Netherton syndrome

INTRODUCTION — Netherton syndrome ([NS] Comel-Netherton; MIM #256500) is a rare autosomal recessive disorder of cornification characterized by the classic triad of congenital ichthyosiform erythroderma, a specific hair shaft abnormality termed trichorrhexis invaginata ("bamboo hair"), and an atopic diathesis [1].

NS is one of the most severe disorders of cornification. Infants typically present at birth with a generalized scaling erythroderma and have a high risk of life-threatening complications, such as hypernatremic dehydration, failure to thrive, and sepsis. In older children, a wide range of allergic manifestations may occur, including severe atopic dermatitis, asthma, hay fever, and markedly elevated serum levels of immunoglobulin E (IgE).

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of NS. Other disorders of cornification and disorders characterized by peeling skin are discussed separately. Other causes of neonatal and infantile erythroderma are also discussed separately.

●(See "Overview and classification of the inherited ichthyoses".)

●(See "Ichthyosis vulgaris".)

●(See "Autosomal recessive congenital ichthyoses".)

●(See "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses".)

●(See "Peeling skin syndromes".)

●(See "Erythroderma in children".)

EPIDEMIOLOGY — The precise incidence of NS is unknown but is estimated at 1:100,000 to 1:200,000 live births [2]. NS is estimated to account for approximately 20 percent of neonatal erythroderma cases [3].

PATHOGENESIS

Genetics

●SPINK5 variants – NS is caused by biallelic loss-of-function variants in the serine protease inhibitor of Kazal type 5 gene (SPINK5) on chromosome 5q32 [4]. SPINK5 encodes a multidomain serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI). Most variants, whether small base deletions/insertions, nonsense, or splice site variants, lead to premature stop codons and protein truncation, resulting in defective expression of LEKTI.

Over 90 distinct SPINK5 variants have been reported. Specific SPINK5 polymorphisms, especially 420Lys (420K), have been associated with atopic dermatitis and atopy [5-7].

●Genotype-phenotype correlations – Potential genotype-phenotype correlations have been recognized. Generally, mutations more proximal in the gene are associated with more severe phenotypes than those located closer to the 3' region [8]. In a small number of Japanese patients, a link has been found between LEKTI domain deficiency and clinical manifestations [9]. There are also reports of variants associated with early lethality or very severe manifestations of the disease [10-12]. Variants located in upstream regions of the LEKTI protein code appear to be associated with more severe phenotypes compared with similar variants located towards the 3' (more distal region of the protein) [8]. Milder forms that escape diagnosis are suspected.

The c.153delT mutation in exon 3 of SPINK5 appears to be associated with more severe phenotypic manifestations, including skin manifestations at birth, hypernatremic dehydration, and a higher death rate. One patient with mutations in exon 1 exhibited very severe and ultimately fatal NS. Conversely, several patients with homozygous mutations in intron 15 exhibited very mild skin findings with no associated systemic manifestations, suggesting that there may be some patients with very mild NS who could go undiagnosed [13].

LEKTI protein function — LEKTI functions as a "super" serine protease inhibitor [14]. Among the proteases it directly inhibits are several kallikreins (KLKs): KLK5, KLK7, and KLK14 [15]. KLKs are critical epidermal proteases, important for regulating skin desquamation, inflammation, and maintaining skin barrier integrity. In fetuses affected by NS, constitutive overactivity of KLK5 and its related peptidases is present in utero. Thus, at birth, the epidermal barrier is greatly impaired, and there is dramatic upregulation of inflammatory signaling molecules. LEKTI activity is influenced by local pH. The neutral pH of the deeper aspects of the epidermis stimulates its activity, while the gradient to a more acidic pH in the outer layers of the epidermis impairs its activity.

●Activation of KLK5 – In NS, LEKTI deficiency results in KLK5 activation in all levels of the epidermis, leading to premature degradation of the corneodesmosomal components of the epidermal barrier. This profoundly and continuously degraded epidermal barrier leads to chronic inflammation and superficial desquamation (ichthyosiform erythroderma). Further emphasizing the importance of KLK5 in the pathogenesis of NS are the findings that KLK5-deficient, LEKTI-deficient mice exhibit a normalized phenotype without the majority of cutaneous and clinical findings present when KLK5 is functional [16]. LEKTI is also expressed in the thymus, the importance of which is unknown.

