Respiratory manifestations as clues to inherited metabolic disorders in children: a phenotype-driven diagnostic approach.

Abstract

UNLABELLED: Inherited metabolic disorders (IMDs) are uncommon but clinically important causes of respiratory morbidity in children. Respiratory involvement may be the first or dominant manifestation, although it may precede, accompany, or follow systemic involvement. Because cough, dyspnea, hypoxemia, recurrent infection, abnormal chest imaging, and ventilatory failure are non-specific, affected children may initially be managed for common respiratory conditions, such as infection, asthma, aspiration, immunodeficiency, or non-metabolic diffuse lung disease, before the underlying IMD is recognized. This narrative mini-review presents a phenotype-driven approach to recognizing IMDs in pediatric respiratory practice. Rather than cataloguing rare disorders by metabolic pathway, it organizes respiratory involvement into practical clinical entry points: diffuse lung disease, pulmonary alveolar proteinosis-like disease, pulmonary vascular disease, recurrent infection or bronchiectasis, upper-airway or thoracic restriction, and neuromuscular respiratory failure and aspiration. For each pattern, we highlight extrapulmonary red flags and first-line biochemical, enzymatic, and genetic tests that may guide early etiological diagnosis. CONCLUSION: Careful recognition of respiratory phenotypes, combined with targeted metabolic and genomic evaluation, may shorten diagnostic delay and allow disease-specific treatment before irreversible pulmonary or neurological injury occurs. WHAT IS KNOWN: • IMDs can involve the respiratory system and may mimic common pediatric respiratory disorders or non-metabolic forms of childhood diffuse lung disease. • Respiratory manifestations may precede, accompany, or follow classical systemic features, and their temporal pattern varies among individual IMDs. WHAT IS NEW: • This mini-review organizes IMD-related respiratory involvement by presenting respiratory phenotype rather than by metabolic pathway. • It links respiratory entry points with extrapulmonary red flags and targeted biochemical, enzymatic, and genetic testing to support earlier diagnosis.