Genetics of Inherited Ichthyoses and Related Diseases

Abstract

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.

Keywords: ARCI; genes; ichthyoses; molecular genetic diagnostics; mutations; Mendelian disorders of cornification.

Fig. 1

Examples of skin signs in non-syndromic ichthyoses. (a, b) Fine, pale-grey scales of ichthyosis vulgaris on thorax and legs of a patient with compound heterozygous filaggrin (FLG) gene mutations. (c, d) Adherent, rhomboid, dark-brown scaling in X-linked recessive ichthyosis; hands and feet are not affected. (e–h) Severe lamellar ichthyosis and thick palmoplantar keratoderma in a patient with autosomal recessive congenital ichthyosis (ARCI) due to homozygous mutations in TGM1. (i–k) Ichthyosiform erythroderma and severe palmoplantar keratoderma in patients with ABCA12 mutations. (l, m) Lamellar ichthyosis and yellow plantar keratoderma in patients with NIPAL4 mutations. (n) Typical palmar hyperlinearity in a patient with CYP4F22 mutations. (o) In patients with PNPLA1 mutations cyclic superficial scaling can be observed.

Fig. 2

Examples of skin signs in non-syndromic (continued from Fig. 1) and syndromic ichthyoses. (a, b) Follicular hyperkeratosis of the body and affected axilla in adults with ichthyosis prematurity syndrome (IPS). (c, d) Verrucous hyperkeratosis in epidermolytic ichthyosis (EI) of the abdomen and legs caused by heterozygous mutations in KRT1. (e) Hyperkeratosis, erythroderma and skin fragility in EI due to a heterozygous mutation in KTR10. (f) Congenital reticular ichthyosiform erythroderma (CRIE) with specific heterozygous mutation in KRT10; white spots (representing normal skin) appeared since the age of 4 years due to revertant mosaicism. (g) Extensive, spiky hyperkeratosis over the extensor surfaces of the lower extremities in ichthyosis hystrix type Curth-Macklin (KRT1). (h) Erythrokeratodermia variabilis (EKV) due to a heterozygous mutation in the GJB3 gene, also known as CX31. (i) EKV due to a heterozygous mutation in CARD14. (j) Ichthyosis linearis circumflexa (polycyclic serpiginous migratory plaques with double-edged scales) in Netherton’s syndrome caused by biallelic SPINK5 mutations. (k) Pronounced, dark pigmented ichthyosis on the neck in a patient with Sjögren-Larsson syndrome and mutations in the ALDH3A2 gene. (l) Mild, ichthyosiform erythroderma in Chanarin-Dorfman syndrome.