●Upregulation of inflammatory cytokines – The KLK5-mediated activation of protease-activated receptor 2 (PAR2) leads to production of a variety of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP), a cytokine strongly upregulated in atopic dermatitis [16,17]. TSLP activates Langerhans cells, which induce T cell differentiation into T helper type 2 (Th2) cells after migration to draining regional lymph nodes.

Additional proinflammatory cytokines upregulated in the setting of LEKTI deficiency include macrophage-derived cytokine, tumor necrosis factor (TNF)-alpha, interleukin (IL) 8, IL-17, and IL-36. In a study of the immune profiles of a variety of ichthyosis subtypes, patients with NS were found to exhibit some upregulation of TNF-alpha as well as significant upregulation of T helper type 17 (Th17)/IL-23 pathway genes very similar to psoriasis [18]. Patients with NS had the highest induction of Th17 pathway genes amongst the ichthyosis subgroups tested, with striking upregulation of IL-19, which leads to amplification of IL-17 effects on keratinocytes.

Transcriptomic and proteomic profiling of NS indicate that the IL-17/IL-36 pathway is the most predominant upregulated pathway in NS [19]. Patients with either ichthyosis linearis circumflexa (ILC) or neonatal scaly erythrodermic phenotype showed IL-17/IL-36 signatures in their skin lesions and peripheral blood samples [19]. However, complement activation was predominant in ILC skin lesions, whereas a type I interferon (IFN) signature was predominant in skin lesions of patients with a scaly erythrodermic phenotype. These findings suggested that the immunologic profile of NS shares features with both atopic dermatitis and psoriasis.

Skin barrier defects — The unrestrained protease activity in NS skin leads not only to degradation of the stratum corneum cell adhesion but also to degradation of secreted lamellar body (LB) protein contents, including two ceramide-generating enzymes (acidic sphingomyelinase and beta-glucocerebrosidase), resulting in a profound barrier defect that contributes to increased risk of infection [15].

Studies have shown that antimicrobial proteins such as the cathelicidin LL-37, which are typically present in normal skin, are reduced in NS. LL-37 is typically loaded in LB to be secreted during cornification of the epidermis. Although LL-37 loading into LB is normal in NS and LB secretion is accelerated, the levels of LL-37 rapidly become undetectable after LB secretion, likely due to degradation by the high levels of active epidermal proteases [20].

Skin microbiome alterations — Studies describe that Staphylococcus aureus and Staphylococcus epidermidis are increased in individuals with NS compared with healthy family controls [21,22]. S. aureus is thought to contribute to inflammation and barrier dysfunction directly, possibly due to secretion of virulence proteins and proteases, such as staphopain A and B [21].

CLINICAL MANIFESTATIONS — NS is characterized by the classic triad of:

●Congenital ichthyosiform erythroderma (picture 1)

●A specific hair shaft abnormality termed "trichorrhexis invaginata" (picture 2)

●Allergic manifestations with elevated serum levels of IgE

However, the phenotype of NS may be quite variable among patients and even within families. Some patients may present with a milder phenotype, possibly associated with residual expression of LEKTI [23]. In other patients, one or more of the classic features may not be present, and changes in phenotype severity may occur over time [14].

Neonatal findings — Neonates with NS are often premature and may exhibit diffuse ichthyosiform erythroderma at birth (picture 1) (see "Erythroderma in children"). Hair is usually sparse and grows slowly. Congenital alopecia may be noted.

Newborns with NS are hemodynamically unstable in the first few weeks of life. They have a high risk of life-threatening complications, including hypernatremic dehydration and hypothermia due to extensive transepidermal water loss [13]. NS cases associated with the c.153delT mutation are often the most severe [13]. Serum sodium should be monitored in these infants, especially if there is failure to thrive or the skin manifestations are severe.

The risk of infection and sepsis is also elevated. Other complications include enteropathy with villous atrophy, chronic diarrhea, and failure to thrive. Many newborns with NS are hospitalized for several weeks for these complications, and more severe cases can require extended hospitalization and intensive care.

Infants with NS have a notably elevated caloric requirement that should be anticipated, sometimes requiring nasogastric tube feeds, gastrostomy, or parenteral nutrition. Neonates exhibiting a phenotype severe enough to develop hypernatremic dehydration require aggressive nutritional support. Hypernatremia is usually associated with notable skin inflammation in the neonatal period (and with the c.153delT mutation), although it can occur in the absence of skin inflammation.

