Autosomal dominant hypocalcemia (ORPHA:428)
A rare disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with disproportionately low/normal levels of parathyroid hormone (PTH) and persistent normal or elevated renal calcium excretion.
Epidemiology
Prevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.
Clinical description
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 autosomal dominant hypocalcemia (ADH) with classical features of Bartter syndrome (BS) have been described (referred to as BS with hypocalcemia). 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.
Etiology
ADH is caused by activating mutations of the gene CASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR is expressed by cells in several tissues and plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and renal 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.
Diagnostic methods
Diagnosis is made through analysis of serum calcium and PTH levels. Molecular analysis of CASR followed by GNA11 confirms diagnosis.
Differential diagnosis
Differential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.
Antenatal diagnosis
Antenatal diagnosis is possible.
Genetic counseling
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, with increased risk of nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and (near-)normal serum calcium levels. 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, but higher doses are sometimes required). Careful monitoring of calciuria and regular kidney ultrasound are recommended. In cases where calcium homeostasis is difficult to achieve, exogenous PTH can be attempted.
Prognosis
The prognosis is variable, depending on the severity of the hypocalcemia /hypercalciuria and the possible consequences of treatment. In adults, it is associated with a reduced quality of life.

                            Last update: 
                            March 2023


                            - Expert reviewer(s): 
                            Pr Lars REJNMARK | Endo-ERN*


                                * European Reference Network