# Singular case report of familial hypocalciuric hypercalcemia: a rare diagnosis of hypercalcemia in the older people

Etienne Ojardias, Mélanie Leman, Ludovic Lafaie, Philippe Oriol, Paul Calmels, Thomas Celarier

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Etienne Ojardias, Mélanie Leman, Ludovic Lafaie, Philippe Oriol, Paul Calmels, et al. Singular case report of familial hypocalciuric hypercalcemia: a rare diagnosis of hypercalcemia in the older people. Aging Male, 2024, 28 (1), pp.2436877. 10.1080/13685538.2024.2436877. hal-05452594

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# Singular case report of familial hypocalciuric hypercalcemia: a rare diagnosis of hypercalcemia in the older people

Etienne Ojardias, Mélanie Leman, Ludovic Lafaie, Philippe Oriol, Paul Calmels & Thomas Celarier

**To cite this article:** Etienne Ojardias, Mélanie Leman, Ludovic Lafaie, Philippe Oriol, Paul Calmels & Thomas Celarier (2025) Singular case report of familial hypocalciuric hypercalcemia: a rare diagnosis of hypercalcemia in the older people, *The Aging Male*, 28:1, 2436877, DOI: 10.1080/13685538.2024.2436877

**To link to this article:** https://doi.org/10.1080/13685538.2024.2436877

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Published online: 09 Dec 2024.

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# Singular case report of familial hypocalciuric hypercalcemia: a rare diagnosis of hypercalcemia in the older people

Etienne Ojardias<sup>a,b</sup>, Mélanie Leman<sup>c</sup>, Ludovic Lafaie<sup>a,d</sup>, Philippe Oriol<sup>a</sup>, Paul Calmels<sup>e</sup> and Thomas Celarier<sup>a</sup>

<sup>a</sup>Clinical Gerontology Department, University Hospital of Saint-Etienne, Saint-Etienne, France; <sup>b</sup>Lyon Neuroscience Research Center, Trajectoires team (Inserm UMR-S 1028, CNRS UMR 5292, Lyon1 & Saint-Etienne Universities), France; <sup>c</sup>Clinical Gerontology Department, Hospital of Saint-Chamond, Saint-Chamond, France; <sup>d</sup>U1059 INSERM – SAINBIOSE, Innovation Campus, Saint-Etienne, France + INSERM CIC1408, University Hospital of Saint-Etienne, Saint-Etienne, France; <sup>e</sup>Inter-university Laboratory of Human Movement Biology, Saint-Etienne "Jean Monnet" & Lyon 1 & "Savoie Mont-Blanc" universities, Saint-Etienne, France

## ABSTRACT

**Objective:** to report a case of familial hypocalciuric hypercalcemia (FHH) in an older patient and highlight the diagnostic challenges in geriatric populations.

**Case presentation:** We report the diagnosis of FHH in an 88-year-old polypathological patient with hypercalcemia discovered during a check-up for cardiac decompensation. Despite a confusing clinical presentation with gout symptoms, including repeated episodes of knee arthritis, persistent hypercalcemia conducted further investigations. Biological tests excluded primary or hyperparathyroidism and malignancy-related hyperparathyroidism, confirming the diagnosis of FHH through the detection of an inhibitory mutation in the calcium-sensing receptor gene.

**Conclusion:** This case suggests to clinicians the possibility of FHH in older patients with unexplained hypercalcemia. In geriatric patients, the diagnosis is complicated because of the polypathology: here hypercalcemia was associated with a confusing gout crisis, which was triggered by diuretic treatment for heart failure.

## ARTICLE HISTORY

Received 19 December 2023

Revised 26 November 2024

Accepted 28 November 2024

Published online 3 December 2024

## KEYWORDS

Hypercalcemia; older people; polypathology; familial hypocalciuric hypercalcemia

## Introduction

Hypercalcemia is a common biological in the general population and it is usually discovered incidentally or associated to few symptoms in the case of a progressive or moderate onset [1,2]. The hypercalcemia has cardiologic consequences as shortening of the QT, rhythm disorders, myocardial infarction or hypertrophy, hypertension due to muscular effects [3,4]. Other non-specific symptoms are observed such as digestive disorders (constipation, nausea, vomiting, pancreatitis ...), osteo-articular signs (arthralgia, muscular fatigability, chondrocalcinosis ...), neurological signs (confusion, paresthesias, behavioural disorders) and an altered general condition.

