Oropharyngeal skeletal disease accompanying high bone mass and novel LRP5 mutation.
Gain-of-function mutation in the gene encoding LRP5 causes high bone mass. A 59-year-old woman carrying a novel LRP5 missense mutation, Arg154Met, manifested skeletal disease affecting her oropharynx as well as dense bones, showing that exuberant LRP5 effects are not always benign.


BACKGROUND
Gain-of-function mutation (Gly171Val) of LDL receptor-related protein 5 (LRP5) was discovered in 2002 in two American kindreds with high bone mass and benign phenotypes. In 2003, however, skeletal disease was reported for individuals from the Americas and Europe carrying any of six novel LRP5 missense mutations affecting the same LRP5 protein domain. Furthermore, in 2004, we described a patient with neurologic complications from dense bones and extensive oropharyngeal exostoses caused by the Gly171Val defect.


METHODS
A 59-year-old woman was referred for dense bones. Three years before, mandibular buccal and lingual exostoses (osseous "tori") were removed because of infections from food trapping between the teeth and exostoses. Maxillary buccal and palatal exostoses were asymptomatic. Radiographic skeletal survey showed marked thickening of the skull base and diaphyses of long bones (endosteal hyperostosis). BMD Z scores assessed by DXA were +8.5 and +8.7 in the total hip and L(1)-L(4) spine (both approximately 195% average control), respectively. LRP5 mutation analysis was carried out for the LRP5 domain known to cause high bone mass.


RESULTS
Biochemical evaluation excluded most secondary causes of dense bones, and male-to-male transmission in her family indicated autosomal dominant inheritance. PCR amplification and sequencing of LRP5 exons 2-4 and adjacent splice sites revealed heterozygosity for a new LRP5 missense mutation, Arg154Met.


CONCLUSIONS
LRP5 Arg154Met is a novel defect that changes the same first "beta-propeller" module as the eight previously reported LRP5 gain-of-function missense mutations. Arg154Met alters a region important for LRP5 antagonism by dickkopf (Dkk). Therefore, our patient's extensive oropharyngeal exostoses and endosteal hyperostosis likely reflect increased Wnt signaling and show that exuberant LRP5 effects are not always benign.
Rickels
Michael R
MR
Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Zhang
Xiafang
X
Mumm
Steven
S
Whyte
Michael P
MP
D000483:Alleles; D001483:Base Sequence; D015519:Bone Density / Q000235:genetics; D001847:Bone Diseases / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging / Q000473:pathology*; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010012:Osteogenesis / Q000502:physiology; D010159:Palate / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D015398:Signal Transduction; D012886:Skull / Q000000981:diagnostic imaging; D013577:Syndrome; D051153:Wnt Proteins
D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051153:Wnt Proteins