Netherton Syndrome

Netherton syndrome (NS; OMIM #256500) is a rare autosomal recessive multisystemic disorder caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene. It is estimated to affect 1 in 200,000 newborns. SPINK5 encodes the serine protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor), which regulates the activity of KLKs (kallikrein-related peptidases). Loss-of-function mutations in SPINK5, which result in the absence or residual expression of LEKTI, promote exacerbated KLK proteolysis in tissues. More info
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The skin, hair, and immune system are particularly affected in individuals with NS. The range and severity of symptoms vary among individuals. Although it can be life-threatening in infants, symptoms usually improve with age. Flares and remissions are common. The clinical hallmark triad of NS includes red and scaly skin (erythroderma), fragile hair shafts (trichorrhexis invaginata or bamboo hair), and atopic manifestations with elevated immunoglobulin E levels. Skin lesions may later develop into either typical ichthyosis linearis circumflexa or scaly erythroderma. An impaired skin barrier can lead to hypernatremic dehydration and recurrent infections. Additionally, NS carriers may present with allergies, enteropathy, nutrient malabsorption, asthma, growth retardation, short stature, and neurological deficits.

Pathogenic mechanisms

Several organs co-express KLKs and LEKTI including those of the integumentary, respiratory, digestive, and immune systems. LEKTI and its fragments inhibit serine proteases KLKs. LEKTI deficiency in NS increases proteolysis in the skin, mainly by KLK5, KLK7, KLK14, and ELA2 (elastase 2) and is associated with excessive desquamation, inflammation, susceptibility to infection, allergy, and impaired barrier function.