Abstract
Background
Cobalamin C (cblC) deficiency, caused by MMACHC mutations, is a rare metabolic disorder with multisystem involvement. Pulmonary hypertension (PH) is an underrecognized but potentially life-threatening complication. This study aimed to characterize the clinical features and treatment outcomes of PH in children with cblC deficiency, particularly those carrying the MMACHC c.80 A > G variant.
Methods
We retrospectively analyzed 17 pediatric patients with genetically confirmed cblC deficiency who presented with PH as the initial manifestation. Clinical, biochemical, imaging, genetic, and therapeutic data were reviewed.
Results
All patients had PH at diagnosis, with 64.7% (11/17) exhibiting moderate-to-severe pulmonary artery systolic pressure (PASP) elevation. Macrocytic anemia and renal dysfunction were common. HRCT revealed centrilobular ground-glass nodules, interlobular septal thickening, and pulmonary hemorrhage. B-type natriuretic peptide (BNP) levels were significantly higher in the moderate-severe group. All patients received metabolic therapy, and 11 received PH-targeted drugs. Glucocorticoids led to rapid clinical improvement in two patients presenting with pulmonary hemorrhage or hypoxemia. PASP normalized in all cases within 18 months. No recurrence occurred during follow-up.
Conclusion
PH is a serious but reversible complication of cblC deficiency. Early diagnosis and combined metabolic and PH-targeted therapy can reverse vascular remodeling. Screening for cblC should be considered in children with unexplained PH and macrocytic anemia or renal involvement.
Impact
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This study presents the largest cohort to date of pediatric patients with cblC deficiency presenting with pulmonary hypertension (PH) as the initial manifestation.
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It identifies a potential genotype–phenotype association between the MMACHC c.80 A > G variant and reversible pulmonary vascular disease.
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The findings highlight the importance of early metabolic and PH-targeted therapy, and support screening for cblC deficiency in children with unexplained PH and macrocytic anemia or renal involvement.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We acknowledge all the patients who participated in this study, and their families.
Funding
This study were supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region (022D01D55).
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H. M. Y. and S. Y. Z. conceptualized and designed the study, supervised the clinical evaluations, and critically reviewed and revised the manuscript for intellectual content. RXH drafted the initial manuscript, collected clinical data, and conducted the initial analysis. J. R. L., X. L. T., H. L., Y. L. S., X. Y. Z., and HML conducted clinical investigations, validated data, and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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The study was approved by the Institutional Review Board of Beijing Children’s Hospital (approval no. 2024-Y-090-D).
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He, R., Liu, J., Tang, X. et al. Reversible Pulmonary Hypertension in CblC Deficiency (MMACHC c.80 A>G): long-term outcomes of metabolic and PH-targeted therapy. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04720-8
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DOI: https://doi.org/10.1038/s41390-025-04720-8
