Authors: Qisi Sun, Nareh M Burgren, Shayan Cheraghlou...

IMPORTANCE

Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish.

OBJECTIVE

To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations.

DESIGN, SETTING, AND PARTICIPANTS

This cohort study recruited an international group of individuals with ichthyosis and describes characteristic and distinguishing features of common genotypes, including genotype-phenotype associations, during a 10-year period from June 2011 to July 2021. Participants of all ages, races, and ethnicities were included and were enrolled worldwide from referral centers and patient advocacy groups. A questionnaire to assess clinical manifestations was completed by those with a genetic diagnosis.

MAIN OUTCOMES AND MEASURES

Genetic analysis of saliva or blood DNA, a phenotyping questionnaire, and standardized clinical photographs. Descriptive statistics, such as frequency counts, were used to describe the cases in the cohort. Fisher exact tests identified significant genotype-phenotype associations.

RESULTS

Results were reported for 1000 unrelated individuals enrolled from around the world (mean [SD] age, 50.0 [34.0] years; 524 [52.4%] were female, 427 [42.7%] were male, and 49 [4.9%] were not classified); 75% were from the US, 12% from Latin America, 4% from Canada, 3% from Europe, 3% from Asia, 2% from Africa, 1% from the Middle East, and 1% from Australia and New Zealand. A total of 266 novel disease-associated variants in 32 genes were identified among 869 kindreds. Of these, 241 (91%) pathogenic variants were found through multiplex amplicon sequencing and 25 (9%) through exome sequencing. Among the 869 participants with a genetic diagnosis, 304 participants (35%) completed the phenotyping questionnaire. Analysis of clinical manifestations in these 304 individuals revealed that pruritus, hypohydrosis, skin pain, eye problems, skin odor, and skin infections were the most prevalent self-reported features. Genotype-phenotype association analysis revealed that the presence of a collodion membrane at birth (odds ratio [OR], 6.7; 95% CI, 3.0-16.7; P < .001), skin odor (OR, 2.8; 95% CI, 1.1-6.8; P = .02), hearing problems (OR, 2.9; 95% CI, 1.6-5.5; P < .001), eye problems (OR, 3.0; 95% CI, 1.5-6.0; P < .001), and alopecia (OR, 4.6; 95% CI, 2.4-9.0; P < .001) were significantly associated with TGM1 variants compared with other ichthyosis genotypes studied. Skin pain (OR, 6.8; 95% CI, 1.6-61.2; P = .002), odor (OR, 5.7; 95% CI, 2.0-19.7; P < .001), and infections (OR, 3.1; 95% CI, 1.4-7.7; P = .03) were significantly associated with KRT10 pathogenic variants compared with disease-associated variants in other genes that cause ichthyosis. Pathogenic variants were identified in 869 (86.9%) participants. Most of the remaining individuals had unique phenotypes, enabling further genetic discovery.

CONCLUSIONS AND RELEVANCE

This cohort study expands the genotypic and phenotypic spectrum of ichthyosis, establishing associations between clinical manifestations and genotypes. Collectively, the findings may help improve clinical assessment, assist with developing customized management plans, and improve clinical course prognostication.

Topics: Cohort Studies; Female; Genomics; Humans; Ichthyosis; Ichthyosis, Lamellar; Male; Phenotype

PubMed: 34851365
DOI: 10.1001/jamadermatol.2021.4242

Review

Authors: M D W Joosten, J M K Clabbers, N Jonca...

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

Topics: Humans; Ichthyosis; Netherton Syndrome; Skin; Skin Neoplasms

PubMed: 35840979
DOI: 10.1186/s13023-022-02430-6

Authors: Inger Lily Dorf, Mette Sommerlund, Uffe Koppelhus...

Ichthyosis – also called fish scale disease – is a group of skin diseases, which are characterised by xerosis and scaling. Most commonly, the diseases are genetically inherited, but an acquired type also exists. Ichthyosis vulgaris (IV), is the most common type, affecting 1:250 individuals. Diagnosing IV can be challenging, because its clinical features are subject to great variation, ranging from mild cases with slight xerosis to severe cases with marked scaling and formation of fissures. In this review, IV and its most relevant differential diagnoses, X-linked ichthyosis, autosomal recessive congenital ichthyosis and acquired ichthyosis are reviewed.

Topics: Humans; Ichthyosis Vulgaris

PubMed: 32400366
DOI: No ID Found

Randomized Controlled Trial

Authors: Rachel Lefferdink, Stephanie M Rangel, Margot Chima...

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.

Topics: Adult; Humans; Ichthyosis, Lamellar; Antibodies, Monoclonal; Interleukin-17; Ichthyosis; Psoriasis; Ichthyosiform Erythroderma, Congenital; Severity of Illness Index; Double-Blind Method; Treatment Outcome

PubMed: 35218370
DOI: 10.1007/s00403-022-02325-3

Review

Authors: Dóra Plázár, Marie Isolde Joura, Norbert Kiss...

