Introduction

Familial hypocalciuric hypercalcemia (FHH), formerly called benign familial hypercalcemia, is an inherited autosomal dominant disorder caused by mutations in the gene expressing the calcium-sensing receptor (CaSR) in the parathyroid glands, kidneys, and other organs. Mutations leading to partial or complete loss of CaSR function cause a shift in the parathyroid cells’ set-point for calcium. Consequently, a higher-than-normal blood calcium concentration is needed to inhibit parathormone (PTH) secretion. In addition, the abnormal function of CaSR in the ascending branch of Henle’s loop results in PTH-independent calcium reabsorption and consequent hypocalciuria (1,2).

Its main differential diagnosis is primary hyperparathyroidism due to an overactive parathyroid adenoma, presenting a broad spectrum of clinical manifestations. Not unlike FHH, in mild cases, primary hyperparathyroidism presents no symptoms. However, the symptoms may include polyuria, polydipsia, or acute pancreatitis when present. This relatively frequent endocrine disease has an estimated prevalence of 0.8% in the adult population. In contrast, FHH is an uncommon and often underdiagnosed disease, with some data suggesting its prevalence is around 74.1 per 100,000 inhabitants. In most cases, no treatment is required (3-6).

There is no data on this disease’s frequency in our population. Therefore, our objective was to describe the case of a patient and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas.

Case presentation

The subject was a 40-year-old male New Zealander living in Colombia for six years; he consulted for having polyuria (>3.5 liters per day) and polydipsia associated with migraine-type headaches for 18 months. His medical history included bilateral knee surgery for chondrocalcinosis; however, no other medical conditions were reported.

Despite being within reference values, mild hypercalcemia with unsuppressed PTH was documented in laboratories. In addition, other causes of osmotic polyuria and polydipsia, such as hyperglycemia, azotemia, or primary polydipsia, were discarded (Table 1). Therefore, an ultrasound and parathyroid scan using sestamibi were performed upon suspicion of a diagnosis of parathyroid adenoma; the results were normal (Figure 1). Subsequently, the calcium/creatinine clearance ratio was calculated; it was 0.0047, suggestive of FHH (Table 2). Finally, the diagnosis was confirmed by a genetic study using the Sanger sequencing of the coding region and intron- exon junctions of the CaSR gene, which confirmed that the patient is a heterozygous carrier of the likely pathogenic variant c.493-2A>G;p? in the CaSR gene.

Figure 1
Parathyroid scan 30 60 and 120 minutes after administration of sestamibi Tc99m radiotracer In these images thyroid gland is observed with the administration of the radiotracer Nevertheless there is no abnormal uptake in the parathyroid gland during the time of the study that could suggest a parathyroid adenoma
Source: prepared by the authors.

Figure 1.Parathyroid scan 30, 60 and 120 minutes after administration of sestamibi Tc-99m radiotracer. In these images, thyroid gland is observed with the administration of the radiotracer. Nevertheless, there is no abnormal uptake in the parathyroid gland during the time of the study that could suggest a parathyroid adenoma.

Source: prepared by the authors.

Table 1.Laboratory tests run on the patient for the study of polyuria and hipercalcemia

Table 1
Laboratory tests run on the patient for the study of polyuria and hipercalcemia

Source: prepared by the authors

Due to the symptomatic persistent hypercalcemia, treatment with Cinacalcet was started at a dose of 30mg orally every 12 hours, and migraine medication was prescribed because the patient referred headaches, besides serum calcium level reductions. Under the clinical suspicion of FHH, the patient was referred to the geneticist to perform the disease’s respective diagnostic test. Once treatment with Cinacalcet was started, the symptoms of polidipsia and polyuria improved significantly. However, the patient’s intense episodes of headache persisted until prescribed the migraine medication with a good response. The patient reported a significant improvement in his quality of life after the diagnosis and treatment were established. However, the patient will require follow-up by the endocrinologist indefinitely.

