Are You Confident of the Diagnosis?

Netherton syndrome is a congenital erythroderma characterized by the triad of (1) ichthyosis linearis circumflexa (ILC), a characteristic serpiginous migratory polycyclic eruption with double-edged scale; (2) trichorrhexis invaginata (TI: Figure 1)), intussusception of the distal hair shaft into the proximal portion (“ball and socket” hairshaft deformity); and (3) atopic diathesis, characterized by asthma, atopic dermatitis, allergic rhinitis, anaphylactic reactions to foods (especially nuts, eggs, and fish), elevated immunoglobulin E (IgE), and/or hypereosinophilia.

Figure 1.

Trichorrhexis invaginata. Drawing by Susan D. Anderson.

What you should be alert for in the history

Patients may present at birth to a few weeks postpartum with erythroderma, which will eventually evolve into ILC over time. ILC waxes and wanes throughout a patient’s life, often changing with seasonal climate variations, infection, or excitement. Hair shaft abnormalities do not develop until later in infancy or early childhood, can improve with age, and vary in density based on the hair location. In addition to TI, other hair shaft defects commonly reported include helical hairs, trichorrhexis nodosa, and pili torti.

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Characteristic findings on physical examination

Patients have sparse, abnormal, brittle hair, which may particularly affect the eyebrows and eyelashes. The majority of older patients will develop flexural plaques, suggestive for atopic dermatitis. All patients develop seborrheic scale and erythema of the face, eyebrows and scalp are also frequent findings. Increased transepidermal water loss inerythroderma can result in significant metabolic abnormalities and hypernatremia, especially in neonates. Failure to thrive, often accompanied by diarrhea and other signs of enteropathy, is often profound in the first year of life.

Expected results of diagnostic studies

Appropriate evaluation of patients with Netherton syndrome may include: light microscopy of hair (eyebrows and eyelashes and specimens of choice),serum IgE, complete blood count with differential (particularly noting the presence of eosinophilia), serum electrolytes, urine amino acids,skin biopsy (particularly to exclude other entities in the differential diagnosis), cultures (skin, blood, etc. as appropriate in setting of secondary infection), testing of the SPINK 5 gene mutation.

Diagnosis confirmation

Netherton syndrome should be strongly considered in the differential diagnosis of erythroderma in neonates with abnormal-appearing hair. The differential diagnosis consists of seborrheic dermatitis (papulosquamous disorder linked to malassezia, resulting in burning, scaling and itching) psoriasis (erythema with silvery scale and inflammation) metabolic conditions such as acrodermatitis enteropathica (inherited zinc deficiency, periorificial dermatitis, alopecia, diarrhea) biotinidase dificiency (intractable seizures, unexplained hearing or vision loss, failure to thrive), hyper IgE (elevated IgE, persistent skin abscesses and infections, sinus infections, atopic dermatitis, bone and tooth defects), and wiskott aldrich syndrome (x-linked recessive, atopic dermatitis with secondary infections, and thrombocytopenia).

Who is at Risk for Developing this Disease?

Netherton syndrome is a rare autosomal recessive genodermatosis. Disease prevalence is estimated to be approximately 1 in 200,000 with equal gender distribution. Netherton syndrome has been described in persons of all races. Affected infants present with erythroderma within 1-6 weeks of birth.

What is the Cause of the Disease?

The inheritance pattern of Netherton syndrome is autosomal recessive. The defect has been localized to chromosome 5q31-32 with more than 40 mutations of the SPINK 5 gene described thus far. SPINK5 encodes LEKTI (Lympho-epithelial Kazal-type related inhibitor), a serine protease inhibitor expressed in epithelial and mucosal surfaces. Abnormal LEKTI results in the phenotypic manifestations of the disease.

Systemic Implications and Complications

The prominent systemic features of Netherton syndrome are those of an atopic diathesis, characterized by asthma, atopic dermatitis, allergic rhinitis, anaphylactic reactions to foods (especially nuts, eggs, and fish), elevated IgE, and/or hypereosinophilia. Evaluation by an allergist is recommended for patients with anaphylaxis. In addition, patients are provided an EpiPen for anaphylactic food reactions.

Patients may present at birth to a few weeks postpartum with erythroderma, which will eventually evolve into ILC over time. The complications of an erythroderma, especially in the neonate are those of an increased transepidermal water loss that can result in significant metabolic abnormalities and hypernatremia. Failure to thrive, often accompanied by diarrhea and other signs of enteropathy, is often profound in the first year of life. Patients are also at risk for developing secondary infections.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Topical Systemic Physical
Topical steroids Acitretin Psoralen and ultraviolet A (PUVA)
Calcipotriol   Balneophototherapy followed by maintenance UVB monotherapy
12% lactic acid    
Salicylic acid    

Optimal Therapeutic Approach for this Disease

No single treatment has consistently shown significant efficacy in Netherton syndrome. Topical steroids effectively treat atopic disease, but provide minimal benefit for ichthyotic lesions. Chronic topical steroids should be used sparingly, as long-term use may lead to local side effects (eg, skin atrophy), as well as systemic side effects (aminioaciduria, pituitary axis suppression), the latter particular in patients with widespread erythroderma. The choice of topical steroid chosen depends on the severity of atopic disease. For example, for mild disease, hydrocortisone or desonide are recommended.

Topical tacrolimus (0.03% for children 2-15 years old and 0.1% for those over 15) appears to be efficacious for ichthyotic lesions; however, several reports have demonstrated significant tacrolimus absorption, increasing the potential for toxic side effects making Netherton Syndrome a relative contraindication to use of topical calcineurin inhibitors.

