DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME X-LINKED RECESSIVE ICHTHYOSIS
Synonymous Steroid sulfatase deficiency
Estimated prevalence 1:2,000-6,000
OMIM 308100
Inheritance X-linked recessive
Gene (s) STS (308100)

Definition

X-linked recessive ichthyosis (XRI) is one of the most frequent genetic skin disorders and - after ichthyosis vulgaris - one of the two common types of ichthyoses with late onset. The disorder almost exclusively occurs in males presenting with ichthyosis mostly during the first year of life. Affected individuals typically develop polygonal dark scales and may present with associated symptoms most important testicular maldescent.

Clinical Description

About 2/3 of the patients show dark brown rhombic scales presenting as "ichthyose noire", while 1/3 show light grey and in part fine scaling reminiscent of ichthyosis vulgaris. The ichthyosis may start at the age of 3 months of life. Only in rare cases a transient mild ichthyosiform erythroderma can be seen shortly after birth. The disorder persists throughout life. Symptoms are often less severe during summer. Cryptorchidism can be seen in about 20% of the affected patients. Birth complications such as delayed cervical dilatation occur in about one third. The disease manifests exclusively in boys. Only rare cases of female XRI patients have been reported in the literature so far, e. g. in Turner syndrome (XO gonadal dysgenesis).

Pathogenesis

The pathogenesis of XRI has been a subject of considerable research. Steroid sulfatase (STS) is a 62 kDA microsomal enzyme responsible for hydrolyzing the 3beta-sulfate esters from both cholesterol sulfate and sulphated steroid hormones, generating their non-sulfated counterparts. As a result of enzyme deficiency in XRI, cholesterol sulphate accumulates in skin and other organs. Disruption of the cholesterol sulphate cycle accounts for both the abnormal desquamation as well as the permeability barrier abnormality. Kinetic studies have demonstrated that the hyperkeratosis in XRI reflects delayed desquamation. The basis of this "retention hyperkeratosis" is the persistence of corneodesmosomes at all levels of the stratum corneum. One explanation is that cholesterol sulphate functions as serine protease inhibitor as such decreasing the chymotryptic and tryptic enzyme activity of SCCE (stratum corneum chymotryptic enzyme) and SCTE (stratum corneum tryptic enzyme), respectively. An explanation for the permeability barrier abnormality in XRI is that increased cholesterol sulphate destabilizes the eutectic mixtures with other lipids.

The STS gene is located on the distal tip of the short arm of the X-chromosome (Xp22.32). Less frequently STS gene deletions can be rather large being part of a "contiguous gene syndrome", which means that neighbouring genes are also involved. Hence, these XRI patient may suffer from a syndromic type of ichthyosis, e. g. a number of patients exhibit both STS deficiency and Kallman-syndrome (OMIM308700) or have clinical symptoms of a hypergonadotropic hypogonadism. Another disorders associated with STS deficiency is Ocular albinism type 1 (OMIM+300500).

DIAGNOSIS

Clinical main criterion is the presence of ichthyosis starting mostly at the age of around 3 months. In some cases neonates show a transient erythematous scaling shortly after birth. Clinically it can sometimes be difficult to make a clear distinction between ichthyosis vulgaris and XRI. The patient’s history should include a detailed family history. Often an affected grandfather of the side of the mother can be identified as is typical of X-linked recessive inheritance. However, the disorder can be unequivocally diagnosed by steroid sulfatase (Arylsulfatase C) testing from EDTA blood or detection of a chromosomal deletion on the STS locus. All patients should be asked for associated symptoms, e. g. whether they can smell excluding Kallman syndrome, and ichthyosis in a child with unexplained neurological symptoms should prompt measurement of steroid sulfatase.

MANAGEMENT

Compared to severe congenital ichthyoses therapy of X-linked recessive ichthyosis usually presents no major problems and can be done with moisturizing creams containing lactic acid, urea or glycerol. It has to be considered that there is an epidermal barrier defect in the ichthyosis, which bears the risk of systemic absorption and toxicity especially in infants. There are some studies demonstrating that short term treatment with topical tazarotene 0.05% or 0.1% gel may have good efficacy and a longer duration of the effect compared to normal keratolytics. Elevated systemic tazarotene levels have been observed in teenagers using the topical therapy over a long period of several months on a BSA of ~40%. Low-dose systemic retinoids can be given over a certain period of time in patients, who are weary of the topical treatment. This is usually possible since males do not have the risk of teratogenicity. However, even in such patients treatment with topical emollients should be continued.