Netherton disease

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

References

 Proteolytic Activation Cascade of the Netherton Syndrome-Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis. Fortugno P, Bresciani A, Paolini C, Pazzagli C, El Hachem M, D’Alessio M, Zambruno G. J Invest Dermatol. 2011 Nov;131(11):2223-32. PMID: 21697885

 A New SPINK5 Mutation in a Patient with Netherton Syndrome: A Case Report. Alpigiani MG, Salvati P, Schiaffino MC, Occella C, Castiglia D, Covaciu C, Lorini R. Pediatr Dermatol. 2011 Jun 22. PMID: 21692842

 New homozygous SPINK5 mutation, p.Gln333X, in a Turkish pedigree with Netherton syndrome. Fong K, Akdeniz S, Isi H, Taskesen M, McGrath JA, Lai-Cheong JE. Clin Exp Dermatol. 2011 Jun;36(4):412-5. PMID: 21564178

 rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients. Roedl D, Oji V, Buters JT, Behrendt H, Braun-Falco M. J Dermatol Sci. 2011 Mar;61(3):194-8. PMID: 21251800