Discussion

The CaSR gene is located on chromosome 3q13.3-21, which contains six exons that encode a 1078-amino acid transmembrane glycoprotein, whose intracellular domain is coupled to a heterodimeric G-protein. Its activity is concentrated in the parathyroid gland and the kidney, inhibiting the PTH secretion and favoring calcium reabsorption in the ascending branch of Henle’s Loop, respectively. Mutations in this and other genes, such as GNA11 and AP2S1, may be triggered in inherited disorders presenting PTH-independent hypercalcemia with relative hypocalciuria. However, the CaSR mutation comprises 65% of the pathogenic mutations of FHH patients (1,2). Although it is often asymptomatic, on some occasions, it can occur with pancreatitis, chondrocalcinosis, and headaches (7). The latter two were present in the patient; however, he did not report abdominal pain, nausea, vomiting, or other clinical manifestations to suggest acute pancreatitis.

The FHH diagnosis began with a biochemical profile of mild hypercalcemia with levels of unsuppressed PTH (PTH > 20-25pg/ml), compatible with primary hyperparathyroidism. Subsequently, the measurement of the calcium/creatinine clearance ratio (Table 2) was suggested to differentiate between FHH and primary hyperparathyroidism by glandular autonomy, where an index lower than 0.01 with a sensitivity of 80% and a specificity of 88% was interpreted as highly suggestive of FHH (Table 2) (7-10). The patient’s parathyroid scan using sestamibi was performed prior to determining the index because sporadic primary hyperparathyroidism is the most frequent cause of hypercalcemia in non- hospitalized patients. Of this frequency, 80% to 90% is caused by an overactive parathyroid gland adenoma, where multiglandular hyperplasia or parathyroid carcinoma are highly rare (3,11,12).

Table 2. Interpretation of the calcium/creatinine clearance ratio

Table 2
Interpretation of the calciumcreatinine clearance ratio

Source: prepared by the authors.

Most cases of FHH do not require any treatment, and the morbidity is often the result of unnecessary surgery. While there are reports of symptoms and morbidity related to hypercalcemia in FHH patients, they are a minority of the cases (6).

Calcimimetic drugs, such as Cinacalcet, are allosteric CaSR agonists. They enhance the effect of extracellular calcium on CaSR in the parathyroid cell, thus decreasing PTH secretion and serum calcium. Cinacalcet’s use has been considered when calcium is 1mg/dl above the upper limit of the reference value or when the patient has symptoms associated with hypercalcemia. Case series have described a response rate in up to 88% of patients with symptom control, even without achieving normal calcium levels in some (13). There are also case reports on the treatment with Cinacalcet to prevent recurrent pancreatitis, demonstrating its safety and prevention of new episodes (14).

A publication compiled the reasons for initiating Cinacalcet treatment in a series of FHH patients. Hypercalcemia was the main reason for starting Cinacalcet treatment in six subjects. Primary hyperparathyroidism was the reason in three patients and pancreatitis in two. Other reasons for starting therapy included muscle cramps, bone pain, poor memory, and psychosis in one case. Improvement of symptoms, associated with the normalization of serum calcium levels, was described in most patients, with adequate safety at three years using a dose between 30-90mg. The most common adverse effects were nausea, hypotension, and hypocalcemia. The symptoms improved after the Cinacalcet dose was reduced without interrupting treatment (15). Another series of four reported cases demonstrated adequate symptomatic control of cramps, memory loss, paresthesia, vertigo, and constipation, with improved calcium levels and without adverse events, with doses of 30- 60mg of Cinacalcet (16).

Conclusions

FHH is an infrequent diagnosis that in some cases may be underdiagnosed, leading to unnecessary surgical procedures. Moreover, there is insufficient local data to estimate the prevalence of this disease in our population. Therefore, patients with mild hypercalcemia, unsuppressed parathyroid hormone (above 25pg/ ml), a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative neck imaging should not undergo surgical neck exploration. In these cases, familial hypocalciuric hypercalcemia should be considered a reliable diagnosis. There is also evidence that supports the use of Cinacalcet in cases of symptomatic hypercalcemia.

Conflicts of interest

The authors declare no conflicts of interest.

Financiation

No funds were received to write this paper.

