Familial Hypocalciuric Hypercalcemia

Overview

The vast majority of FHH is caused by autosomal dominant loss-of-function mutations in the gene CASR, which codes for the calcium-sensing receptor (CASR). CASR is a G-protein coupled membrane receptor expressed in the parathyroid glands and the kidneys, among other tissues.

 

Symptoms

FHH is characterized by hypercalcemia, relative hypocalciuria, slight hypermagnesemia, and inappropriately normal to high levels of parathyroid hormone (PTH). In rare cases, loss-of-function mutations in CASR can also be associated with hypercalciuria. Although hypercalcemia is present from birth, it is often noticed later in life during a routine serum chemistry screen.

In the majority of cases, FHH is asymptomatic and does not lead to the complications associated with primary HPT, such as generalized bone demineralization and kidney stones. In a few FHH patients, pancreatitis, gallstones, chondrocalcinosis, or kidney stones have been reported.

source: Athena Diagnostics

Causes

In the parathyroid glands, CASR mediates the feedback inhibition of parathyroid hormone release in response to a rise in the blood calcium concentration. Loss-of-function mutations in CASR impair the feedback inhibition of parathyroid hormone secretion in response to a rise in the blood calcium concentration. Thus, higher than normal blood calcium levels are necessary to inhibit release of parathyroid hormone, resulting in hypercalcemia associated with inappropriately normal or mildly elevated levels of parathyroid hormone. The degree of hypercalcemia depends on how severely the mutation affects the function of the CASR molecule.

In the kidneys, CASR is involved in the feedback inhibition of parathyroid hormone-independent calcium reabsorption. Loss-of-function mutations in CASR prevent feedback inhibition of calcium reabsorption in response to a rise in the blood calcium concentration. Since calcium continues to be efficiently reabsorbed despite hypercalcemia, the calcium concentration in the urine is unexpectedly low relative to the calcium concentration in the blood (relative hypocalciuria).

source: Athena Diagnostics

Prevention

Since most cases of FHH are associated with loss-of-function mutations in a single gene, calcium-sensing receptor (CASR), genetic testing can assist in the diagnosis of FHH. Genetic testing for FHH-associated mutations in CASR can help to prevent unnecessary and inappropriate parathyroidectomy in patients with FHH.

source: Athena Diagnostics

Diagnosis

FHH is considered in individuals with asymptomatic persistent hypercalcemia accompanied by inappropriately normal or mildly elevated blood levels of parathyroid hormone. Differentiation from primary HPT can often be achieved by measuring the renal calcium/creatinine clearance ratio, which generally is less than 0.01 in patients with FHH and higher in patients with primary HPT.

However, reliable distinction between FHH and primary HPT is not always possible based on blood or urine measurements alone. Blood parathyroid hormone levels may be elevated in both situations, and urine calcium concentrations may not always be strikingly different between FHH and primary HPT. Occasionally, loss-offunction mutations in CASR can even be associated with hypercalciuria, similar to primary HPT.

Genetic testing for FHH-associated mutations in CASR can allow a diagnosis of FHH in cases where biochemical tests remain inconclusive. In addition, the detection of mutations in CASR can confirm a diagnosis of FHH reached on the basis of biochemical tests.

source: Athena Diagnostics

Treatment

Familial Hypocalciuric Hypercalcemia (FHH) is also known as Familial Benign Hypercalcemia because it is generally asymptomatic and does not require treatment. However, FHH is easily confused with milder cases of the more common primary hyperparathyroidism (HPT), which is generally treated by parathyroidectomy. In the case of FHH, parathyroidectomy is not only unnecessary but also inappropriate, since it does not cure FHH-associated hypercalcemia. It is therefore important to identify patients with FHH to prevent unnecessary parathyroidectomy. Unfortunately, current diagnostic methods do not always allow reliable differentiation between FHH and milder cases of primary HPT.

source: Athena Diagnostics