Trichorrhexis Invaginata (Netherton Syndrome or Bamboo Hair)

Updated: Dec 18, 2017
  • Author: Laura F McGevna, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Netherton Syndrome is a rare autosomal recessive genodermatosis characterized by congenital ichthyosiform erythroderma, an atopic diathesis, and a characteristic hair-shaft abnormality known as trichorrhexis invaginata. The condition begets the potential for severe complications for the affected individual, especially in the neonatal period. Chronic skin inflammation results in scaling and exfoliation, predisposing these patients to life-threatening infections, sepsis, and dehydration. Skin manifestations and associated symptoms may vary considerably among individuals with Netherton syndrome.

Historical background

In 1937, Touraine and Solente [1] first noted the association between hair-shaft defects (bamboo node) and ichthyosiform erythroderma. Còmel [2] first coined the term ichthyosis linearis circumflexa in 1949, although more than two decades earlier Rille (Fruhwald [3] ) had previously recorded the distinctive features of ichthyosis linearis circumflexa. The condition is occasionally referred to as Còmel-Netherton syndrome.

In 1958, Netherton [4] described a young girl with generalized scaly dermatitis and fragile nodular hair-shaft deformities, which he termed trichorrhexis nodosa. Later, this was more appropriately renamed as trichorrhexis invaginata (bamboo hair) for a ball-and-socket–type hair-shaft deformity at the suggestion of Wilkinson et al. [5]

In 1974, Mevorah et al [6] established the clinical relationship between ichthyosis linearis circumflexa and Netherton syndrome, and an atopic diathesis was found to occur in approximately 75% of patients with Netherton syndrome.

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Pathophysiology

The Netherton syndrome (Mendelian Inheritance in Man [MIM] #256500) is inherited as an autosomal recessive disorder due to mutations of both copies of the SPINK5 gene (localized to band 5q31-32). [7] Each SPINK5 mutation leads to a different length of LEKTI protein, resulting in genotype/phenotype correlations in cutaneous severity, susceptibility to atopic dermatitis, [8] growth retardation, skin infection, increased stratum corneum protease activities, [9, 10] and elevated kallikrein levels in the stratum corneum. [11, 12, 13]

Trichorrhexis invaginata, or bamboo hair, is a hair shaft abnormality that occurs as a result of an intermittent keratinizing defect of the hair cortex. Incomplete conversion of the sulfhydryl –SH group onto S-S disulfide bonds in the protein of the cortical fibers leads to cortical softness and subsequent invagination of the fully keratinized distal hair shaft into the softer, abnormally keratinized proximal hair shaft. Intussusception of the distal hair shaft into the proximal hair shaft results in a distinctive ball-and-socket hair shaft deformity. The affected hairs are brittle and breakage is common, resulting in short hairs.

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

Increased transepidermal water loss resulting from the disturbance of corneocyte barrier function in erythroderma may cause profound metabolic abnormalities and hypernatremia, [14, 15] particularly in neonates. [16]

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Etiology

Netherton syndrome is a rare autosomal recessive genodermatosis.

Genetics

By linkage analysis and homozygosity mapping in 20 families with Netherton syndrome, Chavanas et al [17] mapped the disease locus to 5q32, which is telomeric to the cytokine gene cluster in 5q31. The SPINK5 gene was mapped to the same region of 5q and, for functional reasons, was considered a candidate gene for Netherton syndrome. [18] Mutations in the SPINK5 gene in 13 families with Netherton syndrome were later reported. [19]

More than 40 distinct SPINK5 mutations have been reported to the Human Gene Mutation Database, with nonsense, splicing, and small insertions/deletions comprising the majority of them.

Biochemical features

Chavanas et al [19] studied steady-state levels of the mRNA encoding LEKTI (lymphoepithelial Kazal-type related inhibitor), the gene product of the SPINK5 gene, in cultured epidermal keratinocytes from a healthy control and 5 Netherton syndrome 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. [20]

SPINK5 mutations lead to truncated LEKTI, with each Netherton syndrome patient possessing LEKTI of a different length. [11] The multidomain proteinase inhibitor LEKTI consists of 15 potential serine proteinase inhibitory domains. LEKTI domain 15 was found to be identical to that of other known Kazal-type inhibitors. [21]

Bitoun et al [22] showed that in contrast to normal skin, LEKTI precursors and proteolytic fragments were not detected in differentiated primary keratinocytes from patients with Netherton syndrome. Defective expression of LEKTI in skin sections was a constant feature in affected individuals, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature.

