Lamellar ichthyosis with a novel NIPAL4 variant showing dramatic response to high-dose vitamin D therapy.

Therapeutic options are limited in cases of autosomal recessive congenital ichthyosis with inadequate response to topical agents. Acitretin is the current standard of care in these patients, but its use is limited by cumulative toxicity when prolonged therapy is needed in children. There is evidence to suggest that high doses of vitamin D can normalize keratinization and suppress inflammatory cytokines. Here, we report a patient with lamellar ichthyosis with a novel mutation in the Nipa-like Domain-Containing 4 (NIPAL4) gene. High dose short-term vitamin D therapy was administered with a dramatic and sustained clinical response.

Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP).

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.

SDR9C7 missense variant in a Chihuahua with non-epidermolytic ichthyosis.

Ichthyoses represent a heterogeneous group of cornification disorders that are associated with skin barrier defects. We investigated a 9-month-old Chihuahua showing excessive scale formation. Clinical and histopathological examinations revealed non-epidermolytic ichthyosis and a genetic defect was suspected. We therefore sequenced the genome of the affected dog and compared the data with 564 genetically diverse control genomes. Filtering for private variants identified a homozygous missense variant in SDR9C7, c.454C>T or p.(Arg152Trp). SDR9C7 is a known candidate gene for ichthyosis in humans and encodes the short-chain dehydrogenase/reductase family 9C member 7. The enzyme is involved in the production of a functional corneocyte lipid envelope (CLE), a crucial component of the epidermal barrier. Pathogenic variants in SDR9C7 have been described in human patients with autosomal recessive ichthyosis. We assume that the identified missense variant in the affected Chihuahua of this study impairs the normal enzymatic activity of SDR9C7 and thus prevents the formation of a functioning CLE, resulting in a defective skin barrier. To the best of our knowledge, this is the first report of a spontaneous SDR9C7 variant in domestic animals.

Developmental cataract in congenital ichthyosis.

A teenage boy who was previously diagnosed to have congenital ichthyosis presented to the eye clinic with complaints of gradually decreasing vision in both eyes since childhood. The best-corrected distance visual acuity was 20/125 in the right eye and 20/40 in the left eye. Clinical examination revealed developmental cataracts in both eyes. He underwent cataract surgery in the right eye and visual acuity improved to 20/25. Hence, we conclude that congenital ichthyosis can be associated with developmental cataracts. Cataract surgery helps in restoring vision in those with visually significant cataracts.

Acquired ichthyosis, asteatotic dermatitis or xerosis? An update on pathoetiology and drug-induced associations.

Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease. The hyperkeratosis in AI can range from the mild, white-to-brown scaling resembling that in ichthyosis vulgaris (IV) to the more prominent dark brown scaling phenotype, similar to that found in lamellar ichthyosis. The disease can wax and wane in relation to endogenous and/or exogenous factors. Histopathology of AI is similar to that found in IV. AI is usually of cosmetic concern to patients but can, in some cases, reflect the presence of more serious conditions, including malignancies, autoimmune diseases or metabolic disorders. In some cases, AI can be an adverse effect of a medication or the cutaneous symptom of a toxic exposure. Other conditions, such as severe xerosis or eczema, can present with clinical findings similar to AI, making diagnosis a challenge. Furthermore, cases of AI are sporadic throughout the literature and have been documented across a wide variety of medical settings distinct from dermatology, which often contribute to misdiagnosis of this disease. Definitive management requires prompt identification and treatment of the inciting factors combined with conservative therapies, which can include topical emollients, keratolytics, retinoids or corticosteroids, and in rare cases, oral retinoids.

Oral manifestations and dental approach in pediatric patient with lamellar congenital ichthyosis: 36-month follow-up

Introduction: Lamellar ichthyosis is an autosomal recessive congenital disease that causes dryness of the skin in the perioral region, which leads to pain during dental hygiene. Thus, the diet of patients with this disease tends to be pasty, which can lead to oral problems. Hyposalivation is suspected to be an oral manifestation of lamellar ichthyosis and may exert an influence on the incidence of carious lesions. Objective: Describe the treatment of a female patient diagnosed with lamellar ichthyosis who sought dental care initially when two years of age with complaints of dental pain, feeding difficulties and low weight. Case report: Atraumatic restorative treatment, extractions and topical application of fluoride varnish were performed in the patient, aesthetic of posterior installation of space, which also functioned as a rehabilitator. Conclusion: This study reinforces the need for the follow-up of the patient with LI by the dental surgeon since the birth of the first tooth, as dryness of the perioral skin and hyposalivation are conditions reported in individuals with lamellar ichthyosis. These conditions can affect oral hygiene and the frequency of carious lesions.

