Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment

Key Points

  • Hypophosphatasia is the autosomal dominant or autosomal recessive inborn error of metabolism with an extraordinary range of severity caused by loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP)

  • Extracellular accumulation of the TNSALP substrate inorganic pyrophosphate results in defective mineralization of the dentition causing tooth loss and often of the skeleton causing rickets or osteomalacia

  • Hypophosphatasaemia (low serum alkaline phosphatase activity) for age and sex is the biochemical hallmark

  • An elevated serum level of the TNSALP substrate pyridoxal 5′-phosphate (the major circulating form of vitamin B6) is expected

  • TNSALP gene (ALPL; also known as TNSALP) mutation analysis is necessary to understand recurrence risks and for prenatal diagnosis

  • Recombinant, bone-targeted TNSALP replacement has been shown to be effective for paediatric-onset hypophosphatasia


Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5′-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from 300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5′-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.

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Figure 1: Adult hypophosphatasia.
Figure 2: Childhood hypophosphatasia.
Figure 3: Infantile hypophosphatasia.
Figure 4: Radiographic features of infantile hypophosphatasia.
Figure 5: Perinatal hypophosphatasia.
Figure 6: Radiographic features of perinatal hypophosphatasia.
Figure 7: Role of TNSALP in vitamin B6 metabolism.
Figure 8: Perinatal hypophosphatasia: response to asfotase alfa treatment.


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This Review was made possible by the skill and dedication of the medical, nursing, laboratory, dietary, radiology and physical therapy staff of the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St Louis, Missouri, USA. S. McKenzie and V. Bijanki assisted in the preparation of this manuscript.

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Correspondence to Michael P. Whyte.

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Competing interests

M.P.W. has received consulting fees and research grant support from Enobia Pharma and honoraria, travel and research grant support from Alexion Pharmaceuticals, who have developed asfotase alfa to treat paediatric-onset hypophosphatasia as approved in Japan, Canada, the Europe Union and the USA.

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Whyte, M. Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12, 233–246 (2016). https://doi.org/10.1038/nrendo.2016.14

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