The present case is an example of severe hypercalcemia in a middle-aged man with known FHH due to the development of a parathyroid adenoma. Treatment with high-dose cinacalcet was necessary to lower iCa and improve the patient’s well-being during the diagnostic period. Parathyroidectomy normalized PTH levels and reduced hypercalcemia, and the patient’s hypercalcemic symptoms resolved. PHPT is a common disease in adults. The high parathyroid state in PHPT causes increased renal absorption of calcium, increased bone turnover, and increased activated vitamin D, which in turn enhances calcium absorption from the intestine. PHPT is often asymptomatic and randomly discovered, and only in rare cases can lead to severe life-threatening hypercalcemia. In contrast to PHPT, FHH is a rare, genetic disorder which predominantly results in asymptomatic hypercalcemia with no significant clinical consequences. Our patient had a known pathogenic (class 5) heterozygous
CASR variant (NM_000388
, c.644A>G, p.Asp215Gly in exon 4). The variant had previously been identified in another family with FHH, and a functional study had confirmed that the variant leads to inactivation of the protein [
14,
15]. The two diseases may share clinical manifestations and biochemical findings as presented in this and other cases. Previous cases of simultaneously diagnosed PHPT and FHH in patients presenting with hypercalcemic symptoms have been described [
6‐
9,
11,
12]. Distinguishing between the two entities can be complicated and must be carefully taken into consideration in the evaluation of hypercalcemia [
16]. Reevaluation is necessary if the patient presents residual hypercalcemia after parathyroidectomy. In this case, as in a few others, PHPT develops in a patient with known FHH, which may lead to diagnostic delay, as the clinicians may be more likely to attribute the hypercalcemia to the known disease [
10,
13]. Later presentation of hypercalcemic symptoms or organ manifestations, as in our patient developing general malaise and chronic pancreatitis with no obvious cause, should lead to diagnostic reevaluation. Pancreatitis secondary to both PHPT and FHH has been described [
17,
18]. The mechanisms, however, are not fully understood. Our patient had persistent nonspecific abdominal symptoms even after parathyroid surgery had restored the calcium levels to FHH baseline levels, probably due to his chronic pancreatitis. These examples of coexisting hypercalcemic disease highlight the importance of following standard diagnostic measures for hypercalcemia as recommended in international guidelines, and reevaluating the patient if changes in clinical or biochemical presentation occur [
2,
19]. The consensus of a standard biochemical measure to differentiate between FHH and PHPT is the calcium–creatinine clearance ratio. This measure is not useful for diagnosing concomitant FHH and PHPT, as in the present case. In addition, a recent study showed limitations of the calcium–creatinine clearance ratio in general in differentiating between FHH and PHPT [
20]. Thus, a combination of clinical symptoms, family history, biochemical testing, parathyroid scintigraphy, and genetic testing is required to distinguish FHH from PHPT and also to exclude MEN1. In our case, there was a known variant of unknown significance in
MEN1 at the first genetic analysis. As the patient developed PHPT years later, the
MEN1 variant was reevaluated and classified as likely benign. The variant was classified in accordance with American College of Medical Genetics and Genomics (ACMG) guidelines [
21]. In conclusion, correct diagnosis of the underlying cause of hypercalcemia is important to ensure the right treatment, as highlighted by the present case of a patient with known FHH developing PHPT. Patients with FHH should avoid operative treatment, and PHPT should be differentiated from MEN1 to determine whether parathyroidectomy should include the removal of one adenoma or 3.5 hyperplastic parathyroid glands.