Hypophosphatasia

Hypophosphatasia is an inherited deficiency of tissue nonspecific alkaline phosphatase (ALPL), causing impaired bone mineralisation.

• Autosomal recessive (severe) or dominant (mild) forms; prevalence of severe disease about 1 in 100,000.
• Forms: perinatal lethal, infantile, childhood, adult, odontohypophosphatasia.
• Accumulation of substrates: inorganic pyrophosphate, pyridoxal 5' phosphate, phosphoethanolamine.

• Perinatal/infantile: poor mineralisation, hypercalcaemia, respiratory failure, vitamin B6 dependent seizures, craniosynostosis, failure to thrive.
• Childhood: premature loss of deciduous teeth with intact roots, rickets, short stature, bone pain.
• Adult: stress fractures, metatarsal fractures, osteomalacia, chondrocalcinosis, muscle pain.

• Persistently low serum alkaline phosphatase (age adjusted), elevated pyridoxal 5' phosphate and urinary phosphoethanolamine.
• Calcium and phosphate normal or high; PTH low or normal.
• Radiographs: undermineralisation, bowed legs, pseudofractures.
• ALPL genetic testing.
• Exclude other causes of low ALP (zinc deficiency, vitamin C deficiency, Wilson, myeloma, bisphosphonates).

• Asfotase alfa 6 mg/kg/week SC (2 mg/kg three times weekly or 1 mg/kg six times weekly) for perinatal/infantile and childhood onset disease; improves survival and mineralisation.
• Supportive: respiratory support, seizure control (pyridoxine), analgesia (avoid NSAIDs impair healing in some), dental care, orthopaedic care.
• Avoid bisphosphonates; avoid vitamin D or calcium supplementation unless deficient (may worsen hypercalcaemia).
• Adults: teriparatide 20 micrograms daily has been used in fractures; treat symptomatic pain.
• Genetic counselling, prenatal diagnosis.