result is deficient myelination in both central and peripheral nervous systems.  No symptoms are evident in heterozygotes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The cataracts may be surgically removed.  There is no known treatment for the progressive neurologic deterioration but physical therapy and special education may be helpful.

References
Article Title: 

Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease

Traverso M, Assereto S, Gazzerro E, Savasta S, Abdalla EM, Rossi A, Baldassari S, Fruscione F, Ruffinazzi G, Fassad MR, El Beheiry A, Minetti C, Zara F, Biancheri R. Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease. Biochem Biophys Res Commun. 2013 Aug 30. [Epub ahead of print] PubMed PMID: 23998934.

PubMed ID: 
23998934

Phenotypic characterization of hypomyelination and congenital cataract

Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol. 2007 Aug;62(2):121-7.

PubMed ID: 
17683097

Cataracts, Congenital with Sclerocornea and Glaucoma

Clinical Characteristics
Ocular Features: 

The ocular features are evident at birth or within the first year of life and may be asymmetrical.  The phenotype is heterogeneous but does not appear to be progressive.  The anterior chambers are of normal depth and the fundi are normal when visualization is possible.  The corneal opacification is usually denser peripherally and resembles corneoscleralization but it can extend centrally to a variable degree.  In individuals with glaucoma and buphthalmos the cornea is more opaque and usually vascularized. In such eyes the cornea is thinned.  In most patients the corneal diameters were 5-8 mm in diameter but in those with elevated pressures the anterior segment was obviously buphthalmic. Iridocorneal adhesions may be present.  The lenses are cataractous but the capsules are normal.  Microphthalmia has been reported in some patients.  Vision is often in the range of hand motions.    

Systemic Features: 

None.

Genetics

Homozygous mutations in PXDN (2p25.3) encoding peroxidasin are believed responsible for this autosomal recessive condition.  Mammalian peroxidasin localizes to the endoplasmic reticulum but is also found in the extracellular matrix and is believed important to the maintainence of basement membrane integrity.  The protein is one of several that aids in the extracellular breakdown of hydrogen peroxide and free radicals.  In mouse eyes it localizes to the corneal and lens epithelium but its role in maintaining transparency of the lens and cornea is unknown.

See also Cataracts, Congenital Zonular Pulverulent 1 (116200) in this database for a condition with a similar phenotype but caused by heterozygous mutations in the GJA8 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No information regarding treatment is available but cataract and corneal surgery may be beneficial.   

References
Article Title: 

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

Choi A, Lao R, Ling-Fung Tang P, Wan E, Mayer W, Bardakjian T, Shaw GM, Kwok PY, Schneider A, Slavotinek A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2014 Jun 18. doi: 10.1038/ejhg.2014.119. [Epub ahead of print] PubMed PMID: 24939590.

PubMed ID: 
24939590

Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma

Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 2011 Sep 9;89(3):464-73.

PubMed ID: 
21907015

Cataracts, Hearing Loss, and Neurodegeneration

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the important ocular feature in this syndrome.

Systemic Features: 

Hearing loss is an important part of this syndrome.  Severe hypomyelination and hypoplasia are seen on MRI.  Marked developmental delay and early death are also seen.  Reduced ceruloplasmin secretion and low serum copper are present.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in SLC33A1 (3q25) encoding an acetylCoA transporter (AT-1).  The defect in hepatic cells results in reduced ceruloplasmin secretion with low serum copper.  Wilson disease (277900), Menkes disease (309400), and aceruloplasminemia (604290), other disorders of copper metabolism, have similar blood findings but due to different mechanisms.

Heterozygous mutations in SLC33A1 result in an autosomal dominant form of spastic paraplegia (SPG42) (612539). No ocular abnormalities have been reported in SPG42 though.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No information on treatment has been reported.

References
Article Title: 

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin

Huppke P, Brendel C, Kalscheuer V, Korenke GC, Marquardt I, Freisinger P, Christodoulou J, Hillebrand M, Pitelet G, Wilson C, Gruber-Sedlmayr U, Ullmann R, Haas S, Elpeleg O, N?ornberg G, N?ornberg P, Dad S, M??ller LB, Kaler SG, G?SSrtner J. Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin. Am J Hum Genet. 2012 Jan 13;90(1):61-8.

