Netherton syndrome (NS) is a skin disorder characterized by congenital ichthyosiform erythroderma (CIE), a distinctive hair shaft defect (trichorrhexis invaginata; TI) and atopic manifestations. Incidence is estimated at 1/200,000 births. Patients generally present at birth with generalized erythroderma and scaling, and failure to thrive. Frequent complications include hypernatremic dehydration, recurrent infections, and diarrhea and intestinal malabsorption. The disease course is heterogeneous: the generalized erythroderma may persist in some patients, but more frequently it evolves during childhood into ichthyosis linearis circumflexa (ILC). ILC is a milder and highly characteristic skin disorder marked by migratory erythematous plaques with a double-edged scale. Hair anomalies usually become apparent after infancy, with sparse and brittle hair caused by TI (bamboo hair viewed by light microscopy) and other hair shaft anomalies (pili torti and/or trichorrhexis nodosa). Eyebrows and eyelashes are also affected. The large majority of NS patients develop atopic manifestations including asthma, atopic dermatitis, food allergies, urticaria, angioedema, and elevated IgE levels. Other clinical findings are delayed growth and development, short stature, and, rarely, intermittent aminoaciduria. Intellectual deficit has been associated in some cases. NS is an autosomal recessive disorder and is caused by mutations in the SPINK5 gene (5q31-q32) encoding the serine protease inhibitor LEKTI. LEKTI deficiency results in an increase in trypsin-like hydrolytic activity in the stratum corneum (SC) leading to SC premature desquamation and a severe skin barrier defect. Early diagnosis may be problematic as the most distinctive findings (TI and ILC) do not generally become apparent until childhood. Immunohistochemistry of skin biopsies revealing LEKTI deficiency has been proposed as a useful diagnostic test for NS, but identification of the disease-causing mutation allows molecular confirmation of the diagnosis. Differential diagnoses include other infantile erythrodermas, particularly nonbullous congenital ichthyosiform erythroderma (see this term) and erythrodermic psoriasis. Atopic dermatitis, lamellar ichthyosis (see this term), primary immunodeficiency syndromes, seborrheic dermatitis, and acrodermatitis enteropathica (see this term) should also be excluded. Molecular prenatal diagnosis is feasible and genetic counseling should be proposed for affected families. Treatment is symptomatic and requires prompt management of the neonatal complications and long-term use of emollients for treatment of the skin disorder. Use of topical steroids and topical immunomodulators (tacrolimus and pimecrolimus) has been described as beneficial in some cases, but these agents are not indicated for long-term use or treatment of large surface areas as the skin barrier defect allows increased systemic drug absorption. The prognosis may be severe in neonates with life-threatening complications and postnatal lethality is high. The skin manifestations and hair anomalies persist throughout life, but the disease usually improves with age and most patients begin to thrive during the second year of life.
Last update: October 2008