X-Linked Ichthyosis

Updated: Jul 19, 2017
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
  • Print
Overview

Background

In 1965, Wells and Kerr [1] first recognized X-linked ichthyosis (XLI) in 81 affected males. X-linked ichthyosis is a genetic disorder caused by a mutation in the enzyme steroid sulfatase (STS). STS is involved in the metabolism of cholesterol sulfate (CSO4), needed for development of a healthy stratum corneum. Clinically, patients develop hyperkeratosis along with skin barrier dysfunction. Approximately 90% of patients with X-linked ichthyosis have complete or partial deletions of the STS gene. No evidence of genotypic-phenotypic correlation has been shown, regardless of the location or type of the STS mutation. X-linked ichthyosis is the second most common type of ichthyosis and one of the most frequent human enzyme deficiency disorders.

There is likely a genetic and biochemical heterogeneity of X-linked ichthyosis. One family pedigree was described with X-linked ichthyosis associated with normal levels of STS and a normal molecular pattern, as detectable with a complementary DNA (cDNA) probe for the STS gene. Therefore, it remains possible that STS deficiency is not always necessary for X-linked ichthyosis, which also may result from a mutational event at an X-chromosome site not linked genetically to the STS locus.

In 2004, Elias et al [2] reported that as a result of these mutations in the gene for STS, its substrate, CSO4, accumulates in the outer epidermis and provokes the typical scaling phenotype and permeability barrier dysfunction. STS is concentrated in lamellar bodies and, along with other lipid hydrolases, is secreted into the subcorneal interstices. There, it degrades CSO4 to produce some cholesterol for the barrier while the progressive decline in CSO4 (a serine protease inhibitor) permits corneodesmosome (CD) degradation leading to normal desquamation.

There are two molecular pathways that may contribute to the pathogenesis of X-linked ichthyosis. First, excess CSO4 leads to separations in the spaces between corneocytes and an abnormal skin barrier. Second, the increased CSO4 in the stratum corneum intercellular spaces sufficiently inhibit activity to delay CD degradation, leading to corneocyte retention. In 2004, Elias et al [2] demonstrated that increased Ca++ in the stratum corneum interstices in recessive X-linked ichthyosis may contribute to corneocyte retention by increasing CD and interlamellar cohesion.

Patients with X-linked ichthyosis, most commonly caused by deletions in the STS gene, should also be evaluated for contiguous gene defects. [3] Syndromic features may be prominent if contiguous genes are affected. [4] Whole-genome sequencing may document the diagnosis, the specific causative mutation(s), and possibly additional diagnoses and mutations. [5] Steroid sulfatase and filaggrin mutations may occur simultaneously. [6]

Other Medscape articles on ichthyosis include the following:

Next:

Pathophysiology

Retention hyperkeratosis results from the delayed dissolution of desmosomes in the stratum corneum. CSO4 is a multifunctional sterol metabolite, produced in large amounts in squamous keratinizing epithelia. It may be both a marker for squamous metaplasia and an inducer of differentiation. STS, which is localized in the endoplasmic reticulum, catalyzes desulfation of 3beta-hydroxysteroid sulfates. STS acts upon COS4, which is a product discharged by the Odland bodies of the granular layer. Since STS is missing in X-linked ichthyosis, it cannot act on COS4, resulting in persistent cellular adhesion and reduced normal desquamation. Patients with X-linked ichthyosis have a 10-fold increase in COS4 levels and a 50% reduction in cholesterol levels. Additional research suggests that COS4 accumulation, rather than cholesterol deficiency, is responsible for the barrier abnormality.

Since 1978, a deficiency in the STS enzyme has been known to be responsible for the abnormal cutaneous scaling. The STS gene has been mapped to the distal part of the short arm of the X chromosome (band Xp22.3). This region escapes X-chromosome inactivation and has the highest ratio of chromosomal deletions among all genetic disorders. Complete or partial deletions have been found in as many as 90% of patients. Deletion of the entire STS gene is the most common molecular defect found in patients with X-linked ichthyosis. The large deletions of the STS gene are generated by inaccurate recombination at the STS locus. Additional flanking sequences are usually missing as well. The STS gene has 10 exons and spans more than 146 kilobases of DNA. Its introns vary considerably in size. It is transcribed into messenger RNA and translated into a protein of 561 residues.

While most affected individuals have extensive deletions of the STS gene, point mutations producing complete STS deficiency have been reported in a number of patients. In 1 patient, a novel mutation was found resulting in the appearance of a stop codon in exon 7 of the STS gene. In another patient with X-linked ichthyosis, an STS missense mutation, Glu560Pro or E560P, was identified.

