Recessive congenital methemoglobinemia: a systematic review of reported cases

TL;DR

This paper reviews all reported cases of a rare genetic disorder called Recessive Congenital Methemoglobinemia, summarizing its symptoms, genetic causes, and treatment options.

Contribution

The study provides a systematic review and meta-analysis of all reported cases of RCM, including a proposed diagnostic flow chart.

Findings

RCM presents in two forms: Type I with isolated cyanosis and Type II with neurocognitive issues.

Genetic analysis of the CYB5R3 gene is key for diagnosis, with specific variants linked to each type.

Ascorbic acid is the most commonly used treatment, though it does not improve neurological outcomes.

Abstract

Recessive congenital methemoglobinemia (RCM) is a rare autosomal recessive disorder characterized by a deficiency of NADH-cytochrome b5 reductase. Under normal conditions, cytochrome b5 reductase and NADH reductase maintain methemoglobin in the physiological range by keeping heme iron in the Fe2
+ state. RCM presents in two clinical forms. Type I presents with isolated cyanosis, while type II presents also with severe neurocognitive manifestations. Genetic analysis of the CYB5R3 gene is often used for diagnosis. Treatment with methylene blue, ascorbic acid, or riboflavin can reduce cyanosis, but does not affect neurological outcomes.

We conducted a systematic review of RCM, identifying all previously reported cases, including one from our center. In addition, we conducted a meta-analysis of individual participant data and provided a comprehensive review of clinical manifestations, genotype-phenotype correlations and treatment options, as well as proposing a diagnostic flow chart.

In the case of RCM, diagnosis is primarily achieved through genetic analysis based on direct sequencing. The described pathogenic variants are specific to either type I or type II RCM when considered in combination with their allelic variants in compound heterozygous cases. Well known variants such as c.757G>A is associated with type I in both homo- and heterozygous state. Whereas c.226G> is associated with type I in compound heterozygous state with c.173G>A or c.827C>T and type 2 in homozygous state. Similar results are observed for multiple other variants. Ascorbic acid is the most commonly used treatment.

Not applicable.

The online version contains supplementary material available at 10.1186/s13023-026-04215-7.

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