autosomal dominant

CHARGE Syndrome

Clinical Characteristics
Ocular Features: 

Both ocular and systemic abnormalities are highly variable, even within families.  Among the most common ocular features are unilateral or bilateral ocular colobomas (80%).  These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve.  A significant number of patients with uveal colobomas have an associated microphthalmia.  The lid fissures often slant downward.  A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.

Systemic Features: 

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

Genetics

Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well.  Advanced paternal age may be a factor in de novo cases.  Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients.  The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.

Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.

Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is lesion dependent but focused on airway, feeding, and cardiac defects at least initially.  Regular ophthalmologic and audiologic evaluations are recommended beginning in infancy.  Evidence for hypogonadism should be evaluated if puberty is delayed.  Nutrition must be monitored especially in those with serious feeding problems.  Hearing devices, with speech, occupational, and education therapy may be required.

References
Article Title: 

Macular Dystrophy, Occult

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Reduced vision may cause symptoms beginning during adolescence but some individuals may have good vision until the 6th decade or even later.  Even those who complain of changes in acuity may still have 20/20 to 20/25 vision but it may also be much worse, in the range of count fingers.  There can be considerable asymmetry in acuity between the two eyes but there is little known about the rate of vision loss.  Mild dyschromatopsia is often present with deficits in both red-green and red-green discrimination but total color blindness has also been reported.  Full field ERGs usually show no rod or cone deficits.  However, multifocal ERG changes suggest dysfunction of the cones in the macula.  Spectral-domain optical coherence tomography can reveal disruptive changes at the photoreceptor inner/outer segment line and in cone outer segment tips.  Disruption of the external limiting membrane and decreased foveal thickness have also been reported.  The retina appears normal to clinical examination even in advanced stages of disease and fluorescein angiography likewise shows no abnormalities.

Systemic Features: 

No systemic disease has been repoted in this condition.

Genetics

This is an autosomal dominant condition resulting from heterozygous mutations in RP1L1 (8p23.1).  A significant number of sporadic cases occur, however, which suggests new mutations are relatively common or that there is etiologic heterogeneity.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Adenomatous Polyposis of the Colon

Clinical Characteristics
Ocular Features: 

The ocular hallmark of this disease is the presence of congenital hypertrophy or hyperplasia of the retinal pigment epithelium (CHRPE).  Singular lesions have little diagnostic significance and are not pathognomonic of FAP but the presence of 4 or more lesions is highly specific for the diagnosis of familial polyposis of the colon.  Lesions are often teardrop-shaped and average between 4 and 5 mm in size.  They are usually located in the midperiphery of the fundus and exhibit autofluorescence.  Malignant changes in the form of adenocarcinomas have been reported but are rare.

CHRPE has been reported in the absence of colonic polyposis but has been reported in up to 90% of patients with some variant of FAP and is a highly sensitive marker.

Systemic Features: 

The signature non-ocular feature of this syndrome is the occurrence of numerous, sometimes thousands, of gastrointestinal polyps located mainly in the colon.  Precancerous colonic polyps generally develop by the age of 16 years.  Many of these eventually show malignant changes with colorectal cancer developing in nearly all patients by the sixth decade of life but the mean age of colon cancer diagnosis is at 39 years.  Extracolonic lesions such as desmoid tumors, sebaceous cysts, osteomas, fibrosarcomas, and other tumors are frequently seen.  Patients are also at higher risk of thyroid, adrenal, and liver cancer.

Dental anomalies, soft tissue tumors, and jaw osteomas are prominent features found in a variant of FPC known as Gardner syndrome.

Genetics

This is an autosomal dominant disorder resulting from mutations in the APC gene (5q22.2).  This gene is a gatekeeper tumor suppressor gene which controls proliferation of colon epithelial cells.   Loss or inactivation of APC is considered to be the basis of several cancer syndromes such as hereditary desmoid disease (135290), somatic gastric cancer (613659), and hepatocellular carcinoma (114550).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Colectomy remains the mainstay of treatment and can be lifesaving if done before the polyps become malignant.  NSAIDs such as sulindac and the use of celecoxib, a COX2 inhibitor, can reduce the number of colorectal polyps but these agents are unlikely to replace colectomy as the primary treatment.  Evaluation and surveillance for at-risk relatives are mandatory.

