X-Linked Ichthyosis 

Updated: May 23, 2019
Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD 

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 and with increased prevalence.[6, 7]

Other Medscape articles on ichthyosis include the following:

  • Ichthyosis Fetalis

  • Hereditary and Acquired Ichthyosis Vulgaris

  • Lamellar Ichthyosis

  • Ichthyosis (ophthalmology focus)

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.[8] 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.[9]

Mutations in X-linked ichthyosis have been found to disrupt the active site structure of estrone/dehydroepiandrosterone (DHEA) sulfatase.[10] 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.[11]

Approximately 90% of X-linked ichthyosis patients have large deletions involving the entire STS gene and flanking regions.[12] . 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.[13, 14] 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.[15]

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.[16]

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.

Etiology

X-linked ichthyosis is a genetic disorder caused by STS deficiency that results from abnormalities in its coding gene.

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.[17] 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[18] 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.

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.

Patient Education

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

 

Presentation

History

X-linked ichthyosis (XLI) is seen at birth or in the immediate neonatal period. Most typically, X-linked ichthyosis appears in infancy with scaling on the posterior neck, upper trunk, and extensor surfaces of the extremities.[19] The scalp is often involved. In childhood, the boy who is affected has a "dirty-face" appearance, with an increase in involvement with age.

Atypical X-linked ichthyosis may be associated with a large deletion involving the steroid sulfatase (STS) gene.[20] One patient has been described with scaling limited to the lower extremities as the sole manifestation.

Physical Examination

Adherent brown scaling is evident in a widespread distribution that often produces a dirty-face appearance, as shown in the images below.

Man with preauricular brownish scaling typical of Man with preauricular brownish scaling typical of X-linked ichthyosis.
Dirty scale in X-linked ichthyosis. Dirty scale in X-linked ichthyosis.

In early childhood, scaling of the scalp, preauricular skin, and posterior neck may be prominent. Flexures may be involved, but palms and soles are usually spared. Polygonal or "dirty" scaling is typically noted. However, a 2015 study documented children in whom the diagnosis was made incidentally by chromosomal microassay that showed mild phenotypes, sometimes strongly resembling simple mild dermatitis.[21]

As the child ages, the mild scaling evident in the first few days of life becomes more evident and assumes a dirty yellow or brown color with dark, polygonal, firmly adherent scales. This generalized eruption tends to fade on the head but becomes more prominent on the trunk and extremities, particularly on the extensor surfaces of the legs. Scaling has a tendency to be more noticeable in cold and dry weather, improving in the summer months. It may rarely be first evident as erythroderma.[22]

Hair and nails are normal in X-linked ichthyosis.

Corneal opacities may be evident with slit-lamp examination both of adult males who are affected and of women who are carriers.[23] The coma-shaped opacities in the posterior stroma are common findings.[24] Ingordo and associates[18] 2003 assessment of the frequency of X-linked ichthyosis in a large representative sample of the Italian male population revealed that 4 (26.6%) of 15 patients had corneal opacities. No other significant associated changes were noted. Approximately 10% of males who are affected and female carriers have diffuse deposits in the posterior capsule or corneal stroma that does not affect vision. Subepithelial stromal keratopathies or epithelial irregularities are seen uncommonly in X-linked ichthyosis. Unique superficial corneal changes have been seen in 1 patient.

Cryptorchidism occurs in 20% of patients. A few cases of testicular cancer have developed in patients with X-linked ichthyosis and cryptorchidism.

Central nervous system electroencephalographic changes have been noted in a few patients.

STS deficiency slows the delivery of an infant because of insufficient cervical dilation. A relative failure occurs in the response to intravenous oxytocin. Since both are indications for cesarean delivery or forceps delivery, an increased perinatal morbidity and mortality may occur.

Syndromes of genetic contiguity have been described. As a result of broader chromosomal deletions, they may have X-linked ichthyosis and additional phenotypical abnormalities, which include short stature, chondrodysplasia punctata, mental retardation, and Kallmann syndrome (hypogonadotrophic hypogonadism).

The enzyme steroid sulfatase is normally expressed in the brain, a deficiency of which perhaps accounting for personality differences and an increased risk of psychopathology in affected individuals and female carriers.[25] There is reportedly an association between X-linked ichthyosis and attention deficit hyperactivity disorder and motor disabilities.[8, 26]

 

DDx

Diagnostic Considerations

Multiple sulfatase deficiency is a rare inborn autosomal recessive disorder that combines the clinical features of metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis (XLI).[27] This phenotype is a combination of the clinical features found in diseases resulting from a deficiency of the individual sulfatases and the X-linked recessive form of chondrodysplasia punctata.[28]

Differential Diagnoses

 

Workup

Laboratory Studies

Diagnosis of patients with X-linked ichthyosis and female carriers is based on biochemical and genetic analysis. Genetic analysis currently is the most accurate diagnostic method in most patients. X-linked ichthyosis can be diagnosed by assaying STS activity in the placenta or in the skin fibroblasts, keratinocytes, or lymphocytes of patients after birth. Patients show a deficiency of arylsulfatase C, which can be demonstrated by biochemical testing.

