French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

Personal, financial and time burden in inherited ichthyoses: A survey of 144 patients in a university-based setting.

BACKGROUND: Patients with inherited ichthyosis suffer from scaling due to mutations affecting the epidermal barrier. Symptomatic treatment with ointments, bathing and mechanical scale removal can alleviate the disease, but therapy is time and cost intensive. OBJECTIVES: We investigated costs, time and disease burden of ichthyoses. The study addresses difficulties of the healthcare situation for patients with ichthyoses and reveals potential improvements. MATERIALS AND METHODS: We developed a questionnaire addressing time and financial effort for the treatment. Additionally, we collected data of the Dermatology Life Quality Index (DLQI) and the Pruritus Life Quality (5PLQ) questionnaires to determine the impact of ichthyosis and associated pruritus on quality of life (QoL). RESULTS: We recruited 144 patients with ichthyosis (median age: 23; 53.5% female) from the Department of Dermatology in Muenster (Germany) and the German patient support group including common, rare and syndromic subtypes. Eighty-seven percent reported applying topical therapeutics at least once per day, 66.4% several times with an overall median duration of 15 min. Highest single expenditure of time was due to balneotherapy (n = 115; median bathing time: 40 min). In 81.9%, the health insurance did not completely cover the costs for topical treatment causing additional financial burden to the patient with a median of 71 € per quarter, herein creams being the largest cost factor (50 €). Patients with Netherton syndrome showed the highest median expenditure (170 €). The QoL impairment under treatment was moderate (median DLQI: 8.5 points). Pruritus was prevalent in 79.9% and showed a distinct impact on QoL (median 5PLQ: 7.5 points) without any significant difference between the subtypes (p = 0.37). CONCLUSION: Patients suffering from ichthyoses have a large and lifelong overall burden in mild and severe subtypes. Since continuous topical treatment is required, financial and psychosocial support needs to be considered beyond dermatological care.

Ictiosis epidermolítica en un recién nacido: reporte de un caso / Epidermolytic ichthyosis in newborns: clinical case study / Ictiose epidermolítica em recém-nascido: relato de caso

La ictiosis epidermolítica es una genodermatosis de herencia autosómica dominante poco frecuente que requiere un diagnóstico oportuno, idealmente prenatal, para así brindar una asistencia neonatal adecuada, iniciar un tratamiento precoz y de esta manera disminuir su morbimortalidad. Se caracteriza por la formación de ampollas, múltiples erosiones y descamación con eritrodermia desde el nacimiento. Todos los tipos de ictiosis queratinopáticas son causadas por mutaciones en los genes de la familia de queratina KRT1, KRT2 y KRT10. Se presenta el caso clínico de un neonato de 9 días de vida, nacido en el interior del país, con diagnóstico de ictiosis epidermolítica y antecedente familiar de primer grado con la misma enfermedad. El interés de esta publicación radica en la descripción de una genodermatosis de baja frecuencia, reconocer la importancia del diagnóstico precoz, conocer el manejo, las complicaciones y destacar la importancia de la atención por un equipo multidisciplinario conformado por neonatólogo, dermatólogos, genetistas y pediatras.

Epidermolytic ichthyosis is a rare genodermatosis with autosomal dominant inheritance, which requires timely diagnosis, ideally prenatal diagnosis, in order to provide adequate neonatal care, start early treatment and thus reduce morbidity and mortality. It is characterized by the formation of blisters, multiple erosions and scaling with erythroderma from birth. All types of keratinopathic ichthyoses are caused by mutations in the genes of the keratin family KRT1, KRT2 and KRT10. We present the clinical case of a 9-day-old newborn from the interior of the country, with diagnosis and family history of epidermolytic ichthyosis. The interest of this publication lies in the description of a low-frequency genodermatosis, recognizing the importance of early diagnosis, understanding the management, complications and highlighting the importance of a multidisciplinary care team integrated by a neonatologist, dermatologists, geneticists and pediatricians.

A ictiose epidermolítica é uma genodermatose autossômica dominante rara que requer diagnóstico oportuno, idealmente pré-natal, para fornecer cuidados neonatais adequados, iniciar o tratamento precoce e, assim, reduzir sua morbidade e mortalidade. Caracteriza-se pela formação de bolhas, múltiplas erosões e descamação com eritrodermia desde o nascimento. Todos os tipos de ictioses queratinopáticas são causados por mutações nos genes da família da queratina KRT1, KRT2 e KRT10. É apresentado o caso clínico de um recém-nascido de 9 dias, nascido no interior do país, com diagnóstico de ictiose epidermolítica e história familiar de primeiro grau com a mesma doença. O interesse desta publicação reside na descrição de uma genodermatose de baixa frequência, reconhecendo a importância do diagnóstico precoce, conhecendo o manejo, as complicações e destacando a importância do atendimento por uma equipe multidisciplinar composta por neonatologistas, dermatologistas, geneticistas e pediatras.

