A homozygous CaSR mutation causing a FHH phenotype completely masked by vitamin D deficiency presenting as rickets.

[familial hypocalciuric hypercalcemia]

Heterozygous inactivating calcium-sensing receptor (CaSR ) mutations lead to familial hypocalciuric hypercalcemia (FHH ), whereas homozygous mutations usually cause neonatal severe hyperparathyroidism .The objective of the study was to investigate the pathophysiological mechanisms of a homozygous inactivating CaSR mutation identified in a 16 -year -old female .Clinical , biochemical , and genetic analyses of the index patient and her family were performed . Functional capacity of CaSRQ 459 R and CaSR mutants causing FHH (Q 27 R , P 39 A , S 417 C ) or neonatal severe hyperparathyroidism (W 718 X ) was assessed . Activation of the cytosolic calcium pathway and inhibition of PTH -induced cAMP signaling were measured .A 16 -year -old girl presented with adolescent rickets , vitamin D deficiency , and secondary hyperparathyroidism . Vitamin D treatment unmasked features resembling FHH , and genetic testing revealed a homozygous CaSRQ 459 R mutation . Two apparently healthy siblings were homozygous for CaSRQ 459 R and had asymptomatic hypercalcemia and hypocalciuria . The CaSRQ 459 R mutation leads to mild functional inactivation in vitro , which explains the FHH -like phenotype in homozygous family members and the grossly exaggerated PTH response to vitamin D deficiency in the index case . The patient 's parents and two other siblings were heterozygous , had normal serum calcium and PTH , but had marked hypocalciuria , which appeared to be associated with impaired in vitro activation of the calcium signaling pathway by CaSRQ 459 R . The Q 459 R mutation responded well to calcimimetic treatment in vitro .CaSR mutations causing mild functional impairment can lead to FHH , even in homozygous patients . The skeletal deformities in the index case were mainly due to severe vitamin D deficiency , and the CaSR mutation did not appear to have played a major independent role in the skeletal phenotype .

Diseases
Validation

Diseases presenting "functional capacity" symptom

achondroplasia

familial hypocalciuric hypercalcemia

familial mediterranean fever

You can validate or delete this automatically detected symptom