Caspase-1 activity of the stratum corneum and serum interleukin 18 are increased in patients with Netherton syndrome. [21]

LEKTI-deficient epidermis leads to unrestricted kallikrein 5 activity, which activates a protease-induced proinflammatory and proallergic pathway: proteinase-activated receptor 2 (PAR2) – mediated expression of pro-Th2 cytokine thymic stromal lymphopoietin. [23]

Genotype/phenotype correlations

Bitoun et al [24] studied 21 families of different geographic origin and identified 18 mutations, of which 13 were novel and 7 (39%) were recurrent. Five mutations, one of which resulted in perinatal lethal disease in 3 families, were associated with certain ethnic groups. Other lethal variants have also been described. [25]

Hachem et al [26] found that serine protease activity and residual LEKTI expression determine a mild, moderate, or severe phenotype in Netherton syndrome. The degree of clinical severity is related to the magnitude of LEKTI activation. Excess LEKTI leads to loss of desmoglein 1 and desmocollin 1, which play a role in both maintaining epidermal integrity and barrier function.

Komatsu et al [27] linked LEKTI domain deficiency with clinical manifestations in Japanese Netherton syndrome patients by testing the hypothesis that the varying lengths of LEKTI (depending what mutation was found in the patient) correlated with protease inhibitory activity.

Several studies, both in vitro and in vivo, have now demonstrated that loss of LEKTI results in unopposed kallikrein-related peptidase activity and the overactivity of a relatively new epidermal proteinase, elastase 2 (ELA2). [28] Kallikrein-related peptidase 5 (KLK 5) initiates the cascade that leads to desmoglein 1 and desmosome degradation, which results in stratum corneum detachment. This begets the classic scaly skin phenotype seen in affected patients. KLK5 also activates KLK7 and ELA2, effectively altering the skin barrier and facilitating microbe penetration and activation of interleukin 1-beta. In many cases, by triggering the protease-activated receptor 2 (PAR-2), it creates a Th2 proinflammatory environment, activating cytokines such as tumor necrosis factor (TNF)alpha. [28] The Th2 environment has not been consistently demonstrated in all cases . [28] However, it is believed that a functional immune defect could contribute to the frequent infections seen in Netherton syndrome. [28]

In 2014, Wang et al generated an in vitro Netherton syndrome model using SPINK5 small interfering RNA segments (siRNA) introduced into normal epidermal keratinocytes in monolayer culture, which recapitulated some of the morphology of skin in patients with the condition. They found that knockdown of kallikreins led to improvement of epidermal architecture, showing that inhibition of serine proteases KLK5 and KLK7 could be therapeutically beneficial. [7]

Mouse model

SPINK5-/- mice exhibit features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation, and a skin barrier defect. [29] In this model, LEKTI deficiency leads to abnormal desmosome cleavage in the upper granular layer through desmoglein 1 degradation by stratum corneum tryptic enzyme and stratum corneum chymotryptic enzymelike hyperactivity.

In 2014, Furio et al created a mouse model that effectively recapitulated the phenotype of patients with Netherton syndrome, in addition to the typical immune milieu. The transgenic mice developed scaly exfoliative erythroderma with a detached stratum corneum, growth restriction, and hair abnormalities. Circulating proinflammatory cytokines, including recruitment of Th2 and Th17 cells in skin, were increased. Serum IgE and IgG were also increased. [30]

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Epidemiology

Frequency

The frequency of trichorrhexis invaginata (bamboo hair) is not known. Approximately 200 cases of trichorrhexis invaginata (bamboo hair) have been reported in the literature, but the true incidence is not known. The incidence of trichorrhexis invaginata (bamboo hair) may be as high as 1 case in 50,000 population. [31]

Race

Netherton syndrome has been described in persons of all races.

Sex

Most cases of this condition have been reported in girls. 

Age

Children affected by Netherton syndrome present with erythroderma within 1-6 weeks of birth.

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Prognosis

Erythroderma and hair abnormality persist. The disease tends to improve as patients age, but the course can be punctuated by intermittent exacerbations. The erythroderma can change to ichthyosis linearis circumflexa periodically.

Skin colonization and cutaneous infections are common. Cutaneous and systemic infections are common and disturbing consequences in almost all patients with Netherton syndrome.

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Patient Education

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