Recessive X-linked ichthyosis

What is recessive X-linked ichthyosis?

Recessive X-linked ichthyosis is a genetic disorder in which there is very dry skin. The features include generalised, fine or rhomboid, adherent, dark brown or light grey, scaling of the skin. The scaling is usually prominent on the back of the neck, upper trunk and extensor surfaces of the limbs. The condition presents usually at birth or within 6 months of birth.

Recessive X-linked ichthyosis is associated with corneal opacities of the eye, undescended testicles and neurological abnormalities.

It is also sometimes just called X-linked ichthyosis.

What causes recessive X-linked ichthyosis?

Recessive X-linked ichthyosis is a disorder caused by a mutation of the enzyme steroid sulfatase (STS). STS is involved in the metabolism of cholesterol sulphate in the skin. STS deficiency leads to accumulation of cholesterol sulphate in the outer layer of the skin leading to a dysfunctional skin barrier and retention of the outer skin cells (corneocytes) causing the typical scaling.

The gene encoding STS has been mapped to the distal part of the X chromosome.

• 90% of patients with X-linked ichthyosis have complete deletions of this gene.
• The other cases include partial deletions or point mutations.
• Deletions can occur in the neighbouring genes causing a contiguous gene defect.

Therefore patients with X-linked ichthyosis should also be evaluated for the contiguous gene defect. Larger chromosomal deletions could result in:

• Kallmann syndrome
• Intellectual disability
• X-linked recessive chondrodysplasia punctata
• Short stature.

Genetics of X-linked ichthyosis* 

*Image courtesy Genetics 4 Medics

Who gets recessive X-linked ichthyosis?

The inheritance of X-linked ichthyosis is recessive because if the individual also has a normal STS gene, the condition is not expressed.

Females have two X-chromosomes and males have one. A male affected by X-linked ichthyosis passes the ichthyosis gene to his daughters via his X-chromosome. The daughters become carriers and usually have one affected gene and one normal gene. They can pass the abnormal gene to roughly half of their daughters and to half of their sons—who then manifest ichthyosis. Thus:

• Males are usually affected.
• Females are usually protected by their second X chromosome. They are carriers.

Approximately 1 in 6,000 males are affected by recessive X-linked ichthyosis, with no evident racial or geographical associations. There have been few cases reported in females. It is thought that these women have inherited the ichthyosis gene from both sides of the family.

What are the clinical features of recessive X-linked ichthyosis?

Recessive X-linked ichthyosis presents with prominent scaling.

• Scaling is usually distributed symmetrically.
• It is more evident on the extensor surfaces of the limbs and the side of the trunk.
• Scales can resemble fish scales; the brown or grey colour can lead to a ‘dirty appearance’.
• The face is usually free of scales except in the area in front of the ears (preauricular). Occasionally, flexures, neck and scalp are also affected.
• Scales on the scalp, neck and the preauricular areas tend to disappear during childhood.
• Palms and soles are very rarely involved.
• Hair and nails are normal.
• Typically desquamation improves during summer and deteriorates during dry and cold weather.

Recessive X-linked ichthysosis 

Recessive X-linked ichthysosis 

Recessive X-linked ichthysosis 

Recessive X-linked ichthysosis 

X linked ichthyosis 

X linked ichthyosis 

Non-skin manifestations of STS deficiency can occur as well.

• Due to low placental STS, pregnant mothers may suffer from prolonged labour when delivering affected infants.
• Corneal opacities can occur in affected males and female carriers.
• Undescended testicles (cryptorchidism) is found more commonly in men with x-linked ichthyosis than the general population.
• There is also an increased risk of testicular cancer, which is independent of the presence of testicular maldescent.
• Possible neurological involvement includes epilepsy, intellectual disability, and reduced ability to smell (hyposmia).

Involvement of the adjacent genes in patients with recessive x-linked ichthyosis can result in a variety of additional features.

How is recessive X-linked ichthyosis diagnosed?

Diagnosis is based mainly on history and clinical findings.

Biochemical analysis after birth on the placenta, skin fibroblasts and keratinocytes includes:

• Serum protein electrophoresis
• STS activity assay.

Genetic analysis includes:

• Southern blot
• Fluorescent in situ hybridisation (FISH)
• Polymerase chain reaction (PCR).

Genetic analyses have missed a few cases of x-linked ichthyosis caused by point mutations.

Pre-natal diagnostic tests for X-linked ichthyosis include:

• Decreased oestrogen levels in maternal urine
• Presence of non-hydrolysed sulfate steroids in maternal urine
• Genetic analysis on chorionic villi or amniotic fluid samples, if the family history of STS gene defect is known.

Skin biopsy is usually not useful in confirming the disease as the epidermal microscopic findings may be subtle. They may include:

• Hyperkeratosis
• Hypergranulosis.

What is the treatment of recessive X-linked ichthyosis?

There is no definitive treatment for x-linked ichthyosis and current evidence is limited. High power studies for the treatments are lacking.

The aim of treatment is to improve the scaling of the skin and to improve the appearance of the skin. In some patients, treatment might not be required. Options include:

• Rubbing with a pumice stone or exfoliating sponge to remove scale
• Emollients applied after the bath to moisturise the skin
• Topical keratolytics containing lactic acid, glycolic acid, salicylic acid and urea; these agents can help with the desquamation and improve the appearance of the skin
• Topical isotretinoin
• Topical tazarotene 0.05% gel (receptor-selective retinoid)
• Calcipotriol ointment less than 100 g/week and liarozole 5% cream (not yet commercially available)
• Oral acitretin; its use is limited due to teratogenicity and adverse effects
• Oral liarozole (a retinoic acid metabolism blocking agent, not yet commercially available).

Genetic counselling can be also offered to patients and their families for further information regarding x-linked ichthyosis and inheritance pattern.

Research is ongoing to see whether patients can be treated with gene transfer.

Males should be advised to perform regular testicular self-examinations.

What is the outcome for recessive X-linked ichthyosis?

Recessive X-linked ichthyosis is a chronic condition and the disease persists through adult life.

• Scaling may improve over time.
• Life expectancy is normal.