Ichthyosis Linearis Circumflexa Research Articles

Netherton Syndrome: Unraveling the Molecular Underpinnings of a Rare Epidermal Disorder

Netherton Syndrome (NS) is a rare and complex autosomal recessive genetic disorder that primarily affects the skin and hair, resulting in a spectrum of dermatological manifestations with profound clinical implications. This article aims to provide a comprehensive overview of NS, shedding light on its etiopathogenesis, clinical presentation, diagnostic modalities, and management strategies. A thorough exploration of the molecular intricacies underlying this condition reveals a captivating interplay of genetics, immunology, and epidermal biology. This syndrome, which arises from mutations in the SPINK5 gene encoding the serine protease inhibitor Kazal-type 5 (LEKTI), manifests with a triad of distinctive features: ichthyosis linearis circumflexa, atopic diathesis, and trichorrhexis invaginata. Notably, NS poses significant diagnostic challenges, and an early and accurate diagnosis is paramount for optimizing therapeutic outcomes. Advances in understanding the disease's pathophysiology have paved the way for innovative treatment modalities, ranging from topical emollients to emerging targeted therapies. This article also explores the ongoing research endeavors and the prospects of gene therapy in the management of NS. Netherton Syndrome remains an intriguing puzzle, with implications extending beyond dermatology, into the realms of immunology, genetics, and personalized medicine.

Neterthon Syndrome Revealed by Recurrent Skin Infections: A Case Report

Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by a triad of symptoms including a scaly skin condition known as circumflex linear ichthyosis, hair shaft abnormalities known as trichorrhexis invaginata, and an atopic terrain which predisposes patients to allergic reactions and asthma.
 The disorder is caused by mutations in the SPINK5 gene which encodes for a serine protease inhibitor called LEKTI. This leads to a disruption in the skin's natural barrier function and a hyperactive immune response, resulting in the characteristic symptoms of NS.
 Newborns with NS may have a poor prognosis, with possible life-threatening complications and high postnatal lethality. However, the symptoms can improve with age and growth, and management of the disorder is aimed at controlling the symptoms and preventing complications such as infections. Symptomatic treatment for cutaneous xerosis and management of infections are commonly used. Additionally, topical emollients and systemic immunoglobulin therapy may be used to help manage the condition.
 We present a clinical case that can help raise awareness about rare diseases such as Netherton syndrome and improve early diagnosis and management. It is important for healthcare providers to be familiar with the clinical and etiological characteristics of these conditions to ensure that patients receive appropriate care and treatment.
 The reported case is an infant of 3 months old, who presents from the age of 2 months a cutaneous xerosis under the care of a dermatologist, and managed by symptomatic treatment. Based on the clinical presentation and examination (The hair trichoscopy), the infant have Netherton syndrome with a superimposed bacterial infection leading to ichthyosis linearis circumflexa superinfected.

Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population.

Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss-of-function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa, itchy skin), except for one patient who has a different skin manifestation-epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous.

Long-term dupilumab therapy in Netherton syndrome with severe atopic manifestations: Case report and review of the literature.

We herein present a unique patient of Netherton syndrome (NS) with ichthyosis linearis circumflexa (ILC) lesions associated with severe atopic manifestations since infancy, showing different responses of atopic and ILC lesions to a 2-year dupilumab therapy. The atopic eczematous lesions and pruritus healed remarkably, dramatically improving the patient's quality of life, whilst the scalp hair showed a clinical and light microscopic improvement. The additional recovery in axillary/pubic/extremity hair growth, sweating and nail growth in the presented case was not previously reported in NS patients treated with dupilumab. However, dupilumab had no therapeutic effect on ILC lesions which were not pruritic and showed a treatment-independent wax and waned course.

Biological treatments for pediatric Netherton syndrome.

Netherton syndrome (NS) is a rare and potentially life-threatening genetic skin disease responsible for skin inflammation and scaling, hair abnormalities and severe allergic manifestations. NS is caused by loss-of-function variants in Serine Peptidase Inhibitor Kazal-Type 5 (SPINK5), encoding the serine protease inhibitor LEKTI. NS patients have a profound skin barrier defect caused by unopposed kallikrein-related proteases activity (KLKs). They develop severe skin inflammation with eczematous-like lesions and high serum IgE levels. Multiomics studies have revealed that the IL-17/IL-36 pathway is the most predominant upregulated pathway in NS. It is associated with a Th2 signature with complement activation in the ichthyosis linearis circumflexa subtype, and with interferon and Th9 activation in the scaly erythrodermic form. Several case reports proved the efficacy of different biotherapies targeting IL-17A, IL-12/IL-23, IL-4R and IL-13R, TNF-a and IL-1β in pediatric NS patients. Intravenous immunoglobulins (IVIG) have also shown efficacy. These studies showed no severe side effects. At present, IL-17 blockade seems to be the most efficient treatment, but case reports remain limited with small numbers of patients and no placebo-control. Additional pathways must also be explored, and more efficient strategies could be used to block IL-17 and IL-23 pathways. In the future, the combination of specific strategies aiming at repairing the initial skin barrier defect could potentiate the efficacy of biologics. The current reports suggest that biological therapy is safe and often effective at pediatric age. However, controlled clinical trials that include a larger number of patients need to be conducted to reach more reliable conclusions.