Polymerase chain reaction (PCR) and Southern blot testing are useful for the genetic diagnosis of X-linked ichthyosis, although a few patients with X-linked ichthyosis carrying point mutations rather than deletions may be missed. PCR is not applicable for carrier detection. Both multiplex quantitative fluorescent PCR (QF-PCR) and fluorescence in situ hybridization (FISH) are effective to detect the complete deletion mutation of the STS gene and identify the female carrier.[29] Multiplex QF-PCR appears to be more convenient and automatic compared with FISH.[30]

X-linked ichthyosis can be diagnosed prenatally using fluorescence in situ hybridization.[31] Maternal peripheral blood metaphase spreads may display 2 hybridization signals on one of the X chromosomes (1 in the STS region [band Xp22.3] and 1 in the centromeric region), but only 1 hybridization signal (in the X centromeric region) on the other X chromosome; therefore, one of the X chromosomes has a deletion in the band Xp22.3 region, a result consistent with the carrier status for STS deficiency and X-linked ichthyosis. In metaphase spreads from amniotic fluid samples, the X chromosome shows 1 hybridization signal in the control region, but no hybridization signal in the STS region. Therefore, the X chromosome of this male fetus has a deletion in the STS region, a result consistent with X-linked ichthyosis.

The deficit in placental STS blocks placental steroid synthesis, resulting in excretion of maternal urinary steroids in much lower amounts than normal. Incorporating unconjugated estriol in maternal serum into the calculation of risk increases the yield of screenings performed during pregnancy for detection of fetal chromosomal and structural anomalies. The differential diagnosis of low and undetectable levels of unconjugated estriol in maternal serum includes X-linked ichthyosis and serious fetal pathologies (eg, adrenal insufficiency, anencephaly, Down syndrome). To diagnose X-linked ichthyosis, examine the urine of these pregnant women for low levels of nonhydrolyzed sulfated steroids.

Other Tests

A patient with X-linked ichthyosis and pre-Descemet corneal dystrophy had a microdeletion within Xp22.3 containing the steroid sulfatase gene, which was detected using microarray-based comparative genomic hybridization, confirming this clinical diagnosis.[32]

Histologic Findings

Histologic changes of X-linked ichthyosis often are subtle. Biopsy specimens from ichthyotic skin with mild scaling may appear normal. Specimens obtained from regions of thick scaling (eg, anterior aspect of legs, extensor aspect of arms) show mild-to-moderate compact laminated eosinophilic orthokeratotic hyperkeratosis, with a normal or slightly thickened granular layer 3-4 cells thick, mild acanthosis, well-preserved rete ridges, and a sparse perivascular and periappendageal lymphohistiocytic infiltrate.

Ultrastructurally, keratohyaline granules are increased in size and number. Normal-appearing keratinocytes appear linked by desmosomal disks all the way up into the stratum corneum, where the anucleated cells have increased numbers of melanosomes, which may account for the dark coloration of scaling in X-linked ichthyosis.

 

Treatment

Medical Care

Topical keratolytics, emollients, and hydrating agents are used to reduce scaling associated with X-linked ichthyosis.[19] Topical retinoids may be beneficial. In a small study, the topical receptor-selective retinoid tazarotene was efficacious.

Patients often choose to use no therapy, although appearance-conscious adolescents and young adults may be eager and willing to treat themselves.

Surgical Care

In cases with cryptorchidism, consider surgical intervention if spontaneous descent has not occurred by age 1 year.

Consultations

An ophthalmologist may detect corneal opacities. An obstetrician should be involved for higher risk delivery in future pregnancies.

Long-Term Monitoring

Address the risk for testicular carcinoma by monitoring X-linked ichthyosis (XLI) patients with periodic physical examinations.

 

Medication

Medication Summary

The goal of pharmacotherapy is the reduction of retained scales.

Keratolytics

Class Summary

Alpha hydroxy acids are effective in the treatment of X-linked ichthyosis.

Ammonium lactate (Lac-Hydrin)

Ammonium lactate contains lactic acid, an alpha hydroxy acid that has keratolytic action, thus facilitating release of comedones. It is available in 12% and 5% strengths. The 12% form may cause irritation on the face. Ammonium lactate causes disadhesion of corneocytes.