Familial hydiopatic hyperphosphatasia/ juvenile Paget’s disease of bone

(OMIM phenotype number #239000)

Familial hydiopatic hyperphosphatasia, also called juvenile Paget’s disease of bone, is a rare autosomal recessive juvenile-onset form of Paget disease, characterized by markedly accelerated bone turnover caused by osteoprotegerin deficiency (for inactivating homozygous or compound heterozygous mutation in the TNFRSF11B gene). This disorder is characterized by: an increase in bone turnover (elevated levels of serum alkaline phosphatase (ALP) and other markers of bone turnover), skeletal deformity, bone expansion, bone pain and an increased risk of pathological fractures. Clinical manifestations present from early infancy and include: skeletal deformity and failure to thrive followed by skull enlargement, difficulty in walking, progressive sensorineural deafness (due to cochlear involvement), kyphosis and acetabular protrusion. Disease severity generally increases during adolescence, but a milder form has been described in some patients.

Currently, there are not guidelines of therapeutic management for this rare disease. Nervetheless, there are some studies on the use of antiresorptive drugs such as calcitonin, bisphosphonates and denosumab, with improvement of clinical, biochemical and radiographic. Recombinant OPG has also been used successfully in treatment, but currently this is not available for routine clinical use.


TNFRSF11B gene, 8q24.12 (OMIM gene/locus number *602643), which encodes osteoprotegerin (OPG), a member of the TNF-receptor superfamily. OPG is a soluble decoy receptor for RANKL which inhibits osteoclast differentiation and bone resorption.


Muscular weakness, deafness in infancy, osteoporosis, expanded long bones, bowed long bones, fragile bones, increased bone formation and destruction, progressive skeletal deformity, short stature, mild involvement of cranial bones, islands of increased skull bone density, premature teeth loss, retinal degeneration in some individuals, and angioid streaks.

Main biochemical alterations

High Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.


Fig. Radiographs from patient 1 at age 9 months, showing characteristic features of juvenile Paget’s disease of bone. (a) and (b) expanded and bowed femoral diaphysis, thin cortices, periosteal new bone formation, and disorganized trabecular architecture with (c) similar appearances in the humerus. 

Reproduced from Bone, Vol 68, Naot D, Choi A, Musson DS et al. Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease, Pages 6-10 Copyright 2014, with permission from Elsevier.

Other resources

The Paget's Association (UK)


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  2. Ralston SH. Juvenile Paget's disease, familial expansile osteolysis and other genetic osteolytic disorders. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):101-11. doi: 10.1016/j.berh.2007.11.005.
  3. Cundy T, Davidson J, Rutland MD, et al. Recombinant osteoprotegerin for juvenile Paget's disease. N Engl J Med. 2005 Sep 1;353(9):918-23.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org