STS – X-Linked Ichthyosis

X-linked ichthyosis (XLI) is an X-linked recessive keratinization disorder characterized by the accumulation of polygonal, dark, adherent scales due to steroid sulfatase (STS) deficiency. It affects approximately 1 in 2 000–6 000 males worldwide and is caused by hemizygous loss-of-function variants in STS leading to impaired cholesterol sulfate desulfation and abnormal stratum corneum desquamation.

Genetic evidence for STS in XLI is robust. A Spanish cohort of 40 unrelated male probands exhibited complete STS deletions in 30 and partial deletions in 10 (40 probands) (PMID:20236202). Large deletions spanning the entire gene account for 85–90% of cases, while partial deletions and point mutations represent the remainder (PMID:11910205; PMID:9764155).

Segregation studies confirm X-linked recessive inheritance, with 36 carrier mothers demonstrating reduced STS activity consistent with obligate segregation in non-familial cases (36 carriers) (PMID:10228635). Recurrence of the common hemizygous microdeletion at Xp22.31 highlights a founder effect with population-specific allele frequency.

The STS variant spectrum includes large hemizygous deletions, partial exon deletions, nonsense and splice-site mutations, and six missense changes. A representative missense allele, c.1100G>C (p.Trp367Ser), abrogates enzyme activity in patient cells and in vitro expression systems (PMID:9252398). Recurrent point mutations such as c.287G>A (p.Trp96Ter) and splice junction variants further define critical functional domains.

Functional assays reveal absent STS protein on Western blot and negligible enzyme activity in leukocytes of affected individuals. Site-directed mutagenesis of patient-derived missense variants in COS-1 cells produces stable but catalytically inactive enzyme, confirming a loss-of-function mechanism (haploinsufficiency) concordant with human phenotype (PMID:9252398; PMID:10679952).

Conflicting evidence is limited to benign copy-number gains: duplications of the STS region in males are inherited from unaffected mothers and do not cause XLI (PMID:21739574).

Integration of genetic and experimental data yields a definitive STS–XLI association. The high prevalence of STS deletions, consistent segregation, and functional loss‐of‐function concordance support clinical utility of genetic testing for diagnosis, carrier detection, and counseling. Key Take-home: Hemizygous STS deletions and loss-of-function variants reliably diagnose X-linked ichthyosis and guide management of affected individuals.

References

• Journal of the European Academy of Dermatology and Venereology • 2010 • Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population PMID:20236202
• Acta Dermato-Venereologica • 1999 • Most “sporadic” cases of X-linked ichthyosis are not de novo mutations PMID:10228635
• The British Journal of Dermatology • 1998 • Deletion pattern of the steroid sulphatase gene in Japanese patients with X-linked ichthyosis PMID:9764155
• Human Mutation • 2000 • PCR diagnosis of X-linked ichthyosis: identification of a novel mutation (E560P) of the steroid sulfatase gene PMID:10679952
• The Journal of Biological Chemistry • 1997 • Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein. PMID:9252398
• Journal of Medical Genetics • 2008 • X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits PMID:18413370
• American Journal of Medical Genetics Part A • 2011 • Duplication of the STS region in males is a benign copy-number variant PMID:21739574

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