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

Joana de Brito Chagas; Carolina Cordinhã; Carmen do Carmo; Cristina Alves; Karen E. Heath; Sérgio B. Sousa; Clara Gomes

doi:10.1055/s-0041-1736559

Journal of Pediatric Genetics, Table of Contents

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

¹Pediatric Department, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal

,

Carolina Cordinhã

²Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal

,

Carmen do Carmo

²Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal

,

Cristina Alves

³Department of Pediatric Orthopaedics, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal

,

Karen E. Heath

⁴Institute of Medical and Molecular Genetics, IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain

⁵Skeletal Dysplasia Multidisciplinary Unit and ERN-BOND, Hospital Universitario La Paz, Madrid, Spain; CIBERER, ISCIII, Madrid, Spain

,

Sérgio B. Sousa

⁶Medical Genetics Unit, Skeletal Dysplasia Multidisciplinary Centre and ERN-BOND, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

⁷University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal

,

Clara Gomes

²Pediatric Department, Pediatric Nephrology Unit, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (HP-CHUC), Coimbra, Portugal

› Author Affiliations

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

Full Text

References

References
1 Chanchlani R, Nemer P, Sinha R. et al. An overview of rickets in children. Kidney Int Rep 2020; 5 (07) 980-990
2 Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nat Rev Dis Primers 2017; 3: 17101
3 Levine MA. Diagnosis and management of vitamin D dependent rickets. Front Pediatr 2020; 8 (June): 315
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
5 Bivona G, Agnello L, Lo Sasso B. et al. Vitamin D in malaria: more hypotheses than clues. Heliyon 2019; 5 (02) e01183
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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