Ichthyoses and related keratinization disorders

The term “ichthyosis” is derived from the Greek word for fish. In the past, occasionally people suffering from ichthyosis were likened to suffer from “fish scale disease”. The literal translation is, however, better avoided, as it may be seen as pejorative and in reality scaling in affected persons does not resemble fish scales. Therefore, it is far better to make use of the medical term “ichthyosis”. First written reports on the disease data back to the 18th century. However, it is obvious that ichthyoses have been present as long as mankind exists.

Ichthyoses are a group or rare, generalized, genetically determined keratinization disorders. They were grouped together because of their heritability and the peculiar scaling affecting the entire skin. Nowadays, localized keratinization disorders such as the group of palmoplantar keratoderma affecting primarily palms and soles are considered as related keratinization disorders. They share with the ichthyoses often similar disease mechanisms and a similar biologic background.

Altogether, ichthyoses are rare diseases and the prevalence of a specific genetic type of congenital ichthyosis is in the range of 1 : 100 000 inhabitants meaning we deal mostly with “ultra-rare” diseases. However, in our consultations (ReCIP) we also care for milder and more frequent forms of ichthyosis such as ichthyosis vulgaris (IV) or recessive x-linked ichthyosis (RXLI). Ichthyoses can be classified into two major groups:

  • non-syndromic ichthyoses (Clinical features restricted to the skin)
  • syndromic ichthyoses (clinical manifestations also in other body organs, e.g. mental retardation or skeletal changes).

The prototype of non-syndromic ichthyoses is the group of autosomal recessive congenital ichthyoses (ARCI). A mutation in the gene TGM1 encoding the enzyme transglutaminase-1 is present in about 32% of all ARCI patients. This enzyme has a pivotal role in the assembly of the “cornified envelope” a protein-membrane surrounding the corneocytes (keratinocytes) in the horny layer of the epidermis. Mutations result in a loss of function of this enzyme. Making use of modern techniques this enzyme deficiency can be visualized and demonstrated directly in cryostat sections of the skin under a fluorescence microscope.

Apart from the TGM1 gene further nine distinct genes have been associated with ARCI, each of them responsible for a distinct subtype of ARCI. In addition the non-syndromic types of ichthyoses encompass the blistering forms of ichthyosis such as epidermolytic ichthyosis (defects of keratin 1 or keratin 10), superficial epidermolytic ichthyosis (keratin 2), annular epidermolytic ichthyosis (keratin 10) and as a related keratinization disease affecting palms and soles epidermolytic palmoplantar keratoderma (keratin 9 defect).

The syndromic types of ichthyoses encompass e.g. the Conradi-Hünermann-Happle Syndrome which is an x-linked disease featuring among else ichthyosis, cataracts and short stature. The genetic defect of this disease concerns emopamil binding protein which has a pivotal role in the late steps of cholesterol biosynthesis. A further x-linked syndrome is congenital hemidysplasia with ichthyosiform nevus and limb defect (CHILD-Syndrome). In this disease the molecular defect concerns the gene NSDHL encoding a 3-beta-hydroxy-steroid dehydrogenase that is interestingly likewise involved in cholesterol biosynthesis.There are many other types of ichthyoses we care for in our network.

A further pretty severe rare skin disease is Netherton Syndrome which is due to a deficiency of a protease inhibitor called LEKTI. This skin disease will be discussed in more detail below.

Thus ichthyoses form a large group of distinct diseases. The individual types of ichthyosis can have different clinical features and mostly take a distinct clinical course and are due to different genetic defects. They share their genetic origin and are all due to distinct genetic defects. In most types of ichthyosis the genetic defect has been elucidated in the meantime allowing now modern genetic screening such as gene panel analysis. In a few remaining types the genetic defect is still unknown. Below the most important types of ichthyosis will be discussed.