Presentation of ichthyosis after substrate reduction therapy in Gaucher type 1.

We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat. There are no reports of ichthyosis in the literature in enzyme replacement or SRT for Gaucher disease. Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?

Revisiting X-linked congenital ichthyosis.

X-linked recessive ichthyosis (XLI) is a hereditary skin disease characterized by generalized dryness and scaling of the skin, with frequent extracutaneous manifestations. It is the second most common type of ichthyosis, with a prevalence of 1/6,000 to 1/2,000 in males and without any racial or geographical differences. The causative gene for XLI is the steroid sulfatase gene (STS), located on Xp22.3. STS deficiency causes an abnormal cholesterol sulfate (CS) accumulation in the stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction and scaling abnormalities. This review summarizes XLI's genetic, clinical, and pathological features, pathogenesis, diagnosis and differential diagnoses, and therapeutic perspectives. Further understanding the role of the STS gene pathogenic variants in XLI may contribute to a more accurate and efficient clinical diagnosis of XLI and provide novel strategies for its treatment and prenatal diagnosis.

X-linked ichthyosis presenting with cryptorchidism for orchidopexy: A rare anesthetic encounter and case report.

Key Clinical Message: Cutaneous scaling and associated clinical syndrome displayed in X-linked ichthyosis mandates multidisciplinary care. Patient with ichthyosis confronts a numerous challenge to an anesthesiologist and demands a rigorous management. As these patients are very vulnerable perioperatively, meticulous care and support are utmost. Abstract: Ichthyosis is a group of genetic conditions distinguished by the appearance of hyperkeratotic scales on the skin's surface. X-linked ichthyosis results from a mutation in the steroid sulfatase (STS) gene, which encodes the steroid sulfatase enzyme. Here we report a case of a 6-year-old child with X-linked ichthyosis. He presented to our operation theater for correction of left-sided undescended testis and underwent surgery uneventfully. To handle X-linked ichthyosis perioperatively, meticulous planning and efficient anesthetic administration are critical.

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

Advances in genetics research for skin diseases such as epidermolysis bullosa and ichthyosis have led to the discovery of many new subtypes of these severe skin conditions. Identifying new subtypes has in turn led to new treatments for these conditions, including gene and cell therapies. Gene and cell therapies aim to address the underlying genetic causes of disease and have already shown success in the clinic. While the development of such treatments for rare skin diseases has been limited, there are notable examples of gene and cell therapies developed for epidermolysis bullosa and ichthyosis. This review highlights recent developments in gene and cell therapy for epidermolysis bullosa and ichthyosis, including a newly approved gene therapy for recessive dystrophic epidermolysis bullosa.

Netherton Syndrome in Thai Children: A Report of Two Cases With a Literature Review.

Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by the triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis. We report two cases that experienced severe congenital exfoliative dermatitis, recurrent infections, and allergic conditions. Examinations of hair under the light microscope revealed trichorrhexis invaginata. Whole exome sequencing identified homologous pathogenic mutations of SPINK5. Optimal skincare and proper nutritional support could improve patients' quality of life.

Exploring the Co-occurrence of dermatophyte infection and ichthyosis: A report of 3 cases.

Dermatophyte infections frequently pose diagnostic challenges, especially when occurring alongside ichthyosis, a genetic skin disorder characterized by dry, thickened, scaly skin. This case series outlines three cases where dermatophyte infections overlapped with ichthyosis, emphasizing the complexities in clinical identification and differential diagnosis. Atypical clinical presentations in these cases led to initial misdiagnoses. Ichthyosis, a genetic skin disorder characterized by thickened and scaly skin, creates an environment conducive to dermatophyte settlement, complicating the diagnostic process. The cases highlight the importance of considering fungal infections, even when clinical features deviate from the expected course. A vigilant diagnostic approach, including mycological examinations, is crucial for accurate identification and timely management.

Variants in the L12 linker domain of KRT10 are causal to atypical epidermolytic ichthyosis.