As the epidermal barrier is substantially impaired, the risk of transcutaneous absorption is extremely high in these infants. Topical medications should be avoided or used with great caution.

Cutaneous manifestations — Beyond the neonatal period, the cutaneous findings of NS are variable. During childhood and adulthood in some patients, the skin lesions evolve toward ichthyosis linearis circumflexa (ILC), while others retain the neonatal scaly erythrodermic phenotype. Pustular lesions, which can mimic pustular psoriasis, have also been described [24,25].

Ichthyosis linearis circumflexa — ILC refers to migratory polycyclic and serpiginous erythematous lesions bordered by a double collar of scales (picture 3). ILC is variable in severity and extent and waxes and wanes with time. In some patients with proven SPINK5 variants, ILC is the only clinical manifestation of NS [26].

Scaling erythroderma — Some patients with NS retain the generalized scaly erythrodermic phenotype observed at birth. The generalized scaly erythrodermic phenotype may be persistent and severe enough at times to be mistaken for other forms of ichthyosis, such as autosomal recessive congenital ichthyosis. (See "Autosomal recessive congenital ichthyoses".)

Complications — Patients with NS have recurrent skin infections, predominantly due to S. aureus and Pseudomonas aeruginosa; Candida may also be an infecting agent [13].

During adulthood, some patients develop striking hypertrophic papillomas in the flexures, most commonly in the inguinal folds, gluteal cleft, and groin [14]. Human papillomavirus deoxyribonucleic acid (DNA), including DNA of epidermodysplasia verruciformis-associated beta-papillomavirus, has been detected in some of these lesions [27]. Buschke-Löwenstein tumors requiring surgical intervention have been reported in a few cases [28-30].

There are a few isolated reports of skin malignancies, including multiple basal cell carcinomas and squamous cell carcinomas, occurring at an early age in patients with NS [31,32]. The overall incidence of this phenomenon is not known.

Hair abnormalities — In many patients with NS, the hair is typically lusterless, dry, short, and hard to style or manage (picture 4). Some patients with longer hairs may have visible nodes along the hair shafts.

●Trichorrhexis invaginata – The pathognomonic finding of trichorrhexis invaginata of hair and eyebrows ("bamboo hair" or "ball and socket deformity") may often be detected on trichogram or trichoscopy by one year of age (picture 2). However, in some patients with genotyped SPINK5 mutations, trichorrhexis invaginata may be absent [33]. (See 'Hair examination' below and "Hair shaft disorders", section on 'Trichorrhexis invaginata'.)

●Trichorrhexis nodosa – Trichorrhexis nodosa is characterized by nodes along the hair shaft that result from separation and fraying of cortical fibers due to disruption of the overlying cuticular cells (picture 5). Affected hairs may fracture through these weak points in the hair shaft, which appear like two brooms or brushes thrust together end to end. (See "Hair shaft disorders", section on 'Trichorrhexis nodosa'.)

●Pili torti – Pili torti are characterized by flattening of the hair shaft at irregular intervals and twisting of the hair (picture 6). (See "Hair shaft disorders", section on 'Pili torti'.)

Atopic manifestations — Most patients with NS have elevated IgE levels and eosinophilia and usually develop multiple airborne and/or food allergies [34]. Manifestations of atopy may become apparent in the neonatal period and increase during childhood. They include atopic dermatitis, which can be severe; food allergies, which are often severe and multiple; hay fever; and asthma. Angioedema and anaphylaxis, especially to foods, have also been reported. The levels of specific IgE to multiple allergens typically increase with age [34].

Extracutaneous manifestations — Children with NS may show a mild developmental delay, short stature and growth hormone deficiency [35], intellectual disability, recurrent cutaneous and systemic infections, and pancreatic insufficiency [36]. Endocrine abnormalities (hypothyroidism, hyperparathyroidism, Cushing syndrome) are rarely noted. Persisting arterial hypertension requiring medical treatment has also been noted [13].

LEKTI is prominently expressed in thymus Hassall corpuscles. Some patients with NS present with notable immunodeficiency and require treatment and management precautions similar to infants with genetic immunodeficiency disorders in the first month or two of life.

