A Heterozygous Mutation in GJA1 Gene in Chinese Family with Serious Erythrokeratodermia Variabilis et Progressive
Erythrokeratodermia variabilis (EKV) is a rare inherited skin disorder characterized by the coexistence of transient, figurate, erythematous patches and localized keratotic hyperkeratosis. The condition exhibits marked phenotypic heterogeneity, even among individuals within the same family who carry the same disease-causing mutation. A severe variant of EKV, known as Erythrokeratodermia variabilis et progressiva (EKVP), encompasses a broader range of phenotypes, from limited hyperkeratotic plaques and erythematous patches to severe progressive symmetric erythrokeratodermia, which can involve more generalized cutaneous manifestations.
In this study, we report a Chinese family with EKVP exhibiting autosomal dominant inheritance. The proband, a 27-year-old man, presented with symptoms that began at one month of age, starting with clear erythema on the palms and soles, accompanied by small scales. Over time, the lesions expanded and became more severe, leading to a diagnosis of generalized verrucous epidermal nevus, EKV, autosomal dominant congenital ichthyosiform erythroderma, and progressive symmetrical erythrokeratodermia across different hospitals. Despite treatment with cod-liver oil, urea cream, and Vitamin E cream, the lesions showed no significant improvement. The patient’s skin was dry, with lesions observed on the palms, feet, legs, arms, elbows, thighs, and hips. These lesions were characterized by clear-border erythema with thick scales and crusts that could be peeled off. Laboratory examinations, including blood, urine, and stool tests, as well as liver and renal function tests, were normal. Histological examination revealed marked hyperkeratosis, granular-layer hypertrophy, acanthosis, and lymphocytic infiltration around superficial blood vessels. The patient’s father exhibited similar clinical features, suggesting a familial pattern of the disease.
To identify the pathogenic gene responsible for this condition, we conducted sequencing studies. Initially, we considered autosomal dominant congenital ichthyosiform erythroderma and assessed the KRT1 and KRT10 genes in both blood and tissue samples. However, no mutations were found in the coding regions or splice sites of these genes. To further investigate, we performed next-generation sequencing using the SeqCap EZ Med exome enrichment kit, which targets 541 genodermatosis-related genes. This analysis revealed a missense mutation in the GJA1 gene (gap junction protein alpha 1) in the proband’s blood (NM_000165; CCDS5123.1: exon2: c.131C→T: p.A44V). Sanger sequencing confirmed this mutation in the proband’s tissue and his father’s blood, but it was absent in unaffected family members. Additionally, the mutation was not found in 200 unrelated, ethnically and geographically matched healthy controls. The mutation was predicted to be pathogenic by software, and the amino acid A44 was highly conserved across orthologs. Immunohistochemistry showed strong positive expression of connexin 43 (Cx43; GJA1; 121014) in the patient’s epidermis, compared to negative or weak expression in controls.
GJA1 encodes the gap junction protein Cx43, which is ubiquitously expressed in various organs, including the epidermis and hair follicles. Mutations in GJA1, along with GJB3 and GJB4 (encoding connexins 31 and 30.3, respectively), have been implicated in EKVP. The p.A44V mutation in GJA1 has been previously associated with EKVP, presenting with figurate erythema, burning sensations, thickened scaly skin, hyperpigmentation, and palmoplantar keratosis. However, the cases reported in previous studies were sporadic, unlike the familial pattern observed in our study. Moreover, the clinical manifestations in our patients were more severe.
The diagnosis of EKVP in this family was confirmed through genetic testing, identifying the GJA1 mutation as the causative factor. This study highlights the importance of genetic diagnosis in understanding the etiology of rare skin disorders and provides further evidence of the role of GJA1 mutations in EKVP. The findings also underscore the phenotypic variability associated with GJA1 mutations, even within the same family.
In conclusion, this study reports a Chinese family with severe EKVP caused by a heterozygous mutation in the GJA1 gene. The clinical and genetic findings contribute to the growing body of knowledge on EKVP and emphasize the need for comprehensive genetic testing in patients with inherited skin disorders. The identification of the GJA1 mutation not only aids in the accurate diagnosis of EKVP but also opens avenues for potential therapeutic interventions targeting the underlying genetic defect.
doi.org/10.1097/CM9.0000000000000011
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