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.

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.

Congenital Ichthyosis: Current Approaches to Prenatal Diagnoses.

INTRODUCTION: Congenital ichthyosis represents a wide spectrum of diseases. This article reviews prenatal testing for ichthyosis. METHODS: We used pubmed.ncbi.nlm.nih.gov to search for 38 types of congenital ichthyosis combined with 17 words related to prenatal testing. RESULTS: Search resulted in 408 publications covering 13 types of ichthyoses and four types of tests. DISCUSSION: Biochemical testing is diagnostic in trichothiodystrophy, but nonspecific in X-linked ichthyosis and Refsum syndrome. Except in X-linked ichthyosis, biochemical testing requires invasive procedures to obtain fetal skin biopsy, amniocytes, or chorionic villus samples. It is superior to histological and cytological examination of fetal skin biopsy or amniocytes because keratinization occurs later in pregnancy and microscopy cannot differentiate between ichthyosis types. Imaging is more acceptable due to noninvasiveness and routine use, although ultrasonography is operator-dependent, nonspecific, and captures abnormalities at late stage. Molecular tests are described in at-risk pregnancies but testing of free fetal DNA was not described.

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.

Ocular phenotype and therapeutic interventions in keratitis-ichthyosis-deafness (KID) syndrome.

BACKGROUND: To report ocular manifestations, clinical course, and therapeutic management of patients with molecular genetically confirmed keratitis-ichthyosis-deafness syndrome. METHODS: Four patients, aged 19 to 46, with keratitis-ichthyosis-deafness syndrome from across the UK were recruited for a general and ocular examination and GJB2 (Cx26) mutational analysis. The ocular examination included best-corrected visual acuity, slit-lamp bio-microscopy, and ocular surface assessment. Mutational analysis of the coding region of GJB2 (Cx26) was performed by bidirectional Sanger sequencing. RESULTS: All four individuals had the characteristic systemic features of keratitis-ichthyosis-deafness syndrome. Each patient was found to have a missense mutation, resulting in the substitution of aspartic acid with asparagine at codon 50 (p.D50N). Main ophthalmic features were vascularizing keratopathy, ocular surface disease, hyperkeratotic lid lesions, recurrent epithelial defects, and corneal stromal scarring. One patient had multiple surgical procedures, including superficial keratectomies and lamellar keratoplasty, which failed to prevent severe visual loss. In contrast, oral therapy with ketoconazole stabilized the corneal and skin disease in two other patients with keratitis-ichthyosis-deafness syndrome. The patient who underwent intracorneal bevacizumab injection showed a marked reduction in corneal vascularization following a single application. CONCLUSIONS: Keratitis-ichthyosis-deafness syndrome is a rare ectodermal dysplasia caused by heterozygous mutations in GJB2 (Cx26) with a severe, progressive vascularizing keratopathy. Oral ketoconazole therapy may offer benefit in stabilizing the corneal and skin disease.

Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction.

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.

Whole exome sequencing identifies novel pathogenic variants in TGM1 and ALOX12B in patients with hereditary ichthyosis.

BACKGROUND: Hereditary ichthyosis is a clinically and genetically heterogeneous disorder associated with more than 50 genes with TGM1, ALOX12B, and ALOXE3 being the most prevalent. Establishing an accurate diagnosis is important for effective genetic counseling and optimal patient management. OBJECTIVE: We studied the diagnostic value of whole exome sequencing (WES) in a small case series with hereditary ichthyosis. METHODS: During a 1-year period, index cases of 5 unrelated families clinically diagnosed with hereditary ichthyosis went through WES, followed by extensive segregation analysis. Prenatal diagnosis (PND) was conducted where indicated. RESULTS: We identified 4 homozygous variants-2 in TGM1 (c.655A > G and c.797A > G) and 2 in ALOX12B (c.527 + 2 T > G and c.1654G > T)-alongside a heterozygous variant in TGM1 (c.428G > A) in 5 families. The variants were all pathogenic/likely pathogenic according to the ACMG classification and segregation analysis, except for c.797A > G in TGM1 which remained a variant of unknown clinical significance. Four variants were novel. All families were referred either during pregnancy or before reproductive planning; 4 benefited from WES as it identified the mutation in the probands and enabled carrier detection in at-risk relatives; PND was conducted in 2 families. CONCLUSION: Our findings further support WES is a powerful tool for the comprehensive, accurate, and rapid molecular diagnosis of hereditary ichthyosis and can offer opportunities for reproductive planning, carrier screening and prenatal diagnosis to at-risk families.

