Congenital Methemoglobinemia in a Vietnamese Adolescent: A Dyshemoglobinemia with Diagnostic Challenges, Literature Review, and Diagnostic Algorithm

Methemoglobinemia is a disorder of hemoglobin redox homeostasis in which the iron in heme is oxidized to the ferric (Fe3+) state, impairing oxygen transport. Congenital methemoglobinemia due to cytochrome b5 reductase (CYB5R) deficiency is a rare autosomal recessive disorder causing persistent central cyanosis. We report the first documented case in Vietnam – a 15-year-old boy with a 10-year history of unexplained central cyanosis (SpO2 85%, PaO2 140.8 mmHg). Methemoglobin (MetHb) level was 33.7%. Whole exome sequencing (WES) identified a heterozygous pathogenic CYB5R3 variant (NM_000398.7: c.218T>C, p.Leu73Pro; ACMG: Likely Pathogenic), confirmed by Sanger sequencing, with markedly reduced CYB5R enzyme activity (NADH-ferricyanide method). No second pathogenic allele was identified in CYB5R3, CYB5A, HBA1/HBA2, or HBB, reflecting the known limitations of short-read WES in detecting structural variants and deep intronic mutations; thus, molecular confirmation remains incomplete despite definitive clinical and enzymatic evidence. Diagnosis was delayed 10 years from symptom onset and 8 hours after admission, attributable to the unavailability of pulse co-oximetry. Acute intravenous methylene blue (MB) produced rapid clinical improvement. Long-term ascorbic acid monotherapy proved insufficient (MetHb 10.4% at 3 months), whereas escalation to oral MB achieved sustained remission (MetHb 2.8% at 12 months). A comprehensive review of 71 published pediatric cases reveals marked geographic disparity (64.8% from India; Southeast Asia is critically underrepresented) and an average diagnostic delay of 6 years. We propose a practical diagnostic algorithm for congenital methemoglobinemia in resource-limited settings. This case underscores the need for heightened clinical awareness of CYB5R3-related hemoglobin disorders in underdiagnosed populations.