X-linked dominant

Meester-Loeys Syndrome

Clinical Characteristics
Ocular Features: 

A variety of nondiagnostic facial features are present at birth including hypertelorism, downward slanting lid fissures, proptosis, frontal bossing, and midface hypoplasia.

Systemic Features: 

Aortic aneurysms with or without dissection have been diagnosed as early as 1 year of age but may not be apparent until teenage years.  Pectus deformities, joint hypermobility, and skin striae may be seen. Hypertrichosis, evidence of skeletal dysplasia such as hip dislocation, platyspondyly, phalangeal dysplasia, joint hypermobility, relative macrocephaly, dysplastic epiphyses of the long bones, and cervical spine instability are often present.

Genetics

This X-linked disorder is caused by a mutation in the BGN gene (Xp28).  No male-to-male transmission has been reported although both sexes are affected.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Individual deformities might be surgically repaired.

References
Article Title: 

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S, Waitzman K, Young L, Markham LW, Vogt J, Richer J, Beauchesne LM, Unger S, Superti-Furga A, Prsa M, Dhillon R, Reyniers E, Dietz HC, Wuyts W, Mortier G, Verstraeten A, Van Laer L, Loeys BL. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med. 2016 Sep 15. doi: 10.1038/gim.2016.126. [Epub ahead of print].

PubMed ID: 
27632686

Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

Clinical Characteristics
Ocular Features: 

Palpebral fissures are generally shortened and may slant up or down.  Cataracts of unknown morphology have been reported and strabismus is common.

Systemic Features: 

The systemic phenotype is highly variable.  Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities.  Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present.  The teeth may be malformed and numerous (29%) of individuals have hypertrichosis.  Nearly a third of individuals have a cleft palate/bifid uvula.   Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common.  Feeding difficulties have been reported while anal atresia is present in about half of patients.   

Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe.  Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.

Genetics

This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4).  X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity.  The majority of cases occur de novo.

In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

There is no known treatment for the general disorder but individual anomalies or defects such as atrial septal defects, cleft palate, and anal atresia might be surgically corrected.

References
Article Title: 

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B; DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A, Kleefstra T. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81.

PubMed ID: 
26833328

Nystagmus 5, Congenital, X-linked

Clinical Characteristics
Ocular Features: 

In the single 4 generation French family reported nystagmus was the only ocular finding.  It is present at birth or within the first year of life.  Visual acuity has not been reported.

Systemic Features: 

None reported.

Genetics

The pattern of inheritance is uncertain.  Both sexes may be affected but no male-to-male transmission was documented in the single family reported.  Apparent incomplete penetrance makes analysis difficult since several unaffected females transmitted the phenotype to male offspring.

No mutation has been identified but a possible locus within Xp11.4-p11.3 may contain the mutant gene.

Autosomal dominant transmission patterns have been reported in other families: NYS2, NYS3, NYS4, and NYS7.

This database contains several additional forms of congenital nystagmus inherited in X-linked recessive patterns: NYS1, and NYS6.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Charcot-Marie-Tooth Disease(s)

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in some patients, particularly in X-linked recessive (CMTX5; 311070), X-linked dominant (CMTX5; 302800), and autosomal recessive (CMT2A2B; 617087) disease.  Congenital and juvenile-onset open-angle glaucoma has been reported among members of 2 consanguineous families with type 4B2, or CMT4B2; (604563).  The mean age of onset was 8 years.

Systemic Features: 

Charcot-Marie-Tooth disease is a large group of clinically and genetically heterogeneous disorders characterized by progressive motor and sensory polyneuropathy.  These can be separated (with overlap) into two large groups on the basis of electrophysiologic criteria: type 1 is the demyelinating form, and type 2 the axonal form.  Patients with primarily distal motor neuropathy are sometimes considered to comprise a third type.

 Symptoms such as weakness in the extremities and digits have a variable age of onset but usually become evident in late childhood or early adulthood.  Small muscles of the hands and feet are often atrophied to some degree.  Some patients develop hearing loss of the neurosensory type.  Foot deformities such as pes cavus are common.  Nerve conduction velocity (reduction) and electromyography can be helpful diagnostically.  It may be helpful to look for characteristic changes such as loss of myelinated fibers and focal myelin sheath folding in sural nerve biopsies.  Intellectual impairment and dementia are usually not features of Charcot-Marie-Tooth disease.

