Precision medicine in pediatric growth disorders: Integrating clinical phenotype, genetics, IGF-1 biology and artificial intelligence: A systematic scoping review of PubMed-indexed literature (2000-2026).

Abstract

Background ecombinant human growth hormone (rhGH) has been used for four decades under a largely population-based dosing paradigm, yet growth response varies substantially among children with apparently similar auxological phenotypes. Advances in genomics, GH-insulin-like growth factor-1 (IGF-1) axis biomarkers, mathematical and machine-learning (ML) prediction models, and digital health technologies now allow individualized characterization of growth disorders, forming the basis of an emerging precision-endocrinology paradigm. Objectives (1) to synthesize evidence on monogenic and polygenic genetic determinants of pediatric growth faltering and/or short stature and their diagnostic yield; (2) to evaluate GH-IGF-1 axis biomarkers and pharmacogenetic markers, including the IGF-1/IGFBP-3 molar ratio as a likely better indicator of bioactive IGF-1 than IGF-1 alone, together with mathematical/ML prediction models, for individualizing rhGH therapy; and (3) to appraise artificial intelligence (AI) and digital-health tools, bone-age algorithms, facial-recognition phenotyping, adherence-prediction models, and smartphone growth-monitoring, as instruments for operationalizing precision endocrinology in children and adolescents with growth disorders. Methods This is a systematic review employing narrative synthesis (a systematic scoping review). Reporting explicitly followed the PRISMA Extension for Scoping Reviews (PRISMA-ScR) checklist rather than the PRISMA 2020 statement for systematic reviews and meta-analyses, because the heterogeneous outcome metrics across genetic, diagnostic-accuracy, prediction-model, and AI/digital-health studies preclude meta-analytic pooling of a single quantitative effect size; PRISMA-ScR is the methodologically appropriate reporting framework for a review mapping evidence across such conceptually distinct domains. PubMed/MEDLINE was searched for English-language, pediatric (0-18 years) studies published between 2000 and 2026. Two-stage screening (title/abstract, then full text) was performed. Quality was appraised using design-appropriate tools: an adapted Newcastle-Ottawa Scale for genetic-association studies, QUADAS-2 for diagnostic-accuracy biomarker studies, PROBAST/TRIPOD-informed criteria for prediction-model and ML studies, and reference-standard/external-validation criteria for AI-imaging studies. Sixty-two studies were retained for qualitative synthesis. Results Monogenic defects (SHOX, ACAN, NPR2) and exome-sequencing panels explain a meaningful minority (approximately one-quarter) of previously "idiopathic" short stature, while genome-wide association studies and polygenic scores capture a substantial share of the remaining heritable variance, with polygenic risk scores achieving areas under the receiver-operating-characteristic curve up to 0.84 for predicting adult short stature. The IGF-1/IGFBP-3 M ratio outperforms IGF-1 alone for diagnosing GH deficiency (sensitivity 87.5%, specificity 83.0%), reflecting the greater bioavailability of free, unbound IGF-1 relative to that carried in the ternary IGF-1/IGFBP-3/acid-labile-subunit complex. GH-receptor exon-3 (d3) pharmacogenetic variants and machine-learning models (random forest, transcriptomic classifiers) improve prediction of individual rhGH response beyond classical mathematical models. AI-based bone-age algorithms achieve near-radiologist accuracy with reduced inter-observer variability, computer-aided facial-phenotyping tools show comparable diagnostic accuracy for syndromic short-stature disorders such as Noonan and Turner syndrome, and connected-device/ML adherence-monitoring and smartphone growth-tracking tools objectively detect suboptimal adherence and growth faltering earlier than conventional clinic-based surveillance; network meta-analyses of once-weekly long-acting rhGH formulations further suggest that reduced injection burden can translate into modestly improved height outcomes relative to daily rhGH. These findings are synthesized into a Precision-Medicine Cascade, a practice-oriented framework showing how genotype, biomarker, and digital data streams can be layered onto routine auxological assessment to guide same-visit clinical decisions on diagnostic work-up, dosing, and monitoring frequency. Conclusion Converging genetic, biomarker, computational, and digital-health evidence supports a feasible, evidence-grounded trajectory toward individualized therapy, including rhGH and emerging growth-plate-targeted agents, in pediatric growth disorders. The Precision-Medicine Cascade proposed here offers pediatric endocrinologists an immediately applicable framework for integrating these tools into everyday practice. However, current tools remain adjunctive rather than replacement for clinical judgment, and prospective, ethnically diverse validation of integrated precision-endocrinology pathways is required before routine adoption.

Plant phenotyping relevance

植物ではなく小児成長障害を対象とするため通常の植物フェノタイピング索引には不適合だが、提示基準上の「plant」要件を満たさないため本来は除外。ただしレビュー自体はAI画像・成長モニタリング等のヒト表現型手法を中心的に扱う。

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