autosomal dominant

Night Blindness, Congenital Stationary, CSNBAD2

Clinical Characteristics
Ocular Features: 

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive.  However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB).  At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves.  However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal.  In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB.  Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision.  Nystagmus and photophobia are usually not features.  Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies.  The amount of pigmentary retinopathy is highly variable.

This disorder (CSNBAD2) is one of three autosomal dominant CSNB conditions.  ERG responses were identical to those found in the Nougaret type of autosomal dominant CSNB.  Rod a-wave responses to single flashes are completely absent suggesting complete lack of rod function.  The residual b-wave suggests some cone response.  Daytime and color vision are normal.

Systemic Features: 

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNBAD2, or type AD2, is one of three congenital nightblindness disorders with autosomal dominant inheritance.  It results from mutations in the PDE6B gene (4p16.3) encoding a subunit of rod cGMP-specific phosphodiesterase.

Other CSNB disorders inherited in an autosomal dominant pattern are CSNBAD1 (610445) and CSNBAD3 (610444).

Three CSNB disorders are transmitted in an autosomal recessive pattern and two as X-linked recessives.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References
Article Title: 

Night Blindness, Congenital Stationary, CSNBAD1

Clinical Characteristics
Ocular Features: 

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive.  However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB).  At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves.  The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal.  In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB.  Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision.  Nystagmus and photophobia are usually not features.  Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies.  The amount of pigmentary retinopathy is highly variable. 

In this disorder (CSNBAD1), one of three autosomal dominant CSNB conditions, the b-wave responses are absent (no scotopic response) with some a-wave decrease in amplitude under dark adapted conditions.  Night vision in dim conditions may be reduced but not with bright backgrounds.  Daytime vision is normal as is color vision.  Older patients can have peripheral bone-spicule pigmentary changes with visual field restriction and narrowing of retinal arterioles.

Systemic Features: 

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNBAD1, or type AD1, is one of three congenital nightblindness disorders with autosomal dominant inheritance.  It results from mutations in the RHO (3q21-q24) gene coding rhodopsin.

Other autosomal dominant CSNB disorders are: CSNBAD2 (163500) and CSNBAD3 (610444).  Three CSNB disorders are transmitted in an autosomal recessive pattern and 2 as X-linked recessives.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References
Article Title: 

Cerebral Amyloid Angiopathy

Clinical Characteristics
Ocular Features: 

Posterior polar cataracts appear during the third decade of life.

Systemic Features: 

Progressive hearing loss has its onset in the third decade and becomes severe in the 5th decade.  Progressive dementia, often in the form of paranoid psychosis, begins about age 50.  Cerebellar ataxia and intention tremor have their onset in midlife.  There is a diffuse atrophy throughout the brain and cranial nerves are demyelinated.  Blood vessels throughout the CNS, spinal cord and retina show an amyloid angiopathy.  Intracranial hemorrhage is a significant risk and, when lobar in location, carries a significant risk of mortality within months.  Death generally occurs in the 5th and 6th decades of life.

Genetics

Pedigree patterns in the few reported families are consistent with autosomal dominant inheritance.  A mutation has been found in the ITM2B gene located at 13q14.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Heredopathia ophthalmo-oto-encephalica

Stromgrem, E. Heredopathia ophthalmo-oto-encephalica. In: Myrianthopoulos, N.C. Handbook of Clinical Neurology. Neurogenetic directory. New York: Elsevier/North Holland (pub.) 42, Part I: 150-152, 1981.

Saethre-Chotzen Syndrome

Clinical Characteristics
Ocular Features: 

The lids are often ptotic and asymmetrically so in keeping with the skull asymmetry.  Strabismus is common.  Optic atrophy, downward slanting lid fissures, epicanthal folds, and dacryostenosis have also been reported.

Systemic Features: 

The skull is acrocephalic and asymmetrical.  The frontal hairline is low.  The external ear and especially the crus of the ear are malformed and the latter is sometimes considered a valuable diagnostic sign.  There is frequently mild soft tissue syndactyly of the third, fourth and fifth toes, and the distal phalanges of the hallux may be bifid.  Syndactyly of the fingers is sometimes present as well.  Clefting of the soft and hard palates is commonly present and a few patients have had joint contractures.  Hearing loss of all types has been reported.  Mental development seems to be normal.  An increased risk of breast cancer has been found among Swedish patients.