Epidermolytic ichthyosis (EI) is a type of congenital ichthyosis, characterized by erythema and blistering at birth followed by hyperkeratosis. EI is caused by pathogenic variants in the genes KRT1 and KRT10, encoding the proteins keratin 1 (KRT1) and keratin 10 (KRT10), respectively, and is primarily transmitted by autosomal-dominant inheritance, although recessive inheritance caused by nonsense variants in KRT10 is also described. The keratins form a network of intermediate filaments and are a structural component of the cytoskeleton, giving strength and resilience to the skin. We present three cases of mild EI caused by pathogenic KRT10 variations in the L12 linker domain. To our knowledge, this is the first time L12 linker domain pathogenic variants are identified in KRT10 for EI. The aim of this study was to identify gene variants for patients with EI in KRT1 or KRT10. To establish the pathogenicity of the found variations in KRT10, we evaluated all patients and available family members clinically. Genetic analyses were performed using Sanger sequencing. Vectors containing wild-type or mutated forms of KRT10 were transfected into HaCaT cells and analyzed by high-resolution confocal microscopy. Genetic analysis of KRT10 identified a heterozygous de novo variant c.910G>A p.(Val304Met) in family 1, a familial heterozygous variant c.911T>C p.(Val304Ala) in family 2, and a familial heterozygous variant c.917T>C p.(Met306Thr) in family 3. All identified missense variants were located in the L12 linker domain of KRT10. In vitro study of aggregate formation of the missense variants in KRT10 only showed a very mild and not quantifiable aggregate formation in the KRT10 network, compared with the wild-type sequence. We report three different novel missense variants in the L12 linker domain of KRT10 in patients with an atypical, milder form of EI resembling peeling skin syndrome.

HELIX Syndrome, a Claudinopathy with Relevant Dermatological Manifestations: Report of Two New Cases.

HELIX syndrome (Hypohidrosis-Electrolyte disturbances-hypoLacrimia-Ichthyosis-Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic CLDN10 variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, highlight the skin anomalies as an important clue, and expand the genotypic spectrum. Two adult brothers from consanguineous parents with suspected ectodermal dysplasia (ED) since early childhood were re-evaluated. A comprehensive phenotypic exam and an aCGH + SNP4 × 180 K microarray followed by Sanger sequencing of the CLDN10 gene were performed. They presented hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, palm hyperlinearity, alacrima, and xerostomia. In adulthood, they also developed a salt-losing nephropathy with hypokalemia and hypermagnesemia. The molecular study in both patients revealed a novel pathogenic homozygous deletion of 8 nucleotides in exon 2 of the CLDN10 gene [CLDN10 (NM_0006984.4): c.322_329delGGCTCCGA, p.Gly108fs*] leading to a premature truncation of the protein. Both parents were heterozygous carriers. Hypohidrosis, ichthyosis, and plantar keratosis associated with alacrima and xerostomia should raise suspicion for HELIX syndrome, which also includes nephropathy and electrolyte disturbances in adults. Given the potential for ED misdiagnosis in infancy, it is important to include the CLDN10 gene in a specific genodermatosis next-generation sequencing (NGS) panel to provide early diagnosis, accurate management, and genetic counseling.

Four cases of Chanarin-Dorfman syndrome presenting with different types of erythrokeratoderma.

Chanarin-Dorfman syndrome (CDS) is a multisystem autosomal recessive disorder due to variants of the ABHD5 gene, characterized by lipid vacuoles in the liver and leukocytes, and possible involvement of eyes, ears, skeletal muscle, and central nervous system. CDS may present with skin changes, most commonly congenital non- bullous ichthyosiform erythroderma, however erythrokeratoderma-like findings have been rarely reported in CDS patients. Herein, we report clinical, histopathological and genetic findings of four patients with CDS presenting with different clinical forms of erythrokeratoderma (three with progressive symmetric erythrokeratoderma-like features and one with erythrokeratoderma variabilis (EKV)-like features), including one patient with a novel mutation in ABHD5. Although the typical skin finding of CDS syndrome is reported as non-bullous congenital ichthyosiform erythroderma, CDS should also be in the differential diagnosis in patients with EKV-like lesions.

Clinico-Epidemiologic Profile of Non-Syndromic Congenital Ichthyosis - A Retrospective Chart Review of 107 Patients.

Background: Congenital ichthyoses are a rare Mendelian group of disorders affecting the integument with a heterogeneous clinical presentation amongst which scaling is a constant feature. There is scanty epidemiologic data regarding the clinical profile and histologic patterns of inherited ichthyosis from resource-poor countries. Aims and Objectives: The study was aimed at assessing the clinic-epidemiologic characteristics associated with the different forms of non-syndromic congenital ichthyosis. Materials and Methods: This was a retrospective chart review of ichthyosis patients that presented between July 2016 and Jun 2020. Details including demographic profile, clinical characteristics along with any relevant investigations done were included. Results: During the study period of 4 years, 107 patients with congenital non-syndromic ichthyosis were seen. The most frequent diagnosis was of common ichthyoses, followed by autosomal recessive congenital ichthyosis, epidermolytic ichthyosis and erythrokeratoderma, in decreasing order. Conclusion: Important clinical findings like erythema and the type of scales as well as histological differences including an absent or reduced granular layer in ichthyosis vulgaris can help differentiate among the clinical phenotypes of inherited non-syndromic ichthyosis especially in resource-poor settings. Also, there is a high prevalence of vitamin D deficiency and hence a need for screening for the same in all patients of congenital ichthyosis including the milder phenotypes.

