Netherton syndrome Q80.9

Very rare hereditary, monogenic dermatosis characterized by the combination of ichthyosis linearis circumflexa, hair shaft anomalies(bamboo hair = trichorrhexis invaginata), elevated IgE levels and immunodeficiency with failure to thrive. Optional associations include disorders of amino acid metabolism, possibly oligophrenia and cerebral seizures.

The incidence is 1:200,000; the prevalence 1:100,000; to date, about 150 patients with Netherton syndrome (Comèl-Netherton syndrome) have been described.

Autosomal recessive inheritance. Mutations of the SPINK5 gene (5q31-q32), which encodes LEKTI, a serine protease inhibitor, have been detected. LEKTI is expressed in epithelia, thymus, tonsils, parathyroid gland and trachea. It can also be detected in the stratum corneum and granulosum as well as in the skin appendages.
This protein inhibits a number of serine proteases, such as the epidermal kallikrein-related peptidases (KLKs), including the peptidases encoded by the KLK5, KLK7 and KLK14 genes (Gouin O et al. 2020), as well as plasmin, trypsin, subtilisin A, cathepsin G and elastase.
The"hyperactivity" of these proteolytic enzymes caused by a LEKTI deficiency leads to a significant disruption of the function of the epidermal barrier. This occurs via increased degradation of desmoglein 1 and increased degradation of desmosomes. The disturbed skin barrier facilitates the penetration of allergens into the skin.

Remark: The particular expression of the SPINK5 gene in the thymus leads to a defective T-cell differentiation, a consecutive unbalanced Th2 response and a strongly increased IgE (there are analogies to the hyper-IgE syndrome).

Integument: Often beginning in childhood with congenital ichthyotic erythroderma, which may regress to ichthyosis linearis circumflexa in clinically mild cases at adolescent age. In this case, large, often circular, migratory, garland-like, brown-red or red, surface-rough, scaly plaques form, fringed by a double scale. Varying degrees of severe itching in the affected skin. Lichenification of the large joints. Temporary blistering possible.

Concomitant hair shaft anomalies(bamboo hairs, trichorrhexis nodosa, pili torti), alopecia, rhagades in the corner of the mouth, and papillomas in the genital area are obligatory.

Evidence of increased activity of acid phosphatases, β-glucuronidase, transglutaminase in skin scales.

Extracutaneous manifestations: Recurrent superinfections with septicemia as a consequence of immunodeficiency are feared.

Type I sensitization to food and environmental allergens is almost obligatory.

A causal therapy does not exist. In this respect, depending on the degree of activity of the skin appearance, a symptomatic therapy is indicated.

Internal therapy (supplement):

Individual case reports indicate a good efficacy of Dupilumab in NS (Off-Label Use). The dosage corresponds to the approved dosage for atopic dermatitis (initial 600mg s.c., followed by 300mg every 14 days).

Ointments, creams or lotions containing urea/lactic acid/polidocanol as well as external agents containing ammonium lactate (e.g. Kerapil, Optiderm, rp. 102 , rp. 104 , rp. 113 ) have proven to be effective.

An application of local retinoids, e.g. Tazarotene, e.g. Zorac 0.05% or 0.1% can be tried. Their irritating potential limits the therapy.

An attempt with Tacrolimus (Protopic) is worthwhile.

Retinoids such as acitretin (neotigason) not only have a positive effect on the skin changes, but also cause a partial normalization of the hair shaft changes. Adults initially 25-30 mg/day, low maintenance dose of 5-10 mg/day p.o. Caution! Dose-dependent severe skin irritations may occur! Dose reduction is sometimes sufficient in such cases. The use of Ciclosporin A is discussed in different ways. As long-term therapy is necessary, caution is recommended.

Other systemic treatments include intravenous immunoglobulins.

Advances in understanding the pathophysiology of NS have led to more targeted therapies with biologics such as infliximab, ixekizumab, secukinumab, ustekinumab and dupilumab.

Other treatments currently under investigation include inhibitors of kallikrein 5, cathelicidins, drugs that activate thenuclear factor erythroid-derived 2-like 2 transcription factor, and gene therapy using autologous keratinocytes induced with a lentiviral vector encoding SPINK5 (Herz-Ruelas ME et al. 2021).

Note: Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), also known as Nuclear Factor Erythroid-Derived 2-Like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that preliminary research suggests may regulate the expression of antioxidant proteins that protect against oxidative damage caused by injury and inflammation. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro, leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome (Ahmed Set al. (2017).

The first description of the clinical picture wrongly named after Netherton goes back to the Italian Comèl, who reported on the clinical picture in 1949 under the name " Ichthyosis linearis circumflexa".

Netherton syndrome is caused by disturbances in the epidermal desquamation process. This is tightly regulated by the balance of the activities of serine proteases of the kallikrein-related peptidase (KLK) family and their cognate inhibitor (LEKTI), which is encoded by the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. An imbalance of proteolytic activity caused by a deficiency of LEKTI leads to excessive desquamation due to increased activities of KLK5, KLK7 and KLK14 with the clinical consequences that characterize Netherton syndrome (NS) (see type of desquamation). Increased activity of KLKs may also be pathologic in other dermatoses such as atopic dermatitis (AD). It is possible that treatment with a bispecific anti-KLK5/7 antibody could be a promising therapy for the clinical development of Netherton syndrome and other inflammatory dermatoses (Chavarria-Smith J et al. 2022).

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