Familial Hypocalciuric hypercalcemia in an infant: diagnosis and management quandaries

Author Department

Pediatrics

Document Type

Article, Peer-reviewed

Publication Date

8-2024

Abstract

Familial hypocalciuric hypercalcemia (FHH) is typically a benign condition characterized by elevated serum calcium, low urinary calcium excretion, and non-suppressed circulating levels of parathyroid hormone (PTH), usually requiring no intervention. FHH is inherited in an autosomal-dominant manner. Three subtypes are described, representing variants in genes with critical roles in extracellular calcium-sensing. FHH1, due to heterozygous inactivating variants in the calcium-sensing receptor gene (CASR) accounts for the majority of cases. FHH2, due to variants in GNA11, encoding the α-subunit of the downstream signaling protein, G11, is the rarest form of FHH. FHH3, resulting from variants in AP2S1, may present with a more pronounced phenotype than FHH1 or FHH2. We describe herein a newborn girl presenting with in utero femoral fractures, hypercalcemia, hypophosphatemia, and elevated circulating PTH. She was diagnosed with mild hyperparathyroidism and provided supplemental phosphate upon hospital discharge. However, serum calcium and PTH remained elevated at 5 months of age. The combination of low-calcium formula and cinacalcet improved the biochemical profile. No pathogenic variants in the coding region of CASR were identified; subsequent whole exome sequencing revealed a G->T transition at c.44 (p.R15L) in AP2S1. Family studies identified this variant in the father and an affected brother. The mother was unexpectedly found to be hypocalcemic and was diagnosed with idiopathic hypoparathyroidism. This case demonstrates successful treatment of FHH3 using a low-calcium formula to limit dietary calcium availability and cinacalcet to modify PTH levels.

Plain language summary

An infant girl with a history of an in utero femoral fracture and a maternal history of hypoparathyroidism presented with persistent hypercalcemia, hypophosphatemia, and elevated parathyroid hormone levels. Despite receiving supplemental phosphorus upon hospital discharge, her serum calcium and PTH levels remained elevated at 4 months of age, and she was diagnosed with FHH type 3. Family studies also identified the presence of this variant in her father and an affected brother. After a trial with bisphosphonate failed to decrease calcium levels, she was treated with a combination of low-calcium formula and cinacalcet, which improved her biochemical profile. The patient remained on a stable clinical course on this regimen until she was weaned off cinacalcet at the age of 4 years.

PMID

39163488

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