Neu Laxova syndrome and megacystis in the first trimester: Broadening the fetal phenotype.

Neu Laxova syndrome (NLS) is a rare and lethal congenital disorder characterized by severe intra-uterine growth retardation (IUGR), ichthyosis, abnormal facial features, limb abnormalities with arthrogryposis and a wide spectrum of severe malformations of the central nervous system (CNS). NLS is due to biallelic variants in three genes previously involved in serine-deficiency disorders (PHGDH, PSAT1 and PSPH), extending the phenotypic spectrum of these disorders.

Acquired Ichthyosis Revealing Lymphocytic Colitis.

A 69-year-old patient with no personal or family history of ichthyosis consulted our dermatology department for diffused cutaneous xerosis with intense pruritus evolving for 3 weeks. Physical examination revealed diffused ichthyosis of large polygonal fine scales on the skin without erythema (Figure 1). The lesions spared the face. Examination of the mucous membranes, hair, and nails revealed no abnormalities. There was no fever or adenomegaly. A skin biopsy revealed an orthokeratotic hyperkeratosis with thinning of granular layer (Figure 2). The initial diagnosis of acquired ichthyosis was maintained. The patient also reported a change in bowel habits since 2 weeks with watery, non-bloody diarrhea and mild steatorrhea. His laboratory investigations presented low serum vitamin B12 level, mild anemia, hypoalbuminemia, and fecal leukocytes; however, antinuclear antibodies, perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), rheumatoid factor, and complement components C3 and C4 were normal. A colonoscopy performed was also normal without any abnormalities. Colon biopsies revealed histologic aspects of lymphocytic colitis with more than 20% increase in lymphocytes in the surface epithelium of colorectal mucosa. Laboratory investigations excluded neoplasia, hemopathies, or autoimmune-associated diseases. The patient was treated with salazopyrin with a remarkable lessening of diarrhea and cutaneous manifestations within 4 weeks (Figure 3).

Case report of self-improving collodion ichthyosis in the newborn.

Self-improving collodion ichthyosis (SICI) is a relatively rare subtype of autosomal recessive congenital ichthyosis (ARCI) that is often characterized by a collodion baby (CB) phenotype at birth. A newborn girl, just 1 hour old, presented with taut, shiny, thick yellow crusts, like parchment, and scales on her trunk and upper limbs. The tightening effect had caused both upper eyelids to appear everted, and her lips and auricles were deformed. Based on whole-exome sequencing and examination of the clinical phenotype, the patient was diagnosed with ARCI. After admission, the exposed mucosa was covered with a sterile Vaseline gauze dressing, and she was placed in an incubator set to a temperature of 32°C with a humidity level of 75%. One week later, the parchment-like scales had begun to flake off, and at the age of 3 weeks, all bodily skin appeared normal. SICI was diagnosed. After discharge, the patient was followed up to 3 months of age, at which time her growth and development were comparable to those of her peers. Clinicians should consider SICI as a possible diagnosis when analyzing the prognosis of patients with CB. Reducing water loss and maintaining the electrolyte balance are particularly important for SICI treatment.

Otological problems in ichthyosis: A literature review.

