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

Bone. 2014 Nov:68:153-61. doi: 10.1016/j.bone.2014.07.019. Epub 2014 Jul 23.


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 3years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2years 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.

Keywords: Bone remodeling; Deafness; Osteolysis; Osteoprotegerin; Tooth loss; Vascular calcification.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Dentition
  • Diphosphonates / pharmacology
  • Diphosphonates / therapeutic use
  • Female
  • Femur / diagnostic imaging
  • Femur / drug effects
  • Femur / pathology
  • Gene Duplication*
  • Heterozygote
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • Osteitis Deformans / diagnostic imaging
  • Osteitis Deformans / drug therapy
  • Osteitis Deformans / genetics*
  • Osteitis Deformans / pathology
  • Pamidronate
  • Receptor Activator of Nuclear Factor-kappa B / chemistry
  • Receptor Activator of Nuclear Factor-kappa B / genetics*
  • Tomography, X-Ray Computed


  • Diphosphonates
  • Receptor Activator of Nuclear Factor-kappa B
  • Pamidronate

Supplementary concepts

  • Hyperostosis corticalis deformans juvenilis