Introduction: Familial hypocalciuric hypercalcemia (FHH) is caused by inactivating autosomal dominant mutations with high penetrance of CaSP gene. Contrary to severe neonatal hyperparathyroidism, caused by homozygous inactivation of the gene, familial hypocalciuric hypercalcemia is usually associated with inactivating variants in heterozygoty.
Case: Male patient, 73 years, with history of Behçets disease and pulmonary sarcoidosis, was refered for evaluation of hypopituitarism. During the evaluation phospho-calcium metabolism abnormalities were detected: calcium 5.5 mEq/l (4.055.2), ionized calcium 2.88 mEq/l (2.262.64) inorganic phosphorous 2.8 mg/dl (2.74.5), magnesium 1.86 mEq/l (1.552.05), confirmed in further studies, intact PTH of 88.9 pg/ml (10.065.0), with subsequent normal values. Urinary calcium to creatinine ratio was 0.004 (urinary calcium 2.2 mEq/24 h; plasma creatinine 1.3 mg/dl; urinary creatinine 1164 mg/24 h). Parathyroid ultrasound and scintigraphy revealed no changes as well as bone densitometry. The high calcium, the inappropriately high/normal intact PTH levels and the low urinary calcium, associated to the absence of symptoms of hyperparathyroidism, prompt us to consider the diagnosis of FHH and to request genetic study. It revealed the presence, in heterozygosity, of the pathogenic mutation c.1311C>A (p.Cys437X), in exon 4, of CaSR gene. Study of descendents and siblings was recommended, stressing the benign nature of this entity.
Discussion: Familial hypocalciuric hypercalcemia is usually asymptomatic and characterized by mild to moderate hypercalcemia, relative hypocalciuria, normal intact PTH, which can be mildly elevated in 20% of the cases, and high-normal levels of magnesium. Urinary calcium to creatinine ratio <0.01 is found in ~80% of individuals with FHH, while a similar proportion of cases of primary hyperparathyroidism have levels higher than this. FHH is a benign entity and usually does not require treatment. The importance of diagnose and screening is due to the need of differential diagnoses, especially with primary hyperparathyroidism, in order to avoid unnecessary therapeutic interventions.