In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

Autosomal recessive congenital ichthyosis due to novel CYP4F22 mutation presenting with a collodion membrane and ocular manifestations.

Autosomal recessive congenital ichthyoses (ARCI) are a range of genetic disorders of keratinization. The rare CYP4F22 gene mutation can present with or without collodion membrane at birth and leads to the development of mild ichthyosis phenotype. We report a case of a novel pathogenic CYP4F22 genetic mutation presenting with collodion membrane and ocular manifestations. Ocular manifestations have recently been reported in a patient with ARCI with known CYP4F22 mutation, which further supports a possible correlation between the CYP4F22 mutation and this distinct phenotype.

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.

Acral collodion membrane associated with ichthyosis due to a heterozygous pathogenic variant of ELOVL4 gene.

A female twin presented at birth with a collodion membrane on the hands and feet. After the membrane resolved over the first months of life, she was initially diagnosed with acral self-healing collodion membrane. However, she subsequently developed brown well-defined geometric scales on the trunk and extremities, consistent with ichthyosis. Genetic testing showed a heterozygous pathogenic variant in ELOVL4, a gene associated with syndromic ichthyosis with developmental delay, seizures, and spasticity. Although acral collodion membrane is considered to be a benign variant of the more generalized collodion, usually described as "self-healing," it may be the initial presentation of more diffuse ichthyosis.

Clinical and molecular characteristics of autosomal recessive congenital ichthyosis in Thailand.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a heterogenous group of rare keratinization disorders. To date, more than 13 causative genes have been identified. However, data on clinical and molecular characteristics including genotype-phenotype correlation are lacking in Thailand. OBJECTIVE: We collected cases diagnosed with non-syndromic ARCI and syndromic recessive congenital ichthyosis at the Institute of Dermatology from 2011 to 2021 and performed genetic testing with next-generation sequencing and assessed clinical details. METHODS: Baseline demographic data, birth history, family history, skin manifestations at birth, current cutaneous manifestations, comorbidities, and response to treatments were assessed. DNA was screened for mutations using targeted gene sequencing of 45 genes related to congenital ichthyosis. RESULTS: A total of 33 patients were analyzed with an average age of 23.8 ± 13.9 years. Congenital ichthyosiform erythroderma (CIE) was most common (60.6%), followed by lamellar ichthyosis (18.2%), self-improving congenital ichthyosis (6.1%), Netherton syndrome (6.1%), ichthyosis prematurity syndrome (3%), Sjögren-Larsson syndrome (3%) and bathing suit ichthyosis (3%). Eight genes were found with pathogenic variants in our cohort as follows: ABCA12 42.4% (14/33), NIPAL4 24.2% (8/33), TGM1 15.2% (5/33), SPINK5 6.1% (2/33), ALDH3A2 3% (1/33), SLC27A4 3% (1/33), CYP4F22 3% (1/33), and ST14 3% (1/33). Clinically, 79% of patients with ABCA12 pathogenic variants in this study had CIE, 79% of w had novel biallelic pathogenic compound heterozygous variants, whereas 21% had homozygous missense variants. CONCLUSIONS: This is the first study to describe clinical and molecular findings of ARCI in a cohort from Thailand. Our findings demonstrate the clinical spectrum of the diseases and expand the molecular findings in a Southeast Asian population.

Ichthyosis, cataracts, and motor delay in an infant: A case of Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.

A case of self-improving collodion ichthyosis associated with a rare variant of the ALOX12B gene.

Collodion baby is usually a manifestation of autosomal recessive congenital ichthyosis, a heterogeneous group of congenital hyperkeratotic genodermatoses with highly variable severity and genetic background. Herein, we report a case of self-improving collodion ichthyosis, a rare subtype of autosomal recessive congenital ichthyosis, characterized by an almost-complete spontaneous resolution of symptoms.

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.

Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) refers to non-syndromic ichthyosis caused by mutations in one of the 13 identified genes. There are limited data on the genotype of ARCI and its phenotypic correlation from India. OBJECTIVES: The aim of this study was to characterize the genotype of ARCI among patients from the Indian subcontinent. METHODS: Twenty-eight patients clinically diagnosed as ARCI were recruited prospectively from September 2017 to June 2019 (21 months). DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel. The variants identified were confirmed by Sanger sequencing and compared with known pathogenic variants to establish pathogenicity. We also attempted to correlate the phenotype with the genotype. RESULTS: Among the 28 patients recruited (M = 17, F = 11), we identified phenotypes of congenital ichthyosiform erythroderma in 12 (42.9%), 8 with lamellar ichthyosis (28.6%), 5 with intermediate phenotype (17.9%), and 3 with bathing suit ichthyosis (10.7%). Pathogenic and likely pathogenic variants were identified in 22 (78.6%) patients, involving 7 out of the 13 known ARCI genes while 6 (21.4%) did not have pathogenic variants. These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each. Previously unknown pathogenic variants were found in 59.1 % of patients. CONCLUSIONS: Our patients with ARCI were found to have genotypes as previously described in other populations.

