Potential therapeutic response in a severe case of autosomal dominant osteopetrosis type I

Abstract

The low-density lipoprotein receptor-related protein 5 gene (LRP5), which encodes a coreceptor within the canonical Wnt signaling pathway, plays a crucial role in bone mass regulation and has been associated with several bone disorders. Autosomal dominant osteopetrosis type I (ADO type I, OMIM 607634) is a rare disease caused by heterozygous, gain-of-function mutations in LRP5. Here we describe a 44-year-old female who presented with thickened calvarium, elevated bone density, torus palatinus, mandibular exostoses, enlarged mandible, and disabling headaches and bone pain. Exome sequencing revealed a previously reported heterozygous missense variant in the LRP5 gene (p.A242T). Post-diagnosis cranial vault volume measurement by computed tomography 3D reconstruction demonstrated decreasing intracranial volume over time. Off-label use of leuprolide acetate was associated with apparent stabilization of skull mineralization. This report documents a severe example of ADO type I and provides anecdotal evidence of the utility of therapy in need of formal evaluation.

Keywords

Lipoprotein receptor-related protein 5 gene (LRP5) / osteopetrosis / high bone mass / whole-exome sequencing (WES) / leuprolide acetate

References

[1] Baron R.Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton.Endocrinology2007;148:2635-43

[2] Krishnan V,Macdougald OA.Regulation of bone mass by Wnt signaling.J Clin Invest2006;116:1202-9 PMCID:PMC1451219

[3] Gong Y,Fukai N.LDL Receptor-related protein 5 (LRP5) affects bone accrual and eye development.Cell2001;107:513-23

[4] Little RD,Del Mastro RG.A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am J Hum Genet2002;70:11-9 PMCID:PMC419982

[5] Boyden LM,Belsky J.High bone density due to a mutation in LDL-receptor-related protein 5.N Engl J Med2002;346:1513-21

[6] Bourhis E,Tam C.Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6.Structure2011;19:1433-42

[7] Whyte MP,Mumm S.High-bone-mass disease and LRP5.N Engl J Med2004;350:2096-9; author reply 2096

[8] Gregson CL,Hardcastle SA.Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases.J Bone Miner Res2016;31:640-9 PMCID:PMC4832273

[9] Gregson CL.The genetic architecture of high bone mass.Front Endocrinol (Lausanne)2020;11:595653 PMCID:PMC7658409

[10] Gahl WA,Toro C.The national institutes of health undiagnosed diseases program: insights into rare diseases.Genet Med2012;14:51-9 PMCID:PMC4098846

[11] Wang C,Zhang H.The A242T mutation in the low-density lipoprotein receptor-related protein 5 gene in one Chinese family with osteosclerosis.Intern Med2013;52:187-92

[12] Van Wesenbeeck L,Gram J.Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density.Am J Hum Genet2003;72:763-71 PMCID:PMC1180253

[13] Karczewski KJ,Tiao G.The mutational constraint spectrum quantified from variation in 141,456 humans.Nature434-43 PMCID:PMC7334197

[14] Khosla S,Monroe DG.Estrogen and the skeleton.Trends Endocrinol Metab2012;23:576-81 PMCID:PMC3424385

[15] Seifert-Klauss V.Progesterone and bone: actions promoting bone health in women.J Osteoporos2010;2010:845180 PMCID:PMC2968416

[16] Prior JC.Progesterone as a bone-trophic hormone.Endocr Rev1990;11:386-98

[17] Balemans W,Cleiren E.Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling.J Bone Miner Res2007;22:708-16

[18] Wilson AC,Bowen RL.Leuprolide acetate: a drug of diverse clinical applications.Expert Opin Investig Drugs2007;16:1851-63

[19] Milani M,Potter DA.Anastrozole use in early stage breast cancer of post-menopausal women.Clin Med Ther2009;1:141-56 PMCID:PMC2753667

[20] Gahl WA.The NIH undiagnosed diseases program: lessons learned.JAMA2011;305:1904-5