Geneskin

Slogan Text

Definition 

Keratinization disorders refers to a large and heterogeneous group of disorders of cornification, the majority of which are genetically determined. Actually, the ichthyoses constitute the predominant portion of keratinisation disorders. The word « ichthyosis » derives from the Greek word « ichthys » which means fish. In most cases, the skin abnormalities appear since birth. The patients develop extensive, often generalized scaling of the skin, associated or not with redness of the skin. Other organs can be affected. The vast majority of ichthyosis are rare diseases due to mutations in one single gene (monogenic disorders). They are transmitted in an autosomal dominant, recessive or recessive X-linked manner.

Classification

Over the past decade, the defective genes underlying a majority of these disorders have been identified. These spectacular progresses allow a classification based on the undelying defect. A first group is caused by defects in structural proteins or enzymes involved in cornified envelope formation. This includes lamellar ichthyosis/non-bullous congenital ichtyosiform erythroderma, congenital ichthyosiform erythroderma and Vohwinkel syndrome without deafness, bullous congenital ichtyosiform erythroderma (or epidermolytic hyperkeratosis) and ichthyosis of Siemens. A second group includes disorders due to defects in lipid metabolism: in the cholesterol pathway, such as X-linked recessive ichthyosis, Conradi-Hünermann-Happle syndrome and CHILD syndrome; or in fatty acids metabolism, including lamellar ichthyosis/non-bullous congenital ichtyosiform erythroderma, Harlequin ichthyosis, Sjögren-Larsson syndrome, Chanarin-Dorfman syndrome and Gaucher disease. A third group  includes ichthyoses due to defects in gap junctions impairing intercellular communication, such as Keratitis-Ichthyosis-Deafness (KID) syndrome, erythroderma variabilis and Vohwinkel syndrome with deafness. A fourth group is represented by defects in epidermal proteases and their inhibitors and includes Netherton syndrome and Papillon Lefevre syndrome. A fifth group comprises peroxisomal disorders (i.e. Refsum disease and Rhizomelic chondrodysplasia punctata). A sixth group consists in a disorder of DNA repair, namely Trichothiodystrophy– this type of ichthyosis belongs to the group of DNA-repair disorders and are discussed elsewhere in this website. A seventh group consists in an intracellular calcium pump disorder and comprises Darier and Hailey-Hailey diseases.

Clinical presentation and disease course

The ichthyoses are present at birth or later in life. At birth, the newborns present with generalised scaling associated or not with generalised redness (erythroderma). Two neonatal forms need to be distinguished because of their severity: collodion baby and Harlequin ichthyosis.
Collodion baby : the newborn’s skin is recovered with a yellow, shiny and tight membrane resembling dried collodion. The eyelids and sometimes the lips are tethered and everted (ectropion and eclabion). Sausage-shaped swelling of the digits is frequent. The collodion membrane desiccates, fissures and sheds in 1-4 weeks, often replaced by an erythrodermic or lamellar ichthyosis.
Harlequin fetus is the most severe expression of ichthyosis, often lethal. The newborn baby is encased in a very thick « coat of armour » made of large yellowish plaques covering the entire body. Soon after birth, red and deep fissures occur giving the appearance of a harlequin’s costume. Severe ectropion and eclabion are constant. Restriction of the chest and limb movement causes respiratory insufficiency and congenital contractures (artrogryposis). The newborns who survive develop a life-long ichthyosis of variable severity.

The clinical manifestations of the different forms of ichthyosis and their disease course are extremely variable. Cutaneous features can be isolated (non syndromic ichthyosis), or associated with extra-cutaneous symptoms (syndromic ichthyosis).

In non syndromic ichthyosis, general scaling develops either in the form of large, dark brown and plate-like scales with minimum erythroderma (X-linked recessive ichthyosis and classical lamellar ichthyosis); or small, white and fine scales with severe erythroderma (congenital ichthyosiform erythrodema). Intermediate phenotypes with variable degrees of erythema and scaling are frequent. In epidermolytic hyperkeratosis, blisters and fissures occur during the neonatal period, and are subsequently replaced by hyperkeratosis which predominates in the folds. In erythrokeratoderma variabilis, « migratory » erythematous patches are associated with persitent ichthyosis. In Darier’s disease, keratotic papules predominate in seborrheic areas and are associated with highly suggestive nail changes.

