Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2
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Pregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery.
Pregnancy-associated osteoporosis (PAO) is a rare skeletal condition, which is characterized by a reduction in bone mineral density (BMD) in the course of pregnancy and lactation. Typical symptoms include vertebral compression fractures and transient osteoporosis of the hip. Since the etiology is not well understood, this prospective study was conducted in order to elucidate the relevance of pathogenic gene variants for the development of PAO.
Seven consecutive cases with the diagnosis of PAO underwent a skeletal assessment (blood tests, DXA, HR-pQCT) and a comprehensive genetic analysis using a custom-designed gene panel.
All cases showed a reduced BMD (DXA T-score, lumbar spine − 3.2 ± 1.0; left femur − 2.2 ± 0.5; right femur − 1.9 ± 0.5), while the spine was affected more severely (p < 0.05). The trabecular and cortical thickness was overall reduced in HR-pQCT, while the trabecular number showed no alterations in most cases. The genetic analysis revealed three novel mutations in LRP5, COL1A1, and COL1A2.
Our data show that previously unrecognized monogenic bone disorders play an important role in PAO. Pregnancy should be considered a skeletal risk factor, which can promote the initial clinical onset of such skeletal disorders. The underlying increased calcium demand is essential in terms of prophylactic and therapeutic measures, which are especially required in individuals with a genetically determined low bone mass. The implementation of this knowledge in clinical practice can enable the partial recovery of the skeleton. Consistent genetic studies are needed to analyze the frequency of pathogenic variants in women with PAO.
KeywordsEarly-onset osteoporosis Genetics Monogenic bone disorders Pregnancy-associated osteoporosis Treatment
This project has received funding from the European Community’s Seventh Framework Programme under grant agreement no. 602300 (SYBIL) and the German Federal Ministry of Education and Research (BMBF) within the project “Detection and Individualized Management of Early Onset Osteoporosis (DIMEOS).”
Compliance with ethical standards
This prospective approach is legitimated by approval through the local ethics committee (No. PV5364) and all investigations were carried out in accordance with the World Medical Association Declaration of Helsinki.
Conflicts of interest
- 8.Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Wahl DA, Stepan JJ, de Vernejoul MC, Kaufman JM, Pathophysiology IOFCoSAWGoO (2012) Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int 23(12):2735–2748. https://doi.org/10.1007/s00198-012-2030-x CrossRefPubMedGoogle Scholar
- 13.Cook FJ, Mumm S, Whyte MP, Wenkert D (2014) Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism. J Bone Miner Res 29(4):922–928. https://doi.org/10.1002/jbmr.2095 CrossRefPubMedGoogle Scholar
- 16.Milovanovic P, Adamu U, Simon MJ, Rolvien T, Djuric M, Amling M, Busse B (2015) Age- and sex-specific bone structure patterns portend bone fragility in radii and tibiae in relation to osteodensitometry: a high-resolution peripheral quantitative computed tomography study in 385 individuals. J Gerontol A Biol Sci Med Sci 70(10):1269–1275. https://doi.org/10.1093/gerona/glv052 CrossRefPubMedGoogle Scholar
- 20.Zemojtel T, Kohler S, Mackenroth L, Jager M, Hecht J, Krawitz P, Graul-Neumann L, Doelken S, Ehmke N, Spielmann M, Oien NC, Schweiger MR, Kruger U, Frommer G, Fischer B, Kornak U, Flottmann R, Ardeshirdavani A, Moreau Y, Lewis SE, Haendel M, Smedley D, Horn D, Mundlos S, Robinson PN (2014) Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci Transl Med 6(252):252ra123. https://doi.org/10.1126/scitranslmed.3009262 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.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(5):783–789. https://doi.org/10.1359/JBMR.050101 CrossRefPubMedGoogle Scholar
- 23.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (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(5):405–424. https://doi.org/10.1038/gim.2015.30 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grunhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparros-Martin JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schonau E, Ruiz-Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B (2013) Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92(4):565–574. https://doi.org/10.1016/j.ajhg.2013.02.010 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, Hyland JC, Korkko J, Prockop DJ, De Paepe A, Coucke P, Symoens S, Glorieux FH, Roughley PJ, Lund AM, Kuurila-Svahn K, Hartikka H, Cohn DH, Krakow D, Mottes M, Schwarze U, Chen D, Yang K, Kuslich C, Troendle J, Dalgleish R, Byers PH (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28(3):209–221. https://doi.org/10.1002/humu.20429 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Rudland VL, Hinchcliffe M, Pinner J, Cole S, Mercorella B, Molyneaux L, Constantino M, Yue DK, Ross GP, Wong J (2016) Identifying glucokinase monogenic diabetes in a multiethnic gestational diabetes mellitus cohort: new pregnancy screening criteria and utility of HbA1c. Diabetes Care 39(1):50–52. https://doi.org/10.2337/dc15-1001 CrossRefPubMedGoogle Scholar
- 35.Foster BL, Ramnitz MS, Gafni RI, Burke AB, Boyce AM, Lee JS, Wright JT, Akintoye SO, Somerman MJ, Collins MT (2014) Rare bone diseases and their dental, oral, and craniofacial manifestations. J Dent Res 93(7 Suppl):7S–19S. https://doi.org/10.1177/0022034514529150 CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Moon RJ, Crozier SR, Dennison EM, Davies JH, Robinson SM, Inskip HM, Godfrey KM, Cooper C, Harvey NC (2015) Tracking of 25-hydroxyvitamin D status during pregnancy: the importance of vitamin D supplementation. Am J Clin Nutr 102(5):1081–1087. https://doi.org/10.3945/ajcn.115.115295 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Cozzolino M, Perelli F, Maggio L, Coccia ME, Quaranta M, Gizzo S, Mecacci F (2016) Management of osteogenesis imperfecta type I in pregnancy; a review of literature applied to clinical practice. Arch Gynecol Obstet 293(6):1153–1159. https://doi.org/10.1007/s00404-016-4012-2 CrossRefPubMedGoogle Scholar