Neonatal and Maternal Ichthyosiform Dermopathy in Association with Kava Use during Pregnancy.

INTRODUCTION: Kava, a substance derived from the Piper methysticum plant, is enjoying a surge in popularity in the United States due to its purported anxiolytic and analgesic effects. Though ichthyosiform dermopathy is a known adverse effect associated with chronic kava exposure in adults, dermopathy in a newborn due to maternal kava use has not yet been described. CASE REPORT: This is a case of a 41-year-old woman who was taking a combination kava/kratom product throughout her pregnancy. She developed an ichthyosiform dermopathy that resolved after she stopped using the product postpartum. Her male infant had a neonatal course complicated by both neonatal opioid withdrawal syndrome, attributed to maternal kratom and buprenorphine use, as well as a diffuse ichthyosiform rash similar to descriptions of kava ichthyosiform dermopathy in adults. His neonatal course was complicated by Group B streptococcus and Serratia marscecens bacteremia (treated with antibiotics) and seizures (treated with lorazepam and phenobarbital). His rash resolved completely by day of life 22. At 9-month outpatient follow-up, he had no dermatologic abnormalities or rash recurrence. DISCUSSION: Maternal kava use during pregnancy may cause fetal dermopathy presenting as an acquired ichthyosis. More public education is needed about the potential consequences of kava use, particularly during pregnancy.

Epidermal nevi and epidermolytic hyperkeratosis: A review of cases, highlighting indications for biopsy and genetics referral.

Epidermal nevi are common benign cutaneous hamartomas that may rarely demonstrate histopathologic evidence of epidermolytic hyperkeratosis (EHK), representing cutaneous mosaicism for pathogenic keratin variants. Rarely, individuals with linear epidermal nevi transmit to their children the inherited form of EHK, also known as epidermolytic ichthyosis, characterized by generalized erythema, blistering, and scaling at birth evolving to widespread hyperkeratosis. We present an updated review of reported cases of linear epidermal nevi with EHK exhibiting transmission of epidermolytic ichthyosis to guide important considerations in the care of individuals with epidermal nevi. Clinical characteristics of linear epidermal nevi do not reliably predict the presence of EHK. All reported cases of transmission to offspring have occurred in individuals with linear epidermal nevi involving more than one anatomic area suggesting increased reproductive risk with involvement of two or more anatomic sites. Therefore, genetics consultation is recommended for these individuals with biopsy-confirmed EHK. For individuals with smaller areas of epidermal nevus involvement, the implications are less well known, though genetics consultation may still be considered for those interested in further discussion of general reproductive risk.

Charcot-Marie-Tooth Disease Type 4C and Autosomal Dominant Heterozygous Ichthyosis Vulgaris, with Bilateral Hearing Loss: A Novel Association with Review of Literature.

A 3-year-old boy, firstborn to nonconsanguineous parents, presented with motor development delay and floppiness of bilateral lower limbs since birth. No significant family history presented at time of check-up. He could stand with support, eat with a spoon without spillage, and speak in two-word sentences. There was no history suggestive of cranial nerve impairment. Examination revealed normal head circumference, dry, scaly skin lesions on the trunk, distal weakness with sluggish deep tendon reflexes in bilateral lower limbs, and a high stepping gait. Nerve conduction studies revealed demyelinating polyneuropathy. Brain stem-evoked response audiometry testing revealed auditory neuropathy. Clinical exome sequencing revealed a known pathogenic variant of 3325C > T in the SH3TC2 gene suggestive of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris with a novel variant of 2218C > T in the FLG gene. We have reviewed the available literature for reported associations of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris. This is probably the first reported association of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris with bilateral hearing loss.

Genetic analysis of seven patients with inherited ichthyosis and Nagashima­type palmoplantar keratoderma.

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole­exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis­like but distinct clinical manifestations. Genetic analysis identified diagnostic variations in the FLG, STS, KRT10 and SERPINB7 genes and clarified the carrying status of each variant in the respective family members. The two residues affected by the detected missense variants remained conserved across multiple species. Of note, the two variants, namely STS: c.452C>T(p.P151L) and c.647_650del(p.L216fs) are novel. In conclusion, a clear genetic differential diagnosis was made for the enrolled ichthyosis­associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis.

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders.