A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer
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CONTEXT: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. OBJECTIVE: We studied the genotype-phenotype correlation in CNC. DESIGN AND SETTING: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. PATIENTS: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. RESULTS: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro. CONCLUSIONS: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.
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ACC has been reported in 2 cases of patients with Carney complex.
“Most recently, ACC has also been reported in 2 cases of patients with Carney complex (73, 74).”
From Adrenocortical carcinoma (2014) · cites this paper as [73]
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“(17) found that the only significant microscopic finding indicative of AC was a mitotic index of more than 20 mitoses per 50 high-power fields.”
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- Authors
- Anselmo, J., Medeiros, S., Carneiro, V., Greene, E., Levy, I., Nesterova, M., Lyssikatos, C., Horvath, A., Carney, J. A., & Stratakis, C. A.
- Affiliations
- Hospital do Divino Espírito Santo (PT)
- National Institutes of Health (US)
- Mayo Clinic (US)
- Corresponding author
- Stratakis, Constantine A.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-02
- Volume
- 97
- Issue
- 2
- Pages
- 351-359
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3275364
- OpenAlex
- W2093790639
- Cited by
- 81
- References
- 26
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 1 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 3 · 2018: 8 · 2017: 3 · 2016: 6 · 2015: 12 · 2014: 1 · 2013: 9 · 2012: 3
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD000642)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- Carney complex, PRKAR1A mutation, adrenocortical carcinoma, primary pigmented nodular adrenocortical disease, Cushing's syndrome, lentigines, genotype-phenotype correlation, protein kinase A, family studies, Azores
- MeSH terms
- Adolescent, Adrenal Cortex Neoplasms, Adrenal Gland Diseases, Adult, Child, Child, Preschool, Family, Female, Glycine, Humans, Male, Middle Aged, Serine, Adrenocortical Carcinoma, Amino Acid Substitution, Mutation, Missense, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Young Adult, Carney Complex
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