NATURAL HISTORY — In most patients, NS evolves with age to a milder cutaneous phenotype, with erythematous patches and scaling mimicking atopic dermatitis. The disease course is characterized by inflammatory flares with intense pruritus and periods of remission.

DIAGNOSIS — The diagnosis of NS may be difficult due to the variability of the clinical presentation and its change over time. A high index of suspicion is required for patients manifesting a mild or incomplete phenotype.

Clinical suspicion — NS should be suspected in all neonates and infants presenting with ichthyosiform erythroderma, as approximately 20 percent will have NS [2]. In older children, the presence of serpiginous erythematous plaques with typical double-edged scale (ichthyosis linearis circumflexa [ILC]) on the trunk and extremities (picture 3) suggests NS.

NS should also be considered in children with recalcitrant atopic eczema that does not respond to standard treatment (table 1).

In both children and adults, the presence of sparse and fragile hair in association with eczematous lesions resembling atopic dermatitis should raise suspicion of NS and prompt careful microscopic or dermoscopic examination of hairs and eyebrows for trichorrhexis invaginata. (See 'Hair examination' below.)

Diagnostic criteria — The diagnosis of NS is made based on the presence of one or more of the following criteria in addition to allergic disease (ie, atopic dermatitis, atopic diathesis, food allergies, hay fever, history of anaphylaxis, elevated IgE levels, eosinophilia):

●Typical skin lesions – Scaling erythroderma, ILC.

●Typical hair findings – Trichorrhexis invaginata, "golf-tee" and "matchstick" hairs.

●Family history – History of NS in a sibling.

●Genetic testing – Identification of biallelic pathogenic germline SPINK5 variants by DNA sequencing will confirm the diagnosis in up to 75 percent of cases meeting clinical diagnostic criteria.

Skin biopsy — Routine histopathologic examination is generally not helpful for the diagnosis of NS. However, it can be helpful to differentiate NS from other disorders that present with similar clinical manifestations. Immunostaining for LEKTI may support the diagnosis.

Histopathologic findings — Skin biopsies of NS typically exhibit psoriasiform hyperplasia, with skin inflammation, thinning, and a diminished granular layer. Additional findings include sub/intracorneal splitting, clear cells in the upper epidermis/stratum corneum, dyskeratosis, a dermal inflammatory infiltrate including neutrophils and/or eosinophils, and vascular dilatation [37]. Electron microscopy of NS exhibits findings associated with abnormal differentiation and accelerated desquamation including granular layer diminution, retained nuclei in the stratum corneum, and premature lamellar body (LB) secretion [14].

LEKTI immunostaining — Many patients with NS exhibit absent LEKTI staining in the epidermis. Some patients with "leaky" variants allowing slight residual LEKTI expression will exhibit diminution of LEKTI. In contrast, a patchy LEKTI staining may be occasionally seen in patients with atopic dermatitis or psoriasis but not in NS [37]. LEKTI immunostaining should be part of the work-up of infants with suspected NS even if the skin involvement is mild.

Hair examination — In a patient suspected to have NS, the examination of the hair and eyebrows under a microscope (trichogram) or a dermatoscope (trichoscopy) can confirm the presence of trichorrhexis invaginata [38,39]. In trichorrhexis invaginata, the distal part of the hair shaft collapses into the proximal aspect of the shaft due to a defect in keratinization of the internal root sheath, creating the bamboo-like node that gives the defect its name (picture 4). Due to this structural weakness, the hairs break easily, leaving behind a cup-shaped end to the fractured hair (the so-called "golf-tee" hairs) [2,40]. (See "Hair shaft disorders".)

Because only a small percentage of hairs are affected in most cases, the appropriate evaluation of hair in these patients should involve the sampling of numerous hairs from various areas of the scalp. Hundreds of hairs must often be examined to find an example of trichorrhexis invaginata [41]. The presence of trichorrhexis invaginata even in a single hair, in association with typical skin findings, is considered sufficient to make the diagnosis of NS. Trichoscopy may aid in this by allowing examination of hairs in vivo on the patient.

Prior to harvesting, the hairs can be rubbed between the fingers to accentuate any underlying defects. In difficult cases, the eyebrows should be examined, as they can exhibit a higher frequency of hair shaft abnormalities [42].