SCS is considered to be one of the more common types of syndromic craniosynostosis.

Genetics

Saethre-Chotzen syndrome is caused by mutations in the TWIST1 (10q26) and possibly FGFR2 genes suggesting genetic heterogeneity.  There is also a great deal of clinical heterogeneity.  This syndrome is sometimes confused with Gorlin-Chaudhry-Moss syndrome (233500).  Pedigrees are consistent with autosomal dominant inheritance.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment except for cranioplasty and repair of palate clefting.

References
Article Title: 

Doyne Honeycomb Macular Dystrophy

Clinical Characteristics
Ocular Features: 

Beginning usually in midlife, the retina has radially localized white, large drusen in the posterior pole.  These may begin as small drusen that later enlarge and become confluent creating a honeycomb pattern.  The disease begins as an accumulation of material between the Bruch membrane and the RPE.  Eventually drusen occupy the entire thickness of the Bruch membrane and are continuous with or internal to the RPE basement membrane.  Vision early is normal and a slow loss of vision occurs sometime after the drusen appear in most individuals.  In some patients geographic atrophy, pigmentary changes, and a subfoveal neovascular net develops with macular scarring, vitreous hemorrhage, and severe reduction of vision.

Systemic Features: 

No systemic disease is associated.

Genetics

Doyne honeycomb macular disease, or dominant drusen, is the result of mutations in the EFEMP1 gene at 2p16 in the majority of cases.  It is an autosomal dominant disorder. The mutant protein product (a member of the fibulin famiy) is folded abnormally and secreted inefficiently.  It is also resistant to degradation which may lead to receptor damage by limiting access to nutrients from the choriocapillaris.  Some genetic heterogeneity may exist since a few cases seem to be linked to a locus at 6q14.    Some have considered Malattia Leventinese and Doyne honeycomb retinal dystrophy as separate entities but mutations in the same gene seem to be responsible for both conditions suggesting they are clinical variations of the same disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The subfoveal net responds to photodynamic therapy.

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 

Sorsby Macular Coloboma Syndrome

Clinical Characteristics
Ocular Features: 

Macular colobomas, usually bilateral, are the major ocular feature of this oculoskeletal disorder.  These are non-progressive and are generally heavily pigmented.  Vision is, of course, severely reduced (20/200) and horizontal or pendular nystagmus is a feature in some cases.

Systemic Features: 

The systemic features are primarily skeletal.  Patients have short-limbed dwarfism and brachydactyly of the type B variety.  The thumbs and sometimes the large toes may be broad and bifid.  The distal two phalanges sometimes short, absent, or duplicated and the nails can be dysplastic or absent. Syndactyly of several digits in both hands and feet is common.  The ears are large and protuberant and some patients have deafness.  Oligodontia may be present.  Cartilage can have diastrophic changes.  Mental development is normal.

Genetics

In the few families reported, the transmission pattern is vertical suggesting autosomal dominant inheritance but no mutation or locus has been reported.  The mutation causing brachydactyly type B1 was not present in several cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical treatment of digital anomalies can be beneficial.  Low vision aids could be helpful as well.

References
Article Title: 

Cryptophthalmos

Clinical Characteristics
Ocular Features: 

It may be that ankyloblepharon occurs in the absence of other abnormalities but in most cases the globes are small and malformed as well.  The combination of upper and lower lid fusion associated with microophthalmia effectively precludes visualization of the globes in many cases, hence the term cryptophthalmos. Lid colobomas may be present in patients with incomplete fusion of the lid margins.  There are often adhesions between the lids and cornea while the anterior chamber may have features of Peters anomaly.  Posterior chamber abnormalities such as optic nerve hypoplasia and retinal dysplasia with other tissues such as bone may also be present.  Rarely patients may respond to bright lights.  The condition may be unilateral or bilateral. The lacrimal drainage system may be malformed or absent while the eyebrows are often missing as well.  In severe cases, the forehead skin appears to be continuous with that of the cheeks.

Cryptophthalmos is also feature of other malformation syndromes most notably that described by Fraser (219000).

