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Home , Methemoglobinemia, Thalassemia

Congenital Identified by Screening Jennifer Ward, BMBS,a Jayashree Motwani, MBBS,b Nikki Baker, MSc,a Matthew Nash, MBChB,a Andrew K. Ewer, MD,a,c Gergely Toldi, MDa

Congenital methemoglobinemia is a rare condition caused by cytochrome b5 abstract reductase deficiency, cytochrome b5 deficiency, or M disease. Newborn pulse oximetry screening was developed for the early detection of critical congenital heart disease; however, it also enables the early identification of other hypoxemic conditions. We present the case of a term neonate who was admitted to the neonatal unit after a failed pulse oximetry screening at 3 hours of age. Oxygen saturations remained between 89% and 92% despite an increase in . Chest radiograph and echocardiogram results were normal. A capillary gas test had normal results except for a raised level of 16%. Improvement was Departments of aNeonatology and bHaematology, seen on the administration of , which also resulted in an Birmingham Women’s and Children’s Hospital, Birmingham, increase in oxygen saturations to within normal limits. Further investigation United Kingdom; and cInstitute of Metabolism and Systems Research, University of Birmingham, Birmingham, United revealed evidence of type I hereditary deficiency as Kingdom a result of a CYB5R3 gene mutation with 2 pathogenic variants involving Drs Ward and Toldi were responsible for neonatal guanine-to-adenine substitutions. Although mild is generally the care and drafted and reviewed the manuscript; Dr only symptom of type I disease, patients may later develop associated Nash and Ms Baker were responsible for neonatal symptoms, such as and shortness of breath. If an early diagnosis is care and reviewed the manuscript; Dr Motwani provided expert advice and follow-up missed, these patients are likely to present later with a diagnostic conundrum and reviewed the manuscript; Dr Ewer acted as an and be subject to extensive investigation. This case represents the success of expert on newborn pulse oximetry screening and pulse oximetry screening in the early identification of subclinical hypoxemia drafted and reviewed the manuscript; and all authors approved the final manuscript as submitted. in this infant. After the exclusion of other pathologies, a routine investigation DOI: of capillary blood gas provided the information that led to a diagnosis, which https://doi.org/10.1542/peds.2018-2814 allowed for early and effective management. Accepted for publication Nov 8, 2018 Address correspondence to Gergely Toldi, MD, Neonatal Unit, Birmingham Women’s Hospital, Mindelsohn Way, Birmingham B15 2TG, United Kingdom. E-mail: [email protected] Methemoglobinemia is a rare condition cyanosis (the leading symptom) may in which there is an abnormally high present early, the diagnosis of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). level of methemoglobin in the blood. In congenital methemoglobinemia is methemoglobin, the iron in the often delayed in affected children Copyright © 2019 by the American Academy of Pediatrics group is in the ferric rather than the because of a failure to recognize due FINANCIAL DISCLOSURE: ferrous state of normal hemoglobin, to its low incidence. In other cases, The authors have indicated they have no financial relationships relevant to this meaning that it cannot bind oxygen. cyanosis may be mild and clinically article to disclose. Therefore, methemoglobin is not not apparent. FUNDING: No external funding. functional in oxygen carriage. Pulse oximetry screening was POTENTIAL CONFLICT OF INTEREST: The authors have In contrast with acquired developed for the early detection of indicated they have no potential conflicts of interest methemoglobinemia caused by critical congenital heart disease and has to disclose. environmental oxidizing agents, innate become a standard screening tool for reductase deficiency resulting in neonates in several countries.4,5 To cite: Ward J, Motwani J, Baker N, et al. congenital methemoglobinemia is However, pulse oximetry also allows for Congenital Methemoglobinemia Identified by a rare condition, with only a few cases the identification of other forms of Pulse Oximetry Screening. Pediatrics. 2019; 143(3):e20182814 reported in the literature.1–3 Although hypoxemic conditions, such as