So-called "matchstick" hairs have been described in the eyebrows of some patients with NS. Characterized by short hair shafts with a bulging tip similar to an unstruck match, these hairs are likely equivalent to "golf-tee" scalp hairs and represent hair shafts that have fractured through an area of trichorrhexis invaginata [43].

Genetic testing — Due to the increasing availability of rapid exome sequencing and mutation analysis, genetic testing for SPINK5 gene variants has become the initial test in patients suspected to have NS [37]. Genetic testing can identify germline SPINK5 mutations in at least 75 percent of cases [44]. The c.153delT mutation appears to be associated with a more severe phenotype and poorer outcomes. (See 'Genetics' above.)

Genetics consultation is recommended for suspected and/or confirmed cases. (See 'Genetic counseling' below.)

DIFFERENTIAL DIAGNOSIS — In neonates, the cutaneous manifestations of NS may closely resemble other infantile erythrodermas, particularly nonbullous congenital ichthyosiform erythroderma and erythrodermic psoriasis. Atopic dermatitis, lamellar ichthyosis, primary immunodeficiency syndromes, seborrheic dermatitis, and acrodermatitis enteropathica should also be excluded. (See "Erythroderma in children".)

●Autosomal recessive congenital ichthyosis – Infants with autosomal recessive congenital ichthyosis, including lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma, exhibit diffuse scaling erythroderma at birth and during early childhood similar to children with NS. However, newborns with autosomal recessive congenital ichthyosis are often born with a collodion membrane (picture 7), which is replaced in the first few weeks of life by thick, plate-like scale with variable erythroderma in infants with lamellar ichthyosis (picture 8) and by small, white scales and prominent erythroderma in congenital ichthyosiform erythroderma (picture 9). In addition, trichorrhexis invaginata and atopic manifestations are not characteristic of autosomal recessive congenital ichthyosis. (See "Overview and classification of the inherited ichthyoses", section on 'Lamellar ichthyosis and congenital ichthyosiform erythroderma'.)

●Erythrodermic psoriasis/pustular psoriasis – There are multiple reports of infants with diffuse pustular erythematous skin eruptions mimicking pustular or erythrodermic psoriasis who were later diagnosed with NS [24,25]. However, the absence of hair abnormalities, atopy, or allergy support the diagnosis of psoriasis. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)

●Atopic dermatitis – Atopic dermatitis is not associated with the hair shaft abnormalities seen in NS nor with ichthyosis linearis circumflexa (ILC). In addition, atopic manifestations are much more severe in NS than in atopic dermatitis. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●Acrodermatitis enteropathica – Acrodermatitis enteropathica is a recessively inherited partial defect of intestinal zinc absorption. Affected infants develop an erythematous and vesiculobullous dermatitis (picture 10), diarrhea, and severe growth retardation. Although hair abnormalities (alopecia) may occur in acrodermatitis enteropathica, the specific trichorrhexis invaginata hair shaft defect is not seen. The incidence of allergic disease is also not increased. (See "Zinc deficiency and supplementation in children", section on 'Acrodermatitis enteropathica'.)

●Primary immunodeficiency syndromes – Some forms of primary immunodeficiency, including Omenn syndrome and hyperimmunoglobulin E syndrome (picture 11), may present with diffuse atopic dermatitis-like eruption or scaly, ichthyosiform erythroderma and increased risk of infection. However, in contrast with NS, trichorrhexis invaginata is absent, and the incidence of allergic disease is not increased. The incidence and types of infections also differ from NS. Trichogram, skin biopsy, or genetic analysis can differentiate difficult cases. (See "Severe combined immunodeficiency (SCID): An overview".)

●Seborrheic dermatitis – Diffuse seborrheic dermatitis can present with erythroderma, although the scaling is typically greasier and not as dry as that seen in NS or other disorders of cornification. Seborrheic dermatitis typically exhibits a scalp/flexural predominance. Additionally, trichorrhexis invaginata and severe allergic disease are not characteristic of seborrheic dermatitis. (See "Cradle cap and seborrheic dermatitis in infants".)

