Marx Stephen J, Lourenço Delmar Muniz
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
Hospital das Clinicas, University of São Paulo School of Medicine Sao Paulo, Sao Paulo, Brazil.
Horm Metab Res. 2017 Nov;49(11):805-815. doi: 10.1055/s-0043-120670. Epub 2017 Nov 14.
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.
1）家族性低钙血症性高钙血症（FHH）表现为出生时即开始的原发性甲状旁腺功能亢进（PHPT），伴有终生高钙血症。外观正常的甲状旁腺腺体分泌的甲状旁腺激素（PTH）未被抑制。它反映了钙敏感受体（CASR）或甲状旁腺激素1受体（PTH1R）中的种系杂合突变。2）新生儿重症原发性甲状旁腺功能亢进是六种综合征中最严重的。婴儿期需要紧急进行甲状旁腺全切术。它通常反映了钙敏感受体基因的双等位基因失活。3）多发性内分泌腺瘤1型（MEN1）最常表现为PHPT，3 - 4个甲状旁腺不对称肿大。在其他30种组织中可能发生良性或恶性肿瘤。它由MEN1基因的种系失活引发，或很少由细胞周期蛋白依赖性激酶抑制剂失活引发，后者称为MEN4。4）由RET激活突变引起的多发性内分泌腺瘤2A型很少表现为家族性甲状旁腺功能亢进，因为甲状腺髓样癌和嗜铬细胞瘤更为突出。5）甲状旁腺功能亢进 - 颌骨肿瘤综合征（HPT - JT）常出现PHPT和良性颌骨肿瘤。20%会发展为甲状旁腺癌。它由CDC73基因的失活突变引发。6）家族性孤立性甲状旁腺功能亢进会导致多个甲状旁腺肿瘤。它可能是FHH、MEN1、HPT - JT的不完全表现，甚至在没有共同驱动突变的亲属中也可能出现。然而，在20%的家族中，它反映了甲状旁腺激素1受体的激活突变。五种PHPT综合征反映了甲状旁腺组织的过度生长；相比之下，家族性低钙血症性高钙血症反映了PTH分泌失调，甲状旁腺很少或没有过度生长。这些差异是临床表现主要差异的基础。
