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Home , Methemoglobinemia, Polycythemia

Reports 2018; volume 10:7221

Congenital missed. Upon extensive review of English misdiagnosed as literature for cases of congenital methemo- Correspondence: Dina Sameh Soliman, globinemia duetodeficiency of cytochrome Department of Laboratory Medicine and vera: Case report and review of b5 reductase, we found 23 cases diagnosed Pathology, National Center for Cancer Care literature as type I (including the case reported here). and Research, Hamad Medical Corporation, 17 cases (~74%) of type I and 6 cases (27%) PO Box 3050, 16060 Doha, Qatar. E-mail: [email protected] Dina Sameh Soliman,1,2 of type II. There is male predominance 73% 3 versus 26% in females. Almost half of Mohamed Yassin Key words: ; congenital; methe- reported cases 12 cases (52%) are Indian, 2 1 moglobinemia. Department of Laboratory Medicine Japanese, 3 English, 2 Arabic, onecase and Pathology, National Center for Spanish and one case Italian. For type I, the Contributions: the authors contributed equally. Cancer Care and Research, Hamad median calculated age is 31 years with Medical Corporation, Doha, Qatar; andshortness of breath being the Conflict of interest: the authors declare no 2Department of Clinical Pathology, most common sign andsymptoms. For type potential conflict of interest. National Cancer Institute, Cairo II: Six cases were reported in English liter- University, Cairo, Egypt; 3Department ature, all in pediatric age group with median Received for publication: 12 May 2017. Accepted for publication: 22 September 2017. of Hematology and Medical Oncology, calculated age at presentation is 6 years National Center for Cancer Care and with neurologic manifestations and mental retardation are the most common type II This work is licensed under a Creative Research, Hamad Medical Corporation, Commons Attribution-NonCommercial 4.0 associated symptoms. Due to lack of sys- Doha, Qatar International License (CC BY-NC 4.0). tematic epidemiological studies, congenital methemoglobinemia is under diagnosed as ©Copyright D.S. Soliman and M. Yassin, 2018 it is under investigated and usually over- Licensee PAGEPress, Italy looked especially when presenting in adult- Hematology Reports 2018; 10:7221 Abstract hoodandin absence of obvious acquired doi:10.4081/hr.2018.7221 Methemoglobinemia is a rare over- agents. looked in patients pre- sented with cyanosis and dyspnea unrelated Based on his persistent polycythemia, to cardiopulmonary causes. Our patient is Introduction the patientwas evaluated in other center 29 year old Indian non-smoker male, his Methemoglobinemia is a rare over- and diagnosed as polycythemiavera (PV), story started 6 months prior to presentation looked differential diagnosis in patients pre- examination revealed ery- to our center whenhehadgeneralized sented with cyanosis and dyspnea unrelated throid hyperplasia, however with no pan- fatigue and discoloration of hands. He pre- to cardiopulmonary causes. myelosis. Although molecular studies sented with persistent polycythemia with Methemoglobinemia is usually asympto- revealed negative JAK-2 mutation; the elevated hemoglobin level. The patientwas matic, even when (metHb) patientwastreated with Imatinib (Indian misdiagnosed in another center as poly- levels are as high as 40% of the total hemo- version) based on the assumeddiagnosis of cythemia andtreated with Imatinib. The globin (Hb) value.1 PV. diagnosis of PV was revisited and ruled out Hereditary congenital methemoglobine- In our institute, the patientwasre-eval- in view of negative JAK2, normal erythro- mia due to deficiency of nicotinamide ade- uated; where was found to have dusky dis- poietin level and absence of features of pan- nine dinucleotide (NADH) cytochrome b5 coloration (cyanosis) of the face and both myelosis. Clinical cyanosis andlowoxygen reductase is even extremely rare upper limbsoflongstanding history back to saturation in the presence of normal arterial recessively inherited disorder that is not nearly age of thirteenbutbecamemore evi- oxygen tension was highly suggestive of well documented in literature. dent in last one yearafter treatment with methemoglobinemia. Arterial gas Here, we report a rare case of methemo- Imatinib. He had no history of chest pain, revealed a methemoglobin level of 38% globinemia