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Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation |
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| Authors: | Antonia Howaldt Anna Floriane Hennig Tim Rolvien Uta Rössler Nina Stelzer Alexej Knaus Sebastian Böttger Jozef Zustin Sven Geißler Ralf Oheim Michael Amling Hans-Peter Howaldt Uwe Kornak |
| Affiliation: | 1. Institut für Medizinische Genetik und Humangenetik, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany BIH Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;2. Institut für Medizinische Genetik und Humangenetik, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany BIH Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany Freie Universität Berlin, Berlin, Germany;3. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;4. Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany;5. Department for Maxillo Facial Surgery, Justus Liebig University Gießen, Gießen, Germany;6. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;7. BIH Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;8. Institut für Medizinische Genetik und Humangenetik, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany |
| Abstract: | Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. |
| Keywords: | LRRK1 NEXT GENERATION SEQUENCING OSTEOPETROSIS OSTEOSCLEROTIC METAPHYSEAL DYSPLASIA TRIO-BASED EXOME SEQUENCING |