Primary hyperparathyroidism, Multiple endocrine neoplasia (MEN)

Primary hyperparathyroidism is due to increased intrinsic activity of the parathyroid gland, altering the secretion of parathyroid hormone (PTH), in the absence of a known or recognized stimulus affecting calcium homeostasis. Primary hyperparathyroidism is a common endocrine disorder, but there are some rare forms of this disease such as: family isolated hyperparathyroidism, hyperparathyroidism familial not isolated, parathyroid cancer, hyperparathyroidism-jaw tumor syndrome, and ectopic hyperparathyroidism associated to carcinomas.
Hyperparathyroidism familial not isolated is associated to multiple endocrine neoplasias, such as multiple endocrine neoplasia (MEN) type 1, 2A and 4.
Primary hyperparathyroidism is the most common feature of MEN1. Patients may have asymptomatic hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, vague symptoms associated with hypercalcemia, or occasionally peptic ulcers. The hypercalcemia is usually mild, and severe hypercalcemia resulting in crisis or parathyroid cancers is rare. Primary hyperparathyroidism associated with MEN1 is characterized by: early age at onset, greater reduction in bone mineral density than primary hyperparathyroidism not associated with MEN1, and an equal male/female ratio (1:1 vs. 1:3). All parathyroid glands may be affected. Subtotal or total parathyroidectomy with heterotopic autotransplantation in patients with MEN1 is the definitive treatment.
Primary hyperparathyroidism develops in 20% to 30% of patients with MEN2A. The mean age of onset is 36 years. It is the first manifestation of the syndrome in less than 5% of cases. The hypercalcemia is usually mild, and most of patients are asymptomatic. The size of the parathyroid glands may vary greatly.

Subtotal parathyroidectomy with preservation of a small remnant of one gland or total parathyroidectomy with heterotopic autotransplantation are the treatment options.
MEN4 is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs.

MEN type 1

(OMIM phenotype number #131100)
Gene: MEN1 gene, 11q13.1 (OMIM gene/locus number *613733).

MEN type 2A

(OMIM phenotype number #171400)
Gene: RET gene, 10q11.21 (OMIM gene/locus number +164761).

MEN type 4

(OMIM phenotype number #610755 OMIM phenotype number #610755)
Gene: CDKN1B gene, 12p13.1 (OMIM gene/locus number *600778).

Phenotype

Primary hyperparathyroidism: Endocrine disorder resulting from a persistent hypercalcemia supported by an inadequate secretion of PTH; rarely it occurs in familial syndromes. Systemic signs: renal (polyuria, hypercalciuria, nephrolithiasis) skeletal, neuromuscular (myopathy, chondrocalcinosis, arthritis), central nervous system (fatigue, cognitive changes), gastrointestinal (peptic ulcer, pancreatitis), cardiovascular (hypertension, reduction QT interval), bone-specific signs: osteoporosis with a reduction of bone mineral density mainly of the cortical bone, osteitis fibrosa cystica in severe cases (subperiostal resorption of the phalange, salt and pepper appearance of the skull, bone cysts, brown tumors of the long bones).
MEN 1: Parathyroid adenoma (90%) + Enteropancreatic tumor (30–70%): gastrinoma (40%), insulinoma (10%), nonfunctioning and PPoma (20–55%), glucagonoma (1%), VIPoma (1%); pituitary adenoma (30–40%): prolactinoma (20%), somatotropinoma (10%), corticotropinoma (5%), nonfunctioning (5%); associated tumors: adrenal cortical tumor (40%), pheochromocytoma (1%), bronchopulmonary NET (neuroendocrine tumor) (2%), thymic NET (2%), gastric NET (10%), lipomas (30%), angiofibromas (85%), collagenomas (70%), meningiomas (8%).
MEN 2A: Parathyroid adenoma (20–30%) + medullary thyroid carcinoma (MTC) (90%), pheochromocytoma (50%).
MEN 4: Parathyroid adenoma + Enteropancreatic endocrine tumors, anterior pituitary tumors, in possible association with tumors of the adrenals, kidneys, and reproductive organs (reproduction organ tumors: e.g. testicular cancer, neuroendocrine cervical carcinoma).

Main biochemical alterations

MEN 1: High Ca, low Pi, high Ur Pi, high Ur Ca, high PTH + other pituitary and/or enteropancreatic hormone alterations.
MEN 2A: High Ca, low Pi, high Ur Pi, high Ur Ca, high PTH + high calcitonin (always), high catecholamine/catecholamine metabolites.
MEN 4: High Ca, low Pi, high Ur Pi, high Ur Ca, high PTH + other pituitary and/or enteropancreatic hormone alterations.

Images

a b

Fig 1. Parathyroid imaging in MEN 1: ultrasonography (US) and computed tomography (CT). (a) Parathyroid adenoma. US image of the neck demonstrates the typical appearance of a parathyroid adenoma in MEN 1: a well-defined, oval hypoechoic mass posterior to the thyroid gland. (b) Parathyroid adenoma in a different patient. Contrast material–enhanced CT scan of the neck shows a right inferior parathyroid adenoma (arrow). 

a b c

Fig 2. Parathyroid imaging in MEN: MR imaging. (a) Parathyroid adenoma. Coronal T2-weighted MR image shows a right parathyroid adenoma with homogeneous high signal intensity (arrow) in the neck. (b, c) Parathyroid adenoma in a patient who presented with persistent hypercalcemia. The patient had previously undergone subtotal parathyroidectomy. (b) Coronal T1-weighted MR image shows a bilobed, low-signal-intensity, left mediastinal parathyroid adenoma (arrow) adjacent to the aortic arch. (c) Corresponding technetium 99m (99mTc)–sestamibi (MIBI) scintigram shows increased radiotracer uptake within the adenoma. 

Reproduced from Scarsbrook AF, Thakker RV, Wass JA, et al., Multiple endocrine neoplasia: spectrum of radiologic appearances and discussion of a multitechnique imaging approach, Radiographics 2006;26:433-51 with permission from The Radiographical Society of North America.

Other resources

 

References

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