diaphragmatic hernias

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:

Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease

Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, D'Amato I, Conte I, Maystadt I, Demuth S, Zvulunov A, Kutsche K, Zeviani M, Franco B. Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease. Am J Hum Genet. 2012 Nov 2;91(5):942-9. doi: 10.1016/j.ajhg.2012.09.016. PubMed PMID: 23122588.

PubMed ID:

23122588

HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations

Wimplinger I, Shaw GM, Kutsche K. HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations? Mol Vis. 2007 Aug 27;13:1475-82.

PubMed ID:

17893649

Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome

Wimplinger I, Morleo M, Rosenberger G, Iaconis D, Orth U, Meinecke P, Lerer I, Ballabio A, Gal A, Franco B, Kutsche K. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2006 Nov;79(5):878-89.

PubMed ID:

17033964

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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