Recessive X-linked ichthyosis
- Jennifer L Hand, MD
Jennifer L Hand, MD
- Section Editor — Genodermatoses
- Associate Professor of Dermatology, Medical Genetics, and Pediatrics
- Mayo Clinic, Rochester, MN
Recessive X-linked ichthyosis (XLI, MIM #308100), also called steroid sulfatase deficiency, is an X-linked recessive, nonsyndromic ichthyosis caused by deletions or mutations in the STS gene encoding the steroid sulfatase enzyme . Due to location of the STS gene within a small region of the X-chromosome that escapes X-inactivation (lyonization), recessive XLI affects almost exclusively males.
The disease presents at birth or in early infancy with dry skin and a tendency to form scales on the extremities and trunk. Along with ichthyosis vulgaris, the phenotype of X-linked ichthyosis tends to be milder than most other hereditary forms of ichthyosis.
This topic will review the clinical features, diagnosis, and management of XLI. An overview of syndromic and nonsyndromic ichthyoses (table 1) is presented separately. (See "Overview and classification of the inherited ichthyoses".)
Recessive XLI is the second most frequent ichthyosis after ichthyosis vulgaris. It is reported worldwide in all ethnic groups and affects almost exclusively males. XLI incidence ranges from 1 in 1300 to 1 in 9000 male births [2-5].
The majority of cases of recessive XLI are caused by complete deletion of the steroid sulfatase gene (STS) on chromosome Xp22.3 [6,7]. Other cases result from partial deletion or point mutations of STS [8,9]. Deletions or mutations of the STS gene cause complete loss of steroid sulfatase enzyme activity. Affected males inherit the X-chromosome bearing a mutated gene from their asymptomatic carrier mothers, although rare sporadic cases have been reported [10,11]. In 5 to 8 percent of cases, the deletion includes genes adjacent to STS, resulting in a number of contiguous gene syndromes [12,13]. (See 'Contiguous gene syndromes' below.)
- Fernandes NF, Janniger CK, Schwartz RA. X-linked ichthyosis: an oculocutaneous genodermatosis. J Am Acad Dermatol 2010; 62:480.
- Craig WY, Roberson M, Palomaki GE, et al. Prevalence of steroid sulfatase deficiency in California according to race and ethnicity. Prenat Diagn 2010; 30:893.
- Sakura N, Nishimura SI, Matsumoto T, Ohsaki M. Frequency of steroid sulfatase deficiency in Hiroshima. Acta Paediatr Jpn 1998; 40:63.
- David M, Israel N, Merksamer R, et al. Very low maternal serum unconjugated estriol and prenatal diagnosis of steroid sulfatase deficiency. Fetal Diagn Ther 1995; 10:76.
- Ingordo V, D'Andria G, Gentile C, et al. Frequency of X-linked ichthyosis in coastal southern Italy: a study on a representative sample of a young male population. Dermatology 2003; 207:148.
- Cañueto J, Ciria S, Hernández-Martín A, et al. Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population. J Eur Acad Dermatol Venereol 2010; 24:1226.
- Ballabio A, Carrozzo R, Parenti G, et al. Molecular heterogeneity of steroid sulfatase deficiency: a multicenter study on 57 unrelated patients, at DNA and protein levels. Genomics 1989; 4:36.
- Oyama N, Matsuda M, Hamada T, et al. Two novel missense mutations of STS gene underlie X-linked recessive ichthyosis: understanding of the mutational and structural spectrum. J Eur Acad Dermatol Venereol 2016; 30:1629.
- Alperin ES, Shapiro LJ. Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein. J Biol Chem 1997; 272:20756.
- Valdes-Flores M, Kofman-Alfaro SH, Jimenez-Vaca AL, Cuevas-Covarrubias SA. Carrier identification by FISH analysis in isolated cases of X-linked ichthyosis. Am J Med Genet 2001; 102:146.
- Cuevas-Covarrubias SA, Valdes-Flores M, Orozco Orozco E, et al. Most "sporadic" cases of X-linked ichthyosis are not de novo mutations. Acta Derm Venereol 1999; 79:143.
- Langlois S, Armstrong L, Gall K, et al. Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols. Prenat Diagn 2009; 29:966.
- Chocholska S, Rossier E, Barbi G, Kehrer-Sawatzki H. Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers. Am J Med Genet A 2006; 140:604.
