J Clin Pathol. 2021 Oct;74(10):635-640. doi: 10.1136/jclinpath-2021-207426. Epub 2021 Apr 30.


Hypophosphatasia (HPP) is a group of inherited disorders characterised by the impaired mineralisation of bones and/or teeth and low serum alkaline phosphatase (ALP) activity. It is caused by a mutation in the ALPL gene encoding the tissue-non-specific isoenzyme of ALP (TNSALP) resulting in a loss of function. The disease is highly heterogenous in its clinical expression ranging from stillbirth without mineralised bone to the mild form of late adult onset with symptoms and signs such as musculoskeletal pain, arthropathy, lower-extremity fractures, premature loss of teeth or an incidental finding of reduced serum ALP activity. A classification based on the age at diagnosis and the presence or absence of bone symptoms was historically used: perinatal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia. These subtypes are known to have overlapping signs and complications. Three forms of HPP distinguishable by their genetic characteristics have been described: severe, moderate and mild. Severe forms of HPP (perinatal and infantile severe) are recessively inherited, whereas moderate HPP may be dominantly or recessively inherited. The biochemical hallmark of HPP is persistently low serum ALP for age and increase in natural substrates of TNSALP, pyridoxal 5'-phosphate and phosphoethanolamine supported by radiological findings. The diagnosis is confirmed by ALPL sequencing. A multidisciplinary team of experts is essential for the effective management. Calcium restriction is recommended in infants/children to manage hypercalcaemia. A targeted enzyme replacement therapy for HPP has become available and correct diagnosis is crucial to allow early treatment.

Keywords: biochemistry; chemistry; clinical; proteins.

Publication types

  • Review

MeSH terms

  • Alkaline Phosphatase / blood
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / therapeutic use
  • Calcium, Dietary / adverse effects
  • Calcium-Regulating Hormones and Agents / therapeutic use
  • Enzyme Replacement Therapy
  • Genetic Predisposition to Disease
  • Humans
  • Hypophosphatasia / epidemiology
  • Hypophosphatasia / genetics
  • Hypophosphatasia / physiopathology*
  • Hypophosphatasia / therapy
  • Immunoglobulin G / therapeutic use
  • Mutation
  • Odontogenesis* / genetics
  • Osteogenesis* / genetics
  • Phenotype
  • Prognosis
  • Recombinant Fusion Proteins / therapeutic use
  • Tooth Demineralization / congenital*
  • Tooth Demineralization / epidemiology
  • Tooth Demineralization / genetics
  • Tooth Demineralization / physiopathology
  • Tooth Demineralization / therapy


  • Calcium, Dietary
  • Calcium-Regulating Hormones and Agents
  • Immunoglobulin G
  • Recombinant Fusion Proteins
  • ALPL protein, human
  • Alkaline Phosphatase
  • asfotase alfa

Supplementary concepts

  • Odontohypophosphatasia