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URL of this page: https://medlineplus.gov/genetics/condition/microphthalmia-with-linear-skin-defects-syndrome/

Microphthalmia with linear skin defects syndrome

Description

Microphthalmia with linear skin defects syndrome is a disorder that mainly affects girls and women. In people with this condition, one or both eyes may be very small or poorly developed (microphthalmia). Affected individuals also typically have unusual skin markings on the head and neck. These markings have a linear pattern because they follow the paths along which cells migrate as the skin develops before birth (lines of Blaschko). Typically, no new skin defects develop after birth, and existing defects can improve over time.

While most people with this condition have both microphthalmia and linear skin defects, about 20 percent of affected individuals do not have microphthalmia and about 15 percent do not have skin defects. The signs and symptoms of microphthalmia with linear skin defects syndrome vary widely, even among affected individuals within the same family. The severity of this condition also varies considerably.

Additional signs and symptoms of microphthalmia and linear skin defects can include other eye problems, most commonly a clouding of the clear front covering of the eye (sclerocornea). About half of people with microphthalmia with linear skin defects syndrome have neurological problems that can include brain abnormalities and developmental delays. Less than half of affected individuals have heart problems, such as abnormal heart rhythms (arrhythmias) or structural changes in one or more parts of the heart.

Some people with microphthalmia with linear skin defects syndrome have distinctive facial features, short stature, an unusually small head (microcephaly), or abnormalities of the genitalia and urinary tract (genitourinary anomalies). In rare cases, a hole in the muscle that separates the abdomen from the chest cavity (a diaphragmatic hernia) may be present and can be life-threatening.

Frequency

The prevalence of microphthalmia with linear skin defects syndrome is unknown. More than 100 affected individuals have been reported in the scientific literature. 

Causes

Structural changes that involve the loss of a large section of DNA on the X chromosome cause about 90 percent of cases of microphthalmia with linear skin defects syndrome. This deleted section always includes the HCCS gene. Changes in the HCCS gene, called pathogenic variants, can also cause microphthalmia with linear skin defects syndrome.

The HCCS gene provides instructions for making 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, holocytochrome c-type synthase 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. Cytochrome c also plays a role in the self-destruction of cells (apoptosis).

Pathogenic variants in the HCCS gene or the deletion of this gene prevent cells from producing functional holocytochrome c-type synthase. Without this enzyme, cytochrome c is not produced and oxidative phosphorylation is impaired. As a result, cells cannot make the ATP they need to function. In addition, nonfunctional cells may not be able to go through the typical apoptosis pathway. Instead, these cells may die through an alternative apoptosis pathway that is more common for nerve cells. Developing cells may have unique responses to the lack of functional holocytochrome c-type synthase and this alternative apoptosis pathway, which could account for the differences in the effects of microphthalmia with linear skin defects syndrome.

Pathogenic variants in other genes on the X chromosome are responsible for a small percentage of cases of microphthalmia with linear skin defects syndrome. These genes are also active in the mitochondria and play roles in oxidative phosphorylation.

Learn more about the gene and chromosome associated with Microphthalmia with linear skin defects syndrome

Additional Information from NCBI Gene:

Inheritance

Microphthalmia with linear skin defects syndrome is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In females (who have two copies of the X chromosome), one altered copy of the gene often causes the features of the condition.

In males (who have only one X chromosome), the pathogenic variants that cause microphthalmia with linear skin defects syndrome appear to be lethal very early in development. As a result, it is very rare for males to be born with microphthalmia with linear skin defects syndrome. When an affected male infant is born, the pathogenic variant that causes the condition typically allows cells to make enough functioning proteins for the baby to survive.

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 structural changes of the X chromosome that occur during the formation of reproductive cells (eggs and sperm) or during early fetal development. They may also result from a new (de novo) variant in an associated gene.

The variety of signs and symptoms seen in people with microphthalmia with linear skin defects syndrome may be due in part because the X chromosome that contains the variant may be turned off due to a process called X-inactivation. Early in female embryonic development, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body's cells. However, in some cases, X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.

Females with a structural change on the X chromosome or a pathogenic variant in a gene that causes microphthalmia with linear skin defects syndrome typically have skewed X-inactivation, which often inactivates the altered X chromosome.

Other Names for This Condition

  • LDSMCA
  • Linear skin defects with multiple congenital anomalies
  • Microphthalmia with linear skin lesions syndrome
  • Microphthalmia, dermal aplasia, and sclerocornea
  • MIDAS syndrome
  • MLS syndrome

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • D'Alessio AM, Indrieri A, Vitiello G, Morleo M, Schelley S, Enns GM, Passarelli C, Tammaro R, Tiranti V, Peron C, Deb W, Novelli A, Isidor B, Iolascon A, Franco B. Revisiting LSDMCA: male lethality escape and genotype-phenotype correlations. Eur J Hum Genet. 2026 Jul;34(7):972-979. doi: 10.1038/s41431-026-02098-7. Epub 2026 Apr 21. Citation on PubMed
  • Indrieri A, Conte I, Chesi G, Romano A, Quartararo J, Tate R, Ghezzi D, Zeviani M, Goffrini P, Ferrero I, Bovolenta P, Franco B. The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes. EMBO Mol Med. 2013 Feb;5(2):280-93. doi: 10.1002/emmm.201201739. Epub 2013 Jan 22. Citation on PubMed
  • Indrieri A, Franco B. Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA): An Unconventional Mitochondrial Disorder. Genes (Basel). 2021 Feb 11;12(2):263. doi: 10.3390/genes12020263. Citation on PubMed
  • 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. Citation on PubMed
  • Morleo M, Franco B. Microphthalmia with Linear Skin Defects Syndrome. 2009 Jun 18 [updated 2018 Jul 26]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK7041/ Citation on PubMed
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  • 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. doi: 10.1093/hmg/11.25.3237. Citation on PubMed
  • Reis LM, Basel D, Bitoun P, Walton DS, Glaser T, Semina EV. Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease. Genes (Basel). 2024 Dec 20;15(12):1636. doi: 10.3390/genes15121636. Citation on PubMed
  • van Rahden VA, Fernandez-Vizarra E, Alawi M, Brand K, Fellmann F, Horn D, Zeviani M, Kutsche K. Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2015 Apr 2;96(4):640-50. doi: 10.1016/j.ajhg.2015.02.002. Epub 2015 Mar 12. Citation on PubMed
  • van Rahden VA, Rau I, Fuchs S, Kosyna FK, de Almeida HL Jr, Fryssira H, Isidor B, Jauch A, Joubert M, Lachmeijer AM, Zweier C, Moog U, Kutsche K. Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome. Orphanet J Rare Dis. 2014 Apr 15;9:53. doi: 10.1186/1750-1172-9-53. 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. doi: 10.1086/508474. Epub 2006 Sep 6. Citation on PubMed or Free article on PubMed Central

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