presented with persistent poly- syncopeorpalpitations with no history of (normal: 0-1.5%). Cytochrome B5 reduc- cythemia in absence of cardiopulmonary medicationsintakeor exposure to oxidant tase (Methemoglobin reductase B) was causes led to false diagnosis of poly- chemicals. There was no history of growth deficient at level of <2.6 U/g Hb) (normal: cythemiavera for which the patient need- or developmental retardation or neurologi- 6.6-13.3), consistent with methemoglobin lessly undergonebone marrow examination cal symptomsandnohepatosplenomegaly. reductase (cytochrome b5) deficiency and and received Imatinib. Oxygen saturation by hence the diagnosis of congenital methemo- showed saturation of 92%,whilethepatient globinemia was established. The role of showed no evidence of respiratory distress Imatinib in provoking methemoglobinemia and his clinical examination was unremark- is questionable and association between Case Report able. Imatinib and methemoglobinemia never The diagnosis of PV was revisited and describedbefore. In our case, there were no Our patient is 29 yearold Indian non- ruled out in view of negative JAK2, normal other offending drugs in aggravating the smoker male, his story started 6 months level and absence of features patients’ symptoms andcyanosis. The prior to presentation to our center whenhe of panmyelosis in the bone marrow biopsy, patient started on 500 mg once had generalized fatigue and discoloration of which was repeated in ourcenterfour daily for which he respondedwell with less hands (Figure 1). His CBC revealed high months after stopping treatment with cyanosis and significant reduction of red cell count6.7 (4.5-5.5 × 106/uL), elevat- Imatinib. methemoglobin level. Congenital methe- ed hemoglobin at 20 (13-17 g/dL) with nor- The patients’ clinical picture including moglobinemia is a rare underreported mal leukocyte and counts and cyanosis in absence of anyevidence of car- hemoglobin disease and often clinically unremarkable peripheral smear. diopulmonary disease; raised the possibility

[Hematology Reports 2018; 10:7221] [page 7] Case Report ofanalternative diagnosis including rare English medical literature around the world. being the most commonly reported symp- such as hemoglobin M That is why the incidence and clinical toms. disease. Hemolysis work up including characteristics of congenital Hereditary type II methemoglobinemia, hemoglobinopathies screening by high per- Methemoglobinemia is basically unknown, is global (affects both red and white blood formance liquid chromatography(HPLC) due to underreporting and of these cases. cells) and is associated with severe neuro- and manualhemoglobin electrophoresis One possible hint to thediagnosis of logic dysfunction and reduced life revealed normal hemoglobin pattern. methemoglobinemia is the presence of a expectancy.8 The enzyme’s activity is less Arterial blood gas showed thefollowing saturation gap.This occurs whenthere is a than 20%ofnormal. results: pH 7.380 (7.35-7.45), PC O2:38 difference betweentheSO2 that hasbeen Type II congenital methemoglobinemia mmHg (35-45 mmHg), NormalPO2 at: 96- measured by meansofpulse oximetry (the constitutes approximately 10% of all cases 101 mmHg (83-108), normal arterial O2 sat- lower value) and the SO2 that hasbeen cal- of congenital methemoglobinemia and usu- uration at 100% (95-99.0%), low HCO3 culated by meansofarterial blood-gas ally causes death within the first few years 21.8 (23-29mmol/L) and low oxygen satu- analysis. Typically, this saturation gap is of life.9 ration (O2 Hb): at 62.4% (94-98%). greater than 5% in cases of methemoglo- There is a significant delay in the onset 3 Clinical cyanosis andlow oxygen satu- binemia. The failure of very high oxygen of symptoms in apatientwith type I hered- ration in the presence of normal arterial saturation to correct cyanosis is very indica- itary methemoglobinemia, as most studies oxygen tension was highly suggestive of tive of methemoglobinemia. indicate thatpatients are asymptomatic in methemoglobinemia. Arterial blood gas Although methemoglobin at level of infancy andchildhood.There is a single (ABG) to check for methemoglobinemia 20% indicates enzyme deficiency, patients reported case wherein the onset of symp- performed and revealed a methemoglobin with congenital disease develop physiologi- toms in the patient started at the