The fundus lesions do not cause symptoms and do not require treatment.  The remote risk of malignant change in CHRPE lesions, however, suggests that they should be kept under observation.

References
Article Title: 

Familial adenomatous polyposis

Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009 Oct 12;4:22. Review.

PubMed ID: 
19822006

Corneal Dystrophy, Fuchs Endothelial, Late Onset 2

Clinical Characteristics
Ocular Features: 

The signs and symptoms of this disorder are similar to those of other adult endothelial dystrophies.  Guttae appear in the fourth or fifth decade of life and gradually increase in number.  Diffuse corneal edema eventually develops with a corresponding decrease in acuity.  In late stages the corneal edema involves all layers including the epithelium, leading to painful corneal erosions. 

Systemic Features: 

Some patients with FECD3 report hearing impairment but this has not been studied and may be simply an age-related association.  It is of interest that among an unclassified series of patients with FCD the frequency of hearing loss was higher than in matched controls.       

Genetics

A mutation in LOXHD1 (18q21.2-q21.32) was originally thought to be responsible for this form of Fuchs in a multigenerational pedigree but is now considered an insignificant variant.  More recent evidence suggests that heterozygous trinucleotide repeat expansions in the TCF4 transcription factor gene at 18q22 are responsible.

There is considerable genetic heterogeneity in adult endothelial dystrophy which makes the nosology confusing especially since the clinical features are similar.  A similar late onset autosomal dominant disease [Fuchs Endothelial Dystrophy, Late Onset (610158)], sometimes labeled FCD2, may result from mutations on chromosome 13, or from changes in ZEB1 on chromosome 10.  Many cases are sporadic, however, and additional genotyping will be necessary in individuals to further clarify the classification of late-onset Fuchs endothelial dystrophy.

There is also an early onset form of Fuchs endothelial dystrophy, (136800).  

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation for symptomatic patients would likely be helpful but results have not been reported specifically for this type of dystrophy.

References
Article Title: 

Coloboma of the Optic Nerve

Clinical Characteristics
Ocular Features: 

Isolated colobomas of the optic nerve in the absence of other malformations may occur unilaterally or bilaterally.  The optic nerve cups are often huge and may have residual glial tissue in them.  Serous detachments of the macula are frequently observed and the risk for extensive retinal detachments is high. Microphthalmos with a cyst (6% of eyes), simple microphthalmos (39% of eyes), and microcornea (84% of eyes) are frequently associated.  The visual prognosis is poor when these occur in combination with an optic nerve coloboma (less than 20/400 acuity in 67% of eyes).  Isolated optic nerve colobomas without other malformations have the best vision (only 7% have acuity of less than 20/400).  Retinal vessels are anomalous as well.  They are often increased in number and have a generally straight course in the peripapillary region.

It has been argued that the morning glory disc anomaly may be an expression of this syndrome but this remains to be established.

Systemic Features: 

No systemic disease is present.

Genetics

This malformation frequently follows an autosomal dominant pattern of transmission secondary to a mutation in the PAX6 gene.

The PAX6 gene impacts DNA transcription and mutations are therefore often associated with a variety of ocular malformations, including uveal colobomas and various forms of anterior chamber dysgenesis.

Optic nerve dysplasia resembling optic pits or the morning glory disc anomaly is a feature of the papillorenal syndrome (120330) but this condition is caused by mutations in the PAX2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None.  Low vision aids may be helpful in some patients.

