دانلود رایگان مقاله هیپوفسفاتازیا و مطالعه 101 کودک تحت تاثیر

ABSTRACT

Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Resultant extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate and potent inhibitor of mineralization, typically leads to tooth loss and sometimes to rickets or osteomalacia. HPP's remarkably broad-ranging severity is largely explained by autosomal dominant versus autosomal recessive transmission from among several hundred usually missense mutations positioned throughout the gene that encodes TNSALP. In 2015, our cross-sectional investigation of 173 affected children validated and expanded the clinical nosology commonly used for pediatric HPP. Herein, for the 101 patients in that cohort with longitudinal data, we explored the natural history of pediatric HPP by assessing their z-scores for height and then for weight, grip strength, and bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA) also after adjusting for patient height. Eighteen patients contributed to “across” puberty evaluation. According to increasing HPP severity, there were 28 odonto HPP, 28 mild childhood HPP, 37 severe childhood HPP, and 8 infantile HPP patients typically studied from early to mid-childhood. The individual values for each parameter were wide-ranging within, and overlapping between, the four successive patient groups. Final mean/median z-scores, like the published initial values, paralleled the nosology. Longitudinal findings were similar for the boys versus girls and across puberty. Mean/median height z-scores remained constant for all four patient groups. In contrast, mean/median weight z-scores increased with aging, including after height-adjustment, resembling the recent trend for American children. However, excessive weight gain was typically not observed and mean/median values became average for height. Mean/median z-scores calculated routinely for chronologic age did not change for grip strength or for lumbar spine or total hip BMD. However, height-correction of the cohort suggested some worsening of grip strength z-scores and indicated improvement in spine BMD z-scores. Overall, in affected children and adolescents, HPP represents a clinically stable but chronic disorder.

4. Discussion

To understand the natural history of HPP during childhood and adolescence, we assessed height, weight, grip strength, and DXA BMD data from the 101 such patients studied longitudinally during the initial 25 years of our Research Center. These parameters were chosen to provide objective measures of HPP severity. In 2015, we had reported a cross-sectional evaluation from the first encounters with the entire cohort of 173 patients [5]. Perinatal HPP was not represented, but our retrospective studies of perinatal HPP reported in 2013 [8] and perinatal and infantile HPP reported in 2016 [9] had helped to delineate these most severe forms of pediatric HPP [6,9,17]. Our publication in 2015 [5] validated and expanded the clinical classification for pediatric HPP [1,3] to include odonto HPP, mild childhood HPP, severe childhood HPP, infantile HPP, and perinatal HPP by documenting increasingly aberrant values as it signified worse disease [5]. Parameters of patient body size (height, weight) and DXA BMD z-scores discriminated best among the four studied HPP groups. Thus, for our natural history investigation of pediatric HPP herein, we used this expanded clinical nosology [5].