In syndromic ichthyosis, associated findings have a strong diagnostic value. Mental retardation and spastic diplegia are associated with generalized ichthyosis and pruritus in Sjögren Larsson syndrome. Atypical retinitis pigmentosa, ataxia, peripheral neuropathy and additional findings (such as anosmia) are seen in Refsum syndrome. Hepatomegaly, myopathy, cataract, sensorineural deafness associated with fine scaling are suggestive of Chanarin-Dorfman syndrome. Hair abnormalities, severe eczema and allergy manifestations are associated with scaling erythroderma in Netherton Syndrome. Brittle hair, photosensitivity, mental retardation, short stature, cataract and other signs are observed in Trichothiodystrophy with ichthyosis. An unilateral ichthyosiiform erythroderma, ipsilateral limb defect and stippled epyphises are suggestive of CHILD syndrome. Various skeletal defects and cataracts are present in Conradi-Hünermann-Happle syndrome. Deafness, recurrent keratitis, hyperkeratotic plaques and palmoplantar keratoderma are highly suggestive of KID syndrome.

The ichthyoses usually persist throughout life with periods of partial improvement and exacerbation.

Pathogenesis and molecular basis

Cornification is the terminal process of epidermal differentiation, by which the most differentiated layers of the living epidermis gives rises to the stratum corneum (the most superficial layer of the skin). The stratum corneum could be compared to a wall made of « bricks » (the corneocytes) and « mortar » (the intercellular lipid lamellae). It has a protective function against external aggressions and prevents the fluid loss. Genetic defects affecting each of its components have now been identified in a majority of ichthyosis. These include major structural proteins of the cornified envelope, enzymes involved in the cornification process, in lipid metabolism, in intracellular calcium homeostasis, in the regulation of protease activity, in peroxisomal transport and processing and DNA repair. Defects in genes encoding proteins involved in these functions will compromise skin barrier formation at different levels, such as impaired formation of the cornified envelope, defective intercellular lipid lamellae, premature cleavage of cell-to-cell adhesion structures, phytanic acid abnormalities, and abnormal DNA excision repair. Most often, this will lead to thickening of the cornified layer (« hyperkeratosis »), although premature desquamation is the major underlying defect in Netherton syndrome.

Diagnostic procedures

Diagnostic procedures for ichthyosis include a detailed clinical interview and examination, with family history. A skin biopsy for histological examination of an affected area is usually required. Routine biological tests (such as blood cell count, immunoglobuline levels, liver tests) are recommended. Microscopic examination of hair is useful. Several specialized tests are orientated by the clinical presentation and include immunostaining and/or electron microscopy analysis on skin biopsy, and enzymatic activity assays or substrate dosage in leucocytes, on cultured fibroblasts or  inthe serum. Detailed evaluation by other specialists, such as opthalmologists, ENTs, and neurologists, could be very helpful in assessing a possible systemic involvement. To date, for several keratinisation disorders a diagnostic molecular test is available at an European level. Molecular diagnosis of these conditions is offered by reference diagnostic centres, authorised to perform genetic tests for clinical application. Identification of the causative mutation(s) in the patient (and possibly his parents) will allow appropriate genetic counselling. The issue of prenatal diagnosis in a future pregnancy can be considered for severe forms of ichthyosis with no satisfactory treatment. This  should be discussed with the couple at risk in the context of a genetic clinic with a geneticist.

Management

The ichthyoses require an appropriate treatment, sometimes specific (Sjögren Larsson syndrome, Refsum disease) but often symptomatic (moistering, keratolytics, prevention of infections, systemic or topical retinoids, tacrolimus). The follow up should carefully monitor ocular, auditory, neurological, skeleton manifestations when appropriate.

 

Disease type/subtype
Annular Epidermolytic Ichthyosis
Chanarin-Dorfman syndrome
CHILD
Congenital reticular ichthyosiform erythroderma
Darier disease
Dowling-Degos disease
Epidermolytic Ichthyosis
Erythrokeratodermia variabilis
Hailey-Hailey disease
Harlequin type ichthyosis congenita
Ichthyosis hystrix of Curth-Macklin
Keratitis-ichthyosis-deafness syndrome (KID syndrome)
Lamellar ichthyosis/Non-bullous congenital ichthyosiform erythroderma
Monilethrix
Mutilating Vohwinkel palmo-plantar keratoderma with deafness
Mutilating Vohwinkel palmo-plantar keratoderma without deafness
Netherton syndrome
Pachyonychia congenita type 1
Pachyonychia congenita type 2
Palmoplantar  Keratoderma
Refsum disease
Sjögren Larsson syndrome
Superficial Epidermolytic Ichthyosis
X-linked recessive ichthyosis