Abstract
ABSTRACTFamilial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant disorders caused by dysfunction of the calcium sensing receptor (CaSR) and its downstream signaling proteins, leading to generally asymptomatic hypercalcemia. During pregnancy, distinguishing FHH from primary hyperparathyroidism (PHPT) is important, as the latter is associated with adverse outcomes and can be treated surgically during pregnancy, whereas the former is benign. This case report highlights the difficulties in diagnosing FHH during pregnancy. A 32‐year‐old woman was found to have asymptomatic hypercalcemia at 14‐weeks’ gestation. Investigations showed a corrected calcium (cCa) of 2.61 mmol/L (2.10 to 2.60), ionized Ca (iCa) of 1.40 mmol/L (1.15 to 1.28), 25OHD of 33 nmol/L (75 to 250), and PTH of 9.5 pmol/L (1.5 to 7.0). The patient was treated with 2000 IU cholecalciferol daily with normalization of 25OHD. The urine calcium / creatinine clearance ratio (CCCR) was 0.0071, and neck US did not visualize a parathyroid adenoma. Upon a retrospective review of the patient's biochemistry from 2 years prior, hypercalcemia was found that was not investigated. The patient was monitored with serial iCa levels and obstetric US. She delivered a healthy boy at 38‐weeks’ gestation. Postnatal iCa was 1.48 mmol/L and remained elevated. Her son had elevated iCa at birth of 1.46 mmol/L (1.15 to 1.33), which rose to 1.81 mmol/L by 2 weeks. He was otherwise well. Given the familial hypercalcemia, a likely diagnosis of FHH was made. Genetic testing of the son revealed a missense mutation, NM_000388.3(CASR):c.2446A > G, in exon 7 of the CaSR, consistent with FHH type 1. To our knowledge, there are only three existing reports of FHH in pregnancy. When differentiating between FHH and PHPT in pregnancy, interpretation of biochemistry requires an understanding of changes in Ca physiology, and urine CCCR may be unreliable. If the decision is made to observe, clinical symptoms, calcium levels, and fetal US should be monitored, with biochemistry and urine CCCR performed postpartum, once lactation is completed © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
A 32-year-old woman was referred to our endocrine pregnancy clinic for hypercalcemia, incidentally detected on her first trimester screening, at 14-weeks’ gestation
Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant disorders caused by dysfunction of the calcium sensing receptor (CaSR) and its downstream signaling proteins, characterized by chronic, nonprogressive hypercalcemia, which is generally asymptomatic.[1]. Differentiation from primary hyperparathyroidism (PHPT) is important, but can be challenging, especially during pregnancy
Both 1,25(OH)2D3 and PTH-related peptide (PTHrP) act on the skeleton to increase bone turnover, and 1,25(OH)2D3 acts on the intestines to increase the absorption of calcium, which doubles from around the 12th week of gestation.[21]. This increase in intestinal absorption causes an increase in 24-hour urine calcium excretion, termed absorptive hypercalciuria, fasting levels may be normal or even low, highlighting the role of intestinal absorption.[21]. One study found that 24-hour urine calcium excretion was 250% to 300% higher in pregnancy when compared with postpartum excretion.[22]
Summary
FHH is a group of autosomal dominant disorders caused by dysfunction of the CaSR and its downstream signaling proteins, characterized by chronic, nonprogressive hypercalcemia, which is generally asymptomatic.[1]. The maternal kidneys are the primary source of 1-alpha hydroxylase, with a relatively minor contribution from placental 1-alpha hydroxylase.[20] Negative feedback on the parathyroid glands from PTHrP reduces PTH levels Both 1,25(OH)2D3 and PTHrP act on the skeleton to increase bone turnover, and 1,25(OH)2D3 acts on the intestines to increase the absorption of calcium, which doubles from around the 12th week of gestation.[21] This increase in intestinal absorption causes an increase in 24-hour urine calcium excretion, termed absorptive hypercalciuria, fasting levels may be normal or even low, highlighting the role of intestinal absorption.[21] One study found that 24-hour urine calcium excretion was 250% to 300% higher in pregnancy when compared with postpartum excretion.[22]. JBMR® Plus n FAMILIAL HYPOCALCIURIC HYPERCALCEMIA IN PREGNANCY: DIAGNOSTIC PITFALLS 3 of 5
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