Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D<sub>3</sub>Catabolism in a Patient With<i>CYP24A1</i>Mutations

Shah, Arti; Hsiao, Edward C.; O’Donnell, Betsy; Salmeen, Kirsten; Nussbaum, Robert L.; Krebs, Michael; Baumgartner‐Parzer, Sabina; Kaufmann, Martin; Jones, Glenville; Bikle, Daniel D.; Wang, Yongmei; Mathew, Allen S.; Shoback, Dolores; Block-Kurbisch, Ingrid

doi:10.1210/jc.2015-1973

Cited by 56 publications

(35 citation statements)

References 10 publications

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“…While breastfeeding, hypercalcemia was milder and serum calcitriol was normal (820). This is consistent with Cyp27b1 stimulation being reduced to nonpregnant levels during lactation.…”

Section: Human Datasupporting

confidence: 77%

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Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

Kovacs

2016

Physiological Reviews

383

524

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During pregnancy and lactation, female physiology adapts to meet the added nutritional demands of fetuses and neonates. An average full-term fetus contains ϳ30 g calcium, 20 g phosphorus, and 0.8 g magnesium. About 80% of mineral is accreted during the third trimester; calcium transfers at 300-350 mg/day during the final 6 wk. The neonate requires 200 mg calcium daily from milk during the first 6 mo, and 120 mg calcium from milk during the second 6 mo (additional calcium comes from solid foods). Calcium transfers can be more than double and triple these values, respectively, in women who nurse twins and triplets. About 25% of dietary calcium is normally absorbed in healthy adults. Average maternal calcium intakes in American and Canadian women are insufficient to meet the fetal and neonatal calcium requirements if normal efficiency of intestinal calcium absorption is relied upon. However, several adaptations are invoked to meet the fetal and neonatal demands for mineral without requiring increased intakes by the mother. During pregnancy the efficiency of intestinal calcium absorption doubles, whereas during lactation the maternal skeleton is resorbed to provide calcium for milk. This review addresses our current knowledge regarding maternal adaptations in mineral and skeletal homeostasis that occur during pregnancy, lactation, and post-weaning recovery. Also considered are the impacts that these adaptations have on biochemical and hormonal parameters of mineral homeostasis, the consequences for long-term skeletal health, and the presentation and management of disorders of mineral and bone metabolism.

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“…While breastfeeding, hypercalcemia was milder and serum calcitriol was normal (820). This is consistent with Cyp27b1 stimulation being reduced to nonpregnant levels during lactation.…”

Section: Human Datasupporting

confidence: 77%

“…More recently, hereditary absence of Cyp24a1 has been shown to lead to maternal and fetal hypercalcemia (249,820), likely because reduced catabolism of calcitriol leads to relatively unopposed actions of the active hormone to stimulate intestinal calcium absorption and potentially induce osteoclast-mediated bone resorption.…”

Section: Yu Etmentioning

confidence: 99%

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

Kovacs

2016

Physiological Reviews

383

524

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“…A low ratio (<0.04 in our case) suggests impaired vitamin D catabolism and may warrant sequencing of the CYP24A1 gene. As reported previously (7,8) and herein, hypercalcemia from CYP24A1 deficiency may be unmasked by the physiologic changes of pregnancy. It is therefore important to establish a pregnancy- or trimester-specific reference range for 24,25(OH) 2 D and its ratio over 25(OH)D.…”

Section: Discussionsupporting

confidence: 83%

“…(5,7,8,10) This report describes a CYP24A1-deficient young woman with gestational hypercalcemia during two consecutive pregnancies, each confounded by acute pancreatitis, a complication not previously attributed to CYP24A1 mutations. The pathogenic 8-nt deletion (c.999_1006del) has not been reported in CYP24A1-related hypercalcemia.…”

Section: Discussionmentioning

confidence: 93%

A Young Woman With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1 Deficiency

Woods

Saitman

Gao³

et al. 2016

Journal of Bone and Mineral Research

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The CYP24A1 gene encodes a mitochondrial 24‐hydroxylase that inactivates 1,25(OH)2D. Loss‐of‐function mutations in CYP24A1 cause hypercalcemia, nephrolithiasis and nephrocalcinosis. We describe a woman with CYP24A1 deficiency and recurrent gestational hypercalcemia. Her first pregnancy, at age 20, resulted with the intrauterine demise of twin fetuses. Postpartum, she developed severe hypercalcemia (14 mg/dL), altered mental status, and acute pancreatitis. Her PTH was suppressed (6 pg/mL) and her 1,25(OH)2D was elevated (165 and 195 pg/mL on postpartum day 1 and 5, respectively). Between one and three months postpartum, her serum calcium decreased from 11.4 to 10.2 mg/dL while her 1,25(OH)2D level decreased from 83 to 24 pg/mL. Her 24‐hour urine calcium was 277 mg. Six months postpartum, she became pregnant again. At 14 weeks, her albumin‐corrected calcium level was 10.4 mg/dL and her 1,25(OH)2D level exceeded 200 pg/mL. To establish the diagnosis of CYP24A1 deficiency, we showed her 24,25(OH)2D level to be undetectable (<2 ng/mL). Exon sequencing of the CYP24A1 gene revealed a homozygous, 8‐nucleotide deletion in exon 8, causing an S334V substitution and premature termination due to a frame shift (c.999_1006del, p.Ser334Valfs*9). To prevent hypercalcemia, she was advised to discontinue prenatal vitamins, avoid sun exposure and calcium‐rich foods, and start omeprazole and a calcium binder (250 mg K‐Phos‐neutral with meals). Despite these measures, both hypercalcemia (11.5 mg/dL) and acute pancreatitis recurred. Labor was induced and a healthy, normocalcemic boy was delivered. In the absence of lactation, maternal hypercalcemia resolved within 2 months. This report shows that CYP24A1‐deficient subjects may be normocalcemic at baseline. Hypercalcemia may be unmasked by pregnancy through the routine use of calciferol‐containing prenatal vitamins, increased 1‐alpha hydroxylation of VitD by the placenta and maternal kidney, and production of PTHrP by the uteroplacental unit. CYP24A1 deficiency should be considered in patients with unexplained vitamin D‐mediated hypercalcemia. © 2016 American Society for Bone and Mineral Research.

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“…Moreover, almost all studies to date have relied on maternal serum concentrations of 25(OH)D3 as the determinant of vitamin D status and function, despite the potential importance of other vitamin D metabolites such as 1,25(OH) 2 D3 [21], 3- epi -25(OH)D3 [22], and 24-hydroxylated vitamin D metabolites (24,25(OH) 2 D3) [23]. Furthermore, placental expression of 1α-hydroxylase suggests that tissue-specific concentrations of 25(OH)D3 and other vitamin D metabolites are likely to be potential determinants of local vitamin D function across gestation [6].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of maternal and placental vitamin D metabolism in preeclampsia

et al. 2017

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Introduction Epidemiology has linked preeclampsia (PET) to decreased maternal serum 25-hydroxyvitamin D3 (25(OH)D3). However, alterations in systemic and placental/decidual transport and metabolism of 25(OH)D3 during pregnancy suggest that other forms of vitamin D may also contribute to the pathophysiology of PET. Methods In a cross sectional analysis of normal pregnant women at 1st (n = 25) and 3rd trimester (n = 21), pregnant women with PET (n = 22), and non-pregnant female controls (n = 20) vitamin D metabolites were quantified in paired maternal serum, placental, and decidual tissue. Results Serum 25(OH)D3 was not significantly different in sera across all four groups. In normal 3rd trimester pregnant women serum active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was significantly higher than non-pregnant, normal 1st trimester pregnant, and PET women. Conversely, PET sera showed highest levels of the catabolites 3-epi-25(OH)D3 and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). Serum albumin was significantly lower in normal 3rd trimester pregnant women and PET relative to normal 1st trimester pregnant women, but there was no change in free/bioavailable 25(OH)D3. In PET placental tissue, 25(OH)D3 and 3-epi-25(OH)D3 were lower than normal 3rd trimester tissue, whilst placental 24,25(OH)2D3 was highest in PET. Tissue 1,25(OH)2D3 was detectable in 1st trimester decidua, which also showed 10-fold higher 25(OH)D3 relative to paired placentae. 3-epi-25(OH)D3 and 24,25(OH)2D3 were not different for decidua and placenta. In normal 3rd trimester pregnant women, total, free and bioavailable maternal 25(OH)D3 correlated with placental 25(OH)D3, but this was not conserved for PET. Discussion These data indicate that PET is associated with decreased activation, increased catabolism, and impaired placental uptake of 25(OH)D3.

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Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D₃Catabolism in a Patient WithCYP24A1Mutations

Cited by 56 publications

References 10 publications

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

A Young Woman With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1 Deficiency

Dysregulation of maternal and placental vitamin D metabolism in preeclampsia

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Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3Catabolism in a Patient WithCYP24A1Mutations

Cited by 56 publications

References 10 publications

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

A Young Woman With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1 Deficiency

Dysregulation of maternal and placental vitamin D metabolism in preeclampsia

Contact Info

Product

Resources

About

Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D₃Catabolism in a Patient WithCYP24A1Mutations