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.
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.
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]
Netherton syndrome is a rare autosomal recessive genodermatosis.
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.
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]
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]
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]
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]
Netherton syndrome has been described in persons of all races.
Most cases of this condition have been reported in girls.
Children affected by Netherton syndrome present with erythroderma within 1-6 weeks of birth.
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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Most children with Netherton syndrome develop congenital erythroderma, which is evident at birth or during the first weeks of life, placing them at risk for thermal and electrolyte imbalances, dehydration, and sepsis, owing to the profoundly altered epidermal barrier.
Some children do not survive the neonatal period.
Pruritus is a near constant feature.
The erythrodermic phenotype may persist in some individuals for life, but it is more commonly replaced by the characteristic atopic appearance.
Failure to thrive may be marked in the first year of life and is often accompanied by symptoms of dermopathic enteropathy, which is a vague condition characterized by steatorrhea that occasionally accompanies erythroderma. Jejunal villous atrophy has been demonstrated in some patients with Netherton syndrome.
Delayed growth and bone development may continue until approximately the second year of life, when most children improve. However, the majority of patients remain below the 25th percentile for height (short stature) and weight secondary to malnutrition.
All patients eventually develop food allergy, particularly to peanuts, eggs, and fish. Most have an atopic predisposition, with a strong family history of asthma, eczema, and hay fever.
The origin of the term ichthyosis comes from the Greek ichthys, meaning scaly. In fact, Netherton syndrome has been classified as an ichthyosiform syndrome given the occurrence of ichthyosis linearis circumflexa. However, in most children, the most common eruption is an eczematous dermatitis, with characteristic periorificial accentuation. 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.
It is generally accepted that collodion membrane is distinct and unrelated to Netherton syndrome. In fact, one study reports that colloidal membrane never leads to Netherton syndrome.[32] However, Netherton syndrome has been described as a rare outcome of collodion baby, and the accuracy of this association is debated.
Ichthyosis linearis circumflexa is characterized by polycyclic and serpiginous migratory pink-red plaques with double-edged scale at the margins. It is a hallmark of Netherton syndrome.
Ichthyosis linearis circumflexa usually occurs after age 2 years and is fairly short-lived, lasting from a few weeks (followed by clearance for months) to years.
Ichthyosis linearis circumflexa appears to last longer in adults than in children.
Ichthyosis linearis circumflexa has been reported as an isolated cutaneous finding in the absence of documented Netherton syndrome in very rare cases,[33] largely prior to our understanding of the genetics of the condition. However, in 2015 its presence was reported in two siblings with a SPINK5 mutation, and it was the only clinical manifestation suggestive of Netherton syndrome.[34] It is likely pathognomonic of the condition.
Trichorrhexis invaginata usually develops after age 1 year.
All patients have sparse, abnormal hair. The hair is short, spiky, lusterless, and brittle. Clinically, these changes are most apparent over pressure areas such as the occipital and temporal scalp.[35]
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.
Microscopic evaluation of clinically normal-appearing hairs may reveal defects. Identifying the bamboo node on the hair shaft using simple microscopy is necessary because unaided visual detection is practically impossible. Dermatoscopic evaluation can aid in detection.[36] Goujon et al described three characteristic dermatoscopic changes, including bamboo hairs, golf-tee hairs, and matchstick hairs, which are short hair shafts with bulging tips, thought to be due to breakage of bamboo hairs.[37]
The relationship with trauma to the severity of hair-shaft defects is probably overemphasized.
The severity is likely defined by the gene penetrance and tends to improve with age, but the course can be punctuated by intermittent exacerbations.
Pili torti is common.
Trichorrhexis nodosa may also occur, but it is not specific for this condition.
Findings include atopic dermatitis, allergic rhinitis, and asthma.
The following complications are recognized:
Some patients affected by Netherton syndrome have shown cognitive impairment and developmental delay. Impaired cellular immunity may also be a feature of this condition. The development of aminoaciduria has been described.[38]
Rare complications have also been described, including intracranial hemorrhage, hypothyroidism, rickets, pulmonary hypertension, renal vein thrombosis, and acute pancreatitis.[28, 39, 40, 41, 42, 43]
It remains unclear whether patients have an increased susceptibility for skin malignancies such as squamous cell carcinoma.[44] However, the development of squamous cell carcinomas has been reported in at least six patients, including in the vulva and on the penis.[45]
At least one case of dilated cardiomyopathy in a patient with Netherton syndrome, ultimately requiring cardiac transplantation, has been described in the literature. In the setting of resulting immune suppression, the patient went on to develop CD 30+ primary cutaneous T-cell lymphoproliferative disorder.[46]
Serum immunoglobulin E (IgE) levels can be increased, sometimes exceeding 10,000 IU/mL.[28]
Specific IgE antibodies to environmental and food allergens can be detected.
