title: An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation.
abstract: Gain-of-function mutations in LRP5 have been shown to cause high BMD disorders showing variable expression of some clinical symptoms, including torus palatinus and neurological complications. In an extended family, we were able to add craniosynostosis and developmental delay to the clinical spectrum associated with LRP5 mutations. We report on an extended four-generation family with 13 affected individuals (7 men and 6 women) in which an autosomal dominant type of osteosclerosis segregates. Osteosclerosis was most pronounced in the cranial base and calvarium, starting in early childhood with variable expression and a progressive character. Craniosynostosis at an early age was reported in four affected family members (two males and two females). The patients also presented with dysmorphic features (macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones, prominent jaw). They have normal height and proportions. Neurological complications like entrapment of cranial nerves resulting in optical nerve atrophy, hearing loss, and facial palsy were reported in two individuals. A mild developmental delay was reported in three affected individuals. None of the patients have torus palatinus, increased rate of fractures, osteomyelitis, hepatosplenomegaly, or pancytopenia. A missense mutation 640G-->A (A214T) in the low-density lipoprotein receptor-related protein 5 (LRP5) gene was found in all affected individuals analyzed, including cases in whom craniosynostosis, a mild developmental delay, and/or macrocephaly is observed. To our knowledge, this is the first report in the literature of patients presenting with autosomal dominant osteosclerosis in whom a variable expression of craniosynostosis, macrocephaly, and mild developmental delay is observed, which is most likely associated with a mutation in the LRP5 gene. These phenotypes can therefore be added to the clinical spectrum of LRP5-associated bone disorders.
authors.affiliation: Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands. ml.kwee@vumc.nl
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Kwee
authors.forename: Wendy
authors.initials: W
authors.lastname: Balemans
authors.forename: Erna
authors.initials: E
authors.lastname: Cleiren
authors.forename: Johan J P
authors.initials: JJ
authors.lastname: Gille
authors.forename: Frits
authors.initials: F
authors.lastname: Van Der Blij
authors.forename: Jan M
authors.initials: JM
authors.lastname: Sepers
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D000328:Adult; D003398:Craniosynostoses / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010026:Osteosclerosis / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011859:Radiography; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D012886:Skull / Q000000981:diagnostic imaging / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D051879:Twist-Related Protein 1
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D009687:Nuclear Proteins; D017468:Receptors, Fibroblast Growth Factor; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3