AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis of unknown cause characterized by the following: erythroderma, trichorrhexis invaginata (TI) (bamboo hair), ichthyosis linearis circumflexa (ILC), atopic diathesis, and failure to thrive.

Touraine and Solente first noted the association between hair-shaft defects (bamboo node) and ichthyosiform erythroderma in 1937. C̣mel first coined the term ichthyosis linearis circumflexa in 1949 to describe a rash in a young Italian woman without referring to the hair-shaft defects; however, Rille (Frühwald) had previously recorded the distinctive features of ILC by 1922.

In 1958, Netherton described a young girl with generalized scaly dermatitis and fragile nodular hair-shaft deformities that he termed trichorrhexis nodosa (bamboo hair). Later, this was more appropriately renamed as trichorrhexis invaginata for a ball-and-socket–type hair-shaft deformity at the suggestion of Wilkinson et al.

In 1974, Mevorah et al established the clinical/statistical relationship between ILC and NS. All cases of ILC in which the hair changes have been carefully sought have been found to show them. The atopic diathesis occurs in approximately 75% of patients with NS. Hurwitz et al questioned the variability of NS and postulated that it is not a single entity but a heterogenous one.

Pathophysiology

The etiology so far is unknown. The condition is inherited as an autosomal recessive gene with variable expressivity. Ali et al reported a familial occurrence in 2 Asian families with consanguineous marriages. In the first family, a girl and her younger brother were affected. The girl (age 10 mo) died from infections and metabolic acidosis. Postmortem examination showed almost complete absence of lymphoid tissue. In the second family, both boys were affected.

Bamboo node or TI is a ball-and-socket hair-shaft deformity caused by invagination of the distal hair shaft into the cup formed by the proximal hair shaft. This invagination occurs at the site of an intermittent keratinizing defect of the hair cortex resulting from incomplete conversion of the sulfhydryl –SH group onto S-S disulfide bonds in the protein of the cortical fibers. This defect leads to cortical softness, bulging, and the bamboo deformity.

Migratory lesions of ILC may be caused by a dermal influx of inflammatory cells that undergo phagocytosis and digestion by keratinocytes, resulting in disruption of keratinization.

Like other severe congenital dermatoses, inflammatory changes are common in skin biopsy samples, but whether they are a primary or a secondary phenomenon is not known. Focal disruption of the epidermis and abnormalities of hair-shaft maturation are seen at histopathologic examination. Increased transepidermal water loss resulting from the disturbance of corneocyte barrier function in erythroderma may cause profound metabolic abnormalities and hypernatremia, particularly in neonates.

Histologically, lesions may resemble atopic dermatitis with spongiosis and exocytosis. In one histochemical study, Arico et al reported increased numbers of CD1 cells similar to atopic dermatitis but also showed raised CD8 positivity rather than CD4 positivity in the dermis, unlike atopic dermatitis. Judge et al reported that atopic manifestations are characteristic and universal. All patients have high immunoglobulin E (IgE) levels, sometimes raised beyond the laboratory reference range.

Retinoid therapy almost always adversely affects patients with NS. A parallel has been described in transgenic mice with negative retinoic acid receptors. These mice also develop erythroderma and impaired skin barrier function. NS has been attributed to impaired transcription of relevant retinoic acid receptor genes affecting differentiation.

Other minor and inconsistent immunologic abnormalities have been reported; these abnormalities include transient neutrophil function defects, impaired cellular and immune responses, and raised complement levels (C3 and C4).

The NS gene has recently been localized to band 5q32 by linkage analysis and homozygosity mapping. This finding is a significant breakthrough because a definitive diagnosis of NS has always been a problem in the first years of life.

Frequency

United States

The frequency is not known.

International

Same as that in the United States.

Mortality/Morbidity

Cutaneous and systemic infections are common and disturbing consequences in almost all patients with NS (see Complications).

Race

The condition is described in all races.

Sex

Girls are affected more often than boys.

Age

Children who are affected present with erythroderma within 1-6 weeks of birth.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Erythroderma
• • Children with NS develop congenital erythroderma, which is evident at birth or during the first weeks of life. It may not be pronounced in some neonates who are affected.
  • Pruritus is universal and can be distressing.
  • NS has been classified as an ichthyosiform syndrome, but, in most children, the rash appears to be an eczematous/seborrheic dermatitis, with a characteristic periorificial accentuation of the rash.
  • Collodial membrane has not been reported in patients with NS. In one study, flexural lichenification was found in all 7 patients, and 2 patients had verrucous hypertrophy of the axillae, the inguinal folds, and the lower legs. Ectropion and taut facial skin can develop in older patients with severe disease.
• Ichthyosis linearis circumflexa
• • ILC is a characteristic serpiginous migratory annular/polycyclic rash with double-edged scale. It is pathognomonic for NS.
  • It usually occurs after age 2 years and is fairly short-lived, lasting from a few weeks (followed by clearance for months) to years.
  • ILC appears to last longer in adults than in children.
• Failure to thrive
• • Failure to thrive is often profound in the first year of life. This condition is accompanied by diarrhea and symptoms of malabsorption. Jejunal villous atrophy that spontaneously resolved at age 10 months has been reported in 1 patient with NS. In another French study, 3 out of 5 children had jejunal villous atrophy.
  • This malabsorption is essentially dermopathic enteropathy, which is a recognized problem with congenital and some acquired erythrodermas. It is not specific to NS.
  • By the second year of life, most children start to thrive, though most remain below the 25th percentile for height and weight.
• Allergic manifestations
• • All patients at some stage in their disease develop allergy to foodstuffs, especially nuts.
  • Most have an atopic predisposition, with a strong family history of asthma, eczema, and hay fever.

