Molecular basis of symptomatic sporadic primary hyperparathyroidism: New frontiers in pathogenesis.

Primary hyperparathyroidism is a common endocrine disorder characterized by inappropriate elevation of parathyroid hormone and hypercalcemia. While predominantly an asymptomatic disease in Western populations, symptomatic presentations are more prevalent in Eastern countries. The molecular pathogenesis of sporadic PHPT primarily involves genetic and epigenetic alterations leading to abnormal parathyroid cell proliferation and altered calcium sensing mechanism. To date, MEN1 and cyclin D1 are the only established drivers of sporadic PHPT. Somatic MEN1 gene mutations occur in 30-40 % of sporadic parathyroid adenomas (PA), with a recent study on symptomatic cases reporting germline variants.Cyclin D1 overexpression in sporadic PA has been observed in 20-40 % of cases in Western populations and 80 % of cases in Eastern populations, with an inverse association with cyclin-dependent kinase inhibitors CDKN2A and CDKN2B expression. The calcium-sensing receptor expression was significantly lower in symptomatic compared to asymptomatic PHPT, strongly supported by epigenetic deregulation (promoter hypermethylation and histone methylation). Recent studies have highlighted the potential involvement of EZH2, a histone methyltransferase, in parathyroid tumorigenesis. Additionally, parathyroid-specific transcription factors like GCM2, PAX1, and GATA3 are emerging as putative tumor suppressors, especially from the symptomatic PHPT. Next-generation sequencing has identified novel potential drivers such as PIK3CA, MTOR, and NF1 in sporadic PC, alongside CDC73. The molecular landscape of sporadic PHPT appears to differ between Eastern and Western populations. This heterogeneity underscores the need for further large-scale studies, particularly in symptomatic cases from developing nations, to comprehensively elucidate the molecular drivers of parathyroid tumorigenesis.