Misdiagnosed as idiopathic pulmonary arterial hypertension: Methylmalonic acidemia as a reversible cause of pediatric pulmonary hypertension.

BACKGROUND

Methylmalonic acidemia (MMA)-induced pulmonary hypertension (PH) is a rare but treatable cause of pediatric PH, often misdiagnosed as idiopathic pulmonary arterial hypertension (IPAH).

METHODS

We conducted a 10-year, multicenter retrospective study of children with clinically unexplained PH. Thirteen patients with MMA-PH were compared to 113 with idiopathic or hereditary PAH (IPAH/HPAH) regarding clinical features, hemodynamics, and outcomes.

RESULTS

MMA-PH accounted for 2.7% of pediatric PH cases. Patients presented younger (7±4 vs. 11±5 years, p=0.008) and exhibited higher rates of growth failure (84.6% vs. 15.9%, p<0.001), anorexia/malnutrition (76.9% vs. 14.2%, p<0.001), recurrent pneumonia (46.2% vs. 13.3%, p=0.003), microscopic hematuria (84.6% vs. 1.8%, p<0.001), and proteinuria (31% vs. 4.4%, p=0.007) than IPAH/HPAH. All had the combined MMA subtype with markedly elevated homocysteine (median 87 µmol/L vs. 18 µmol/L, p<0.001). With metabolic therapy (hydroxocobalamin, betaine, etc.) and short-term pulmonary vasodilators, all achieved complete clinical and hemodynamic remission within 1 year. Median follow-up was 7.0 years; no relapse occurred.

CONCLUSIONS

Elevated total homocysteine and multisystem involvement should prompt metabolic screening in children with unexplained PH. Early diagnosis and metabolite-targeted treatment can lead to sustained, nearly curative outcomes, distinguishing MMA-PH from IPAH/HPAH. Routine homocysteine testing is recommended in the diagnostic workup of pediatric PH.