Diagnosis of Hemoglobin M Disease in a Toddler Presenting With Hypoxemia and Hemolysis

Case Presentation

A 20-month-old male presented to a local emergency department (ED) with complaints of 1 day of fever in the setting of 2 weeks of upper respiratory symptoms. Mom reported that the patient had a maximum temperature of 103.1°F. Family history is remarkable for anemia (of unknown type) in the mother, aunt, maternal grandmother, and patient’s sister. On presentation to the ED, the patient was febrile, fussy, and tachypneic with a respiratory rate of 55 breaths/min. He was noted to have perioral cyanosis despite normal lung sounds bilaterally. Vital signs were significant for temperature of 105°F and oxygen saturations between 40% and 60% on room air. Laboratory evaluation was remarkable for a hematocrit of 28%, and a methemoglobin level was 21% (performed by bedside I-STAT). Basic metabolic panel, coagulation studies, rapid influenza test, rapid Group A Strep testing, chest X-ray, and bedside echocardiogram were all unremarkable.

Due to the significant hypoxia, the patient was transferred to the tertiary children’s hospital for further evaluation. On arrival, the patient’s vital signs were remarkable for a temperature of 102.6°F, tachycardia to 177 beats per minute, and oxygen saturation of 51%. Physical examination was remarkable for an alert child in no distress with a 2/6 systolic murmur, pallor, and perioral cyanosis. The patient was placed on a non-rebreather at 10 liters per minute (LPM) during transfer; however, the patient’s oxygen saturation improved only from 60% to 70%.

Of note, prior to the current presentation, the patient had been referred to hematology clinic at 1 year of age for family history of anemia. At the time of that visit, the patient had an oxygen saturation of 99% on room air and a normal physical examination. He tested negative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PD level of 22.1 U/g) but did have mild anemia with hemoglobin of 10.6 g/dL. Mean corpuscular volume, red cell distribution width, platelet count, iron levels, and total iron binding capacity were all normal at that time. Ferritin was >50 ng/mL. At this time, his mild anemia was considered secondary to his age and diet; iron supplementation and dietary modifications were encouraged.

Hospital Course

In the pediatric ED, a venous blood gas was within normal limits (pH 7.42, pCO₂ 37 mmHg, pO₂ 18 mmHg, bicarb 24 mmol/L) and a methemoglobin of 5.7% was noted on the I-STAT. Further laboratory assessment included a respiratory viral panel remarkable for adenovirus and a complete blood count (CBC) that showed a hemoglobin of 7.5 g/dL, mean corpuscular volume of 88.6 fl, percent reticulocytes of 1.42%, and lactate dehydrogenase of 394 U/L. CBC was otherwise unremarkable. His iron level was 10 µg/dL (reference range = 16-128 µg/dL), ferritin level was 184 ng/mL (reference range = 21.8-322.0 ng/mL), and transferrin was 178.7 ng/mL (low). On admission to the pediatric intensive care unit, supplemental oxygen was continued, but his oxygen saturations did not change despite varying degrees of respiratory support. Due to the family history, oxygen saturation was also measured in the patient’s mother and maternal aunt, which revealed saturations in the 50% to 60% range. Due to the significant anemia (with noted hemolysis), hemoglobin analysis with high-performance liquid chromatography was performed, which revealed an abnormal hemoglobin at 13.5% that could not be identified by the hospital laboratory. Additional hemoglobin assessments were sent to the Mayo Clinic Laboratory. He remained tachypneic, and the decision was made to transfuse him due to the significant anemia and reticulocytopenia. The patient was transfused with 10 cc/kg of packed red blood cells, which he tolerated without complication. He was discharged the morning after the completion of the transfusion, resolution of tachypnea, and slight increase in O₂ saturation on room air. Posttransfusion hemoglobin increased to 7.9 g/dL, with the remainder of his CBC grossly unchanged. Discharge vitals demonstrated a temperature of 98.4°F, pulse of 119 beats per minute, and oxygen saturation of 79%.

