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.