Congenital Methemoglobinemia: A Rare Cause of Cyanosis in the Newborn—A Case Report

Shonola S. Da-Silva, MD*; Imran S. Sajan, MD*; and Joseph P. Underwood III, MS‡

ABSTRACT. Cyanosis is a physical finding that can yanosis is a physical finding of multiple occur at any age but presents the greatest challenge when causes that can occur at any age but poses the it occurs in the newborn. The cause is multiple, and it greatest diagnostic and management chal- usually represents an ominous sign, especially when it C lenges when it involves the newborn infant. The occurs in association with neonatal sepsis, cyanotic con- clinical manifestation of cyanosis depends on the genital heart disease, and airway abnormalities. Cyanosis amount of reduced hemoglobin in the circulation. caused by abnormal forms of hemoglobin can also be Approximately 5 g/dL reduced hemoglobin is re- life-threatening, and early recognition is mandatory to quired to produce the clinical manifestation of cya- prevent unnecessary investigations and delay in manage- nosis in disorders involving deoxygenated hemoglo- ment. Abnormal hemoglobin, such as hemoglobin M, is bin. However, only 1.5 g/dL is required for disorders traditionally discovered by electrophoresis, so the new- involving nonfunctional hemoglobin.1 The differen- born screen, which is mandatory in several states, is a tial diagnosis of cyanosis therefore can be divided useful tool for the diagnosis. Although acquired methe- moglobinemia, caused by environmental oxidizing into 2 major groups: disorders involving deoxygen- agents, is common, congenital deficiency of the innate ated hemoglobin and disorders of abnormal hemo- reducing enzyme is so rare that only a few cases are globin. The former and more common group can be documented in the medical literature around the world. further categorized on the basis of anatomic location We present a neonate with cyanosis as a result of con- of the disorder: the central nervous system and mus- genital deficiency of the reduced nicotinamide adenine cle, the upper airway, the lungs, the heart, and the dinucleotide-cytochrome b5 reductase enzyme. This in- circulatory system. fant was found to be blue at a routine newborn follow-up Abnormal forms of hemoglobin such as methemo- visit. Sepsis, structural congenital heart disease, prenatal globin can also cause cyanosis when present in sig- administration, and ingestion of oxidant dyes were ex- nificant amounts. Methemoglobinemia is an uncom- cluded as a cause of the cyanosis by history and appro- mon clinical problem in the newborn infant and priate tests. Chocolate discoloration of arterial blood pro- when present is usually caused by environmental vided a clue to the diagnosis. A normal newborn screen toxicity from strong oxidizing agents and only very and hemoglobin electrophoresis made the diagnosis of rarely from an inherited disorder of hemoglobin me- hemoglobin M unlikely as the cause of the methemoglo- tabolism.2–5 Although an autosomal recessive form binemia (Hb A 59.4%, A2 1.8%, and F 38.8%). Red blood of methemoglobinemia was described in 1845, it is so cell enzyme activity and DNA analysis revealed a ho- rare that no known incidence and prevalence has mozygous form of the cytochrome b5 reductase enzyme been established.6 deficiency. He responded very well to daily methylene blue and ascorbic acid administration, and he has normal CASE REPORT growth and developmental parameters, although he shows an exaggerated increase in his methemoglobin A 24-day-old 3.4-kg infant was seen in the office for a routine postnatal follow-up appointment. He was born at full term from level with minor oxidant stress such as diarrhea. Pediat- spontaneous vaginal delivery to a 26-year-old gravida 5 mother rics 2003;112:e158–e161. URL: http://www.pediatrics.org/ with full antenatal care and no perinatal problems. Apgar score cgi/content/full/112/2/e158; cyanosis, methemoglobinemia, was 8 and 9 at 1 and 5 minutes, respectively. He was discharged newborn, NADPH-cytochrome b5 reductase. from the hospital on the second day after his first hepatitis B immunization. He had been well since discharge, taking approx- imately 4 oz of premixed formula every 4 hours, and his devel- ABBREVIATIONS. PRBC, packed red blood cell; NADH, reduced opment had been appropriate. His mother did not recognize that nicotinamide adenine dinucleotide. his coloration was unusual and denied use of any medications. Parental consanguinity was denied. Mild central cyanosis was noted on physical examination. Pulse oximetry was 87% in room air, so he was transferred to the emergency department of our regional children’s hospital. In the From the *Division of Pediatric Critical Care Medicine, Children’s Regional emergency department, the vital signs were T° 99°F, heart rate Hospital, Cooper Hospital/University Medical Center, Camden, New Jer- 182/min, respiratory rate 36/min, saturation on pulse oximetry sey; and ‡University of Medicine and Dentistry, Robert Wood Johnson 91% with fraction of inspired oxygen 1.0 and a Dextrostix of 78 Medical School, Camden, New Jersey. mg/dL. Blood pressure measurement could not be obtained, de- Received for publication Nov 25, 2002; accepted Apr 21, 2003. spite rapid infusion of 20 mL/kg crystalloid fluids. He continued Reprints requests to (S.S.D.) Division Head, PCCM, Children’s Regional to appear dusky and cyanotic and was electively intubated with a Hospital, Cooper Hospital/University Medical Center, Camden, NJ 08103. presumed diagnosis of septic shock. Appropriate cultures were E-mail: [email protected] obtained, broad-spectrum intravenous antibiotic coverage was PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- started, and he was transferred to our multidisciplinary pediatric emy of Pediatrics. intensive care unit.

