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.

Characteristics and outcomes for participants with congenital ichthyosis who responded to treatment with the topical isotretinoin formulation TMB-001: results from the Phase IIb CONTROL study.

BACKGROUND: Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis (CI). Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects. OBJECTIVES: This analysis from the randomized Phase IIb CONTROL study investigated the characteristics of participants who responded to treatment with TMB-001, a novel topical isotretinoin ointment formulation. METHODS: Participants ≥ 9 years of age with genetically confirmed CI and ≥ 2 (out of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%, TMB-001 0.1% or vehicle, twice daily for 12 weeks. Efficacy endpoints included the proportion of participants with ≥ 50% reduction in VIIS-scaling (VIIS-50) compared with baseline and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score compared with baseline. Changes in body surface area (BSA) involvement, Dermatology Life Quality Index (DLQI) scores and Itch-Numeric Rating Scale (I-NRS) scores were assessed. RESULTS: Among the 33 participants (11 randomized to TMB-001 0.05%, 10 to TMB-001 0.1% and 12 to vehicle), median age was 29 years (range 9-80), and most were male (64%) and White (79%). Baseline demographics were generally similar among participants who did or did not achieve TMB-001 treatment success. Participants who had lower mean BSA involvement and higher DLQI and I-NRS scores at baseline were more likely to achieve VIIS-50. Similarly, higher baseline DLQI and I-NRS scores were associated with IGA response; BSA involvement was similar for IGA responders vs. nonresponders. CONCLUSIONS: Higher DLQI and I-NRS scores at baseline were associated with participants achieving treatment success by VIIS-50 and IGA response. Lower BSA involvement was associated with VIIS-50 success.

Phase IIb randomized CONTROL study demonstrates a novel topical isotretinoin formulation, TMB-001, is safe and effective in participants with either recessive X-linked or autosomal recessive lamellar congenital ichthyosis.

BACKGROUND: In two severe congenital ichthyosis subtypes, autosomal recessive lamellar ichthyosis (ARCI-LI) and X-linked recessive ichthyosis (XLRI), cutaneous manifestations include widespread scaling. Approved topical treatment options are limited to emollients and keratolytics. AIM: This analysis from the randomized phase IIb CONTROL study assessed whether the efficacy and safety of TMB-001, a novel topical isotretinoin ointment formulation, differed between ARCI-LI and XLRI subtypes. METHODS: Participants ≥ 9 years with genetically confirmed XLRI or ARCI-LI and ≥ 2 (of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%/TMB-001 0.1%/vehicle, twice daily for 12 weeks. The proportion of participants with ≥ 50% reduction vs. baseline in VIIS scaling (VIIS 50; primary endpoint) and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score vs. baseline (key secondary endpoint) were evaluated. Adverse events (AEs) were monitored. RESULTS: Among enrolled participants (TMB-001 0.05%, n = 11; 0.1%, n = 10; and vehicle, n = 12), 52% had ARCI-LI and 48% XLRI subtypes. Mean age was 33.6 and 35.4 years for participants with ARCI-LI and XLRI, respectively. Overall, 33%, 50% and 17% of participants with ARCI-LI and 100%, 33% and 75% of participants with XLRI achieved VIIS 50 in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.24 for 0.05% vs. vehicle, intent-to-treat population). Improvement of ≥ 2-grade IGA score was observed in 33%, 50% and 0% of participants with ARCI-LI and 83%, 33% and 25% of participants with XLRI in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population). Most AEs were application-site reactions. CONCLUSION: Regardless of congenital ichthyosis subtype, TMB-001 demonstrated greater proportions of participants achieving VIIS 50 and ≥ 2-grade IGA improvement vs. vehicle.

Secukinumab responses vary across the spectrum of congenital ichthyosis in adults.

IMPORTANCE: Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity. OBJECTIVE: To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes. DESIGN: Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively. SETTING: Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York. PARTICIPANTS: Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma. RESULTS: IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels. LIMITATIONS: Small sample size; heterogeneous ichthyosis subsets. CONCLUSION: IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses. GOV REGISTRATION NUMBER: NCT03041038; first posted on 02/02/2017.

