Ichthyosis: Causes

Pathogenesis (development of disease)

In people with healthy skin, there is a balance between cell renewal and sloughing off of dead skin cells. Approximately every four weeks, the epidermis (cuticle) renews itself. It consists of several layers. In the lowest layer, the basal layer, the horn-forming cells are created, which migrate upward through the other layers. On their way, they keratinize and die. The top layer of the epidermis is the stratum corneum (horny cell layer). It consists of thin layers of flat dead cells. It serves as a barrier to the environment and prevents water loss through the skin. In the context of ichthyosis, physiological (natural) shedding is disturbed. There is a thickening of the stratum corneum as cells accumulate in the stratum corneum, and visible skin scales (hyperkeratosis). The thickened horny layer cannot bind sufficient water and becomes dry. Rhagades (fissures) form, which deepen and widen. This results in the typical scale pattern of ichthyosis.Ichthyosis also affects the ability to sweat, which can cause the body to overheat during physical exertion. There are several inheritance patterns in hereditary ichthyosis: autosomal dominant (autosomal = the gene defect is located on a normal chromosome and not on a sex chromosome), autosomal recessive and sex-linked. Various gene mutations are present. In ichthyosis vulgaris, a gene defect is present that leads to a deficiency of the protein filaggrin. Among other things, this protein is responsible for the moisture of the horny layer. This leads to a cornification disorder and to a delayed rejection of horny cells and their aggregation into scales, which is called retention hyperkeratosis. Barrier dysfunction results in increased water loss and dry, rough scaling. In X-linked recessive ichthyosis vulgaris, an enzyme defect is present on the X chromosome. This causes a steroid sulfatase deficiency, which results in a disturbance of the lipid-containing intercellular layer of the stratum corneum (horny cell layer) and delayed rejection of the horny cells (retention hyperkeratosis). Lamellar ichthyosis belongs to the group of autosomal recessive congenital ichthyoses (ARCI). Mutations have been found in the transglutaminase gene. It results in cornification disorder in the “cornified envelope” (membrane, around the horny cells of the horny layer of the skin) and proliferation hyperkeratosis. In the meantime, further genes have been found. A mutation in the keratin-1 gene or keratin-10 gene is found in epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma Brocq), which also belongs to the ARCI group. There is a synthesis disorder of keratin filaments with an unstable keratinocyte cytoskeleton. This results in cell lability, intraepidermal blistering (epidermolysis) and hyperkeratosis (cornification). Furthermore, there is the group of ichthyosis syndromes in which autosomal recessive enzyme defects are present, leading to cutaneous and extracutaneous sequelae. One example is the Comél-Netherton syndrome. Here, mutations of the SPINK5 gene are present, which codes for the protease inhibitor LEKTI. LEKTI inhibits trypsin-like enzymes in the skin. If the inhibition is lost, massive inflammation of the skin and a reduced horny layer occur. The rarer hereditary forms are associated with the most severe skin changes.

Etiology (Causes)

Hereditary (inherited) ichthyoses (primary ichthyoses).

Biographic causes

• Genetic burden
  • Genetic risk depending on gene polymorphisms:
    • Genes/SNPs (Single Nucleotide Polymorphism; variation of a single base pair in a DNA strand; see SNPedia below for details):
      • Genes: ABCA12, FLG
      • SNP: rs28940268 in gene ABCA12
        • Allele constellation: AA (triggers lamellar ichthyosis, type 2).
      • SNP: rs28940568 in the ABCA12 gene.
        • Allele constellation: AA (triggers lamellar ichthyosis, type 2).
      • SNP: rs28940270 in the ABCA12 gene.
        • Allele constellation: AA (triggers lamellar ichthyosis, type 2).
      • SNP: rs28940271 in the ABCA12 gene.
        • Allele constellation: AA (triggers lamellar ichthyosis, type 2).
      • SNP: rs28940269 in the ABCA12 gene.
        • Allele constellation: GG (triggers ichthyosis, type 4A).
      • SNP: rs137853289 in the ABCA12 gene.
        • Allele constellation: TT (triggers ichthyosis, type 4B).
      • SNP: rs726070 in the gene ABCA12
        • Allele constellation: AA (triggers ichthyosis, type 4B).
      • SNP: rs387906284 in the ABCA12 gene.
        • Allele constellation: DD (triggers ichthyosis, type 4B).
      • SNP: rs387906285 in the ABCA12 gene.
        • Allele constellation: DD (triggers ichthyosis, type 4B).
      • SNP: rs267606622 in the ABCA12 gene.
        • Allele constellation: AA (triggers ichthyosis, type 4B).
      • SNP: rs61816761 in the FLG gene.
        • Allele constellation: AG (triggers a mild form of ichthyosis vulgaris).
        • Allele constellation: AA (triggers a severe form of ichthyosis vulgaris).
      • SNP: rs558269137 in the FLG gene.
        • Allele constellation: DI (triggers a mild form of ichthyosis vulgaris).
        • Allele constellation: II (triggers a severe form of ichthyosis vulgaris).

Acquired ichthyoses (secondary ichthyoses).

Disease-related causes

• Hormonal disorders
• Hypothyroidism (underactive thyroid gland)
• Hypovitaminosis (vitamin A, vitamin B6)
• Leprosy
• Malnutrition
• Sarcoidosis
• Metabolic disorders – e.g., dialysis patients.
• Syphilis
• Trisomy 21 (Down syndrome) – genetic disease that usually occurs sporadically; in which the entire 21st chromosome or parts of it are present in triplicate (trisomy) (occurrence usually sporadic). In addition to physical features considered typical for this syndrome, the cognitive abilities of the affected person are usually impaired.
• Tuberculosis
• Tumors – lymphomas and carcinomas

Drugs

• Butyrophenone (antipsychotic effect, e.g., for the treatment of schizophrenia).
• Nicotinic acid* (lipid-lowering agent).

* Taken off the market in 2013