X-linked recessive

Myopia 1, X-linked, Nonsyndromal

Clinical Characteristics
Ocular Features: 

Nonsyndromal high myopia of -6D to -23D has been reported in multigenerational families.  No other ocular abnormalities have been found.  Detection is usually late in the first decade of life. 

Systemic Features: 

No systemic disease has been reported.

Genetics

Only males were reported to be highly myopic in two large multigenerational Indian families.  The transmission pattern was consistent with an X-linked recessive mode of inheritance.  Only males were affected and no male-to-male transmission was observed.  In another nonAsian family, 3 brothers with myopia had 5 myopic grandsons, all offspring of their daughters.  The daughters had low grade myopia not requiring correction.

The presumed locus for MYP1 is located at Xq28, in the same location as the presumed gene for Bornholm Eye Disease (300843) in which high myopia is also found.

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

No treatment beyond corrective lenses has been reported.

References
Article Title: 

Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing

Ratnamala U, Lyle R, Rawal R, Singh R, Vishnupriya S, Himabindu P, Rao V, Aggarwal S, Paluru P, Bartoloni L, Young TL, Paoloni-Giacobino A, Morris MA, Nath SK, Antonarakis SE, Radhakrishna U. Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing. Invest Ophthalmol Vis Sci. 2011 Aug 29;52(9):6814-9. Erratum in: Invest Ophthalmol Vis Sci. 2011 Oct;52(11):7909.

PubMed ID: 
21357393

X-linked form of myopia

Bartsocas CS, Kastrantas AD. X-linked form of myopia. Hum Hered. 1981;31(3):199-200.

PubMed ID: 
7262894

Microphthalmia, Syndromic 4

Clinical Characteristics
Ocular Features: 

In several generations of an Irish family, 7 males with clinical anophthalmia were identified.  Ankyloblepharon was also present and X-rays of the orbits were identified.

Systemic Features: 

One patient was born with a cleft soft palate and had preauricular skin tags.  All individuals were considered to be mentally retarded with IQ's less than 50.

Genetics

MCOPS4 is an X-linked condition based on a single reported family.  The responsible mutation has not been identified but a locus (Xq27-q28) likely to contain the gene has been identified by multipoint linage analysis.

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

No treatment is known.

References
Article Title: 

Nystagmus 6, Congenital, X-linked

Clinical Characteristics
Ocular Features: 

In several Chinese families, nystagmus was limited to males with onset in one case in the first 6 months.  Foveal dysplasia was present along with mottled fundus pigmentation.  Carrier females did not have nystagmus or changes in fundus pigmentation (except for one with mottling). Vision is in the range of 20/50-20/60.

Systemic Features: 

Skin and hair pigmentation was normal. No systemic disease was identified.

Genetics

Mutations in GPR143 (Xp22.2) have been identified in this form of nystagmus. The family pedigrees are consistent with X-linked recessive inheritance.

Two additional X-linked isolated nystagmus conditions are contained in this database: nystagmus 1 (310700), the result of mutations in FRMD7, and nystagmus 5 (300589) of unknown gene causation.

Several autosomal dominant forms have been linked to chromosomal regions 6p12 (NYS2; 164100), 7p11 (NYS3, 608345), 13q (NYS4, 193003), 1q31.3-q32.1, and NYS7 (614826).  Autosomal recessive inheritance has been proposed for several pedigrees but adequate documentation is lacking (see 257400).

Ocular albinism (OA1) (300500) can also result from mutations in GPR143.  However, there was no evidence of ocular or systemic hypopigmentation in the Chinese families.

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

No treatment has been reported.

References
Article Title: 

Aprataxin gene mutations in Tunisian families

Amouri R, Moreira MC, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F. Aprataxin gene mutations in Tunisian families. Neurology. 2004 Sep 14;63(5):928-9.

PubMed ID: 
15365154

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

Spastic Paraplegia 2

Clinical Characteristics
Ocular Features: 

Nystagmus is common but variable in age of onset, and half of affected individuals have optic atrophy.

Systemic Features: 

This is a complex form of spastic paraplegia in which primarily lower limb spasticity is associated with dysarthria, sensory disturbances, cognitive deficits, muscle wasting and mild ataxia.  There is, however, considerable variability in age of onset and rate of symptom progression.  The first motor symptoms are often evident when children start walking, which is often delayed and clumsy.  However, evidence of spasticity may be present in children under 1 year of age.   Some patients have normal mental functions while others are considered mentally retarded.  The MRI reveals patchy leukodystrophy and degeneration of both corticospinal and spinocerebellar tracks was found in an autopsied individual.  Progression is relentless with many individuals requiring assistive devices such as crutches or walkers by early adult life.

Genetics

This is an X-linked disorder secondary to a mutation in the PLP1 gene at Xq22.2which codes for 2 major proteins found in myelin.  SPG2 is allelic to the more severe Pelizaeus-Merzbacher disease (312080).

Treatment
Treatment Options: 

Mobility devices and physical therapy can be helpful, especially in younger individuals.

References
Article Title: 

IFAP (BRESHECK) Syndrome

Clinical Characteristics
Ocular Features: 

The eyelashes and eyebrow hair is sparse or completely absent.  Keratitis with secondary photophobia is often seen during infancy and progresses to corneal vascularization and scarring, sometimes resembling trachomatous disease.  Cataracts do not seem to be part of this syndrome unlike some other genodermatoses.