e158 PEDIATRICS Vol.Downloaded 112 No. 2 from August www.aappublications.org/news 2003 http://www.pediatrics.org/cgi/content/full/112/2/ by guest on September 27, 2021 e158 Chest radiograph revealed a normal heart shadow with clear rocytes arises as a consequence of either an acceler- lung fields. Echocardiography confirmed a normal cardiac anat- ation of an oxidation reaction or a diminution of a omy with adequate function. On obtaining femoral arterial access, 2 his blood had a dark chocolate appearance despite documentation reduction reaction, ie, a redox imbalance. In cases of of arterial pulsations and a transduced arterial wave form on the acquired methemoglobinemia, the erythrocytes are cardiorespiratory monitor. His initial hematocrit was 20%, prob- presented with an enormous exogenous oxidant load ably iatrogenic as a result of technical difficulty in obtaining that simply overwhelms the protective cellular re- vascular access and multiple fluid boluses, so he was given a 20 duction mechanisms. Conversely, in cases of congen- mL/kg packed red blood cell (PRBC) transfusion, which im- proved his hematocrit to 30%. ital methemoglobinemia, cytochrome b5 reductase Arterial blood gas analysis revealed a pH 7.42/Paco2 36/PaO2 activity is diminished and there is a resultant de- Ϫ 334/HCO3 24/base deficit 2 with a calculated hemoglobin sat- crease in the rate of methemoglobin reduction. The uration of 100% on fraction of inspired oxygen 1.0. Serum lactic ϭ oxidant load under these circumstances is derived acid was 1.2 mmol/L (n 0.5–1.6). Serum methemoglobin level 8 was 26.0% and carboxyhemoglobin was 0.2% by co-oximetry. from endogenous sources. There was no clinical or culture support for sepsis, and he was In 1845, Francois, a French physician, described a quickly weaned off the ventilator and extubated to room air, patient with enduring congenital cyanosis in the ab- which he tolerated very well with oxygen saturations on pulse sence of any obvious cardiac or pulmonary dysfunc- oximetry ranging between 87% and 94%. tion.6 Although this was the first documented case of He received a diagnostic dose of methylene blue, 2 mg/kg on the second day of admission. He tolerated the dose without side congenital methemoglobinemia in the professional effects. Methemoglobin level 12 hours after the methylene blue literature, it was not until 1932 that Hitzenberger was 7.9% dropping to 1.5% 24 hours after the medication. recognized idiopathic cyanosis to be a familial ail- Over the next 3 days, monitored in the PICU, fed only pre- ment.9 In the 1940s, Gibson10,11 argued and subse- mixed infant formula, his methemoglobin level increased to 28.6% with no change in his clinical status. Daily serum lactic acid levels quently showed that there was a diminution in the remained Ͻ2.0 mmol/L. ability of the erythrocytes to reduce methemoglobin He developed diarrhea, averaging 8 stools/d with a subsequent in such individuals. increase in the methemoglobin level to 44% and significant met- In 1959, Scott and Griffith12 identified the enzyme abolic acidosis. The diarrhea resolved with a change to soy-based responsible for reducing methemoglobin in normal formula, and his acidosis resolved with fluid replacement. At this point, a deficiency in reduced nicotinamide adenine erythrocytes. They called this NADH-requiring en- dinucleotide (NADH)-cytochrome b5 reductase was suspected, zyme diaphorase. Now generally referred to as and whole blood samples from the infant and his parents and 2 NADH-cytochrome b5 reductase, a functional defi- full siblings were obtained. The samples were analyzed for cyto- ciency in this enzyme is universally recognized as chrome b5 reductase (methemoglobin reductase B) enzyme activ- ity. This assay was performed spectrophotometrically by measur- the underlying cause of congenital methemoglobin- 13 ing the oxidation of NADH at a wavelength of 340 nm. The test emia. In 1986, Jaffe proposed a clinical-biochemical was performed by the Mayo Clinics laboratories. His initial en- classification scheme based on important differences zyme activity level was 7.2 IU/g (n 10.1–19.4 IU/g). This level, in