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Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation.
J Bone Miner Res. 2006 Oct; 21(10):1666-71.JB

Abstract

Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder.

INTRODUCTION

Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations.

MATERIALS AND METHODS

A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland.

RESULTS

Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson "two hit" concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation.

CONCLUSIONS

Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors.

Authors+Show Affiliations

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8064, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16995822

Citation

Kelly, Thomas G., et al. "Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial Isolated Hyperparathyroidism Associated With a Germline HRPT2 Mutation." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 21, no. 10, 2006, pp. 1666-71.
Kelly TG, Shattuck TM, Reyes-Mugica M, et al. Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. J Bone Miner Res. 2006;21(10):1666-71.
Kelly, T. G., Shattuck, T. M., Reyes-Mugica, M., Stewart, A. F., Simonds, W. F., Udelsman, R., Arnold, A., & Carpenter, T. O. (2006). Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 21(10), 1666-71.
Kelly TG, et al. Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial Isolated Hyperparathyroidism Associated With a Germline HRPT2 Mutation. J Bone Miner Res. 2006;21(10):1666-71. PubMed PMID: 16995822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. AU - Kelly,Thomas G, AU - Shattuck,Trisha M, AU - Reyes-Mugica,Miguel, AU - Stewart,Andrew F, AU - Simonds,William F, AU - Udelsman,Robert, AU - Arnold,Andrew, AU - Carpenter,Thomas O, PY - 2006/9/26/pubmed PY - 2007/3/14/medline PY - 2006/9/26/entrez SP - 1666 EP - 71 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 21 IS - 10 N2 - UNLABELLED: Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder. INTRODUCTION: Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations. MATERIALS AND METHODS: A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland. RESULTS: Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson "two hit" concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation. CONCLUSIONS: Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/16995822/Surveillance_for_early_detection_of_aggressive_parathyroid_disease:_carcinoma_and_atypical_adenoma_in_familial_isolated_hyperparathyroidism_associated_with_a_germline_HRPT2_mutation_ L2 - https://doi.org/10.1359/jbmr.060702 DB - PRIME DP - Unbound Medicine ER -