- Elias PM, Williams ML, Choi EH, Feingold KR. Role of cholesterol sulfate in epidermal structure and function: lessons from X-linked ichthyosis. Biochim Biophys Acta 2014; 1841:353.
- Reed MJ, Purohit A, Woo LW, et al. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 2005; 26:171.
- Elias PM, Williams ML, Maloney ME, et al. Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis. J Clin Invest 1984; 74:1414.
- Sato J, Denda M, Nakanishi J, et al. Cholesterol sulfate inhibits proteases that are involved in desquamation of stratum corneum. J Invest Dermatol 1998; 111:189.
- Zettersten E, Man MQ, Sato J, et al. Recessive x-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality. J Invest Dermatol 1998; 111:784.
- Hand JL, Runke CK, Hodge JC. The phenotype spectrum of X-linked ichthyosis identified by chromosomal microarray. J Am Acad Dermatol 2015; 72:617.
- Kent L, Emerton J, Bhadravathi V, et al. X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. J Med Genet 2008; 45:519.
- Brookes KJ, Hawi Z, Kirley A, et al. Association of the steroid sulfatase (STS) gene with attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:1531.
- Bradley LA, Canick JA, Palomaki GE, Haddow JE. Undetectable maternal serum unconjugated estriol levels in the second trimester: risk of perinatal complications associated with placental sulfatase deficiency. Am J Obstet Gynecol 1997; 176:531.
- Hernández-Martín A, González-Sarmiento R, De Unamuno P. X-linked ichthyosis: an update. Br J Dermatol 1999; 141:617.
- Ramesh R, Chen H, Kukula A, et al. Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations. J Dermatol Sci 2011; 64:159.
- Liao H, Waters AJ, Goudie DR, et al. Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis. J Invest Dermatol 2007; 127:2795.
- Cuevas-Covarrubias SA, Valdes-Flores M, Rivera-Vega MR, et al. Ichthyosis vulgaris and X-linked ichthyosis: simultaneous segregation in the same family. Acta Derm Venereol 1999; 79:494.
- Hung C, Ayabe RI, Wang C, et al. Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. Cornea 2013; 32:1283.
- Lykkesfeldt G, Bennett P, Lykkesfeldt AE, et al. Testis cancer. Ichthyosis constitutes a significant risk factor. Cancer 1991; 67:730.
- Lykkesfeldt G, Høyer H, Lykkesfeldt AE, Skakkebaek NE. Steroid sulphatase deficiency associated with testis cancer. Lancet 1983; 2:1456.
- Mishra K, Batra VV, Basu S, et al. Steroid-resistant nephrotic syndrome associated with steroid sulfatase deficiency-x-linked recessive ichthyosis: a case report and review of literature. Eur J Pediatr 2012; 171:847.
- Krishnamurthy S, Kapoor S, Yadav S. Nephrotic syndrome with X-linked ichthyosis, Kallmann Syndrome and unilateral renal agenesis. Indian Pediatr 2007; 44:301.
- Matsukura H, Fuchizawa T, Ohtsuki A, et al. End-stage renal failure in a child with X-linked ichthyosis. Pediatr Nephrol 2003; 18:297.
- Song Y, Chen J, Yi Z, et al. Genetic analysis of a 12-year-old boy with X-linked ichthyosis in association with sclerosing glomerulonephritis. Mol Med Rep 2013; 8:1183.
- Ballabio A, Bardoni B, Carrozzo R, et al. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci U S A 1989; 86:10001.
- Van Esch H, Hollanders K, Badisco L, et al. Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis. Hum Mol Genet 2005; 14:1795.
- Ozawa H, Osawa M, Nagai T, Sakura N. Steroid sulfatase deficiency with bilateral periventricular nodular heterotopia. Pediatr Neurol 2006; 34:239.
- Ballabio A, Parenti G, Tippett P, et al. X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome. Hum Genet 1986; 72:237.
- Curry CJ, Magenis RE, Brown M, et al. Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 1984; 311:1010.
- Bick DP, Schorderet DF, Price PA, et al. Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion. Prenat Diagn 1992; 12:19.
- Ballabio A, Parenti G, Carrozzo R, et al. X/Y translocation in a family with X-linked ichthyosis, chondrodysplasia punctata, and mental retardation: DNA analysis reveals deletion of the steroid sulphatase gene and translocation of its Y pseudogene. Clin Genet 1988; 34:31.