Various aetiologies should be considered when hypercalcemia is detected: primary hyperparathyroidism (adenoma, hyperplasia, neoplasia), other malignancies with lytic bone metastases (mainly lung, oesophagus, uterus, ovary, kidney, bladder) causing

direct bone resorption, and that secrete parathyroid hormone-related protein (PTHrP) which increases calcium levels by mimicking parathormone. Multiple myeloma, lymphoma, and acute hematological disorders are also important causes. Less common aetiologies to be considered include as granulomatosis, dysthyroidism, adrenal insufficiency, acromegaly, bed rest, drugs and familial hypocalciuric hypercalcemia (FHH).

Due to the asymptomatic nature of hypercalcemia, the prevalence of FHH is difficult to estimate and often leading to underdiagnosis [5]. Dershem et al. estimate the prevalence at 74/10,000 people [6]. There are three types of FHH according to different genetic mutation: the most frequent type is FHH1 (65%), due to a calcium-sensing receptor (CASR) inactivating mutation on chromosome 3, FHH2 due to a mutation of the GNA11 gene on chromosome 19 and FHH3 due to the AP2S1 inactivating mutation. Classically, the diagnosis of FHH is revealed by biological tests which
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reveal elevated serum calcium levels, a decreased calcium excretion fraction, associated with an inappropriate decrease of calciuria, a normal or elevated PTH level, a normal 25-hydroxy-vitamin D with a normal or elevated 1,25-dihydroxy-vitamin D level. Renal function is usually preserved.

Usually, the diagnosis is observed during the middle age or in young family members after a genetic investigation. Here we report the diagnosis of FHH in an 88-year-old patient hospitalized in a geriatric unit for cardiac decompensation.

## Case presentation

Mr S. was an 88-year-old patient, retired, construction worker, widowed, living alone in a first floor apartment with stairs. He had solely a daughter, his primary caregiver. He had no home help before his hospitalization.

His clinical history was marked by repeated arthritis described as gout, heart failure on a tight aortic valve stenosis that subsequently benefited from TAVI, moderate chronic renal insufficiency (clearance 45 mL/min/ 1.73m²), stenting bi-femoral aorto-bi-femoral stenting, high blood pressure, transient ischemic stroke, essential tremor and a right sural venous thrombosis. He had no toxic habits or allergies.

The 7th of November, this patient was admitted to the emergency department for cardio-renal decompensation consecutive to a pneumopathy. Patient recovered with antibiotic associate to diuretic therapy. After five days, he was transferred to a geriatric ward for a standardized geriatric assessment and for rehabilitation in front of exercise deconditioning.

Initial blood samples of November 13th, found a calcium level of 2.55 mmol/L, corrected at 2.84 mmol/L. There was severe denutrition with a dosage of albu-min measured at 28.3 mmol/L. A PTH increased to 94 ng/L and a collapsed 25-hydroxy-vitamin D at 15 nmol/L were found. Clinically, he showed no clinical signs suggestive of hypercalcemia. Chest x-ray showed no anomalies. In December, given the suspicion of secondary hyperparathyroidism due to hypovitamino-sis D and not in line with standard recommendations, a parathyroid ultrasound revealed no suspicious nodules. Colecalciferol supplementation was introduced. In addition, nutritional management was started. M. S presented at the same time knees painful arthritis with joint effusion associate to biological inflammatory syndrome. Chondrocalcinosis was suspected but acid uric level was high 478 µmol/L. A puncture was realized: 920 nucleated cells per mm³ and sodium urate

crystals were found in the joint fluid. Treatment with colchicine and then the addition of allopurinol improved the symptoms. The cardiac status and physical improvements allowed the patient to return home on the 2nd of January.

Unfortunately, a new cardiac decompensation required re-hospitalization on January the 23rd. During this subsequent hospitalization, blood calcium levels remained slightly increased (2.64 mmol/L) and PTH was significantly increased (191 ng/L) despite vitamin D supplementation. In March, a 24-h urine sample was collected for calciuria measurement, which revealed a decreased urinary calcium concentration of 1.23 mmol/L. The fractional excretion of calcium was 1.2%. Due to these uncharacteristic results, a MIBI parathyroid scintigraphy revealed no abnormalities in favour of an adenoma or parathyroid hyperplasia. In April, a genetic analysis to detect the inhibitory mutation of the CASR gene coding for the calcium-sensitive receptor (gene 3q21.1) revealed a pathogenic variant classified as FHH type 1 according to ACMG guidelines. The patient's family was informed and genetic screening was organized to avoid unnecessary additional tests. The patient was finally able to go home. Patient and his family gave their informed consent for this case report. Ethical Approval was not required for this manuscript. Consent for publication from daughter of the patient was obtained.

