Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

Abstract

Autosomal recessive congenital ichthyoses (ARCI) include several severe subtypes including harlequin ichthyosis (HI), lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Patients with these severe types of ichthyoses frequently show severe hyperkeratosis and scales over a large part of the body surface form birth and their quality of life is often severely affected. Recently, research into the pathomechanisms of these severe congenital ichthyoses have advanced dramatically and led to the identification of several causative genes and molecules underlying the genetic defects. To date, seven loci have been identified that are associated with ARCI and, among them, five causative genes and molecules have been detected. The five genes are transglutaminase 1 gene (TGM1), ABCA12, two lipoxygenase genes, ALOXE3 and ALOX12B and ichthyin. One of these components, ABCA12, has recently been shown to be a keratinocyte lipid transporter associated with lipid transport in lamellar granules and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in the HI phenotype. Transglutaminse 1 deficiency was reported to cause a malformed cornified cell envelope leading to a defect in the intercellular lipid layers in the stratum corneum and defective stratum corneum barrier function resulting in an ichthyosis phenotype. Thus, defective intercellular lipid layers are major findings in autosomal recessive congenital ichthyoses. Information concerning ARCI genetic defects and disease pathomechanisms are beneficial for providing better treatments and genetic counseling including prenatal diagnosis for families affect by ichthyoses.