Final Diagnosis

Hemoglobin electrophoresis performed by Mayo Clinic later confirmed Hemoglobin M-Hyde Park (also known as hemoglobin M-Milwaukee-2 or hemoglobin M-Akita), a cause of hereditary methemoglobinemia. The Mayo Clinic confirmed high amounts of methemoglobin 7.7% (reference value = 0.0-1.5%) and sulfhemoglobin 1.7% (reference value = 0.0-0.3%).

Discussion

Hemoglobin is composed of 4 different subunits, each composed of their own globin polypeptide chain and heme unit. ¹ Each polypeptide subunit is defined as either an alpha or a non-alpha chain. ¹ The 2 non-alpha chains may include the 2 beta chains of adult hemoglobin, 2 fetal gamma chains, or 2 delta chains. ¹ Various mutations in both alpha and non-alpha chains may affect the ability of hemoglobin to bind and deliver oxygen. ¹ Sufficient hemoglobin saturation with oxygen controls the ability of oxygen delivery to tissue.

There are 2 different mechanisms of methemoglobinemia: acquired and inherited. The iron component of the heme unit is usually in the ferrous state (Fe²⁺), which indicates the ability to bind and transport oxygen. ¹ The iron component is noted to have 2 separate amino acid attachments within the heme structure. ¹ There is direct attachment of iron to a proximal histidine and indirect attachment to the distal histidine via oxygen. ¹ Oxygen carrying occurs between the distal histidine and the iron component. ¹ The presence or absence of oxygen at this site correlates with oxygenated or deoxygenated hemoglobin, respectively. ¹ Oxidation of Fe²⁺ to ferric iron (Fe³⁺) creates methemoglobin.^1,2 In acquired methemoglobinemia, environmental exposures/toxins are responsible for indirectly oxidizing the iron component of hemoglobin to its ferric state.^1-3 This occurs secondary to inhibition of cytochrome b5 reductase.^2,3

There are also inherited hemoglobinopathies that result in methemoglobinemia. Specifically, an amino acid mutation within the heme structure results in an unstable hemoglobin that causes methemoglobin. ¹ A second cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency. ⁴ This enzyme is ultimately responsible for reducing the ferric component of hemoglobin to its ferrous form, allowing for the binding and carrying of oxygen to peripheral tissues. ⁴ In the first type of this enzyme deficiency, the lack of NADPH cytochrome b5 reductase is only present in the red blood cells, limiting symptoms to that found with methemoglobinemia. ⁴ The second type results in enzyme deficiency in all body tissues, subsequently causing a broad array of symptoms found shortly after birth, and further resulting in likely death by the age of 2 years. ⁴ Both forms of methemoglobin are unable to properly bind and carry oxygen.^1,2

The differential diagnosis for a child presenting with hypoxia is vast. Potential causes include respiratory disease affecting diffusion, anatomical defects, infectious etiologies, congenital heart disease, and blood abnormalities resulting in anemia or deficiencies of oxygen-carrying capacity including methemoglobinemia. Diagnostic features of methemoglobinemia include chocolate brown–colored blood and lack of improvement of peripheral oxygen saturation with supplemental oxygen.^2,3,5 Acquired methemoglobin is more common than an inherited methemoglobinemia and is usually caused by environmental exposure/toxicity.^2,3

The range of environmental insults that result in methemoglobin is very broad and can include medications, ingestion, or exposure to a toxic dose of certain agents. These agents include benzocaine, lidocaine, prilocaine, topical anesthetics, dapsone, metoclopramide, nitrates, nitric oxide, silver nitrate, aniline dyes, and particular insect/pesticides.^2,3,6,7 Cyanosis appears visible in patients with 15% methemoglobin.^2,3 Levels of methemoglobin >50% to 70% can precipitate lethal complications.^2,3 In patients with symptomatic methemoglobinemia and concentrations of methemoglobin >20%, methylene blue is a potential treatment modality.^3,8 Methylene blue aids the erythrocyte in reducing ferric iron to ferrous iron, restoring its ability to bind and transport oxygen. ⁸ This occurs in the red blood cell as methylene blue is reduced to leukomethylene blue in coordination with nicotinamide adenine dinucleotide phosphate (NADPH). ⁸ It is important to note that methylene blue may induce severe hemolysis in patients with G6PD deficiency.^3,4,8 For this reason, knowing patients’ family and past medical histories prior to treatment for acquired methemoglobinemia is vital. Vitamin C (ascorbic acid) has also been reported as a potential treatment for methemoglobinemia.^6,9 It is postulated that the antioxidant potential of vitamin C aids in reduction of heme to its ferrous state.^6,9 Current evidence for effective use of vitamin C is lacking and, if available, methylene blue should be first-line therapy.^3,9