BACKGROUND: Ichthyoses are a rare group of keratinization disorders characterized by scaling of the skin due to an impaired barrier function. Few studies have addressed ear involvement in patients with ichthyosis, although it is a probably underestimated aspect of the disease. OBJECTIVE: This study aims to provide an overview of the otological manifestations in ichthyosis and propose specific treatment options. METHODS: Articles were collected using PubMed, EMBASE, and Web of Science. A total of 53 articles were included in this literature review. RESULTS: The most common ear problem in patients with ichthyosis is scale accumulation in the ear canals, which can lead to conductive hearing loss and increases the risk of ear infections. Furthermore, some types of ichthyosis are associated with outer ear malformations. Lastly, sensorineural hearing loss is common in syndromic forms of ichthyosis. CONCLUSIONS: Otological problems are present in all types of ichthyoses and their treatment is challenging. The involvement of ear, nose, and throat specialists in the routine care of ichthyosis patients is essential for early identification and treatment of these manifestations. More research is needed to provide more insight into the otological problems in ichthyosis and to ameliorate treatment options.

Ichthyosis: presentation and management.

PURPOSE OF REVIEW: This review focuses on the presentation and management of ichthyoses and highlights recent advances in treatment that hold promise for better targeted therapy. RECENT FINDINGS: The ichthyoses are a group of rare genetic diseases with a wide phenotypic spectrum, characterized most often by generalized hyperkeratosis and scaling with variable erythema. The highly visible scaling and frequent itch contribute to decreased quality of life. Management for ichthyosis focuses on symptomatic relief and scale reduction with emollients, keratolytics, and retinoids. Recent advances in immune profiling and genotype-phenotype mapping have increased understanding of ichthyosis and shifted focus to pathogenesis-based targeted therapies with emerging biologics, small molecular inhibitors, and gene therapy. SUMMARY: This article discusses clinical assessment and genotyping to make the diagnosis of specific forms of ichthyosis, provides guidance for management, and reviews new treatment options with systemic agents.

Emergency approach in a rare congenital coexistence-ichthyosis and amniotic band syndrome.

Ichthyosis is caused by Mendelian cornification disorders. Hereditary ichthyoses are divided into non-syndromic and syndromic ichthy-oses. Amniotic band syndrome involves congenital anomalies that most frequently cause hand and leg rings. The bands can wrap around the developing body parts. In this study, it is aimed to present an emergency approach to amniotic band syndrome accompanying a case of congenital ichthyosis. We were asked by the neonatal intensive care unit to consult on the case of a 1-day-old baby boy. On physical examination, congenital bands were found to be present on both hands, the toes were rudimentary, skin scaling was present on the entire body, and the consistency of the skin was stiff. The right testicle was not in the scrotum. Other system examinations were normal. However, the blood circulation in the fingers in the distal of the band had become critical. With the help of sedation, the bands on the fingers were excised, and after the procedure, it was observed that the circulation in the fingers was more relaxed than it had been before the procedure. Coexistence of congenital ichthyosis and amniotic band is very rare. Emergency approach to these patients is very important in terms of saving the limb and preventing growth retardation in the limb. As further developments take place in terms of prenatal diagnoses, these cases will be able to be prevented through the early diagnosis and treatment.

Association of Somatic ATP2A2 Damaging Variants With Grover Disease.

Importance: Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown. Objective: To determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD. Design, Setting, and Participants: In this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023. Main Outcomes and Measures: Comparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue. Results: Overall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue. Conclusions and Relevance: In this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.

A Brazilian case of IFAP syndrome with severe congenital ichthyosis and limb malformations caused by a rare variant in MBTPS2.

OBJECTIVE: The classic triad, which defines IFAP syndrome, is ichthyosis follicularis, alopecia, and photophobia. It is a rare X-linked genetic disorder characterized by multiple congenital anomalies with variable severity, caused by pathogenic variants in the MBTPS2 gene, which encodes a zinc metalloprotease that is essential for normal development. This study aimed to report a case of a Brazilian patient with IFAP syndrome presenting skeletal anomalies, which is a rare finding among patients from different families. CASE DESCRIPTION: We describe a male proband with IFAP syndrome showing severe ichthyosis congenita, cryptorchidism, limb malformation, and comprising the BRESHECK syndrome features. Using whole-exome sequencing, we identified a rare missense variant in hemizygosity in the MBTPS2 gene, which had not been identified in other family members. COMMENTS: This is the first diagnosis of IFAP syndrome in Brazil with a molecular investigation. The present case study thus expands our knowledge on the mutational spectrum of MBPTS2 associated with IFAP syndrome.