arrhythmias

Angiopathy, Hereditary, with Nephropathy, Aneurysms, and Muscle Cramps

Clinical Characteristics
Ocular Features: 

Tortuosity of second and third order arterioles is usually present bilaterally but does not involve first order branches.  Intraretinal hemorrhages may also be seen and are sometimes associated with minor stress and trauma.  No fluorescein leakage is present.  Vision usually remains good but transient vision loss may be reported if the retinal hemorrhages involve the fovea and parafoveal areas.

Systemic Features: 

Nail bed capillaries may appear tortuous.  Aneurysms of the internal carotid and middle cerebral arteries can be present and cerebrovascular accidents sometimes occur.  Brain imaging may show degrees of leukoencephalopathy.  Large renal cysts, mild hematuria both microscopic and gross, and mild renal failure are sometimes seen.  Some patients experience Raynaud phenomena.  Muscle cramps lasting seconds to hours are not uncommon.  Some patients have supraventricular cardiac arrhythmias.

Alterations in basement membrane morphology can be seen on electron microscopy in many areas of the body but that of the glomeruli is normal even though the filtration rate is decreased.

Genetics

This is an autosomal dominant condition as the result of heterozygous mutations in COL4A1 (13q34).  Mutations in the same gene have also been found in a simpler autosomal dominant disease known as Retinal Arteriolar Tortuosity (180000).  The latter may be an allelic condition or the same disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the underlying disease although symptomatic relief for cramps, arrhythmias, and renal failure may be beneficial.

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
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