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Year : 2016  |  Volume : 7  |  Issue : 3  |  Page : 108-110

Hereditary methemoglobinemia manifesting in adolescence

1 Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Hematology, King Abdulaziz University, Jeddah, Saudi Arabia
3 Department of Medicine, King Abdullah Medical City, Makkah, Saudi Arabia

Date of Web Publication26-Oct-2016

Correspondence Address:
Maha A Badawi
Department of Hematology, Faculty of Medicine, King Abdulaziz University, P.O. Box 80215, Jeddah 21589
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1658-5127.192983

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Methemoglobinemia is an uncommon cause of cyanosis that may present at any age. Although acquired methemoglobinemia secondary to exposure to oxidative stressors is the most common cause of methemoglobinemia in adults, hereditary methemoglobinemia has to be considered in patients presenting with cyanosis during infancy and childhood. We report the case of a patient who was investigated for cyanosis that was only noted at the age of 15 years. Despite the negative family history, he was diagnosed with hereditary autosomal recessive methemoglobinemia with no other factors that can be identified to cause such an elevation of methemoglobin level. This case illustrates that hereditary methemoglobinemia has to be considered in such patients even if they were completely asymptomatic for many years of their lives.

Keywords: Cyanosis, cytochrome b5 reductase deficiency, methemoglobinemia

How to cite this article:
Badawi MA, Badawi MA, Wali SO, Alsaggaf RZ. Hereditary methemoglobinemia manifesting in adolescence. J Appl Hematol 2016;7:108-10

How to cite this URL:
Badawi MA, Badawi MA, Wali SO, Alsaggaf RZ. Hereditary methemoglobinemia manifesting in adolescence. J Appl Hematol [serial online] 2016 [cited 2022 Nov 27];7:108-10. Available from: https://www.jahjournal.org/text.asp?2016/7/3/108/192983

  Introduction Top

Methemoglobinemia is an uncommon cause of cyanosis that results from oxidation of the ferrous (Fe++) iron of heme to the ferric (Fe+++) state. This results in reduced ability of the red blood cells to release oxygen to the tissues leading to tissue hypoxia and functional anemia.[1]

Methemoglobinemia can be congenital or acquired. Congenital methemoglobinemia is commonly caused by deficiency of cytochrome b5 reductase, the reducing enzyme of methemoglobin. Additional causes of congenital methemoglobinemia include hemoglobin M disease or cytochrome b5 deficiency. Methemoglobinemia may also be acquired following exposure to an oxidative agent, including certain medications.

Congenital methemoglobinemia is a disease that typically presents in infancy. When an adolescent or an adult presents with methemoglobinemia, the evaluation usually starts with the search for exposure to oxidative stressors. In this study, we discuss a patient with congenital autosomal recessive methemoglobinemia who did not have cyanosis or features suggestive of the disease until the age of 15 years. This is the most delayed presentation reported in the literature.

  Case History Top

A 16-year-old male patient, who previously appeared normal, presented with blue discoloration of the lips and finger tips [[Figure 1] and [Figure 2]]. The patient’s family and teachers had noticed a sudden blue discoloration of his lips 1 year prior to presentation. The blue discoloration remained constant throughout the year and was not related to cold exposure or high altitude. The patient also reported experiencing fatigue, shortness of breath on exertion, and headache after climbing stairs. All of these associated symptoms started at the same time when the blue discoloration was noticed. He had no other respiratory or cardiovascular symptoms. He did not have any illnesses during his infancy and childhood. The systemic review was otherwise unremarkable. He was not taking any medications and denied smoking and using illicit drugs. There is consanguinity in the family as his parents are from the same tribe. He had six brothers who were completely asymptomatic. There was no family history of cyanosis or hemoglobin disorders.
Figure 1: Blue discoloration of the lips

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Figure 2: Blue discoloration of the finger tips

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Physical examination revealed central cyanosis. Vital signs were within normal limits. The remainder of the physical examination, including full respiratory and cardiovascular systems, was unremarkable.

An echocardiogram and a chest CT scan did not show any structural abnormality.

The results of the complete blood count were as follows: white blood cell count 3.66 × 103/μL, red blood cell count 5.51 × 106/μL, hemoglobin 17 g/dL, mean corpuscular volume 88 fL, red cell distribution 12.6%, hematocrit 48.5%, and platelet count 361 × 103/μL. Arterial blood gas showed the following results: pH 7.385, pCO2 37.8 mmHg, pO2 125.6 mmHg, HCO3 22.2 mmol/L, O2 saturation 97.7%, and methemoglobin 40%. On repeating the test on a different occasion, the methemoglobin level was 38%.

Cytochrome b5 reductase (methemoglobin reductase) enzyme activity was measured spectrophotometrically at Mayo Medical Laboratories, and the level was <2.6 U/g Hb (reference value 6.6–13.3 U/g Hb).

