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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 428
A rare disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with abnormally low levels of parathyroid hormone (PTH) and persistant normal or elevated calciuria.
Prevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.
Clinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients (in whom the diagnosis is made by chance during a routine exam) to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures). In addition to hypocalcemia, hypercalciuria or relative hypercalciuria (hypercalciuria within the normal range, but relatively high in the presence of hypocalcemia) is present. Hyperphosphatemia, hypomagnesemia and hypermagnesuria are also common. Nephrocalcinosis and impaired renal function have been reported and cases of AD hypocalcemia with classical features of Bartter syndrome (BS; see this term) have been described (referred to as BS with hypocalcemia; see this term). Serum levels of PTH are normal or low. In addition to regulation by PTH, environmental factors also influence calcium homeostasis and may explain why an initially well-controlled hypocalcemia may become symptomatic at various stages of life.
AD hypocalcemia is caused by activating mutations of the gene CASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and urinary calcium excretion in response to variations in serum calcium levels. Gain-of-function CASR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal. Activating mutations in GNA11 (19p13.3) have also been described.
Diagnosis is made through analysis of calcium levels in the serum and urine and PTH levels, Molecular analysis of CaSR followed by GNA11 confirms diagnosis.
Differential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.
Antenatal diagnosis is possible.
Genetic counseling may be proposed but patients should be informed about the wide variability in clinical presentation.
Management and treatment
Treatment to normalize calcemia levels should be considered with caution, as any increase in calcium levels (even within the normal range) will be perceived by renal cells as hypercalcemia and lead to increased urinary calcium excretion, and possibly to nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and maintenance of calcium homeostasis, without being iatrogenic. Urine calcium levels should be monitored in order to avoid hypercalciuria rather than adapting treatment towards hypocalcemia. In asymptomatic and mildly symptomatic patients, treatment may not be necessary. Special care must be given to children as chronic hypocalcemia has deleterious effects on intellectual development. Treatment is based on administration of 1-alpha hydroxylated vitamin D (doses ranging from 0.5 to 1.5 micrograms/day in adults; higher doses are sometimes required in children). Careful monitoring of calciuria and regular kidney ultrasound are required. In cases where calcium homeostasis is difficult to achieve, exogenous PTH administered by infusion pump can be proposed.
The prognosis is variable, depending on the severity of the hypocalcemia and the possible consequences of inadequate treatment.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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