Netherton syndrome

Overview

Netherton syndrome is a rare, inherited skin disorder characterized by a triad of clinical features: congenital ichthyosiform erythroderma or scaling red skin, hair shaft abnormalities (notably trichorrhexis invaginata), and a predisposition to atopic manifestations such as eczema, asthma, food allergies, and elevated immunoglobulin E (IgE) levels. It is part of a group of conditions known as autosomal recessive congenital ichthyoses (ARCI).

The syndrome presents at birth or during infancy and typically involves severe skin barrier dysfunction, leading to increased risk of dehydration, infections, and failure to thrive. Because it affects both the skin and immune system, Netherton syndrome often requires a multidisciplinary approach for diagnosis and management.

Causes

Netherton syndrome is caused by mutations in the SPINK5 gene (serine protease inhibitor Kazal-type 5), located on chromosome 5q32. This gene encodes a protein called LEKTI (lymphoepithelial Kazal-type related inhibitor), which is responsible for regulating the activity of serine proteases involved in skin barrier formation and immune response.

When LEKTI is deficient or dysfunctional, uncontrolled protease activity leads to excessive breakdown of skin components, resulting in inflammation, scaling, and barrier dysfunction. The condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two defective copies of the SPINK5 gene (one from each parent) to develop the disorder.

Symptoms

The severity of Netherton syndrome varies among individuals, but most patients show signs within the first few weeks of life. The main clinical features affect the skin, hair, and immune system.

Dermatological Features

• Congenital erythroderma: Generalized redness and scaling of the skin at birth or soon after

• Ichthyosis linearis circumflexa: Migratory, serpiginous, red patches with double-edged scale, seen later in childhood

• Severe desquamation: Persistent skin peeling and dryness

• Pruritus: Intense itching and discomfort

• Frequent secondary infections: Due to compromised skin barrier

Hair Abnormalities

• Trichorrhexis invaginata (bamboo hair): A diagnostic hallmark; the hair shaft telescopes into itself, visible under microscopy

• Brittle, sparse hair: Particularly scalp hair, eyebrows, and eyelashes

Immunologic and Atopic Features

• Atopic dermatitis-like skin lesions

• Food allergies and gastrointestinal symptoms

• Asthma and allergic rhinitis

• Elevated serum IgE levels and eosinophilia

Other Features

• Failure to thrive in infancy

• Heat intolerance due to impaired thermoregulation

• Delayed developmental milestones in some severe cases

Diagnosis

Diagnosing Netherton syndrome involves a combination of clinical assessment, microscopic hair analysis, laboratory findings, and genetic testing. Early diagnosis is essential to manage complications and improve quality of life.

Diagnostic Steps

• Clinical examination: Identification of erythroderma, migratory plaques, and atopic symptoms

• Trichoscopy or light microscopy: Confirms trichorrhexis invaginata in hair shafts

• Serological tests: Elevated IgE levels and eosinophilia are common

• Skin biopsy: Shows non-specific features like parakeratosis and epidermal hyperplasia, but may aid in ruling out other ichthyoses

• Genetic testing: Confirms diagnosis by identifying mutations in the SPINK5 gene

Treatment

There is currently no cure for Netherton syndrome. Treatment is supportive and aims to manage symptoms, improve skin barrier function, and reduce the risk of complications. Management often requires collaboration between dermatologists, allergists, immunologists, and nutritionists.

Skin Care

• Emollients and moisturizers: Regular use to maintain skin hydration and reduce scaling

• Barrier repair creams: May include ceramides or urea-containing products

• Topical corticosteroids or calcineurin inhibitors: Used cautiously to control inflammation and eczema-like lesions

• Antibiotics: For secondary skin infections, either topical or systemic

Allergy and Immune Management

• Antihistamines: For itch control and allergic symptoms

• Food allergy management: Elimination diets based on allergy testing

• Immunomodulators: In selected cases, systemic immunosuppressants like cyclosporine may be used under specialist supervision

Other Supportive Measures

• Nutritional support: High-calorie diets and supplementation for growth and immune function

• Infection prevention: Good skin hygiene and early treatment of infections

• Psychological support: Counseling and support groups to address self-esteem and emotional health

Prognosis

The prognosis of Netherton syndrome varies depending on the severity of the disease and the effectiveness of symptom management. Many infants experience life-threatening complications such as dehydration, infections, or poor weight gain, but with proper care, survival into adulthood is possible.

Chronic symptoms often persist into adulthood, though some individuals experience improvement in skin symptoms over time. Lifelong dermatologic and immunologic monitoring is essential. Advances in genetic research may offer potential future treatments, including gene therapy or targeted biologics.

With early diagnosis and comprehensive care, many individuals with Netherton syndrome can lead improved lives despite ongoing challenges.