Systemic Features: 

The type of cryptophthalmos described here is sometimes called simple or isolated since no systemic malformations are associated.  It should be noted, however, that other ocular abnormalities are almost always associated and the clinical features of the hidden eye are anything but isolated or simple.

Genetics

A small number of families with a vertical pattern of inheritance suggest that at least some cases are inherited in an autosomal dominant pattern but no locus has been identified.  This pattern distinguishes such cases from those with the Fraser cryptophthalmos syndrome (219000) which has an autosomal recessive pattern of inheritance.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Attempts have been made to surgically create a lid fissure but the lack of conjunctival cul de sacs and fusion of the lids to the cornea in many cases can lead to irreparable complications.

References
Article Title: 

Isolated and syndromic cryptophthalmos

Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA, Jones MC. Isolated and syndromic cryptophthalmos. Am J Med Genet. 1986 Sep;25(1):85-98. Review.

PubMed ID: 
3099574

Dyskeratosis, Hereditary Benign Intraepithelial

Clinical Characteristics
Ocular Features: 

The conjunctival surface has elevated, granular-appearing white epithelial plaques usually in the interpalpebral areas.  These may extend onto the cornea and cause interference with vision.  The plaques may also shed spontaneously.  The lesions may have prominent blood vessels with associated conjunctival hyperemia with considerable cosmetic implications.

The plaque-like growths remain localized and do not invade tissue.  The surface epithelium is hyperkeratotic with acanthosis and individual cell dyskeratoses.

Systemic Features: 

The oral and lingual mucosa may also be involved.

Genetics

A segment of DNA localized at 4q35 is duplicated resulting in triple alleles for 2 linked markers suggesting that gene duplication is responsible for the disorder.  It occurs almost exclusively among members of a triracial isolate (Haliwa Indians) in North Carolina.

Families with autosomal dominant transmission have been reported.  In one French Canadian family in which mother and son were affected a nonsense mutation in NLRP1 (17p13.2) was found.  This may be a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Local excision as needed.

References
Article Title: 

Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis

Soler VJ, Tran-Viet KN, Galiacy SD, Limviphuvadh V, Klemm TP, St Germain E, Fourni?(c) PR, Guillaud C, Maurer-Stroh S, Hawthorne F, Suarez C, Kantelip B, Afshari NA, Creveaux I, Luo X, Meng W, Calvas P, Cassagne M, Arne JL, Rozen SG, Malecaze F, Young TL. Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis. J Med Genet. 2013 Jan 24. [Epub ahead of print].

PubMed ID: 
23349227

Corneal Dystrophy, Reis-Bücklers

Clinical Characteristics
Ocular Features: 

This is an anterior corneal dystrophy involving the epithelium and Bowman membrane.  Opacities consisting of spots and lines form in the central portion of the anterior cornea creating haziness with relative sparring of the periphery.  These can be seen as early as 4-5 years of age but few symptoms occur until the epithelium breaks down causing painful corneal erosions.  Visual acuity eventually drops as the corneal haze increases along with increasing irregularity of the epithelial surface.

Ultrastructural studies reveal degenerative changes in all epithelial cells and almost complete Bowman membrane replacement with disoriented collagen fibrils.

A comparative histological study of Reis-Bucklers and Thiel-Behnke dystrophies concluded that these are distinct CDB (corneal dystrophy Bowman) disorders and suggested the former be called CDB type I, and the latter CDB type II.  Type II is considered unique on the basis of the ‘curly’ fibers seen in the Bowman and subepithelial layers, while type I has bandshaped granular Masson-positive subepithelial deposits and ‘rod-shaped bodies’ resembling granular dystrophy.  Type I described here generally leads to greater vision loss than type II.

Systemic Features: 

No systemic disease is associated with Reis-Bucklers corneal dystrophy.

Genetics

This disorder seems to be closely related to the more common Thiel-Behnke dystrophy as the corneal disease is caused in both cases by missense mutations in the TGFBI gene on chromosome 5 (5q31). The mutation in Reis-Bucklers results in a p.Arg124Leu amino acid substitution whereas most cases of Thiel-Behnke dystrophy are the result of a p. Arg555Gln substitution.  Both disorders are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ablation of the diseased cornea can improve vision and provide temporary relief from the erosions.

References
Article Title: 

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature

Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995 Jul;14(4):333-54. Review.

PubMed ID: 
7671605

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