Netherton Syndrome

A number sign (#) is used with this entry because of evidence that Netherton syndrome (NETH) is caused by homozygous or compound heterozygous mutation in the SPINK5 gene (605010), encoding the serine protease inhibitor LEKTI, on chromosome 5q32.

Description

Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).

Clinical Features

The features of this disorder, which was first reported by Netherton (1958), are 'bamboo hair' (trichorrhexis nodosa, or, because of the nodes, invaginata), congenital ichthyosiform erythroderma, and atopic diathesis. It has been observed almost only in females. The parents of the patient reported by Wilkinson et al. (1964) were third cousins. The authors suggested that the disorder is an autosomal recessive inborn error of metabolism. Their patient also had hypogammaglobulinemia.

Stankler and Cochrane (1967) described affected sisters of Italian extraction. Porter and Starke (1968) reported an affected male. Several males in the family, including the proband, had histologically typical X-linked ichthyosis and the relationship of these males was consistent with X-linkage. Stevanovic (1969) reported 2 cases, and Julius and Keeran (1971) described another. Altman and Stroud (1969) suggested that Netherton disease and ichthyosis linearis circumflexa are manifestations of the same entity. The term psoriasiform ichthyosis was proposed by them for including both diseases under the same denominator based on the report of 7 cases with both disorders.

Smith et al. (1995) reviewed 43 previously reported patients and described a 'new' case in a male. They listed the features as greatly elevated IgE levels with atopic manifestations, an ichthyotic skin condition (ichthyosis linearis circumflexa and/or congenital lamellar ichthyosis), and trichorrhexis invaginata. The disorder may be confused with atopic dermatitis but does not respond to topical corticosteroid treatment. Smith et al. (1995) described successful treatment in their patient with 12% ammonium lactate lotion and management of his allergic disease. The patient was born of nonconsanguineous parents and had a generalized erythematous rash at birth. Smith et al. (1995) noted that 20 of the 44 patients were male.

Fartasch et al. (1999) noted that the infant with Netherton syndrome typically displays a generalized erythroderma covered by fine, translucent scales, which can be difficult to distinguish clinically from erythrodermic psoriasis, nonbullous congenital ichthyosiform erythroderma, or other infantile erythrodermas. Some infants with Netherton syndrome develop progressive hypernatremic dehydration, failure to thrive, and enteropathy. These complications can be fatal. Typically, diagnosis is delayed until the appearance of a pathognomonic hair shaft anomaly, trichorrhexis invaginata (bamboo hair). To facilitate the early diagnosis of Netherton syndrome, Fartasch et al. (1999) obtained biopsy specimens from 7 patients with erythrodermic Netherton syndrome and compared their morphologic findings to those of 3 patients with erythrodermic psoriasis and 2 with congenital ichthyosiform erythroderma. In Netherton syndrome, and often in the other 2 conditions, the stratum corneum layer was largely replaced by parakeratotic cells. A distinctive feature occurred only in Netherton syndrome: premature secretion of lamellar body contents. Furthermore, lamellar body-derived extracellular lamellae and stratum corneum lipid membranes were separated extensively by foci of electron-dense material. Finally, transformation of the lamellar body-derived lamellae into mature lamellar membrane structures was disturbed in the Netherton syndrome. These ultrastructural features could permit the early diagnosis of NS before the appearance of the hair shaft abnormality. These abnormalities could explain the impaired permeability barrier in NS, and account for hypernatremia and dehydration in infants with NS.

Folster-Holst et al. (1999) described a 28-year-old woman with characteristic clinical signs of Netherton syndrome in which human papillomaviruses were identified in papillomatous skin lesions and plane warts. They suggested that the viruses played a cofactor pathogenic role in the development of the verrucous skin lesions in patients with this disorder. A female sib had died due to widespread congenital erythroderma at the age of 6 weeks. The proband showed severe ichthyotic erythroderma at birth and subsequently developed alopecia involving the scalp, eyelashes, and eyebrows. Marked growth retardation was noted at the age of 2 years. Papillomatous skin lesions developed in the groin at the age of 15 years.

Stoll et al. (2001) described an infant who succumbed to hypernatremic dehydration, a major neonatal complication of Netherton syndrome. The child died at 11 days of age. The patient was found to be homozygous for a nonsense mutation in exon 3 of the SPINK5 gene. Prenatal diagnosis by chorionic villus sampling of a second pregnancy revealed the same mutation. Because the conceptus was homozygous for the mutation, the parents requested termination of pregnancy.

