Ichthyosis (X‐linked)

 

Epidemiology

The worldwide incidence is 1:4000 male births. It is an X-linked recessive disorder that is transmitted by asymptomatic female carriers and almost exclusively affects boys and men.

 

Pathophysiology

 

Recessive X‐linked ichthyosis is caused by mutations in the STS gene encoding steroid sulphatase. Around 90% of patients, diminution or complete absence of steroid sulfatase activity is caused by a deletion of the entire STS gene on chromosome Xp22.31. Steroid sulfatase deficiency results in impaired hydrolysis of cholesterol sulfate and dehydroepiandrosterone sulfate (DHEAS), with subsequent accumulation of cholesterol 3-sulfate in the epidermis. STS normally is concentrated in lamellar bodies and secreted into the spaces between stratum corneum cells. It degrades cholesterol sulfate, generating cholesterol for the epidermal barrier. Cholesterol sulfate is a product of the odland bodies that is discharged with them from the granular cells in to the intercellular space and provides cell cohesion in the lower stratum corneum. As a result of enzyme deficiency, cholesterol sulphate cannot be degraded and so it accumulates in the epidermis which results in persistent cell cohesion even in the upper stratum corneum. Beyond that, high concentrations of cholesterol sulphate inhibit proteases such as kallikrein 5 and kallikrein 7 that are pivotal for normal degradation of corneodesmosomes. This in turn leads to decreased desquamation, and as consequence corneocyte retention. RXLI can thus be considered as a prototypic example of a retention hyperkeratosis. Increase of transepidermal water loss is even more pronounced than in IV patients.

In women pregnant with an affected fetus, steroid sulfatase deficiency in the fetal placenta causes low or absent levels of estrogen in the urine and amniotic fluid because of inadequate deconjugation of DHEAS (which is necessary for estrogen synthesis). As a result, labor often fails to initiate spontaneously or progress, due to insufficient dilation of the cervix. This can only be partially overcome by oxytocin administration, often necessitating cesarean section or forceps delivery. 

 

 

XLI occurs as a result of steroid sulfatase (SSase) deficiency, leading to an accumulation of cholesterol sulfate (CSO₄) in the outer epidermis, erythrocyte cell membranes, and lipoprotein fractions of plasma. Whereas CSO₄ levels normally comprise ~1% of lipid mass in the stratum corneum, in XLI, CSO₄ contents can reach ~10–12%. Although the hydrolysis of CSO₄ generates some of the cholesterol required for the barrier, CSO₄ is also a potent inhibitor of HMG CoA reductase, a key enzyme involved in cholesterol synthesis, thus further reducing cholesterol levels in XLI. The accumulation of CSO₄ coupled with cholesterol deficiency disrupts lamellar membrane architecture, accounting for the barrier abnormality in XLI.

 

Clinical features

Onset is before 3 months of life. In ~90% of affected boys, steroid sulfatase deficiency presents during the neonatal period with mild erythroderma and generalized peeling, often with exfoliation of large, translucent scales. The typical large thick dark-brown, polygonal, adherent scales develop later during infancy or childhood and are distributed symmetrically on the extremities, trunk, and neck. The scales may encroach on the antecubital and popliteal fossae unlike IV. The palms, soles and central face are characteristically spared, with the exception of the preauricular area; some clinicians consider the latter to be a pathognomonic feature. In around 30% of patients, the color of the scale is light grey and these patients are often misdiagnosed as having IV. Dark hyperkeratosis giving the lateral aspects of the trunk and the back of the neck a ‘dirty look’ is a further feature which is typical of RXLI, and is usually not present in IV. Fine scaling of the scalp is frequently seen during early childhood but diminishes over time. In the summertime, often spontaneous marked improvement can be observed, while in winter the skin condition becomes worse, but (in contrast to ichthyosis vulgaris) does not significantly subside with age.

Distribution of X-linked ichthyosis: trunk, buttocks, and arms 

 

Comma shaped corneal opacity is a frequent finding in 10–50% of male patientsand in some female carriers, if they undergo an expert slit-lamp examination, but it usually does not affect vision. Male patients have a 20-fold increased incidence of cryptorchidism and, independent of testicular maldescent, are thought to be at higher risk for developing testicular cancer and hypogonadism. A higher prevalence of attention deficit hyperactivity disorder has also been reported. Although steroid sulfatase activity is measurably reduced in 85% of female carriers, the remaining activity seems sufficient to prevent any skin manifestations.

 

Investigations

 

Pathology

Histology shows orthohyperkeratosis and a thickened stratum granulosum. Ultrastructurally, a marked increase of persistent corneodesmosomes typical for retention hyperkeratosis can be seen.

 

Other diagnostic tests

 

Fluorescent in situ hybridization analysis (FISH) for the STS gene shows deletion of the gene found in 90% of patients which, when known in a female carrier, may also be utilized for prenatal diagnosis (via chorionic villi or amniotic fluid samples). However, non-invasive prenatal diagnosis is the presence of non-hydrolyzed sulfated steroid hormone in maternal urine is preferred. Cholesterol sulfate levels are elevated in the serum, epidermis and scales. Accumulation of (hydroxy) cholesterol sulfate can be detected indirectly by increased migration of the β-fraction in serum lipoprotein electrophoresis, or measured directly by liquid chromatography-mass spectrometry (LC-MS) of serum, epidermal scale, placental tissue, or amniotic fluid. In addition, it is possible to measure steroid sulphatase enzymatic activity biochemically in leukocytes, fibroblasts, keratinocytes, or placental tissue.

 

Differential Diagnosis

 

Clinically, ichthyosis vulgaris is distinguished by its sparing of the neck and other flexural areas as well as the presence of hyperlinear palms and keratosis pilaris.

 

 

Treatment

 

Recessive X‐linked ichthyosis patients benefit from the same therapeutic strategy that is applied for icthyosis vulgaris, namely the use of moisturizers. Again, excellent results can be achieved with a glycerol containing cream. Systemic retinoids are rarely necessary.