Familial hypocalciuric hypercalcemia as a differential diagnosis of primary hyperparathyroidism with negative images

Introduction. Familial hypocalciuric hypercalcemia is a rare inherited calcium metabolism disorder in which an alteration of the parathyroid hormone secretion set-point causes hypercalcemia with relative hypocalciuria. Some data suggest that i-SSN 0123-7047 e-ISSN 2382-4603 Edwin Antonio Wandurraga-Sánchez, Mario Alejandro Buitrago-Gómez, María Camila Uribe-Forero, Néstor Andrés Díaz-Posa, María Camila Amaya-Muñoz Familial hypocalciuric hypercalcemia as a differential diagnosis of primary hyperparathyroidism with negative images 348 its prevalence is around 74.1 per 100,000 inhabitants. Often, patients are asymptomatic. However, they can develop mild symptoms and an overactive parathyroid adenoma, its main differential diagnosis. The objective was to describe a patient’s case and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas. Case report. This is the case of a 40-year-old man with a biochemical profile compatible with primary hyperparathyroidism with anatomical and functional images negative for adenoma and a calcium/creatinine clearance ratio below 0.001, considering familial hypocalciuric hypercalcemia. Genetic studies evidence a mutation in the calcium sensor receptor gene and confirm the diagnosis. Discussion. Familial hypocalciuric hypercalcemia’s main differential diagnosis is an overactive parathyroid adenoma. For both, mild or no symptoms may be present; serum calcium exceeds the upper limit, and parathormone is more than 25pg/ml. The calcium/creatinine clearance ratio should be used to differentiate one from the other and avoid unnecessary surgical neck explorations. Besides the lack of information on this topic, evidence supports the use of calcimimetics to treat symptomatic hypercalcemia. Conclusions. Patients with mild hypercalcemia with parathyroid hormone readings above 25pg/ml and a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative imaging, should not undergo surgical neck explorations. In these cases, familial hypocalciuric hypercalcemia is a reliable diagnosis; Cinacalcet may be administered in cases of symptomatic hypercalcemia.

its prevalence is around 74.1 per 100,000 inhabitants. Often, patients are asymptomatic. However, they can develop mild symptoms and an overactive parathyroid adenoma, its main differential diagnosis. The objective was to describe a patient's case and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas. Case report. This is the case of a 40-year-old man with a biochemical profile compatible with primary hyperparathyroidism with anatomical and functional images negative for adenoma and a calcium/creatinine clearance ratio below 0.001, considering familial hypocalciuric hypercalcemia. Genetic studies evidence a mutation in the calcium sensor receptor gene and confirm the diagnosis. Discussion. Familial hypocalciuric hypercalcemia's main differential diagnosis is an overactive parathyroid adenoma. For both, mild or no symptoms may be present; serum calcium exceeds the upper limit, and parathormone is more than 25pg/ml. The calcium/creatinine clearance ratio should be used to differentiate one from the other and avoid unnecessary surgical neck explorations. Besides the lack of information on this topic, evidence supports the use of calcimimetics to treat symptomatic hypercalcemia. Conclusions. Patients with mild hypercalcemia with parathyroid hormone readings above 25pg/ml and a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative imaging, should not undergo surgical neck explorations. In these cases, familial hypocalciuric hypercalcemia is a reliable diagnosis; Cinacalcet may be administered in cases of symptomatic hypercalcemia.

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)(4)(5)(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.
Sanger sequencing of the coding region and intronexon 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. 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 polydipsia 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 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.
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 nonhospitalized 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). 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.
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