autosomal dominant

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 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: 

Spinocerebellar Ataxia 1

Clinical Characteristics
Ocular Features: 

Early manifestations include gaze-evoked nystagmus and saccadic hypermetria.  Ophthalmoplegia develops later in the disease process.  Some patients experience a decrease in acuity and dyschromatopsia.  The ERG shows evidence of generalized rod and cone photoreceptor dysfunction in some patients.  Optic atrophy, central scotomas, central RPE changes, retinal arteriolar attenuation, and blepharospasm have also been reported.

Time-domain OCT has revealed microscopic changes in the macula with thinning of the inner-outer segment junction and nuclear layer in areas with RPE hypopigmentation. 

Systemic Features: 

This is a progressive cerebellar syndrome characterized by systems of ataxia, dysarthria, and bulbar palsy.  Speech is often scanning and explosive.  DTRs can be exaggerated, and dysmetria is common.  The mean age of onset is about age 40.  Some cognitive decline may occur.  Muscle atrophy, and symptoms of peripheral neuropathy can be present.  MRI shows atrophy in the cerebellum, spinal cord, and brainstem.  There is considerable variation in clinical expression.  Individuals with adult onset of symptoms can survive for 10-30 years whereas those with a juvenile-onset often do not live beyond the age of 16 years.

Genetics

This disorder is caused by an expanded CAG repeat in the ataxin-1 gene (ATXN1) at 6p23.  It is an autosomal dominant disorder.  Alleles with 39-44 or more CAG repeats are likely to be associated with symptoms. 

A male bias and the phenomenon of anticipation have been demonstrated in this disorder as in spinocerebellar ataxia 7 (SCA7) (164500), in which affected offspring of males with SCA develop disease earlier and symptoms progress more rapidly than in offspring of females.  This is often explained by the fact that males generally transmit a larger number of CAG repeats.

SCA7 (164500), also inherited in an autosomal dominant pattern and caused by expanded CAG repeats on chromosome 3, has many similar ocular and neurologic features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive care is often required.          

References
Article Title: 

Cataracts, Anterior Polar 2

Clinical Characteristics
Ocular Features: 

Lens opacities are located in the central anterior capsule and cortex.  They usually do not interfere significantly with vision.

Systemic Features: 

None.

Genetics

Most cases probably occur sporadically but multigenerational families have been reported in which the transmission pattern is autosomal dominant.  In one family the phenotype was mapped to 17p13 but the gene responsible has not been identified.

Another type (CTAA1) of anterior polar cataract is associated with chromosomal aberrations (115650).

Yet another form of autosomal dominant anterior polar cataract is associated with corneal disease (Cataracts, Anterior Polar with Guttata) (121390).

Other cataracts that map to chromosome 17 are zonular sutural cataract (600881) with a locus at 17q11-q12 and cerulean or ‘blue dot’ cataract (115660) at 17q24.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens removal is indicated only if these opacities interfere with vision.

References
Article Title: 

Vitreoretinal Degeneration, Snowflake Type

Clinical Characteristics
Ocular Features: 

The retina and vitreous are primarily affected in this disorder.  The age of onset is unknown but characteristic signs can be seen early in the second decade of life.   Early changes include thickening of the cortical vitreous and white dots in the superficial layers of the retina.  The latter are minute yellow-white crystalline deposits more common in the peripheral retina.  Many (83%) patients have early onset cataracts.  Corneal guttae are common (80% of patients).  The vitreous undergoes fibrillar degeneration with liquefaction and eventually appears optically empty.  Many patients experience symptoms of floaters.  The vitreous changes most closely resemble that seen in Wagner syndrome (143200) but with important differences.  In the latter disorder the vitreous changes are membranous, the retinal changes are deeper in location, RPE changes are evident, the choroid and RPE are involved, and the risk of retinal detachment is much higher.  Only 21% of patients with snowflake vitreoretinal degeneration have retinal detachments compared with about 50% in Wagner syndrome.  Retinal vasculature change such as perivascular sheathing and attenuation of arterioles may be seen in both disorders but occur far less commonly in snowflake degeneration.

Based on lack of visual symptoms, the photoreceptors are minimally involved.  Electrophysiologic studies reveal an elevated dark adaptation and reduced scotopic B waves.  Most patients retain excellent vision.  However, the optic nerve may have a waxy pallor and frequently appears flat and lacks a visible cup. 

Systemic Features: 

None.