Topical vitamin D preparation, such as calcipotriol, have been shown to relieve both erythema and scale when used for limited periods of time. In addition, 12% lactic acid, emollients, and salicyclic acid may also be effective topical therapies. Systemid absorption of salicylic acid could lead to salicylism. Avoid use of salicylic acid products in infants and children with extensive skin disease.

Psoralen and ultraviolet A light has been reported to provide improvement of ichthyotic lesions, but long-term maintenance therapy is required. Other beneficial physical treatment modalities reported include balneophototherpay followed by maintenance UVB monotherapy.

Consultation with an allergist is recommended.

Patient Management

There is no cure for Netherton syndrome and lifelong treatment is required. Erythroderma and hair abnormalities persist, but may improve with age. The disease is punctuated by periodic exacerbations. Skin colonization and secondary infections are common. Maintenance therapy typically consists of use of topical steroids and treatment of secondary infections with topical or systems antibiotics as appropriate.

Patients require serial clinical observations and should undergo routine skin cancer screening. Netherton syndrome patients are at an increased risk for cutaneous neoplasms, specifically basal and squamous cell carcinomas. Any suspicious skin lesions should be reported, as they may require a biopsy. SPINK 5 gene DNA testing can aid in genetic counseling, as it is useful in prenatal diagnosis, early diagnosis, and carrier detection in unaffected family members.

Unusual Clinical Scenarios to Consider in Patient Management

Netherton syndrome is associated with a multitude of clinical abnormalities. Failure to thrive and mild growth and development delay, including short stature, are common and likely result secondary to the large energy requirement related to the rapid skin turnover, increased insensible water and heat loss through the skin, enteropathy with villous atrophy and malnutrition, or a combination of these factors. Neurological deficits including seizure disorders or spastic diplegia have also been reported. Intellectual deficiency may occur.

Netherton Syndrome patients are also at increased risk for immunological deficiences. Impared cellular and humoral immunity with selective antibody deficiencies (hypo- or hypergammaglobulinemia) to bacterial polysaccharide antigens may be present, resulting in recurrent sinopulmonary, skin, and systemic infections.

Metabolic and electrolyte abnormalities, such as transient aminoaciduria, are common and may be related to the treatment with systemic or topical steroids. Varying degrees of hypernatremia have been described, including cases resulting in seizure activity.

What is the Evidence?

Chavanas, S, Garner, C, Bodemer, C. “Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosisty maping”. Am J Hum Genet. vol. 66. 2000. pp. 914-21. (This study concludes that Netherton syndrome is linked to chromosome 5q32. Conclusions were reached through linkage analysis and studying 20 families affected by this disease. This study was the first step toward positional cloning of the netherton syndrome gene.)

Bitoun, E, Chavanas, S, Irvine, AD. “Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families”. J Invest Dermatol. vol. 118. 2002. pp. 352-61. (This paper describes the intron-exon organization of the SPINK 5 gene, which is responsible for coding the dysfunctional serine protease inhibitor implicated in netherton syndrome. No clear correlation between disease and mutations could be demonstrated.)

Sun, J, Linken, K. “Netherton syndrome: A case report and review of the literature”. Int. J Dermatol. vol. 45. 2006. pp. 693-697. (Case report of a previously undiagnosed Netherton syndrome patients who was diagnosed after enrolling in a clinical trial investigating the benefit of 0.03% tacrolimus. This patient was not able to tolerate the medication and did not receive benefit from therapy.)

Lurie, R, Garty, BZ. “Helical hairs: a new hair anomaly in a patient with Netherton's syndrome”. Cutis. vol. 55. 1995. pp. 349-52. (This report reviews “helical hair” hair disorder.)

Greene, SL, Muller, SA. “Netherton's syndrome. Report of a case and a review of the literature”. J Am Acad Dermatol. vol. 13. 1985. pp. 329-37. (This case report describes a Netherton syndrome patient who experienced transient aminioaciduria that resolved after discontinuing topical corticosteroids. This report describes how the aminoaciduria may be artifactual secondary to the effect of corticosteriods on renal tubules.)

Krasagakis, K, Ioannidou, DJ, Stephanidou, M, Manios, A, Panayiotides, JG, Tosca, AD. “Early development of multiple epithelial neoplasms in Netherton syndrome”. Dermatol. vol. 207. 2003. pp. 182-4. (This report documents an increase in aggressive epithelial neoplasms during early adulthood in Netherton syndrome patients. The underlying genetic defect may be responsible as similar findings are present in other syndromes characterized by congenital ichthyosis.)

Allen, A, Siegfried, E, Silverman, R. “Significant absoprion of topical tacrolimus in 3 patients with Netherton syndrome”. Arch Dermatol. vol. 137. 2001. pp. 747-50. (Netherton patients have a skin barrier abnormality that which puts them at risk for increased absorption of topically applied medications. Topical tacrolimus should be used with caution in Netherton patients as they are at risk for increased systemic absorption. If used, monitoring of tacrolimus is recommended.)

Smith, DL, Smith, JG, Wong, SW, deShazo, RD. “Netherton's syndrome: a syndrome of elevated IgE and characteristic skin and hair findings”. J Allergy Clin Immunol. vol. 95. 1995. pp. 116-23. (This case report documents the successful treatment of a Netherton syndrome patient with 12% ammonium lactate. The author suggests this disorder should be included with other hyper IgE conditions.)

Cernik, C, Trevino, J, Janik, M. “An unusual dermatitis with annular lesions”. Pediatr Dermatol. vol. 25. 2008. pp. 253-4. (Case report and review of the literature focusing on phenotypic features, hair abnormalities, and treatment.)