A Young Woman With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1 Deficiency.
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.
Department of Medicine, University of California, San Diego, CA, USA. gwoods@ucsd.edu.
Gina N
GN
Woods
Department of Pathology, University of California, San Diego, CA, USA.
Alec
A
Saitman
Fulgent Diagnostics, Temple City, CA, USA.
Hanlin
H
Gao
Mass Spectrometry R&D Department, Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Nigel J
NJ
Clarke
Department of Pathology, University of California, San Diego, CA, USA.
Robert L
RL
Fitzgerald
Department of Medicine, University of California, San Diego, CA, USA.
Nai-Wen
NW
Chi
D000208:Acute Disease; D000328:Adult; D001483:Base Sequence; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D010195:Pancreatitis / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D011247:Pregnancy; D011644:Puerperal Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D017384:Sequence Deletion; D065668:Vitamin D3 24-Hydroxylase / Q000172:deficiency*
C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
CYP24A1; HYPERCALCEMIA; PANCREATITIS; VITAMIN D