High Turnover Bone Disease Due to a Novel 27-Base Pair Tandem Duplication in TNFRSF11A leading to Constitutively Active RANK

Presentation Number: OR08-5
Date of Presentation: April 1st, 2017

Sean J. Iwamoto*1, Micol S. Rothman1, Shenghui Duan2, Steven Mumm2, Kelsey Burr1 and Michael P. Whyte3
1University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 2Washington University School of Medicine at Barnes-Jewish Hospital, Saint Louis, MO, 3Shriners Hospital for Children, Saint Louis, MO

Abstract

Background: With better access to mutation analysis, diagnosis of rare genetic diseases has improved. Examples include the monogenic disorders of receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and osteoprotegerin. Specifically, heterozygous 12-, 15-, 18-, and 27-base pair insertional duplications are known within exon 1 of TNFRSF11A, the gene that encodes the signal peptide of RANK. These autosomal dominant mutations cause remarkably different skeletal diseases called panostotic expansile bone disease, expansile skeletal hyperphosphatasia (ESH), familial expansile osteolysis (FEO), and early-onset Paget’s disease of bone (PDB2), respectively (1-3). Mechanistically, they constitutively increase RANK activity and promote high-turnover bone disease via osteoclast formation and activation.

Clinical Case: A 48-year-old Mexican man with HIV was evaluated for severely low BMD and multiple atraumatic fractures starting in adulthood, including bilateral femur fractures. His viral load was suppressed on HAART. Transient hypercalcemia had followed hip surgery. He lost teeth at age 28. He had difficultly hearing the TV but never had formal audiometry. He did not report familial bone disease, but his father had short stature and multiple fractures. Physical exam noted a height of 5’2”, edentulous mouth, subjective right > left decreased hearing, white sclerae, thoracic kyphosis, enlarged fingers, and anteriorly bowed tibias. Serum alkaline phosphatase (ALP) was 330 U/L (n: 39-117 U/L) and bone-specific ALP was 87.6 ug/L (n: 6.5-20.1 ug/L), whereas PTH, Ca, Vit D and phosphorus were normal. Bone turnover markers were strikingly elevated: serum CTX 2477 pg/mL (n: 60-700 pg/mL) and osteocalcin 281 ng/mL (n: 11-50 ng/mL). DXA spine BMD was 0.488 g/cm2 with Z-score -5.5. Skeletal survey showed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. We identified a unique, heterozygous 27-base pair duplication (77dup27) in exon 1 of TNFRSF11A. Alendronate 70 mg/week modestly decreased bone turnover markers in 6 weeks. Family investigation is planned.

Conclusion: Our patient’s high-turnover bone disease involves a novel 27-base pair duplication in TNFRSF11A, the gene encoding the signal peptide of RANK. Similar duplications have been identified in Japanese (75dup27) and Chinese (78dup27) PBD2 cohorts, although they seem to predict the same 9-amino acid duplication (4). Our patient shares features of their PDB2 with presentation in his late 20s, painless enlarged fingers, transient hypercalcemia, and absence of childhood tooth or hearing loss. Bisphosphonate therapy improves bone turnover markers in PBD2 patients. Our experience supports mutation analysis in the diagnosis and management of high-turnover bone diseases, including those involving constitutively active RANK.

 

Nothing to Disclose: SJI, MSR, SD, SM, KB, MPW