Because the initial symptoms of methemoglobinemia can be vague, especially with low levels of methemoglobinemia, this condition can easily be misdiagnosed or go unrecognized. Lack of awareness of this condition often leads to delayed and missed diagnosis.
Cyanosis (presence of more than 5 g/dL of deoxygenated hemoglobin) associated with hypoxia may be caused by cardiac or pulmonary disease. Cyanosis may also be present in polycythemia but is generally without hypoxia. The hallmark of methemoglobinemia is cyanosis that is unresponsive to high oxygen concentrations in the absence of cardiac or pulmonary disorders. Pulmonary diseases generally respond to oxygen administration, whereas cardiac disease may not. Right-to-left shunts in the cardiovascular system, especially when large, do not respond to oxygen administration.
Sulfhemoglobinemia, skin contamination with blue/gray/black-colored dyes, or ingestion/treatment with methylene blue causes cyanosis that is unresponsive to oxygen. Darkish discoloration of the skin may be due to excessive exposure to silver compounds (argyria) and can mimic methemoglobinemia. [55, 56] Methylene blue can impart a cyanotic discoloration to the skin after the treatment of patients with methemoglobinemia; therefore, bluish discoloration following treatment does not necessarily imply treatment failure.
Hemoglobin variants with altered oxygen affinity should also be considered in the differential diagnosis of patients with cyanosis. In infants, this may be due to the presence of hemoglobin M (hemoglobins F M-Osaka and F M-Fort Ripley), resulting in the formation of methemoglobinemia).
Decreased oxygen affinity may also be due to the presence of a nonmethemoglobin low-affinity fetal hemoglobin variant as a result of an allosteric abnormality in the hemoglobin. Hemoglobin F-Cincinnati is a γ-chain substitution described at residue 41.  Substitution at residue 41 has been reported for the f3 globin chain (4l(C7) Phe → Ser) as hemoglobin Denver, which has been shown to have decreased oxygen affinity. 
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