Physical

• Hair features (TI)
• • All patients have sparse, abnormal hair. The hair is short, spiky, lusterless, and brittle.
  • Scalp hair grows for a few centimeters before breaking. This finding is particularly evident at the areas of friction, especially the occiput and the temples. The eyebrows also have sparse, broken hair. Older patients may lose their eyebrows and eyelashes altogether.
  • Some patients also show fragility of the reduced body hair.
  • A few older children have normal-looking hair that is microscopically defective. Identifying the bamboo node on the hair shaft by unaided visual inspection is practically impossible.
  • The relationship of trauma to the severity of hair-shaft defects is probably overemphasized.
  • In the authors' experience, the severity is defined by the gene penetrance. Having said that, the disease tends to improve with age, but the course can be punctuated by intermittent exacerbations.
• Atopic diathesis
• Failure to thrive (see History)

Causes

The condition is a rare autosomal recessive genodermatosis.

• Mapping
• • The candidate gene has now been mapped by linkage analysis and homozygosity mapping to band 5q32.
  • By linkage analysis and homozygosity mapping in 20 families with Netherton syndrome, Chavanas et al (2000) mapped the disease locus to 5q32. The NETH locus is telomeric to the cytokine gene cluster in 5q31. Five known genes and 38 expressed sequence tags mapped within the critical region, but the authors concluded that these were not obvious candidates. Magert et al (1999) mapped the SPINK5 gene to the same region of 5q, thus making it a candidate gene for NS. Functional reasons caused the researchers to suspect that this gene might be involved in NS.
• Biochemical features
• • Chavanas et al (2000) studied steady-state levels of the mRNA encoding LEKTI, the gene product of the SPINK5 gene, in cultured epidermal keratinocytes from a healthy control and 5 NS patients. These extracts showed a marked reduction of signal on Northern blot analysis, suggesting nonsense-mediated decay of mutated transcripts, as is frequently observed in recessive disorders (Culbertson, 1999).
  • Bitoun et al (2003) showed that in contrast to normal skin, LEKTI precursors and proteolytic fragments were not detected in differentiated primary keratinocytes from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS.
• Molecular genetics
• • Identification of the NS gene will permit early DNA-based diagnosis; heretofore, a definite early diagnosis within the first 2 years of life has been almost impossible.
  • Chavanas et al (2000) detected 11 different mutations in 13 families in the SPINK5 gene, at least 9 of which generated premature termination codons of translation and predicted mRNA instability.
• Genotype/phenotype correlations
• • Bitoun et al (2001) studied 21 families of different geographic origin and identified 18 mutations, of which 13 were novel and 7 (39%) were recurrent. Five mutations, 1 of which resulted in perinatal lethal disease in 3 families, were associated with certain ethnic groups.
  • No clear correlation between disease and phenotype was seen, suggesting that the degree of severity may be influenced by other factors.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Erythroderma in a newborn can be misdiagnosed as nonbullous congenital ichthyosiform erythroderma (NBCIE), generalized seborrheic dermatitis, acrodermatitis enteropathica, or erythrokeratoderma variabilis. Most of these children's conditions are misdiagnosed as Leiner disease, which is a descriptive term for congenital erythroderma, failure to thrive, and diarrhea, and not a specific disease entity.

NS should be at the top of the differential diagnosis list in a newborn with erythroderma and abnormal-looking scalp hair.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Light microscopy of the hair
• • Examine eyebrows or eyelashes for TI. Lesions of TI appear as bamboo nodes when seen under the light microscope.
  • TI is the focal cup-and-ball hair-shaft deformity with the invagination of the distal hair shaft (ball) into the expanded proximal hair shaft (cup) seen on scanning.
  • The authors have noted that eyebrows and eyelashes may develop TI (bamboo nodes) earlier; therefore, they should be the specimen of choice. Obtain the hair specimen by clipping because plucking fractures the hair shaft at the node, rendering microscopy difficult.
• Scanning electron microscopy
• • Electron microscopy (EM) shows TI in 10-30% of clipped hair after age 2 years.
  • The hair fractures at the invaginate node, which is the weakest point in the hair shaft. EM can be used to identify these proximal halves of invaginate nodes, which show a cuplike appearance from which the ball of the distal hair has fallen out.
• DNA studies for SPINK5 mutations/abnormalities may be performed.
• The descriptive term golf tee hair describes the cup of the fractured proximal hair shaft that looks like a golf tee. This feature is characteristic and as pathognomonic as the entire node.
• TI and ILC usually develop after age 2 years, but hair should be examined every 6 months because it rarely may occur earlier.
• Ultrastructural studies have shown a reduced number of tonofilament-keratohyaline structures, desmosomes, and distorted lamellar bodies. The stratum corneum may lose its lamellar structure.
• All patients have other hair-shaft defects (eg, pili torti [twisted hair], weathering).