Genodermatoses are a group of inherited skin diseases whose diagnosis is challenging due to their rarity as well as their clinical and genetic diversity. The majority of genodermatoses are autosomal or X‑linked inherited, but mosaic forms are also observed. Genodermatoses comprise various phenotypes ranging from limited cutaneous disease to severe cutaneous and extracutaneous involvement and may also be early warning signs of a multisystemic disorder. Despite recent advances in genetic technology and skin imaging modalities, dermoscopy can be useful for screening, diagnosis, and treatment follow-up. In ectopic mineralization and lysosomal storage disorders (pseudoxanthoma elasticum and Fabry disease, respectively), cutaneous manifestations may indicate involvement of other organs. In keratinization diseases (e.g., ichthyoses) and acantholytic skin fragility disorders (e.g., Darier and Hailey-Hailey disease), dermoscopy may help to assess treatment response by visualizing background erythema, hyperkeratosis, and interkeratinocyte space prominence. Dermoscopy is a noninvasive, easily accessible, useful, in vivo assessment tool that is well established in dermatology to recognize characteristic features of genodermatoses.

Topics: Humans; Dermoscopy; Skin; Ichthyosis; Keratosis; Pemphigus, Benign Familial

PubMed: 36882583
DOI: 10.1007/s00105-023-05124-7

Authors: Vinoth Kumar Perumal, Krishna Prasanth Baalann

Topics: Collodion; Humans; Ichthyosis; Ichthyosis, Lamellar; Infant

PubMed: 34804344
DOI: 10.11604/pamj.2021.40.77.26789

Review

Authors: Ken Natsuga

The epidermis functions as a physical barrier to the external environment and works to prevent loss of water from the skin. Numerous factors have been implicated in the formation of epidermal barriers, such as cornified envelopes, corneocytes, lipids, junctional proteins, proteases, protease inhibitors, antimicrobial peptides, and transcription factors. This review illustrates human diseases (ichthyoses) and animal models in which the epidermal barrier is disrupted or dysfunctional at steady state owing to ablation of one or more of the above factors. These diseases and animal models help us to understand the complicated mechanisms of epidermal barrier formation and give further insights on epidermal development.

Topics: Animals; Antimicrobial Cationic Peptides; Biomarkers; Epidermis; Humans; Ichthyosis; Lipid Metabolism; Serine Proteases; Serine Proteinase Inhibitors; Skin Physiological Phenomena; Tight Junctions

PubMed: 24692192
DOI: 10.1101/cshperspect.a018218

Review

Authors: Neil Gordon

Sjögren-Larsson syndrome is a recessively inherited syndrome caused by deficiency of fatty aldehyde dehydrogenase. The most common symptoms and signs are described, especially ichthyosis, spastic diplegia, and severe learning difficulties; but also other less frequent ones. Special investigations include sensory evoked potentials, electromyography, and proton magnetic resonance spectroscopy. Post-mortem examination shows, in particular, an accumulation of lipid substances in specific regions of the brain. The diagnosis depends on the measurement of fatty aldehyde dehydrogenase in cultured fibroblasts from skin biopsies, and by identifying known mutations by allele-specific polymerase chain reaction assay. Prenatal diagnosis is possible by using the same technique. The disorder is located on gene 17, and many mutations have been identified. Most mutations are unique to an affected family, but clinical variations may be due to unknown genetic and environmental factors. The deficiency of the enzyme impairs the oxidation of medium and long chain fatty aldehydes, and this may explain the link between the brain and skin disorders. The treatment of affected children needs input from a number of specialists, and their contributions are discussed.

Topics: Humans; Sjogren-Larsson Syndrome

PubMed: 17254005
DOI: 10.1111/j.1469-8749.2007.00152.x

Authors: Yumeng Wang, Anqi Zhao, Naihui Zhou...

PURPOSE

In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism.

METHODS

Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis.

RESULTS

Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes.

CONCLUSIONS

Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

Topics: Humans; Deafness; Phospholipase C beta; Female; Male; Ichthyosis; Pedigree; Heterozygote; Ubiquitination; Keratinocytes; Exome Sequencing; Adult; Syndrome; HEK293 Cells; Receptors, Steroid

PubMed: 38701954
DOI: 10.1016/j.bbadis.2024.167207

Authors: Semih Kalyon, Yasemin Gökden, Naciye Demirel...

Chanarin Dorfman syndrome is a multisystem, very rare, autosomal recessive lipid storage disorder, characterized by the accumulation of lipid vacuoles in neutrophils, and was first described by Dorfman in 1974. Due to a mutation in the ABHD5 gene of the short arm of chromosome 3, lipid is stored in the granulocytes at various sites in the human body, such as the muscle, liver, eye, ear, central nervous system, and bone marrow. Clinically, the disease is presented with ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation. A 38-year-old male patient was referred to our Internal Medicine Clinic for consultation with laboratory findings as follows: high aspartate aminotransferase (AST; 203 U/L), alanine aminotransferase (ALT; 151 U/L), gamma-glutamyl transferase (GGT; 167 U/L), creatine kinase (CK; 1127 U/L) levels and low platelet levels (108000). After ultrasonography and gastroscopy, the patient was diagnosed with liver cirrhosis. Bilateral mixed-type hearing loss on audial tests and bilateral punctuate keratopathy, ectropion, and cataract in the left eye on ophthalmological tests were found. For the definitive diagnosis of Chanarin Dorfman syndrome, peripheral blood was examined, which revealed lipid accumulation in the neutrophils (Jordan's anomaly). We emphasize that if a patient has unusual findings, such as ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation, the possibility of Chanarin Dorfman syndrome should be considered.

Topics: Adult; Cataract; Diagnosis, Differential; Fibrosis; Hearing Loss; Hepatomegaly; Humans; Ichthyosiform Erythroderma, Congenital; Ichthyosis; Intellectual Disability; Lipid Metabolism, Inborn Errors; Male; Muscular Diseases; Splenomegaly

PubMed: 30457558
DOI: 10.5152/tjg.2018.18014