Familial acromegaly with a novel PRKAR1A splice-acceptor variant and marked intrafamilial phenotypic variability.
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Acromegaly is usually sporadic but may rarely occur as part of inherited endocrine tumor syndromes, particularly when disease onset is early or multiple family members are affected. Carney complex is an autosomal dominant disorder, most often due to inactivating PRKAR1A mutations, with diverse endocrine and nonendocrine manifestations. We report a 33-year-old man with long-standing acromegaly, growth hormone (GH)-positive pituitary adenoma with focal prolactin positivity, cutaneous and cardiac myxomas, and bilateral large-cell calcifying Sertoli cell tumors. He achieved biochemical remission after endoscopic transsphenoidal surgery. His younger sister had childhood-onset acromegaly requiring pituitary surgery in adolescence and has persistent disease with mildly elevated insulin-like growth factor-1 (IGF-1). She subsequently had a spontaneous pregnancy and delivered a healthy child. Genetic analysis of the index case, sister, and mother identified a novel monoallelic intronic PRKAR1A splice-acceptor variant, c.709-7T>G, in intron 7 near exon 8, causes retention of 6 base pairs from the 3' end of intron 7, leading to a frameshift and premature truncation, p. (Gly237insPhefs*2), consistent with a likely pathogenic variant. The mother did not develop any endocrine manifestations till date (62 years of age). This report expands the PRKAR1A mutational spectrum and highlights marked intrafamilial phenotypic variability, supporting genetic evaluation in early-onset or familial acromegaly to guide surveillance and family screening.