Erythroderma in a neonate

Erythroderma in a neonate

Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype\u2013phenotype correlation

BackgroundIchthyosis is a heterogeneous group of Mendelian cornification disorders that includes syndromic and non-syndromic forms. Autosomal Recessive Congenital Ichthyosis (ARCI) and Ichthyosis Linearis Circumflexa (ILC) belong to non-syndromic forms. Syndromic ichthyosis is rather a large group of heterogeneous diseases. Overlapping phenotypes and genotypes between these disorders is a major characteristic. Therefore, determining the specific genetic background for each form would be necessary.MethodsA total of 11 Tunisian patients with non-syndromic (8 with ARCI and 2 with ILC) and autosomal syndromic ichthyosis (1 patient) were screened by a custom Agilent HaloPlex multi-gene panel and the segregation of causative mutations were analyzed in available family members.ResultsClinical and molecular characterization, leading to genotype–phenotype correlation in 11 Tunisian patients was carried out. Overall, we identified 8 mutations in 5 genes. Thus, in patients with ARCI, we identified a novel (c.118T > C in NIPAL4) and 4 already reported mutations (c.534A > C in NIPAL4; c.788G > A and c.1042C > T in TGM1 and c.844C > T in CYP4F22). Yellowish severe keratoderma was found to be associated with NIPAL4 variations and brachydactyly to TGM1 mutations. Two novel variations (c.5898G > C and c.2855A > G in ABCA12) seemed to be features of ILC. Delexon13 in CERS3 was reported in a patient with syndromic ichthyosis.ConclusionsOur study further extends the spectrum of mutations involved in ichthyosis as well as clinical features that could help directing genetic investigation.

228 IL-36 is a hallmark of Netherton syndrome with type I IFN, Th2 and Th9 responses distinguishing its dual clinical presentation

Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI. NS patients suffer from a severe skin barrier defect, display inflammatory skin lesions and superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Here we employed a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells and allergic phenotypes of 9 NS-ILC and 4 NS-SE patients.

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.

Duality of Netherton syndrome manifestations and response to ixekizumab

To the Editor: Netherton syndrome (NS) is a rare autosomal recessive ichthyosis due to loss-of-function mutations in SPINK5 encoding LEKTI.1 Patients with NS typically present with ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE) associated with trichorrhexis invaginata and severe atopic manifestations with high serum immunoglobulin E levels.2 Current NS treatment is only symptomatic. Recent studies showed that patients with NS display a prevailing T helper (Th) type 17 immune response,3,4 suggesting that blocking the Th17 axis could be a therapeutic strategy.

Skin barrier lipid enzyme activity in Netherton patients is associated with protease activity and ceramide abnormalities

Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum (SC) ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, β-glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) SC ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in SC ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered SC ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS.

A case of netherton syndrome with novel mutation in SPINK5 gene expressing incomplete phenotype

Netherton syndrome (NS) is characterized by ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic diathesis. It is also considered a probable primary immunodeficiency as many patients have shown increased tendency for infections and abnormal levels of various immunoglobulins. Primary defect in NS is mutation in SPINK5 (serine protease inhibitor Kazal-type 5) gene which leads to the defective expression and function of lymphoepithelial Kazal-type-related inhibitor. We describe a case of a 7-year-old male born out of first-degree consanguineous marriage with findings of novel mutation, noninvolvement of the hair shaft, and unusual histopathology.

A child with erythroderma and hair defects

Erythroderma in the early years of life can have a wide array of differential diagnosis. We present a case of infantile erythroderma who presented to us at the age of 3 years with characteristic manifestations of ichthyosis linearis circumflexa and trichorrhexis invaginata, thus helping us arrive at a diagnosis of Netherton syndrome without the aid of expensive genetic analysis. This case is presented for its rarity and to highlight the importance of clinical examination of the appendages which may be an important clue to the diagnosis.

245 Successful treatment of Netherton syndrome with dupilumab

Netherton syndrome (NS) is a rare syndromic ichthyosis, characterized by erythroderma, ichthyosis linearis circumflexa, hair shaft defects and atopic diathesis. It is caused by biallelic SPINK5 mutations with deficient serine protease inhibitor LEKTI resulting in an activation of the KLK5-PAR2-TSLP signaling pathway, impaired skin barrier and inflammation. Treatment of NS is challenging, monoclonal antibodies targeting specific proinflammatory molecules are promising therapeutic approaches. Dupilumab inhibits by targeting IL4Ra both IL-4 and IL-13 signaling and is approved for the treatment of atopic dermatitis. Three adult patients with genetically confirmed NS were individually treated with dupilumab 300mg injections every two weeks for 8, 6 and 7 months, respectively. EASI scores at baseline were 30.0, 29.0 and 18.2. Total-IgE levels were 3352.0, 632.0 and 8270.0KU/L. Clinical improvement was observed after 8 weeks treatment. EASI scores improved continuously to 15.5, 16.9 and 9.0 after 24 weeks, respectively. Interestingly all patients showed an improvement in hair phenotype, particularly patient 1 noted a beard growth. Total-IgE significantly decreased around 50% (53.7+/-1.24) of baseline levels in all patients after 24 weeks of treatment. DLQI clearly improved with dupilumab. TEWL was measured in patient 1 at the lesional forearm and improved after 24 weeks (62.5 versus 37.5 g/m/h), indicating an amelioration in skin barrier function. Degree of erythema measured by mexameter did only slightly change. No severe side effects occured, yet two patients reported headache for up to two days after injection of dupilumab. These data for the first time show the potential use of dupilumab in NS.

