Genotype-Phenotype Correlations in the Hyperparathyroidism-Jaw Tumor Syndrome

Establishing genotype-phenotype correlations in disorders of hereditary endocrine neoplasia is important for clinical screening, genetic counseling, prognostication, surveillance, and surgical strategy, and may also provide clues about disease pathogenesis. Important genotype-phenotype correlations are recognized, for example, in pheochromocytoma/paraganglioma and multiple endocrine neoplasia type 2A. The presence of such correlations has been less clear in other familial endocrine disorders associated with primary hyperparathyroidism including multiple endocrine neoplasia type 1, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). Characteristic features of HPT-JT, apart from fibro-osseous jaw tumors and uterine lesions, include renal neoplasms, such as Wilms tumor and mixed epithelial and stromal tumor (“renal hamartomas”), and a high incidence of parathyroid cancer. Emerging evidence suggests two different genotype-phenotype correlations in HPT-JT based on the type of variant in the CDC73 tumor suppressor gene. Although multiple CDC73 genotypes can give rise to the Wilms tumor phenotype in HPT-JT, the development of mixed epithelial and stromal tumor of the kidney specifically correlates with the presence of a start-loss variant affecting the initiator methionine codon of parafibromin, the protein product encoded by CDC73. Furthermore, the risk of parathyroid cancer in HPT-JT also appears to correlate with genotype: CDC73 frameshift indel, splice-site, and stop-gain genotypes are associated with a greatly increased risk of parathyroid carcinoma compared to carriers of CDC73 missense and nonframeshift indel variants. The recognition of such genotype-phenotype correlations in HPT-JT may impact genetic counseling, patient care and disease surveillance.