Hemizygous individuals with X-linked types of CMT such as CMTX2-5 seem to be more likely to have intellectual disabilities, hearing loss, spasticity, and optic neuropathy.

Genetics

Charcot-Marie-Tooth disease can also be classified on the basis of their hereditary patterns including autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant.  Each of these contains yet more distinct subtypes as defined by mutations in at least 40 genes.

The wide range of disease severity and the overlapping of many signs can make pedigree construction and the determination of recurrence risks and prognosis challenging.  The only recourse may be genotyping.

See Charcot-Marie-Tooth Disease with Glaucoma (604563) for a form of this disease in which glaucoma occurs early.

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

The widespread and debilitating polyneuropathy requires a multidisciplinary management approach with neurologists, physical and occupational therapists, audiologists, pain specialists, and orthopedists.  Pharmaceuticals such as gabapentin may be used for neuropathic pain.  Surgery for pes cavus and joint dysplasias can be helpful.

References
Article Title: 

Charcot-Marie-Tooth disease

Carter GT, Weiss MD, Han JJ, Chance PF, England JD. Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2008 Mar;10(2):94-102.

PubMed ID: 
18334132

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53.

PubMed ID: 
12687498

Danon Disease

Clinical Characteristics
Ocular Features: 

The ocular features of Danon disease are less well known than the systemic manifestations and are as yet not fully delineated likely because not all patients have visual symptoms or fundus changes.  The most commonly described fundus abnormalities are pigmentary changes variously called a peripheral pigmentary retinopathy or a pigmentary atrophy in some cases.   Changes in pigmentation may be mild in both affected males and carrier females, but are generally more severe in males.  A bulls-eye maculopathy and color vision deficiencies have been described.  Loss of visual acuity is variable and may lead to symptoms before myopathy is evident.  Vision loss is usually progressive and may be reduced to hand motions.  OCT shows thinning of the photoreceptor and RPE layers.  The full field ERG is reduced in amplitude consistent with a generalized cone-rod dystrophy.

Systemic Features: 

This disorder, originally believed to be a type of glycogen storage disease, is actually a form of autophagic vacuolar myopathy.    The characteristic vacuoles are found in muscle cytoplasm surrounded by sarcolemmal proteins and basal lamina.  The primary extraocular disease occurs in the myocardium although skeletal muscle may also be involved.  Intellectual disability is a variable and inconsistent feature.  

Cardiac rhythm abnormalities are common and include AV nodal block, atrial fibrillation, and Wolff-Parkinson-White EKG findings.  Hypertrophic cardiomyopathy (and sometimes dilated cardiomyopathy) with primary involvement of the left ventricle is common.  Symptoms typically occur in males before the age of 20 years and somewhat later in females.

Some patients have muscular weakness and exercise intolerance.  Diagnosis can be made when the characteristic vacuoles are present in a muscle biopsy but their absence does not rule out the diagnosis.

Genetics

This is an X-linked dominant disorder caused by mutations in LAMP2 (Xp24).  Females are generally less severely affected than males. Most men with Danon disease have some intellectual disability as well as skeletal myopathy but these features are found in less than half of affected women.  

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

No known treatment is available for the ocular disease.  Transplantation can be an effective treatment for the cardiomyopathy which can be lethal even in adolescents.

References
Article Title: 

Cardiac arrhythmias in patients with Danon disease

Konrad T, Sonnenschein S, Schmidt FP, Mollnau H, Bock K, Ocete BQ, Munzel T, Theis C, Rostock T. Cardiac arrhythmias in patients with Danon disease. Europace. 2016 Oct 14. pii: euw215.

PubMed ID: 
27742774

Cone-rod dystrophy in Danon disease

Brodie S. Cone-rod dystrophy in Danon disease. Graefes Arch Clin Exp Ophthalmol. 2012 Mar 10. [Epub ahead of print].

PubMed ID: 
22407291

Microphthalmia, Syndromic 2

Clinical Characteristics
Ocular Features: 

Microphthalmia with congenital cataracts are the outstanding ocular features of this syndrome.  Some patients have glaucoma.  Blepharophimosis, ptosis, and ankyloblepharon have also been reported.

