Primary Hyperparathyroidism as the First Clinical Manifestation of Multiple Endocrine Neoplasia Type 2A in a 5-Year-Old Child

Introduction

M ultiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism, with a high degree of penetrance and variability of expression. The estimated prevalence for the general population is 2.5/100,000 individuals (1) and it is related to germline mutations in the RET proto-oncogene (2,3).

MTC occurs in 90%–95% of patients with MEN2A and usually is the first clinical manifestation of MEN2A, whereas 40%–50% of patients develop pheochromocytoma. In contrast, primary hyperparathyroidism (PHPT) is the least frequent component of the syndrome (10%–30% of patients) and seldom is the only clinical manifestation (4).

There are reports of a diagnosis of PHPT from ages as early as 9 years (5) up to more advanced ages such as 70 years (6), although it is more commonly seen between 17 and 49 years (7).

We report here a patient carrying the RET p.C634R mutation, who presented with asymptomatic PHPT as the first clinical manifestation of MEN2A at 5 years of age.

Patient

A clinically asymptomatic 5-year-old girl, carrying the same mutation (RET p.C634R) as her mother, who has MEN2A, was recommended for prophylactic thyroidectomy. She was born at term by cesarean section with normal weight (2650 g) and length (46 cm) and had no history of disease or remarkable medical therapy. Examination revealed a child in good general condition, with normal blood pressure (94 × 76 mmHg) and heart beat (94 bpm). The child showed a normally palpable thyroid and no nodules were detected. In addition, there was no clinical evidence of lymphadenopathy or of other cervical nodules. Examination of the abdomen revealed no palpable masses. Her height and weight were 106 cm and 15.7 kg, respectively, and Tanner stage was B1H1. Preoperative assessment laboratory investigation detected hypercalcemia associated with high parathyroid hormone (PTH) serum levels (calcium = 11.2 mg/dL {reference value [RV]: 8.4–10.5 mg/dL}, calcium ion = 1.48 mmol/L {RV: 1.12–1.32 mmol/L}, phosphorus = 4.0 mg/dL {RV: 4–7 mg/dL}, alkaline phosphatase = 625 U/L {RV: <645 U/L}, PTH = 998 pg/mL {RV: 10–69 pg/mL}). An ultrasound revealed no thyroid abnormality and a parathyroid scintigraphy with ^99mTc-Sestamibi revealed an area of radioconcentration in the upper half of the left thyroid lobe suggesting hyperfunctioning parathyroid tissue. The results of the remaining examinations were as follows: thyrotropin = 2.2 μIU/mL (RV: 0.4–4.0 μIU/mL), calcitonin = 15.3 pg/mL (RV: <10 pg/mL), carcinoembryonic antigen (CEA) = 1.84 ng/mL (RV: <2.5 ng/mL), plasma catecholamines: adrenaline = 86 pg/mL (RV: <464 pg/mL); dopamine = <10 pg/mL (RV: <60 pg/mL); noradrenaline = 331 pg/mL (RV: <1251 pg/mL); vanilmandelic acid (VMA) =4 mg/24 hours (RV: 1.8–7.2 mg/24 hours). She underwent total thyroidectomy and parathyroidectomy and developed hypocalcemia. Surgical findings included a normally located thyroid with normal morphology and absence of cervical lymphadenopathy. A 2 × 1 cm parathyroid gland was identified close to the left upper thyroid pole and removed. The left inferior parathyroid and a single contralateral parathyroid gland were also found, removed, and cryopreserved. Parathyroid tissue autotransplantation was not performed. Histopathology examination revealed parathyroid adenoma, with no malignancy in the thyroid gland. Intravenous replacement with calcium gluconate was started during the immediate postoperative period and later switched to calcium carbonate in combination with oral calcitriol. PTH levels were undetectable (<3 pg/mL) on the 1st and 30th postoperative days. The patient is now 10 years old and she is on levothyroxine. She received calcium carbonate and calcitriol therapy during 3 years. Calcitriol was withdrawn because she developed a high total calcium (10.8 mg/dL) and ionized calcium (1.32 mmol/L). After 4 months without vitamin D treatment, the total calcium, ionized calcium, phosphorus, and PTH levels were 8.4 mg/dL, 1.16 mmol/L, 7.3 mg/dL, and 19 pg/mL, respectively, allowing us to conclude that she has a compensated hypoparathyroidism. She has normal growth, development, and blood pressure. Plasma catecholamines have been measured on a yearly basis.

