Endocrine Abstracts

Publication: L. Veldeman et al. Calcif Tissue Int 2020 Epub 2020 Apr 19

We describe the case of an adult female patient with symptomatic familial hypocalciuric hypercalcemia requiring a step-wise therapeutic approach and the eventual need for a total parathyroidectomy and thyroidectomy to cure symptoms. Genetic analysis demonstrated a heterozygous R227L inactivating CASR gene variant, previously only described in neonatal severe hyperparathyroidism. Postoperative histology showed diffuse hyperplasia of all four parathyroid glands along with the presence of intrathyroidal parathyroid tissue. With regard to clinical management this case suggests that familial hypocalciuric hypercalcemia should be classified as an atypical form of primary hyperparathyroidism rather than a distinct entity.

Case presentation: A 42-year old woman consulted the general practitioner with a 4-month symptomatology of diffuse muscle cramps, tiredness, nausea, and constipation. Symptoms worsened with exercise. Biochemistry at presentation showed a marked PTH-mediated hypercalcemia along with a decreased fractional calcium excretion (cf Table 1). No serum calcium had been determined in earlier years. Neck ultrasonography showed no parathyroid glands. Bone mineral densitometry showed osteopenia. Parathyroid scintigraphy showed discrete tracer accmulation at the lower pole of the right thyroid lobe.

Sequencing analysis of the CASR gene on peripheral blood-derived DNA showed a heterozygous variant NM_001178065.1:c.680G>T (p.Arg227Leu/R227L) in exon 4 of CASR Under treatment with intravenous rehydration serum calcium and symptomatology were controlled, but relapsed after cessation of IV fluid. Because of symptomatic PTH-mediated hypercalcemia and dubious scintigraphy, a surgical neck exploration was planned. Surgery showed four mildly enlarged parathyroid glands in situ. Parathyroid A, C, and D were resected. Histology showed lipomatous parathyroid tissue with discrete hyperplasia. Persistent marked hypercalcemia and PTH elevation were present in the postoperative phase. Because of progressive symptomatology (muscle cramps and tiredness) Cinacalcet was started, resulting in effective lowering of the serum calcium. However, this treatment had to be interrupted because of intolerance. A definitive treatment by totalisation parathyroidectomy was carried out. Because of the macroscopic normal appearance of the remaining parathyroid B and negative neck exploration for surnumeric or ectopic parathyroid glands, also a total thyroidectomy was performed. Histologic examination confirmed lipomatous parathyroid tissue with mild hyperplasia, but also unraveled ectopic parathyroid tissue in the left mid and lower pole of the thyroid.

Hypercalcemia resolved after the second surgery, along with resolution of muscle cramps, gastro-intestinal symptoms, and tiredness.

The resulting hypoparathyroidism and hypothyroidism were treated with calcium supplementation, cholecalciferol, alphacalcidol and Levothyroxine. Currently, she is 3 years post-operative, with normal calcemia and TSH under her substitution treatment and without noticeable symptoms.

Discussion

This report describes for the first time a patient with FHH due to a heterozygous R227L variant in the CaSR gene with adult-onset symptomatic hypercalcemia.

In this case surgical therapy was opted for because of the presentation with symptomatic and biochemically overt PTH-related hypercalcemia.

The course of the case presented supports the theory to define FHH as an atypical presentation of PHPT.¹ The patient had multiple characteristic features of PHPT. Elevated PTH and parathyroid hyperplasia represent failure of suppression of the chief cell by chronic hypercalcemia, which defines PHPT. After ¾ parathyroidectomy, the patient had persisting symptomatic hypercalcemia and it was only after total removal of parathyroid tissue that durable remission of the symptoms occurred. Hence hypercalcemia was dominantly PTH-dependent rather than secondary to abnormal renal calcium handling.¹ The patient is cured and free of symptoms, but at the expense of chronic hypoparathyroidism and hypothyroidism necessitating lifelong supplementation.

The challenge and complexity of this case is that by opting for (sub)total parathyroidectomy the issue of symptomatic hypercalcemia is potentially replaced, by an issue of symptomatic hypocalcemia. Prior to proceeding to extensive parathyroid surgery, it is therefore primordial to discuss the risks, benefits, and uncertainties with the patient, in order to take a shared clinical decision. The risk of persistent symptomatic hypercalcemia in case of minimal parathyroid surgery should be balanced against the risk of chronic hypoparathyroidism, in case of total parathyroidectomy. In our case the patient is free of symptoms under standard treatment with calcium supplements and active vitamin D analogs, but of course she needs lifelong follow-up including screening for long-term complications of hypoparathyroidism according to the guidelines^2,3.

This case also underlines that potential intrathyroidal parathyroid localization should be taken into account during surgery, especially when bilateral neck exploration fails to identify a missing gland or adenoma.^4,5

In the presented case, we show also that the genotype–phenotype correlation in inactivating mutations in CASR does not always hold.

In conclusion, this report shows that in adult cases of FHH surgery can be a necessary treatment modality depending on symptoms and complications, and supports classification of FHH as a form of hereditary primary hyperparathyroidism.

References: 1. Marx SJ: Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2018;33:27–31.

2. Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OM, European Society of E: European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol 2015;173:G1–20.

3. Bollerslev J, Schalin-Jantti C, Rejnmark L, Siggelkow H, Morreau H, Thakker R, Sitges-Serra A, Cetani F, Marcocci C: MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders. Eur J Endocrinol 2019;181:P1–P19.

4. Chen M, Zhou WB, Xu JF, Sun K: Primary hyperparathyroidism caused by mediastinal ectopic parathyroid adenoma. Hong Kong medical journal=Xianggang yi xue za zhi 2017;23:411–413.

5. Yabuta T, Miyauchi A, Inoue H, Yoshida H, Hirokawa M, Amino N: A patient with primary hyperparathyroidism associated with familial hypocalciuric hypercalcemia induced by a novel germline CaSR gene mutation. Asian journal of surgery 2009;32:118–122.