Identification of a novel compound heterozygous mutation and a homozygous mutation of SLURP1 in Chinese families with Mal de Meleda.

BACKGROUND: Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family. METHODS: We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis. RESULTS: Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL. CONCLUSIONS: Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.

Malignancy in dermatomyositis: a mono-centric retrospective study of 134 patients in China and a potential predictive model.

Objectives: To describe the demographics and phenotypes of malignancies-associated dermatomyositis (MADM) in east China and pinpoint potential factors indicative of malignancies in patients with dermatomyositis and establish a predictive model. Methods: We retrospectively analyzed clinical data from 134 patients with adult-onset dermatomyositis hospitalized between January 2019 and May 2022 in one comprehensive hospital. Clinical data including disease course, initial symptoms and signs, and demographic information were retrieved from the Electronic Medical Records System. Other parameters including myositis-specific autoantibodies profiles, ferritin, sedimentation, etc. were all referable. Multivariable multinomial logistic regression was employed to simulate a model to predict cancer risks. Receiver operating characteristic curve was adopted to evaluate the potency of the model. Results: 134 patients with adult-onset dermatomyositis were aptly enrolled in this study based on inclusive and exclusive criteria: 12 (8.96%) with malignancies, 57 (42.53%) with aberrant tumor biomarkers but no malignancies, 65 (48.51%) with neither malignancies nor abnormal tumor biomarkers. Senior diagnostic age, higher LDH, higher ferritin, positive anti-TIF1γ and anti-Mi2 rather than anti-NXP2 autoantibodies were positive indicators of malignancies. Additionally, neither initial complaints nor signs were found to be correlated to a tendency towards malignancies. Digestive system, nasopharyngeal, and lung malignancies were mostly documented in east China. One multivariable multinomial logistic regression model was established to predict the phenotypes of dermatomyositis on the basis of potential malignancies and the overall sensitivity and specificity was satisfactory. Conclusion: Positivity of anti-TIF1γ and anti-Mi2 autoantibodies are highly indicative of malignancies while the role of anti-NXP2 autoantibody in MADM in the Chinese population remains unclear. The phenotypes of malignancies can be predicted through the model and the predictive power is sufficient. More attention should be paid to malignancies screening in patients with aberrant tumor biomarkers but no malignancies, particularly digestive system, nasopharyngeal, and lung malignancies in patients with dermatomyositis but without malignancies.

Case report: Apalutamide-induced severe lethal cutaneous adverse effects in China.

Introduction: Apalutamide is a novel agent for castration-resistant prostate cancer while skin rashes are the most common untoward reactions. Up to now, most of the reported dermatologic adverse events (dAEs) allocated to mild and moderate with a fair prognosis. Herein, we report a case series of severe dAEs in China caused by apalutamide. Case presentation: The four patients all developed severe and lethal drug eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis with a mean incubation period of 40 days. On the basis of the medical condition, all the patients were suggested to withdraw apalutamide and three of them recovered. Of note, attempts of rechallenges of apalutamide may be fatal. Discussion: The incidence of dAEs in previously conducted clinical trials exceeded 20%, with maculopapular rashes being the most common feature. However, the incidence and severity varied in different geographic regions and ethnicities. Inadequate attention was paid to severe cutaneous adverse reactions. Long latency may easily lead to the misdiagnosis of dAEs, and immediate withdrawal of apalutamide is the cornerstone of therapies. Conclusion: Special and adequate attention should be paid to apalutamide-attributed severe cutaneous adverse effects. Besides, the prognosis of severe drug eruptions may be disappointing, and in-time withdrawal is vital.

Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.

AIMS: To identify potential causative gene mutations in a large Han Chinese pedigree with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK). METHODS: We enrolled 11 patients and 8 healthy individuals from a pedigree with NEPPK and 100 randomly selected healthy controls. Biopsy samples were obtained from the proband. Genomic DNA was extracted from a peripheral blood sample from each participant. Mutation detection via polymerase chain reaction and Sanger sequencing of relevant potential causative genes, including KRT1, KRT6C, KRT10, KRT16, AQP5, and SERPINB7, was performed. Comparisons were made between sequencing outcomes and currently available reference genome databases, including HGMD Pro, Pubmed, 1000 Genomics, and dbSNP. RESULTS: Histological findings, clinical features, and medical history were in accordance with the diagnosis of diffuse NEPPK. We identified a novel splice-site mutation c.1255-1G > C in intron 6 of KRT1 in all individuals with NEPPK in the pedigree. CONCLUSIONS: Diffuse NEPPK is a relatively rare subtype of palmoplantar keratoderma. The results of this study expand the spectrum of KRT1 mutations in diffuse NEPPK and provide insights into the understanding of its underlying pathological mechanisms and phenotype-genotype correlations.

Eight Novel Mutations of the ADAR1 Gene in Chinese Patients with Dyschromatosis Symmetrica Hereditaria.

AIMS: To identify potential novel gene mutations in Chinese patients with dyschromatosis symmetrica hereditaria (DSH). METHODS: We enrolled 8 Chinese patients with familial DSH, 5 Chinese patients with sporadic DSH, and 100 randomly selected healthy individuals in this study. The genome of each participant was extracted from peripheral blood samples. Sanger sequencing of the ADAR1 gene was performed after polymerase chain reaction amplifications. Comparisons between the DNA sequences of the affected individuals and the NCBI database were performed. RESULTS: We detected eight novel heterozygous mutations and five previously reported mutations in the ADAR1 gene in our patients. The novel mutations include c.1934 + 3A>G, c.2749A>G, c.2311insA, c.3233G>A, c.3019 + 1G>T, c.2894C>A, c.1202_1205del, and c.2280C>A. These detected novel mutations are predicted to induce two frame-shift mutations, one nonsense mutation, three missense mutations, and two splice-site mutations. CONCLUSIONS: The findings of this study expand our knowledge of the range of ADAR1 gene mutations in DSH and will contribute to identifying correlations between the various DSH phenotypes and genotypes. Furthermore, they may provide insight into the underlying pathogenic mechanism.