summary Hypophosphatasia is a metabolic bone disease caused by a mutation in the isoenzyme of alkaline phosphatase that leads to low levels of alkaline phosphate and generalized impairment of bone mineralization. Patients present with clinical manifestations similar to rickets with bow legs, short stature, abnormal teeth, and increased susceptibility to fractures. Diagnosis is made with the presence of phosphoethanolamine in the urine. Treatment modalities include enzyme replacement therapy, anti-inflammatories, and multidisciplinary care Epidemiology Incidence severe forms (perinatal/infantile) estimated to be 1 in 100,000 to 1 in 300,000 milder forms (adult) estimated to be 1 in 500 to 1 in 3,000 significant diagnostic delay is common in both adults and children Etiology Pathophysiology low levels of alkaline phosphate result in decreased synthesis of inorganic phosphate necessary for bone matrix formation extracellular accumulation of inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), and phosphoethanolamine (PEA) excess PPi inhibits hydroxyapatite crystal formation osteoid that forms in the hypertrophic zone of the growth plate fails to mineralize the zone of provisional calcification never forms and growth is inhibited Genetics inheritance pattern severe forms (perinatal/infantile): autosomal recessive mild/adult forms: often autosomal dominant caused by a loss-of-function mutation in the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) Associated conditions orthopaedic manifestations may resemble rickets short stature non-orthopaedic manifestations abnormal tooth formation loss of teeth due to bone loss and dental caries respiratory compromise and lung hypoplasia hypercalcemia muscle weakness and fatigue Presentation Clinical findings presentation similar to rickets genu varum short stature perinatal (severe) hypomineralization long bone bowing, including pretibial bowing osteochondral spurs infantile craniosynostosis rachitic ribs flared metaphyses childhood short stature bone pain frequent fractures adult femoral pseudofractures metatarsal stress fractures chondrocalcinosis poor fracture healing osteopenia/osteoporosis abnormal dentition Imaging Radiographs recommended AP and lateral of affected bone findings abnormal bone formation "deossification of bone" adjacent to growth plate physeal widening flared metaphyses Evaluation Labs serum decreased serum alkaline phosphatase urine phosphoethanolamine in the urine diagnostic for hypophosphatasia Treatment Nonoperative no approved therapies phosphate therapy under investigation but not utilized at this time