Hypophosphatasia: Principal biochemical features validate the clinical nosology for affected children

Hypophosphatasia (HPP) is the heritable dento-osseous disease characterized by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase (ALP). Consequently, its natural substrates inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) accumulate extracellularly. PPi inhibits mineralization and its excess in HPP can cause rickets or osteomalacia and dental disease. Here, we support our clinical nosology for pediatric HPP by contrasting these principal biochemical features captured in data from the first admission of 165 pre-teenage HPP patients to our research center. Data were acquired using consistent testing methods. Our nosology comprises “infantile HPP” (n = 12), “severe childhood HPP” (n = 53), “mild childhood HPP” (n = 38), and “odonto HPP” (n = 62). Fasting serum ALP and bone-specific ALP (BAP) were invariably below published reference ranges and our in-house control values. Serum BAP was highly correlated with ALP (r = 0.97, p < 0.0001). ALP and BAP both reflected HPP severity captured in this nosology, with the values distinguishing the HPP groups except the two groups at either extreme of HPP severity. Similarly, plasma PLP concentration was elevated in virtually all patients, and discriminated (ps < 0.05) among the four patient groups except between odonto/mild childhood HPP and mild/severe childhood HPP (Figure). As an exception, mean serum inorganic phosphate (Pi) levels at referral were elevated to a similar degree in all patient groups (p < 0.001), although serum ionized calcium levels did not differ from controls. Hyperphosphatemia from enhanced renal reclamation of Pi is a recognized feature of HPP. Plasma PLP correlated inversely (r = 0.41, p < 0.001) with serum ALP. Height Z-scores correlated positively with ALP (r = 0.32, p < 0.0001) and negatively with PLP (r = 0.34, p < 0.001). Hence, as we have previously reported for demographic and DXA parameters, the principal biochemical aberrations of HPP too reflect our clinical nosology for pediatric HPP.