DISEASE CARD

Definition

X-linked recessive ichthyosis (XRI) is the second most common type of ichthyosis. The disorder almost exclusively occurs in males, whereas females are disease carriers. It is the only ichthyosis form that can be both syndromic and nonsyndromic. XRI is associated with mutations in the steroid sulphtase (STS) gene (Xp22.3).^{1, 2}

Clinical Description

Patients with XRI show dark brown rhombic scales, symmetrically distributed. They occur primarily on extensor surfaces of the extremities. Increased desquamation is found on the scalp. The dark scales give the typical appearance of a “dirty look”. Some patients show light grey, fine scaling reminiscent of ichthyosis vulgaris. The folds (antecubital, popliteal) are usually involved but may as well be spared. Hair, nails are not involved. Involvement of the palmoplantar area is rare, but does not exclude XRI.³ The ichthyosis frequently starts by the age of 2-6 months of life. In estimated 15-40% a transient mild ichthyosiform erythroderma can be seen shortly after birth. The disorder persists throughout life. Symptoms are often less severe or resolving during summer.²

The disease manifests exclusively in boys, but females can be disease carriers and have reduced STS expression/activity relative to non-carrier females. Mothers of the patients frequently report birth complications such as delayed cervical dilatation, weakness of labour and prolonged delivery due to the enzyme defect in the placenta. Female carriers are also at increased risk of psychopathology, including the postpartum period. Only rare cases of female XRI patients have been reported in the literature so far, e.g. in Turner syndrome (XO gonadal dysgenesis).^4-6

The most common extracutaneous manifestation is cryptorchidism that occurs in 5-20% of the affected patients. Diffuse corneal desposits not affecting the visual acuity are present in about 50% of adults, attention-deficit hyperactivity syndrome in 40% and autism in 25% of patients.⁷

Syndromic XRI describes patients showing additional associated phenotypic anomalies, usually caused by larger chromosomal deletions, a “contiguous gene syndrome”, where neighbouring genes are also involved. This may cause Kallmann syndrome, short stature, recessive X-linked chondrodysplasia punctata, hypergonadotropic hypogonadism, brain abnormalities, unilateral polymicrogyria or retinitis pigmentosa.⁸

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.^{3, 9, 10}

Pathogenesis

XRI is caused by mutations in STS (steroid sulfatase) gene leading to a STS deficiency. Most patients have extensive deletions. 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.^{9, 11, 12}

DIAGNOSIS

The patient’s history should include a detailed family history. Often an affected grandfather (mother's side) can be identified and is typical of X-linked recessive inheritance. De novo STS mutation has also been described. 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. STS activity can be measured biochemically in e.g. plasma or fibroblasts.¹³

Histologic features include orthohyperkeratosis and a thickened stratum granulosum. Electon microscopy might reveal an increase of corneodesmosomes, typical for retention hyperkeratosis.

MANAGEMENT

The management is similar to ichthyosis vulgaris and aims at decreasing skin dryness and improving appearance. It involves emollients and keratolytic agents containing urea (10%, 20%), lactic acid, glycerol and/or salicylic acid (salicylic acid should not be used in very young children). Also tazarotene gel (0.05%) has been reported to be effective.¹⁴  Topical retinoids are frequently limitied because of their irritation causing potential. Low-dose systemic retinoids are effective but mainly useful for periods of increased disease severity. The disease tends to improve during summer months and sun-exposure over a few days can even lead to complete disease resolution.

Urological evaluation should be performed if cryptorchidism is present. Involvement of a neuropsychiatrist in the multidisciplinary management is recommended.

References: 

^{1. Wells R, Kerr C. Genetic classification of ichthyosis. Arch Dermatol. 1965;92(1):1-6.}

^{2. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses - an update. J Dtsch Dermatol Ges. 2014;12(2):109-121.}

^{3. Diociaiuti A, Angioni A, Pisaneschi E, et al. X-linked ichthyosis: Clinical and molecular findings in 35 Italian patients. Exp Dermatol. 2019;28(10):1156-1163.}

^{4. Bradshaw KD, Carr BR. Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis. Obstet Gynecol Surv. 1986;41(7):401-413.}

^{5. Afzal S, Ramzan K, Ullah S, et al. A novel nonsense mutation in the STS gene in a Pakistani family with X-linked recessive ichthyosis: including a very rare case of two homozygous female patients. 2020;21(1):20.}

^{6. Cavenagh A, Chatterjee S, Davies W. Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis. 2019;14(2):e0212330.}

^{7. Kent L, Emerton J, Bhadravathi V, et al. X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. J Med Genet. 2008;45(8):519-524.}

^{8. Ballabio A, Bardoni B, Carrozzo R, et al. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci U S A. 1989;86(24):10001-10005.}

^{9. Elias PM, Crumrine D, Rassner U, et al. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol. 2004;122(2):314-319.}

^{10. Berges-Raso I, Giménez-Palop O, Gabau E, Capel I, Caixàs A, Rigla M. Kallmann syndrome and ichthyosis: a case of contiguous gene deletion syndrome. Endocrinol Diabetes Metab Case Rep. 2017;2017.}

^{11. Hernandez-Martin A, Gonzalez-Sarmiento R, De Unamuno P. X-linked ichthyosis: an update. British Journal of Dermatology. 1999;141:617-627.}

^{12. Sánchez-Guijo A, Neunzig J, Gerber A, et al. Role of steroid sulfatase in steroid homeostasis and characterization of the sulfated steroid pathway: Evidence from steroid sulfatase deficiency. Mol Cell Endocrinol. 2016;437:142-153.}

^{13. Cañueto J, Ciria S, Hernández-Martín A, Unamuno P, González-Sarmiento R. Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population. J Eur Acad Dermatol Venereol. 2010;24(10):1226-1229.}

^{14. Cotellessa C, Cuevas-Covarrubias SA, Valeri P, Fargnoli MC, Peris K. Topical tazarotene 0.05% versus glycolic acid 70% treatment in X-linked ichthyosis due to extensive deletion of the STS gene. Acta Derm Venereol. 2005;85(4):346-348.}