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Abstract

Abstract 

  1. Steroid sulfatase (STS) deficiency (MIM 308100) is an inborn error of metabolism causing X-linked ichthyosis, a skin disorder inherited as an X-linked trait. The condition affects between 1 in 2000 and 1 in 6000 males in many different populations from a range of geographic locations and racial and ethnic backgrounds.

  2. The phenotype of STS deficiency is characterized by the presence of dark scaly skin starting between birth and 4 months of age. Mild corneal opacities, which do not affect vision, are present in approximately one quarter of patients. In fetal life, placental deficiency of STS causes a diminished estrogen biosynthesis by the maternal-fetal-placental pregnancy unit. This often results in prolonged labor due to difficulty in cervical effacement, which leads to cesarean section in many cases. Patients with STS deficiency have increased levels of cholesterol sulfate in both plasma and stratum corneum. The increase of cholesterol sulfate levels in the stratum corneum appears to be responsible for the ichthyotic changes observed in patients with STS deficiency.

  3. STS is localized primarily in the rough endoplasmic reticulum. The human STS polypeptide is composed of 583 amino acids encoded by a gene located on the distal short arm of the X chromosome (Xp22.3). It is composed of 10 exons spanning approximately 140 kb of DNA. The gene shares significant homology with all the other members of the sulfatase gene family. The sequence and organization of the STS gene appear to be particularly similar to that of a cluster of three sulfatase genes also located in the Xp22.3 region, suggesting the occurrence of duplication events in this region during recent mammalian evolution.

  4. A highly homologous unprocessed STS pseudogene is located on the proximal long arm of the human Y chromosome. In human females, the STS gene escapes X chromosome inactivation (at least partially), being expressed by both the active and the inactive X chromosomes. This lack of dosage compensation and the presence of a Y-linked homologue suggests an ancestral pseudoautosomal location for the STS gene. This hypothesis is supported by the pseudoautosomal location of the murine STS gene. Human and murine STS genes share a low degree of sequence similarity (only 63 percent in the coding region), consistent with a high evolutionary divergence of pseudoautosomal regions in mammals.

  5. Most patients with STS deficiency (85 to 90 percent) have submicroscopic deletions spanning the entire STS gene and flanking markers. Most of these deletions appear to be due to abnormal recombination caused by the presence of low-copy-number repeats. Approximately 10 percent of patients with STS deficiency have point mutations in the STS gene. Rare patients with STS deficiency (~5 percent) have a complex phenotype resulting from the presence of a contiguous gene syndrome involving a deletion of additional disease genes located in the Xp22.3 region, such as the Kallmann syndrome gene, the gene for X-linked recessive chondrodysplasia punctata, and that for ocular albinism. Some of these patients with Xp22.3 contiguous gene syndromes have cytogenetically visible abnormalities such as large terminal Xp deletions or X/Y translocations. STS deficiency also occurs as a manifestation of multiple sulfatase deficiency, an extremely rare autosomal recessive disorder affecting the activity of many sulfatases and resulting in a very severe and complex phenotype.

  6. STS deficiency may be readily diagnosed either prenatally or postnatally by a combination of enzymatic, endocrinologic, and molecular methods. Treatment of STS deficiency focuses on the ichthyosis. The topical application of 12 percent ammonium lactate provides considerable benefit.

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