Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2017) 6 P065 | DOI: 10.1530/boneabs.6.P065

ICCBH2017 Poster Presentations (1) (209 abstracts)

A novel form of congenital rickets due to a recurrent gain of function mutation in CYP3A4

Christine P Rodda 1 , Michael A Levine 2 , Jeffrey D Roizen 2 , Muhammad K Javaid 3 , Peter R Ebeling 4 , Hanh Nguyen 4 , Peter Dewez 5 & Nicholas J Shaw 6

1Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Paediatric Department, Sunshine Hospital, St Albans 3021, Australia; 2Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 3National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK; 4Monash University, Monash Medical Centre, Clayton 3168, Australia; 5Paediatrician, 44 Docker Street, Wangaratta 3677, Australia; 6Birmingham Children’s Hospital and University of Birmingham, Birmingham, UK.

Although Vitamin D deficiency is the most common form of rickets worldwide, when there is a failure to respond to cholecalciferol, inborn errors of vitamin D metabolism should be considered. We describe two unrelated individuals who presented with early onset rickets characterised by reduced serum levels of 25(OH)D and 1,25(OH)2D, and a deficient response to Vitamin D2/D3 and calcitriol. Case 1: A Caucasian Australian girl with non-consanguineous parents was referred aged 2.5 years with refractory rickets. Bow legs and an unsteady gait were noted from aged 20 months. She was otherwise healthy, with regular direct sun exposure. Cholecalciferol 5000 IU daily and calcitriol 0.25 μg orally daily for 1 month, resulted in no clinical improvement. Cholecalciferol 6 00 000 IU was given nasogastrically as a vitamin D generation test. Five days later, her serum calcium increased to near normal to 2.02 mmol/l and her 25 (OH)D increased to 97 nmol/l. She was commenced on cholecalciferol syrup 50 000 IU daily, which resulted in healing of her rickets radiologically and biochemically. Case 2: A girl born to non-consanguineous parents in Jordan developed bowed legs in infancy, with delayed walking at 4.5 years. Calcitriol was commenced in early childhood, with no improvement. She came to the UK in 2009, aged 16 years. Despite large doses cholecalciferol doses, she was unable to achieve a satisfactory level of 25(OH)D or normalise PTH. Using whole exome sequencing (WES), an identical heterozygous single nucleotide change in exon 10 of the CYP3A4 gene (c.902T>C) resulting in replacement of isoleucine by threonine at codon 301 (p.I301T) was identified in both girls (1). This change was not present in other first-degree relatives, nor in any public databases searched. The mutant CYP3A4 (p.I301T) was nearly 10-fold more active than the wild type enzyme. In summary, a recurrent missense mutation in CYP3A4 resulted in increased CYP3A4 activity with enhanced inactivation of vitamin D metabolites. This gain-of-function mutation of CYP3A4 causes a novel form of congenital rickets, (Vitamin D dependant rickets Type 3) responsive to large doses of oral cholecalciferol.

Disclosure: The authors declared no competing interests.

1. Roizen J., et al., Presentation No. 1063 ASBMR Annual Scientific Meeting, Atlanta, GA, USA, September 2016.

Volume 6

8th International Conference on Children's Bone Health


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