PubMed ID: 
22243965

Cataracts, Congenital, with Cleft Palate

Clinical Characteristics
Ocular Features: 

Bilateral congenital cataracts are usually present together with upward-slanting and narrowed lid fissures.  The upper eyelids appear abnormally thick and epicanthus is common.  Nothing is known about the location or morphology of the lens opacities.

Systemic Features: 

Anomalies of the palate consisting of clefting, bifid uvula, and sub-mucous clefts are consistently present.  Oral anomalies such as thickening of the lower lid and small mouth are commonly seen.  The nose may be both long and broad.  The face usually appears oval and the forehead is prominent.  A cartilaginous nodule often appears on the helix of low-set and anteriorly rotated ears.  The fingers may be long and thin.

No cardiac or neurologic defects have been reported.

Genetics

Based on the transmission pattern in the single 4 generation family reported, autosomal dominant inheritance is likely.  Array comparative genomic hybridization revealed an interstitial amplification at Xp21.1 but this did not segregate precisely with the clinical pattern and is possibly a copy number polymorphism.  Both sexes are about equally affected. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No data on vision or surgical treatment have been reported but surgery for cleft palate and cataracts may be indicated.

References
Article Title: 

Cataracts, Congenital Zonular With Sutural Opacities

Clinical Characteristics
Ocular Features: 

This form of heritable congenital cataracts consists of both zonular and sutural opacities.  Both anterior and posterior Y sutures are involved with fine dots.  The zonular opacities consist of a hazy cloud of fine, minute dots so  vision is usually good as the opacities are not dense.  The dots are arranged in a lamellar or clumped pattern with the fetal nucleus most consistently involved.  There is often a faint cloud of white dots at the suture ends.  Most of the phenotypic variation is in the density of the opacities rather than their location.  Older individuals often develop nuclear and posterior subcapsular sclerosis.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant disorder.  A mutation in the CRYBA1 gene (17q11-q12) segregates with the phenotype.

A form of congenital cerulean cataract (115660) also maps to the long arm of chromosome 17 but in the q24 region.

Another type of autosomal dominant congenital sutural cataract (607133) has been reported in a single 5 generation Indian family in which a mutation in CRYBB2 on chromosome 22 was associated.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery can be considered if vision is significantly impacted.

References
Article Title: 

Cataracts, Ataxia, Short Stature, and Mental Retardation

Clinical Characteristics
Ocular Features: 

Cataracts are present in both sexes but the opacification is more extensive in males and only partial in females.  The cataracts are congenital in males but apparently develop later in females who complain of blurred vision from early childhood or during teenage years.  The lenses in females have punctate and pulverulent opacities as well as posterior subcapsular sclerosis.  Vision has been estimated as hand motion from early childhood in boys and about 20/40 in females in the first two decades of life.

Systemic Features: 

Males have mild to moderate mental retardation, muscle hypotonia and weakness with postural tremor.  Their standing position is broad-based and they are unable to sit or stand otherwise without some support.  They are usually unable to walk unassisted.  Speech is dysarthric and its development is delayed.  Females are neurologically normal.

Genetics

A locus containing the disease allele at Xpter-q13.1 cosegregates with the cataract phenotype in both sexes.  The gene mutation has not been identified.  This can be called an X-linked recessive disorder with partial expression in heterozygous females.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Cataract surgery may be indicated in young females and may be beneficial in infant boys.

References
Article Title: 

Rubinstein-Taybi Syndrome 1

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Few patients have all of the clinical features and there is much variation in the severity of these.  Almost all segments of the eye can be involved.  The lashes are often lush and the eyebrows may be highly arched and bushy.  Lid fissures are often downward slanting (88%).  Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported.  Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested.  Retinal pigmentary changes have been seen in some patients.  Refractive errors (usually myopia) occur in 56% of patients.  Visual acuities vary widely but about 20% of patients are visually handicapped.

Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity.  The AV transit time was prolonged with delayed venous filling and late small vessel leakage. 

Systemic Features: 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

Genetics

Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have been associated with a similar disease (see Rubinstein-Taybi Syndrome 2; 613684).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific clinical features such as glaucoma and strabismus.  Special education and vocational training may be helpful.  Hearing loss may respond to standard treatment.  Fractures and dislocations should receive prompt attention.  Cardiac anomalies may require surgical correction.

References
Article Title: 

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