Microphthalmia-Linear Skin syndrome deletion Xp22.2 in females

Individuals with deletions of the short arm of the X chromosome encompassing the p22.2 segment present with a condition called Microphthalmia-Linear Skin syndrome (MLS). This condition is characterized by ocular malformations, skin defects, and occasionally abnormalities of the heart, brain, and gastrointestinal system¹.

Ocular features are seen in >75% of individuals with Microphthalmia-Linear Skin Syndrome ². Individuals will typically present with microphthalmia in either one or both eyes. Additionally, corneal opacity, Peters anomaly, corneal staphyloma and/or corneal ectasia, defects of the iris, and congenital aphakia (absence of the lens) have all been previously seen². As a result of these ocular features, children may have significant visual impairments, causing them to present with motor delays. For example, some children with Microphthalmia-Linear skin Syndrome do not walk independently until age 2¹.

Skin findings, specifically skin lesions along Blaschko lines, are also identified in >75% of individuals with MLS². These findings are typically limited to the face and/or neck but can exist elsewhere on the body¹.

Some individuals with MLS may also present with various abnormalities of the brain, heart, and gastrointestinal system. Central nervous system defects have been identified in ~50% of patients and include malformations of the corpus callosum, septum pellucidum, or ventricles². While not as common, cardiac anomalies such as congenital heart defects, cardiomyopathy or tachycardia have also been seen in roughly 25-33% of individuals². Lastly, gastrointestinal tract abnormalities such as an ectopic anus or anal atresia can be seen³.

It should be noted that rare X-linked deletions, including deletions of Xp22.2, are usually lethal to males while in utero. This means that almost all individuals with MLS are females¹. The gene HCCS, which is located within Xp22.2, is thought to be the cause of MLS. HCCS produces a protein that plays a key role in apoptosis (programmed cell death) and absence of this gene (when deleted) or mutations in this gene cause abnormal development of the eye, brain, and other systems¹. There are no clear genotype-phenotype correlations between size of deletion or position of a mutation and clinical manifestations³.

REFERENCES

¹Margari L, Colonna A, Craig F, et al. (2014). Microphthalmia with linear skin defects (MLS) associated with autism spectrum disorder (ASD) in a patient with familial 12.9Mb terminal Xp deletion. BMC Pediatr, 14:220.

²Reis LM, Basel D, Bitoun P, et al. (2024). Novel intragenic and genomic variants highlight the phenotypic variability in HCCS-related disease. Genes (Basel), 15(12): 1636.

³Banganho D, Oliveira I, Machado C, et al (2019). Microphthalmia with linear skin defects syndrome (MIDAS). BMJ Case Rep, 12(4):e227791.