References
Article Title: 

Waardenburg Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Waardenburg syndrome is a disorder of pigmentation, sensorineural deafness, and a characteristic facial (nasal root) morphology.  Some have neural tube defects.  Based on clinical criteria, the syndrome has been divided into types 1, 2, 3, and 4, with subtypes of 2 and 4.  Types 1 and 3 are caused by mutations in the same gene.

Patients often have a white forelock and iris heterochromia.  The latter may be partial in individual irides, or the entire iris in one eye with the fundus hypopigmentation often matching the iris pattern.  The fundus may also have segmental areas of pigmentary changes corresponding to the iris heterochromia. The hypopigmented portion of the iris is often a brilliant blue.  Dystopia canthorum is a prominent and nearly constant (>95%) feature of type 1, and together with the prominent nasal root and increased intercanthal distance may suggest hypertelorism.  Synophrys is often present and the medial portions of the eyebrows can be exceptionally bushy.  Sometimes the poliosis involves the lashes and eyebrows.

Systemic Features: 

Congenital sensorineural deafness is an important feature.  Individuals with type 1 often have a white forelock (29%), premature graying (44%), and hypopigmented skin patches (55%).  A few patients have cleft palate and/or lip. Neural tube defects have also been reported. The considerably more rare type 3 is caused by mutations in the same gene as type 1, but it is claimed by some to be a separate disorder because of the association of limb anomalies. 

Genetics

Autosomal dominant inheritance is typical for the Waardenburg syndrome.  Types 1 and 3 are caused by mutations in the PAX3 gene (2q35) and, of these, type 1 is far more common.  Type 1 is caused by a heterozygous mutation whereas type 3 may result from either a heterozygous, compound heterozygous, or homozygous mutation.  Both types have been reported to occur in the same pedigree.  PAX genes act as transcription factors that attach to specific sections of DNA and regulate protein production.  PAX3 gene products, among other things, specifically influence neural crest cells important to the development of cranialfacial bones and melanocytes.  Paternal age plays a role in new mutations which probably account for many sporadic cases.

Waardenburg syndrome is an excellant example of genetic heterogeneity as types 1 (193500), 2 (193510), 3 (148820  and 4 (277580) can all result from mutations in different genes.  In addition, types 2 and 4 are each caused by mutations in several different genes. 

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3. Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations. In addition the face showed marked patchy pigmentation. One parent contributed the MITF mutation and the other added the mutation in PAX3.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary.  Patients may benefit from cochlear implants.

References
Article Title: 

Coloboma, Isolated

Clinical Characteristics
Ocular Features: 

Colobomas of the uveal tract are often found in association with other ocular anomalies including those with systemic disease. They are usually located in the inferonasal quadrant as a result of defective closure of the embryonic fissure in the optic cup.  Most involve the nearly complete iris and resemble a keyhole but they may also be partial resulting in an oval pupil.  They are sometimes unilateral in which case the involved iris may be more heavily pigmented than the contralateral one.  They may involve only the iris (simple coloboma) but often are more extensive with involvement of the ciliary body, retina, lens, choroid, and even the optic nerve.  They are frequently associated with microphthalmia (or microphthalmia with cyst [5.6%]) and microcornea (79%). 

Systemic Features: 

None by definition.

Genetics

Isolated colobomas are clinically and genetically heterogeneous resulting from mutations in SHH (7q36.3), PAX6 (11p13), and ABCB6 (2q35) among others.  Large pedigrees with typical autosomal dominant transmission patterns have been reported.

Homozygous mutations in SALL2 (14q11.1-q12.1) have also been reported in patients with isolated colobomas.  Studies of sall2-deficient mice show defects in closure of the anterior optic fissure while posterior closure proceeds normally.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Simple iris colobomas usually do not require treatment.  The visual prognosis depends upon the structures involved.  Those with microcornea usually have a lower acuity and, of course, eyes with the most extensive involvement of the uveal tract and/or the optic nerve may have the least vision. Low vision aids can be helpful in selected individuals.

