|Ichthyosis Hystrix Curth Macklin
|KRT1 (139350), KRT10 (148080)
Ichthyosis Curth-Macklin (ICM) is a rare, severe ichthyosis caused by mutations in the KRT1 gene (12q13.13) or (rarely) KRT10 (17y21.2). Characteristic for ICM is the presence of extensive hyperkeratotic lesions and severe palmoplantar keratoderma. 1-4
The disease starts in early childhood with severe hyperkeratosis of yellow-brown or grey color, and of spiky, cobblestone-like (hystrix) or verrucous appearance. Hyperkeratosis may be generalized/diffuse or limited to extensor sites of the extremities (elbows, knees) and the trunk. Lesions may be also nevoid, following the lines of Blaschko. In addition, patients are affected by mutilating, progressive striate or diffuse palmoplantar keratoderma (PPK). PKK is often complicated by painful, deep fissures, bleeding and may lead to flexural contractures and edema of the digits, impairing mobility. Massive PPK (up to 3 cm thick) can cause pseudoainhum (circular constriction band), necessitating amputation. The skin is malodorous and frequently infected. Nail dystrophy may be present. Unlike other keratinopathic ichthyoses, no blistering, peeling or increased skin fragility has been reported. The phenotypical expression shows intrafamiliar variability, from localized hyperkeratotic plaques with PPK to generalized hyperkeratosis. Failure to thrive may occur, but life expectancy is within normal limit. 3, 5-7
Deletion/insertion mutations in the variable (V2) domain (C-terminal tail domain) of KRT1 produce an aberrant and truncated protein tail, which only shows seven out of ten glycine loops. This results in an abnormal organization of keratin intermediate filaments and may be related to defects in cytoplasmic trafficking and integrity of cellular structures such as organelles and the nucleus. Intracellular misdistribution of loricrin has also been reported. A report about a mutation in KRT10, changing the end of the 2B domain in the keratin 10 protein and thus modifying the structure of the paired 2B and V2 K1/10 domains, has also been reported. 3
Histopathologic investigation reveals papillomatous hyperplasia with hyperorthokeratosis and hypergranulosis as well as cellular vacuolization or binucleated cells in the granular/spinous layers. Ultrastructurally, keratin intermediate filaments (KIF) form continuous, peripheral shells around the nucleus. Diagnosis can be confirmed by molecular analysis of the KRT1 and KRT10 gene.8
Treatment is symptomatic. PPK may be reduced by topical keratolytics, oral retinoids and mechanical debridement.