INTRODUCTION — Netherton syndrome ([NS] Comel-Netherton; MIM #256500) is a rare autosomal recessive disorder of cornification caused by mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5), which encodes a serine protease inhibitor expressed in epithelial and mucosal surfaces. NS is clinically characterized by the classic triad of congenital ichthyosiform erythroderma, a specific hair shaft abnormality termed trichorrhexis invaginata ("bamboo hair"), and an atopic diathesis .
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.
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 "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 . NS is estimated to account for approximately 20 percent of neonatal erythroderma cases .
PATHOGENESIS — NS is caused by autosomal recessive mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5; OMIM 605010) on chromosome 5q32 . More than 70 distinct SPINK5 mutations specific to an individual or family have been reported.
SPINK5 encodes a multidomain serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI). Most mutations, whether small base deletions/insertions, nonsense, or splice site mutations, lead to premature stop codons and protein truncation, resulting in defective expression of LEKTI.
LEKTI functions as a "super" serine protease inhibitor . Among the proteases it directly inhibits are several kallikreins, especially kallikrein 5 (KLK5). Kallikreins are critical epidermal proteases, important for regulating skin desquamation, inflammation, and maintaining skin barrier integrity. Importantly, the constitutive overactivity of kallikrein 5 (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. Specific SPINK5 polymorphisms, especially 420Lys (420K), have been associated with atopic dermatitis and atopy [6-8].
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, allowing KLK5 (among others) to become active, leading to protein degradation and desquamation of the outer epidermal layers in an organized, regulated fashion. 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, superficial desquamation (ichthyosiform erythroderma), and the KLK5-mediated activation of protease-activated receptor-2, which leads to production of a variety of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP), a cytokine strongly upregulated in atopic dermatitis .
TSLP activates Langerhans cells, which induce T cell differentiation into Th2 cells after migration to draining regional lymph nodes. Additional cytokines upregulated in the setting of LEKTI deficiency include macrophage-derived cytokine, tumor necrosis factor (TNF)-alpha, interleukin (IL) 8, and thymus- and activation-regulated cytokine. In the setting of LEKTI deficiency, these overly activated pathways are constitutive and unremitting. 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 . LEKTI is also expressed in the thymus, the importance of which is unknown.
The constitutive 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, which contributes to increased risk of infection. Studies have shown that antimicrobial proteins such as the cathelicidin LL-37, which typically are 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 .
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 . NS patients 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.
CLINICAL MANIFESTATIONS — NS is characterized by the classic triad of congenital ichthyosiform erythroderma, a specific hair shaft abnormality termed trichorrhexis invaginata, and allergic manifestations with elevated serum levels of immunoglobulin. 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 lymphoepithelial Kazal type inhibitor (LEKTI) . In other patients, one or more of the classic features may not be present, and changes in phenotype severity may occur over time . Of note, the original patient described by Netherton had significant improvement in her skin and hair findings as she aged .
Clear genotype-phenotype correlations have not been identified, although in a small number of Japanese patients a link has been found between LEKTI domain deficiency and clinical manifestations . There are also reports of mutations associated with early lethality or very severe manifestations of the disease [15-17].
Neonatal findings — Neonates with NS are often premature and may exhibit diffuse ichthyosiform erythroderma at birth (picture 1). There are reports of NS infants being born with a collodion membrane, although this is not common, if it occurs at all. Hair is usually sparse and grows slowly. Congenital alopecia may be noted.
Newborns with NS are quite labile 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. The risk of infection and sepsis is also elevated. Other complications include severe failure to thrive and enteropathy with villous atrophy. (See "Erythroderma in children".)
Additionally, 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 and tend to improve over time. However, in some patients, a generalized scaling erythroderma may be persistent and at times severe enough to be mistaken for other forms of ichthyosis, such as autosomal recessive congenital ichthyosis.
Most patients evolve with age to a milder cutaneous phenotype, with erythematous patches and scaling mimicking an eczematous eruption such as atopic dermatitis. The erythema may be symmetrical and exhibit patterned shapes. Pustular lesions, which can mimic pustular psoriasis, have also been described [18,19].
Eventually, many patients will manifest ichthyosis linearis circumflexa (ILC), which is the distinctive cutaneous feature of NS. ILC usually appears after two years of age and is characterized by migratory serpiginous erythematous plaques with peripheral double-edged scaling (picture 2). ILC is variable in severity and extent and waxes and wanes with time. In some patients with proven serine protease inhibitor of Kazal type 5 (SPINK5) gene mutations, ILC is the only clinical manifestation of NS .