Otological problems in ichthyosis: A literature review.

BACKGROUND: Ichthyoses are a rare group of keratinization disorders characterized by scaling of the skin due to an impaired barrier function. Few studies have addressed ear involvement in patients with ichthyosis, although it is a probably underestimated aspect of the disease. OBJECTIVE: This study aims to provide an overview of the otological manifestations in ichthyosis and propose specific treatment options. METHODS: Articles were collected using PubMed, EMBASE, and Web of Science. A total of 53 articles were included in this literature review. RESULTS: The most common ear problem in patients with ichthyosis is scale accumulation in the ear canals, which can lead to conductive hearing loss and increases the risk of ear infections. Furthermore, some types of ichthyosis are associated with outer ear malformations. Lastly, sensorineural hearing loss is common in syndromic forms of ichthyosis. CONCLUSIONS: Otological problems are present in all types of ichthyoses and their treatment is challenging. The involvement of ear, nose, and throat specialists in the routine care of ichthyosis patients is essential for early identification and treatment of these manifestations. More research is needed to provide more insight into the otological problems in ichthyosis and to ameliorate treatment options.

Ichthyosis: presentation and management.

PURPOSE OF REVIEW: This review focuses on the presentation and management of ichthyoses and highlights recent advances in treatment that hold promise for better targeted therapy. RECENT FINDINGS: The ichthyoses are a group of rare genetic diseases with a wide phenotypic spectrum, characterized most often by generalized hyperkeratosis and scaling with variable erythema. The highly visible scaling and frequent itch contribute to decreased quality of life. Management for ichthyosis focuses on symptomatic relief and scale reduction with emollients, keratolytics, and retinoids. Recent advances in immune profiling and genotype-phenotype mapping have increased understanding of ichthyosis and shifted focus to pathogenesis-based targeted therapies with emerging biologics, small molecular inhibitors, and gene therapy. SUMMARY: This article discusses clinical assessment and genotyping to make the diagnosis of specific forms of ichthyosis, provides guidance for management, and reviews new treatment options with systemic agents.

Emergency approach in a rare congenital coexistence-ichthyosis and amniotic band syndrome.

Ichthyosis is caused by Mendelian cornification disorders. Hereditary ichthyoses are divided into non-syndromic and syndromic ichthy-oses. Amniotic band syndrome involves congenital anomalies that most frequently cause hand and leg rings. The bands can wrap around the developing body parts. In this study, it is aimed to present an emergency approach to amniotic band syndrome accompanying a case of congenital ichthyosis. We were asked by the neonatal intensive care unit to consult on the case of a 1-day-old baby boy. On physical examination, congenital bands were found to be present on both hands, the toes were rudimentary, skin scaling was present on the entire body, and the consistency of the skin was stiff. The right testicle was not in the scrotum. Other system examinations were normal. However, the blood circulation in the fingers in the distal of the band had become critical. With the help of sedation, the bands on the fingers were excised, and after the procedure, it was observed that the circulation in the fingers was more relaxed than it had been before the procedure. Coexistence of congenital ichthyosis and amniotic band is very rare. Emergency approach to these patients is very important in terms of saving the limb and preventing growth retardation in the limb. As further developments take place in terms of prenatal diagnoses, these cases will be able to be prevented through the early diagnosis and treatment.

Novel mixed-method, inclusive protocol involving global key stakeholders, including carers as experts, to co-develop relevant Caregiver-Reported Outcome Domains (CRODs) in skin disease.