Discussion

MEN2A is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene, which encodes a transmembrane tyrosine kinase receptor responsible for the transduction of signals for cell proliferation, growth, and differentiation in tissues derived from the neural crest (1,8). More than 50 different missense mutations have already been identified in families with MEN2A (9). It is accepted that there is an association between codon-specific mutations in the RET proto-oncogene and the age of onset and the aggressiveness of MTC, as well as the presence of other endocrine tumors (pheochromocytoma and hyperparathyroidism) (8). PHPT is more frequent in families with MEN2A harboring mutations in codon 634 of the RET proto-oncogene, and it is much less prevalent or even absent in patients with other mutations (6,10,11). It is controversial as to whether or not there is an association between the codon 634 mutation and the familial risk of PHPT (6). An association between the p.C634R mutation and the development of PHPT was found in some studies (10,12) but was not observed in others (11,13). In the Brazilian population, the most prevalent RET mutation in patients with MEN2A and PHPT was p.C634Y (14,15). PHPT occurs in 10%–30% of patients with MEN2A and rarely is the first manifestation of the syndrome. It is usually mild and asymptomatic (16), and when clinical signs occur, they do not differ from those observed in sporadic hyperparathyroidism (6,8). The diagnosis is established by a nonsuppressed PTH level in the presence of hypercalcemia. The pathological findings are hyperplasia of one or multiple parathyroid glands or adenoma of the parathyroid.

Although there are reports of MTC in children with MEN2A as young as 1 year of age (17), PHPT more commonly manifests after the third decade of life and is rarely the first manifestation of MEN2A (6). Familial hyperparathyroidism, regardless of its etiology (MEN1, hyperparathyroidism-jaw tumor syndrome and isolated familial hyperparathyroidism), is an infrequent clinical condition during childhood, being quite rare in children <10 years of age (18).

Guidelines of the last two decades unanimously recommend parathyroidectomy for asymptomatic PHPT in adults aged <50 years (19). In young adults, there is evidence that bone loss can be an early sign of PHPT (20). In addition, there are some concerns that the metabolic profile typically present in PHPT (i.e., high circulating levels of PTH and calcium as well as hypophosphatemia) potentially predisposes to insulin resistance (21,22) and cardiovascular disease (23). Currently, the impact of asymptomatic PHPT on bone mass development and general health in children is not clear, and there is a lack of consensus on the ideal management of asymptomatic PHPT in children. Further, it remains to be determined whether children harboring RET mutations have a similar susceptibility to develop PHPT complications as patients with sporadic PHPT. This is a crucial point needed to develop the most appropriate approach to PHPT in children, namely the ideal time for parathyroid surgery. At present, the decision to perform parathyroidectomy should be balanced, weighing all potential benefits obtained by surgical cure with the risks of surgical complications.

In this article, we reported a child with the RET p.C634R mutation whose primary clinical manifestation was asymptomatic PHPT diagnosed at 5 years of age. Her minimally elevated serum calcitonin level might have been caused by MTC or C cell hyperplasia. As the histopathological thyroid examination showed no sign of either, the increase in serum calcitonin levels can probably be assigned to hypercalcemia, a well-recognized cause of hypercalcitoninemia (24). To our knowledge, this is the only report in literature of a patient carrying the RET p.C634R mutation to be diagnosed with hyperparathyroidism at an age as early as when she presented. Previously, a 9-year-old carrying a different mutation in this same codon was reported to be the youngest patient presenting with hyperparathyroidism (5). Similar to our patient, that child was referred for evaluation and prophylactic thyroidectomy for a status of being a carrier of the RET p.C634Y. However, unlike our patient, her serum calcium was normal (10.2 mg/dL) and the diagnosis of hyperparathyroidism was only obtained after the intraoperative finding of a parathyroid adenoma.

The genotype–phenotype association has implications for the clinical management of patients with MEN2A and their families not only in terms of the planning of thyroidectomy (age of surgical indication and extent of surgery) as a prophylactic measure for MTC, but also for screening for pheochromocytoma and hyperparathyroidism (25). In the case of hyperparathyroidism, the current recommendation is annual calcium measurements starting at 8 years of age for carriers of the mutation in codon 634 (9). Regarding other mutations in the RET proto-oncogene, it is recommended that screening should be started at 20 years of age (9). Our finding of a patient already presenting overt PHPT at the age of 5 years raises the important question of the usefulness of screening for hyperparathyroidism in all carriers of mutations affecting the codon 634 of the RET proto-oncogene, irrespective of their age. Our concern is reinforced by the report of Jackson et al. (5) describing the presence of a parathyroid adenoma in a normocalcemic 9-year-old child. This finding strengthens the need to measure PTH when evaluating families with MEN2A who are carriers of mutations in the RET proto-oncogene considered to be of high risk, such as those in codon 634, because higher PTH levels can be found in normocalcemic patients, suggesting a diagnosis of hyperparathyroidism.

Conclusion

The natural history of PHPT will be probably modified because of the indication of prophylactic thyroidectomy in relatives of patients with MEN2A who are carriers of mutations in the RET proto-oncogene. It is likely that an increased frequency of diagnoses of hyperparathyroidism will be obtained in the early years of life, leading to a lowering of the age at which screening is started. In a small number of MEN2A patients, PHPT may be the sole clinical manifestation. Therefore, the present case supports the importance of early screening for hyperparathyroidism in families with MEN2A, even before 8 years of age, particularly in children carrying mutations in codon 634 of the RET proto-oncogene.