Analysis of some patients has shown a distinctive single base pair substitution within exon 8 encoding the C-terminal half of the STS polypeptide. The mutations resulted in the transversion of functional amino acids, ie, a G-->C substitution at nucleotide 1344, causing a predicted change of glycine to arginine, and a C-->T substitution at nucleotide 1371, producing a change from a glutamine to a stop codon. In vitro STS cDNA expression using site-directed mutagenesis revealed that the mutations are pathogenic and reflect the levels of STS enzyme activity in each patient with X-linked ichthyosis. In another study, 6 point mutations were identified. The mutations were located in a 105–amino acid region of the C-terminal half of the polypeptide.

Of the mutations, 5 of 6 involved the substitutions of proline or arginine for tryptophan 372, arginine for histidine 444, tyrosine for cysteine 446, or leucine for cysteine 341. The other mutation was in a splice junction and resulted in a frameshift causing premature termination of the polypeptide at residue 427. These data suggest that exon 7, or an area in its downstream region, and the C-terminal region of the STS enzyme are important for STS enzymatic function. A separate study showed that both the N-terminal region and C-terminal region are important for STS enzyme activity and that the C-terminal mutant has a dominant negative effect on wild-type STS. [7]

Mutations in X-linked ichthyosis have been found to disrupt the active site structure of estrone/dehydroepiandrosterone (DHEA) sulfatase. [8] The substitution may cause disruption of the active site architecture or may interfere with STS's putative membrane-associating motifs crucial to the integrity of the catalytic cleft, thereby providing an explanation for the loss of STS activity. Three-dimensional mapping of the genetic mutations into the steroid sulfatase or estrone/dehydroepiandrosterone sulfatase structure provides an explanation for the loss of enzyme function in X-linked ichthyosis. [9]

Approximately 90% of X-linked ichthyosis patients have large deletions involving the entire STS gene and flanking regions. [10] . Another STS gene analysis showed that 30 patients in Spain had complete deletions (75%), while 10 patients had partial deletions (25%), a rate higher than that reported in other studies. [11, 12] Some correlation was noted between phenotype and the extent of the deletions. Novel point mutations have been reported in the STS gene in patients with X-linked recessive ichthyosis. [13]

Segregation analysis of paternal transmission of the affected X chromosome was performed. STS gene deletion may occur in male meiosis as a result of an intrachromosomal event, recombination between S232 sequences on the same DNA molecule, or during the process of DNA replication. [14]

A large number of patients with X-linked ichthyosis appear to correspond to nonfamilial cases that represent de novo mutations. However, in one study, the mothers of 42 nonfamilial patients were examined for the X-linked ichthyosis carrier state. STS activity compatible with the carrier state of X-linked ichthyosis was found in 36 mothers (85%). Therefore, most of the patients developed the disorder from their mother's carrier state.

Previous
Next:

Epidemiology

Frequency

United States

X-linked ichthyosis is a relatively common disease, affecting approximately 1 in 6000 males.

Steroid sulfatase deficiency prevalence among California's racial and ethnic groups was evaluated. [15] In males, prevalence was highest among non-Hispanic whites (1:1230) compared with Hispanics (1:1620) and Asians (1:1790); however, the differences were statistically insignificant. The overall prevalence estimate was 1:1500 males.

International

X-linked ichthyosis is a relatively common disease, affecting approximately 1 in 6000 males worldwide, with no geographic or racial variations. In 2003, Ingordo and associates [16] reported their assessment of the frequency of X-linked ichthyosis in a large representative sample of the Italian male population. From January 1998 through February 2002, 75,653 young men were examined and 15 cases of X-linked ichthyosis were diagnosed, with a frequency of 1 per 5043 or 1.98 cases per 10,000 males (95% confidence interval based on the Poisson distribution, 1.01-2.9). Four (26.6%) of 15 patients had corneal opacities. No other significant associated pathological change was observed. The frequency of X-linked ichthyosis was estimated to be approximately 1.98 cases per 10,000 males, which is similar to estimates from other European surveys.

Race

No racial predisposition is noted.

Sex

Males are affected overwhelmingly; however, a few female heterozygotes have been reported. Women may be a carrier for the condition. X-linked ichthyosis was described in 3 homozygous women who were daughters of a father with the disorder and a mother who was a carrier.

Age

X-linked ichthyosis occurs at birth or in early infancy. It may become more prominent as the child ages.

Previous
Next:

Prognosis

X-linked ichthyosis is a clinically mild genetic disorder. Some morbidity may occur in terms of cosmesis for adolescents. Most patients perceive it as more of an annoyance than a serious medical problem.

Previous
Next:

Patient Education

Instruct patients in techniques for regular self-examination to detect testicular carcinoma.

Previous