Adult Hypophosphatasia (HPP)

(OMIM #146300)

Adult hypophosphatasia (HPP) is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase (see also Perinatal - Infantile - Childhood Hypophosphatasia (HPP)). The adult form of hypophosphatasia appears after middle age, and it is mainly characterized by osteomalacia, pseudofractures, pathologic fractures after minimal trauma, chondrocalcinosis, osteoarthropathy, as well as by muscle and joint pain. Sometimes the disease can be asymptomatic except the typical laboratory findings.

There are no established medical treatments for HPP, except treatments to alleviate symptoms and reduce complications. Bisphosphonates or too high doses of vitamin D are contraindicated and potentially dangerous in the case of HPP. In the future, new therapies are being evaluated.

Gene

ALPL gene, 1p36.12 (OMIM gene/locus number #171760). HPP is caused by any mutation in the ALPL gene that causes decreased TNSALP activity and increased levels of its substrates (about 275 mutations have been identified). The inheritance mechanism can be autosomal recessive or dominant.

Phenotype

Premature loss of primary and secondary teeth, severe dental caries, decreased alveolar bone, enlarged pulp chamber; osteomalacia recurrent fractures, long bone pseudofractures, calcium pyrophosphate arthropathy, chondrocalcinosis metatarsal, and stress fracture.

Main biochemical alterations

Low ALP, normal Ca, high Pi due to high TmP/GFR, high levels of ALP substrates: inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP, the active metabolite of vitamin B6), and phosphoethanolamine (PEA).

Images

Fig. (a)

hypophosphatasia

Fig. (b)

hypophosphatasia

Fig. (a) X-ray (oblique view) and (b) MRI (axial view) of the left lateral proximal femur of a 32-year-old male patient diagnosed with adult HPP. A pseudofracture in the femoral neck is indicated by the arrow.

Reproduced from Osteoporos Int, Skeletal mineralization defects in adult hypophosphatasia - a clinical and histological analysis, 2011;22:2667-75, Barvencik F, Beil FT, Gebauer M,  et al., with permission of Springer.

 

Other resources

Hypophosphatasie Europe
Hypophosphatasie Deutschland e.V.

References

  1. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010 Mar;1192:190-200.
  2. Whyte MP. Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res. 2009 Jun;24(6):1132-4
  3. Bianchi ML, Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015 Aug 6. [Epub ahead of print]
  4. Sutton RA, Mumm S, Coburn SP et al. "Atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012 May;27(5):987-94. doi: 10.1002/jbmr.1565.
  5. Weiss MJ, Cole DE, Ray K, et al. First identification of a gene defect for hypophosphatasia: evidence that alkaline phosphatase acts in skeletal mineralization.Connect Tissue Res. 1989;21(1-4):99-104; discussion 104-6.
  6. Barvencik F, Beil FT, Gebauer M, et al. Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis. Osteoporos Int. 2011 Oct;22(10):2667-75.
  7. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  8. http://www.omim.org