Familial hypocalciuric hypercalcemia(FHH) is caused by inactivating mutations in the calcium-sensing receptor(Ca SR) gene. The loss of function of Ca SR presents with rickets as the predominant skeletal abnormality in mice, but is rarely reported in humans. Here we report a case of a 16-year-old boy with FHH who presented with skeletal manifestations of rickets. To identify the possible pathogenic mutation, the patient was evaluated clinically, biochemically, and radiographically. The patient and his family members were screened for genetic mutations. Physical examination revealed a pigeon breast deformity and X-ray examinations showed epiphyseal broadening, both of which indicate rickets. Biochemical tests also showed increased parathyroid hormone(PTH), 1,25-dihydroxyvitamin D, and elevated ionized calcium. Based on these results, a diagnosis of FHH was suspected. Sequence analysis of the patient's Ca SR gene revealed a new missense mutation(c.2279 T4 A) in exon 7, leading to the damaging amino change(p.I760 N) in the mature Ca SR protein, confirming the diagnosis of FHH. Moreover, the skeletal abnormities may be related to but not limited to vitamin D abnormity. Elevated PTH levels and a rapid skeletal growth period in adolescence may have also contributed. Our study revealed that rickets-like features have a tendency to present atypically in FHH patients who have a mild vitamin D deficiency, and that Ca SR mutations may have a partial role in the pathogenesis of skeletal deformities.
Hereditary vitamin D-resistant rickets(HVDRR) is a rare autosomal recessive disorder characterized by severe rickets,hypocalcemia,hypophosphatemia,secondary hyperparathyroidism,and elevated alkaline phosphatase.This disorder is caused by homogeneous or heterogeneous mutations affecting the function of the vitamin D receptor(VDR),which lead to complete or partial target organ resistance to the action of 1,25-dihydroxy vitamin D.A non-consanguineous family of Chinese Han origin with one affected individual demonstrating HVDRR was recruited,with the proband evaluated clinically,biochemically and radiographically.To identify the presence of mutations in the VDR gene,all the exons and exon–intron junctions of the VDR gene from all family members were amplified using PCR and sequenced.The proband showed rickets,progressive alopecia,hypocalcemia,hypophosphatemia,secondary hyperparathyroidism,and elevated alkaline phosphatase.She also suffered from epilepsy,which is rarely seen in patients with HVDRR.Direct sequencing analysis revealed a homozygous missense mutation c.122G4A(p.C41Y) in the VDR gene of the proband,which is located in the first zinc finger of the DNA-binding domain.Both parents had a normal phenotype and were found to be heterozygous for this mutation.We report a Chinese Han family with one individual affected with HVDRR.A homozygous missense mutation c.122G4A(p.C41Y) in the VDR gene was found to be responsible for the patient's syndrome.In contrast to the results of treatment of HVDRR in other patients,our patient responded well to a supplement of oral calcium and a low dose of calcitriol.