Systemic Features: 

Dry, scaly skin and alopecia are usually evident at birth.  There is marked absence of hair throughout the body.  The skin is generally ichthyotic and erythematous, with continuous lamellar desquamation of surface skin.  Generalized follicular hyperkeratosis is present on the scalp, dorsal surface of the limbs and on the abdomen.  Most patients are completely bald.

In some patients the skin, hair and corneal disease is accompanied by severe internal anomalies such as kidney dysplasia, brain anomalies and mental retardation, Hirschsprung disease, cleft palate, external ear malformations, cryptorchidism, and skeletal deformities, a combination of signs that some have called BRESEK/BRESHECK syndrome.  Depending upon how extensive the organ involvement, the prognosis is usually guarded and patients may not live beyond early childhood. 

It is uncertain if IFAP refers to a single disorder or if two disorders are involved (see Genetics).

Genetics

This is generally considered to be an X-linked recessive disorder most likely due to mutations in MBTPS2, at least in patients considered to have the BRESHECK condition.  Female carrier may have some similar skin and hair signs albeit to a lesser degree than males.

Since the amount of MBTPS2 activity has been shown to vary with different mutations, it is possible that all cases of IFAP with or without the added BRESHECK findings are part of the clinical spectrum of a single disorder (variable expressivity).  

Other genodermatoses with severe keratitis are KID syndrome (148210) and Hereditary Mucoepithelial Dysplasia (158310).

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

No effective treatment is known.

References
Article Title: 

MBTPS2 mutation causes BRESEK/BRESHECK syndrome

Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102.

PubMed ID: 
22105905

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response

Oeffner F, Fischer G, Happle R, Konig A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casano A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009 Apr;84(4):459-67.

PubMed ID: 
19361614

Hoyeraal-Hreidarsson Syndrome

Clinical Characteristics
Ocular Features: 

Little is known about the ocular signs in this rare disorder.  As many patients have systemic features of dyskeratosis congenita, however, it is possible that some of the ocular findings such as conjunctival and corneal scarring and lid margin distortion might be similar.  Hoyeraal-Hreidarsson syndrome, though, is a more severe disease and many infants may die before the mucocutaneous manifestations appear.  At least one patient has had an exudative retinopathy similar to that seen in Revesz syndrome (268130).  Epiphora and a preretinal hemorrhage have also been reported.

Systemic Features: 

Features of pancytopenia usually appear after 5 months of age while growth retardation and microcephaly are evident soon after birth.  The marrow may show progression to myelodysplasia.  Birth weight is usually low.  Truncal ataxia and axial hypotonia have been reported and MRI imaging reveals cerebellar hypoplasia.  Global developmental delay is a common feature and a few patients have seizures.  Susceptibility to infection has been noted but the basis for an immunodeficiency remains elusive.  Some patients have signs of dyskeratosis congenita such as sparse hair, nail dysplasia, and a reticular pattern of skin pigmentation.

Genetics

This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence.  As expected, the vast majority of affected individuals are male but at least 3 females have been reported. The same gene is also mutated in the X-linked form of dyskeratosis congenita (305000) suggesting that the two are allelic or that both are the same disease.  There are clear clinical differences, however, as severe developmental delay, immunodeficiency, cerebellar hypoplasia, and microcephaly are generally not present in the latter disorder.

There is evidence for telomere length variations in this syndrome and in dyskeratosis congenita.  Homozygous mutations in RTEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions.

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

No effective treatment has been reported.

References
Article Title: 

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.  At least one patient has been reported to have an exudative retinopathy. 

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for Revesz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia. 

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

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

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
Article Title: 

Retinitis Pigmentosa 2, X-Linked

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa consists of a group disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The later is sometimes described as having a 'bone corpuscle' appearance with a perivascular distribution.  A ring scotoma is sometimes evident.  Age of onset and rate of progression is highly variable, even within families.

The X-linked form described here is a pigmentary retinopathy but sometimes labeled chorioretinal degeneration because of the extensive involvement of the choroid.  The clinical picture is sometimes referred to by the out-dated term 'choroidal sclerosis'.  It is often apparent in males during early childhood and they usually have early deterioration in central vision.  Some carrier females experience vision loss and have mild fundus abnormalities but these do no usually appear until middle age and are usually slowly progressive.  The ERG shows abnormalities in both sexes but these are highly variable.  Older males may have a waxy pallor of the optic nerve.  Posterior subcapsular cataracts are common.  The vitreous may contain fine, colorless particles even before fundus changes are evident.  Prognosis is highly variable but many patients eventually become legally blind by the age of 30 years.

Systemic Features: 

None.

Genetics

Mutations in more than 100 genes may be responsible for retinitis pigmentosa but sporadic disease occurs as well.  Between 5 and 10% of individuals have X-linked disease.

In this form of X-linked retinitis pigmentosa mutations in RP2 (Xp11.3) have been found.  The frequent occurrence of mild disease in females can cause diagnostic confusion with autosomal dominant RP but the disease in females in the latter disorder is usually as severe as in males.

This type of X-linked retinitis pigmentosa is far less common than RP3 (300029)caused by mutations in RPGR.  The two are clinically similar and genotyping is necessary to distinguish them.

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

High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.  Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinioin, sildenafil, and vitamin E.

References
Article Title: 

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling

Pelletier V, Jambou M, Delphin N, Zinovieva E, Stum M, Gigarel N, Dollfus H, Hamel C, Toutain A, Dufier JL, Roche O, Munnich A, Bonnefont JP, Kaplan J, Rozet JM. Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat. 2007 Jan;28(1):81-91.

PubMed ID: 
16969763

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: 

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