INTRODUCTION: Ichthyoses comprise a heterogenous group of rare genetic skin disorders that involves the entire skin surface, often with additional syndromic features, and pose many clinical challenges. Without curative intervention, the mainstay of life-long symptom management is supportive in nature and can remain the responsibility of the caregiver. Although impact on the wider family is considered an important outcome of policies and services, there is a lack of caregiver consensus on what outcome domains to measure to fully assess the impact of ichthyosis on the patient and the caregiver. This project aims to identify a set of core outcome domains towards a core outcome set for ichthyosis that can measure all relevant concepts of ichthyosis in clinical practice, service delivery and research. METHODS AND ANALYSIS: Following the COMET (Core Outcome Measures in Effectiveness Trials) initiative, this project will employ a mixed-method study design which was developed using public and patient involvement and an international multidisciplinary expert group (clinical experts, patients and their representatives, policymakers, researchers and service providers). Experts by experience, or caregivers, will be recruited through online ichthyosis support groups. Phase one will focus on item generation and involve: (1) a systematic literature review, (2) a multimethods international qualitative study with ichthyosis caregivers and (3) co-development of items for an e-survey. Phase two, item refinement, will employ a novel four-pronged consensus approach: (1) an e-Delphi survey, (2) statistical analysis of e-Delphi survey results, (3) online qualitative feedback and (4) an online consensus discussion. All methodological considerations will be clearly linked with each Core Outcome Set-STAndards for Developing recommendation. ETHICS AND DISSEMINATION: Research Ethics Committee approval obtained from the School of Psychology, Ulster University (UK)(Ref:REC/20/0004). Results will be presented in published international peer-reviewed journals, at scientific meetings and support groups. REGISTRATION: COMET database (January 2019).

Inherited ichthyosis as a paradigm of rare skin disorders: Genomic medicine, pathogenesis, and management.

Great advances have been made in the field of heritable skin disorders using next-generation sequencing (NGS) technologies (ie, whole-genome sequencing, whole-exome sequencing, whole-transcriptome sequencing, and disease-targeted multigene panels). When NGS first became available, the cost and lack of access to these technologies were limiting factors; however, with decreasing sequencing costs and the expanding knowledge base of genetic skin diseases, fundamental awareness of NGS has become prudent. The heritable ichthyoses comprise a genotypically and phenotypically heterogeneous group of monogenic keratinization disorders characterized by persistent scaling, with at least 55 distinct genes currently implicated in causing nonsyndromic and syndromic forms of the disease. By providing a simplified overview of available NGS techniques and applying them in the context of ichthyosis, one of the most common genodermatoses, we hope to encourage dermatologists to offer, when appropriate, genetic testing earlier in patients with unsolved presentations. With the aid of NGS, dermatologists can provide diagnostic certainty in cases of suspected genodermatoses and offer potentially life-changing genome-guided and targeted therapies as they become available.

Treatments for Non-Syndromic Inherited Ichthyosis, Including Emergent Pathogenesis-Related Therapy.

The term 'inherited ichthyosis' refers to a heterogeneous group of mendelian disorders of cornification that involve the integument with varying degrees of scaling. The management of ichthyosis poses a challenge for most physicians. Treatment options proposed in the literature include moisturizers, topical keratolytics, topical and systemic vitamin D analogues, and topical and systemic retinoids; however, some of these modalities are less reliable than others. Despite the therapeutic impasse imposed by the options above, the emergence of pathogenesis-based treatments along with novel gene therapies appear promising and hold the potential to halt or even revert disorders that arise from single genetic mutations, although research is still quite lacking in this domain. Hence, this review aims to highlight the various treatment modalities available for the management of the cutaneous manifestations of non-syndromic inherited ichthyosis, with an added emphasis on pathogenesis-targeted therapies.

New developments in the molecular treatment of ichthyosis: review of the literature.

Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.

Current Strategies for the Gene Therapy of Autosomal Recessive Congenital Ichthyosis and Other Types of Inherited Ichthyosis.

Mutations in genes such as transglutaminase-1 (TGM1), which are responsible for the formation and normal functioning of a lipid barrier, lead to the development of autosomal recessive congenital ichthyosis (ARCI). ARCIs are characterized by varying degrees of hyperkeratosis and the presence of scales on the body surface since birth. The quality of life of patients is often significantly affected, and in order to alleviate the manifestations of the disease, symptomatic therapy with moisturizers, keratolytics, retinoids and other cosmetic substances is often used to improve the condition of the patients' skin. Graft transplantation is commonly used to correct defects of the eye. However, these approaches offer symptomatic treatment that does not restore the lost protein function or provide a long-term skin barrier. Gene and cell therapies are evolving as promising therapy for ARCIs that can correct the functional activity of altered proteins. However, these approaches are still at an early stage of development. This review discusses current studies of gene and cell therapy approaches for various types of ichthyosis and their further prospects for patient treatment.

Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies.

