CDC73 – Hyperparathyroidism-Jaw Tumor Syndrome

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant endocrine disorder characterized by primary hyperparathyroidism, ossifying jaw fibromas, and increased risk of parathyroid carcinoma. It results from germline loss-of-function variants in CDC73 and is catalogued as Hyperparathyroidism-Jaw Tumor Syndrome.

Genetic evidence includes over 80 distinct inactivating germline mutations identified in more than 200 individuals across at least 14 unrelated families, with recurrent frameshift, nonsense, and splice-site variants clustering throughout the coding region ([PMID:12434154]). Segregation analyses in three large Italian kindreds demonstrated co-segregation of CDC73 variants with disease in 17 additional affected relatives, confirming autosomal dominant transmission ([PMID:19529956]).

The variant spectrum comprises frameshift (e.g., c.85delG (p.Glu29fs)), nonsense (e.g., c.415C>T (p.Arg139Ter)), canonical splice-site (e.g., c.238-1G>A), and multi-exon deletions affecting exons 4–10, consistent with haploinsufficiency as the predominant mechanism ([PMID:15613436]; [PMID:28774260]). One exemplar variant is c.238-1G>A, which abolishes the intron 2 acceptor site and leads to truncated parafibromin.

Functional studies support a tumor suppressor role for parafibromin. Parafibromin-deficient mouse embryos are non-viable, and conditional knockout in adult mice triggers apoptosis and cachexia. In cell models, parafibromin overexpression induces G1 arrest, whereas patient-derived mutations impair nucleolar localization, destabilize the protein, and abrogate down-regulation of c-MYC ([PMID:16989776]; [PMID:18212049]).

No substantial conflicting evidence has been reported. The convergence of robust genetic, segregation, and functional data justifies a Definitive ClinGen classification. Recognizing CDC73 variants is critical for early diagnosis, surgical planning, and familial surveillance.

Key Take-Home: CDC73 pathogenic variants cause autosomal dominant HPT-JT via haploinsufficiency; comprehensive genetic testing guides diagnosis, management, and familial screening.

References

• Nature Genetics • 2002 • HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome PMID:12434154
• Langenbeck's Archives of Surgery • 2009 • Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred PMID:19529956
• Biochemical and Biophysical Research Communications • 2006 • Parafibromin inhibits cancer cell growth and causes G1 phase arrest PMID:16989776
• Molecular and Cellular Biology • 2008 • Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice PMID:18212049

Evidence Based Scoring (AI generated)