Renner et al. (2009) studied 9 unrelated children from diverse ethnic backgrounds with Comel-Netherton syndrome. All of the children exhibited the classic triad of congenital ichthyosis, bamboo hair, and allergic diathesis, except for 1 patient who lacked bamboo hair. Recurrent or persistent lesion-associated Staphylococcus aureus skin infections occurred in 8 patients, some of whom developed S. aureus-related sepsis. Recurrent upper and lower respiratory tract infections were present in 8 patients, along with recurrent otitis media and/or externa. Overall, S. aureus was the most frequent infectious agent, followed by Pseudomonas aeruginosa and Klebsiella oxytoca. The majority of patients had recurrent acute gastroenteritis associated with failure to thrive and hypernatremic dehydration, requiring repeated hospitalizations. Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed Th1 phenotype and elevated proinflammatory cytokine levels, whereas serum concentrations of the chemokine (C-C motif) ligand-5 (CCL5; 187011) and natural killer cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin (IVIG) resulted in remarkable clinical improvement and temporarily increased natural killer cell cytotoxicity. Renner et al. (2009) concluded that the immunopathology of Comel-Netherton syndrome is characterized by cognate and innate immunodeficiency that responds favorably to IVIG. :

Smigiel et al. (2017) reported an 8-month-old Polish boy with Netherton syndrome, who from birth had generalized erythroderma covered by fine translucent scales all over the body and scalp. Eyebrows and eyelashes were thin and sparse, and he was hypotonic. He had recurrent episodes of hypernatremic dehydration. Skin infections caused by S. aureus and P. aeruginosa were followed by sepsis, meningitis, and respiratory failure requiring ventilatory assistance, as well as chronic diarrhea. Immunologic examination showed a decreased concentration of IgG and C3 components. Echocardiography revealed tricuspid and pulmonary valve insufficiency as well as conduction abnormalities on electrocardiography. At age 7 months, he was diagnosed with bilateral hypoacusis, and at 8 months showed psychomotor developmental delay. The proband's mother reported that she had absence of scalp hair, eyebrows, and eyelashes from early childhood, and also lacked axillary and pubic hair. Her skin was observed to be smooth with no keratinizing changes.

Nevet et al. (2017) reported a Muslim Arab female infant with Netherton syndrome, who at the age of 2 days underwent partial resection of the small intestine for 'apple peel' intestinal atresia. By age 9 months, she had severe failure to thrive and had been repeatedly hospitalized for pulmonary and intestinal infections complicated by sepsis, as well as hypernatremia, hypothermia, osteopenia, and fractures. Skin biopsy showed psoriasiform epidermal hyperplasia and parakeratosis, and immunohistochemistry confirmed the absence of LEKTI in the involved epidermis. The proband died of sepsis at 11 months of age.

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 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 (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 Netherton syndrome patients. Defective expression of LEKTI in skin sections was a constant feature in Netherton syndrome patients, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of Netherton syndrome.

Pathogenesis

Sarri et al. (2017) reviewed published reports of 172 patients from 144 families with Netherton syndrome. They noted that the identified SPINK5 loss-of-function mutations cause epidermal protease hyperactivity, resulting in detachment of stratum corneum, skin barrier defect, and overdesquamation. In addition, upregulation of kallikrein-5 (KLK5; 605643) induces skin inflammation and allergy. They suggested that the consistently observed failure to thrive and/or growth retardation might be explained by dysregulation of human growth hormone (hGH; see 139250) through increased kallikrein activity and hGH proteolysis.

Inheritance

In a review of 44 cases of Netherton syndrome, Smith et al. (1995) found at least 6 reports of affected sibs and 2 reports of parental consanguinity, suggesting autosomal recessive inheritance.

Mapping

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 as well as 38 ESTs mapped within the critical region, but the authors concluded that these were not obvious candidates. Magert et al. (1999) mapped the SPINK5 gene (605010) to the same region of 5q, thus making it a candidate gene for Netherton syndrome. There were functional reasons to suspect that this gene might be involved in Netherton syndrome.

Molecular Genetics

Among 13 families segregating Netherton syndrome, Chavanas et al. (2000) detected 11 different mutations in the SPINK5 gene (see, e.g., 605010.0001-605010.0003), at least 9 of which generated premature termination codons and predicted mRNA instability.