ageof8 10 level of 38% (normal: 0-1.5%). cal compensatory mechanisms andcantol- years. With such late presentations, treat- (Methemoglobin erate elevated levels of methemoglobin (up ing physicians would usually think of reductase B) was measured spectrophoto- to 40%) withoutsymptoms. Levels of acquired methemoglobinemia, investigating 1 metrically at Mayo Clinic Medical >70% are usually incompatible with life. exposure to an as the most Laboratories; and came deficient at level of These adaptation mechanisms include likely cause of the findings. <2.6 U/g Hb) (normal: 6.6-13.3), consistent changes in the concentration of 2,3- Clinical cyanosis is diagnostically chal- with methemoglobin reductase (cytochrome Diphosphoglycerate and pH, synthesis of lenging as causes are multiple; especially in globin chains, and secondary absence of cardiopulmonary causes. In the b5) deficiency and hence the diagnosis of 4,5 congenital methemoglobinemia was estab- polycythemia. case reported here, the cyanosis was origi- lished. Karyotyping was done to screen for Compensatory elevation of hemoglobin nally overlooked and hematology work-up chromosomal abnormalities and came nor- concentration is observed in patients with was misdirected towards investigating poly- mal. Otherfamily members were asympto- recessive hereditary methemoglobinemia, cythemia. In heterozygous cytochrome b5 matic with no family history of cyanosis or because of the methemoglobinemia- reductase deficiency, methemoglobin induced left shift in the oxyhemoglobin dis- reductase activity is low, andthepatient hemoglobin disorders. Family screening for sociation curve.6 Congenital methemoglo- will have a lower threshold for acquired methemoglobinemia cannotbeconducted. binemia is further classified into two main methemoglobinemia in response to exoge- Due to lack of oral tablets of methylene types with one due to methemoglobin nous oxidative stress. blue, the patient started on Vitamin C 500 reductase enzyme deficiency and the other The role of Imatinib in provoking mg once daily.After one month of treat- due to an abnormal oxygen affinity hemo- methemoglobinemia is questionable and ment, the cyanosis became clinically less globin termed hemoglobin M.7 association betweenImatinib and methemo- evident with significant reduction of methe- Methemoglobin reductase enzyme defi- globinemia never describedbefore. In our moglobin concentration measured by ABG ciency is either type I or type II; type I: case, there were no other offending drugs in (methemoglobin levels 19.2 %). Cytochrome b5 reductase deficiency, aggravating the patients’ symptoms and demonstrable only in theerythrocytes, pres- cyanosis. ents as uncomplicated, benign methemoglo- Whencongenital methemoglobinemia binemia, and associated with a normal life is suspected, enzyme activity in all immedi- Discussion expectancy with only fatigue and dyspnea ate family members should be evaluated. As Methemoglobin results from oxidation of ferrous iron to ferric iron within the -moiety of hemoglobin.1 In healthy individuals, less than 1% of hemoglobin is present in the oxidized form (methemoglo- bin), which has limited ability to carry oxy- gen, however with increased oxygen affini- ty at the remaining binding sites.2 This results in decrease of oxygen deliverytotis- sue leading to hypoxemiaandlactic acido- sis. Acquired methemoglobinemia caused by oxidizing agents andusuallypresents in older age groups is not uncommon; howev- er, congenital deficiency of the methemo- globin reductase enzyme is extremely rare Figure 1. Peripheral cyanosis of patient’s hand at diagnosis compared to his brothers’ that only a few cases are reported in the palm: anterior (A) and posterior view (B).

