Disease Clinical Pages
Heterozygous loss-of-function mutations in CASR give rise
to familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong
hypercalcemia is generally asymptomatic. The characteristic symptoms and
complications afflicting patients with other forms of hypercalcemia appear not
to be a part of FHH. Affected individuals from some FHH kindreds may experience
pancreatitis, gall stones or chondrocalcinosis.
With respect to degree of hypercalcemia, the majority of
FHH patients are similar to patients with mild primary hyperparathyroidism. In
contrast to primary hyperparathyroid patients, those with FHH have serum
magnesium levels at the upper end of the normal range or slightly above. FHH
patients demonstrate inappropriately normal serum concentrations of parathyroid
hormone (PTH) despite hypercalcemia, indicative of the derangement in the blood
calcium sensing mechanism of the parathyroid. While the majority of primary
hyperparathyroid patients have clearly elevated circulating intact PTH,
diagnostic difficulties can arise in differentiating the ten percent of primary
hyperparathyroid patients with PTH levels at the upper limit of normal.
Another important characteristic of FHH is the unusually
high renal tubular reabsorption of calcium and magnesium in the face of
hypercalcemia. In the majority of FHH patients, the renal calcium/creatinine
clearance ratio is less than 0.01, while it is usually much higher in patients
with primary hyperparathyroidism and other hypercalcemic disorders. However,
occasionally affected members of some FHH families have hypercalciuria and/or
In FHH, in contrast to primary hyperparathyroidism, urine
concentrating ability is normal. The renal CASR may mediate the polyuria and
diminished urinary concentrating ability characteristic of hypercalcemia as seen
in primary hyperparathyroidism.
Before identification of FHH as a clinical entity distinct
from primary hyperparathyroidism, FHH patients often underwent
parathyroidectomy. In the vast majority of cases the patient remained
hypercalcemic, and the present consensus is that surgery is to be avoided if the
patient is asymptomatic. Moreover, the enhanced renal tubular reabsorption of
calcium persists following induction of hypoparathyroidism by total
parathyroidectomy, illustrating the fact that the abnormal renal handling of
calcium in FHH is independent of PTH.
Homozygous loss-of-function CASR mutations manifest as
neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by
extreme hypercalcemia and the bony changes of hyperparathyroidism which occur in
infancy. The cases of NSHPT almost invariably have involved multiglandular
parathyroid hyperplasia rather than a single adenoma. If not treated by
parathyroidectomy, NSHPT can be a devastating neurodevelopmental disorder and is
often fatal. However, some forms of neonatal hyperparathyroidism, particularly
those due to de novo mutations of the CASR gene, present with milder, less
symptomatic disease that can be transient.
Activating mutations in the CASR gene have been identified
in several families previously diagnosed with autosomal dominant hypocalcemia
(ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciura. In
the parathyroid gland, the activated CASR suppresses PTH secretion and in the
kidney it induces hypercalciuria which contributes to the hypocalcemia. In most
cases of ADH, a family history is clear, but de novo mutations are known. ADH
affected individuals may have mild hypocalcemia, and relatively few symptoms.
Seizures can occur, especially in younger patients, and these often happen
during febrile episodes due to intercurrent infection. Parathesias, tetany and
laryngospasm - other symptoms of hypocalcemia - are uncommon. There is a
tendency towards hyperphosphatemia, although serum phosphate may be normal.
Serum magnesium concentrations can be at the lower end of the normal range or
even subnormal in untreated patients.
Serum intact PTH levels are usually within the normal
range. Urinary calcium excretion is higher than in typical hypoparathyroid
patients, despite serum PTH levels being lower in hypoparathyroid patients than
in ADH-affected individuals. Because of the marked hypercalciuria, there is a
risk of other renal complications such as nephrocalcinosis, renal stones, and
impaired renal function. Renal tubular cells, excessively inhibited from
absorbing calcium by the overactive CASR, sustain the hypercalciuria. Thus
caution should be exercised to avoid overtreatment of ADH with Vitamin D (and
its metabolites) or calcium supplements.