eMedicine Specialties > Dermatology > Pediatric Diseases

Ichthyosis, X-Linked

Author: Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: May 29, 2009

Introduction

Background

In 1965, Wells and Kerr¹ first recognized X-linked ichthyosis (XLI) as a distinct entity by studying its characteristics in 81 affected males. X-linked ichthyosis is the second most common type of ichthyosis and one of the most frequent human enzyme deficiency disorders. X-linked ichthyosis is a clinically mild genetic disorder of keratinization, with extracutaneous manifestations in some cases. It is caused by a steroid sulfatase (STS) deficiency resulting from abnormalities in its coding gene (STS). The 2 best-known substrates for this microsomal enzyme are cholesterol sulfate (CSO4) and dehydroepiandrosterone sulfate. 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.

Some reports have suggested 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 al² 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.

The 2 molecular pathways that may contribute to X-linked ichthyosis pathogenesis are (1) excess CSO4 producing nonlamellar phase separation in the stratum corneum interstices, explaining the barrier abnormality, and (2) the increased CSO4 in the stratum corneum interstices sufficiently inhibiting activity to delay CD degradation, leading to corneocyte retention. In 2004, Elias et al² 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

Other eMedicine articles on ichthyosis include the following:

• Ichthyosis Fetalis
• Ichthyosis Vulgaris, Hereditary and Acquired
• Ichthyosis, Lamellar
• Ichthyosis (ophthalmology focus)

Pathophysiology

Retention hyperkeratosis results from the delayed dissolution of desmosomes in the stratum corneum. COS4 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.⁴

Mutations in X-linked ichthyosis have been found to disrupt the active site structure of estrone/dehydroepiandrosterone (DHEA) sulfatase.⁵ 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.⁶ Approximately 90% of X-linked ichthyosis patients have large deletions involving the entire STS gene and flanking regions.⁷

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.⁸

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.

Frequency

United States

X-linked ichthyosis is a relatively common disease, affecting approximately 1 in 6000 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 associates⁹ 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.

Mortality/Morbidity

Clinically, X-linked ichthyosis is usually a relatively mild eruption that rarely can be emotionally challenging for children and adolescents. Most patients perceive it as more of an annoyance than a serious medical problem.

Race

No racial predisposition is noted.

Sex

Males are affected overwhelmingly; however, a few female heterozygotes have been reported. 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.

Clinical

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. 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.¹⁰ One patient has been described with scaling limited to the lower extremities as the sole manifestation.

Physical

• Adherent brown scaling is evident in a widespread distribution that often produces a dirty-face appearance.

• 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.
• 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.
• Hair and nails are normal in X-linked ichthyosis.
• Corneal opacities may be evident with slit-lamp examination both of adults who are affected and of women who are carriers.¹¹ The flourlike opacities in the posterior stroma are common findings.¹² Ingordo and associates⁹ 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).
• Brookes et al report an association between the STS gene and attention deficit hyperactivity disorder.¹³

Causes

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

• Search for CME/CE on This Topic »

• Ichthyosis (Ophthalmology)
• Ichthyosis Vulgaris, Hereditary and Acquired (Dermatology)
• Ichthyosis, Lamellar (Dermatology)
• Ichthyosis Fetalis (Dermatology)

• Gene on X Chromosome Plays Critical Role in Systemic Lupus Erythematosus
• Enzyme Therapy With Agalsidase Alfa May Slow Kidney Function Decline in Fabry Disease
• Newly Identified Genetic Variant for Alzheimer's Disease Risk is Sex-Specific

• Hair and Nail Disorders of Childhood
• Management of Primary Cicatricial Alopecias: Options for Treatment
• Skewed X Chromosome Inactivation and Breast and Ovarian Cancer Status: Evidence for X-Linked Modifiers of BRCA1