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Focusing attention on X-linked ichthyosis

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Ichthyosis vulgaris
Credit: JAAD

By Warren R. Heymann, MD
Jan. 2, 2019

I thought it was me. Like every dermatologist, I learned the classical appearance of the ichthyoses, and wonder why I’m not sure if I am looking at a patient with ichthyosis vulgaris (IV) or X-linked ichthyosis (XLI). This commentary will focus on some new literature about XLI that demands our attention.

XLI is the second most common type of ichthyosis, following IV, affecting 1 in 2,500 to 6000 males. The disorder usually presents within the first year of life, appearing congenitally in 15% to 20% of patients, rarely as a collodion baby. Characteristically mild scaling and erythema are seen at birth. Over time, larger polygonal scales (unfortunately described as “dirty”) on the scalp, extensor aspects of the lower extremities, and other extensor surfaces are observed. The flexures (popliteal and antecubital fossae), palms, and soles are spared. Scales tend to increase throughout childhood and continue into adolescence. Pruritus usually is absent. Desquamation is typically mild during the summer months and is exacerbated by cold, dry weather. Asymptomatic corneal opacities are the most common eye finding (present in up to 50% of affected males and 25% of female carriers). Cryptorchidism has been reported in up to 20% of XLI patients. (1)

XLI is caused by mutations in the STS gene encoding for the steroid sulfatase (STS) enzyme, a membrane‐bound protein expressed at high levels in placenta, but also present in most organs including the skin, reproductive tract, breast, blood, liver and brain. The STS gene is located on chromosome Xp22.31. In 85%‐90% of patients, the defect is a deletion comprising the entire STS gene and flanking sequences, while point mutations or partial deletions account for about 10% of cases. In addition, larger deletions involving contiguous genes may result in syndromic conditions, for example X‐linked recessive chondrodysplasia punctata (OMIM #302950), Kallmann syndrome (OMIM #308700), ocular albinism type I (OMIM #300500), and short stature (OMIM #300582) (2).

Regarding dermatologic clinical vagaries, in a retrospective study of 30 patients with XLI (belonging to 25 different families carrying a deletion in the STS locus) one-third demonstrated flexural involvement, making this a poorly specific sign in differentiating XLI from IV. Only one patient with XLI had palmar involvement, making that a more remarkable sign in favor of IV. (3) This contrasts with Diociaiuti et al, who observed palmoplantar involvement in 20% of XLI patients (7/35), manifesting mainly as hyperlinear palms. (2). It is possible that some overlapping features of XLI and IV may be due to the recent finding that 17.6% of XLI patients demonstrate a FLG (filaggrin) mutation (4) — it does not explain all cases, however. Personally, the saving grace of these studies is that they are allowing me to forgive myself for what I assumed was my clinical ineptitude. 

The most disconcerting findings of these recent studies is the strikingly common prevalence of neurological disorders in patients with XLI. Rodrigo-Nicolás et al reported epilepsy in 13% and attention deficit hyperactivity disorder (ADHD) in 30% of their series of 30 patients. (3). In the report of 35 XLI patients, 14 (42%) presented with neuropsychiatric symptoms, most frequently ADHD. (The worldwide‐pooled prevalence of ADHD is estimated at around 5% in school‐age children.) (2) The need for a multidisciplinary approach for patients with XLI, including neuropsychiatry, is clear.

Although the precise pathophysiology linking XLI and ADHD remains to be defined, the theory presented by Baek and Aypar is compelling: “STS belongs to the sulfatase family and hydrolyzes several 3-beta-hydroxysteroid sulfates, converting specifically the sulfated form of dehydroepiandrosterone, otherwise known as DHEA-S to DHEA. These are both neurosteroids which exhibit effects on neurophysiological and behavioral processes. Lower levels of DHEA in the blood have been associated with ADHD phenotype. This could explain the link between loss of STS gene function and ADHD in XLI patients.” (5)

My attention deficit was in being unaware of the association of neurological disorders in patients with XLI. Dermatologists must focus on assisting patients with XLI to get the appropriate evaluations, to tip the “scale” in their favor.

Point to remember: Assessing males with XLI requires a careful look at the skin, testicles, and neuropsychiatric function.

1. Wu B, Paller AS. Ichthyosis, X-linked. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-2018 Jun 26.
2. Diociaiuti A, et al. X-linked ichthyosis: Clinical and molecular findings in 35 Italian patients. Exp Dermatol 2018; Apr 19 [Epub ahead of print].
3. Rodrigo-Nicolás B, et al. Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: A retrospective case series.  Br J Dermatol 2018; 179:933-939.
4. Süßmuth K, et al. Increased prevalence of filaggrin deficiency in 51 patients with recessive X-linked ichthyosis presenting for dermatological examination. J Invest Dermatol 2018; 138: 709-11.
5. Baek WS, Aypar U. Neurological manifestations of X-linked ichthyosis: Case report and review of the literature. Case Rep Genet 2017;2017:9086408.

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