the pathophysiology of the disorder. Accordingly, although low according to the established range at the Mayo he asserted that hereditary enzymopenic methemo- Clinic, was falsely elevated as a result of the PRBC transfusion. The enzyme activity level was repeated after 3 months, an ade- globinemia could be stratified into 4 distinct classes quate interval for destruction of most of the transfused PRBC. The or types. Type 1, the most common and least debil- repeat level was 4.2 IU/g. This is consistent with a homozygous itating, involves a deficiency in cytochrome b5 reduc- deficiency of the cytochrome b5 reductase enzyme (Table 1). tase limited to erythrocytes.7,14 Type 2 congenital The infant was started on daily oral methylene blue (1.5 mg/ kg) and ascorbic acid (5 mg/kg). Methemoglobin level remained methemoglobinemia is more pervasive and is asso- 4.8%, and he was discharged from the hospital with only mild ciated with a generalized systemic deficiency affect- central cyanosis. ing a multitude of tissues, particularly the central nervous system.14–16 After additional study with a DISCUSSION more sensitive assay, type 3 hereditary enzymopenic Methemoglobin is produced from oxidation of fer- methemoglobinemia was shown by Nagai et al17 to ϩ ϩ rous iron (Fe2 ) to ferric iron (Fe3 ) within the heme be virtually identical to type 1. As such, an indepen- moiety of hemoglobin.7 Methemoglobin, which nor- dent type 3 classification was proved to be superflu- mally constitutes Ͻ1% of the total hemoglobin, can- ous and is not currently used. Type 4 is unique in not carry oxygen. Furthermore, as a consequence of that it does not actually involve a deficiency in the allosteric interactions within the molecule, there is an cytochrome b5 reductase itself. This class of the dis- increased affinity for oxygen at the remaining bind- ease, which has been reported only in a single case, is ing sites, causing a left shift in the oxygen dissocia- manifested by an attenuated concentration of cyto- tion curve.3 Both of these phenomena contribute to a chrome b5.18 reduction in the delivery of oxygen to tissues and, if Type 1 presents with little more than visible cya- severe enough, hypoxemia and lactic acidosis. nosis. In the words of Jaffe and Hultquist, “These Elevation of the methemoglobin content of eryth- patients are really more blue than sick.”7 Although the slate gray, bluish appearance of these infants may be alarming to physicians who are unaware of the TABLE 1. NADH-Cytochrome b5 Reductase Activity underlying pathophysiology, the methemoglobin- Father Mother Sibling A Sibling B Proband emia is usually well tolerated. These individuals gen- Enzymatic 9.2 7.7 8.4 7.5 7.2 erally do not become symptomatic until their methe- Activity 4.2† moglobin levels exceed 25% of the total hemoglobin, (IU/g)* and the most commonly reported symptoms are be- * Normal Mayo Clinics enzymatic activity range 10.1 to 19.4 IU/g. nign, including headache, fatigue, and exertional † Repeat level 3 months after transfusion. dyspnea.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/112/2/ by guest on September 27, 2021 e158 e159 Type 2 congenital methemoglobinemia does not hemoglobin reductase activity is low, as seen in both run such a benign course. It constitutes approxi- parents of our patient. Heterozygotes (both parents mately 10% of all cases and usually causes death and the 2 siblings) will have a lower threshold for within the first few years of life.7 The severity of acquired methemoglobinemia in response to exoge- disease is a direct consequence of the global defi- nous oxidative stress. However, their level of en- ciency in NADH-cytochrome b5 reductase activity zyme activity is not low enough to produce clinical that characterizes this class of the disorder. The dis- disease under normal circumstances. All other mem- tinguishing feature of type 2 and the sine qua non is bers of our patient’s family had methemoglobin lev- an unremitting, progressive neurologic deteriora- els below 2%. tion. First described in a paper published in the In the treatment of hereditary enzymopenic met- British Medical Journal, this