Alternative titles; symbols
SNOMEDCT: 9723006; ORPHA: 2801; DO: 0081368;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.12 | Paget disease of bone 5, juvenile-onset | 239000 | Autosomal recessive | 3 | TNFRSF11B | 602643 |
A number sign (#) is used with this entry because of evidence that Paget disease of bone-5 (PDB5), also known as juvenile Paget disease, results from osteoprotegerin deficiency caused by homozygous or compound heterozygous mutation in the TNFRSF11B gene (602643) on chromosome 8q24.
Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014).
For discussion of genetic heterogeneity of Paget disease of bone, see 167250.
Bakwin and Eiger (1956) and Bakwin et al. (1964) described a familial disorder manifesting itself from early in life by large head and expanded and bowed extremities. Alkaline phosphatase was elevated. The long bones are greatly expanded with osteoporosis and coarse trabeculations. The calvaria is markedly thickened with islands of increased bone density. Muscular weakness may be striking. In Bakwin's family, 2 sisters, of Puerto Rican parentage, were severely affected. Both had retinal degeneration. In one, the changes included angioid streaks. The parents were first cousins and the mother was mildly affected. The findings in her would probably have escaped detection if x-rays had not been made. The authors thought this to be the same as the condition described in 2 sisters by Swoboda (1958) as hyperostosis corticalis deformans juvenilis and by Choremis et al. (1958) as Paget disease in an 11-year-old boy. Caffey (1961) and Rubin (1964) presented cases.
Fanconi et al. (1964) described the x-ray and histologic changes in a young Brazilian male and suggested the designation osteochalasia desmalis familiaris. The condition called familial osteoectasia by Stemmermann (1966) appears to be the same. His cases were in brother and sister, aged 2 and 3, of Puerto Rican ancestry.
Brother and sister of mixed Hawaiian, Filipino, and Puerto Rican ancestry were described by Eyring and Eisenberg (1968). Fragile bones, premature loss of teeth, and dwarfism were features. Increased bone formation and destruction were thought to be present. Both acid and alkaline phosphatases and leucine aminopeptidase were elevated. Increased hydroxyproline in blood and urine and hyperuricemia were also demonstrated. Thompson et al. (1969) and Smith (1976) reported further on the brother and sister described by Eyring and Eisenberg (1968). Singer et al. (1994) provided a 20-year follow-up of the same family. Of 8 sibs, 3 were affected. One brother, at the age of 36, had roentgenographic signs only. The second affected brother suffered from recurrent renal colic from calcium-containing stones. The affected sister had died at the age of 30 from pneumonia and respiratory failure.
Caffey (1973) reviewed the findings in 14 patients distributed in 10 families.
Golob et al. (1996) investigated extensively a mentally retarded 21-year-old woman with unusually mild juvenile Paget disease. Progressive bowing deformity of her lower limbs began at age 1.5 years. Nontraumatic fractures of both femurs and both tibias occurred between ages 9 and 14 years. During adulthood, cortical thickening, osteosclerosis, and bowing affected these bones. Serum alkaline phosphatase activity was persistently elevated. They found that her serum osteocalcin (112260) and urinary hydroxyproline and pyridinoline:deoxypyridinoline activities were also increased. The skeletal histopathology was considered to be quite different from that of classic Paget bone disease. Electron microscopy revealed no cytoplasmic or nuclear inclusions. Whyte et al. (1996) found that the patient's circulating monocytes were free of viral transcripts that have been associated with classic Paget bone disease.
Naot et al. (2014) reported 2 unrelated patients with PDB5. A 3.5-year-old boy, born of consanguineous Turkish parents, had a severe phenotype, with delayed development, short stature, brachycephaly, bowing of the limbs, and severe sensorineural hearing loss with inability to speak. Laboratory studies showed increased alkaline phosphatase. Pamidronate treatment resulted in decreased pain. The second patient was less severely affected. He presented with frequent fractures in infancy and delayed motor development. At age 19, he needed a wheelchair to walk long distances, had barrel chest, long bone deformities, kyphosis, short stature, and hearing loss. Radiographs showed skull expansion of the diploic space with mottled mineralization, ankylosis of the vertebral bodies and sacroiliac joints, shortening of the humeri with thickened cortices, and areas of sclerosis and demineralization in the temporal bones. He also had angioid streaks and macular scarring in the retina. Laboratory studies showed increased alkaline phosphatase and low vitamin D.
Singer et al. (1994) reported benefit from disodium etidronate in the treatment of this disorder.
Spindler et al. (1992) described the case of a 38-year-old woman with 24 years of progressive skeletal deformity resulting from this disorder. Treatment with a bisphosphonate caused a drop in serum alkaline phosphatase with relief of bone pain and return of skin temperature to normal.
Cundy et al. (2005) reported the use of recombinant osteoprotegerin in the treatment of juvenile Paget disease in a 31-year-old woman and her 24-year-old brother, originally described by Cundy et al. (2002). In both patients, bone deformity began to develop at around 5 years of age, and by the age of 15 years both were wheelchair-bound. Both had severe kyphosis as a result of widespread vertebral deformity as well as severe acetabular protrusion, short stature, macrocephaly, and deafness. Bone resorption (assessed by N-telopeptide excretion) was suppressed by once-weekly subcutaneous doses of 0.3 to 0.4 mg per kilogram of body weight. After 15 months of treatment, radial bone mass increased in one patient by 9% and in the other by 30%, skeletal bisphosphonate retention decreased by 37% and 55%, respectively, and there was radiographic improvement. Apart from mild hypocalcemia and hypophosphatemia, no apparent adverse effects occurred.
The transmission pattern of PDB5 in the families reported by Naot et al. (2014) was consistent with autosomal recessive inheritance.
In 2 patients with juvenile Paget disease, Whyte et al. (2002) identified a causative homozygous deletion in the TNFRSF11B gene (602643.0001).
In a consanguineous family of Iraqi origin, Cundy et al. (2002) found that all 3 sibs affected with idiopathic hyperphosphatasia were homozygous for a 3-bp in-frame deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue (602643.0002). Recombinant wildtype and mutant osteoprotegerin (OPG) cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wildtype OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation.
Chong et al. (2003) studied 8 patients with juvenile Paget disease and identified homozygosity for mutations in the TNFRSF11B gene in 5 of them. Missense mutations in the cysteine residues (see, e.g., 602643.0003), predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype in which deformity developed before 18 months of age and caused major disability. Noncysteine missense mutations in the ligand-binding domain (see, e.g., 602643.0004) were associated with an intermediate phenotype, with deformity recognized around the age of 5 years and an increased rate of long bone fracture. An insertion/deletion mutation in exon 5 (602643.0005) was associated with the mildest phenotype. Chong et al. (2003) concluded that mutations in TNFRSF11B account for the majority of, but not all, cases of juvenile Paget disease, and that there are distinct genotype-phenotype relationships.
In 2 unrelated patients with PDB5, Naot et al. (2014) identified 2 different homozygous mutations in the TNFRSF11B gene (602643.0006 and 602643.0007). One patient with a more severe phenotype had a large intragenic deletion resulting in a severely truncated protein predicted to be nonfunctional.
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Naot, D., Choi, A., Musson, D. S., Simsek Kiper, P. O., Utine, G. E., Boduroglu, K., Peacock, M., DiMeglio, L. A., Cundy, T. Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease. Bone 68: 6-10, 2014. [PubMed: 25108083] [Full Text: https://doi.org/10.1016/j.bone.2014.07.034]
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