Although the hemoglobin electrophoresis showed a wide peak tracing of unknown significance, molecular testing of alpha- and beta-hemoglobin genes did not show any additional hemoglobinopathy or thalassemia.

The patient was started on oral vitamin C therapy without significant change in his symptoms.

Family screening showed that one of his brothers, who was 12 years of age at the time of testing, had a methemoglobinemia level of 25%. The patient was lost to follow-up before the exact mutation of CYB5R3 could be identified.

  Discussion Top

Naturally, 1% of hemoglobin can exist in the methemoglobin form. Although levels of 20% indicate enzyme deficiency, symptoms are expected to be seen when the level is at 25% or more. Levels of >70% are usually incompatible with life.[2]

There are 40 different mutations that can affect the CYB5R3 gene that encodes the cytochrome b5 reductase.[3] Some of these mutations are responsible for cytochrome b5 reductase deficiency type 1 while some cause cytochrome b5 reductase deficiency type 2. Although type 1 tends to affect the red blood cells only, type 2 involves many cell lines and is more severe with significant neurological involvement.

In heterozygous cytochrome b5 reductase deficiency, methemoglobin reductase activity is low, and the patient will have a lower threshold for acquired methemoglobinemia in response to exogenous oxidative stress. However, the level of enzyme activity is not low enough to produce clinical disease under normal circumstances.

In our patient, his symptoms began late, and he was absolutely asymptomatic in his childhood. He had normal growth and development. Cyanosis was completely absent up to the age of 15, and this was confirmed by the authors by viewing childhood pictures of the patient. There is a significant delay in the onset of symptoms in a patient with hereditary methemoglobinemia, as most studies indicate that patients are symptomatic in infancy and childhood. There is a single reported case wherein the onset of symptoms in the patient started at the age of 8 years,[4] i.e., 7 years younger than our patient. With such late presentations, treating physicians would usually think of acquired methemoglobinemia, with exposure to an oxidative stress as the most likely cause of the findings. In our patient, on assessing a full list of potential stressors, he and his mother denied any recent exposure to unusual chemicals or fumes. Their water for consumption is obtained from the public water network of desalinated water, and not from water wells. There was no obvious increased dietary intake of nitrites.

The other uniqueness in our patient is that he had a completely normal infancy. Infants are particularly susceptible to methemoglobinemia until the age of 4 months, as the activity of cytochrome b5 reductase is reduced (50–60% of adults). Fetal hemoglobin is also more easily oxidized than HbA.[5]

Patients with congenital disease develop physiological adaptations and can tolerate elevated levels of methemoglobin (up to 40%) without symptoms. These adaptations include changes in the concentration of 2,3-Diphosphoglycerate and pH, synthesis of globin chains, and polycythemia.[6],[7] Compensatory elevation of hemoglobin concentration is observed in patients with recessive hereditary methemoglobinemia, because of the methemoglobinemia-induced leftward shift in the oxyhemoglobin dissociation curve.[8]

In summary, this case illustrates that patients with hereditary autosomal recessive methemoglobinemia may have a delay in the onset of symptoms in comparison to cases previously reported in the literature. Although assessment for acquired causes of methemoglobinemia is essential in all cases, investigations for hereditary methemoglobinemia may be required, even in the absence of a significant family history.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: From diagnosis to treatment. Rev Bras Anestesiol 2008;58:651-64.  Back to cited text no. 1
Jaffé ER. Methemoglobin pathophysiology. Prog Clin Biol Res 1981;51:133-51.  Back to cited text no. 2
Percy MJ, Lappin TR. Recessive congenital methaemoglobinaemia: Cytochrome b(5) reductase deficiency. Br J Haematol 2008;141:298-308.  Back to cited text no. 3
Londhey V, Khadilkar K, Gad J, Chawla B, Asgaonkar D. Congenital methaemoglobinaemia: A rare cause of cyanosis in an adult patient. J Assoc Physicians India 2014;62:269-71.  Back to cited text no. 4
Greer FR, Shannon M, American Academy of Pediatrics Committee on Nutrition, American Academy of Pediatrics Committee on Environmental Health. Infant methemoglobinemia: The role of dietary nitrate in food and water. Pediatrics 2005;116:784-6.  Back to cited text no. 5
Kern K, Langevin PB, Dunn BM. Methemoglobinemia after topical anesthesia with lidocaine and benzocaine for a difficult intubation. J Clin Anesth 2000;12:167-72.  Back to cited text no. 6
Maurtua MA, Emmerling L, Ebrahim Z. Anesthetic management of a patient with congenital methemoglobinemia. J Clin Anesth 2004;16:455-7.  Back to cited text no. 7
Fermo E, Bianchi P, Vercellati C, Marcello AP, Garatti M, Marangoni O et al. Recessive hereditary methemoglobinemia: Two novel mutations in the NADH-cytochrome b5 reductase gene. Blood Cells Mol Dis 2008;41:50-5.  Back to cited text no. 8


  [Figure 1], [Figure 2]

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