Other Tests

• DNA studies may be performed.

Procedures

• Skin biopsy of the skin abnormality may be performed.

Histologic Findings

The histologic features are not diagnostic and vary according to the type of the lesion and when the biopsy sample was obtained. Features of nonspecific dermatitis and psoriasiform hyperplasia are the most common histologic appearances. Hyperkeratosis is mild in comparison with other ichthyoses. Parakeratosis and an absent granular layer may occur at the spreading edge. A mixed inflammatory cell infiltrate is seen in a perivascular distribution. Eosinophilic material (probably a glycoprotein) may accumulate within the granular or parakeratotic horny layer in ILC lesions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Emollients, keratolytics, and antibiotics remain the mainstays of treatment.

• Management essentially relies on the treatment of cutaneous infections and other complications.
• Topical steroids are helpful, but reports exist of complications with aminoaciduria and pituitary adrenal axis suppression.
• With rare exceptions, treatment is not helpful.
• • In one case, split body treatment with 12% lactic acid lotion surprisingly cleared the eruption on the treated side (control side emollient).
  • One Japanese woman's condition has been reported to respond to psoralen plus ultraviolet light A (PUVA).
  • Retinoids are not helpful, though 1 report of improvement with a low dose has been published.
• Although topical tacrolimus is useful in the treatment of atopic dermatitis, it is absorbed such that toxicity may result when used in children with NS.

Consultations

• Consult a pediatrician for systemic infections, hypernatremic dehydration, and failure to thrive.
• Consult a gastroenterologist for failure to thrive, diarrhea, and villous atrophy of the small bowel.
• Consult a geneticist for genetic studies and counseling.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Management is conservative. Emollients are the mainstay of treatment in NS. White, soft paraffin and liquid paraffin in a ratio of 50:50 have been used as a topical treatment.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties but may cause varied metabolic effects. They modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care is needed early in life when erythroderma is generalized and complicated with cutaneous infections and other infections.
• Patients may need admission to an inpatient ward for severe angioedema.

Further Outpatient Care

• Regular outpatient appointments are necessary to monitor the following:
• • Failure to thrive
  • Atopic manifestations
  • Allergies
  • Erythroderma and ILC

In/Out Patient Meds

• Moisturizers are the mainstay of treatment.
• • Moderate-potency topical steroids can be helpful.
  • Use caution in widespread erythroderma because significant absorption of the topical steroid with pituitary/adrenal suppression may occur.
  • The inflammatory dermatitis seems like it should respond to tacrolimus ointment, but it is absorbed to a degree that may be dangerous; therefore, if it is recognized that the patient has NS, then this modality should be avoided.

Complications

• Cutaneous and systemic infections may occur.
• Failure to thrive and diarrhea may also occur.
• Complications of generalized erythroderma (eg, inability to regulate body temperature) may occur. Neonates in particular are prone to develop complications of erythroderma, with temperature instability and cutaneous and systemic infections.
• Hypernatremic dehydration may occur as the skin barrier function is lost in erythroderma. It has been reported in a few patients.

Prognosis

• Erythroderma and hair abnormality persist. The disease tends to improve with age, but the course can be punctuated by intermittent exacerbations.
• The erythroderma can change to ILC periodically.
• Skin colonization and cutaneous infections may commonly occur.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Delay in diagnosis results from the fact that the characteristic changes of NS (ie, TI, ILC) usually do not occur before the age of 2 years. With a low index of suspicion, the conditions can be misdiagnosed as NBCIE, atopic dermatitis, or Leiner disease. In fact, Altman and Stroud reported in 1969 that most cases described as NBCIE were in fact ILC.
• NS may be misdiagnosed. The pathognomonic changes of bamboo hair (TI) or the characteristic ILC do not usually manifest before the age of 2 years. Common misdiagnoses include Leiner disease, nonbullous ichthyosiform erythroderma, severe seborrheic dermatitis, and atopic dermatitis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Stoll C, Alembik Y, Tchomakov D, et al. Severe hypernatremic dehydration in an infant with Netherton syndrome. Genet Couns. 2001;12(3):237-43. [Medline].
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Article Last Updated: May 25, 2006