Congenital lamellar ichthyosis complicated with erosive pseudo pustulosis: A rare clincal entity. About a case and review of the literature.

INTRODUCTION: Lamellar ichthyosis is a rare congenital disorder that can be encountered by plastic surgeon in a daily practice. Its clinical diagnosis makes it an significant pathology to identify and to know how to treat. MATERIAL AND METHODS: We report the case of a patient suffering from lamellar ichthyosis complicated by erosive pseudo pustulosis of the scalp. Our treatment protocol with two intra-lesional delayed-corticoids (Kenacort ®) injections three months apart showed significant clinical improvement of the lesions. DISCUSSION: Congenital lamellar ichthyosis regroups various clinical presentations. Most of the therapeutic strategies described in the literature involve local and systemic treatments, weighing on patients and leading to modest results. Surgical treatment or hyaluronic injections have also been reported but they raise problematics regarding morbidity and efficiency. CONCLUSION: Our therapeutic strategy by two Kenacort ® injections three months apart is simple, reproductible and has shown efficiency in the treatment of our patient suffering from congenital lamellar ichthyosis complicated with erosive pseudo pustulosis of the scalp.

Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis.

Lamellar ichthyosis (LI) is a genetic skin disorder characterized by dark brown scales, palmoplantar hyperkeratosis, pain, and itching. LI severity could have implications in psychological aspects, causing depression and impairment in the quality of life (QoL) of patients. In this study, we used the Congenital Ichthyosis Severity Index, the Depression Beck Inventory-II (DBI-II), and the Dermatologic Life Quality Index (DLQI) to assess severity, level of depression, and impairment in QoL in a group of patients with LI. We observed that the majority of the patients presented a high severity level concerning the presence of scales (57.7%), while for erythema and alopecia, the severity was less 80% of the analyzed patients presented depression, while only 20.8% of individuals of the control group presented it (P < .001, OR = 15.2). While for QoL, only 4.3% of the patients did not exhibit any impairment. Finally, the increase in the score obtained in DBI-II was correlated with the DLQI score (rs = 0.663, P = .0014). Our results suggest that patients with LI have an increased risk of suffering depression and impairment in their QoL; thus, the management of their disease should be performed from a multidisciplinary perspective to improve the global aspects of their lives.

Vitamin D Status in Distinct Types of Ichthyosis: Importance of Genetic Type and Severity of Scaling.

Data on vitamin D status of patients with inherited ichthyosis in Europe is scarce and unspecific concerning the genetic subtype. This study determined serum levels of 25-hydroxyvitamin D3 (25(OH)D3) in 87 patients with ichthyosis; 69 patients were additionally analysed for parathyroid hormone. Vitamin D deficiency was pronounced in keratinopathic ichthyosis (n = 17; median 25(OH)D3: 10.5 ng/ml), harlequin ichthyosis (n = 2;7.0 ng/ml) and rare syndromic subtypes (n = 3; 7.0 ng/ml). Vitamin D levels were reduced in TG1-proficient lamellar ichthyosis (n = 15; 8.9 ng/ml), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/ml), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/ml), Netherton syndrome (n = 7; 10.7 ng/ml) and X-linked ichthyosis (n = 8; 13.9 ng/ml). In ichthyosis vulgaris 25(OH)D3 levels were higher (n = 10; 19.7 ng/ml). Parathyroid hormone was elevated in 12 patients. Low 25(OH)D3 levels were associated with high severity of scaling (p = 0.03) implicating scaling as a risk factor for vitamin D deficiency. Thus, this study supports our recent guidelines for ichthyoses, which recommend screening for and substituting of vitamin D deficiency.

The Burden of Autosomal Recessive Congenital Ichthyoses on Patients and their Families: An Italian Multicentre Study.

Autosomal recessive congenital ichthyoses (ARCI) are characterized by generalized skin scaling, hyperkeratosis, erythroderma, and disabling features affecting the skin (palmoplantar keratoderma, fissures, pain, itch), eyes, ears, and joints. Disease severity and chronicity, patient disfigurement, and time and costs required for care impose a major burden on quality of life. This multicentre cross-sectional study investigated the impact of ARCI on quality of life of patients and families, using the Dermatology Life Quality Index (DLQI), the Children DLQI (CDLQI) and Family Burden of Ichthyosis (FBI) questionnaires. Disease severity was assessed by a dermatologist. A total of 94 patients were recruited, of whom 52 (55.3%) children. Mean age was 20.1 (median 13.5) years. The mean CDLQI/DLQI score was 7.8, and 21 patients scored >10, indicating a major impairment in quality of life: symptoms, feelings and treatment problems were the most affected domains of quality of life. FBI showed a major repercussion on psychological factors and work. The results of this study highlight the impact of ARCI on specific aspects of patient and family life, underlining the need for psychological support.

Successful correction of ichthyosis-related ectropion by autografts.

