Wnt/β-catenin signaling is important for skeletal development and health. Eleven heterozygous gain-of-function missense mutations within the first β-propeller of low-density lipoprotein receptor-related protein 5 (LRP5) are known to cause the autosomal dominant disorder called high bone mass (HBM). In 2019, different heterozygous LRP6 missense mutations were identified in two American families with the HBM phenotype but including absent lateral maxillary and mandibular incisors. We report a 19-year-old Argentinian man referred for "osteopetrosis" and nine years of generalized, medium-intensity bone pain and arthralgias of both knees. His jaw and nasal bridge were broad and several teeth were missing. Routine biochemical testing, including of mineral homeostasis, was normal. Urinary deoxypyridinoline and serum CTX were slightly increased. Radiographic skeletal survey showed diffusely increased radiodensity. DXA revealed substantially elevated BMD Z-scores. Digital orthopantomography confirmed agenesis of his maxillary and mandibular lateral incisors and his second left superior premolar. Cranial magnetic resonance imaging showed diffuse thickening of the calvarium and skull base, dilation of the sheath of the optic nerves containing increased fluid and associated with subtle stenosis of the optic canal, and narrow internal auditory canals. Mutation analyses identified a heterozygous indel mutation in exon 4 of LRP6 involving a single nucleotide change and 6-nucleotide deletion (c.678T>Adel679-684, p.His226Gln-del227-228ProPhe) leading to a missense change and 2-amino acid deletion that would compromise the first β-propeller of LRP6. Experience to date indicates LRP6 HBM is indistinguishable from LRP5 HBM without mutation analysis, although in LRP6 HBM absence of adult lateral incisors may prove to be a unique feature.
Keywords: Albers-Schönberg disease; Bone modeling; Creatine kinase; DXA; Endosteum; Exostosis; Hyperostosis; LRP5; LRP6; Lactate dehydrogenase; Mutation; Osteopetrosis; Osteosclerosis; Sclerostin; Skeletal dysplasia; Torus palatinus; Wnt signaling; β-catenin.
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