Despite its rarity, congenital methemoglobinemia should be considered in patients presenting with methemoglobinemia and no history of environmental or medicinal exposures concerning for acquired methemoglobinemia. It is important to perform a hemoglobin analysis prior to transfusion to identify potential hereditary M-hemoglobins, which are unstable hemoglobins that can lead to methemoglobinemia.^2,10

Our patient’s diagnosis was confirmed via genetic testing and found to be the unstable, easily oxidized hemoglobin M variant of Hemoglobin M-Hyde Park (also known as Hemoglobin M-Milwaukee-2). This particular variant is classically inherited in an autosomal dominant manner but may also occur sporadically.^10-12 Hb-M-Hyde Park is classified as a structure change on the beta globin protein (histidine replaced by tyrosine at the proximal residue), leading to an unstable variant of hemoglobin, thereby making oxygen binding and delivery difficult.^1,13 Patients with this variation of hemoglobinopathy will classically become cyanotic and symptomatic after infancy after gradual downtrend of fetal hemoglobin. ¹⁰ Some hemoglobin M variants do present in the newborn period and have been reported as the cause of cyanosis in infants as young as 1 day old. ⁵ Diagnosis is not routinely identified by hemoglobin electrophoresis and usually requires genetic confirmation or mass spectrometry. ¹⁰ Mass spectrometry in our patient demonstrated a 35% variant of Hb-M-Hyde Park. This finding is clinically relevant as our patient presented with perioral cyanosis and hypoxemia, which would have been unlikely in settings of <10% methemoglobinemia as initially measured at the time of presentation. Furthermore, this patient had more severe anemia than is typical in the setting of this hemoglobin abnormality, thus we hypothesize that the patient’s concurrent viral respiratory infection provided physiological, oxidative stress inducing hemolysis and worsening his fraction of Hb-M-Hyde Park.

In the acute setting, no treatment or intervention is warranted for patients with Hb-M-Hyde Park. Patients with a diagnosis of hemoglobin M will not respond to methylene blue or similar treatments as these therapies are directed toward inhibited enzymatic reduction pathways; pathways that are normal in patients with a diagnosis of hemoglobin M.^4,8-10 However, physical examination assessment is especially important with additional attention paid to other findings of respiratory distress such as tachypnea and increased work of breathing as noted in this patient. It is useful to have baseline assessments such as CBCs, oxygen saturations, and lactate dehydrogenase in order to notice an acute change. When patients demonstrate worsened anemia with increased hemolysis and signs of respiratory distress, transfusion of healthy packed red blood cells or oxygen supplementation can be considered. Overall, patients with any co-inherited hemoglobin M should expect a normal life span unless a compound heterozygote with hemoglobin S. ¹⁰

Conclusion

In conclusion, it is important that providers are aware of the signs and symptoms of methemoglobinemia. The hallmark features of methemoglobinemia in the acute care setting are cyanosis, chocolate brown–colored blood, and hypoxemia that does not respond to supplemental oxygen.^2,3,5 In this scenario, additional respiratory interventions such as intubation were not necessary and would not have benefited this patient. Furthermore, it is important to note that a proper history must point to acquired methemoglobinemia prior to treatment. It is also necessary to clinically assess the patient for other findings of respiratory dysfunction and treat as needed. Although an unusual cause of hypoxia, methemoglobinemia should be recognizable in the acute setting. Additional research is needed to address management of those patients when presenting with acute illness.

Author Contributions

AP, MR, MTG, and MS drafted and revised the manuscript. JK reviewed and edited the manuscript.