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X-linked recessive ichthyosis

  • Author(s): Hazan, Carole
  • Orlow, Seth J
  • Schaffer, Julie V
  • et al.
Main Content

X-linked recessive ichthyosis
Carole Hazan MD, Seth J Orlow MD PhD, and Julie V Schaffer MD
Dermatology Online Journal 11 (4): 12

Department of Dermatology, New York University School of Medicine

Abstract

A 13-year-old boy presented with a lifelong history of tightly-adherent, brown, polygonal scales that covered the extensor surfaces of the extremities, lateral aspects of the trunk, and neck. The clinical presentation and the history of a similar skin condition in the patient's male maternal relatives helped establish the diagnosis of X-linked recessive ichthyosis (XLI). Systemic manifestations of the steroid sulfatase (STS) deficiency underlying XLI include cryptorchidism, asymptomatic corneal opacities, and maternal failure to progress during labor. Most cases of XLI are caused by deletions of the STS gene, and contiguous gene syndromes may occur when the deletions extend to neighboring genes on the distal short arm of the X chromosome.


A 13-year-old boy presented to the Dermatologic Associates at New York University Medical Center in February 2005 with a history of scaly skin present since birth. The patient was born at term via Cesarean section done because of maternal failure to progress in labor; the baby had no collodion membrane. After generalized exfoliation of large, lightly-pigmented scales during the neonatal period, brown scales appeared over much of the cutaneous surface. The scale has tended to be less severe during the summertime. There was no history of cryptorchidism, and ophthalmologic examination showed no corneal opacities or other abnormalities. Medical history included repair of a congenital umbilical hernia and panic disorder; his growth and development have been normal. Several male maternal relatives had a similar skin condition.

Regular use of emollient preparations containing glycolic acid, lactic acid, or salicylic acid, and, most recently, a ceramide-dominant, physiologic lipid-based emollient (TriCeram® cream) have helped to reduce the scale.

Tightly-adherent, brown, polygonal scales covered the extensor surfaces of the extremities, trunk (particularly the lateral aspects), neck, scalp, and preauricular areas. There was relative sparing of the flexural surfaces of the extremities and complete sparing of the central face, palms, and soles. The hair and nails were normal, and both testes were descended.


Comment

X-linked recessive ichthyosis (XLI), an inherited disorder of keratinization due to steroid sulfatase (STS) deficiency, affects approximately 1 in 6000 boys and men [1]. Patients present during the first few weeks of life with generalized desquamation of large, loosely-adherent, translucent scales. This phase is followed by the appearance of tightly-adherent, dark brown, polygonal scales that are distributed symmetrically on the preauricular areas of the cheeks, neck, lateral areas of the trunk, and extremities, with relative sparing of flexural surfaces [2]. Extracutaneous manifestations of XLI include corneal opacities that do not affect vision (found in 25-50 % of adult patients), cryptorchidism (10-20 % of patients), and an increased risk of testicular cancer, which is independent of testicular maldescent [3, 4]. In women pregnant with an affected fetus, placental steroid sulfatase deficiency leads to low levels of unconjugated estriol in maternal serum, which is typically detected during routine second trimester prenatal screening; there may be also a failure to progress during labor [5].

In 1979, the gene encoding STS was mapped to the distal portion of the short arm of the X chromosome (Xp22.3) [6]. This region escapes lyonization (random inactivation of one of the two X chromosomes), which explains the absence of skin lesions in female carriers of XLI. In addition, this portion of the X chromosome is particularly susceptible to deletions. More than 90 percent of patients with XLI have complete deletion of the STS gene and flanking sequences, which represents one of the highest incidences of chromosomal deletions among all genetic disorders [2, 7]. Deletions that extend to neighboring genes can result in contiguous gene syndromes of XLI in association with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), ocular albinism type 1, X-linked recessive chondrodysplasia punctata, short stature, and mental retardation [8].

The STS enzyme is responsible for hydrolysis of cholesterol sulfate (CS; a serine protease inhibitor) to cholesterol in the epidermis. In patients with XLI, accumulation of CS in the epidermis leads to barrier instability and inhibits the desmosomal degradation, which is required for normal desquamation, thereby leading to corneocyte retention [9, 10]. Detection of increased serum levels of CS can confirm the diagnosis of XLI. Although not so sensitive as directly measuring CS levels, serum lipoprotein electrophoresis may also be helpful in establishing the diagnosis because high levels of cholesterol sulfate increase the mobility of the β-fraction of low-density lipoproteins [2].

References

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2. Hernandez-Martin A, et al. X-linked ichthyosis: an update. Br J Dermatol 1999;141:617

3. Ingordo V, et al. X-linked ichthyosis in Southern Italy. J Am Acad Dermatol 2003;49:962

4. Al Jasmi F, Al-Khenaizan S. X-linked ichthyosis and undescended testes. Int J Dermatol 2002;41:614

5. Keren DF, et al. Low maternal serum unconjugated estriol during prenatal screening as an indication of placental steroid sulfatase deficiency and X-linked ichthyosis. Am J Clin Pathol 1995;103:400

6. Mohandas T, et al. Regional assignment of the steroid sulfatase-X-linked ichthyosis locus: implications for a non-inactivated region on the short arm of the human X-chromosome. Proc Nat Acad Sci 1979;76: 5779

7. Cuevas-Covarrubias SA, et al. X-linked ichthyosis in Mexico: high frequency of deletions in the steroid sulfatase-encoding gene. Am J Med Genet 1997;72:415

8. Paige DG, et al. A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects. Br J Dermatol 1994;131:622

9. Zettersten E, et al. Recessive X-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality. J Invest Dermatol 1998;111:784

10. Elias PM, et al. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol 2004;122;314

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