Atypical skeletal manifestations of rickets in a familial hypocalciuric hypercalcemia patient

Abstract

Familial hypocalciuric hypercalcemia (FHH) is caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene. The loss of function of CaSR 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 CaSR gene revealed a new missense mutation (c.2279T>A) in exon 7, leading to the damaging amino change (p.I760N) in the mature CaSR 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 CaSR mutations may have a partial role in the pathogenesis of skeletal deformities.

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“…In addition, metastatic bone lesions contribute to a poor prognosis, despite current therapeutic strategies. 1 – 3 Hence, it is imperative to develop novel effective treatments for bone metastasis through a better understanding of malignant bone metastases in the clinical setting. Cancer cells naturally inhabit a three-dimensional (3D) architecture within host microenvironments.…”

A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

“…The proband's unexpected bone lesion in the iliac wing revealed pathology suggestive of osteitis fibrosis cystica and complicated the evaluation. While the CaSR is present in cartilage and bone and contributes to skeletal homeostasis, the bone pathology reported in rare variants of FHH is associated with excess PTH rather than being independent of it [ 12 , 13 ]. This lesion was stable over 5 years on imaging, and repeat biopsy results were less specific suggesting that the finding may be unrelated yet parathyroidectomy may have altered its characteristics.…”

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“…This last process triggers RANKL expression, causing preosteoclasts to transform into osteoclasts that dissolve the bone matrix to release calcium and phosphorus into the blood (Brickley et al, 2020, p. 93). Genetic polymorphisms affecting phosphorus regulation (hypophosphatemic rickets) (Bitzan and Goodyer, 2019), calcium-sensing receptors (CaSR) (Wu et al, 2017), or VDR function (vitamin D-resistant rickets) (Liberman, 2007) can also result in skeletal rickets. Many diseases and iatrogenic factors also affect the bioavailability, synthesis, or metabolism of vitamin D, such as hyperparathyroidism, celiac disease, cystic fibrosis, chronic kidney disease, or medications used to treat high cholesterol (Holick, 2007).…”