Genetics

Snowflake vitreoretinal degeneration is an autosomal dominant disorder.   Heterozygous missense mutations have been found in KCNJ13 (2q37) in a single family.  Mutations in the same gene have been identified in rare cases of Leber congenital amaurosis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may be removed.  Patients need to be observed throughout life to enable prompt intervention when retinal detachments occur.

References
Article Title: 

Cornea, Ring Dermoid

Clinical Characteristics
Ocular Features: 

Dermoids in this condition are found at the limbus extending onto the cornea anteriorly and into the conjunctiva posteriorly.  They may be unilateral or bilateral and some contain functional hair follicles.  They are present at birth and appear as raised yellow-white tissue which can be segmental or extend for the full limbal circumference.  Some present as a dark ring around the cornea.  The apophyses can be elevated 2-3mm and extend for 3-5mm laterally.  Corneal changes, primary or secondary, lead to progressive vision loss in older individuals. Corneal distortion can result in significant astigmatism.  Some patients have glaucoma and congenital cataracts.

Histological studies have not been reported.

Systemic Features: 

No systemic disease is part of this condition.

Genetics

Two families, one Peruvian and one Chinese, have been reported with autosomal dominant patterns of transmission.  A G185A substitution in the PITX2 gene (4q25) cosegregated with the ocular disease in the Chinese family.

PITX2 encodes a transcription factor important to the development of multiple organs including the eye.  Mutations in this gene have also been found in patients with Peters anomaly (604229), a form of iris hypoplasia with goniodysgenesis (IRID2) (137600), and in Type 1 Axenfeld-Rieger syndrome (180500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical excision may be necessary in patients with extensive disease.  Patients need to be monitored for cataracts, amblyopia, and glaucoma.

References
Article Title: 

Cerebral Cavernous Malformations

Clinical Characteristics
Ocular Features: 

Cavernous capillary hemangiomas usually occur singly in the fundus, often at the disc.  Fewer than 5% of individuals with CCM have retinal lesions.  As opposed to the systemic hemangiomas, those in the eye tend to be stable.  However, they may result in vitreous hemorrhages because they lack the usual structural support of normal vessels.  Fluorescein angiography often reveals blood-fluid levels in the saccules that comprise the grape-like cluster of the tumor.

Systemic Features: 

Cavernous angiomas may involve any part of the CNS, brain stem, and spinal cord.  These are benign aberrant growths of capillary endothelium which develop shortly after birth and cause a variety of signs and symptoms including seizures, intracranial hemorrhage, and focal neurologic deficits. New lesions can appear throughout life. The blood –containing clusters are lined with endothelium only and the walls lack muscle or fibrous tissue.  Up to 25% are diagnosed in children. They may be angiographically silent but MRI is diagnostically useful.  Cutaneous hemangiomas are uncommon but helpful diagnostically when present.  The overlying skin may be hyperkeratotic.

Many patients (25-50%) remain asymptomatic throughout life.

Genetics

This is an autosomal dominant disorder caused by mutations in three genes.  CCM1 (116860) results from mutations in the KRIT1 gene located at 7q11.2-q21, the disease called CCM2 (603284) is caused by mutations in the CCM2/malcavernin gene (7p13), and CCM3 (603285) by mutations in the PDCD10 gene at 3q26.1.  The majority of familial cases have mutations in one of these genes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The fundus lesions seldom require treatment but photocoagulation can be used to seal those that lead to recurrent vitreous hemorrhages.  Embolism may be beneficial for CNS lesions but the lesions in many locations are relatively easy to remove surgically. Seizures are treated symptomatically.  Pharmaceutical agents that alter blood clotting should be administered with careful monitoring.

References
Article Title: 

Genotype-phenotype correlations in cerebral cavernous malformations patients

Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E; Soci?(c)t?(c) Fran?ssaise de Neurochirurgie. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann Neurol. 2006 Nov;60(5):550-6.

PubMed ID: 
17041941

Multiple Endocrine Neoplasia, Type IIB

Clinical Characteristics
Ocular Features: 

Corneal nerves are medullated and appear prominent.  Neuromas of the lid margins and sometimes the conjunctiva are common features.  Thickening of the entire eyelids may be present.