Formulación magistral en pacientes con genodermatosis. Impacto en la calidad de vida: un estudio transversal / Effect of Drug Compounding on Quality of Life in Patients With Genodermatoses: A Cross-Sectional Study

Introducción El abordaje terapéutico de las manifestaciones cutáneas de las enfermedades raras es complejo. El objetivo principal de este trabajo consistió en determinar el impacto de la formulación magistral de dispensación hospitalaria en la calidad de vida de los pacientes con genodermatosis. Material y métodos Se diseñó un estudio descriptivo transversal. Se incluyeron pacientes con genodermatosis que recibieron tratamientos tópicos elaborados y dispensados por el Servicio de Farmacia Hospitalaria del Complejo Hospitalario Universitario de Pontevedra. Se recogieron datos demográficos, cuestionarios generales y específicos sobre la calidad de vida, y cuestionarios que evaluaban los tratamientos administrados y la adherencia terapéutica. Resultados Se incluyeron 9 pacientes. Se observó que, tras la terapia con fórmulas magistrales, hubo una reducción estadísticamente significativa del impacto en la calidad de vida de los pacientes. La satisfacción con los productos fue 2,8 sobre 25 (siendo 0 la mejor puntuación). La adherencia terapéutica superó el 89%. Conclusiones La formulación magistral permite el acceso a medicamentos huérfanos y no comercializados para numerosas enfermedades raras. Su impacto en la calidad de vida de los pacientes afectos de estas enfermedades ha sido escasamente estudiado. En la serie de pacientes que se presenta, la elaboración y dispensación hospitalaria de fórmulas magistrales específicas conllevó efectos positivos en su calidad de vida. Este estudio inicial ha derivado en otro trabajo multicéntrico, centrado en las ictiosis, donde previsiblemente aumentará el número de pacientes a incluir y permitirá confirmar nuestros resultados (AU)

Background Cutaneous manifestations are complicated to treat in rare diseases. The main aim of this study was to analyze the impact of compounded drugs prepared by hospital pharmacists on the quality of life of patients with genodermatoses. Material and methods We undertook a cross-sectional study of patients with genodermatoses treated with topical medications compounded and dispensed by the pharmacy at Complejo Hospitalario Universitario in Pontevedra, Spain. We collected demographic data and answers to questionnaires examining generic and disease-specific quality of life, treatment satisfaction, and treatment adherence.Results Nine patients were included. We observed a significant improvement in health-related quality of life following treatment with compounded drugs. Satisfaction with the topical medications was 2.8 on a scale of 0 (greatest satisfaction) to 25. Treatment adherence was 59%. Conclusions Drug compounding facilitates access to orphan drugs that are not available for many rare diseases. Few studies, however, have analyzed impact on quality of life in this setting. In this series of patients with genodermatoses, topical medications compounded and dispensed by a hospital pharmacy improved health-related quality of life. This preliminary study has given rise to a multicenter study of compounding for ichthyosis. We expect that analysis of a larger sample will confirm our findings (AU)

[Translated article] Effect of Drug Compounding on Quality of Life in Patients With Genodermatoses: A Cross-Sectional Study / Formulación magistral en pacientes con genodermatosis. Impacto en la calidad de vida: un estudio transversal

Background Cutaneous manifestations are complicated to treat in rare diseases. The main aim of this study was to analyze the impact of compounded drugs prepared by hospital pharmacists on the quality of life of patients with genodermatoses. Material and methods We undertook a cross-sectional study of patients with genodermatoses treated with topical medications compounded and dispensed by the pharmacy at Complejo Hospitalario Universitario in Pontevedra, Spain. We collected demographic data and answers to questionnaires examining generic and disease-specific quality of life, treatment satisfaction, and treatment adherence.Results Nine patients were included. We observed a significant improvement in health-related quality of life following treatment with compounded drugs. Satisfaction with the topical medications was 2.8 on a scale of 0 (greatest satisfaction) to 25. Treatment adherence was 59%. Conclusions Drug compounding facilitates access to orphan drugs that are not available for many rare diseases. Few studies, however, have analyzed impact on quality of life in this setting. In this series of patients with genodermatoses, topical medications compounded and dispensed by a hospital pharmacy improved health-related quality of life. This preliminary study has given rise to a multicenter study of compounding for ichthyosis. We expect that analysis of a larger sample will confirm our findings (AU)