●Peeling skin syndrome type B – Inflammatory peeling skin syndrome (peeling skin syndrome type B) is an autosomal recessive disorder caused by loss-of-function mutations in the corneodesmosin gene and shares striking clinical similarities with NS, including ichthyosiform erythroderma at birth, superficial skin peeling, failure to thrive, food allergies, asthma, urticaria, angioedema, and recurrent skin infections [41,45,46]. A deficiency of corneodesmosin, a protein involved in maintaining cell adhesion in the stratum corneum, either due to genetic mutations (as in the peeling skin syndrome type B) or to excess proteolysis from lymphoepithelial Kazal type inhibitor (LEKTI) deficiency (as in NS), results in aberrant regulation of epidermal desquamation, barrier impairment, skin inflammation, and increased IgE levels [47]. (See "Peeling skin syndromes", section on 'Generalized inflammatory (type B) peeling skin syndrome'.)

●SAM (severe dermatitis, multiple allergies, and metabolic wasting) syndrome – SAM syndrome is a newly described autosomal recessive genodermatosis caused by homozygous mutations in the desmoglein-1 gene. SAM syndrome shows significant clinical overlap with NS, including congenital erythroderma, scaling, skin erosions, and poor hair growth, but not trichorrhexis invaginata, increased IgE levels, and severe food allergies [47]. Failure to thrive and recurrent skin and respiratory infections are also common. Skin histopathology reveals acantholysis with subcorneal and intragranular cellular separation. (See "Peeling skin syndromes", section on 'SAM syndrome'.)

●Exfoliative ichthyosis – Autosomal recessive exfoliative ichthyosis is a rare ichthyosis caused by mutations in cystatin A (also known as cysteine protease inhibitor A) [48]. It is characterized by congenital erythroderma, hyperhidrosis, and diffuse fine skin scaling. Peeling of the palms and soles beginning in childhood and worsened by immersion in water or occlusion occurs. In contrast with NS, autosomal recessive exfoliative ichthyosis is not associated with a severe alteration of the skin barrier function, atopy, and hair abnormalities. The presence of palmoplantar hyperkeratosis, sometimes with extension to the dorsum, is a further differentiating feature from NS.

MANAGEMENT — There is no specific therapy for NS. Neonates with erythroderma need in-hospital treatment and monitoring due to the potential for severe failure to thrive, metabolic abnormalities, and sepsis. In children and adults with NS, treatment is largely symptomatic and should be tailored to the needs of the individual patient [49].

Neonates — The erythrodermic neonate with NS should be managed in a neonatal intensive care unit. The initial management involves:

●Monitoring of fluids and electrolytes – Due to transepidermal water loss, neonates with NS are at risk of hypernatremic dehydration. (See "Fluid and electrolyte therapy in newborns".)

●Monitoring of body temperature – The transepidermal water loss is always accompanied by heat loss, resulting in hypothermia and increased metabolic rate.

●Prevention and treatment of infection, particularly skin infection from S. aureus, Streptococcus, or gram-negative bacteria.

●Providing adequate nutrition – Failure to thrive is common due to increased metabolic rate and significant protein loss from skin desquamation. Early institution of a hypoallergenic diet is often considered. For some infants with severe failure to thrive and poor nutritional uptake, gastrointestinal tube (G-tube) supplemental feedings may be necessary.

●Skin care – Regular bathing and liberal application of petrolatum-based ointment multiple times per day may be helpful in restoring the skin barrier function. Awareness of the risk for transcutaneous absorption and avoidance of topical medicaments (eg, topical corticosteroids) that could be absorbed percutaneously is important.

Infants and older children — The choice of treatment should be individualized based on patient age, severity of disease, and patient and family preferences. The skin manifestations of NS are usually severe during infancy and childhood but tend to improve over time. Therapies are aimed at restoring the skin barrier and decrease skin inflammation and pruritus.

Skin care — Careful skin care is a central part of management. Minimal amounts of mild cleansers should be used for daily baths or showers, combined with liberal, frequent use of bland emollients and moisturizers. Clinically infected skin may be treated with antiseptics (eg, diluted bleach baths) and topical or systemic antibiotics.

Limited skin involvement

●Topical anti-inflammatory agents – For patients with limited inflammatory skin lesions (eg, sparse patches of ichthyosis linearis circumflexa [ILC]), we suggest topical anti-inflammatory agents, including low- to mid-potency topical corticosteroids (table 2) and topical calcineurin inhibitors (topical tacrolimus, pimecrolimus). Topical agents should be used for the shortest possible period of time. Due to a severely impaired skin barrier, percutaneous absorption of topical agents has been documented in patients with NS [50-53].