Introdução: A ictiose lamelar é uma doença congênita autossômica recessiva que causa ressecamento da pele na região peribucal, o que leva à dor durante a higiene dental, por isso a alimentação dos pacientes com essa doença tende a ser pastosa, podendo levar a problemas bucais. Suspeita-se que a hipossalivação possa ser uma manifestação oral da ictiose lamelar, podendo influenciar na incidência de lesões cariosas. Objetivo: Descrever o tratamento de uma paciente do sexo feminino, inicialmente com 2 anos de idade, diagnosticada com ictiose lamelar (IL), que procurou atendimento odontológico com queixa de dor dentária, dificuldade na alimentação e baixo peso. Relato do caso: Tratamento restaurador atraumático, exodontias e aplicação tópica de verniz fluoretado foram realizados na paciente, além de posterior instalação de mantenedor de espaço, o qual também funcionou como reabilitador estético. Conclusão: Este estudo reforça a necessidade do acompanhamento do paciente com IL pelo cirurgião dentista desde o nascimento do primeiro dente, pois secura da pele perioral e hipossalivação são condições relatadas em indivíduos com ictiose lamelar. Essas condições podem afetar a higiene bucal e a frequência de lesões cariosas.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies.

Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Harlequin fetus: A case report.

Harlequin ichthyosis (HI) is the most severe type of congenital ichthyosis. It is extremely rare with very few cases reported in India. It is inherited in an autosomal recessive fashion. The importance of antenatal diagnosis by ultrasonography, DNA-based molecular studies on chorionic villus sampling, and amniocentesis has been emphasized. We report a new case of HI in an infant, diagnosed postnatally by correlation of clinical and histopathological features on skin biopsy. The infant succumbed on the second day of birth despite intensive supportive care. A short review of the literature regarding the condition is also presented.

Development of a carbocysteine 10% + urea 5% cream for the topical treatment of congenital ichthyosis.

OBJECTIVE: Optimization of a topical formula of N-acetylcysteine and urea for  the topical treatment of ichthyosis. METHOD: We reviewed the chemical structure of the N-acetylcysteine molecule  and its metabolic processes. A search was conducted of possible alternative  molecules with a chemical structure similar to that of N-acetylcysteine that  could have improved organoleptic properties. The following databases were  used: PubChem®, Botplus®, the Drug Information Centre of the Spanish  Agency of Medicines and Medical Devices. The molecule selection criteria were  as follows: structural similarity, same therapeutic group, same mechanism of  action, same authorized indication, absence of unpleasant smell, and being  marketed as raw material in Spain. To complete the pharmaceutical  development and validation of the compound, several tests and controls were  conducted following the emulsion production procedure of the National  Formulary. In order to establish the validity period, we followed the  recommendations of the "Guide to Good Drug Preparation Practices in Hospital  Pharmacy Services". RESULTS: N-acetylcysteine has a free sulfhydryl group, which is responsible for  its smell, and undergoes deacetylation. Its main metabolites are cystine and  cysteamine. The following molecules were assessed: cystine, cysteamine,  carbocisteine, cysteine and methionine. Carbocisteine was selected because it met all the selection criteria. Carbocisteine is  ractically insoluble in water and soluble in mineral acids and alkaline hydroxides solutions. Unlike N-acetylcysteine, it does not have a fetid smell. It reaches its  maximum stability at pH 5.5 to 7.5. The composition of the compound (100 g)  was as follows: carbocisteine (10 g), urea (5 g), glycerine (15 g), water (44  mL), sodium hydroxide (1 g), and Neo PCL® Oil/Water (O/W) (25 g). It has an expiration period of 30 days. The organoleptic characteristics, emulsion type,  and pH remained stable within the established expiration period. The  arbocisteine compound has been incorporated into the group of topical  treatments available for the treatment of patients with ichthyosis in our  hospital. CONCLUSIONS: The carbocisteine molecule is a good therapeutic alternative that  lacks the unpleasant smell of N-acetylcysteine. The  arbocisteine compound developed has been included as topical treatment for  ichthyosis due to its tolerability, acceptability, and effectiveness in the  treatment of patients affected by this genodermatosis.

