DISEASE CARD

Definition

Netherton syndrome (NS) is a rare and severe autosomal recessive keratinizing disease, characterized by the classical triad of congenital ichthyosiform erythroderma, a specific hair shaft defect (trichorrhexis invaginata or bamboo hair) and severe atopic manifestations with high IgE levels. NS is caused by mutations in SPINK5 (serine protease inhibitor Kazal-type 5) gene encoding LEKTI (lympho-epithelial Kazal-type related inhibitor).^1-3

Clinical Description

The phenotype in NS varies from mild desquamative dermatitis to lethal forms. Infants with NS 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 become manifest usually after the first year of life. 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.⁴

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.⁵

Hypernatremic dehydration, recurrent infections, failure to thrive and malnutrition are major problems during the neonatal period and result in high postnatal mortality. Growth retardation is frequent. Bronchopneumonia and enteropathy can occur^{.6, 7}

Pathogenesis

SPINK5 gene, located on chromosome 5q32 encodes the LEKTI protein, 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 follicles. The majority of pathogenic SPINK5 mutations result in premature termination codons and null or very low LEKTI expression.⁸

A consequence of LEKTI deficiency is epidermal overactivation of SCTE (stratum corneum trypsin like enzyme) and SCCE (stratum corneum chymotrypsin like enzyme), two members ob the kallikrein (klk) family (klk5, klk7) with prematurely cleaving of corneodesmosomes. This results in detachment of the stratum corneum from the granular layer, causing a profound skin barrier defect that facilitates the penetration of allergens and initializes immune responses leading to atopy.9 Hyperactivated klk5 due to deficient LEKTI can further upregulate the epidermal protease 2, leading to excessive degradation of (pro-)filaggrin and alteration of intercorneocyte lipid formation in the skin barrier.¹⁰

Diagnosis

A skin biopsy with LEKTI immunostaining should be performed in cases, where NS is suspected based on clinical grounds (i.e. unexplained neonatal erythroderma, hypernatraemia dehydration, unexplained failure to thrive), as clinical features are not always diagnostic.⁷ Histological 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 abnormalities 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.^{11, 12}

Trichorrhexis invaginata (TI) is considered to be specific for NS. Trichoscopy of a hair shows a ball and socket hair shaft abnormality due to the invagination of the distal hair shaft into the proximal hair shaft. TI is often not detectable during the first months of life.

Treatment

Treatment is symptomatic and patients should be managed in a multidisciplinary setting from early on. During the neonatal period, prevention and treatment 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. Pediatric allergists and dieticians play an important role in the infancy period and childhood. For desquamative skin lesions, topical immunomodulators (tacrolimus or pimecrolimus) are usually effective, although their use is controversial due to the risk of systemic absorption. Therefor careful monitoring of blood levels is warranted.

Topical steroids should be avoided due to the risk of increased percutaneous absorption. Oral retinoids (acitretin) should be avoided as well, since they may exacerbate the disease and induce extensive skin erosions. Several therapies have been tried in experimental settings and reported beneficial, including intravenous/subcutaneous immunoglobulin, infliximab, omalizumab, dupilumab and IL-17-targeting therapies. Preclinical studies involve serine protease inhibitor targeted therapies and ex vivo gene therapy with a SIN-lentiviral vector encoding the corrected SPINK5 gene.^13-20

References

^{1. Comel M. Ichthyosis linearis circumflexa. Dermatology. 1949;98(3):133-136.}

^{2. NETHERTON EW. A unique case of trichorrhexis nodosa—Bamboo hairs. AMA archives of dermatology. 1958;78(4):483-487.}

^{3. Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25(2):141-142.}

^{4. Ito M, Ito K, Hashimoto K. Pathogenesis in trichorrhexis invaginata (bamboo hair). Journal of investigative dermatology. 1984;83(1).}

^{5. Smith DL, Smith JG, Wong SW, deShazo RD. Netherton's syndrome: a syndrome of elevated IgE and characteristic skin and hair findings. Journal of allergy and clinical immunology. 1995;95(1):116-123.}

^{6. Jones S, THOMASON LM, SURBRUGG SK, Weston W. Neonatal hypernatraemia in two siblings with Netherton's syndrome. British Journal of Dermatology. 1986;114(6):741-743.}

^{7. Bellon N, Hadj-Rabia S, Moulin F, et al. The challenging management of a series of 43 infants with Netherton syndrome: unexpected complications and novel mutations. Br J Dermatol. 2021;184(3):532-537.}

^{8. Bitoun E, Chavanas S, Irvine AD, et al. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. Journal of investigative dermatology. 2002;118(2):352-361.}

^{9. Descargues P, Deraison C, Prost C, et al. Corneodesmosomal Cadherins Are Preferential Targets of Stratum Corneum Trypsin- and Chymotrypsin-like Hyperactivity in Netherton Syndrome. Journal of investigative dermatology. 2006;126(7):1622-1632.}

^{10. Bonnart C, Deraison C, Lacroix M, et al. Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J Clin Invest. 2010;120(3):871-882.}

^{11. Leclerc-Mercier S, Bodemer C, Furio L, et al. Skin biopsy in Netherton syndrome: a histological review of a large series and new findings. Am J Dermatopathol. 2016;38(2):83-91.}

^{12. Ong C, O'Toole EA, Ghali L, et al. LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. British Journal of Dermatology. 2004;151(6):1253-1257.}

^{13. Yalcin AD. A case of netherton syndrome: successful treatment with omalizumab and pulse prednisolone and its effects on cytokines and immunoglobulin levels. Immunopharmacology and immunotoxicology. 2016;38(2):162-166.}

^{14. Fontao L, Laffitte E, Briot A, Kaya G, Roux-Lombard P. Infliximab infusions for Netherton syndrome: sustained clinical improvement correlates with a reduction of thymic stromal lymphopoietin levels in the skin. Journal of investigative dermatology. 2011;131(9):1947-1950.}

^{15. Paller AS, Renert-Yuval Y, Suprun M, et al. An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis. Journal of allergy and clinical immunology. 2017;139(1):152-165.}

^{16. Di W-L, Mellerio JE, Bernadis C, et al. Phase I study protocol for ex vivo lentiviral gene therapy for the inherited skin disease, Netherton syndrome. Human Gene Therapy Clinical Development. 2013;24(4):182-190.}

^{17. Aktas M, Salman A. Netherton syndrome: Temporary response to dupilumab. 2020;37(6):1210-1211.}

^{18. Zhang Z, Pan C, Wei R, et al. Netherton syndrome caused by compound heterozygous mutation, c.80A>G mutation in SPINK5 and large-sized genomic deletion mutation, and successful treatment of intravenous immunoglobulin. 2021:e1600.}

^{19. Zelieskova M, Banovcin P. A novel SPINK5 mutation and successful subcutaneous immunoglobulin replacement therapy in a child with Netherton syndrome. 2020;37(6):1202-1204.}

^{20. Süßmuth K, Traupe H, Loser K, et al. Response to dupilumab in two children with Netherton syndrome: Improvement of pruritus and scaling. J Eur Acad Dermatol Venereol. 2021;35(2):e152-e155.}