Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 16, 2017

Hereditary vitamin D-resistant rickets in Lebanese patients: the p.R391S and p.H397P variants have different phenotypes

  • Rabih Andary , Abdul-Karim El-Hage-Sleiman ORCID logo , Theresa Farhat , Sami Sanjad EMAIL logo and Georges Nemer ORCID logo EMAIL logo

Abstract:

Background:

Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder caused by mutations in the vitamin D receptor (VDR) gene. Variable phenotypes have been associated with these mutations, and some of these were linked to the effects they have on the interacting partners of VDR, mainly the retinoic X receptor (RXR).

Methods:

We examined four patients with HVDRR from three unrelated Lebanese families. All parents were consanguineous with normal phenotype. We used Sanger sequencing to identify mutations in the coding exons of VDR.

Results:

Two homozygous mutations (p.R391S and p.H397P), both in exon 9 of the VDR gene, were identified. Phenotype/genotype association was not possible even for the same mutation. Alopecia was seen only with the p.R391S mutation. Despite a comparable rachitic bone disease, the patients showed different responsiveness to large doses of alfacalcidol (1-α-hydroxy vitamin D3) supplementation.

Conclusions:

This is the first report of VDR mutations in Lebanon with promising clinical outcomes despite the severity of the phenotypes.


Corresponding author: Georges Nemer, PhD, Department of Biochemistry and Molecular Genetics, American University of Beirut, Bliss Street P.O. Box 11-0236, Beirut, Lebanon; and Sami Sanjad, MD, Department of Pediatrics and Adolescent Medicine, American University of Beirut, Bliss Street, Beirut, Lebanon
aRabih Andary and Abdul-Karim El-Hage-Sleiman contributed equally to this work.

Acknowledgments

We thank the patients and their families for their contribution to this research. Special thanks to Mrs Inaam El-Rassy for Sanger sequencing at the Molecular Core Facilities at the faculty of Medicine at the American University of Beirut.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This study was partially funded by a grant from Union Pharmaceutique d’Orient s.a.l. (Ms Norma Audi).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Lucock M, Jones P, Martin C, Beckett E, Yates Z, et al. Vitamin D: Beyond Metabolism. J Evid Based Complementary Altern Med 2015;20:310–22.10.1177/2156587215580491Search in Google Scholar PubMed

2. Yamada S, Yamamoto K, Masuno H. Structure-function analysis of vitamin D and VDR model. Curr Pharm Des 2000;6:733–48.10.2174/1381612003400353Search in Google Scholar PubMed

3. Hughes M, Malloy P, Kieback D, McDonnell D, Feldman D, et al. Human vitamin D receptor mutations: identification of molecular defects in hypocalcemic vitamin D resistant rickets. Adv Exp Med Biol 1989;255:491–503.10.1007/978-1-4684-5679-0_52Search in Google Scholar PubMed

4. Ma NS, Malloy PJ, Pitukcheewanont P, Dreimane D, Geffner ME, et al. Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy. Bone 2009;45:743–6.10.1016/j.bone.2009.06.003Search in Google Scholar PubMed PubMed Central

5. Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, et al. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997;99:297–304.10.1172/JCI119158Search in Google Scholar PubMed PubMed Central

6. Malloy PJ, Feldman D. The role of vitamin D receptor mutations in the development of alopecia. Mol Cell Endocrinol 2011;347:90–6.10.1016/j.mce.2011.05.045Search in Google Scholar PubMed PubMed Central

7. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242:1702–5.10.1126/science.2849209Search in Google Scholar PubMed

8. Malloy PJ, Tasic V, Taha D, Tutunculer F, Ying GS, et al. Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets. Mol Genet Metab 2014;111:33–40.10.1016/j.ymgme.2013.10.014Search in Google Scholar PubMed PubMed Central

9. Chuma M, Endo-Umeda K, Shimba S, Yamada S, Makishima M. Hairless modulates ligand-dependent activation of the vitamin D receptor-retinoid X receptor heterodimer. Biol Pharm Bull 2012;35:582–7.10.1248/bpb.35.582Search in Google Scholar PubMed

10. El-Rassy I, Bou-Abdallah J, Al-Ghadban S, Bitar F, Nemer G. Absence of NOTCH2 and Hey2 mutations in a familial Alagille syndrome case with a novel frameshift mutation in JAG1. Am J Med Genet A 2008;146:937–9.10.1002/ajmg.a.32225Search in Google Scholar PubMed

11. Nguyen M, d’Alesio A, Pascussi JM, Kumar R, Griffin MD, et al. Vitamin D-resistant rickets and type 1 diabetes in a child with compound heterozygous mutations of the vitamin D receptor (L263R and R391S): dissociated responses of the CYP-24 and rel-B promoters to 1,25-dihydroxyvitamin D3. J Bone Miner Res 2006;21:886–94.10.1359/jbmr.060307Search in Google Scholar PubMed

12. Aljubeh JM, Wang J, Al-Remeithi SS, Malloy PJ, Feldman D. Report of two unrelated patients with hereditary vitamin D resistant rickets due to the same novel mutation in the vitamin D receptor. J Pediatr Endocrinol Metab 2011;24:793–9.10.1515/JPEM.2011.341Search in Google Scholar PubMed

13. Malloy PJ, Zhou Y, Wang J, Hiort O, Feldman D. Hereditary vitamin D-resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor. J Bone Miner Res 2011;26:2710–8.10.1002/jbmr.484Search in Google Scholar PubMed

14. Fahed AC, Safa RM, Haddad FF, Bitar FF, Andary RR, et al. Homozygous familial hypercholesterolemia in Lebanon: a genotype/phenotype correlation. Mol Genet Metab 2011;102:181–8.10.1016/j.ymgme.2010.11.006Search in Google Scholar PubMed

15. Fahed AC, El-Hage-Sleiman AK, Farhat TI, Nemer GM. Diet, genetics, and disease: a focus on the middle East and north Africa region. J Nutr Metab 2012;2012:109037.10.1201/b18536-4Search in Google Scholar

16. Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, et al. Parental consanguinity and congenital heart malformations in a developing country. Am J Med Genet A 2003;116A:342–7.10.1002/ajmg.a.10020Search in Google Scholar PubMed

17. Shibbani K, Fahed AC, Al-Shaar L, Arabi M, Nemer G, et al. Primary carnitine deficiency: novel mutations and insights into the cardiac phenotype. Clin Genet 2014;85:127–37.10.1111/cge.12112Search in Google Scholar PubMed

18. Engelhard A, Bauer RC, Casta A, Djabali K, Christiano AM. Ligand-independent regulation of the hairless promoter by vitamin D receptor. Photochem Photobiol 2008;84:515–21.10.1111/j.1751-1097.2008.00301.xSearch in Google Scholar PubMed PubMed Central

19. Hsieh JC, Estess RC, Kaneko I, Whitfield GK, Jurutka PW, et al. Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes. J Endocrinol 2014;220:165–78.10.1530/JOE-13-0212Search in Google Scholar PubMed PubMed Central

Received: 2016-8-26
Accepted: 2017-1-31
Published Online: 2017-3-16
Published in Print: 2017-4-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 29.3.2024 from https://www.degruyter.com/document/doi/10.1515/jpem-2016-0338/html
Scroll to top button