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Four cases of neonatal severe primary hyperparathyroidism occurred in three families; familial hypocalciuric hypercalcemia was present in each kindred. The diagnosis of familial hypocalciuric hypercalcemia was based on the following features; hypercalcemia in many relatives (eight to 16 per kindred), without other features of the multiple endocrine neoplasia syndromes; recognition of hypercalcemia before the age of 10 in one to three relatives; hypocalciuric hypercalcemia in all relatives tested (five to 14 per kindred); and abnormal serum calcium levels despite parathyroidectomy in all additional relatives (one to five per kindred) undergoing this operation. The association of two uncommon syndromes (neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia) in these kindreds suggests that the two syndromes share a common genetic cause within each kindred.

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We report a patient with neonatal severe primary hyperparathyroidism whose parathyroid cells were markedly refractory to regulation by calcium in vitro. He showed life-threatening hypercalcemia (4.8-5.2 mM vs. normal of 2.1-2.7 mM). A sibling had been treated previously for an identical disorder. At age 6.5 months, four hyperplastic parathyroid glands were removed, and portions of one were immediately grafted into the forearm. Serum calcium again became elevated post-operatively and then fall to the normal range after excision of grafted parathyroid tissue. Dispersed parathyroid cells from the first operation showed no suppression of PTH secretion by 2 mM calcium; however, there was normal maximal suppressibility at 4 mM calcium with half-maximal suppression at 2.53 mM (the calcium set point). This contrasts with much lower set points previously established for suppressible cells from normal (1.02 +/- 0.10 mM, mean +/- 1 SD), from primary hyperplastic (1.10 +/- 0.14 mM), or from adenomatous (1.26 +/- 0.14 mM) parathyroid glands. The strikingly high set point may not be unique because a small number of glands previously classified as nonsuppressible (by the criterion of failing to suppress below 50% maximum at calcium concentration up to 2-3 mM) might have shown similarly high set points if tested at higher calcium concentrations. We conclude that an unusual abnormality of PTH secretory control accounts, in large part, for both the marked hypercalcemia and for its refractoriness to surgical treatment in this patient.