OBJETIVO: Optimización de una fórmula magistral tópica de N-acetilcisteína y urea para el tratamiento tópico de la ictiosis.Método: Se revisó la estructura química de la molécula de N-acetilcisteína y  sus procesos metabólicos. Se realizó una búsqueda de posibles moléculas  alternativas con una estructura química similar a la N-acetilcisteína que  pudiesen mejorar sus propiedades organolépticas. Bases de datos: PubChem®, Botplus®, Centro de Información de Medicamentos de la  Agencia Española de Medicamentos y Productos Sanitarios. Criterios de  selección de la molécula: similitud estructural, mismo grupo terapéutico,  mismo mecanismo de acción, misma indicación autorizada, ausencia de olor desagradable y estar comercializada como materia prima en España. Para el desarrollo galénico y validación de la fórmula se realizaron varios  ensayos y controles siguiendo el procedimiento de elaboración de emulsiones del Formulario Nacional. Para establecer el periodo de validez se  siguieron las recomendaciones de la "Guía de buenas prácticas de preparación  de medicamentos en los servicios de farmacia hospitalaria". RESULTADOS: La N-acetilcisteína presenta grupo sulfhidrilo libre, responsable del olor, sufre desacetilación y sus principales metabolitos son cistina y cisteamina. Las moléculas evaluadas fueron: cistina, cisteamina, carbocisteína, cisteína y metionina. Se seleccionó la carbocisteína  por  cumplir todos los criterios de selección. La carbocisteína es prácticamente insoluble en agua y soluble en disoluciones de ácidos minerales e hidróxidos  alcalinos. A diferencia de la N-acetilcisteína, carece de olor fétido.Presenta su  máxima estabilidad a pH 5,5-7,5. La composición de la fórmula magistral (100  g): carbocisteína (10 g), urea (5 g), glicerina (15 g), agua (44 ml), hidróxido  sódico (1 g) y Neo PCL® Oil/Water (O/W) (25 g). Periodo de caducidad: 30  días. Los caracteres organolépticos, signo de la emulsión y pH permanecieron  estables durante el periodo de caducidad establecido. La fórmula magistral de  carbocisteína elaborada se ha incorporado al arsenal de tratamientos tópicos  disponibles para los pacientes con ictiosis de nuestro centro. CONCLUSIONES: La molécula de carbocisteína resultó ser una buena alternativa  terapéutica que subsana el olor desagradable de la N-acetilcisteína. La fórmula  magistral de carbocisteína desarrollada fue incluida como tratamiento tópico de  la ictiosis gracias a su tolerabilidad, aceptabilidad y efectividad en el  tratamiento de pacientes afectos de esta genodermatosis.

[Clinical and genetic analysis of a patient with autosomal recessive congenital ichthyosis due to compound heterozygous variants of ALOX12B gene].

OBJECTIVE: To explore the clinical and genetic characteristics of a pediatric patient suspected for Autosomal Recessive Congenital Ichthyosis (ARCI). METHODS: Clinical data of the patient was analyzed. Peripheral blood samples were collected from the patient and his parents for the extraction of genomic DNA. Next-generation sequencing (NGS) was then carried out. Candidate variants were confirmed by Sanger sequencing. A variety of bioinformatic tools including Mutation Taster, PROVEAN, and PolyPhen2 were used to predict the pathogenicity of the variants based on guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patient, a 1-month-and-7-day-old male, had presented with cutaneous erythema and fine scaling of the whole body. NGS revealed that he has harbored compound heterozygous variants c.1579G>A (p.Val527Met) (paternal) and c.923T>C (p.Leu308Pro) (maternal) of the ALOX12B gene. The former was known to be likely pathogenic, while the latter was unreported previously and categorized as "likely pathogenic" based on the ACMG guidelines. Based on the clinical and genetic findings, the patient was diagnosed with ARCI. CONCLUSION: The c.1579G>A and c.923T>C variants of the ALOX12B genes probably underlay the ARCI in this patient. Above finding has enriched the spectrum of ALOX12B mutations and enabled molecular diagnosis of the patient, based on which genetic counseling and prenatal diagnosis may be provided.

