Familial Hyperparathyroidism – Disorders of Growth and Secretion in Hormone-Secretory Tissue

Abstract

Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in or. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression.

Normocalcemic Primary Hyperparathyroidism: A Comparison with the Hypercalcemic Form in a Tertiary Referral Population

“…Ionized serum calcium levels were measured in only a few patients and these results were not included. Familial Hypocalciuric Hypercalcemia (FHH) can be distinguished from PHPT by a low urinary calcium excretion and Ca/Cr ratio clearance ratio < 0.01 [2,19]. The plasma PTH concentration and 25-OH vitamin D were both measured by electro chemiluminescence: PTH (Cobas e411-1 analyzer) with reference interval: 15.0-65.0 ng/l and 25-OH vitamin D (Cobas 6000 analyzer) with reference interval: 20-50 μg/l.…”

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…Hypophosphatemia and renal phosphate wasting due hyperparathroidism can be the result of inactivating mutations in the calcium sensing receptor (CaSR), the G-alpha protein (GNA11), the clathrin adaptor protein AP2 (AP2S1), the tumor suppressor menin (MEN1), the cyclin dependent kinase inhibitor (CDKN1B), parafibromin (CDC73), or activating mutations of the proto-oncogene RET (RET) or the chorion specific transcription factor (GCM2) [70]. Clinically these syndromes are frequently dominated more by the presence of hypercalcemia than by abnormalities in phosphate metabolism.…”

Questions and Controversies About Parathyroid Pathophysiology in Children With Multiple Endocrine Neoplasia Type 1

“…Since PHPT has a high penetrance in adolescents with MEN1, it would be of some interest to know how early parathyroid tumors and PHPT begin in MEN1. PHPT in neonatal severe PHPT always or often begins in utero ( 11 ). This is usually from mutation in CASR encoding the calcium-sensing receptor, and expressed mainly upon parathyroid cells ( 12 ).…”

“…Thus, MEN1 becomes more relevant in the differential diagnosis of hypercalcemia after the age of 8 years. More rare causes of hypercalcemia that might be encountered after age 8 are the hyperparathyroid-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hyperparathyroidism without known mutation, and nonfamilial hyperparathyroidism ( 11 ). Before age 8, almost all cases of PTH-dependent hypercalcemia are caused by familial hypocalciuric hypercalcemia (mostly from mutation in CASR, AP2S1, or GNA11 ) or by neonatal severe primary hyperparathyroidism, both of which have near 100% penetrance for hypercalcemia already in the neonate ( 12 , 18 ).…”

“…Thus, the age at the diagnosis of hypercalcemia is one of the important clues for diagnosis of MEN1. Importantly, different strategies of clinical management are recommended in each of these genetic disorders ( 11 ).…”