Systemic Features: 

Some manifestations may be seen in early childhood.  Prominent physical features include full lips, thickened eyelids, high arched palate and a marfanoid habitus.  Medullary carcinoma of the thyroid is almost always present and can be the cause of death in relatively young individuals. Metastases are usually to the regional lymph nodes or to liver, lungs, or bone. Pheochromocytomas and megacolon secondary to gastrointestinal neuromas are commonly seen.  The esophagus sometimes lacks normal motility for the same reason.  Neuromas often lead to thickening of the lips and tongue and can also appear as pedunculated nodules on these structures.  Cafe-au-lait spots and increased pigmentation of the hands, feet, and circumoral areas are frequently present.  Many patients have dysmorphic features suggestive of Marfan syndrome including a typical habitus, pectus excavatum, scoliosis, and pes cavus. Proximal myopathy and peripheral neuropathy are sometimes seen.

Another form of multiple endocrine neoplasia, called MEN2A, differs in the absence of mucosal neuromas and the marfanoid habitus.  MEN2A patients are more likely to have parathyroid hyperplasia.

Genetics

This is an autosomal dominant disorder caused by mutations in the tyrosine kinase domain of the RET gene (10q11.2). This disorder (MEN2B) may be allelic to MEN2A.  Perhaps half of MEN2B cases occur sporadically and in these the mutant RET allele is usually of paternal origin.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment of local lesions is sometimes indicated.  Biochemical testing for pheochromocytoma should be done before any surgery.

References
Article Title: 

Cataracts, Lamellar

Clinical Characteristics
Ocular Features: 

This type of heritable cataract is progressive and has a variable phenotype both within and between families.  It is usually seen bilaterally in early childhood but may be congenital in onset.  Fine, dispersed, pulverulent opacities of the primary lens fibers are seen in the embryonic nucleus often with increased density at the ends of the Y suture at 12, 2, and 6 o'clock presenting a triangular appearance.  However, the entire nucleus may be opaque as well.  Zonular and posterior subcapsular opacities may appear later but there is considerable variation among patients and they may also appear in a stellate pattern.  The lamellar pattern consists of a zone of opacification around a clear embryonic nucleus.  There may be considerable difference in the rate of progression of the opacities among patients and even between the two eyes.

This may be among the most common type of congenital, autosomal dominant cataract.  The first family was reported in 1878 and the family data has been updated and reported several times since then.  The most recent reported pedigree consisted of 965 individuals in 9 generations.  Among the 70 individuals added, 56 had cataract surgery performed between the ages of 1 month and 26 years with a mean of 8 years.  However, some adults never had cataract surgery. 

Another family with early onset, progressive, autosomal dominant cataracts mapping to the same locus has been reported (see Maumenee, 1979) but the opacification involves the secondary lens fibers at the posterior pole.  These may be variants of the same condition.

Systemic Features: 

This is a non-syndromal cataract disorder and no systemic disease has been associated.  

Genetics

This type of congenital cataract may be caused by mutations in the heat-shock transcription factor-4 gene (HSF4) located at 16q21-q22.1.  It is inherited in an autosomal dominant pattern. 

Another morphologically different autosomal dominant congenital cataract has been linked to the same locus (see Maumenee, 1979).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Volkmann type (115665), Coppock-like (604307), and congenital posterior polar (116600) 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 opacities require surgery. Amblyopia, if present, should be treated early.  

References
Article Title: 

Cataracts, Coppock-Like

Clinical Characteristics
Ocular Features: 

Coppock-like cataracts consist of bilateral progressive opacities of the embryonic lens nucleus.  They are characterized by a pulverulent opacification with a gray disc appearance associated with variable zonular opacities.  Visual symptoms often begin during adolescence and some patients require cataract surgery by the 5th decade of life. 

Systemic Features: 

There is no systemic disease associated with this type of cataract.  

Genetics

CCL cataracts are embryonic in origin, developing during the time when gamma-crystallin genes are active.  The gamma E-crystallin gene is a pseudogene and the mutation in its promoter reactivates its activity 10-fold.  It is postulated that overexpression of the gamma-crystallin fragment is responsible for the nuclear opacification.

Mutations in at least 3 genes have been associated with this type of cataract.  In some families the mutations are in the CRYGC gene (2q33-q35), and in others mutations in CRYBB2 (22q11.2-q12.2) seem to be responsible.  It is of interest that one form of congenital cerulean cataract, CCA3 (608983), found in a single family, results in mutations in CRYGD also located at 22q11.2-q12.2.  A five-generation Chinese family has been reported in which mutations in GJA3 (13q12.11) was associated with this type of lens opacity.

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Volkmann type (115665), lamellar (116800), and congenital posterior polar (116600) 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: 

Cataract surgery may be indicated.

References
Article Title: 

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