Topical corticosteroids and topical calcineurin inhibitors for NS have not been evaluated in clinical trials or large observational studies. Their use is based on indirect evidence of efficacy in other inflammatory skin diseases (eg, atopic dermatitis, psoriasis).

●Phototherapy – Several reports have noted benefit to patients with NS from narrowband ultraviolet B phototherapy [54-56].

Severe disease — Patients with severe disease (widespread ILC, persisting scaling erythroderma, recurrent infections, failure to thrive) are candidates for systemic therapies. However, robust data on systemic therapies in NS are limited [57]. Better understanding of the role of inflammation and other factors in the resulting systemic phenotype of these patients has led to the use of several systemic immunomodulating therapies to mitigate the manifestations of NS. Intravenous immune globulin (IVIG) replacement therapy and biologic drugs targeting signaling pathways important in inflammation have shown the most promise.

●Intravenous immune globulin – IVIG therapy has led to improvement in some patients with severe NS, emphasizing the role of immune and inflammatory dysregulation in the symptoms of the disease.

The evidence of efficacy of immunoglobulin replacement therapy for NS is limited to a few case reports and small case series [58-60].

•In one study, five children aged six months to nine years with NS and recurrent skin and pulmonary infections from S. aureus were treated with IVIG at the dose of 0.4 g/kg/month for one year [58]. For all patients, families reported improvement of inflammation and itching of the skin, infection, and hair fragility.

•In another report, two patients experienced improvement of erythema and scaling with IVIG 0.4 and 0.8 g/kg/month, respectively [59]. Relapses occurred in both patients after 2.5 years and 6 months, respectively.

●Biologics – The observation that the interleukin (IL) 17/IL-36 pathway is upregulated in NS, with either complement activation and T helper type 2 (Th2) allergic response or interferon (IFN) response and T helper type 9 (Th9) response, has led to the repurposed use of several biologics for the treatment of NS. However, data on the efficacy of biologics for NS are limited and insufficient to guide the choice of a specific agent over another in the individual patient [59]. Moreover, their efficacy seems to decline over time [59].

•Secukinumab – Secukinumab, a human antibody that binds IL-17A, has been reported as beneficial in several patients with severe NS [61-64]. In a series of four patients with severe NS, secukinumab decreased the Ichthyosis Area and Severity Index (IASI) of 55 to 88 percent after six months of treatment [61].

•Ustekinumab – Ustekinumab, a human monoclonal antibody that targets IL-12 and IL-23, has been successfully used in a patient with NS presenting with erythroderma and scaling [65]. However, in a report of three patients with NS, two patients experienced a modest improvement of IASI with no improvement in pruritus and overall quality of life [66].

•Dupilumab – Dupilumab targets the IL-4 receptor subunit alpha, which is a component of both the IL-4 and IL-13 receptors. There are several reports of successful use of dupilumab in children and adolescents with NS, with rapid improvement of pruritus, erythema, and desquamation [67-71]. A clinical trial of dupilumab for NS is underway (NCT04244006).

•Anakinra – Anakinra, a recombinant IL-1 receptor antagonist, induced a rapid decrease of erythema, scaling, and itch in four patients with NS [59]. However, its efficacy decreased over time.

•Ixekizumab – Ixekizumab, a humanized anti-IL-17A/F antibody, was effective in improving erythema, pruritus , and scaling in three patients with severe NS and especially in the two patients with an ILC phenotype [72].

•Infliximab – Infliximab has been used in a few patients with NS [73-75]. In a six-month-old infant, infliximab was administered for 12 months with improvement in skin and scalp lesions [74]. Improvement persisted after interruption of treatment.

Experimental therapies — Kallikrein (KLK) inhibitors are under investigation and development and appear to ameliorate symptoms of NS in animal models [76,77].

Gene therapy using a lentiviral vector expressing SPINK5 gene is also under investigation [78,79].

Surveillance — Adults with NS may develop cutaneous squamous cell carcinomas and basal cell carcinomas at an early age. Routine skin examination, once a year until first skin cancer and then more often as needed, is recommended. Providers should have a low threshold for biopsying suspicious lesions to rule out malignancy [14].

GENETIC COUNSELING — Parents of a patient with NS are obligate heterozygotes. They are typically asymptomatic and carry one of the variants in the SPINK5 gene.

