Definition

Keratinization disorders encompass a wide array of disorders that affect the formation of the tough outer layer of the skin (= cornification), and are primarily caused by genetic factors. Among these disorders, the predominant subset is referred to as ICHTHYOSES.

The word « ichthyosis » derives from the Greek term « ichthys » meaning fish. Typically, the skin abnormalities manifest at birth. Patients experience widespread, often generalized scaling of the skin, along with occasional redness. Additionally, other organs may also be affected. Most forms of ichthyosis are rare, resulting from mutations in one single gene (monogenic disorders). They are inherited in an autosomal dominant, recessive or recessive X-linked manner.

Clinical presentation

ichthyoses can present either at birth or later in life. Newborns with ichthyosis typically exhibit generalised scaling, with or without redness (erythroderma). Two distinct neonatal forms need to be distinguished that differ in severity: collodion baby and Harlequin ichthyosis.

Collodion baby: the newborn’s skin is encovered by a tight, yellow and shiny membrane resembling dried collodion. The eyelids and sometimes the lips may be tethered and everted (ectropion and eclabion). Sausage-shaped swelling of the digits is common. The collodion membrane dries, cracks and sheds in 1-4 weeks, often replaced by a generalized scaling / ichthyosis.

Harlequin fetus is the most severe expression of ichthyosis and often lethal. The newborn is covered with a thick « coat of armour » made up of large yellowish plaques covering the entire body. Shortly after birth, red and deep fissures appear, giving the appearance of a harlequin’s costume. Restriction of the chest and limb movement may cause severe respiratory problems. 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 highly variable. Cutaneous features may be isolated (non syndromic ichthyosis), or associated with extra-cutaneous symptoms (syndromic ichthyosis). Ichthyoses generally persist throughout life with periods of partial improvement and exacerbation.

Non syndromic ichthyoses:

• Generalized scaling in the form of large, dark brown and plate-like scales with minimum erythroderma (X-linked recessive ichthyosis and classical lamellar ichthyosis)
• Generalized scaling with small, white and fine scales with severe erythroderma (congenital ichthyosiform erythrodema).
• Intermediate phenotypes with variable degrees of erythema and scaling are frequent.
• Occurence of blisters and fissures during the neonatal period, which are subsequently replaced by hyperkeratosis predominating in the folds (epidermolytic hyperkeratosis).
• Migratory erythematous patches, associated with persitent ichthyosis (erythrokeratodermia figurata et variabilis)
• Keratotic papules predominating in seborrheic areas and specific nail changes (Darier's disease)

Syndromic ichthyoses: 

• Mental retardation and spastic diplegia, associated with generalized ichthyosis and pruritus (Sjögren Larsson syndrome)
• Atypical retinitis pigmentosa, ataxia, peripheral neuropathy and additional findings (such as anosmia) (Refsum syndrome)
• Hepatomegaly, myopathy, cataract, sensorineural deafness associated with fine scaling (Chanarin-Dorfman syndrome)
• Hair abnormalities, severe eczema and allergy manifestations, associated with scaling erythroderma (Netherton Syndrome)
• Brittle hair, photosensitivity, mental retardation, short stature, cataract and other signs (Trichothiodystrophy with ichthyosis)
• Unilateral ichthyosiiform erythroderma, ipsilateral limb defect and stippled epyphises (CHILD syndrome)
• Various skeletal defects and cataracts (Conradi-Hünermann-Happle syndrome)
• Deafness, recurrent keratitis, hyperkeratotic plaques and palmoplantar keratoderma (KID syndrome)

Classification

Over the past decade, the defective genes underlying a majority of these disorders have been identified, which has allowed for classification based on the undelying defect:

1^st group: 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.

2^nd 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.

3^rd group: encompasses ichthyoses due to defects in gap junctions impairing intercellular communication, such as Keratitis-Ichthyosis-Deafness (KID) syndrome, erythroderma variabilis and Vohwinkel syndrome with deafness.

4^th group: is represented by defects in epidermal proteases and their inhibitors and includes Netherton syndrome and Papillon Lefevre syndrome.

5^th group: comprises peroxisomal disorders (i.e. Refsum disease and Rhizomelic chondrodysplasia punctata)

6^th group: consists of a disorder of DNA repair, namely Trichothiodystrophy– which belongs to the group of DNA-repair disorders and is discussed elsewhere in this website.

7^th group: consists of an intracellular calcium pump disorder and comprises Darier and Hailey-Hailey diseases.

Pathogenesis and molecular basis

The process of cornification is the final stage of epidermal differentiation, during which the topmost layers of the living epidermis produce the stratum corneum (the outermost layer of the skin). The stratum corneum acts like a protective barrier against external damage and prevents loss of fluids. It is composed of « bricks » (the corneocytes) and « mortar » (the intercellular lipid lamellae), similar to a wall.

Genetic defects affecting the components of the stratum corneum have been linked to a majority of ichthyosis. These include major structural proteins of the cornified envelope, enzymes involved in the cornification process,  lipid metabolism,  intracellular calcium homeostasis, regulation of protease activity, peroxisomal transport and processing and DNA repair.

Impaired formation of the cornified envelope, defective intercellular lipid lamellae, premature cleavage of cell-to-cell adhesion structures, abnormalities in phytanic acid, and abnormal DNA excision repair are some of the ways in which genetic defects in these proteins compromise skin barrier formation. This often leads to thickening of the cornified layer (« hyperkeratosis »), although premature desquamation is the major underlying defect in Netherton syndrome.

Diagnostic procedures

A detailed clinical interview and examination with family history are usually the first steps in diagnosing ichtyosis

• Skin biopsy: for histological examination (small sample of skin is taxen) of an affected area
• Blood tests: such as blood cell count, immunoglobuline levels, liver tests, lipid metabolism
• Microscopic examination of hair: useful in several ichthyoses types.
• Specialized tests: Additional tests, such as imaging studies (x-rays), immunostaining and/or electron microscopy analysis on skin biopsy, may be necessary based on the clinical presentation
• Detailed evaluation by other specialists, such as opthalmologists, ENTs, and neurologists, can also aid in assessing a possible systemic involvement.
• Genetic testing: analyzing the DNA of the affected individual to detect mutations in genes associated with ichthyosis. To date, for several keratinisation disorders, molecular tests are available at an European level, allowing for appropriate genetic counseling and consideration of prenatal diagnosis in severe cases with no satisfactory treatment.

Management

The management of ichthyoses is primarily symptomatic and supportive with a focus on reducing the severity of symptoms and improve quality of life. The goals of treatment include softening and removing scales, reducing inflammation and maintaining adequate hydration of the skin. Thus moisturizers and emollients are the cornerstone of therapy and should be applied fequently to affected areas in order to restore the skin barrier and prevent water loss. 

Topical agents like urea, lactic acid and alpha-hydroxy acids may also be helpful to soften and exfoliate thickened skin. Topical corticosteroids for short-time application, can reduce inflammation and itch. 

More severe cases may profit from an oral treatment of retinoids that reduces hyperkeratosis and improves scaling. As these therapies can have significant side effects, they must be closely monitored by a physician. 

Further treatment modalities: phototherapy (e.g. UVA, UVA-1), oral antibiotics for bacterial infections, mechanical removal of thickened skin (palmoplantar keratoses).

Patients with ichthyoses should avoid triggers such as harsh soaps, hot water and low humidity, that may worsen symptoms. 

Psychological support and counseling can help individuals with ichthyoses to cope with the physical and emotional impact of their condition. 

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