Renner et al. (2009) sequenced the SPINK5 gene in 9 unrelated children from diverse ethnic backgrounds with Comel-Netherton syndrome and identified biallelic mutations in 8 patients (see, e.g., 605010.0005 and 605010.0006); in 1 patient, only 1 mutation was detected, and in another patient, no mutations were found. However, in all 9 patients, LEKTI protein expression was absent or present as small immunoreactive foci in fewer than 2% of epithelial cells from skin biopsies and/or buccal mucosa.

In an 8-month-old Polish boy with Netherton syndrome, Smigiel et al. (2017) identified compound heterozygosity for mutations in the SPINK5 gene (605010.0005 and 605010.0007). His mother, who had alopecia from early childhood but no skin changes, was heterozygous for 1 of the mutations; DNA was unavailable from the father.

In an 8-year-old girl with Netherton syndrome, who had previously been diagnosed with atopic dermatitis or psoriasis and exhibited dry skin with facial scaling erythema, flexural lichenification, and erythematous serpiginous skin lesions on the trunk and lower limbs, as well as bamboo hair, Shi et al. (2017) identified homozygosity for a SPINK5 missense mutation (T808I). The girl was also found to be heterozygous for a nonsense mutation (E2422X) in the filaggrin gene (FLG; 135940); no mutations were found in 10 other ichthyosis-associated genes. Her parents were both heterozygous for the SPINK5 mutation, and the FLG mutation was inherited from her mother, who reported mild skin dryness in the winter. The authors suggested that mutations in additional genes such as FLG might contribute to the pathogenesis of Netherton syndrome or modify its phenotype.

In a Muslim Arab girl with Netherton syndrome and intestinal atresia, who died of sepsis at 11 months of age, Nevet et al. (2017) identified homozygosity for a 1-bp deletion in the SPINK5 gene (605010.0008). Her unaffected parents were heterozygous for the mutation.

Genotype/Phenotype Correlations

Bitoun et al. (2002) studied 21 families of different geographic origin segregating Netherton syndrome 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.

Sarri et al. (2017) reviewed published reports of 172 patients from 144 families with Netherton syndrome, who were homozygous or compound heterozygous for 80 different mutations in the SPINK5 gene. Mutations located more upstream in LEKTI correlated with more severe phenotypes than similar mutations located towards the 3-prime region. The authors noted that no variants had been reported downstream of exon 27, suggesting that such changes may remain undetected because they do not have a dramatic effect on LEKTI function. The authors commented that the quality of health care systems in patients' countries may affect whether outcomes are lethal or not, citing several instances in which patients with the same mutations had disparate outcomes. Sarri et al. (2017) stated that if patients survive their first year of life, they will likely achieve milder disease severity or even partial recovery, noting that no deaths had been recorded in patients older than 9 months of age.

Animal Model

Hewett et al. (2005) created mice with an R820X mutation in the Spink5 gene. Newborn homozygotes developed a severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours. Biochemical analysis of skin revealed a substantial increase in the proteolytic processing of profilaggrin (FLG; 135940) into its constituent filaggrin monomers. Hewett et al. (2005) suggested that in the absence of SPINK5 there is an abnormal increase in the processing of profilaggrin, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.

In a Spink5 -/- mouse model, Sales et al. (2010) demonstrated that the membrane protease matriptase (606797) initiated Netherton syndrome by premature activation of a pro-kallikrein (see 147910) cascade. Autoactivation of proinflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from Spink5 -/- mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis.

Furio et al. (2014) generated a transgenic mouse model expressing human KLK5 (605643), a protease that is overactive in Netherton syndrome, in the granular layer of the epidermis. Transgenic mice had increased proteolytic activity attributable to KLK5 and its downstream targets Klk7 (604438), Klk14 (606135), and Ela2 (ELANE; 130130). The transgenic mice developed exfoliative erythroderma with scaling, growth delay, and hair abnormalities, as well as defective skin barrier and a detached stratum corneum due to desmosomal cleavage. The mice also displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. Levels of Ccl8 (602283) and Ccl20 (601960), as well as of cytokines associated with inflammation and with recruitment of Th2 and Th17 cells in skin, were increased. Serum IgE and IgG, particularly IgG1, were also increased. Furio et al. (2014) concluded that the transgenic KLK5 model recapitulates the major cutaneous and systemic features of Netherton syndrome and proposed that KLK5 may be a promising treatment target.