Two siblings affected by Netherton/Comèl syndrome. Diagnostic pathology and description of a new SPINK5 variant

Netherton syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the SPINK5 gene encompassing three main clinical findings: 1) ichthyosiform dermatitis and/or ichthyosis linearis circumflexa, 2) hair shaft defects with peculiar "trichorrhexis invaginata" (bamboo pole hair) findings, 3) atopic dermatitis. We describe two siblings affected by Netherton/Comèl syndrome who were referred to our Center for Genodermatosis. A diagnostic pathway and the description of a new SPINK5 variant has been determined for these two patients. A novel genetic mutation has been found.

Netherton Syndrome: A Case Report and Review of Literature

Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by a triad of congenital ichthyosiform erythroderma (CIE) or ichthyosis linearis circumflexa (ILC), hair shaft abnormalities, and atopic diathesis (elevated serum IgE ). We report a case of a two-year-old boy presented with intractable pruritus, scaling, dry skin and generalized eczematous lesions resistant to atopic dermatitis therapy. Netherton syndrome misdiagnosed as atopic dermatitis due to the presence of eczematous skin lesions and allergic problems. The family counseled about the diagnosis and need of genetic testing for confirmation, but they refused for genetic testing. The patient got treatment with topical corticosteroids and skin moisturizers. There is no cure or satisfactory treatment currently available for NS. Further understanding of the underlying pathophysiology of integumentary changes will lead to more effective treatment. Netherton syndrome should be in the differential diagnosis when characteristic skin manifestation of CIE or ILC, and elevated serum IgE present.

Ichthyosis linearis circumflexa with bamboo hair: challenges in the diagnosis and management

A 15-year-old boy had persistent and refractory erythroderma since early childhood. His parents noticed polycyclic skin lesions and hair fragility around the age of 5 years. He was treated by...

Comèl–Netherton's syndrome in siblings

The syndrome is characterized by the association of two classical clinical presentations:“Trichorrhexis invaginata”, reported by Netherton and the“Ichthyosis linearis circumflexa”, described by Comel. Comel - Netherton syndrome is an autosomal recessive disorder characterized by congenital ichthyosis linearis circumflexa, hair shaft defects, atopy, markedly elevated IgE levels and immune deficiency.1,2,3 It is caused by mutation in Spink5 gene that encodes for protein Latki, which inhibits the enzyme serine proteinase, deficiency of which leads to desquamation of horny layer.4,5 We hereby report this case in a pair of siblings who presented with Ichthyosis linearis circumflexa, trichorrhexis invaginata, pili torti and atopic features. Investigations of skin, hair and blood confirmed the clinical findings. The case is being reported for its rare and classical occurrence.

Netherton syndrome presenting as recurrent erythroderma: A rare case report

Netherton syndrome (NS) is a rare autosomal recessive ichthyosiform disease. The incidence is 1 in 200,000. It is caused by mutation in the serine protease inhibitor Kazal-type 5 gene which encodes the lymphoepithelial Kazal type-related inhibitor. It presents with ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopy. A 20-year-old male presented with erythroderma and further examination revealed atopic features. Dermoscopy was a convenient tool in identifying trichorrhexis nodosa. We are reporting a case of NS presenting as recurrent erythroderma.

Ichthyosis Linearis Circumflexa as the Only Clinical Manifestation of Netherton Syndrome

Ichthyosis linearis circumflexa (ILC) presents as serpiginous and migratory erythematous patches with double-edged scales. ILC is rarely an isolated skin manifestation, but most commonly a part of Netherton syndrome (NS). NS is caused by SPINK5 mutations, which lead to absent or sometimes reduced expression of the serine protease inhibitor LEKTI. NS is characterised by congenital ichthyosiform erytroderma, trichorrhexis invaginata (TI) and atopy. We report 2 children who presented since the first months of life cheek erythema followed by the appearance of sparse ILC lesions on the face, trunk and proximal extremities. Erythroderma at birth, TI and atopy were absent. LEKTI immunoreactivity was reduced in patient epidermis, and serine protease activity was modestly increased, while desmoglein-1 expression remained unaffected. SPINK5 mutation and expression analysis in patient keratinocytes revealed compound heterozygous splicing variants, which allowed residual LEKTI secretion. Our results show that ILC can be the only clinical manifestation of NS.