fulminant disease is asso- hemoglobinemia, many variables have to be taken ciated with mental retardation, microcephaly, opis- into consideration. Often, patients will remain com- thotonus, athetoid movements, and generalized hy- pletely asymptomatic. However, methemoglobin- pertonia.14 emia causes a leftward shift of the oxygen-hemoglo- Individuals with congenital methemoglobinemia bin dissociation curve. Furthermore, in the neonatal will typically present with cyanosis in the neonatal period, there is a persistence of fetal hemoglobin and period. In managing a cyanotic patient, physicians a more pronounced difficulty of oxygen dissociation will often obtain an arterial blood gas analysis, in at the cellular level. These factors, combined with the addition to monitoring pulse oximetry. Unfortu- deleterious effects of reduced arterial oxygen content nately, the patient with methemoglobinemia will of- in the neonatal period, make it reasonable to attempt ten have normal values for both. In interpreting ar- to keep the methemoglobin level under 10% during terial blood gas data, the clinician must remember this period.2 that the Pao2 refers to the amount of dissolved oxy- Methylene blue is the treatment of choice for se- gen in the blood and in no way reflects hemoglobin vere methemoglobinemia.2,21 In the presence of nic- saturation and thus arterial oxygen content. Patients otinamide adenine dinucleotide phosphate with life-threatening methemoglobinemia may have (NADPH), methylene blue is converted to leucom- a normal Pao2 and a falsely elevated pulse oximetry ethylene blue, which results in nonenzymatic reduc- reading.19 tion of methemoglobin.2,22 Ascorbic acid directly re- Unlike a pulse oximeter, which measures light ab- duces methemoglobin, but the rate of the reaction is sorbance at 2 wavelengths (660 nm and 940 nm, too slow for it to be effective when used alone.10 corresponding to the absorption of oxyhemoglobin Finally, if the combination of ascorbic acid and meth- and deoxyhemoglobin, respectively), a co-oximeter ylene blue fails to reduce the methemoglobin level, measures light absorbance at 4 different wave- then hyperbaric oxygen and exchange transfusions lengths. These wavelengths correspond to the ab- are alternative therapy.21 sorption characteristics of deoxyhemoglobin, oxyhe- Our patient demonstrated all of the classical fea- moglobin, carboxyhemoglobin, and methemoglobin. tures of congenital methemoglobinemia on presenta- As a consequence, co-oximetry can distinguish be- tion. He was treated in the emergency department as tween these 4 configurations while providing a more a child in septic shock as a result of the usual pre- accurate measurement of oxygen saturation. There- sentation of a rare disease. His initial level of the fore, in patients who present with cyanosis of uncer- cytochrome b5 reductase enzyme level was skewed tain cause, co-oximetry measurements are a valuable as a result of the PRBC transfusion. A repeat level 3 diagnostic tool.2 months after the transfusion revealed his actual en- Hemoglobin electrophoresis is also a very helpful zyme level of 4.2. It is impossible at this point to adjunct in differentiating the different causes of con- determine whether he will be classified as having genital cyanosis. It will identify hemoglobin M, a type 1 or 2. This has significant prognostic implica- hemoglobin variant that causes cyanosis as a result tions, and full genetic analysis of the family is in of structural changes in the ␣ or ␤ chains that stabi- progress. In summary, congenital methemoglobin- lize the hemoglobin in the ferric state. These struc- emia is a very rare but treatable cause of neonatal tural changes are attributable to amino acid substi- cyanosis that should be considered in the differential tutions at positions close to the heme groups in the diagnosis of cyanosis and septic shock in the neona- hemoglobin molecule. Cyanosis is noticed at birth or tal period. within 4 to 6 months thereafter. Once the diagnosis of methemoglobinemia has REFERENCES been made, there are various assays available to 1. 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