Congenital methemoglobinemia is a rare autosomal recessive disorder due to the deficiency of NADH-cytochrome b5 reductase. The hallmark finding of this disease is cyanosis in the absence of cardiopulmonary etiology. The type I form is benign while type II is life-threatening and features severe neurological and developmental delay.
Congenital methemoglobinemia is a genetic disease resulting from the deficiency of NADH-cytochrome b5 reductase due to mutations on chromosome 22  . This enzyme is responsible for converting methemoglobin to hemoglobin. There are 2 forms of congenital methemoglobinemia, known as type I and type II . Patients with type I lack the soluble form of this important enzyme in erythrocytes whereas those with type II are deficient in the membrane-bound form of the enzyme in somatic cells . The first type is benign while the second is associated with significant morbidity and mortality .
Patients with congenital methemoglobinemia present with cyanosis often at birth. Another hallmark feature of this disease is that the cyanosis is not corrected with the administration of supplemental oxygen .
The cyanosis in type I is not accompanied by other symptoms. However, type II is characterized by severe neurological manifestations such as impaired psychomotor skills, dystonia, encephalopathy, progressive microcephaly, strabismus, and growth retardation . Other features may include refractory epilepsy, skeletal deformities, and behavior abnormalities .
Methemoglobinemia is associated with methemoglobin levels greater than 1%. Symptoms are correlated to methemoglobin concentration. For example, a methemoglobin level greater than 35% is associated with tachycardia, tachypnea, headache, dizziness, nausea, emesis, and fatigue whereas a concentration above 55% is reflected by lethargy, arrhythmia, acidosis, and loss of consciousness. Fatality is connected to levels exceeding 70%  .
Patients with this disease exhibit an overall slate-blue appearance and a discoloration of their mucus membranes and the blood. Mental status changes, cardiac arrhythmias, skeletal deformities, and other manifestations may be present as well. Also, corneal epitheliopathy has been noted in a handful cases .
Neonates with cyanosis should undergo a complete workup consisting of the patient, maternal, and family history, as well as a complete physical exam and the appropriate studies.
In patients with congenital methemoglobinemia, the arterial blood gas (ABG) values and pulse oximetry readings are typically normal . Even severe cases of this disease may exhibit normal Pao2 and pulse oximetry . Of importance, these patients exhibit a"saturation gap," which refers to the discrepancy between the oxygen saturation on the pulse oximetry and the value derived from the ABG.
To determine the presence of hemoglobin M, hemoglobin electrophoresis and gene sequencing are key tests . When methemoglobinemia is established, specific enzyme assays are useful to help diagnose this disease .
Co-oximetry, if available, will diagnose methemoglobinemia as it measures and differentiates methemoglobin from other types of hemoglobin.
Note that brown colored blood is a characteristic feature of methemoglobinemia. The color will remain brown upon exposure to oxygen, which makes for a simple test.
To exclude hemolysis, the workup should include a complete blood count (CBC), reticulocyte count, liver and renal function tests as well as the levels of lactate dehydrogenase (LDH), bilirubin, haptoglobin, and electrolytes. Moreover, Heinz body preparation and peripheral smear examination must be performed.
Brain magnetic resonance imaging (MRI) and computed tomography (CT) in patients with type II reveal cortical and subcortical atrophy   .
Note that cardiopulmonary disease should be excluded with echocardiography and chest imaging.