Systemic Features: 

Facial dysmorphism, dental anomalies and cardiac defects are consistently present.  The face may appear elongated while the nose can be short with a broad tip and long philtrum.  The primary teeth often persist into the second decade but oligodontia, hyperdontia, and dental radiculomegaly may be seen as well.  Reported cardiac defects include ASD, VSD and floppy valves.  Some patients have cleft palate.  Renal, and intestinal malformations have also been described and some patients exhibit psychomotor delays.

Genetics

This is an X-linked disorder secondary to a mutation in the BCOR gene at Xp11.4.  Because virtually all patients are female, it has been suggested that this is an X-linked dominant mutation with lethality in hemizygous males (mother-daughter transmission has been reported).  This is one of several disorders [others being Incontinentia pigmenti (308300)and focal dermal hypoplasia (305600)] in which skewed X-chromosome inactivation has been demonstrated.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Cataracts can be removed and glaucoma requires treatment.

References
Article Title: 

Microphthalmia, Syndromic 7

Clinical Characteristics
Ocular Features: 

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder.  Corneal leukomas and some degree of sclerocornea are usually present as well.  Orbital cysts have been observed.  Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features: 

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male.  Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome.  Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients.  In several additional cases deleterious mutations have been found in the X-linked COX7B gene.  However, familial occurrence is uncommon.  X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050).  The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities.   Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias.  Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References
Article Title: 

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID: 
9737776

Nance-Horan Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts are a feature of this X-linked disorder.  These consist of bilateral, dense nuclear opacification (in most males) but sutural opacities are also seen, especially in carrier females.  If the nuclear cataracts are not treated promptly, severe amblyopia, nystagmus, and strabismus may result.  Microcornea, congenital glaucoma, scleral staphylomas, and retinal cystoid degeneration may also be present.  Microphthalmia has been described. These ocular signs are present in 90% of heterozygous females but they may be subtle and careful examination is required to identify them.  Cataract surgery is usually not required in females. 

Systemic Features: 

This is a developmental disorder in which facial dysmorphism and dental anomalies are consistent systemic features in affected males.  Some patients (30%) also have some intellectual impairment while others have developmental delays and behavior problems.  The pinnae may be anteverted and often appear large while the nose and nasal bridge are prominent.  The teeth in males are small and pointed or 'screwdriver shaped' and are widely separated (sometimes called Hutchinson teeth).  The enamel may be hypoplastic and dental agenesis can be present.  Supernumerary incisors have been described.  The facial and dental features may be present in female carriers but are less pronounced.  Females do not have intellectual impairment. 

Genetics

This is an X-linked recessive (dominant?) disorder resulting from mutations in the NHS gene located at Xp22.13.  However, heterozygous females may have clinical manifestations, including dense cataracts, and all offspring of such females need ophthalmological evaluations at birth.

It is likely that at least some cases of X-linked congenital cataract (CXN; 302200) represent this disorder because the facial dysmorphism may be subtle and easily missed in Nance-Horan.  Of course, the two disorders may also be allelic.  A variety of alterations in the NHS gene, including copy number variations, intragenic deletions, and duplication/triplication arrangements, have been found.  The occasionally subtle facial dysmorphology and the dental abnormalities are easily missed in patients in whom congenital cataracts are the primary clinical concern.  

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

Visually significant cataracts should be removed early to allow for normal visual maturation.  Glaucoma must be treated appropriately.  At risk males and females should have dental X-rays and dental surgery may be required.  Special education may be beneficial in males. 

References
Article Title: 

X-linked cataract and Nance-Horan syndrome are allelic disorders

Coccia M, Brooks SP, Webb TR, Christodoulou K, Wozniak IO, Murday V, Balicki M, Yee HA, Wangensteen T, Riise R, Saggar AK, Park SM, Kanuga N, Francis PJ, Maher ER, Moore AT, Russell-Eggitt IM, Hardcastle AJ. X-linked cataract and Nance-Horan syndrome are allelic disorders. Hum Mol Genet. 2009 Jul 15;18(14):2643-55.

PubMed ID: 
19414485

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation

Burdon KP, McKay JD, Sale MM, Russell-Eggitt IM, Mackey DA, Wirth MG, Elder JE, Nicoll A, Clarke MP, FitzGerald LM, Stankovich JM, Shaw MA, Sharma S, Gajovic S, Gruss P, Ross S, Thomas P, Voss AK, Thomas T, Gecz J, Craig JE. Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet. 2003 Nov;73(5):1120-30.