## Discussion

The loss of function in the calcium-sensing receptor (gene 3q21.1) leads to a decrease in the calcium sensitivity of renal and parathyroid cells, which explains the hypercalcemia perceived as physiologically normal, accompanied by low renal excretion of calcium. This case report serves as a reminder to consider FHH as a potential diagnosis even at an advanced age, such as 88 years, as the literature reports a mean age of diagnosis of 73 ± 4 years in case reports [7-9] and a range of 18-75 years in the largest cohort [10], particularly after ruling out more common causes of hypercalcemia. In these case reports, symptoms of hypercalcemia are often absent, but chondrocalcinosis and arthritis are frequently noted. Chronic hypercalcemia appears to induce articular chondrocalcinosis through increased nucleation of inorganic pyrophosphate. In our case, gout arthritis is a confounding factor and should not be considered as an association within FFH but rather as a condition exacerbated by the diuretics prescribed for cardiac decompensation. There is likely no direct link between these two pathologies.
We initially supplemented vitamin D deficiency despite hypercalcemia in the hypothesis of tertiary hyperparathyroidism linked to hypovitaminosis D, very frequent in the geriatric population [11]. In addition, our patient had chronic renal insufficiency that could be classified as tertiary hyperparathyroidism. But the persistent low level of vitamin D despite supplementation is normal in patients with FHH and explained with impaired 1α-hydroxylase activity secondary to persistent elevated PTH level [12].

Clinical presentations of FHH are varied, and studies are not unanimous. Law Jr et al. showed in their study that patients with FHH tend to have a higher prevalence of gallstones, arthritis and hypertension than normocalcemic patients [13]. On the other hand, they did not present the classic clinical signs of primary hyperparathyroidism (urolithiasis, bone disease, peptic ulcer disease, pancreatitis ...). Lee et al. reported more fatigue, decreased muscle strength, arthralgia in patients with FHH compared to those with normal blood calcium levels [5]. Moreover, there are more pancreatitis and renal lithiasis. In geriatric patients, the interpretation of hypercalcemia symptoms is often complicated by multiple comorbidities and loss of autonomy often complicate the interpretation of hypercalcemia signs e.g. fatigue could not be considerate as a specific symptom. On the other side, long-term exposure to chronic hypercalcemia in older adults can lead to several consequences such as vascular and valvular calcification which may contribute to cardiac decompensation, as observed in our patient. Due to the inhibition of the CaSR expressed on ventricular cardiomyocytes, smooth muscle cells and blood vessel endothelium, the protective effect on vascular calcifications and myocardial infarction is decreased according to the level of increased blood calcium [14,15]. Given the patient's advanced age and the presence of FHH, it remains unclear whether some of the cardiovascular issues, such as the need for multiple stents, are primarily age-related or potentially influenced by the condition. This highlights the challenge of distinguishing symptoms caused by a rare disease like FHH from those attributable to the aging process.

Asymptomatic FHHs do not require treatment. Hypercalcemia does not respond to diuretics or biphosphonates. In certain situations, Mayr et al. [16] showed in their study the possibility of introducing cinacalcet in particular for symptomatic patients. Total parathyroidectomy may be considered in cases of recurrent pancreatitis, but the reduction of blood calcium levels after surgery remain debated [17]. The

diagnosis of FHH is therefore important even at an advanced age in order to avoid unnecessary parathyroidectomies. On the other hand, a late diagnosis allows useful genetic research in the descendants.

## Conclusion

FHH is mostly asymptomatic condition, and diagnosis may therefore be delayed or undiscovered. In the older people, the discrete symptoms could not be perceived due to several associated illness and often detected during a standardized geriatric evaluation. It is important to identify this disease also in older people to avoid unnecessary treatment and allow genetic family survey.

## Ethical approval

All authors approved the entirety of the submitted material and contributed actively to the study. The authors had obtained signed written consent for publication from the next of kin (daughter of the patient).

## Disclosure statement

No potential conflict of interest was reported by the author(s).

## Funding

The publication fees for this article were funded by the University Hospital of Saint-Étienne (CHU de Saint-Étienne).

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