Juvenile Paget's disease: the second reported, oldest patient is homozygous for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT), which elevates circulating immunoreactive osteoprotegerin levels.
The oldest person (60 yr) with juvenile Paget's disease is homozygous for the TNFRSF11B mutation 966_969delTGACinsCTT. Elevated circulating levels of immunoreactive OPG and soluble RANKL accompany this genetic defect that truncates the OPG monomer, preventing formation of OPG homodimers.


BACKGROUND
Juvenile Paget's disease (JPD), a rare autosomal recessive disorder, features skeletal pain, fracture, and deformity from extremely rapid bone turnover. Deafness and sometimes retinopathy also occur. Most patients have diminished osteoprotegerin (OPG) inhibition of osteoclastogenesis caused by homozygous loss-of-function defects in TNFRSF11B, the gene that encodes OPG. Circulating immunoreactive OPG (iOPG) is undetectable with complete deletion of TNFRSF11B but normal with a 3-bp in-frame deletion.


METHODS
We summarize the clinical course of a 60-yr-old Greek man who is the second reported, oldest JPD patient, including his response to two decades of bisphosphonate therapy. Mutation analysis involved sequencing all exons and adjacent mRNA splice sites of TNFRSF11B. Over the past 4 yr, we used ELISAs to quantitate his serum iOPG and soluble RANKL (sRANKL) levels.


RESULTS
Our patient suffered progressive deafness and became legally blind, although elevated markers of bone turnover have been normal for 6 yr. He carries the same homozygous mutation in TNFRSF11B (966_969delTGACinsCTT) reported in a seemingly unrelated Greek boy and Croatian man who also have relatively mild JPD. This frame-shift deletes 79 carboxyterminal amino acids from the OPG monomer, including a cysteine residue necessary for homodimerization. Nevertheless, serum iOPG and sRANKL levels are persistently elevated.


CONCLUSIONS
Homozygosity for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT) causes JPD in the second reported, oldest patient. Elevated circulating iOPG and sRANKL levels complement evidence that this deletion/insertion omits a cysteine residue at the carboxyterminus needed for OPG homodimerization.
Whyte
Michael P
MP
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St Louis, Missouri 63131, USA. mwhyte@shrinenet.org
Singhellakis
Panagiotis N
PN
Petersen
Michael B
MB
Davies
Michael
M
Totty
William G
WG
Mumm
Steven
S
D000469:Alkaline Phosphatase / Q000097:blood; D002116:Calcitonin / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004164:Diphosphonates / Q000627:therapeutic use; D016368:Frameshift Mutation; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D053244:Osteoprotegerin / Q000097:blood* / Q000235:genetics*; D053245:RANK Ligand / Q000097:blood
D004164:Diphosphonates; D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D002116:Calcitonin; D000469:Alkaline Phosphatase