ESPE Abstracts

Background: The calcium-sensing receptor (CaSR) regulates calcium metabolism by modulating PTH secretion, as well as by direct effect on osteoblasts and osteoclasts, balancing bone formation and resorption. Loss-of-function heterozygous mutations on CASR gene can lead to Familial Hypocalciuric Hypercalcemia (FHH; OMIM #145980), a benign autosomal dominant condition of undefined incidence. Dysplasia Epiphysealis Hemimelica (DEH; OMIM #127800) is a rare disorder of unknown etiology that causes a unilateral abnormal osteochondral overgrowth that can affect single or multiple epiphysis.

Case report: We present a 9-year-old boy with progressively growing dysplasia in his right ankle, documented since he was 1.9 years old. There is no history of consanguinity, medication use, trauma, or previous procedures. Radiographs of the lower limbs indicated asymmetrical bone hypertrophy in the distal epiphysis of the tibia, fibula, and the entire talus, with irregularities and sclerotic margins. The right hip had sclerosis, irregular margins, and verticalization of the acetabulum. The proximal femur also presented an asymmetric epiphyseal enlargement. His right knee had irregularities at the lateral femoral condyle. This radiographic pattern is compatible with DEH. A targeted next-generation sequencing panel depicted a heterozygous variant (Chr3:122.282.171A>AG) in the CASR gene, responsible for a loss-of-function mutation by creating a premature stop codon at the position (p.Glu558Glyfs*7). Blood work indicated an elevated serum and ionized calcium (10.9 mg/dL and 1.46 mmol/L, respectively), with normal magnesium, PTH, phosphate, and vitamin D. The 24-hour urinary calcium was 10 mg/24h, confirming the diagnosis of FHH, based on the genetic and laboratory results. Blood and urine samples from his parents and brother detected elevated total and ionized calcium and decreased urinary calcium in both his father and brother, also confirming the diagnosis of FHH. Bone and cartilage fragments from patient’s lesions were excised and NGS sequencing are undergoing.

Discussion: We hypothesize that mutations of the CaSR in bone matrix or growth plate tissue may cause DEH. We are currently investigating two mechanisms: the loss of heterozygosity of the CASR gene in the affected tissue, following the “two-hit” model, or alternatively, a mutation in another gene. These theories are still being tested, and further studies about DEH and the CASR gene are needed to confirm the proposed mechanisms. Consequently, more precise treatment may improve the quality of life of these patients.