- Ross JB, Allderdice PW, Shapiro LJ, et al. Familial X-linked ichthyosis, steroid sulfatase deficiency, mental retardation, and nullisomy for Xp223-pter. Arch Dermatol 1985; 121:1524.
- Sunohara N, Sakuragawa N, Satoyoshi E, et al. A new syndrome of anosmia, ichthyosis, hypogonadism, and various neurological manifestations with deficiency of steroid sulfatase and arylsulfatase C. Ann Neurol 1986; 19:174.
- Jari SD, Fraer LM, Hogge WA. Association of undetectable unconjugated estriol on multiple marker screening with steroid sulfatase deficiency. Fetal Diagn Ther 2004; 19:43.
- Bedin M, Fournier T, Cabrol D, et al. Incidence of placental sulfatase deficiency on the mode of termination of pregnancy. Gynecol Obstet Invest 1987; 24:86.
- Gånemo A, Sjöden PO, Johansson E, et al. Health-related quality of life among patients with ichthyosis. Eur J Dermatol 2004; 14:61.
- Dreyfus I, Pauwels C, Bourrat E, et al. Burden of inherited ichthyosis: a French national survey. Acta Derm Venereol 2015; 95:326.
- Gånemo A. Quality of life in Swedish children with congenital ichthyosis. Dermatol Reports 2010; 2:e7.
- Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol 2008; 88:4.
- Milstone LM. Scaly skin and bath pH: rediscovering baking soda. J Am Acad Dermatol 2010; 62:885.
- Ramírez ME, Youseef WF, Romero RG, et al. Acute percutaneous lactic acid poisoning in a child. Pediatr Dermatol 2006; 23:282.
- Brubacher JR, Hoffman RS. Salicylism from topical salicylates: review of the literature. J Toxicol Clin Toxicol 1996; 34:431.
- Chiaretti A, Schembri Wismayer D, Tortorolo L, et al. Salicylate intoxication using a skin ointment. Acta Paediatr 1997; 86:330.
- Küster W, Bohnsack K, Rippke F, et al. Efficacy of urea therapy in children with ichthyosis. A multicenter randomized, placebo-controlled, double-blind, semilateral study. Dermatology 1998; 196:217.
- Hofmann B, Stege H, Ruzicka T, Lehmann P. Effect of topical tazarotene in the treatment of congenital ichthyoses. Br J Dermatol 1999; 141:642.
- Cotellessa C, Cuevas-Covarrubias SA, Valeri P, et al. Topical tazarotene 0.05% versus glycolic acid 70% treatment in X-linked ichthyosis due to extensive deletion of the STS gene. Acta Derm Venereol 2005; 85:346.
- Lucker GP, Verfaille CJ, Heremans AM, et al. Topical liarozole in ichthyosis: a double-blind, left-right comparative study followed by a long-term open maintenance study. Br J Dermatol 2005; 152:566.
- Verfaille CJ, Vanhoutte FP, Blanchet-Bardon C, et al. Oral liarozole vs. acitretin in the treatment of ichthyosis: a phase II/III multicentre, double-blind, randomized, active-controlled study. Br J Dermatol 2007; 156:965.
- Nguyen V, Cunningham BB, Eichenfield LF, et al. Treatment of ichthyosiform diseases with topically applied tazarotene: risk of systemic absorption. J Am Acad Dermatol 2007; 57:S123.
- Lykkesfeldt G, Høyer H. Topical cholesterol treatment of recessive X-linked ichthyosis. Lancet 1983; 2:1337.
- CLINICAL MANIFESTATIONS
- Cutaneous features
- Extracutaneous features
- - Ocular
- - Genitourinary
- - Cognitive and behavioral
- Contiguous gene syndromes
- PERINATAL MANIFESTATIONS OF STEROID SULFATASE DEFICIENCY
- Clinical suspicion
- Biochemical diagnosis
- Molecular diagnosis
- Prenatal diagnosis
- Carrier detection
- DIFFERENTIAL DIAGNOSIS
- General considerations
- Control of scaling and dryness
- - Infants and young children
- - Older children and adults
- - Patients with severe XLI
- Management of extracutaneous manifestations
- Genetic counseling
- PROGNOSIS AND FOLLOW-UP
- SUMMARY AND RECOMMENDATIONS