Introducción El abordaje terapéutico de las manifestaciones cutáneas de las enfermedades raras es complejo. El objetivo principal de este trabajo consistió en determinar el impacto de la formulación magistral de dispensación hospitalaria en la calidad de vida de los pacientes con genodermatosis. Material y métodos Se diseñó un estudio descriptivo transversal. Se incluyeron pacientes con genodermatosis que recibieron tratamientos tópicos elaborados y dispensados por el Servicio de Farmacia Hospitalaria del Complejo Hospitalario Universitario de Pontevedra. Se recogieron datos demográficos, cuestionarios generales y específicos sobre la calidad de vida, y cuestionarios que evaluaban los tratamientos administrados y la adherencia terapéutica. Resultados Se incluyeron 9 pacientes. Se observó que, tras la terapia con fórmulas magistrales, hubo una reducción estadísticamente significativa del impacto en la calidad de vida de los pacientes. La satisfacción con los productos fue 2,8 sobre 25 (siendo 0 la mejor puntuación). La adherencia terapéutica superó el 89%. Conclusiones La formulación magistral permite el acceso a medicamentos huérfanos y no comercializados para numerosas enfermedades raras. Su impacto en la calidad de vida de los pacientes afectos de estas enfermedades ha sido escasamente estudiado. En la serie de pacientes que se presenta, la elaboración y dispensación hospitalaria de fórmulas magistrales específicas conllevó efectos positivos en su calidad de vida. Este estudio inicial ha derivado en otro trabajo multicéntrico, centrado en las ictiosis, donde previsiblemente aumentará el número de pacientes a incluir y permitirá confirmar nuestros resultados (AU)

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.

Juvenile idiopathic arthritis in Harlequin ichthyosis, a rare combination or the clinical spectrum of the disease? Report of a child treated with etanercept and review of the literature.

BACKGROUND: Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases. CASE PRESENTATION: We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events. CONCLUSION: The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.

Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis.

Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.

3D model of harlequin ichthyosis reveals inflammatory therapeutic targets.

The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.

Ictiosis Lamelar autosómica recesiva: revisión de la literatura y caso clínico / Autosomal recessive lamellar ichthyosis: review of the literature and clinical case

Resumen Las ictiosis congénitas autosómicas recesivas (ICAR) son poco frecuentes a nivel mundial con una incidencia de 1:300,000 nacimientos, se caracterizan por trastornos de la queratinización, entre sus variantes engloban las formas no sindrómicas de ictiosis, como la ictiosis laminar (IL), la eritrodermiaictiosiforme congénita (EIC) y actualmente se incluyen la ictiosis arlequín, el bebé colodión autorresolutivo, el bebé colodión autorresolutivoacral y la ictiosis en traje de baño. Desde el punto de vista genético son heterogéneas, originadas por una mutación en el gen de la transglutaminasa 1 y se las haasociado a TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 y ABCA12. Clínicamente, la ictiosis se caracteriza principalmente por piel gruesa, escamas laminares adherentes con hendiduras profundas. En este trabajo pretende revisar los conocimientos actuales en el campo de las ICAR, incluyendo aspectos clínicos, histológicos, ultraestructurales, genético-moleculares, tratamiento,y también su manejo clínico.

Abstract The autosomal recessive congenital ichthyosis (ARCI) is a rare worldwide condition with an incidence of (1: 300,000 births), characterized by disorders of keratinization, among its variants encompass the non-syndromic forms of ichthyosis, such as laminar ichthyosis (IL) , congenital ichthyosiform erythroderma (EIC) and currently include harlequin ichthyosis, self-healing colodion baby, acral self-healing colodion baby and ichthyosis in swimsuits. From a genetic point of view, they're heterogeneous, originated by a mutation in the gene of transglutaminase 1 and associated with TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 and ABCA12. Clinically, ichthyosis is mainly characterized by thick skin, adherent lamellar scales with deep clefts. The aim of this work is to review the current knowledge in the field of ICAR, including clinical, histological, ultrastructural, genetic-molecular and therapeutic aspects as well as its clinical management.

