Download PDF
J Pediatr Genet 2024; 13(01): 043-049
DOI: 10.1055/s-0041-1736559
Case-Based Review

Vitamin D-Dependent Rickets Type 1A in Two Siblings with a Hypomorphic CYP27B1 Variant Frequent in the African Population

Joana de Brito Chagas 
1   Pediatric Department, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal
,
Carolina Cordinhã
2   Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal
,
Carmen do Carmo
2   Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal
,
Cristina Alves
3   Department of Pediatric Orthopaedics, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal
,
Karen E. Heath
4   Institute of Medical and Molecular Genetics, IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain
5   Skeletal Dysplasia Multidisciplinary Unit and ERN-BOND, Hospital Universitario La Paz, Madrid, Spain; CIBERER, ISCIII, Madrid, Spain
,
Sérgio B. Sousa
6   Medical Genetics Unit, Skeletal Dysplasia Multidisciplinary Centre and ERN-BOND, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
7   University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
,
Clara Gomes
2   Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Vitamin D-dependent type 1A rickets (VDDR-1A) is a rare autosomal recessive disease due to the inability to convert 25-hydroxyvitamin D [25(OH)D] to the active form 1.25-dihydroxyvitamin D [1.25(OH)2D] by the enzyme 25(OH)D-1α-hydroxylase leading to low or low-normal serum levels of [1.25(OH)2D].

We report two sisters with rickets in whom the diagnosis of VDDR-1A was a challenge. They had normal 1.25(OH)2D levels, which are unusual with this condition but may be explained by the identified genotype. Both have compound heterozygous for two, most likely, hypomorphic CYP27B1 alleles: the novel p.(Arg117Gly) variant, and p.(Ala129Thr), which are present in 0.43% of the African population.

This report illustrates the variability of clinical, laboratory, and radiological presentation between two sisters with the same genotype, during phases of faster or slower growth. Genetic testing was crucial for establishing the diagnosis that optimized the management and genetic counseling.

Keywords

rickets - children - vitamin D - osteomyelitis


Publication History

Received: 24 April 2021

Accepted: 15 September 2021

Article published online:
25 October 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Chanchlani R, Nemer P, Sinha R. et al. An overview of rickets in children. Kidney Int Rep 2020; 5 (07) 980-990
    CrossrefPubMedSearch in Google Scholar
  • 2 Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nat Rev Dis Primers 2017; 3: 17101
    CrossrefPubMedSearch in Google Scholar
  • 3 Levine MA. Diagnosis and management of vitamin D dependent rickets. Front Pediatr 2020; 8 (June): 315
    CrossrefPubMedSearch in Google Scholar
  • 4 Özcabı B, Tahmiscioğlu Bucak F, Jaferova S. et al. A case of vitamin d-dependent rickets type 1a with a novel mutation in the Uzbek population. J Clin Res Pediatr Endocrinol 2016; 8 (04) 484-489
    CrossrefPubMedSearch in Google Scholar
  • 5 Bivona G, Agnello L, Lo Sasso B. et al. Vitamin D in malaria: more hypotheses than clues. Heliyon 2019; 5 (02) e01183
    CrossrefPubMedSearch in Google Scholar
  • 6 Bivona G, Lo Sasso B, Iacolino G. et al. Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer's disease and Parkinson's disease. Clin Chim Acta 2019; 497 (July): 82-87
    CrossrefPubMedSearch in Google Scholar
  • 7 Sentchordi-Montané L, Benito-Sanz S, Aza-Carmona M. et al. Clinical and molecular description of 16 families with heterozygous IHH variants. J Clin Endocrinol Metab 2020; 105 (08) dgaa218
    CrossrefPubMedSearch in Google Scholar
  • 8 Jacobs ET, Van Pelt C, Forster RE. et al. CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells. Cancer Res 2013; 73 (08) 2563-2573
    CrossrefPubMedSearch in Google Scholar
  • 9 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
    CrossrefPubMedSearch in Google Scholar
  • 10 Saijo T, Ito M, Takeda E. et al. A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: utility of single-strand conformation polymorphism analysis for heterozygous carrier detection. Am J Hum Genet 1991; 49 (03) 668-673
    PubMedSearch in Google Scholar
  • 11 Alzahrani AS, Zou M, Baitei EY. et al. A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. J Clin Endocrinol Metab 2010; 95 (09) 4176-4183
    CrossrefPubMedSearch in Google Scholar
  • 12 Wang X, Zhang MYH, Miller WL, Portale AA. Novel gene mutations in patients with 1α-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002; 87 (06) 2424-2430
    PubMedSearch in Google Scholar
  • 13 Dursun F, Özgürhan G, Kırmızıbekmez H, Keskin E, Hacıhamdioğlu B. Genetic and clinical characteristics of patients with vitamin d dependent rickets type 1A. J Clin Res Pediatr Endocrinol 2019; 11 (01) 34-40
    CrossrefPubMedSearch in Google Scholar
  • 14 Bak NR, Song ES, Yang EM, Kim CJ, Vitamin D. Dependent rickets type 1a caused by CYP27B1 mutation. Child Kidney Dis 2019; 23 (02) 111-115
    CrossrefPubMedSearch in Google Scholar
  • 15 Giannakopoulos A, Efthymiadou A, Chrysis D. A case of vitamin-D-dependent rickets type 1A with normal 1,25-dihydroxyvitamin D caused by two novel mutations of the CYP27B1 gene. Horm Res Paediatr 2017; 87 (01) 58-63
    CrossrefPubMedSearch in Google Scholar
  • 16 Kaygusuz SB, Alavanda C, Kirkgoz T. et al. Does genotype-phenotype correlation exist in vitamin D-dependent rickets type IA: report of 13 new cases and review of the literature. Calcif Tissue Int 2021; 108 (05) 576-586
    CrossrefPubMedSearch in Google Scholar
  • 17 Dhull RS, Jain R, Deepthi B. et al. Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature. J Bras Nefrol 2020; 42 (04) 494-497
    CrossrefPubMedSearch in Google Scholar
  • 18 John M, Al-Jadiri A, Co C, Abulfaraj M, Santiago LJ. Acute hematogenous osteomyelitis in a five-month-old male with rickets. Case Rep Pediatr 2017; 2017: 4627905
    CrossrefPubMedSearch in Google Scholar
  • 19 Maier GS, Horas K, Seeger JB, Roth KE, Kurth AA, Maus U. Is there an association between periprosthetic joint infection and low vitamin D levels?. Int Orthop 2014; 38 (07) 1499-1504
    CrossrefPubMedSearch in Google Scholar
  • 20 Schwartz G. Clinical assessment of renal function. In: Kher KK, Schnaper HW, Greenbaum LA. Clinical Pediatric Nephrology. Third Ed.. Taylor & Francis Group; 2017: 63
    Search in Google Scholar