Juvenile Paget disease

Alternate names

JPD; Hyperostosis corticalis deformans juvenilis; Hyperphosphatasia, familial idiopathic; Hyperphosphatasemia, chronic congenital idiopathic; Paget disease juvenile type; Paget disease of bone 5, juvenile-onset; Hereditary hyperphosphatasia; Hyperostosid corticalis deformans juvenilis; JPG; Juvenile Pagets disease

Definition

Juvenile Paget disease is a very rare condition that affects bone growth. This condition causes bones to be abnormally large, misshapen, and easily broken (fractured).

Epidemiology

Juvenile Paget disease is rare; about 50 affected individuals have been identified worldwide.

Cause

• Juvenile Paget disease is caused by mutations in the TNFRSF11B gene.
• This gene provides instructions for making a protein that is involved in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it.
• Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.

Gene mutations

• Mutations in the TNFRSF11B gene lead to a much faster rate of bone remodeling starting early in life.
• Bone tissue is broken down more quickly than usual, and when new bone tissue grows it is larger, weaker, and less organized than normal bone.
• This abnormally fast bone remodeling underlies the problems with bone growth characteristic of juvenile Paget disease.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Onset

The signs of juvenile Paget disease appear in infancy or early childhood.

Signs and symptoms

• As bones grow, they become progressively weaker and more deformed.
• These abnormalities usually become more severe during the adolescent growth spurt, when bones grow very quickly.
• Juvenile Paget disease affects the entire skeleton, resulting in widespread bone and joint pain.
• The bones of the skull tend to grow unusually large and thick, which can lead to hearing loss.
• The disease also affects bones of the spine (vertebrae).
• The deformed vertebrae can collapse, leading to abnormal curvature of the spine.
• Additionally, weight-bearing long bones in the legs tend to bow and fracture easily, which can interfere with standing and walking.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormal clavicle morphology(Abnormal collarbone)
• Abnormality of the dentition(Abnormal dentition)
• Bowing of the long bones(Bowed long bones)
• Coarse metaphyseal trabecularization
• Cranial hyperostosis
• Hyperuricemia(High blood uric acid level)
• Macrocephaly(Increased size of skull)
• Osteoporosis
• Recurrent fractures(Increased fracture rate)
• Short stature(Decreased body height)

30%-79% of people have these symptoms

• Abnormality of retinal pigmentation
• Hearing impairment(Deafness)
• Hypertension
• Optic atrophy
• Pectus carinatum(Pigeon chest)

5%-29% of people have these symptoms

• Macular scar
• Melanocytic nevus(Beauty mark)
• Motor delay
• Retinopathy(Noninflammatory retina disease)
• Subcutaneous nodule(Firm lump under the skin)

Diagnosis

• The clinical manifestations are both skeletal - progressive skeletal deformity that develops in childhood - and extra-skeletal, including hearing loss, retinopathy, vascular calcification and internal carotid artery aneurysm formation.<ref>Polyzos SA, Cundy T, Mantzoros CS. Juvenile Paget disease. Metabolism. 2018 Mar;80:15-26. doi: 10.1016/j.metabol.2017.10.007. Epub 2017 Nov 22. PMID: 29080812.</ref>
• JPD is characterized biochemically by very high alkaline phosphatase activity, as well as other bone turnover markers.

Treatment

• Bisphosphonates are commonly used to reduce the greatly accelerated bone turnover and can ameliorate the skeletal phenotype, if started early enough in childhood and continued at least until growth is complete. <ref>Polyzos SA, Cundy T, Mantzoros CS. Juvenile Paget disease. Metabolism. 2018 Mar;80:15-26. doi: 10.1016/j.metabol.2017.10.007. Epub 2017 Nov 22. PMID: 29080812.</ref>
• Limited evidence from patients treated with recombinant OPG or denosumab also provided favorable results.
• Recombinant OPG would represent a replacement treatment, but it is unavailable for clinical use.
• It seems that life-long treatment with anti-resorptives is required, since the disease is reactivated after treatment discontinuation.

References

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NIH genetic and rare disease info

• NIH info on Juvenile Paget disease

Juvenile Paget disease is a rare disease.

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