Pregnancy‐Associated Osteoporosis With a Heterozygous Deactivating LDL Receptor‐Related Protein 5 (LRP5) Mutation and a Homozygous Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism. (April 2014)

• Record Type: Journal Article
• Authors: Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah
• Is Part Of: Journal of bone and mineral research. Volume 29:Number 4(2014:Apr.)
• Page Start: 922
• Page End: 928
• Publication Date: 2014-04
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2095
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2095-sec-0001" sec-type="section"> <p>Pregnancy‐associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26‐year‐old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (<italic>MTHFR</italic>) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss‐of‐function mutation(s) in the gene that encodes LDL receptor‐related protein 5 (LRP5), <italic>LRP5</italic> exon and splice site sequencing was also performed. This revealed a unique heterozygous 12‐bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous <italic>LRP5</italic> mutation together with her homozygous <italic>MTHFR</italic> polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the <italic>LRP5</italic> mutation, the homozygous <italic>MTHFR</italic> polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this enigmatic disorder and identify some at‐risk women. © 2013 American Society for Bone and Mineral Research.</p> </sec> </abstract>