References
Article Title: 

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Kelberman D, Islam L, Lakowski J, Bacchelli C, Chanudet E, Lescai F, Patel A, Stupka E, Buck A, Wolf S, Beales PL, Jacques TS, Bitner-Glindzicz M, Liasis A, Lehmann OJ, Kohlhase J, Nischal KK, Sowden JC. Mutation of SALL2 causes recessive ocular coloboma in humans and mice. Hum Mol Genet. 2014 Jan 12. [Epub ahead of print].

PubMed ID: 
24412933

ABCB6 Mutations Cause Ocular Coloboma

Wang L, He F, Bu J, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li DY, Phillips JD, Yang Z. ABCB6 Mutations Cause Ocular Coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8.

PubMed ID: 
22226084

Branchiooculofacial Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmos, or anophthalmia, and an imperforate nasolacrimal duct are the primary ocular features in this syndrome.  The nasolacrimal ducts may open onto the skin adjacent to the lacrimal sac.  Uveal tract and optic nerve colobomas are present in nearly half of patients. Strabismus is sometimes seen.  Cataracts are present in about 25% of patients as well.  The lid fissures are often slanted upwards.

Systemic Features: 

A cleft lip and/or palate are common features.  There may be preauricular pits, lip pits, a highly arched palate, and hypodontia.  Some individuals have subcutaneous cysts in the scalp.  Postauricular cervical branchial and supraauricular defects are often present as well.  It is not unusual to see some skin discoloration behind the ears.  The nasal bridge is broad, the top of the nose is flattened, and the philtrum is often short.  The ears are often enlarged or malformed and in 70% of patients there is some hearing loss which is usually conductive in origin but neurosensory deafness has also been documented.  Premature graying of hair is common.  Kidney malformations and dysfunction have been documented.  Mental function is usually normal.  Preaxial polydactyly is an uncommon feature.

Genetics

This is an autosomal dominant disorder resulting from mutations in the TFAP2A gene (6p34.3).  Both deletions and insertions have been identified.  However, 50-60% of patients have de novo mutations.  As in many autosomal dominant disorders there is considerable clinical heterogeneity and few patients have all of the signs.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment requires a multidisciplinary approach with oculoplastic, ophthalmic, and ENT surgeons.  Physical, speech, hearing, and learning specialists can be helpful.

References
Article Title: 

Further delineation of the branchio-oculo-facial syndrome

Lin AE, Gorlin RJ, Lurie IW, Brunner HG, van der Burgt I, Naumchik IV, Rumyantseva NV, Stengel-Rutkowski S, Rosenbaum K, Meinecke P, et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet. 1995 Mar 13;56(1):42-59. Review.

PubMed ID: 
7747785

Spherophakia with Inguinal Hernia

Clinical Characteristics
Ocular Features: 

Individuals with this condition have small spherical lenses that are usually displaced superiorly.  Myopia, both lenticular and axial, is often present and retinal detachments can occur.  Glaucoma was reported in one patient but this followed surgery for a retinal detachment.  Iridodenesis and nystagmus may be present.  The single report mentions strong zonules that created difficulties during intracapsular lens removal.  None of the spherical lenses were reported to migrate into the anterior chamber nor was lens-induced glaucoma present.

Systemic Features: 

Inguinal hernias are the only systemic manifestation of this disorder.  Four of 11 affected individuals in the family reported required surgery.  Physical examination and skeletal measurements were used to rule out the Marfan and Weill Marchesani syndromes.

Genetics

A single family with 11 affected individuals in 4 generations has been reported.  The four generation pedigree suggested autosomal dominant inheritance but nothing is known regarding the mutation or locus.

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).  Autosomal recessive isolated spherophakia (251750) has been found in several families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction may be necessary for vision rehabilitation if it is partially displaced.

References
Article Title: 

Dominant microspherophakia

Johnson VP, Grayson M, Christian JC. Dominant microspherophakia. Arch Ophthalmol. 1971 May;85(5):534-7.

PubMed ID: 
5087595

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 

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