SAT-353 Familial Hyperparathyroidism - Due to a Rare Genetic Mutation

Introduction: Hyperparathyroidism occurs most commonly in middle age patients, predominantly in women. It can be caused by parathyroid adenoma, hyperplasia or parathyroid carcinoma. Genetic predisposition can be found in about 10% of primary hyperparathyroidism due to certain gene mutations. This case emphasizes the importance of taking a detailed family history when patients present with hyperparathyroidism at a young age, so that familial hyperparathyroidism, if present, can be detected and relatives screened. Clinical case: A 26 y.o. male presented with symptoms of fatigue and polydipsia for several years. He was noted to have a serum calcium of 12.4 mg/dL(8.5–10.5), with parathyroid hormone of 213 pg/ml (15–65). He denied any history of kidney stones, fractures and no palpable neck masses. The patient’s family history was significant for his paternal half-sister who had parathyroidectomy for hyperparathyroidism at 20yrs old and paternal grandmother died of parathyroid cancer in her 50s. The patient’s father died of pancreatic cancer at 41yrs old. A neck ultrasound revealed a mass posterior to the left inferior thyroid. A Sestamibi parathyroid scan revealed a parathyroid adenoma at the posteroinferior aspect of the left hemithyroid. Labs for free metanephrines and normetanephrine, prolactin and gastrin levels were all normal. Due to his young age and the possibility of having familial hyperparathyroidism, he underwent bilateral neck exploration and parathyroidectomy, with removal of his left inferior, right superior, left superior parathyroid glands and left upper thymus. Surgical pathology revealed, hypercellular parathyroid tissue. Post operatively, his calcium and vitamin D remained within the normal range. Genetic studies revealed a mutation in the parafibromin gene - CDC73 (also called HRPT2), a tumor suppressor gene, which is on chromosome 1q25. The patient currently has 6 children ranging from age 5 months to 6 years. He was advised to have his children tested any time from age 7 years for the gene mutation. The patient has remained stable 4yrs post operatively, with normal calcium and PTH levels. He does not have any history of jaw tumor. He never had an ultrasound kidney done. He is being monitored with yearly lab tests. Conclusion: CDC73 gene mutation-associated disorders are inherited as an autosomal dominant fashion, with variable penetrance. This gene mutation can be found in conditions such as hyperparathyroidism jaw tumor, familial hyperparathyroidism and parathyroid cancer. Reference: 1. CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4534–4540.

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

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 CASR, GNA11, or AP2S1. 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 CASR. 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 MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET 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 CDC73. 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 GCM2 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.

Calcium and Bone Metabolism Disorders

The causes of hypercalcemia are categorized as either parathyroid hormone (PTH) dependent or PTH independent. Primary hyperparathyroidism is the most common cause of hypercalcemia in ambulatory patients. A single parathyroid adenoma is the cause in 85% of patients, and multiglandular disease is the cause in the remainder. Parathyroid carcinoma is a rare cause of hypercalcemia. Primary hyperparathyroidism may be sporadic or familial. Familial hyperparathyroidism is usually multiglandular and most commonly a manifestation of multiple endocrine neoplasia (MEN) type 1 or type 2 syndromes.