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Microphthalmia with linear skin defects syndrome

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Description

Microphthalmia with linear skin defects syndrome is a disorder that mainly affects females. In people with this condition, one or both eyes may be very small or poorly developed (microphthalmia). Affected individuals also typically have unusual linear skin markings on the head and neck. These markings follow the paths along which cells migrate as the skin develops before birth (lines of Blaschko). The skin defects generally improve over time and leave variable degrees of scarring.

The signs and symptoms of microphthalmia with linear skin defects syndrome vary widely, even among affected individuals within the same family. In addition to the characteristic eye problems and skin markings, this condition can cause abnormalities in the brain, heart, and genitourinary system. A hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a diaphragmatic hernia, may occur in people with this disorder. Affected individuals may also have short stature and fingernails and toenails that do not grow normally (nail dystrophy).

Frequency

The prevalence of microphthalmia with linear skin defects syndrome is unknown. More than 50 affected individuals have been identified.

Causes

Mutations in the HCCS gene or a deletion of genetic material on the X chromosome that includes the HCCS gene cause microphthalmia with linear skin defects syndrome. The HCCS gene carries instructions for producing an enzyme called holocytochrome c-type synthase. This enzyme is active in many tissues of the body and is found in the mitochondria, the energy-producing centers within cells.

Within the mitochondria, the holocytochrome c-type synthase enzyme helps produce a molecule called cytochrome c. Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate (ATP), the cell's main energy source. It also plays a role in the self-destruction of cells (apoptosis).

HCCS gene mutations result in a holocytochrome c-type synthase enzyme that cannot perform its function. A deletion of genetic material that includes the HCCS gene prevents the production of the enzyme. A lack of functional holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without the holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye abnormalities and other signs and symptoms of microphthalmia with linear skin defects syndrome.

Inheritance

This condition is inherited in an X-linked dominant pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. Some cells produce a normal amount of the holocytochrome c-type synthase enzyme and other cells produce none. The resulting overall reduction in the amount of this enzyme leads to the signs and symptoms of microphthalmia with linear skin defects syndrome.

In males (who have only one X chromosome), mutations result in a total loss of the holocytochrome c-type synthase enzyme. A lack of this enzyme appears to be lethal very early in development, so almost no males are born with microphthalmia with linear skin defects syndrome. A few affected individuals with male appearance but who have two X chromosomes have been identified.

Most cases of microphthalmia with linear skin defects syndrome occur in people with no history of the disorder in their family. These cases usually result from the deletion of a segment of the X chromosome during the formation of reproductive cells (eggs and sperm) or in early fetal development. They may also result from a new mutation in the HCCS gene.

Other Names for This Condition

  • MCOPS7
  • microphthalmia syndromic 7
  • microphthalmia with linear skin lesions syndrome
  • microphthalmia, dermal aplasia, and sclerocornea
  • microphthalmia, syndromic 7
  • MIDAS syndrome
  • MLS syndrome
  • syndromic microphthalmia-7

Additional Information & Resources

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Morleo M, Franco B. Microphthalmia with Linear Skin Defects Syndrome. 2009 Jun 18 [updated 2018 Jul 26]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK7041/ Citation on PubMed
  • Morleo M, Pramparo T, Perone L, Gregato G, Le Caignec C, Mueller RF, Ogata T, Raas-Rothschild A, de Blois MC, Wilson LC, Zaidman G, Zuffardi O, Ballabio A, Franco B. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases. Am J Med Genet A. 2005 Aug 30;137(2):190-8. Citation on PubMed
  • Prakash SK, Cormier TA, McCall AE, Garcia JJ, Sierra R, Haupt B, Zoghbi HY, Van Den Veyver IB. Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome. Hum Mol Genet. 2002 Dec 1;11(25):3237-48. Citation on PubMed
  • Sharma VM, Ruiz de Luzuriaga AM, Waggoner D, Greenwald M, Stein SL. Microphthalmia with linear skin defects: a case report and review. Pediatr Dermatol. 2008 Sep-Oct;25(5):548-52. doi: 10.1111/j.1525-1470.2008.00724.x. Review. Citation on PubMed
  • 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. Epub 2006 Sep 6. Citation on PubMed or Free article on PubMed Central
  • Wimplinger I, Rauch A, Orth U, Schwarzer U, Trautmann U, Kutsche K. Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome. Eur J Med Genet. 2007 Nov-Dec;50(6):421-31. Epub 2007 Aug 6. Citation on PubMed
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