Abstract

Familial Hypocalciuria Hypercalcemia (FHH) is an inherited disease with autosomal dominant transmission characterized by the presence of usually mild-to-moderate hypercalcemia, hypophosphatemia, hypocalciuria, and normal or moderately increased PTH values. Generally, FFH is asymptomatic although symptoms related to elevated plasma calcium values such as asthenia, intense thirst, polyuria, polydipsia or confusional state may occur.
Three types of FHH, which differ in the genetic alterations underlying the condition, are described.
The majority of FHH cases are classified as type 1 (about 65 percent of cases), due to mutation in the gene for the calcium-sensitive receptor CASR, expressed on chromosome (Chr) 3q13.3-21, which encodes for a calcium-sensitive receptor G-protein-coupled protein of the plasma membrane.
FHH types 2 and 3 are due to GNA11 and AP2S1 mutations, respectively, and other genes involved in the pathogenesis of the disease have likely yet to be identified.
Rarely, familial hypocalciuric hypercalcemia may not recognize a genetic cause but be caused by autoantibodies directed against CASR.
The frequency of the disease is not known and is estimated, probably by default, because of paucisymptomatic presentation of the disease, to be around 1:80000 cases.
Recognition of FHH is especially important for differential diagnosis with primary hyperparathyroidism, which has a much higher incidence, about 1:1000 cases. This allows for the identification of patients at risk for chondrocalcinosis and/or pancreatitis. Clinical suspicion must be raised in cases of hypercalcaemia associated with hypocalciuria, and genetic analysis is fundamental in the differential diagnosis toward forms of primary hyperparathyroidism that might result in unnecessary surgical interventions.
We describe a clinical case in which a novel inactivating mutation of CASR leading to FHH type 1 was found.

Keywords: Familial Hypocalciuric Hypercalcemia, CASR, Gene, Parathyroid, Calcium