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 143, number 3, March 2019:e20182814 CASE REPORT respiratory disease, , and sample was taken, revealing normal involved in converting metabolic conditions.6 results except for a raised methemoglobin to hemoglobin. It methemoglobin level of 16%. The does so by converting the ferric iron In this article, we present the case of methemoglobin level in a maternal in the heme group to ferrous iron so a term neonate who was admitted to capillary blood sample taken at the that hemoglobin can function. The the neonatal unit after a failed pulse same time was 1.1%. patient’s gene analysis revealed 2 oximetry screening. The initial pathogenic variants involving diagnosis of methemoglobinemia was Following the advice of the pediatric guanine-to-adenine substitutions. established within the first 24 hours hematology team, the patient was One of these variants has previously of life. To our knowledge, this is the given a 1 mg/kg intravenous dose of been reported in the literature as first case of congenital methylene blue, which resulted in the being pathogenic in congenital methemoglobinemia in which the methemoglobin falling to 1.1% in the methemoglobinemia type 1.8 diagnosis was facilitated by neonatal first 24 hours. This resulted in an pulse oximetry screening. improvement in oxygen saturations, The patient was discharged from the and oxygen was weaned. In addition, hospital at 2 weeks of age. She was regular ascorbic acid was commenced breastfeeding and generally well at CASE REPORT at a dose of 30 mg/kg per day orally the time of discharge. She was The patient was born postterm by divided into 4 doses. The managed after discharge and normal delivery as the third child of methemoglobin again gradually continued to have twice-weekly nonconsanguineous parents. The increased, reaching a maximum of measurements of methemoglobin delivery was uncomplicated, and there 18%, and additional doses of levels and to receive methylene blue were no risk factors for . The methylene blue were required every as required. The 2 older siblings as patient presented to the neonatal team 3 to 4 days. A limit of 10% well as both parents of the patient within 3 hours of birth after routine methemoglobin was set before giving had normal methemoglobin levels. pulse oximetry screening because both additional methylene blue. A lower preductal and postductal saturations threshold for oxygen saturations of were found to be low (right hand 92% 80% was tolerated, and oxygen was DISCUSSION and foot 94% and right hand 93% and discontinued. Standard pulse oximeters measure foot 97% on repeat). There was no Because of a raised C-reactive protein oxygen saturation by passing 2 evidence of respiratory distress, but level at 24 hours of age (maximum wavelengths of light through the because of the unexplained low 17 mg/L), the patient received 5 days tissues into a detector. By measuring saturations, the infant was screened of ; however, the blood the changes in absorbance at each for possible infection and commenced culture result was negative. wavelength, they can identify the on antibiotics. The oxygen saturations absorbance caused by hemoglobin improved to within normal limits at Hemoglobin electrophoresis revealed bound to molecular oxygen in the the time of commencing antibiotics, so a fetal hemoglobin of 71.6%, which is pulsing arterial blood. However, pulse the patient was transferred back to the normal for a newborn (range oximetry only measures the postnatal ward for routine care. After 60%–80%). Hemoglobin DNA studies percentage of bound hemoglobin, a few hours, the patient had an revealed heterozygosity for the 3.7 resulting in a false reading when additional pulse oximetry assessment kilobase single a-globin gene hemoglobin binds to something other in the postnatal ward, at which time deletion, resulting in a carrier state of than oxygen. The finding that the oxygen saturations were between a plus , which is a benign postductal saturations were initially 89% and 92%. The infant was and common condition.7 There is no found to be higher in our patient may otherwise asymptomatic but was evidence to suggest any link between be related to this inaccuracy. Because transferred to the neonatal unit for this gene deletion and standard pulse oximeters are not low-flow nasal prong oxygen therapy methemoglobinemia, and this is an capable of differentiating between and further investigation. incidental finding. Glucose-6- different forms of bound hemoglobin, phosphate dehydrogenase revealed The oxygen saturations remained including dyshemoglobins, they do normal activity. unchanged despite oxygen therapy. not necessarily distinguish between Despite an escalation of oxygen Gene analysis was performed on the severe and mild methemoglobinemia. therapy to 100% high-flow oxygen, CYB5R3 gene from which the A noninvasive method that allows for the saturations remained between cytochrome b5 reductase is the continuous measurement of 89% and 92%. A chest radiograph transcribed. This enzyme exists in 2 dyshemoglobins is co-oximetry. This and echocardiogram revealed no isoforms, soluble and membrane device employs a greater number of abnormality. A capillary blood gas bound, and the soluble form is wavelengths, allowing researchers to

Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 WARD et al determine and patients may later develop associated 4. Narayen IC, Blom NA, Ewer AK, Vento M, methemoglobin levels. symptoms, such as fatigue and Manzoni P, te Pas AB. Aspects of pulse shortness of breath. If an early oximetry screening for critical Congenital methemoglobinemia is congenital heart defects: when, how rarely diagnosed, and the true diagnosis is missed, these patients are likely to present later with and why? Arch Dis Child Fetal Neonatal incidence remains unknown. It has Ed. 2016;101(2):F162–F167 a distinct pathology and is unrelated a diagnostic conundrum and be subject to extensive investigation. 5. Plana MN, Zamora J, Suresh G, to acquired methemoglobinemia, Fernandez-Pineda L, Thangaratinam S, which occurs as a consequence of This case represents the success of pulse oximetry screening in the early Ewer AK. Pulse oximetry screening for exposure to toxins. The causes of critical congenital heart defects. identification of subclinical congenital methemoglobinemia can Cochrane Database Syst Rev. 2018;3: be cytochrome b5 reductase hypoxemia in this infant. After the CD011912 fi fi exclusion of other pathologies, de ciency, cytochrome b5 de ciency, 6. Singh A, Rasiah SV, Ewer AK. The impact 9 a routine investigation of a capillary and hemoglobin M disease. In the of routine predischarge pulse oximetry blood gas provided the information case described, there is evidence of screening in a regional neonatal unit. that led to the diagnosis of type I hereditary cytochrome b5 Arch Dis Child Fetal Neonatal Ed. 2014; reductase deficiency as a result of methemoglobinemia, which allowed 99(4):F297–F302 a CYB5R3 gene mutation. for early and effective management. Performing a capillary blood gas 7. Okpala I. Practical Management of Haemoglobinopathies. New York, NY: Hereditary cytochrome b5 reductase analysis can therefore be routinely fi fi John Wiley & Sons; 2008:40–43 de ciency is mainly classi ed into 2 recommended after a positive pulse phenotypes. Both are inherited in an oximetry screen result to aid in 8. Katsube T, Sakamoto N, Kobayashi Y, autosomal recessive pattern. Type I is . et al. Exonic point mutations in caused by an enzyme deficiency that NADH-cytochrome B5 reductase is only present in the erythrocytes, genes of homozygotes for REFERENCES which results in mild cyanosis in hereditary methemoglobinemia, types I and III: putative mechanisms homozygotes and is generally well 1. Da-Silva SS, Sajan IS, Underwood JP III. of tissue-dependent enzyme tolerated. Methemoglobin levels Congenital methemoglobinemia: a rare deficiency. Am J Hum Genet. 1991;48(4): cause of cyanosis in the newborn–a typically range from 10% to 35%. 799–808 Patients have a normal life case report. Pediatrics. 2003;112(2). expectancy, and methemoglobin Available at: www.pediatrics.org/cgi/ 9. Hegesh E, Hegesh J, Kaftory A. content/full/112/2/e158 Congenital methemoglobinemia with levels can be well controlled with adeficiency of cytochrome b5. N Engl 10 2. Kedar PS, Colah RB, Ghosh K, Mohanty methylene blue and ascorbic acid. J Med. 1986;314(12):757–761 Type II disease is less common and is D. Congenital methemoglobinemia due caused by an enzyme deficiency in all to NADH-methemoglobin reductase 10. Percy MJ, Lappin TR. Recessive deficiency in three Indian families. congenital methaemoglobinaemia: tissues, leading to both cyanosis and Haematologia (Budap). 2002;32(4): cytochrome b(5) reductase deficiency. neurologic impairment. Life 543–549 Br J Haematol. 2008;141(3):298–308 expectancy is significantly reduced because treatment has no effect on 3. Aslan D, Türköz-Sucak G, Percy MJ. 11. Ewenczyk C, Leroux A, Roubergue A, Recessive congenital et al. Recessive hereditary the neurologic dysfunction.11 methemoglobinemia in immediate methaemoglobinaemia, type II: Although mild cyanosis is generally generations. Turk J Pediatr. 2016;58(1): delineation of the clinical spectrum. the only symptom of type I disease, 113–115 Brain. 2008;131(pt 3):760–761

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 143, number 3, March 2019 3 Congenital Methemoglobinemia Identified by Pulse Oximetry Screening Jennifer Ward, Jayashree Motwani, Nikki Baker, Matthew Nash, Andrew K. Ewer and Gergely Toldi Pediatrics 2019;143; DOI: 10.1542/peds.2018-2814 originally published online February 7, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/143/3/e20182814 References This article cites 10 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/143/3/e20182814#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Neonatology http://www.aappublications.org/cgi/collection/neonatology_sub Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology _sub Blood Disorders http://www.aappublications.org/cgi/collection/blood_disorders_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 25, 2021 Congenital Methemoglobinemia Identified by Pulse Oximetry Screening Jennifer Ward, Jayashree Motwani, Nikki Baker, Matthew Nash, Andrew K. Ewer and Gergely Toldi Pediatrics 2019;143; DOI: 10.1542/peds.2018-2814 originally published online February 7, 2019;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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