DISEASE CARD

Disease group Keratinization disorders
DISEASE NAME ICHTHYOSIS HYSTRIX OF CURTH-MACKLIN
Synonymous None
Estimated prevalence Unknown
OMIM 146590
Inheritance Autosomal dominant
Gene (s) KRT1 (139350)

Definition

In a consensus conference in 2009, a new classification system and terminology has been established for ichthyoses [1]. Ichthyoses are determined as Mendelian disorders of cornification (MeDOC) that are characterized by universal scaling of the skin. In two main categories, non-syndromic forms (phenotype restricted to the skin) are distinguished from syndromic forms (involvement of other organs). A further distinction is made between common and rare forms. Within the non-syndromic forms the term keratinopathic ichthyosis is used as an umbrella term to describe all forms of ichthyosis that are based on mutations in keratin genes. The keratinopathic ichthyoses manifest at birth and sometimes involve blistering [2, 3].

Ichthyosis hystrix of Curth-Macklin (IHCM) is a rare keratinopathic ichthyosis caused by mutations in the KRT1 gene (12q13.13). Characteristic for IHCM is the presence of severe hyperkeratotic lesions and palmoplantar keratoderma, and the absence of blistering [4, 5].

Clinical description

The skin usually presents normal at birth. 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 is often diffuse and more pronounced on extensor areas of the limbs, extremities and the trunk. Lesions may also be nevoid following the lines of Blaschko. Patients are also affected with mutilating striate or diffuse palmoplantar keratoderma (PPK). PKK can be complicated by painful, deep fissures, bleeding, flexural contractures and edema of the digits. Massive PPK (up to 3 cm thick) can compromise the ability to walk. Amputation of toes has been reported necessary in two patients, due to pseudoainhynum (circular constriction band) and infection. The skin is malodorous and frequently infected. Nail dystrophy may be present. Contrary to other keratinopathic ichthyoses, no blistering, peeling or increased skin fragility has been reported [6, 7].

Pathogenesis

Mutations in the variable (V2) domain of KRT1 produce an aberrant and truncated protein tail, which lacked seven out of ten glycine loops. This may lead to 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 [5, 7].

Diagnosis

Skin lesion biopsies reveal papillomatous hyperplasia with hyperorthokeratosis and hypergranulosis. Ultrastructurally, keratin intermediate filaments (KIF) form continuous, peripheral shells around the nucleus. Further hallmarks are perinuclear vacuolization and bi-nucleated cells. No epidermolysis occurs in IHCM. On the molecular level, DNA sequencing reveals mutations in the variable tail domain (V2) of KRT1.

Treatment

Treatment is symptomatic. Treatment of PPK with 40% urea cream has been shown effective [8].

References

1
Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, Coudiere P, DiGiovanna JJ, Elias P, Fischer J, Fleckman P, Gina M, Harper J, Hashimoto T, Hausser I, Hennies HC, Hohl D, Hovnanian A, Ishida-Yamamoto A, Jacyk WK, Leachman S, Leigh I, Mazereeuw-Hautier J, Milstone L, Morice-Picard F, Paller AS, Richard G, Schmuth M, Shimizu H, Sprecher E, Van Steensel M, Taïeb A, Toro JR, Vabres P, Vahlquist A, Williams M, Traupe H. (2010) Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 63:607-641.

2
Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, Gruber R. (2013) Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet 21:123-133.

3
Traupe H, Fischer J, Oji V. (2013) Nonsyndromic types of ichthyoses – an update. J Dtsch Dermatol Ges Oct 11. doi: 10.1111/ddg.12229. [Epub ahead of print]

4
Ollendorff Curth H, Macklin MT. (1954) The genetic basis of various types of ichthyosis in a family group. Am J Hum Genet 6:371-382.

5
Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. (2011) Keratin Gene Mutations in Disorders of Human Skin and its Appendages. Arch Biochem Biophys 508:123-137.

6
Information retrieved from Orphanet. Dr Nathalie Jonca, Pr Juliette Mazereeuw-Hautier
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79503 Last updated December 2012.

7
Sprecher E, Ishida-Yamamoto A, Becker OM, Marekov L, Miller CJ, Steinert PM, Neldner K, Richard G. (2001) Evidence for Novel Functions of the Keratin Tail Emerging from a Mutation Causing Ichthyosis Hystrix . J Invest Dermatol 116:511-519.

8
Richardson ES, Lee JB, Hyde PH, Richard G. (2006) A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma of the Ichthyosis Hystrix Curth–Macklin Type . J Invest Dermatol 126:79-84.