Novel heterozygous variants in the EP300 gene cause Rubinstein–Taybi syndrome 2: Reports from two Chinese children

BACKGROUND: Rubinstein–Taybi syndrome (RSTS) is a rare autosomal‐dominant genetic disease caused by variants of CREBBP (RSTS1) or EP300 (RSTS2) gene. RSTS2 is much less common, with less than 200 reported cases worldwide to date. More reports are still needed to increase the understanding of its clinical manifestations and genetic characteristics. METHODS: The clinical data of two children with RSTS2 were analyzed retrospectively, and their clinical manifestations, auxiliary examinations, and mutational spectrum were summarized. Liquid chromatography–tandem mass spectrometer (LC–MS/MS) technology was used to detect the levels of steroid hormones if possible. RESULTS: After analyzing the clinical and genetic characteristics of two boys with RSTS2 (0.7 and 10.4 years old, respectively) admitted in our hospital, we identified two novel heterozygous variants in the EP300 exon 22 (c.3750C > A, p. Cys1250*, pathogenic; c.1889A > G, p. Tyr630Cys, likely pathogenic), which could account for their phenotype. In addition to common clinical manifestations such as special facial features, microcephaly, growth retardation, intellectual disability, speech delay, congenital heart defect, recurrent respiratory infections, and immunodeficiency, we found one of them had a rare feature of adrenal insufficiency, and LC–MS/MS detection showed an overall decrease in steroid hormones. CONCLUSION: In our study, we identified two novel variants in the EP300 exon 22, and for the first time, we reported a case of RSTS2 associated with adrenal insufficiency, which will enrich the clinical and mutational spectrum of this syndrome.