Ectropion is a rather frequent complication of ichthyosis with negative functional and esthetic impact. Lid surgery can provide significant improvement. We report on a series of four ichthyosis patients with ongoing bilateral eye problems despite intense medical treatment (mean age 27.8 ± 14.1 years). All patients suffered from lagophthalmos. Two of the patients had only lower lid ectropion. In two of the patients' ectropion was forming on the upper lid in addition to the lower lid when closing the eye. In three of four patients, ectropion was repaired by skin grafts from the supraclavicular region. In a child with lower and upper lid ectropion prepuce was used for repair surgery. At the end of the follow-up period of about 23.0 ± 12.7 months, none of the patients revealed lagophthalmos or corneal exposure. No intraoperative or postoperative complications have been observed in our patients. Ichthyosis patients with ectropion resistant to medical treatment, benefit from surgical treatment with full layer autografts. In boys, prepuce can be successfully used as autograft.

Transepidermal water loss in the orphan forms of ichthyosis.

As a surrogate measure of skin barrier dysfunction, we sought to determine differences in transepidermal water loss (TEWL) among ichthyosis subtypes and correlate TEWL with clinical severity. Subjects with Netherton syndrome had the highest TEWL values (increased water loss), while TEWL values were lowest in subjects with epidermolytic ichthyosis. TEWL correlated with severity only in lamellar ichthyosis and age was inversely correlated with TEWL (rs  = -.213, P = .02). TEWL is an objective measure that complements disease severity in ichthyosis and may be used as an adjuvant to monitor treatment response.

A case of self-improving collodion ichthyosis in Vietnam.

Autosomal recessive congenital ichthyosis is a heterogeneous group of congenital disorders characterized by aberrant skin cornification and diffuse skin scaling. Some patients with this condition are born encased in a collodion membrane which is later shed, revealing the underlying skin disorder. Self-healing collodion baby (SHCB) is a less common phenotype of this disorder, accounting for about 10% of the patients, in which the membrane peels after several weeks, leaving no underlying skin aberration. Here, we report and discuss the diagnosis and management of an infant with SHCB in Vietnam due to compound heterozygous pathogenic mutations in TGM1.

Bathing suit ichthyosis: Two Burmese siblings and a review of the literature.

Bathing suit ichthyosis (BSI) is a subtype of autosomal recessive congenital ichthyosis (ARCI) characterized by the development of large platelike scales mainly limited to the trunk. It is caused by temperature sensitive variants in transglutaminase 1, encoded by the gene TGM1. We describe a rare case of intrafamilial variation in phenotypic expressivity in two Burmese siblings with BSI that demonstrates the heterogeneity of the disorder within the same family and even in the same individual across time. We also present a concise review of the genotypic spectrum of BSI from 54 cases reported in the literature as evidence that both environmental and additional genetic factors can significantly alter the clinical phenotype.

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families.

Autosomal recessive congenital ichthyosis (ARCI), a phenotypically heterogeneous group of non-syndromic Mendelian disorders of keratinization, is caused by mutations in as many as 13 distinct genes. We examined a cohort of 125 consanguineous families with ARCI for underlying genetic mutations. The patients' DNA was analyzed with a gene-targeted next generation sequencing panel comprising 38 ichthyosis associated genes. The interpretations of results of genomic data were assisted by genome-wide homozygosity mapping and transcriptome sequencing. Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families. Among the 85 distinct mutations in 10 different genes, 45 (53%) were previously unreported. Phenotype-genotype correlations allowed assignment of specific genes in the majority of the families to a specific subtype of ARCI, lamellar ichthyosis (LI) versus congenital ichthyosiform erythroderma (CIE). Interestingly, mutations in several genes could give rise to an overlapping phenotype consistent with either LI or CIE. Also, this is the third report for SDR9C7 and SULT2B1, and fourth report for CERS3 mutations. Direct comparison of our results with previously published regional cohorts highlights the global mutation landscape of ARCI, however, population specific differences were noted.

Novel and Recurrent PNPLA1 Mutations in Spanish Patients with Autosomal Recessive Congenital Ichthyosis; Evidence of a Founder Effect.

Autosomal recessive congenital ichthyosis (ARCI) is a group of rare non-syndrome diseases that affect cornification. PNPLA1 is one of the 12 related genes identified so far. Mutation screening of this gene has resulted in the identification of 13 individuals, from 10 families, who carried 7 different PNPLA1 mutations. These mutations included 2 missense, 2 frame-shift and 3 nonsense, 3 of them being novel. One of the identified variants, c.417_418delinsTC, was highly prevalent, as it was found in 6 out of 10 (60%) of our ARCI families with PNPLA1 mutations. Clinical manifestations varied significantly among patients, but altered sweating; erythema, palmar hyperlinearity and small whitish scales in flexor-extensor and facial areas were common symptoms. Haplotype analyses of c.417_418delinsTC carriers confirmed the existence of a common ancestor. This study expands the spectrum of the PNPLA1 disease, which causes variants and demonstrates that the c.417_418delinsTC mutation has founder effects in the Spanish population.

A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings.

BACKGROUND: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism. METHODS: Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure. RESULTS: Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein. CONCLUSIONS: These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.