Diagnosis and Treatment > Signs and Symptoms

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Nirusha Arnold Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Victor O’Toole Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Tien Huynh Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Howard C Smith Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Catherine Luxford Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Roderick Clifton-Bligh Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Creswell J Eastman Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia
Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Summary

Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del).

Learning points:

  • Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management.

  • In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered.

  • Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis.

  • In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months.

  • Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.

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Naoya Toriu Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Masayuki Yamanouchi Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Rikako Hiramatsu Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Noriko Hayami Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Junichi Hoshino Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Akinari Sekine Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Masahiro Kawada Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Eiko Hasegawa Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Tatsuya Suwabe Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Keiichi Sumida Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Toshiharu Ueno Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Naoki Sawa Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan

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Kenichi Ohashi Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan
Department of Pathology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan

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Takeshi Fujii Department of Pathology, Toranomon Hospital, Tokyo, Japan

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Kenmei Takaichi Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan
Okinaka Memorial Institute for Medical Research, Tokyo, Japan

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Motoko Yanagita Department of Nephrology, Kyoto University Graduate School of Medicine, Japan

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Tetsuro Kobayasi Okinaka Memorial Institute for Medical Research, Tokyo, Japan

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Yoshifumi Ubara Nephrology Center and Department of Rheumatology, Toranomon Hospital, Tokyo, Japan
Okinaka Memorial Institute for Medical Research, Tokyo, Japan

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Summary

We report the case of a 67-year-old Japanese woman with type 1 diabetes mellitus. At 47 years of age, her hemoglobin A1c (HbA1c) was 10.0%, and she had overt nephropathy. The first renal biopsy yielded a diagnosis of diabetic nephropathy. Intensive glycemic control was initiated and her HbA1c improved to 6.0%. Renal dysfunction showed no progression for 15 years. At 62 years of age, a second renal biopsy was performed. Glomerular lesions did not show progression but tubulointerstitial fibrosis and vascular lesions showed progression compared with the first biopsy. Intensive glycemic control can prevent the progression of glomerular lesions, but might not be effective for interstitial and vascular lesions.

Learning points:

  • Intensive control of blood glucose can prevent the progression of glomerular lesions.

  • Intensive control of blood glucose may not be able to prevent progression of interstitial and vascular lesions.

  • CSII reduces HbA1c without increasing the risk of hypoglycemia.

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