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Familial hypocalciuric hypercalcemia
Familial hypocalciuric hypercalcemia (FHH) is a generally asymptomatic genetic disorder of phosphocalcic metabolism characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration.
ORPHA:405Classification level: Disorder
Prevalence is unknown.
FHH is biologically characterized by moderate but significant hypercalcemia associated with levels of PTH and urinary calcium excretion that appear inappropriate in the presence of the hypercalcemia: serum levels of PTH are, in general, normal or slightly increased and calciuria is low. FHH is usually asymptomatic but rarely symptoms of fatigue, weakness, excessive thirst and concentration problems are experienced. Some adults suffer from relapsing pancreatitis, chondrocalcinosis and premature vascular calcification.
There are 3 genetic types of FHH based on chromosome location. FHH type 1 accounts for 65% of cases and is due to inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR). Loss of CaSR function results in a reduction in the sensitivity of parathyroid and renal cells to calcium levels so hypercalcemia is perceived as normal. The other 35% have either a mutation GNA11 (19p13.3) seen in FHH type 2 or AP2S1 (19q13.2-q13.3) seen in FHH type 3 (see these terms) or in genes not yet discovered. FHH is rarely caused by auto-antibodies against CaSR in those without a mutation.
FHH is suspected when mild hypercalcemia is seen along with normal or slightly elevated PTH, relative hypocalciuria, and normal phosphate levels. FHH must be suspected in the presence of persistent hypercalcemia despite surgical removal of a parathyroid adenoma. Family members are screened for serum calcium concentrations and CASR mutation analysis is performed in order to confirm a diagnosis. As de novo mutations are frequently described, the CASR gene must also be sequenced in the presence of typical biological features even in the absence of familial history of hypercalcemia. In FHH type 2, marked hypocalciuria is noted. FHH type 3 exhibits mild hypophosphatemia and elevated plasma PTH concentrations.
Primary hyperparathyroidism is clinically similar to FHH, apart from the presence of hypercalcemia. Other differential diagnoses include humoral malignant hypercalcemia and sarcoidosis (see this term).
As FHH is benign, prenatal testing is not recommended. It can be considered if both parents have FHH type 1, as their offspring have a higher risk of developing neonatal severe primary hyperparathyroidism (NSHPT; see this term), a particular clinical identity which can be life-threatening.
FHH is inherited as a dominant trait. Genetic counseling can be offered to family members of affected individuals and genetic screening for the CASR familial mutation.
Management and treatment
As FHH is usually asymptomatic, treatment is not necessary. The hypercalcemia seen in FHH does not respond to diuretics or bisphosphonates. For those with constantly elevated serum calcium concentrations >14mg/dL or in those with NSHPT or relapsing pancreatitis, a total parathyroidectomy can be beneficial. Pregnant women with FHH must be identified, as in the developing fetus a context of marked hypercalcemia leads to the inhibition of endogenous secretion of PTH and a high risk of developing severe hypocalcemia during the first days of life. In newborns of two FHH parents, calcium levels should be monitored for the first days of life as NSHPT can develop.
FHH does not lower life expectancy and has a benign, stable course.