SAT-384 Identification of Heterozygous LRP5 Mutation and a TGFβ-1 Variant of Unknown Significance in a Patient with Hearing Loss, High Bone Mass, and Oropharyngeal Exostoses

Abstract

Background: Manifestations of the high bone mass (HBM) disorders not only include strong bones, but also excessive bones causing cranial nerve palsies and oropharyngeal exostoses. Due to overlap of clinical phenotype in dense bone diseases, one or more distinct genes may be involved. Up-regulation in bone formation can result from gain of function mutation of the low-density lipoprotein receptor-related protein 5 (LRP5), which mediates activation of the canonical Wnt pathway via co-binding with the frizzled protein, but may also be a consequence of activating mutations in the transforming growth factor β1 (TGFβ-1) gene that associate with stimulated osteogenesis. Clinical Case: Here we report a 41 year-old woman referred for incidentally found dense bones on screening dual-energy X-ray absorptiometry (DXA) that led to subsequent revelation of several family members sharing similar histories including inability to float in water, strong bones on skeletal surgery, and presence of palatal exostoses. Her childhood history included mandibular pain developing at age 15 years due to bony overgrowth of her lower jaw requiring multiple drilling for removal. At age 33, she manifested trigeminal neuralgia initially responsive to medical management but eventually needed microvascular decompression for unremitting pain. Preoperative brain magnetic resonance imaging (MRI) noted significant hyperostosis of the skull as well as mild narrowing of internal auditory canals, for which auditory testing showing mild mixed hearing loss in her right ear. Skeletal survey revealed diffuse thickening of axial and appendicular skeleton with characteristic endosteal hyperostosis. DXA demonstrated Z scores of +8.3 and +5.3 in the lumbar spine and total hip, respectively. Torus palatinus was also identified on exam. Mutational analysis disclosed a heterozygous LRP5 missense mutation, c.844A>G, p.Met282Val, together with a variant of unknown significance in TGFβ-1 (c.887G>A, p.Arg296Gln) possibly linked to Camurati-Engelmann disease (progressive diaphyseal dysplasia). As transmission in both conditions follows an autosomal dominant pattern, multigenerational family history was elicited from patient that her mother, who underwent knee replacement in her 80’s, was described by the surgeon as “having bones of a 30-year old man,” and that her deceased maternal grandmother possibly had “thickened” bones. Half of patient’s 18 siblings reportedly also carry features suggestive of high bone mass phenotype. Genetic testing of family members is planned. Conclusion: While HBM disorders protect against fractures, it is important to recognize that these relatively benign conditions may present with neurological and oropharyngeal complications prompting the need for their surveillance and surgical precautions during orthopedic procedures.