AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1965, Wells and Kerr¹ first recognized X-linked ichthyosis (XLI) as a distinct entity by studying its characteristics in 81 affected males. XLI is the second most common type of ichthyosis and one of the most frequent human enzyme deficiency disorders. XLI 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 XLI 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 XLI. One family pedigree was described with XLI 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 XLI, 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 XLI 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 XLI may contribute to corneocyte retention by increasing CD and interlamellar cohesion.

Patients with XLI, 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 XLI, it cannot act on COS4, resulting in persistent cellular adhesion and reduced normal desquamation. Patients with XLI 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 XLI. 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 XLI, 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 XLI. 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 XLI 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 XLI.⁶ Approximately 90% of XLI 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 replication⁸

A large number of patients with XLI 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 XLI carrier state. STS activity compatible with the carrier state of XLI was found in 36 mothers (85%). Therefore, most of the patients developed the disorder from their mother's carrier state.

Frequency

United States

XLI is a relatively common disease, affecting approximately 1 in 6000 males.

International

XLI 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 XLI 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 XLI 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 XLI was estimated to be approximately 1.98 cases per 10,000 males, which is similar to estimates from other European surveys.

Mortality/Morbidity

Clinically, XLI 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. XLI was described in 3 homozygous women who were daughters of a father with the disorder and a mother who was a carrier.

Age

XLI occurs at birth or in early infancy. It may become more prominent as the child ages.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• XLI is seen at birth or in the immediate neonatal period.
• Most typically, XLI 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.

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 XLI.
• Corneal opacities may be evident with slit-lamp examination both of adults who are affected and of women who are carriers.¹⁰ The flourlike opacities in the posterior stroma are common findings.¹¹ Ingordo and associates⁹ 2003 assessment of the frequency of XLI 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 XLI. 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 XLI 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 XLI and additional phenotypical abnormalities, which include short stature, chondrodysplasia punctata, mental retardation, and Kallmann syndrome (hypogonadotrophic hypogonadism).

Causes

XLI is a genetic disorder caused by STS deficiency that results from abnormalities in its coding gene.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to Be Considered

Multiple sulfatase deficiency is a rare inborn autosomal recessive disorder that combines the clinical features of metachromatic leukodystrophy, mucopolysaccharidosis, and XLI.¹²

WORKUP

Section 5 of 11  

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• Miscellaneous
• Multimedia
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Lab Studies

• Diagnosis of patients with XLI and female carriers is based on biochemical and genetic analysis. Genetic analysis currently is the most accurate diagnostic method in most patients.
• • XLI 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 XLI, although a few patients with XLI carrying point mutations rather than deletions may be missed. PCR is not applicable for carrier detection.
• XLI can be diagnosed prenatally using fluorescence in situ hybridization.¹³
• • 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 XLI.
  • 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 XLI.
• 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 XLI and serious fetal pathologies (eg, adrenal insufficiency, anencephaly, Down syndrome).
  • To diagnose XLI, examine the urine of these pregnant women for low levels of nonhydrolyzed sulfated steroids.

Histologic Findings

Histologic changes of XLI 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 XLI.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Topical keratolytics, emollients, and hydrating agents are used to reduce scaling.
• Topical isotretinoin 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.

MEDICATION

Section 7 of 11  

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The goal of pharmacotherapy is the reduction of retained scales.

Drug Category: Keratolytics

Alpha hydroxy acids are effective in the treatment of XLI.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Address the risk for testicular carcinoma by monitoring patients with periodic physical examinations.

Prognosis

• XLI is a clinically mild genetic disorder. Some morbidity may occur in terms of cosmesis for adolescent boys.

Patient Education

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

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to reassure parents that this is not a problem for which abortion should be considered, since XLI is usually a relatively minor disorder
• Failure to consider possible complications or problems related to prolonged labor or delayed delivery

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Man with preauricular brownish scaling typical of X-linked ichthyosis.
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Media type:  Photo

Media file 2:  Dirty scale in X-linked ichthyosis.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Follow-up
• Miscellaneous
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• References

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3. Ramesh R, Bouloux P, Dorkins HR, Ellis R, Buch M, Batta K. Oral 4, X-linked ichthyosis with a contiguous gene defect in three successive generations. Br J Dermatol. Jun 2007;156(6):1404. [Medline].
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15. Aviram-Goldring A, Goldman B, Netanelov-Shapira I, Chen-Shtoyerman R, Zvulunov A, Tal O, et al. Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques. Int J Dermatol. Mar 2000;39(3):182-7. [Medline].
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19. Cuevas-Covarrubias SA, Valdes-Flores M, Rivera-Vega MR, Diaz-Zagoya JC, Kofman-Alfaro SH. Ichthyosis vulgaris and X-linked ichthyosis: simultaneous segregation in the same family. Acta Derm Venereol. Nov 1999;79(6):494-5. [Medline].
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25. Oyama N, Satoh M, Iwatsuki K, Kaneko F. Novel point mutations in the steroid sulfatase gene in patients with X-linked ichthyosis: transfection analysis using the mutated genes. J Invest Dermatol. Jun 2000;114(6):1195-9. [Medline].
26. Robledo R, Melis P, Schillinger E, Casciano I, Balazs I, Rinaldi A, et al. X-linked ichthyosis without STS deficiency: clinical, genetical, and molecular studies. Am J Med Genet. Nov 6 1995;59(2):143-8. [Medline].
27. Sugawara T, Nomura E, Hoshi N. Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity. J Endocrinol. Feb 2006;188(2):365-74. [Medline].
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Article Last Updated: May 9, 2008