Presented by: Catherine Warner, MD, Lauren Ogrich, MD, and Herbert Allen, MD
Drexel University College of Medicine
May 16, 2016
The term autosomal recessive congenital ichthyosis (ARCI) is used to refer to harlequin ichthyosis (HI) and disorders of the lamellar ichthyosis/congenital ichthyosiform erythroderma (LI/CIE) phenotypic spectrum. Mutations in nine genes have been described in ARCI to date, and most of these mutated genes have been related to both LI and CIE. These include TGM1 (transglutaminase), ABCA12, NIPAL4, CYP4F22, LIPN, PNPLA1, CERS3, and the lipoxygenase genes ALOX12B and ALOXE3. The most common of these mutations is TGM1, which crosslinks several proteins to form the cornified envelope surrounding corneocytes. Transglutaminase is generally undetectable in frozen skin specimens from these patients. HI has been shown to result from nonsense mutations in the ABCA12 lipid transporter gene. ABCA12 defects leading to LI/CIE phenotypes tend to be missense mutations, which results in a present but functionally decreased protein and milder phenotype.
LI is generally characterized by coarse and brown/dark scaling. Affected individuals are often born with collodion membrane and pronounced ectropion/eclabium. Scales are most prominent over the face, trunk and extremities, with a predilection for the flexor areas. The scalp is often scaly with scarring alopecia. The palms and soles are almost always affected.
Classic nonbullous CIE is characterized by fine, white scaling with varying degrees of erythema. Individuals with CIE may also be born with collodion membrane and later develop generalized fine scaling and pronounced erythroderma. The degree of ectropion is variable, but often milder than LI. There is also less PPK. These phenotypes can change over time and in response to treatment.
HI is the most severe form of ARCI. Patients with HI are born with profoundly thickened skin. Rigidity of the skin results in marked ectropion, everted lips and distorted nose and ears. This skin rigidity can restrict respiratory movements, sucking and swallowing. Flexion deformities are common, and the nails may be hypoplastic or absent.
Treatment of patients with most forms of ichthyosis involves topical application of keratolytic agents as well as topical or systemic retinoids. Management of water loss and pruritis are also important. Αlpha hydroxy acid preparations such as lactic and glyocolic acids are helpful to desquamate excessive scale and increase hydration. Urea can also help to soften and moisturize the stratum corneum, which is helpful to control the patients’ dry skin and pruritis. Patients with milder forms of LI often respond well to topical tazarotene. Similarly, N-acetylcysteine has been shown to be effective by inhibiting keratinocyte proliferation. In a recent study, recombinant tranglutaminase-1 enzyme encapsulated in liposomes reversed the ichthyosis phenotype and barrier function in a skin-humanized mouse model of LI. This suggests topical enzyme replacement therapy may be a promising future treatment.
Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol, 63 (2010): 607–641.
Paller A, Mancini A. (2016) Hurwitz Clinical Pediatric Dermatology.Chicago, IL, Elsevier.
Aufenvenne K, Larcher F, Hausser I, et al. Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. Am J Hum Genet, 2013. 93(4): 620-30.
