M. Whyte, F. Zhang, M. Benigno, J. Zerega, K. Mack, V. Lim, S. Coburn, K. Ericson, W. McAlister, S. Mumm, D. Wenkert

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by deactivating mutation(s) within the gene that encodes the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP), natural substrates for this ectoenzyme, accumulate extracellularly. PPi excesses block skeletal mineralization causing rickets or osteomalacia. Pediatric HPP spans stillbirth (from profound skeletal hypomineralization) to premature loss of deciduous teeth without skeletal disease.

During the past 25 years, we have cared for 177 pediatric patients with HPP from throughout the United States and Canada. Each had one or more inpatient evaluations when fasting blood and 24-hour urine was collected while we matched ad libitum dietary calcium intakes. Disturbances in endochondral bone formation were followed radiographically using single views of wrists and knees. In order of increasing disease severity, we evaluated the pediatric forms of HPP: 65 odonto-HPP (dental disease only), 99 childhood HPP (41 mild), 12 infantile HPP, and 1 perinatal/infantile HPP patients. To date, 52 of our 177 patients, ~1/3 of our HPP population, had 4 - 14 admissions (usually occurring once every few years).

Serum total ALP activity, analyzed for ages ≤ 10 yr, reflected HPP severity (Table). As anticipated, lower values reflected more severe disease. The ALP values often showed 'physiological' decrements after puberty. Elevated plasma PLP levels also reflected disease severity (Table), but in contrast to ALP did not change over time according to a two-stage statistical analysis. Hence, assay of plasma PLP is a good diagnostic test that generally correlates with disease severity even when measured once. Height z-scores were without gender differences and also reflected HPP severity, with the more severely affected children being shorter (Table). Longitudinal analyses showed no significant alterations for height z-scores over time, for girls or boys. Hence, height assessments at > 2 yrs of age predicted adult heights. Radiographic features were highly individualized (physeal widening, irregularity of zones of calcification, “tongues of radiolucency”, metaphyseal osteopenia or osteosclerosis, and cortical thinning), but typically changed little during follow-up.

Accordingly, we have defined several major features of the natural history of HPP during childhood which will serve as a basis for assessment of future therapies.

Disclosures: M. Whyte, Enobia Pharma, Montreal, Canada: Research Grants. M. Whyte, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. D. Wenkert, Enobia Pharma, Montreal, Canada: Research Grants.

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