Discussion
Netherton syndrome is a rare and severe autosomal recessive genodermatosis in the group of congenital ichthyosis. Clinically, it is first evident as the triad of ichthyosiform erythroderma (IE), trichorrhexis invaginata (bamboo hair), and atopic diathesis.4 IE is present at birth or shortly thereafter as generalized erythroderma with desquamation. In some individuals, the erythrodermic endotype may persist throughout life, but it more often is periodically or completely replaced by another endotype called ichthyosis linearis circumflexa (ICL), manifested by polycyclic and serpiginous migratory erythematous plaques with double-edged scales at the periphery.
Due to the disrupted epithelial barrier, the neonatal period is crucial and life-threatening complications such as electrolyte imbalances, including dehydration, hypothermia, gastrointestinal symptoms, skin/respiratory/systemic infections, and sepsis may occur due to increased transepidermal water loss and superficial scaling of the skin.4 Patients are highly susceptible to cutaneous and systemic infections. Immunophenotyping of patients from NS revealed no evidence of immunodeficiency. Variable T- and B-cell imbalances are found in a limited number of patients, but these changes are likely secondary to chronic skin infections and inflammation.11 However, the most recent International Union of Immunological Societies (IUIS) classification of inborn errors of immunity places NS in the group of hyper-IgE syndromes (HIES), which are combined immunodeficiencies with associated or syndromic features.12 Due to increased catabolic rate, malabsorption, chronic inflammation and recurrent infections, these children suffer from failure to thrive, growth retardation and short stature. Extracutaneous manifestations such as acute pancreatitis, hypothyroidism, thymic atrophy, and acute bilateral renal vein thrombosis have been rarely reported. 4 Cognitive impairment and developmental delays have been identified in some patients. Adult patients may develop cutaneous squamous cell carcinoma.13
The diagnosis of NS can be enhanced with histologic examination of involved skin showing detachment of the stratum corneum, hyperkeratosis, acanthosis, focal hypergranulosis, and superficial perivascular lymphocytic infiltration.5 Laboratory findings show peripheral eosinophilia and elevated IgE levels. It is very difficult to distinguish atypical NS from other types of ichthyosis; detection of gene mutations in SPINK5 is essential for diagnosis.
There is currently no ideal treatment, particularly in childhood.14 The first successful therapy of a genetic disorder, specifically ichthyosis linearis circumflexa (Netherton syndrome), was achieved by the legendary Edmund Klein and associates, including a coauthor of this current paper (RAS),15 in the late 1970s utilizing oral low dose cyclophosphamide, possibly related to selective effects of this agent on lymphocyte subpopulations and portending many other options. However, this syndrome tends to improve as patients age, but the clinical course may be disturbed by intermittent exacerbations. The predominant therapy for patients with NS is mostly supportive, as there is neither curative nor specific therapy specifically for children with NS, but targeted therapies are currently in development. The challenge is to find therapies that both repair the disrupted skin barrier and stop chronic inflammation. Current treatment options include skin cleansing, bleach baths, emollients/moisturizers, calcineurin inhibitors and oral antihistamines. Antibiotics, topical corticosteroids, and intravenous immunoglobulins (IVIG) can be used during exacerbations. The likely mechanism of action of intravenous immunoglobulin is the ability of IgG to opsonize bacteria, stimulate phagocytosis, and reduce the incidence of infection and inflammation. Immunoglobulin replacement therapy is preferred in severe cases of NS with frequent infections and failure to thrive and can be used at any age. Many reports describe a remarkable clinical response with no significant adverse effects.14 Primarily, a reduction in recurrent infections and improvement in skin condition have been reported, as the therapy is well tolerated by patients (mainly neonates and children with NS). The disadvantage of the therapy is the cost and the fact that it has to be performed in a hospital. 4Systemic therapy in NS patients with chemically synthesized vitamin A derivatives has shown a variable degree of efficacy and tolerability. Partial improvement or exacerbation has been reported for acitretin or isotretinoin. The side effects with bone toxicity and teratogenicity and questionable therapeutic response outweigh the benefits of taking these drugs. 4 In our patient, treatment with acitretin was also discontinued due to worsening of the condition. Another modern approach to consider is the use of topical tacrolimus.16 There is a wide range of potential target therapies such as kallikrein inhibitors, monoclonal antibodies blocking IL-36, IL-17, IL-12/IL-23, IL-4/IL-13 (targeting allergic manifestations), IL-9, JAK/STAT inhibitors, complement inactivation. None of these treatment options represents a complete cure from NS. Of the therapies used to date, anti-IL-17A therapy may be the most effective. Currently, some gene therapy approaches are being developed.
The best therapeutic strategy for the moment may be a combination of anti-inflammatory therapy and therapy that restores the disrupted skin barrier in NS patients. Unfortunately, all therapeutic options have been applied only in a limited number of cases, and variable responses have been shown.15 Limited data published to date suggest that biologics therapy is safe and often effective in adults and children with NS, but long-term efficacy and tolerability remain unknown.14 Randomized controlled trials with sufficient numbers of patients stratified and treated according to their specific immune profile and clinical phenotype are needed to assess the safety and efficacy of treatment options for patients with NS.16 Studies based on stratification of patients using omics-based techniques such as genomics, transcriptomics, proteomics, metabolomics, and bioinformatics would thus be a step toward precision medicine in Netherton Syndrome.
Thus, Netherton syndrome is multisystemic disease with considerable clinical variability. Based on the reported cases and the authors’ recommendations, we recommend consideration of IVIG therapy, based on this child’s favorable response noting reduced recurrent severe infections and enhanced growth. If his condition worsens, we would consider therapy blocking IL-17A, which may be the best therapeutic option for improving persistent inflammatory skin diseases and/or preventing acute relapses. Insights into the cytokine-mediated pathogenesis of NS and the increasing use of biologic therapies are opening new possibilities for NS patients. However, the various therapeutic options have been used in a limited number of cases and have shown variable responses. There is a great need for randomized controlled trials with enough patients stratified and treated according to their specific immune profile and clinical phenotype to evaluate the safety and efficacy of treatment alternatives for patients with NS.