Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review

Manjunath Havalappa Dodamani; Manjeetkaur Sehemby; Saba Samad Memon; Vijaya Sarathi; Anurag R. Lila; Aaron Chapla; Vishwambhar Vishnu Bhandare; Virendra A. Patil; Nalini S. Shah; Nihal Thomas; Ambarish Kunwar; Tushar R. Bandgar

doi:10.1515/jpem-2021-0403

Article

Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review

Manjunath Havalappa Dodamani , Manjeetkaur Sehemby , Saba Samad Memon , Vijaya Sarathi , Anurag R. Lila , Aaron Chapla , Vishwambhar Vishnu Bhandare , Virendra A. Patil , Nalini S. Shah , Nihal Thomas , Ambarish Kunwar and Tushar R. Bandgar

Published/Copyright: September 8, 2021

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 34 Issue 12

Abstract

Background

Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1-α hydroxylase gene. We describe our experience with systematic review of world literature to describe phenotype and genotype.

Methods

Seven patients from six unrelated families with genetically proven VDDR1 from our cohort and 165 probands from systematic review were analyzed retrospectively. The clinical features, biochemistry, genetics, management, and long-term outcome were retrieved.

Results

In our cohort, the median age at presentation and diagnosis was 11(4–18) and 40(30–240) months. The delayed diagnoses were due to misdiagnoses as renal tubular acidosis and hypophosphatemic rickets. Four had hypocalcemic seizures in infancy whereas all had rickets by 2 years. All patients had biochemical response to calcitriol, however two patients diagnosed post-puberty had persistent deformity. Genetic analysis revealed two novel (p.Met260Arg, p.Arg453Leu) and a recurring variant (p.Phe443Profs*24). Systematic review showed that seizures as most common presentation in infancy, whereas delayed motor milestones and deformities after infancy. Diagnosis was delayed in 27 patients. Patients with unsatisfactory response despite compliance were >12 years at treatment initiation. Inappropriately normal 1,25(OH)2D may be present, however suppressed ratio of 1,25(OH)2 D/25(OH)D may provide a clue to diagnosis. Various region specific and hot-spot recurrent variants are described. Patients with truncating variants had higher daily calcitriol requirement and greatly suppressed ratio of 1,25(OH)2D/25(OH)D.

Conclusion

Delayed diagnosis may lead to permanent short stature and deformities. Truncating variants tend to have severe disease as compared to non-truncating variants. Diagnostic accuracy of 1,25(OH)2 D/25(OH)D ratio needs further validation.

Keywords: 1-alpha hydroxylase; calcitriol; VDDR1A

Corresponding author: Tushar R. Bandgar, Department of Endocrinology OPD, Seth G.S Medical College and KEM Hospital, Parel, Mumbai 400012, India, Phone: (+91) 02224162917, Fax: (022) 24162883, Mobile: 9820025037, E-mail: drtusharb@gmail.com

Acknowledgments

We acknowledge Vyankatesh Shivane, Neeta Doiphode, Neelam Jaguste for administrative help in the study conduct and Sneha Arya and Samiksha Chandrashekhar Hegishte for help in review of the genetic data.

Research funding: No research funding was provided for this study by any specific grant from any funding agency in the public, commercial or nonprofit sector.
Author contributions: MHD did data search, performed statistical analysis, interpreted data and contributed to writing the manuscript and revising the same. MS & SM, did data search and contributed to writing the manuscript and revising it. AC conducted laboratory experiments and contributed writing the manuscript, VP clinically evaluated the patients and contributed to writing the manuscript. ARL provided intellectual expertise and assisted with manuscript development. VS contributed in both writing and revising the manuscript. VVB and AK performed computational protein modeling and docking. NT, NSS and TB supervised the study and critically revised the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Consent was waived by the institutional ethical committee due to retrospective nature of the study.
Ethical approval: The study was conducted after approval from the institutional ethical committee, seth G.S. medical college (EC/OA-154/2018) with waiver of consent.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2021-0403).

Received: 2021-06-14

Revised: 2021-08-24

Accepted: 2021-08-26

Published Online: 2021-09-08

Published in Print: 2021-12-20

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Articles in the same Issue

https://doi.org/10.1515/jpem-2021-0403

Keywords for this article

1-alpha hydroxylase; calcitriol; VDDR1A