At conception, each sibling of a patient with NS has a 25 percent chance of being affected, a 50 percent chance of being an asymptomatic carrier, and a 25 percent chance of being homozygous wild type and, thus, not affected and not a carrier. Once born and known to be unaffected, the sibling's risk changes to having a two-thirds chance of being an asymptomatic carrier. Prenatal diagnosis is possible [44,80].

Children of a patient with NS are obligate heterozygotes. In the rare chance that a reproductive partner is a carrier of a SPINK5 variant, the offspring have a 50 percent risk of being affected with NS and a 50 percent risk of being carriers.

Each sibling of a proband's parents has a 50 percent risk of being a carrier. Carrier testing is possible once both pathogenic SPINK5 variants are known.

PROGNOSIS — The erythrodermic newborn with NS has a very high risk of potentially life-threatening complications, such as hypernatremic dehydration, sepsis, and hypothermia. The prognosis is favorable for patients with NS who evolve to a milder phenotype over time.

In a single-institution retrospective study of 43 infants with NS, four patients (9 percent) died in the first nine months of life [13]. Deaths were caused by sepsis associated with respiratory or skin infections. Severe hypernatremia was noted in these patients.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Netherton syndrome (NS) is a rare and severe autosomal recessive disorder of cornification characterized by the clinical triad of congenital ichthyosiform erythroderma, a specific hair shaft abnormality termed "trichorrhexis invaginata," and atopic manifestations with elevated serum levels of IgE. NS is caused by biallelic loss-of-function variants in the SPINK5 gene, which encodes a serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI). Loss of inhibition of kallikrein (KLK)-related peptidases results in a severe skin barrier defect and skin inflammation. (See 'Pathogenesis' above.)

●Clinical presentation – The phenotype of NS is variable. Newborns typically present with severe scaly erythroderma and a high risk of life-threatening complications, including hypernatremic dehydration, hypothermia, and sepsis. (See 'Neonatal findings' above.)

With age, most patients evolve to a milder cutaneous phenotype, with erythematous patches and scaling mimicking an eczematous eruption such as atopic dermatitis. Eventually, many develop the characteristic ichthyosis linearis circumflexa (ILC) (picture 3). Hair findings include the pathognomonic trichorrhexis invaginata and trichorrhexis nodosa. (See 'Cutaneous manifestations' above and 'Hair abnormalities' above.)

●Atopic manifestations – Most patients with NS have elevated IgE levels and eosinophilia. Manifestations of atopy include atopic dermatitis, food allergies, hay fever, and anaphylaxis. (See 'Atopic manifestations' above.)

●Diagnosis – The diagnosis of NS is based on one or more of the following findings in addition to atopic diathesis (ie, atopic dermatitis, food allergies, hay fever, history of anaphylaxis, elevated IgE levels):

•Typical hair findings (eg, trichorrhexis invaginata, "golf-tee" and "matchstick" hairs)

•History of NS in a sibling

•Identification of a germline SPINK5 variant by DNA sequencing (see 'Diagnosis' above)

●Management

•Neonates – The erythrodermic neonate with NS should be managed in a neonatal intensive care unit to monitor fluids, electrolytes, and body temperature; prevent and treat infection; and provide adequate nutrition. (See 'Neonates' above.)

•Infants and older children – The treatment of NS is largely symptomatic and should be adapted based on the severity of the systemic phenotype in individual patients.

-Skin care – All patients benefit from careful skin care, which includes gentle skin cleansing with mild detergents and liberal and frequent use of bland emollients and moisturizers. (See 'Skin care' above.)

-Limited inflammatory skin lesions – For patients with limited inflammatory skin lesions, we suggest treatment with topical anti-inflammatory medications rather than general skin care measures only (Grade 2C). Low- to mid-potency topical corticosteroids (table 2), topical tacrolimus, or topical pimecrolimus should be used for the shortest possible time due to the elevated risk of systemic absorption through a defective skin barrier. (See 'Limited skin involvement' above.)

-Severe disease – Patients with severe disease (eg, widespread ILC, persisting scaling erythroderma, recurrent infections, failure to thrive) may benefit from treatment with systemic immunomodulating agents, including intravenous immune globulin (IVIG) and select biologics targeting signaling pathways upregulated in NS. However, evidence on the efficacy of systemic therapies for NS is limited and insufficient to support the choice of one agent over others. (See 'Severe disease' above.)