Purpose or Case Report: Hypophosphatasia (HPP) is the rare inherited metabolic bone disease caused by loss-of-function mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Resultant TNSALP deficiency leads to extracellular excess of inorganic pyrophosphate, an inhibitor of bone mineralization. Rickets in infants and children has distinctive radiographic features. Here, we report the validity and reproducibility of a novel scoring system to quantify HPP-specific radiographic changes in pediatric patients (pts).
Methods & Materials: The Radiographic Global Impression of Change (RGI-C) is a 7-point ordinal scale (-3=severe worsening; 0=no change; +3=near/complete healing) designed to provide a comprehensive evaluation of skeletal health in pediatric pts with HPP. Sequential radiographic studies (chest [<5 years of age only], knees, and wrists) are assessed for improvement or worsening using age-specific (< or ≥5 years of age) hallmarks of HPP developed by expert consensus. Features common to both age groups include metadiaphyseal sclerosis, apparent physeal widening, and metaphyseal radiolucencies and/or fraying. Age-specific features include gracile and/or absent bones and chest deformity for pts <5 years, and osteopenia, “popcorn calcification,” and physeal corner defects for pts ≥5 years. Inter- and intrarater agreements for 6 raters across 3 treatment studies were assessed using intraclass correlation coefficients (ICC) and weighted kappa coefficients (KC). Concurrent validity was assessed via correlation between RGI-C scores and simultaneous changes from baseline in: 1) Rickets Severity Scale (RSS)¹; 2) Pediatric Outcomes Data Collection Instrument (PODCI) Global Function scale; 3) Child Health Assessment Questionnaire (CHAQ) Disability Index; 4) 6 Minute Walk Test (6MWT); and 5) height z- scores, in children ≥5 years.
Results: ICC revealed moderate-to-good interrater agreement for pts <5 years (0.65, 227 radiographs; P<0.0001) and pts ≥5 years (0.57, 136 radiographs; P<0.0001). Most raters achieved substantial (n=4, KC >0.6) or almost perfect (n=4, KC>0.8) intrarater agreement (n=1, moderate agreement, KC>0.5). The linear regressions revealed significant correlations with RSS, PODCI Global Function, CHAQ Disability Index, 6MWT, and height z-scores (Table 1).
Conclusions: The RGI-C scale is a reproducible and valid measure for assessing over time clinically important changes in skeletal manifestations of HPP in pediatric pts.

1. Thacher TD, et al. J Trop Pediatr 2000;46:132-9.