| Entity | Carney complex syndrome, type I |
| Disease | A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors. |
| Prognosis | According to the severity of the disease in a given patient, and to the quality of a regular follow up; life span is decreased in patients with CNC. 57% of the deaths are due to heart related causes; others due to the postoperative complications or evolution of the malignant process; presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease. |
| Cytogenetics | Limited data; some of myxomas and PPNAD from CNC patients showed telomeric associations, dicentric chromosomes, aneuploidy, polyploidy and chromosomal rearrangements. |
| Hybrid/Mutated Gene | Half of CNC patients show PRKARIA mutations. |
| Oncogenesis | PRKARIA is frequently affected by bi-allelic inactivation in tumors of CNC patients. However 1 kindred was described where a splice site mutation led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with CNC. |
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| Entity | PPNAD - Primary pigmented nodular adrenocortical disease Primary pigmented nodular adrenocortical disease |
| Disease | PPNAD is a cause of ACTH-independent Cushing's syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor. |
| Hybrid/Mutated Gene | Inactivating PRKAR1A germline mutations are frequent in sporadic and isolated cases of PPNAD. |
| Oncogenesis | Both alleles are frequently inactivated. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. |
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| Entity | Adrenocortical tumors, sporadic |
| Disease | Patients frequently present with ACTH-independent Cushing's syndrome. |
| Hybrid/Mutated Gene | Somatic mutations in the PRKAR1A gene were identified in 3 cases of sporadic adrenocortical tumor. All 3 mutations predicted premature termination of the protein. 17q23-24 loss-of-heterozygosity is a frequent event in adrenal carcinomas. |
| Oncogenesis | Haploinsufficiency of PRKARIA and a reversal of the ratio of R1A to R2B have been proposed to cause tumorigenesis, at least in some cases. |
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| Entity | Myxoma, intracardiac |
| Disease | Benign neoplasms that occur in 7 per 10,000 individuals. These slowely proliferating lesions arise from subendocardial pluripotent primitive mesenchymal cells, which can differentiate within myxomas along a variety of lineages including epithelial, hematopoietic, and muscular. |
| Prognosis | Life span is decreased in patients with myxomas. Morbidity and mortality are the result of embolic stroke, heart failure due to intracardiac obstruction, and rheumatologic symptoms attributed to myxoma-mediated production of IL-6. |
| Cytogenetics | Limited data; 15 cases of myxomas contained clonal numerical and structural abnormalities including telomeric associations. |
| Hybrid/Mutated Gene | Mutations of PRKARIA detected in the coding region of the gene, exons 5, 7 and 8. |
| Oncogenesis | No somatic mutations were detected in cardiac myxomas; haploinsufficiency of PRKARIA and a reversal of the ratio of RIA to R2B have been proposed may contribute in tumorigenesis. |
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| Entity | Papillary thyroid carcinoma |
| Cytogenetics | Reciprocal translocation between chromosomes 10 and 17 |
| Hybrid/Mutated Gene | RET/PTC2 is formed by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit |
| Abnormal Protein | RET/PTC2 |
| Oncogenesis | The fusion of the RET tyrosine kinase domain with a portion of the RIA gene leads to the expression of RET in the thyroid cells, where it is normally transcriptionally silent. |
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