Non-surgical management of congenital ichthyosis using hyaluronic acid gel injection.

AIM: To test if hyaluronic acid gel injection in the upper eyelid achieves correction of congenital cicatricial ectropion and reduction in lagophthalmos, in preparation for intraocular surgery. METHODS: This case reports the long-term outcome of hyaluronic acid gel injection in the upper eyelid for the correction of ectropion prior to cataract surgery. One millilitre of hyaluronic acid gel was injected in both the upper eyelids of a child with congenital ichthyosis in the suborbicularis plane, prior to cataract surgery. RESULTS: Lagophthalmos reduced by 15 mm in the right eye and 13 mm in the left eye. Subsequently, the child underwent cataract surgery without any complications. CONCLUSION: We demonstrate the long-term outcome of using hyaluronic acid gel injection for successful, non-surgical correction of cicatricial ectropion in ichthyosis.

Autosomal recessive congenital ichthyosis due to homozygous variants in NIPAL4 with a dramatic response to ustekinumab.

Autosomal recessive congenital ichthyosis is a genetically and phenotypically heterogenous group of scaling skin disorders. We describe a patient with ARCI caused by homozygous variants in NIPAL4, in whom the dermatologic phenotype and an associated arthropathy, markedly improved with ustekinumab.

A harlequin ichthyosis pig model with a novel ABCA12 mutation can be rescued by acitretin treatment.

Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.

Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses.

Importance: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders caused by defects in signaling pathways involved in epidermal proliferation and differentiation, leading to a wide range of skin manifestations. Therapeutic options are limited and often unsatisfactory. Topical cholesterol and statin as a combined formulation has proven successful in the treatment of patients with CHILD syndrome (congenital hemidysplasia ichthyosis and limb defects). Objective: To assess change in disease severity score after a 3-month therapeutic regimen consisting of a glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. Design, Setting, and Participants: This case series of 15 patients with ARCI was conducted at the American University of Beirut, a referral center in the Middle East region for genodermatoses, between May 2017 and January 2018. No age groups were excluded; all patients were from the Middle East area; and all were initially not responsive to treatment with hydrating creams in combination with urea creams, 30% to 40%, or glycolic acid, 10% to 20%. Excluded were patients who had been taking systemic retinoids within 3 months before the start of the study. Interventions: A 3-month therapeutic regimen of glycolic acid, 10% to 20%, cream and a combination of lovastatin, 2%, with cholesterol, 2%, cream. Main Outcomes and Measures: Percentage change in disease severity scores following 2 and 3 months of study treatment. Results: Of the 15 patients included in the study, 10 were male (mean age, 11.2 years; age range, 2-38 years). The average percentage reduction in the disease severity score was 33.7% at 2 months (from 60.8 to 40.2) and 57.5% at 3 months (from 60.8 to 21.9). Adverse effects were mild and consisted mainly of irritation and burning. Conclusions and Relevance: These findings suggest a benefit from a treatment regimen consisting of glycolic acid, 10% to 20%, and a combination of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. This combination of creams might also prove to be beneficial in other types of ichthyoses and other dermatological diseases with a defective skin barrier.

Long-term safety and efficacy of continuous acitretin monotherapy for three children with different severe hyperkeratotic disorders in China.

Long-term systemic treatment with acitretin for severe hyperkeratotic disorders is needed to maintain quality of life of afflicted patients, but treatment has been limited owing to its potential side-effects including skeletal malformations, particularly for children during their growth and development. A retrospective investigation was conducted with three children afflicted with a severe hyperkeratotic disorder, namely Darier's disease, bullous ichthyosiform erythroderma or lamellar ichthyosis, who were continuously maintained on 0.2-0.3 mg/kg per day acitretin for more than 12 years after an initial period at a larger acitretin dose to bring each disease under control. The patients had good responses to acitretin treatment, which was assessed for safety, skeletal abnormalities, growth retardation and other potential side-effects. Acitretin monotherapy was an effective treatment for these children, and maintenance doses were well tolerated with no skeletal or other observable side-effects during the course of the study.