Netherton Syndrome — SCE Dermatology MCQ

Correct answer: C — SPINK5, encoding the serine-protease inhibitor LEKTI

The correct answer is C, SPINK5 (encoding LEKTI, lympho-epithelial Kazal-type inhibitor). Netherton syndrome is an autosomal recessive disorder caused by loss-of-function mutations in SPINK5, which normally produces LEKTI, a serine protease inhibitor that restrains kallikrein-mediated proteolysis in the epidermis and hair follicle. Absent or reduced LEKTI causes unchecked desquamation, a defective skin barrier, and unregulated allergen penetration, producing the classic triad of ichthyosiform erythroderma (often with ichthyosis linearis circumflexa), trichorrhexis invaginata (bamboo hair, with ball-and-socket nodes on the hair shaft), and marked atopic diathesis with very high IgE. This gene-protein-phenotype link is the discriminating feature that separates Netherton syndrome from the other cornification disorders listed. Why the other options are wrong: E. TGM1: encodes transglutaminase 1 and is mutated in autosomal recessive congenital ichthyosis (lamellar ichthyosis), which causes collodion baby and plate-like scale but not bamboo hair or the atopic triad. A. KRT1: keratin 1 mutations cause epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma), characterised by blistering and hyperkeratosis, not hair shaft abnormalities or LEKTI deficiency. D. KRT10: also causes epidermolytic ichthyosis; it pairs with KRT1 in suprabasal keratinocytes and gives the same blistering phenotype, unrelated to trichorrhexis invaginata. B. FLG: filaggrin loss-of-function mutations are the classic cause of ichthyosis vulgaris and a major risk factor for atopic dermatitis, but they do not cause the specific hair shaft defect or the severe erythrodermic, immunodeficiency-prone phenotype of Netherton syndrome. Key point: Bamboo hair (trichorrhexis invaginata) plus congenital erythroderma plus severe atopy points to SPINK5/LEKTI deficiency, not the keratin or filaggrin disorders.

Reference: DermNet Netherton syndrome review: https://dermnetnz.org/topics/netherton-syndrome