References

1. Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and related disorders. Best Pract Res Clin Endocrinol Metab [Internet]. 2018;32(5):609-619. doi: https://doi.org/10.1016/j.beem.2018.05.004

2. D’Souza-Li L, Yang B, Canaff L, Bai M, Hanley DA, Bastepe M, et al. Identification and Functional Characterization of Novel Calcium-Sensing Receptor Mutations in Familial Hypocalciuric Hypercalcemia and Autosomal Dominant Hypocalcemia. J Clin Endocrinol Metab [Internet]. 2002;87(3):1309-18. doi: https://doi.org/10.1210/jcem.87.3.8280

3. Builes-Montaño CE. Hiperparatiroidismo primario. Med. Lab [Internet]. 2017;23(1-2):45-4. doi: https://doi.org/10.36384/01232576.59

4. Dershem R, Gorvin CM, Metpally RPR, Krishnamurthy S, Smelser DT, Hannan FM, et al. Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population. Am J Hum Genet [Internet]. 2020;106(6):734–47. doi: https://doi.org/10.1016/j.ajhg.2020.04.006

5. Mahajan A, Buse J, Kline G. Parathyroid hormone-dependent familial hypercalcemia with low measured PTH levels and a presumptive novel pathogenic mutation in CaSR. Osteoporos Int [Internet]. 2020;31:203–7. doi: https://doi.org/10.1007/s00198-019-05170-9

6. Brown EM. Clinical lessons from the calcium-sensing receptor. Nat Rev Endocrinol [Internet]. 2007;3:122–133. doi: https://doi.org/10.1038/ncpendmet0388

7. Merino M, Vega B, Guijarro G, Navea C, Torán C, Civantos S. Familial hypocalciuric hypercalcemia: sometimes it is not what it seems. Rev Osteoporos Metab Miner [Internet]. 2015;7(1):20-22. doi: https://doi.org/10.4321/S1889-836X2015000100005

8. Renaghan AD, Rosner MH. Hypercalcemia: etiology and management. Nephrol Dial Transplant [Internet]. 2018;33(4):549-551. doi: https://doi.org/10.1093/ndt/gfy054

9. Silva BC, Cusano NE, Bilezikian JP. Primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab [Internet]. 2018;32(5):593-607. doi: https://doi.org/10.1016/j.beem.2018.09.004

10. Fuleihan GEH, Silverberg SJ. Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation. Post TW, ed. Waltham, MA: UpToDate Inc [Internet]. 2020. Available from: https://www.uptodate.com/contents/primary-hyperparathyroidism-diagnosis-differential-diagnosis-and-evaluation?search=primary%20hyperparathyroidism&source=search_result&selectedTitle=1~119&usage_type=default&display_rank=1

11. Pulgar D, Jans J, D’Aguzan N, León A, Goñi I, González G, et al. Hiperparatiroidismo primario: manejo quirúrgico. Rev Chil Cir [Internet]. 2014;66(4):313-319. doi: https://doi.org/10.4067/S0718-40262014000400004

12. Bilezikian JP. Primary Hyperparathyroidism. J Clin Endocrinol Metab [Internet]. 2018;103(11):3993–4004. doi: https://doi.org/10.1210/jc.2018-01225

13. Marx SJ. Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology. J Clin Endocrinol Metab [Internet]. 2017;102(11):3933-3936. doi: https://doi.org/10.1210/jc.2017-01606

14. Scheers I, Sokal E, Limaye N, Denoncin C, Stephenne X, Pirson Y, et al. Cinacalcet sustainedly prevents pancreatitis in a child with a compound heterozygous SPINK1/AP2S1 mutation. Pancreatology [Internet]. 2019;19(6):801-804. doi: https://doi.org/10.1016/j.pan.2019.07.045

15. Mayr B, Schnabel D, Dörr HG, Schöfl C. GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts. Eur J Endocrinol [Internet]. 2016;174(5):R189-R208. doi: https://doi.org/10.1530/EJE-15-1028

16. Rasmussen AQ, Jørgensen NR, Schwarz P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series. J Med Case Rep [Internet]. 2011;5:564. doi: https://doi.org/10.1186/1752-1947-5-564

Notas de autor

Edwin Antonio Wandurraga Sánchez. Centro Médico Carlos Ardila Lulle, Torre B, Piso 8, Módulo 55, Consultorio 806. Floridablanca, Santander, Colombia. Email. edwinwandurraga@gmail.com

Información adicional

How to cite.: How to cite. Wandurraga-Sánchez EA, Buitrago-Gómez MA, Uribe-Forero MC, Díaz-Posada NA, Amaya-Muñoz MC. Familial hypocalciuric hypercalcemia as a differential diagnosis with negative images for primary hyperparathyroidism. MedUNAB [Internet]. 2021;24(3):347-352. doi: https://doi.org/10.29375/01237047.4072

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