This issue highlights the 8th edition of EBR – a mock-exam with more than 240 clinical case questions. Hear expert commentary and read in-depth answer rationales. Available on the online store.
A 34-year-old woman presents with nausea, vomiting, mental confusion, and dehydration. Her history is positive for a Wilms tumor as a child and uterine fibroids. Both her mother and older brother have a history of primary hyperparathyroidism and a maternal aunt had a benign fibroma removed from her mandible.
On physical examination, the patient is lethargic and disoriented with a 3-cm firm mass on the left side of the neck that moves with swallowing.
In addition to the multiple endocrine neoplasia syndromes, it is important to be aware of another multi-organ hereditary syndrome associated with primary hyperparathyroidism known as hyperparathyroidism–jaw-tumor syndrome. It is caused by mutations in the CDC73 gene (also known as HRPT2 or parafibromin) and should be considered in the following clinical situations:
Familial hyperparathyroidism (at least 2 first- or second-degree relatives have primary hyperparathyroidism)
Primary hyperparathyroidism in a young person (<35 years)
Ossifying fibromas of the maxilla or mandible in patient or family member (found in 25%-50%)
Renal abnormalities such as Wilms tumors, renal cell carcinoma, hamartomas, polycystic kidneys (found in 15%)
Uterine tumors (benign or malignant) (75% of females with the syndrome)
Parathyroid carcinoma (found in 15%)
Inheritance of this multiple neoplasia syndrome is autosomal dominant with variable penetrance. Parafibromin is a tumor suppressor gene, and mutations or deletions may occur in germline or somatic cells. In the patient in this vignette, the presence of the syndrome coupled with the very high serum calcium and PTH levels is most suggestive of parathyroid carcinoma (Answer C). None of the other listed options (Answers A, B, D, or E) would explain the severe primary hyperparathyroidism, the neck mass, and the notable family and patient history.
Parathyroid carcinoma is rare, occurring in less than 0.5% of cases of primary hyperparathyroidism, but it can be highly aggressive. With the exception of the hyperparathyroidism–jaw-tumor syndrome discussed above, parathyroid carcinoma does not seem to evolve through a benign intermediate, such as a parathyroid adenoma, but rather, occurs de novo. Women and men are affected equally and patients usually present with very symptomatic hypercalcemia and a neck mass. Occasionally, parathyroid carcinoma is found incidentally and is non-secretory. When parathyroid carcinoma is suspected, FNAB should be avoided as both bleeding and tumor seeding along the needle track have been reported. Optimal treatment is surgical resection of the entire tumor with negative margins, as well as resection of the ipsilateral thyroid lobe and any other involved structures. Bisphosphonates and
high-dosage cinacalcet have been used for management of hypercalcemia when surgery is not curative.
Multiple endocrine neoplasia type 4 (Answer B) is a rare disorder in which gonadal, adrenal, renal, and thyroid tumors may exist along with the usual pituitary, parathyroid, and pancreatic tumors characteristic of multiple endocrine neoplasia type 1. It is caused by mutations in a unique tumor suppressor gene.
Educational Objective: Diagnose parathyroid carcinoma in a patient with hyperparathyroidism–jaw tumor syndrome.
References: Cao J, Chen C, Wang QL, Xu JJ, Ge MH. Parathyroid carcinoma: a report of six cases with a brief review of the literature. Oncol Lett. 2015;10(6): 3363-3368.
Shifrin A, LiVolsi V, Shifrin-Douglas S, et al. Primary and metastatic parathyroid malignancies: a rare or underdiagnosed condition? J Clin Endocrinol Metab. 2015;100(3):E478-E481.
Bricaire L, Odou MF, Cardot-Bauters C, et al; GTE Group. Frequent large germline HRPT2 deletions in a French national cohort of patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2013;98(2):E403-E408.
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