CSTA – Acral peeling skin syndrome

Acral peeling skin syndrome (APSS) is an autosomal recessive disorder characterized by asymptomatic peeling of the stratum corneum on the dorsal aspects of the hands and feet, leading to focal epidermal detachment and superficial erosions.

Biallelic loss-of-function variants in CSTA, encoding cystatin A, have been implicated in APSS. Whole-exome sequencing in a consanguineous Jordanian–American pedigree identified a homozygous nonsense variant c.64A>T (p.Lys22Ter) in CSTA (PMID:23534700). Subsequent Sanger sequencing confirmed cosegregation of this variant with disease in affected family members. In an independent family, two affected sisters harbored a large homozygous deletion encompassing exon 1 of CSTA, consistent with loss of function (PMID:26684698). Together, these studies describe three affected individuals from two unrelated families with homozygous CSTA lesions.

Inheritance is consistent with autosomal recessive transmission. Both parents in each pedigree were heterozygous carriers and phenotypically unaffected, while all affected individuals were homozygous. Segregation analysis demonstrated variant segregation with disease in two siblings in the exon 1 deletion kindred (PMID:26684698), providing strong familial support.

All reported variants in APSS are predicted to abolish CSTA function. The c.64A>T (p.Lys22Ter) variant introduces a premature termination codon in exon 1, whereas the exon 1 deletion eliminates the translation start site. No missense or in-frame indel variants have been reported to date, indicating a spectrum limited to truncating loss-of-function alleles.

Cystatin A is a type 1 cystatin protease inhibitor localized to the cornified cell envelope. Loss of cystatin A disrupts regulation of papain-like proteases, compromising keratinocyte adhesion in acral skin. This haploinsufficiency mechanism is supported by prior associations of CSTA loss-of-function with exfoliative ichthyosis and by the known role of cystatin A in barrier integrity.

The identification of homozygous CSTA loss-of-function variants in APSS across unrelated families establishes moderate clinical validity for CSTA as an APSS gene. Genetic testing for CSTA truncations is recommended for patients presenting with acral peeling phenotypes. Key Take-home: Biallelic truncating CSTA mutations cause autosomal recessive acral peeling skin syndrome, guiding diagnosis and carrier testing.

References

• Pediatric dermatology • 2013 • Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding cystatin A. PMID:23534700
• Clinical and experimental dermatology • 2016 • Acral peeling skin syndrome associated with a novel CSTA gene mutation. PMID:26684698

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