ESPE Abstracts

Background: Familial Hypocalciuric Hypercalcemia (FHH) type 1 is a benign condition of hypercalcemia with autosomal dominant inheritance caused by pathogenic variants in the calcium-sensing receptor gene (CASR). CaSR plays a crucial role in the regulation of calcium balance. Inactivating mutations in CASR result in altered calcium-sensing and inappropriate parathyroid hormone (PTH) release concerning the calcium concentration. Dysplasia Epiphysealis Hemimelica (DEH) is another rare developmental bone disorder characterized by localized, asymmetric osteochondral overgrowth affecting single or multiple epiphyses, mainly the distal femur, proximal tibia, and talus. It is more often in boys with no evidence of a simple mendelian basis.

Case report: We report a 9-year-old boy with dysplasia in his right ankle, associated with a leg length discrepancy observed since 1.9 years old. He had no history of consanguinity, previous surgery, and medication use. Laboratory tests showed slightly elevated calcemia (total and ionized calcium were 10.9 mg/dL and 1.46 mmol/l, respectively), a high normal magnesium (3.2 mg/dL), normal PTH (30.1 pg/ml), normal phosphate (5.1 mg/dL), and decreased 24-hour urinary calcium (10 mg/24h). Vitamin D was marginally low (18.5 ng/ml). Skeletal X-ray depicted asymmetric epiphyseal enlargement of the proximal right femur, thinner in the medial portion with dysplasia of the acetabular roof characterized by verticalization and sclerosis with irregular margins. Right knee radiography showed distinctive bone densities that involve lateral femoral condyle. Ankle and foot radiography revealed asymmetrical mass-like osseous hypertrophy in the distal epiphyses of the fibula and tibia, and talus, associated with irregularities and sclerosis of talus margins. These skeletal findings resembled DEH. Patient was referred to a Geneticist who suggested a targeted sequencing panel which revealed a heterozygous variant of uncertain significance (VUS; Chr3: 122.282.171A>AG) in the CASR. It promotes the replacement of the amino acid glutamate in position 558 by glycine and creates a premature stop codon for protein translation (p.Glu558Glyfs*7). Considering the NGS result associated with clinical findings, we diagnosed this patient with FHH type 1. Parents have not performed laboratory and mutational analyses yet.

Conclusion: The CaSR is expressed in chondrocytes, osteoblasts, osteoclast precursors, and osteoclasts. It may also play a role in the embryonic development of the skeleton, postnatal bone formation, and osteoblast differentiation. To the best of our knowledge, patients with FHH type 1 did not present skeletal dysplasia. Our findings open up the possibility for further investigation relating DEH and FHH type 1 and/or the CaSR.