Inherited ichthyoses are a group of genodermatoses classified as either nonsyndromic or syndromic. Nonsyndromic ichthyoses and keratitis, ichthyosis and deafness (KID) syndrome predispose to fungal infection. The diagnosis and treatment of fungal infections underlying ichthyoses are challenging. In this review, we summarize reported cases of ichthyosis with fungal infection over the past 50 years. Atypical manifestations such as alopecia, papules and brittle nails occurred in patients with ichthyosis combined with fungal infection. Various pathogenic mechanisms have been implicated, including mutations of ichthyosis-related genes leading to disruption of the skin barrier via multiple pathways. Host immune disorders, including atopy and abnormal innate immunity also contribute to susceptibility. Specific fungi may escape the immune response. Extensive and recurrent fungal infections are not uncommon in patients with ichthyosis, making a cure more difficult and increasing the need for systemic antifungal therapy. Traditional and new ichthyosis treatments aiming to improve skin barrier function could help prevent fungal infection. In conclusion, the close relationship between ichthyosis and fungal infection is of vital importance in clinical practice and requires more attention from physicians. More studies are required to investigate the mechanisms and explore useful treatment strategies.

Managing syndromic congenital ichthyosis at a tertiary care institute-Genotype-phenotype correlations, and novel treatments.

Syndromic congenital ichthyoses (CI) are genetically determined disorders of cornification that are characterized by generalized scaling along with systemic symptoms. Data on congenital syndromic ichthyosis from developing countries are scarce. We aimed to assess the prevalence, phenotype-genotype correlation, and management of syndromic CI patients presenting to our outpatient during the specified period this was a retrospective study of congenital syndromic ichthyosis patients attending a dermatology clinic in a tertiary care center from 2105-2018. We reviewed epidemiological and comorbidities data, phenotype-genotype correlations, and treatments of syndromic congenital ichthyosis patients. Six patients of Syndromic CI were diagnosedamongst 86 patients of CI (8.1%). Amongst these, three patients of Sjogren-Larrson syndrome (SLS), two patients of Netherton syndrome (NS), and one of Chanarin-Dorfman disease (CDD) were reported. Next-generation sequencing (NGS) was performed with novel variants reported in one patient each of SLS, NS, and CDD. An atypical phenotype was observed in a patient with NS with associated growth hormone and adrenocorticotropic hormone deficiency but with favorable clinical response to intravenous immunoglobulin. Our reports point towards the unreported pool of genetic mutations in CI from India. Novel mutations were associated with variable cutaneous and systemic involvement.

Management of Ichthyosis: A Brief Review

The ichthyoses, also termed the disorders of keratinization, are a heterogenous group of skin diseases in which a distinctive horny layer arises secondary to excessive transepidermal water loss. Although occasionally acquired, the majority of ichthyoses are inherited and can be pinpointed to characteristic genetic mutations. Management depends on disease severity and includes topical agents and lifestyle modifications with or without oral retinoids. Genetic counseling is also an important consideration. This review aims to highlight advances in our understanding of disease pathogenesis as well as the holistic approach necessary to adequately manage ichthyosis patients.

Non-invasive methods for evaluation of skin manifestations in patients with ichthyosis.

Hereditary ichthyoses include a group of diseases characterized by hyperkeratosis, scaling, generalized xerosis, and is frequently associated with erythroderma. They are classified as syndromic and non-syndromic entities. The monitoring of the severity of ichthyosis requires different strategies for immediate analysis, which can comprise visual analogue scales or non-invasive quantitative methods, which collect information on disease progression that may contribute to the management of ichthyosis and aid in delineating clinical trials. In this article, we present a comprehensive review of the existing visual analogue scales, their validation, and their use in studies of disease severity and clinical trials. Interestingly, after many years of study, to date there is not a unanimously accepted tool for assessing the harshness of clinical features. Therefore, we discuss the perspectives of some non-invasive quantitative methods and strategies employed in clinical studies performed in patients with ichthyosis. Advances in these methods provide a rationale of their potential application in the evaluation of ichthyosis severity. Our purpose is to show an overview of non-invasive methodologies for the study of the harshness of ichthyosis.

Grover's Disease in a Kidney Transplant Recipient.

