CDSN – Peeling Skin Syndrome 1

Peeling Skin Syndrome 1 (PSS1) is an autosomal recessive genodermatosis characterized by lifelong superficial exfoliation, inflammatory erythema, and elevated serum IgE. Biallelic loss‐of‐function variants in the corneodesmosin gene CDSN underlie this condition, disrupting epidermal integrity and corneodesmosome function. The consistent phenotype across unrelated patients and concordant molecular data establish a robust gene–disease link.

Genetic evidence includes five unrelated probands: a 50-year-old woman with a homozygous nonsense variant c.424G>T (p.Gly142Ter) (PMID:23957618), two Japanese patients with large homozygous deletions spanning CDSN and adjacent loci (PMID:24116970; PMID:24794518; PMID:24372652), and a compound heterozygote carrying c.598C>T (p.Gln200Ter) and c.164_167dup (p.Thr57ProfsTer6) in one individual (PMID:31663161). All mutations are predicted or shown to abolish full-length protein function, with parental carrier segregation confirmed in four studies.

Inheritance is strictly autosomal recessive. No additional affected relatives beyond index cases were reported, but heterozygous parents and unaffected carriers in control cohorts support recessive segregation ([PMID:24116970]; [PMID:24794518]; [PMID:24372652]; [PMID:31663161]).

Functionally, immunohistochemistry, Western blot, and real-time PCR of patient skin biopsies demonstrate absence of full-length corneodesmosin and presence of a nonfunctional 16-kDa truncated protein in the upper epidermis ([PMID:23957618]). Large genomic deletions completely abrogate CDSN expression in the epidermis, confirming loss-of-function as the pathogenic mechanism.

No conflicting evidence has been reported. The mutation spectrum—nonsense, frameshift and multi‐exon deletions—consistently yields corneodesmosin deficiency, with clinical features of superficial peeling, hyperkeratosis, scaling, and erythema with pruritus and elevated IgE (HP:0003212; HP:0000962; HP:0010783; HP:0040189).

Integration of these data supports a ClinGen Moderate gene‐disease association based on five unrelated probands with biallelic loss‐of‐function variants and concordant functional assays. Genetic evidence is Moderate, reflecting multiple LoF alleles in an AR pattern; functional evidence is Moderate, owing to direct demonstration of protein deficiency and pathogenicity. Key take-home: Biallelic CDSN loss‐of‐function variants cause recessive peeling skin syndrome 1, and CDSN testing should be included in diagnostic panels for congenital exfoliative dermatoses.

References

• The British Journal of Dermatology • 2013 • Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B PMID:23957618
• Clinical Genetics • 2014 • Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease PMID:24116970
• Journal of Dermatological Science • 2014 • Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease PMID:24794518
• Experimental Dermatology • 2014 • Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene PMID:24372652
• The Journal of Dermatology • 2020 • Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp PMID:31663161

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