Acral Melanoma in an Elderly Patient with Congenital Ichthyosis Vulgaris.

Ichthyoses are a heterogeneous group of skin disorders featuring erythroderma and generalized scaling. The relationship between ichthyosis and melanoma has not been well-characterized. Herein we present a unique case of acral melanoma of the palm developing in an elderly patient with congenital ichthyosis vulgaris. Biopsy revealed a superficially spreading melanoma with ulceration. To the best of our knowledge, no acral melanomas have been reported so far in patients with congenital ichthyosis. Nevertheless, considering the potential for invasion and metastasis, patients with ichthyosis vulgaris should undergo regular clinical and dermatoscopic screening for melanoma.

A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle.

The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle.

A multicenter study on quality of life of the "greater patient" in congenital ichthyoses.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) are a genetically heterogeneous group of rare and chronic disorders characterized by generalized skin scaling and hyperkeratosis, erythroderma, and palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking problems, recurrent infections, as well as pruritus and pain. No curative therapy is available and disease care mainly relies on daily application of topical emollients and keratolytics to the whole-body surface. Altogether, disease signs and symptoms and treatment modalities have a major impact on quality of life of patients and their caregivers. However, very few studies have evaluated the family disease burden in ARCI. METHODS: We have performed an Italian multicenter cross-sectional study to assess the secondary disease impact on family members of pediatric and adult patients with ARCI, using a validated dermatology-specific questionnaire, the family dermatology life quality index (FDLQI). Disease severity was assessed by the dermatologist in each center. RESULTS: Seventy-eight out of 82 patients who were accompanied by at least one family member filled the FDLQI. Forty-eight (61.5%) patients were aged less than 18 years. The mean FDLQI score was 10.3 (median 10), and the most affected dimensions were (1) time needed for care, (2) extra-housework, and (3) household expenditure. Higher total FDLQI score significantly correlated with more severe disease score (P = 0.003). Features associated with greater family burden included recurrent infections (P = 0.004), foul-smell (P = 0.009), palmoplantar keratoderma (P = 0.041), but also presence of scales on the face (P = 0.039) and ear deformities (P = 0.016). CONCLUSIONS: Our findings highlight the major socio-economic and psychological burden imposed by ARCI on the QoL of family caregivers. In addition, they show that global evaluation of disease impact also on family members is an essential part of patient-reported outcomes. Finally, our data underline the need to develop specific measures for family support.

Preclinical Evaluation of a Modified Herpes Simplex Virus Type 1 Vector Encoding Human TGM1 for the Treatment of Autosomal Recessive Congenital Ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a diverse group of cornification diseases associated with severe clinical complications and decreased quality of life. Germline mutations in the TGM1 gene, which encodes the enzyme TGM1, are the predominant cause of ARCI. These TGM1 mutations trigger the abnormal epidermal differentiation and impaired cutaneous barrier function observed in patients with ARCI. Unfortunately, current ARCI therapies focus solely on symptomatic relief. Thus, there is a significant unmet need for therapeutic strategies aimed at correcting the TGM1 deficiency underlying ARCI. In this study, we investigated the ability of KB105, a gene therapy vector encoding full-length human TGM1, to deliver functional human TGM1 to keratinocytes. In vitro, KB105 efficiently infected TGM1-deficient human keratinocytes, produced TGM1 protein, and rescued transglutaminase enzyme function. In vivo studies demonstrated that both single and repeated topical KB105 administration induced TGM1 protein expression in the target epidermal layer without triggering fibrosis, necrosis, or acute inflammation. Toxicity and biodistribution assessments on repeat dosing indicated that KB105 was well-tolerated and restricted to the dose site. Overall, our results demonstrate that rescuing TGM1 deficiency in patients with ARCI through topical KB105 application represents a promising strategy for safely and noninvasively treating this debilitating disease.