A Case of Familial Hypocalciuric Hypercalcemia

Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder that is the leading benign cause of hypercalcemia. It may occur due to autonomous hypersecretion of parathyroid hormone (PTH), independently of serum calcium levels. Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant rare genetic diseases only affecting the regulation of calcium metabolism. It is usually caused by one of many heterozygous missense mutations in the calcium-sensing receptor (CaSR) gene, which could up-regulate the set point of parathyroid cells. When the CaSR receptor is inactivated, PTH is not suppressed despite relatively high calcium, which makes FHH similar to PHPT. We present a unique case of concomitant FHH and suspected parathyroid adenoma. Case summary: A 10-year-old girl with symptomatic severe hypercalcemia, high PTH, and genetically diagnosed as FHH was referred to the department of otolaryngology-head and neck surgery due to surgical excision of suspected parathyroid adenoma. Her biochemical evaluation showed elevated serum calcium and PTH. The calcium– creatinine clearance ratio was >0.01 (0.16). Her parathyroid scintigraphy showed negative for parathyroid adenoma, but the ultrasonography of the neck revealed an enlarged right inferior parathyroid gland. She underwent surgical excision of both the right superior and inferior parathyroid glands. However, the patient’s serum calcium and parathyroid hormone increased in the postoperative period, and her symptoms remained unchanged. Conclusion: The correct diagnosis of the underlying cause of hypercalcemia is essential to ensure the proper treatment. Patients with FHH should avoid operative treatment, and PHPT should be differentiated to determine whether surgery should include parathyroidectomy with the removal of suspected parathyroid adenoma.

).Her elder sister is also diagnosed as a case of familiar hypocalciurichypercalcaemia but asymptomatic.Other family members are also asymptomatic.

Investigations
Blood investigations revealed severe hypercalcaemia (serum calcium of 17.5 mg/ dl) with a PTH of222.1 pg/ml at time of presentations (Table 2).The calculated CCCR was 0.16 (Table 3).A 24 h urine metanephrines assay was normal.Preoperative workup with an ultrasound neck revealed an enlarged (11×6mm) right inferior parathyroid gland (Figure 1) suspected for parathyroid adenoma but a sestamibi scan demonstrated no focal area of increased radiotracer concentration in and around thyroid gland or mediastinal region.

Intervention
In department of otolaryngology-head and neck surgery, she underwent surgical excision of both right superior and inferior parathyroid gland.

Outcome and follow-up
An unusual association of serum parathyroid hormone and serum calcium levels (Table IV) were shown during follow-up period.The patient remained symptomatic with both raised serum calcium level and serum parathyroid hormone level.
Discussion: This case is an example of primary hyperparathyroidism secondary to suspected parathyroid adenoma in a patient with concomitant type 1 FHH.A small number of similar cases have been reported [12][13][14][15][16] .In 2002, the first case of a parathyroid adenoma with FHH was reported.A 45 year old woman had a history of severe symptomatic hypercalcemia, elevated PTH levels, hypocalciuria and a family history of hypercalcemia.A parathyroid adenoma was identified by scintigraphy and the genetic analysis for FHH was positive.The parathyroid adenoma was surgically removed, significantly improving symptoms and serum calcium levels 12 .The other reported cases occurred in patients with FHH who developed worsening hypercalcaemia on follow-up with corresponding elevations in PTH levels.After locating parathyroid adenomas with scintigraphy, a parathyroid surgery was performed and postoperatively, their serum calcium levels dropped to just above the normal range [13][14][15][16] .
It can be challenging to differentiate between primary hyperparathyroidism and FHH as many overlapping clinical features exist.Although a raised serum PTH in the setting of hypercalcaemia suggests a diagnosis of primary hyperparathyroidism, PTH may also be elevated in FHH.In 2008, a published cross-sectional study reported the prevalence of elevated PTH levels in patients with FHH to be 23% 17 .
According to the consensus guidelines, performing 24 h urinary calcium is part of the initial evaluation of patients with hypercalcaemia 18 .It showed the characteristic hypocalciuria and urinary calcium/creatinine clearance ratio <0.01, which prompted genetic testing 19,20

Table I :
Result of genetic analysis.
5,6However, for the same disorder, the term "familial hypocalciuric hypercalcemia" (FHH) was first used by Marx and his co-workers in 19774.Type 1 FHH is the commonest variant representing 65% of the cases, first reported by Pollack et al. in 19935,6.It is usually caused by one of and had got several time hospital admissions as a case of chronic calcific pancreatitis.She underwent two times ERCP for removal of pancreatic duct calculi and placement of pancreatic duct stenting.She received monthly bisphosphonates according to serum calcium report.Her genetic study revealed mutation in CaSR gene which is likely compound heterozygous missense variants in exon 3 and exon 4 (Table

Table II :
Results of biochemical blood tests.

Table III :
Results of urine analysis.

Table IV :
Pre, per and post operative serum parathyroid hormone and serum calcium levels.
23wever, in contrast, our patient's serum calcium and parathyroid hormone increased in the postoperative period, and her symptoms remained unchanged, which was unclear and unusual.It is also unclear whether the development of suspected parathyroid adenomas in patients with FHH is coincidental or not.Although CaSR expression is decreased in parathyroid adenomas22, previous studies have shown no mutations in the CaSR gene in parathyroid adenomas.Therefore, a causal link between the two conditions has not yet been established23.4. Marx SJ, Spiegel AM, Brown EM, Aurbach GD.Family studies in patients with primary parathyroid hyperplasia.The American Journal of Medicine.1977 May; 62 (5): 698-706.