Netherton disease
MIM.256500 5q32
Definition: Netherton syndrome (NS) is a severe autosomal recessive skin disorder caused by mutations in serine protease inhibitor Kazal-type 5 (SPINK5), which encodes the lymphoepithelial Kazaltype-related inhibitor (LEKTI).
Lack of LEKTI causes stratum corneum detachment secondary to the hyperactivity of epidermal proteases, which leads to skin barrier defect, thus facilitating allergen penetration and contributing to atopy in NS.
Affected individuals have chronic and severe skin inflammation and allergic manifestations, including atopic dermatitis–like lesions and elevated serum IgE levels.
Recent studies have shown that thymic stromal lymphopoietin (TSLP) and tumor necrosis factor-alpha (TNFA) are overexpressed in the LEKTI deficient epidermis of NS patients and SPINK5-null mice.
This is due to unrestricted activity of epidermal proteases, including kallikrein-5, which activates PAR2 signaling in keratinocytes, leading to NF-kB activation and TSLP expression.
TSLP is produced by keratinocytes as well as airway epithelial cells and is necessary and sufficient for inducing atopic response in mice. It regulates innate immunity and polarizes T cells toward a T helper type 2 (Th2) phenotype through the conditioning of antigen-presenting cells. TNF-a and IL-1 induce expression of TSLP, which can synergize with these pro-inflammatory cytokines to amplify pro-Th2 cytokine secretion by activated mast cells.
The KLK5–PAR2–TSLP molecular pathway is critical for initiating atopic dermatitis–like lesions in NS, whereas stratum corneum detachment induces secondary skin inflammation.
Synopsis
failure to thrive
sparse eyebrows
asthma
enteropathy with villous atrophy
cutaneous anomalies
- ’bamboo hair’ (trichorrhexis nodosa, or, because of the nodes, trichorrhexis invaginata)
- congenital ichthyosiform erythroderma
- atopic diathesis
- generalized erythroderma
- ichthyosis linearis circumflexa
- congenital lamellar ichthyosis
- urticaria
- sparse, brittle scalp hair
- sparse eyebrows
angioedema
developmental delay
hypernatremic dehydration
hypereosinophilia
atopy
- elevated immunoglobulin E (IgE)
- recurrent infections
- hay fever
- asthma
- angioedema
- food allergy
Etiology
germline mutations in the SPINK5 gene (MIM.605010) encoding the serine protease inhibitor LEKTI (Kazal type, 5)
See also
genodermatoses