Fragile bones and macrocranium

Bakwin, Harry; Eiger, Marvin S.

doi:10.1016/s0022-3476(56)80143-1

Cited by 59 publications

(26 citation statements)

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“…At 2.5 years-of-age, her findings were again typical for JPD (3–11) and included widened osteopenic long bones with coarse trabeculae and indistinct corticomedullary junctions (Figure 5). The diploic space of the skull was wide with coarse vertical trabeculae giving a “hair-on-end” appearance, and the outer table of the skull was thin and indistinct.…”

Section: Iv) Resultsmentioning

confidence: 98%

Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Saki

Karamizadeh

Nasirabadi

et al. 2013

Journal of Bone and Mineral Research

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Juvenile Paget’s disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene that encodes OPG. We report a 3-year-old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year-of-life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year-of-age, biochemical studies of serum revealed marked hyperphosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds receptor activator of NF-κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient’s serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective treatment for the skeletal disease caused by the OPG deficiency form of JPD.

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Section: Iv) Resultsmentioning

confidence: 98%

Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Saki

Karamizadeh

Nasirabadi

et al. 2013

Journal of Bone and Mineral Research

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“…In 1958, Choremis et al (1) reported an 11‐yr‐old Greek boy born in 1946 who seemed to be the first individual in the pediatric age group with Paget's disease of bone (PDB) (2) . In fact, 2 yr earlier in 1956, a report from Bakwin and Eiger (3) from Bellevue Hospital in New York City of a 7‐yr‐old Puerto Rican girl with fragile bones, skeletal deformities, and macrocranium represented the initial description of this distinctive condition labeled “juvenile Paget's disease” (JPD) by Doyle et al in 1974 (4) …”

Section: Introductionmentioning

confidence: 99%

Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the TNFRSF11B “Balkan” Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels

Whyte

Singhellakis

Petersen

et al. 2007

Journal of Bone and Mineral Research

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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.Introduction: 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. Materials and 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.

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“…It is by no means certain that all reports have described exactly the same disease. The patient recorded under the title "Fragile Bones and Macrocranium" had normal levels of serum alkaline phosphatase in intervals between fractures (Bakwin and Eiger, 1956). The necropsy study (Mitsudo, 1971) on the Yugoslavian patient described by Caffey (1967) revealed evidence of pseudoxanthoma elasticum as well as a mosaic pattern in the bones consistent with Paget's disease.…”

Section: Discussionmentioning

confidence: 96%

“…A bewildering variety of names has been used, including the latest proposal of "Familial Chronic Hyperphosphatasemia, with Ateliosis and Hypermetabolism of Growing Membranous Bone" (Caffey, 1973b;Bakwin and Eiger, 1956;Bakwin, Golden and Fox, 1964;Stemmermann, 1966;Fanconi et ah, 1964;Marshall, 1962;Eyring and Eisenberg, 1968;Thompson et ah, 1969;Mitsudo, 1971). It is by no means certain that all reports have described exactly the same disease.…”

Section: Discussionmentioning

confidence: 99%

Healing of the bones in juvenile Paget's disease treated by human calcitonin

Doyle¹,

Woodhouse²,

Glen³

et al. 1974

BJR

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A 6-year-old boy with juvenile Paget's disease and recurrent fractures has been treated by daily intramuscular injections of 1 mg of synthetic human calcitonin for 16 months. Regression of the bony abnormalities was apparent within seven months of the start of treatment. Levels of serum alkaline phosphatase and urine hydroxyproline fell during the first four months, but have remained high ever since. We suggest that these continuing high levels reflect in part the healing of the diseased bones.

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Fragile bones and macrocranium

Cited by 59 publications

References 0 publications

Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the TNFRSF11B “Balkan” Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels

Healing of the bones in juvenile Paget's disease treated by human calcitonin

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