Knowledge on rare diseases and orphan drugs

The prevalence of syndromic RXLI is estimated at 1/50,000-1/150,000. It affects almost exclusively males.

Cutaneous manifestations include generalized scaling of the skin commonly more pronounced on the extensor surfaces of the limbs (mostly lower extremities). Non-cutaneous manifestations may include cryptorchidism, attention-deficit and hyperactivity disorder (ADHD), and corneal opacity. Manifestations due to contiguous gene syndrome include neurological abnormalities such as epilepsy and hyposmia, intellectual disability and/or short stature. This mechanism can be observed in Kallmann syndrome, hypergonadotropic hypogonadism, ocular albinism type 1, or hypertrophic pyloric stenosis.

RLXI is due to deletions in the steroid sulfatase STS gene located on chromosome Xp22.3. STS codes for a lipid hydrolase that participates in the regulation of permeability, barrier homeostasis and desquamation. STS mutations result in abnormal desquamation, decreased corneodesmosomal degradation and retention hyperkeratosis.

Diagnosis is based on clinical findings and family history (scaling in male relatives, history of delayed birth). It is confirmed by biochemical analysis such as serum protein electrophoresis, and STS activity test of fibroblasts or leukocytes, and molecular/cytogenetic analyses such as polymerase chain reaction (PCR), multiple ligation-dependent probe amplification (MLPA), comparative genomic hybridization/comparative microarray analysis (CMA), and fluorescent in situ hybridization (FISH). Histology and ultrastructure of the skin is helpful for the differentiation of ichthyosis vulgaris.

Differential diagnosis includes non-syndromic RXLI, ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), namely lamellar ichthyosis, or multiple sulfatase deficiency.

Maternal urine and serum steroid measurements may show decreased estrogen levels. Therefore, RXLI may be detected in utero when maternal estriol levels are measured during prenatal screening. Genetic analysis can be performed for families with an identified causing mutation.

XLRI has an X-linked recessive mode of inheritance: it affects males and is inherited through female carriers. Female patients have rarely been reported.

Cutaneous therapy consists in hydrating and softening the skin with the use of lubricating bath oils and emollients containing humectants and keratolytics (e.g. urea, lactic acid, and glycolic acid). For adult patients, systemic retinoids are an option, e.g. during winter, when the ichthyosis is generally more severe. Additional supportive treatments should be proposed depending on systemic findings.

RXLI represents a complex form of ichthyosis whose prognosis depends on the systemic involvement (central nervous system and cognitive impairment are variable). Scaling may improve with age.

Last update: December 2022 - Expert reviewer(s): Dr Ángela HERNÁNDEZ MARTÍN