Development Of Parathyroid Adenomas Research Articles

MON-541 Successful Treatment of Normocalcemic Hyperparathyroidism in Children

Childhood and adolescence are the critical periods for the establishment of lifelong bone health. Normocalcemic primary hyperparathyroidism (NPHPT) has been recognized as a variant of primary hyperparathyroidism (PHPT) 15 years ago and it is characterized by elevated PTH level with persistently normal concentrations of albumin-adjusted total and ionized calcium, in the absence of secondary causes of hyperparathyroidism and it is related to increased risk in development of osteopenia or osteoporosis as well as development of parathyroid adenoma and hypercalcemia-hypercalciuria with renal consequences. In order to identify biochemical disorders of PTH in normocalcemic children we performed in all patients that visited our pediatric endocrine unit for two years (1-Nov 2016 until 31-Oct 2018), a complete calcium metabolism evaluation (Ca, P, ALP, 25OHD, intact PTH). A total of 3060 patients - excluding those that consulted for vitamin D deficiency, Ca metabolism abnormalities or known renal pathology (i.e. Bartter syndrome) - were included. We identified 157 patients (5.1%) with hyperparathyroidism (PTH > 45 pg/ml, Horm Res Paediatr 2015;84:124-129) and normal total serum calcium levels; adequate data on laboratory results and follow up were available in 114 patients; 67 (58.7%) of them were vitamin D replete (25OHVitD >30 ng/ml, group 1) and forty-seven were vitamin D deficient (41.3 %) (25OHVitD <30 ng/ml, group 2). All patients were treated with cholecalciferol (8000-16000 IU daily). All patients in groups 1 and 2 who did not normalize their PTH (< 45 pg/ml) within 6 months of monotherapy with vitamin D, received additional calcium supplementation (1000 mg/day). Evaluation of calcium metabolism (Ca, P, ALP, 25OHD, 1,25OHD, PTH) was performed every 3 months. In 6 patients (4 from group 1 and 2 from group 2) elevated PTH did not respond to 6 months of combined cholecalciferol/calcium therapy. These patients were switched to the non-calcemic synthetic 1-25(OH)2-vitamin D analogue, paricalcitol, at the dose of 2 mcg x 1-3/day. Evaluation of calcium metabolism (Ca, P, ALP, 25OHD, 1,25OHD, PTH, urine Ca/Cr) was performed every 3 months. Parathormone levels normalized in 5 patients by 3 months of treatment and in one by 10 months of treatment with calcium in serum and urine being within normal range for age during treatment in all patients. We propose that all normocalcemic children that are checked for vitamin D deficiency undergo concomitant measurement of PTH levels. Subclinical hyperparathyroidism (PTH > 45 pg/ml) should be treated with cholecalciferol (8000-16000 IU/day) and calcium supplementation (1000 mg/day) and if unresponsive after a minimum of 3 months, with paricalcitol 2-6 mcg/day in order to normalize PTH and protect their bone and general health. Further studies are needed to standardize this approach.

The Parathyroid Adenoma

Parathyroid adenomas are benign neoplasms with a predilection for the inferior parathyroid glands. Genetic mutations identified as contributing to development of parathyroid adenomas include MEN 1 and cyclin D1. Predisposing factors include female gender and radiation exposure. The natural history of parathyroid adenomas, including malignant potential, is poorly understood. Specific indications for surgical removal in addition to surgical and non surgical therapeutic modalities are discussed in this review.

Cyclin D1 in parathyroid disease.

Primary hyperparathyroidism (HPT), most commonly due to parathyroid adenoma, is a disorder characterized by excessive secretion of PTH. So far, abnormalities in two genes, cyclin D1 and MEN1, have been implicated in the development of parathyroid adenomas. Cyclin D1, now an established Oncogene involved in numerous human cancers, was first identified and recognized as an Oncogene in the study of parathyroid tumors. A subset of parathyroid adenomas contains a clonal rearrangement that places the PTH gene's regulatory sequences in proximity to the cyclin D1 Oncogene causing its overexpression, and 20-40% of parathyroid adenomas overexpress the cyclin D1 protein. Transgenic animal models have further confirmed the role of cyclin D1 as a driver of abnormal parathyroid cell proliferation. Future studies on the mechanism of cyclin D1's oncogenicity and its interactions with other parathyroid growth regulators will further our understanding of parathyroid cell biology and may prove useful clinically.

Analysis of the RAD54 gene on chromosome 1p as a potential tumor-suppressor gene in parathyroid adenomas.

Parathyroid adenomas causing primary hyperparathyroidism (pHPT) frequently exhibit allelic loss of DNA markers on the short arm of chromosome 1, indicating the presence of one or more tumor-suppressor genes on 1p. Since the development of pHPT is enhanced in individuals exposed to ionizing radiation to the neck, it could be anticipated that genes involved in DNA repair and recombination may be special targets for mutation in parathyroid tumorigenesis, whether irradiation-associated or not. RAD54 is a member of a family of genes involved in such functions, and RAD54 knockout mice show increased sensitivity to ionizing radiation. The localization of the RAD54 gene to 1p32 has therefore elevated it to a most compelling candidate parathyroid tumor-suppressor gene. Twelve parathyroid adenomas demonstrating allelic loss at chromosome 1p were selected from 55 parathyroid adenomas previously analyzed for loss of heterozygosity using polymorphic microsatellite markers. All 18 exons of the RAD54 gene were fully analyzed by automated sequencing for detection of point mutations or micro-deletions in each parathyroid adenoma. No mutational aberrations were detected in the RAD54 gene, strongly suggesting that complete somatic inactivation of RAD54 is infrequently, if ever, associated with the development of parathyroid adenomas. Whether genes controlling DNA repair and recombination are involved in parathyroid neoplasia remains to be determined.

Parathyroid adenoma in a cancer center patient population

The association of parathyroid adenoma and antecedent events or relationships was examined retrospectively in 103 patients with parathyroid adenoma drawn from a cancer institute patient population. Patients were divided into two study groups by the referral pattern-intramural or community. The major contrast between the two groups was that the intramural patients had cancer diagnoses. The factors of advanced age, female gender, and prior regional irradiation appeared to be associated with the development of parathyroid adenoma. An interrelationship of incidental cancer and parathyroid adenoma, however, was not supported. Breast and differential thyroid cancers were most frequently associated with parathyroid adenoma, but age, gender, and irradiation were bias influences.

Calcium metabolism in sarcoidosis.

Summary Fifteen patients with hypercalcaemia and sarcoidosis have been studied. Twelve were males of average age 34; the three females averaged 53. Cases included widely varying sarcoid manifestations, but five gave a clear history of rather excessive ingestion of low-dosage vitamin D preparations. The data confirm that in most cases there is an undue sensitivity to all the actions of vitamin D, the situation therefore mimicking vitamin D intoxication. Two patients volunteered to receive ultra-violet irradiation and became hypercalcaemic with corresponding clinical and biochemical changes. Steroids make normal the calcium abnormalities just as they do in straight vitamin D intoxication. However, in three further patients the hypercalcaemia did not respond to steroids and was shown to be due to the presence of an over-acting parathyroid gland, removal of which corrected the abnormality. There are a sufficient number of other similar cases in the literature to suggest that the development of parathyroid adenomas is another even rarer complication of sarcoidosis which must be carefully distinguished from vitamin D sensitivity.