Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Osteoporosis International
Published in: Osteoporosis International 7/2017

01-07-2017 | Original Article

Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta

Authors: G. Bardai, L. M. Ward, P. Trejo, P. Moffatt, F. H. Glorieux, F. Rauch

Published in: Osteoporosis International | Issue 7/2017

Login to get access

Abstract

Summary

In 26 of 94 individuals (28%) below 21 years of age who had a significant fracture history but did not have extraskeletal features of osteogenesis imperfecta (OI), we detected disease-causing mutations in OI-associated genes.

Introduction

In children who have mild bone fragility but do not have extraskeletal features of OI, it can be difficult to establish a diagnosis on clinical grounds. Here, we assessed the diagnostic yield of genetic testing in this context, by sequencing a panel of genes that are associated with OI.

Methods

DNA sequence analysis was performed on 94 individuals below 21 years of age who had a significant fracture history but had white sclera and no signs of dentinogenesis imperfecta.

Results

Disease-causing variants were detected in 28% of individuals and affected 5 different genes. Twelve individuals had mutations in COL1A1 or COL1A2, 8 in LRP5, 4 in BMP1, and 2 in PLS3.

Conclusions

DNA sequence analysis of currently known OI-associated genes identified disease-causing variants in more than a quarter of individuals with a significant fracture history but without extraskeletal manifestations of OI.
Appendix
Available only for authorised users
Literature
1.
Rauch F, Neu C, Manz F, Schoenau E (2001) The development of metaphyseal cortex--implications for distal radius fractures during growth. J Bone Miner Res 16:1547–1555CrossRefPubMed
2.
Farr JN, Amin S, Melton LJ 3rd, Kirmani S, McCready LK, Atkinson EJ, Muller R, Khosla S (2014) Bone strength and structural deficits in children and adolescents with a distal forearm fracture resulting from mild trauma. J Bone Miner Res 29:590–599CrossRefPubMedPubMedCentral
3.
Ward LM, Konji VN, Ma J (2016) The management of osteoporosis in children. Osteoporos Int 27:2147–2179CrossRefPubMed
4.
Trejo P, Rauch F (2016) Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment. Osteoporos Int 27:3427–3437CrossRefPubMed
5.
6.
Bardai G, Moffatt P, Glorieux FH, Rauch F (2016) DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27:3607–3613CrossRefPubMed
7.
Rauch F, Lalic L, Roughley P, Glorieux FH (2010) Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I. Eur J Hum Genet 18:642–647CrossRefPubMedPubMedCentral
8.
Lindahl K, Astrom E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren O, Kindmark A (2015) Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet 23:1042–1050CrossRefPubMedPubMedCentral
9.
Rauch F, Plotkin H, Dimeglio L, Engelbert RH, Henderson RC, Munns C, Wenkert D, Zeitler P (2008) Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 pediatric official positions. J Clin Densitom 11:22–28CrossRefPubMed
10.
11.
Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL (2002) Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45–60CrossRefPubMed
12.
Kalkwarf HJ, Zemel BS, Yolton K, Heubi JE (2013) Bone mineral content and density of the lumbar spine of infants and toddlers: influence of age, sex, race, growth, and human milk feeding. J Bone Miner Res 28:206–212CrossRefPubMedPubMedCentral
13.
Zemel BS, Kalkwarf HJ, Gilsanz V et al (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160–3169CrossRefPubMedPubMedCentral
14.
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081CrossRefPubMed
15.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefPubMedPubMedCentral
16.
17.
18.
Richards S, Aziz N, Bale S et al (2015) 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 17:405–424CrossRefPubMedPubMedCentral
19.
Fahiminiya S, Al-Jallad H, Majewski J, Palomo T, Moffatt P, Roschger P, Klaushofer K, Glorieux FH, Rauch F (2015) A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children. Hum Mol Genet 24:516–524CrossRefPubMed
20.
Fahiminiya S, Majewski J, Al-Jallad H, Moffatt P, Mort J, Glorieux FH, Roschger P, Klaushofer K, Rauch F (2014) Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J Bone Miner Res 29:1805–1814CrossRefPubMed
21.
Korvala J, Juppner H, Makitie O et al (2012) Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet 13:26CrossRefPubMedPubMedCentral
22.
Dawson PA, Kelly TE, Marini JC (1999) Extension of phenotype associated with structural mutations in type I collagen: siblings with juvenile osteoporosis have an alpha2(I)Gly436 --> Arg substitution. J Bone Miner Res 14:449–455CrossRefPubMed
23.
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192CrossRefPubMed
24.
25.
Ben Amor IM, Roughley P, Glorieux FH, Rauch F (2013) Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res 28:2001–2007CrossRefPubMed
26.
Rauch F, Travers R, Parfitt AM, Glorieux FH (2000) Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 26:581–589CrossRefPubMed
27.
Brunetti G, Papadia F, Tummolo A et al (2016) Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-alpha. Osteoporos Int 27:2355–2365CrossRefPubMed
28.
Hendrickx G, Boudin E, Van Hul W (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11:462–474CrossRefPubMed
29.
Rivadeneira F, Makitie O (2016) Osteoporosis and bone mass disorders: from gene pathways to treatments. Trends Endocrinol Metab 27:262–281CrossRefPubMed
30.
Hartikka H, Makitie O, Mannikko M, Doria AS, Daneman A, Cole WG, Ala-Kokko L, Sochett EB (2005) Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res 20:783–789CrossRefPubMed
31.
32.
Mao W, Wordinger RJ, Clark AF (2011) Functional analysis of disease-associated polymorphism LRP5.Q89R. Mol Vis 17:894–902PubMedPubMedCentral
33.
Saarinen A, Mayranpaa MK, Lehesjoki AE, Makitie O (2010) Low-density lipoprotein receptor-related protein 5 (LRP5) variation in fracture prone children. Bone 46:940–945CrossRefPubMed
34.
Franceschi R, Vincenzi M, Camilot M, Antoniazzi F, Freemont AJ, Adams JE, Laine C, Makitie O, Mughal MZ (2015) Idiopathic juvenile osteoporosis: clinical experience from a single centre and screening of LRP5 and LRP6 genes. Calcif Tissue Int 96:575–579CrossRefPubMed
Metadata
Title
Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta
Authors
G. Bardai
L. M. Ward
P. Trejo
P. Moffatt
F. H. Glorieux
F. Rauch
Publication date
01-07-2017
Publisher
Springer London
Published in
Osteoporosis International / Issue 7/2017
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-017-4031-2

Other articles of this Issue 7/2017

Osteoporosis International 7/2017 Go to the issue

Review

Economic burden of osteoporosis-related hip fracture in Asia: a systematic review

Original Article

Association between obesity and femoral neck strength according to age, sex, and fat distribution

Short Communication

Associations between hip bone mineral density, aortic calcification and cardiac workload in community-dwelling older Australians

Original Article

Reduced bone mass and preserved marrow adipose tissue in patients with inflammatory bowel diseases in long-term remission

Original Article

Tumor-induced osteomalacia: experience from a South American academic center

Case Report

Case report: fast reversal of severe osteoporosis after correction of excessive levothyroxine treatment and long-term follow-up