Hypereosinophilia can be present.
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).
Examine eyebrows or eyelashes for trichorrhexis invaginata, which appears as bamboo nodes when seen under the light microscope.
Trichorrhexis invaginata 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. This finding is described as a “golf tee” and is characteristic.[50]
Trichorrhexis invaginata may be limited to just a few hairs. Eyebrows and eyelashes may develop trichorrhexis invaginata earlier, and the eyebrows may be the sole site of involvement; therefore, they should be the specimen of choice.[35, 51, 52] Obtain the hair specimen by clipping, because plucking fractures the hair shaft at the node, rendering microscopy difficult.
All patients have other hair-shaft defects (eg, pili torti, weathering).
Electron microscopy shows trichorrhexis invaginata in 10-30% of clipped hair after age 2 years.
The hair fractures at the invaginated node, which is the weakest point in the hair shaft. Electron microscopy 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.
Ultrastructural studies have shown a reduced number of tonofilament-keratohyaline structures, desmosomes, and distorted lamellar bodies. The stratum corneum may lose its lamellar structure.[53, 54, 55]
DNA testing of the SPINK5 gene makes several options possible, including prenatal diagnosis, early diagnosis via postnatal testing, and carrier detection in unaffected family members. Mutations can be identified in two thirds to three quarters of patients with clinically suspected Netherton syndrome. Genetic testing can aid in genetic counseling. Testing is available through the following organizations[56] :
The histologic features of Netherton syndrome 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 features. Hyperkeratosis is mild in comparison with other ichthyoses. Parakeratosis and an absent granular layer may occur at the spreading edge in ichthyosis linearis circumflexa. A mixed inflammatory cell infiltrate is seen in a perivascular distribution. Arico et al[57] 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. Eosinophilic material (probably a glycoprotein) may accumulate within the granular or parakeratotic horny layer in ichthyosis linearis circumflexa lesions.
Similar to 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.
Management is conservative. Emollients, keratolytics, and antibiotics are the mainstay of treatment in Netherton syndrome. White, soft paraffin and liquid paraffin in a ratio of 50:50 have been used as a topical treatment.
Management essentially relies on the treatment of cutaneous infections and other complications.
Topical steroids of moderate potency may be helpful, but reports have described complications such as aminoaciduria and pituitary adrenal axis suppression, especially in patients with widespread erythroderma, and thus should be used with caution.
In one case, split body treatment with 12% lactic acid lotion surprisingly cleared the eruption on the treated side (control side emollient).[58]
Although topical tacrolimus or pimecrolimus was previously discouraged in the treatment of Netherton syndrome due to toxicity from absorption of the medication,[59] newer evidence suggests that pimecrolimus 1% cream applied twice daily may be well tolerated and lead to improvement of skin involvement, with low, safe levels absorbed systemically.[60] Further, larger studies are necessary to elucidate the safety and efficacy of pimecrolimus in Netherton syndrome patients.[60]
Psoralen plus ultraviolet light A (PUVA) and narrowband ultraviolet light B (NBUVB) have been shown to be beneficial in some case reports,[61, 62, 63] though patients treated with these modalities need to be monitored for the development of skin malignancy.[64]
Retinoids are generally not helpful,[65] although a few reports of improvement with a low dose have been published.[66, 67]
Infliximab was found to lead to sustained clinical improvement and clearance of ichthyosis linearis circumflexa in one study.[68]
The potential of treating Netherton syndrome patients with gene therapy[69, 70] and epidermal stem cell therapy[71] is currently being investigated.
A patient allergic to antibiotics showed significant improvement after treatment with several antistaphylococcal bacteriophage preparations.[72]
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.
Consider consultation for pelvic examination for men and women with this condition.
Trichorrhexis invaginata and ichthyosis linearis circumflexa usually develop after age 2 years, but hair should be examined every 6 months because it rarely may occur earlier.