What is the primary differential diagnosis in the hypophosphatasias?
The hypophosphatasias may look like rickets in children and osteomalacia in adults. Subtle radiographic findings may allow the distinction to be made, but the diagnosis of hypophosphatasia is ultimately based on the findings of an exceptionally low serum ALP in conjunction with high serum levels of inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate and high urine phosphorylethanolamine levels. Mutations of ALPL on chromosome 1, which codes for tissue-nonspecific ALP (TNSALP), are responsible for this disease. These mutations lead to low levels of tissue ALP leading to less cleavage of PPi. The accumulation of PPi inhibits hydroxyapatite crystal formation. It also leads to chondrocalcinosis. Consideration of hypophosphatasia is warranted in any case of suspected rickets or osteomalacia, especially in patients with early loss of deciduous teeth. Many adult patients present with poorly healing metatarsal stress fractures. Recently, asfotase alfa (Strensiq) has been approved as an enzyme replacement therapy for young patients with severe hypophosphatasia. The annual cost of this therapy is $300,000.
Pearl: Consider hypophosphatasia in any patient with poorly healing metatarsal stress fractures who has a low serum ALP level.