Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective

Abstract

We review advancing and overlapping stages for our understanding of 6 hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903-1967), the introduction of serum calcium measurement was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects. Inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased towards severe or striking manifestations. During stage 2 (1959-1985), syndromes were more fully formulated. Radioimmunoassays (PTH, gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981-2006), the assembly of many cases enabled recognition of further details. Age-related penetrance of a syndrome could be derived. Hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. Genetic linkage could now be used for carrier detection. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes (“principal” implies mutated or deleted in 50% or more probands for its syndrome) ( MEN1, RET, CASR, CDC73) were identified for 5 syndromes. During stage 5 (1993 to the present), 7 syndromal genes other than a principal gene were identified ( CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole exome sequencing. During stages 4 and 5, the identified genes enabled many studies, including robust detection of mutation carriers and non-carriers. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future.