Abstract
Background: The calcium-sensing receptor (CaSR) mediates PTH production and renal calcium excretion by sensing circulating calcium levels. Activating mutations in the CaSR can cause a spectrum of phenotypes from overt hypoparathyroidism to isolated hypercalciuria. Inactivating mutations of the CaSR lead to the syndrome of familial hypocalciuric hypercalcemia (FHH) where the protein produced is less sensitive to calcium. A mutation in the start codon of the CaSR leading to FHH has not previously been reported. Case: 60-year-old female was seen for evaluation of osteoporosis with lowest T- score of -2.9 at spine. She had no family history of calcium disorders. Biochemical evaluation for secondary etiologies of bone loss showed persistent PTH-dependent hypercalcemia (with albumin-corrected serum calcium of 10.4-10.8 mg/dl, and PTH 64-78 pg/ml), initially raising suspicion for primary hyperparathyroidism. Subsequent testing showed a low 24-hour urine calcium (82 mg/day) despite adequate daily calcium intake, robust 25-hydroxy vitamin D levels (47 ng/ml), and normal renal function. Calcium/creatinine clearance ratio was low at 0.0064 and FHH was suspected. CaSR gene sequencing revealed two heterozygous abnormalities: (1) a likely pathogenic mutation in the start codon of the CaSR (c.3G>A (p.M1?)) that has not been previously reported (p.M1? indicates that it is not known whether the mutation leads to no CaSR being produced from that allele or if an abnormal protein is produced using an alternate methionine start codon) and (2) a low-prevalence activation mutation variant of the CaSR (p.R990G), which is associated with hypercalciuria and increased risk of kidney stones but generally does not cause hypocalcemia. Genetic testing was unable to determine if these two mutations were on the same (cis) or opposite (trans) alleles. If they are on opposite alleles, the phenotype represents the heterozygous loss-of-function CaSR abnormality with compensation by an activating mutation in the opposite allele. If they are on the same allele, the activating variant is either not expressed at all due to nontranslation or is located on an abnormal/shortened protein. CaSR sequencing of the patient’s daughter was normal. In the absence of recombination occurring between the two loci, this strongly suggests the two were on the same allele in this case. Discussion: Thus far, > 100 mutations in the CaSR gene causing FHH have been described; but to our knowledge, this case is the first report of a start codon mutation causing FHH. This happened to be identified in the setting of a low-prevalence hypercalciuric variant. Familial testing strongly suggested the two mutations were on the same allele. The activating mutation, therefore, was likely functionally silenced in this case.
A Korean child diagnosed with malonic aciduria harboring a novel start codon mutation following presentation with dilated cardiomyopathy
