DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME NETHERTON SYNDROME
Synonymous Comel-Netherton, Ichthyosis Linearis Circumflexa
Estimated prevalence -
OMIM 256500
Inheritance Autosomal recessive
Gene (s) SPINK5 (605010)

Definition

Netherton syndrome (NS) is a rare and severe autosomal recessive keratinizing disease characterized by the classical triad made of congenital ichthyosiform erythroderma, a specific hair shaft defect (trichorrhexis invaginata or bamboo hair) and severe atopic manifestations with high IgE levels.

Clinical Description

NS infants typically present with generalized exfoliative erythroderma at birth, which persists throughout life in the most severe cases (continuous redness and peeling) or gradually evolves into a milder condition known as ichthyosis linearis circumflexa (migratory serpiginous scaling erythema with peripheral double edged scale). Hair changes develop usually after the first year.

The hair is thin, fragile, sparse, slow growing and show trichorrhexis invaginata (TI), namely "bamboo hair", under microscopic examination. Eyelashes and eyebrows are also affected. Patients display a broad range of allergic manifestations including atopic dermatitis with elevated serum IgE concentrations, chronic and severe skin inflammation with pruritus, asthma and multiple food allergies. Hypernatremic dehydration, recurrent infections, failure to thrive, malnutrition are major problems during the neonatal period and result in high postnatal mortality. Growth retardation is frequent. Bronchopneumonia and enteropathy can occur. Lichenification of the flexures and severe atopic manifestations are frequent.

Pathogenesis

NS is due to mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding LEKTI (lympho-epithelial Kazal-type related inhibitor). LEKTI is a secreted serine protease multi-domain inhibitor expressed in the most differentiated viable layers of stratified epithelia. In the skin, LEKTI is highly expressed in the granular layer and the inner root sheath of the hair folicles. The majority of causative SPINK5 mutations result in premature termination codons and loss of LEKTI expression.

As a consequence, SCTE (stratum corneum trypsin like enzyme) and SCCE (stratum corneum chymotrypsin like enzyme) are overactive and cleave corneodesmosomes prematurely. This results in detachment of the stratum corneum from the granular layer, leading to a major defect in skin barrier. This is likely to facilitate the penetration of allergens and to initialize immune responses leading to atopy.

Diagnosis

stological skin examination shows epidermal hyperplasia with papillomatosis, hyperkeratosis with parakeratosis (persistance of nuclei in the stratum corneum which can be detached), reduced of absent granular layer. There may be an inflammatory infiltrate in the dermis. Although highly suggestive, these abnormalites are not specific for NS. Diagnostic confirmation relies on loss of LEKTI expression in the granular layer of the epidermis. Immunostaining of a skin section using LEKTI antibodies shows complete loss of LEKTI expression in the vast majority of patients. In rare patients, a very faint staining in the granular layer and/or in the inner root sheath of the hair folicles can be detected.

Trichorrhexis invaginata (TI) is considered to be specific for NS. Light microscopy examination of a hair shows a ball and socket hair shaft abnormality resulting from the invagination of the distal hair shaft into the proximal hair shaft. TI is often not recognized during the first months of life. It can also affect eyelids and eyelashes.

Treatment

During the neonatal period, prevention and treatement of hypernatremic dehydration by appropriate fluid and electrolyte support are essential. Ointment-based emollients are useful to reduce transepidermal water loss. The prevention and treatment of skin infections are also important. Nutritional support, hypoallergenic diet (Neocate), a nutrician and dietetician are essential to maintain normal growth and development. During childhood, topical immunomodulators (Tacrolimus or Pimecrolimus, which shows reduced systemic absorption) are effective, but they should be used on a limited surface of the skin and they require careful monitoring of blood levels due to increased absorption through the skin.

Topical steroids are not effective and there is the risk of increased percutaneous absorption. Oral retinoids (acitretin) can exacerbate the disease by causing extensive skin erosions and are not recommended.