In adulthood, some NS patients develop striking hypertrophic papillomas in the flexures, most commonly in the inguinal folds, gluteal cleft, and groin . Human papillomavirus DNA, including DNA of epidermodysplasia verruciformis-associated beta-papillomavirus, has been detected in some of these lesions . Buschke-Lowenstein tumors requiring surgical intervention have been reported in a few cases [22,23].
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 [24,25]. The overall incidence of this phenomenon is not known.
Hair abnormalities — In many NS patients, the hair is typically lusterless, dry, short, and hard to style or manage (picture 3). Some patients with longer hairs may have visible nodes along the hair shafts.
The pathognomonic finding of trichorrhexis invaginata (TI) of hair and eyebrows ("bamboo hair" or "ball and socket deformity") may be often detected on trichogram or trichoscopy by one year of age. However, in some patients with genotyped SPINK5 mutations, TI may be absent . (See 'Hair examination' below.)
Other hair shaft defects that may occur in NS include trichorrhexis nodosa (TN) and pili torti. TN 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. Affected hairs may fracture through these weak points in the hair shaft, which appear like two brooms or brushes thrust together end to end.
Atopic manifestations — Most patients with NS have elevated immunoglobulin E (IgE) levels and eosinophilia . 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 .
Extracutaneous manifestations — Children with NS may show a mild developmental delay, short stature and growth hormone deficiency , intellectual disability, recurrent cutaneous and systemic infections, and pancreatic insufficiency .
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 .
In older children, the presence of serpiginous erythematous plaques with typical double-edged scale (ichthyosis linearis circumflexa, [ILC]) on the trunk and extremities (picture 2) suggests NS. This diagnosis 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 (TI). (See 'Hair examination' below.)
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 lymphoepithelial Kazal type inhibitor (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 . 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 .
LEKTI immunostaining — Many NS patients exhibit absent LEKTI staining in the epidermis. Some patients with "leaky" mutations 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 .
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 TI [31,32]. In TI, 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 which gives the defect its name (picture 3). 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) [2,33].
Because in most cases only a small percentage of hairs are affected, the appropriate evaluation of hair in these patients should involve the sampling of numerous hairs from various areas of the scalp. Often hundreds of hairs must be examined to find an example of TI . The presence of TI 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 .
So-called "matchstick" hairs have been described in the eyebrows of some NS patients. 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 TI .
Genetic testing — Due to the increasing availability of rapid exome sequencing and mutation analysis, genetic testing for serine protease inhibitor of Kazal type 5 (SPINK5) gene mutations has become the initial test in patients suspected to have NS . Genetic testing will identify a germline SPINK5 mutation and confirm the diagnosis in approximately 66 to 75 percent of cases .
Mutational analysis is available from several laboratories in the United States and other countries.
Diagnostic criteria — The diagnosis of NS is made based upon 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 – TI, "golf-tee" and "matchstick" hairs
●History of NS in a sibling
●Identification of a germline SPINK5 mutation by DNA sequencing
Genetic testing will identify a germline SPINK5 mutation and confirm the diagnosis in approximately 66 to 75 percent of cases; in some patients, the diagnosis of NS relies upon clinical suspicion and findings.
DIFFERENTIAL DIAGNOSIS — In neonates, the cutaneous manifestations of NS may closely resemble other infantile erythrodermas, particularly nonbullous congenital ichthyosiform erythroderma (CIE) 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 (ARCI), including lamellar ichthyosis (LI) and nonbullous CIE, exhibit diffuse scaling erythroderma at birth and during early childhood as NS children. However, newborns with ARCI are often born with a collodion membrane (picture 4), which is replaced in the first few weeks of life by thick plate-like scale with variable erythroderma in infants with LI (picture 5) and by small white scales and prominent erythroderma in CIE (picture 6). In addition, trichorrhexis invaginata (TI) and atopic manifestations are not characteristic of ARCI. (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 [18,19]. 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 7), diarrhea, and severe growth retardation. Although hair abnormalities (alopecia) may occur in acrodermatitis enteropathica, the specific TI 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 8), may present with diffuse atopic dermatitis-like eruption, or scaly, ichthyosiform erythroderma, and increased risk of infection. However, in contrast with NS, TI 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, TI 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 [34,38,39]. 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 immunoglobulin E levels . (See "Peeling skin syndromes", section on 'Generalized inflammatory (type B) peeling skin syndrome'.)
●Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome – Severe dermatitis, multiple allergies, and metabolic wasting (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 TI, increased IgE levels, and severe food allergies . 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 (AREI) is a rare ichthyosis caused by mutations in cystatin A, also known as cysteine protease inhibitor A . 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, AREI 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 older children and adults, treatment is largely symptomatic and should be tailored to the needs of the individual patient.
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 Staphylococcus 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 transcutaneously is important.
Infants and older children
General measures — Patients with NS exhibit a variable severity of the skin involvement, and some improve over time. Careful skin care is a central part of management and involves the use of minimal amounts of mild cleansers combined with liberal, frequent use of bland emollients.
Oral antihistamines may be helpful in controlling pruritus. Topical or systemic antibiotics may be needed for the treatment of bacterial skin superinfection.
Inflammatory skin lesions may respond to topical and systemic anti-inflammatory therapies. Several reports have noted benefit to patients from narrowband ultraviolet B phototherapy [42-44].
Topical therapies — The use of low-potency corticosteroids as well as topical calcineurin inhibitors has been of benefit in some cases of NS. However, increased absorption of these agents due to the severe skin barrier dysfunction has been documented in several patients:
●Cushing syndrome from percutaneous absorption of a low-potency topical corticosteroid has been reported in a single patient with NS .
●In a small series of three children with NS treated with pimecrolimus 1% cream twice daily for 18 months, pimecrolimus was detected in the blood of all patients, with levels ranging from 0.625 to 7.08 ng/mL .
●In another study of three children with severe skin involvement treated with tacrolimus 0.1% ointment twice daily for up to eight months, significant systemic absorption 2 to 30 hours after application was documented in all, ranging from 10 to 37 ng/mL (therapeutic trough range in organ transplant recipients 5 to 20 ng/mL) .
Based upon these observations, topical corticosteroids and topical calcineurin inhibitors should be used with great caution and for limited periods of time in patients with NS who have extensive skin involvement. In particular, topical tacrolimus is associated with a high risk of systemic toxicity in these patients.
Systemic therapies — Intravenous immunoglobulin (IVIG) replacement 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. 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 (0.4 g/kg/month) for one year . For all patients, families reported improvement of inflammation and itching of the skin, infection, and hair fragility.
There are isolated reports of successful use of tumor necrosis factor (TNF)-alpha inhibitors (eg, infliximab) and the humanized monoclonal antibody against interleukin (IL) 17A ixekizumab for the treatment of the inflammatory skin lesions in NS [49,50].
Experimental therapies — Kallikrein inhibitors are under investigation and development and appear to ameliorate symptoms of NS in animal models . Gene therapy using a lentiviral vector encoding the serine protease inhibitor of Kazal type 5 (SPINK5) gene is also under investigation [52,53].
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 .
GENETIC COUNSELING — Parents of a patient with NS are obligate heterozygotes. They are typically asymptomatic and carry one of the mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5).
At conception, each sibling of an NS patient 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 [37,54].
Children of a patient with NS are obligate heterozygotes. In the rare chance that a reproductive partner is a carrier of a SPINK5 mutation, the offspring have a 50 percent risk of being affected with NS and 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 mutations 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 reported mortality rate is approximately 20 percent in the first year of life .
The prognosis is favorable for patients with NS who evolve to a milder phenotype over time. Multiple cutaneous squamous cell carcinomas and basal cell carcinomas may develop at an early age .
SUMMARY AND RECOMMENDATIONS
●Definition – Netherton syndrome (NS) is a rare autosomal recessive disorder of cornification presenting with inflammatory and scaly skin lesions along with characteristic hair abnormalities and an increased incidence of allergic disease.
●Pathogenesis – NS is caused by germline mutations in the serine protease inhibitor of Kazal type 5 (SPINK5) gene, which encodes a serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI). (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 (picture 2). Hair findings include the trichorrhexis nodosa and the pathognomonic trichorrhexis invaginata. (See 'Cutaneous manifestations' above and 'Hair abnormalities' above.)
●Atopic manifestations – Most patients with NS have elevated immunoglobulin E (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 upon one or more of the following findings in addition to allergic disease (ie, atopic dermatitis, atopic diathesis, 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 mutation by DNA sequencing (see 'Diagnosis' above)
●Management – The treatment of NS is largely symptomatic and involves primarily a gentle skin care with mild detergents and liberal and frequent use of bland emollients. Inflammatory skin lesions may benefit from topical corticosteroids or topical calcineurin inhibitors. However, due to the elevated risk of systemic absorption, topical medications should be used with great caution in these patients. Intravenous immune globulins have been reported as beneficial in a few patients. (See 'Management' above.)
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