PubMed ID: 
14564667

Cone-Rod Dystrophies, X-Linked

Clinical Characteristics
Ocular Features: 

Three X-linked forms of progressive cone-rod dystrophies each with mutations in different genes have been identified.  Central vision is often lost in the second or third decades of life but photophobia is usually noted before vision loss.  Cones are primarily involved but rod degeneration occurs over time.  The ERG reveals defective photopic responses early followed by a decrease in rod responses.   All three types are rare disorders affecting primarily males with symptoms of decreased acuity, photophobia, loss of color vision, and myopia.  The color vision defect early is incomplete but progressive cone degeneration eventually leads to achromatopsia.    Peripheral visual fields are usually full until late in the disease when constriction and nightblindness are evident.  The retina may have a tapetal-like sheen.  RPE changes in the macula often give it a granular appearance and there may be a bull's-eye configuration.   Fine nystagmus may be present as well.  The optic nerve often has some pallor beginning temporally.  Carrier females can have some diminished acuity, myopia, RPE changes, and even photophobia but normal color vision and ERG responses at least among younger individuals.

There is considerable variation in the clinical signs and symptoms in the X-linked cone-rod dystrophies among both affected males and heterozygous females.  Visual acuity varies widely and is to some extent age dependent.  Vision can be normal into the fourth and fifth decades but may reach the count fingers level after that. 

Systemic Features: 

None.

Genetics

Mutations in at least 3 genes on the X chromosome cause X-linked cone-rod dystrophy.

CORDX1 (304020) is caused by mutations in an alternative exon 15 (ORG15) of the RPGR gene (Xp11.4) which is also mutant in several forms of X-linked retinitis pigmentosa (300455, 300029).  These disorders are sometimes considered examples of X-linked ocular disease resulting from a primary ciliary dyskinesia (244400).

CORDX2 (300085) is caused by mutations in an unidentified gene at Xq27.  A single family has been reported.

CORDX3 (300476) results from mutations in CACNA1F.  Mutations in the same gene also cause a form of congenital stationary night blindness, CSNB2A (300071).  The latter, however, is a stationary disorder with significant nightblindness and mild dyschromatopsia, often with an adult onset, and is associated with high myopia. Aland Island Eye Disease (300600) is another allelic disorder.   

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

There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent.  Low vision aids can be helpful. 

References
Article Title: 

Focal Dermal Hypoplasia

Clinical Characteristics
Ocular Features: 

Features have considerable heterogeneity and few patients have all of them.  Some ocular abnormalities are found in 40% of patients.  Microphthalmia is common and many patients (30%) have colobomas of the iris and choroid.  Some patients have dislocated lenses.  Distinctive peripheral corneal lesions consisting of discrete vascularized subepithelial opacities have been described.  Occasional patients have conjunctival or lid margin papillomas.  Strabismus and nystagmus are common.

Systemic Features: 

This disorder has a wide variety of clinical features and many occur in only a few patients.  The skin has focal areas of hypoplasia with hypopigmentation, often appearing in a streak or linear pattern.  These areas may be present at birth and contain bullae or urticarial lesions with signs of inflammation.  Telangiectases and herniated fat may appear in these areas.   Oral, esophageal, and laryngeal fibrovascular papillomas occur but they may also be seen in the perineal, vulvar, and perianal areas.  These may be large, friable, and recurrent.  The teeth erupt late and are usually hypoplastic.  The nails are often dysplastic and the hands and feet may be 'split' with syndactyly of the third and fourth fingers giving a 'lobster claw' appearance.  Polydactyly may be present.  Most have thin 'protruding' ears.  A variety of skeletal anomalies have been reported including absence of metatarsals and metacarpals.  A considerable number of patients have mild to moderate mental deficits.  Severely affected females may die in infancy.

Genetics

This is considered an X-linked dominant disorder with lethality in males.  However, numerous affected males (>30) and rare instances of father-to-daughter transmission have been reported and it has been suggested that half-chromatid mutations or postzygotic somatic mosaicism in these males might be responsible.  Mutations in the PORCN gene (Xp11.23) have been associated with FDH.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Surgery may be required for the papillomas if they are obstructive.

References
Article Title: 

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