Juvenile Paget's disease

Synonyms: chronic congenital idiopathic hyperphosphatasemia, familial idiopathic hyperphosphatasia, familial osteoectasia, hereditary hyperphosphatasia, hyperostosis corticalis deformans juvenilis

Juvenile Paget’s disease is a rare, autosomal recessive disorder which was originally described in the 1950’s. The disease is characterised by markedly increased bone turnover; skeletal deformities reminiscent of classical Paget’s disease of bone, bone expansion, bone pain, and an increased risk of pathological fractures.¹

Juvenile Paget's disease is most commonly caused by recessive loss-of-function mutations in the TNFRSF11B locus on chromosome 8q24, which encodes osteoprotegerin, although a similar phenotype has been reported in a patient with a mutation of TNFRSF11A.¹ Osteoprotegerin inhibits osteoclast differentiation and bone resorption.²

Juvenile Paget's disease epidemiology

This is an extremely rare condition.

Juvenile Paget's disease symptoms (presentation)¹

The presentation is during infancy or childhood with skeletal deformity, growth retardation and failure to thrive.

• Other clinical features include enlargement of the skull, immobility or difficulty in walking, progressive sensorineural deafness, kyphosis and acetabular protrusion.

• The phenotype is variable, depending on the type of mutation. In all except the very mildest, bone deformity increases during adolescence and this is often accompanied by loss of mobility.

• Fractures occur more commonly in patients with a mild or intermediate phenotype, presumably because they are more mobile.

• Extra-skeletal manifestations may become prominent later in life.

• Most develop a retinopathy by the second decade. This is detectable on fundoscopy by the appearance of angioid streaks, pallor of the optic disc, peripapillary atrophy and evidence of choroidal neovascularization.

• Vascular calcification is another recognised feature which becomes more penetrant with increasing age. Aneurysms of the internal carotid artery have also been reported.

• Other features which have been reported include contractures, which seem most likely to be secondary to deformity, sinus aplasia, hormone deficiencies and hypertension.

• Difficulties with intubation have been reported due to calcification of tracheal cartilage. Auricular calcification may also occur.

• Premature shedding of the teeth has also been reported.³

Associated diseases

• Retinal degeneration (± angioid streaks).

• Recurrent renal colic from calcium-containing stones.

• Internal carotid aneurysms (one case report).⁴

Investigations¹

Concentrations of serum alkaline phosphatase, and other markers of bone turnover are greatly elevated in JPD, reflecting the generalised increase in the rate of bone remodelling. The bones are enlarged with radiological features reminiscent of Paget’s disease of bone.

Differential diagnosis

• Rickets.

• Osteomalacia.

• Other genetic bone disorders, eg, familial expansile osteolysis.

Juvenile Paget's disease treatment and management¹

Medical management has mainly focused on the use of the osteoclast inhibitors calcitonin and bisphosphonates but replacement therapy with osteoprotegerin has also be investigated.

Calcitonin can reduce serum alkaline phosphatase concentrations and improve bone pain. However, calcitonin does not restore normal levels of bone turnover and there is a rapid relapse when treatment is stopped.

Because of this, and the availability of bisphosphonates, calcitonin has now been superseded. Various bisphosphonates have been used, including etidronate, alendronate, pamidronate, ibandronate, risedronate and zoledronic acid. All have been shown to reduce biochemical markers of bone turnover to varying extent and to improve bone pain.

It is thought that high dose bisphosphonates might help to prevent progression of bone deformity, but there isn’t any firm evidence to show that this strategy is effective in altering the natural history of juvenile Paget's disease.

In recent years, denosumab have been used and found to suppress markers of bone turnover, but severe hypocalcaemia has been reported as an adverse effect.

Complications¹

• Bone pain.

• Pathological fractures.

• Kyphoscoliosis.

• Acetabular protrusion.

• Sensorineural deafness.

• Osteoporosis.

• Delayed motor development.⁵

Prognosis⁶

Severity of the disease increases as the child progresses towards adolescence. Morbidity is very severe and majority of children become wheelchair bound by 15 years if untreated.

However the severity of disease is variable, with variable morbidity and mortality. Some patients will survive beyond the age of 50 years.

Due to the rarity of the disease, few long-term follow-up data on the clinical course are available.⁷