Phenotypic Variability in a Family with Carney Complex Accompanied by a Novel Mutation Involving <i>PRKAR1A</i>

Phenotypic Variability in a Family with Carney Complex Accompanied by a Novel Mutation Involving PRKAR1A

Haremaru Kubo,¹ Yuya Tsurutani,¹ Chiho Sugisawa,^1,2 Takashi Sunouchi,¹ Rei Hirose¹ and Jun Saito¹

¹Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan
²Division of Endocrinology and Metabolism, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan

Carney complex is a rare, autosomal dominant disease accompanied by multiple endocrine neoplastic syndromes. Mutations in the PRKAR1A gene have recently been reported as a cause of Carney complex, but genotype-phenotype correlations vary widely. A 15-year-old Japanese man (Case 1) with short stature visited our hospital with suspected Cushing’s syndrome. Biochemical investigations suggested corticotropin-independent Cushing’s syndrome. Computed tomography revealed multiple bilateral adrenal tumors, and a two-staged partial adrenalectomy was performed. Pathological findings revealed primary pigmented nodular adrenocortical disease (PPNAD). The patient also exhibited distinctive spotty skin pigmentation. Based on these features, the patient was diagnosed as Carney complex. Cascade screening of family members was performed, and the mother (Case 2) and elder brother (Case 3) were diagnosed as Carney complex. Case 2 showed cardiac myxoma, acromegaly, spotty skin pigmentation, and mammary myxoid fibroadenoma. Case 3 exhibited gigantism, spotty skin pigmentation, and thyroid nodules. Target gene testing in Case 1 and 2 revealed the same novel mutation in PRKAR1A gene (c.503G>T, p.Gly168Val). This mutation was predicted as a pathogenic variant by multiple in silico analyses. Here, we present a family of Carney complex cases with a novel PRKAR1A pathogenic variant exhibiting varied clinical phenotypes within each case. In these cases, some specific phenotypes of Carney complex, such as pigmentary disorders, myxomas, and PPNAD are important as clues for diagnosis and prognostic factors. Clinicians should consider further examination in patients with Carney complex-specific phenotypes.

Keywords —— Carney complex; heart myxoma; primary pigmented nodular adrenocortical disease; PRKAR1A gene; spotty skin pigmentation

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Tohoku J. Exp. Med 2022, 257, 337-345.

Correspondence: Yuya Tsurutani, M.D., Ph.D., Endocrinology and Diabetes Center, Yokohama Rosai Hospital, 3211 Kozukue-cho, Kouhoku-ku, Yokohama, Kanagawa 222-0036, Japan.

e-mail: yuya97tsuru1055@gmail.com