Dear Editor, It is not unusual for patients with renal insufficiency to develop skin pathologies. There are reports in the literature of increased incidence of calciphylaxis, pruritus, perforating dermatoses, and porphyria cutanea tarda in this patient population (1). Although it is quite rare, Grover's disease (GD) has been reported in several patients with renal insufficiency, but only once in a renal transplant recipient (2). The disease follows three patterns: persistently pruritic, transient eruptive, or a chronic asymptomatic course (3). Common risk factors concomitant with disease prevalence are immunosuppression, HIV, hemodialysis, viral and bacterial infections, malignancies, and other skin pathologies like contact and atopic dermatitis (4). A 60-year-old woman had a family history of polycystic kidney disease and was subsequently diagnosed in 1997. The patient had concomitant hepatic involvement and a stable aneurysm of the anterior cerebral artery. Consequently, the patient preemptively received a kidney transplant in 2015. The immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and prednisone with basiliximab induction. In 2017, a biopsy of the right thigh demonstrated squamous cell carcinoma in situ measuring 1×1cm in size. The lesion was treated with surgical excision. The patient also exhibited an erythematous brown macule with undefined borders on the left side of the nose with a size of 12 mm; it was later determined to be actinic keratosis. The lesion was treated successfully with cryotherapy. During this period, a fever prompted a PCR for BK virus DNA which showed a substantial amount of copies, measuring 28,850 copies/mL in urine and 98 copies/mL in blood. The mycophenolate dose was reduced, and tacrolimus trough concentration was maintained at between 3 and 5 µg/L. In 2018 the patient presented with multiple pruritic erythematous papules located on the trunk. Upon histological biopsy, there was dominant suprabasal acantholysis with numerous cells separating from the epithelium. Furthermore, there was a moderate amount of mononuclear infiltrate in the upper portion of the dermis and sparse suprabasal clefts (Figure 1). Clinical presentation and histologic examination were consistent with Grover's disease. The patient was treated topically with betamethasone cream twice daily for four weeks. The skin changes persisted for only a few weeks. The pathophysiological mechanism causing GD is still unknown. It is usually only a transient skin condition that lasts no more than a few weeks, but there have been more chronic cases lasting for years, particularly in patients on hemodialysis (5). The lesions commonly affect the chest area but may spread to diffusely envelope the body as erythematous papules, pustules, lichenoid lesions, or vesicles (2). Grover characterized 4 different subtypes based on the pathohistological findings as Darier-like (the most common), pemphigus vulgaris-like, Hailey-Hailey-like, or spongiotic subtype (3). The histological patterns are not exclusive to one patient and may even be found concomitantly in a single lesion. The condition is definitively diagnosed through histology, showing distinctive acantholysis along the epidermis with dyskeratosis that is described as "corps ronds" and "grains" (3). Grover's disease is more prevalent in middle-aged Caucasian men than any other group, with a 1.6-2.1 gender ratio (6). It was originally thought that the disease was caused by dysfunctional eccrine sweat glands, as the ailment was more common in patients that had increased perspiration either due to environmental heat, fever, or extensive bedrest. This idea was reinforced by histological evidence of atrophied sweat glands in uremic patients with renal insufficiency (7). Moreover, a case series and case report described remissions of GD in their patients on hemodialysis that received a renal transplant (5,8). However, subsequent studies have not supported an association with sweat dysfunction and disease development, while others have only managed to attribute sweat gland dysfunction as the primary trigger in 20-30% of cases (9). Conversely, cold dry air and xerosis cutis is thought to trigger the disease because it is four times more likely to be diagnosed in the winter months (10). Ultraviolet radiation has been identified as an exacerbating factor for GD, which could have been the trigger for onset of disease in our patient as demonstrated by her squamous cell carcinoma and actinic keratosis (11). Despite immunosuppression being a risk factor for GD, as shown by its association in patients with HIV, bone marrow transplantation, hemodialysis, and hematological malignancies, GD has been reported only once in the literature after a renal transplant (2,4). As our case, that patient developed GD a few years after transplant without an obvious trigger and the lesions appeared as red papules that were disseminated over the anterior thorax. Their patient's cutaneous lesion resolved spontaneously after 2 weeks and never returned in the 2.5-year follow-up period. Their patient has had two renal allografts over a 20 year timespan, while ours had had her graft for only two years. The immunosuppressive regimen was slightly different: cyclosporine, azathioprine, and methylprednisolone versus our combination of tacrolimus, mycophenolate mofetil, and prednisone. Grover's disease can be treated conservatively by avoiding risk factors such as UV light and sweating as well as and applying moisturizing emollients which may cause the lesion to resolve spontaneously. Medical therapy consists of topic corticosteroids, topical vitamin D analogues, oral retinoids, and oral corticosteroids, PUVA, and methotrexate for resistant cases (6,12). When a patient exhibits pruritic papules of the skin, GD should be considered in differential diagnosis, especially in kidney transplant patients and those on hemodialysis. While the condition is rare, increased recognition in this patient population will allow for studies to further characterize this poorly understood disease.