Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

Michael P. Whyte, Cristina Tau, William H. McAlister, Xiafang Zhang, Deborah V. Novack, Virginia Preliasco, Eduardo Santini-Araujo, Steven Mumm

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Mendelian disorders of RANKL/OPG/RANK signaling feature the extremes of aberrant osteoclastogenesis and cause either osteopetrosis or rapid turnover skeletal disease. The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget's disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK. Juvenile Paget's disease (JPD), an autosomal recessive disorder, manifests extremely fast skeletal remodeling, and is usually caused by loss-of-function mutations within TNFRSF11B that encodes OPG. These disorders are ultra-rare. A 13-year-old Bolivian girl was referred at age 3. years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2. years involved missing ossicles and eroded cochleas. Teeth often had absorbed roots, broke, and were lost. Radiographs had revealed acquired tubular bone widening, cortical thickening, and coarse trabeculation. Biochemical markers indicated rapid skeletal turnover. Histopathology showed accelerated remodeling with abundant osteoclasts. JPD was diagnosed. Immobilization from a femur fracture caused severe hypercalcemia that responded rapidly to pamidronate treatment followed by bone turnover marker and radiographic improvement. No TNFRSF11B mutation was found. Instead, a unique heterozygous 15-bp insertional tandem duplication (87dup15) within exon 1 of TNFRSF11A predicted the same pentapeptide extension of RANK that causes expansile skeletal hyperphosphatasia (84dup15). Single nucleotide polymorphisms in TNFRSF11A and TNFRSF11B possibly impacted her phenotype. Our findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the Mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

Original languageEnglish
Pages (from-to)153-161
Number of pages9
JournalBone
Volume68
DOIs
StatePublished - Nov 1 2014

Keywords

  • Bone remodeling
  • Deafness
  • Osteolysis
  • Osteoprotegerin
  • Tooth loss
  • Vascular calcification

Fingerprint

Dive into the research topics of 'Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK'. Together they form a unique fingerprint.

Cite this