[page 8] [Hematology Reports 2018; 10:7221] Case Report 2.8 (n:<1.5%) therapy (n:<1.5%) 2.8 asthma symptoms asthma Father Indian Indian Father Japanese skeletal anomalies lympho cytes (18-31), fibrobl ast (50) (50) ast fibrobl (18-31), cytes lympho anomalies skeletal Japanese Bilateral ptosis day Aspirin Phlebotomy Aspirin day ptosis Bilateral Nationality mg/kg (vit C) treatment (%) treatment C) (vit mg/kg Nationality Italian Italian Indian microcephaly generalized C 500 twice a day Cyanosis when vit C vit when Cyanosis a day twice C 500 Indian generalized microcephaly Indian Indian Arabic dyspnea on exertion symptoms persisted symptoms exertion on dyspnea Arabic Indian Indian stopped hypertonia N/M persisted N/M Vit C (5) C (5) Vit (11.51-29.9) (11.51-29.9) Mother Indian Indian Mother Prabhakar [24] 5/F 11 Cyanosis cerebral palsy, II 51 Pos 6.0 MB (0.5) followed by vit - Re-developed Re-developed - vitby followed (0.5) MB 6.0 Pos II 51 palsy, cerebral Cyanosis 11 5/F [24] Prabhakar Vives [22] 2 year/F Spanish - Neurological symptoms II - Pos ------Pos - II symptoms Neurological Spanish- 2 year/F [22] Vives Melanie [21] English/ M Father - - I Pos 6.37 - - - - - 6.37 Pos I - - M Father [21]English/ Melanie Prabhakar [20] 34/ M 15 No symptoms I 2.8 Pos 24 Not needed - - - needed Not 24 Pos 2.8 I symptoms No 15 M 34/ [20] Prabhakar Prabhakar [24] 8/M 14 - II 42 Pos 9.60 - - - - - 9.60 Pos II 42 - 14 8/M [24] Prabhakar Prabhakar [20] 1 month/M Indian 14 Central cyanosis I 29 Pos 9.36 (30-40) MB - Good response to MB MB to - response Good MB (30-40) 9.36 Pos 29 I cyanosis Central 14 [20] Prabhakar Indian 1 month/M Author [ref] Age/Sex Hb (gm/dL) Presentation Type MetHb level Family study (NADH)-cyto b5 reductase Management (MB), (MB), Management after MetHb reductase b5 (NADH)-cyto Follow-up study Family level MetHb Type Age/Sex [ref] Author (gm/dL) Hb Presentation 4.8improved (1.5) Cyanosis MB Oral (10.1-19.4) 4.2 Pos 26 I cyanosis central Mild - days/M 24 [11] Shonola cyanosis Mild - N/M Deficient Neg 29 dyspnea I exertional -cyanosis Mild 21/MIndian [14] Yasmin and N/M Cyanosis C Vit Oral (6.6-13.3) <2.6 Pos 40 I fatigue Cyanosis 17 M 16/ [16] Badawi N/A - N/A (35.0±5.00) 16 Neg 30 I Cyanosis Syncope [17]Weakness 15 Indian 55/M Ramanamurty N/A 25 C Vit Oral value normal 5% Pos 36 I Markedcyanosis - 64/M [19] Gerli - - needed Not 20 Pos I <1.5%) (n: 7.5 REPL 14 y/F 32 [20] Prabhakar - - - I <0.1 Pos I - Mother - F/English [21] Melanie - - I 7.75 Pos I - - M English/ [21] Melanie - - - (13-27), PLT (0.3-4) RBC: - - II retardation Mental - M [23] Yawata - - - 6.21 Pos II 13 - 9 13/M [24] Prabhakar improved Symptoms - dose C high Vit - - II 24 - - 1/F [25] Nellicka (MB); ascorbic acid (vit C); not mentioned (N/M); recurrent early pregnancy loss (REPL). Londhei [10] 18/M Indian 19 Cyanosis Headache I 37 Pos (sister) 14 (30-35) Oral Vit C thrice/ 18 Cyanosis improved Cyanosis 18 C thrice/ Vit Oral (30-35)14 (sister) Pos 37 I Headache Cyanosis 19 Indian 18/M [10] Londhei Dhiraj [18] 33/M Indian 18 Incidental cyanosis I 20-30 Neg N/A N/A N/A N/A N/A N/A N/A Neg I 20-30 cyanosis Incidental 18 Indian 33/M [18] Dhiraj Badawi [16] 12/M Arabic - No symptoms I 25 Brother ------Brother 25 I symptoms No - Arabic 12/M [16] Badawi Takishe [13] 38/F japanese - Cyanosis Convulsion I 33 Neg N/M N/M N/M N/M N/M N/M N/M Neg 33 I Convulsion Cyanosis - japanese 38/F [13] Takishe Canturk [15] 20/M - Cyanosis Bronchial I 40 Pos N/M MB 8-9 MetHb decreased MetHb 8-9 MB N/M Pos 40 I Bronchial Cyanosis - 20/M [15] Canturk Table 1. Clinical characteristics Table of reported cases of Congenital Methemoglobinemia due to (NADH)-cyto b5 Reductase deficiency reported in English literature.

[Hematology Reports 2018; 10:7221] [page 9] Case Report a result of autosomal recessive transmis- 14.Hamirani YS, Franklin W, Grifka RG, sion, In heterozygous deficiency, methemo- References Stainback RF. Methemoglobinemia in a globin reductase activity is low andhence young man. TexHeart Inst J 2008; 1. Jaffe ER, Hultquist DE, et al, eds. The heterozygotes will have alower threshold 35:76-7. Metabolic and Molecular Basis of b5 for acquired methemoglobinemia in 15.Tasci C, Nevruz O,Candir N,Bilgic H. reductase deficiency and enzymopenic response to exogenousoxidative stress. Amethemoglobinemia case who was hereditary methemoglobinemia. In: However, the level of enzyme activity is not previously diagnosed and treated as Inherited Disease. 7th ed.NewYork, low enough to produce clinical disease asthma. Respir Med Case Rep NY: McGraw-Hill; 1995. pp 2267- undernormal circumstances.11 2012;6:11-12. 2280. This category of rare hemoglobin dis- 16.Badawi MA, Badawi MA, Wali SO, 2. Baraka AS, AyoubCM,Kaddoum RN, ease is underreported and often clinically Alsaggaf RZ.Hereditary methemoglo- et al.. Severe oxyhemoglobin desatura- missed, In 1943, the first description of binemia manifesting in adolescence. J tion during induction of anesthesia in a familial idiopathic methemoglobinemia in Appl Hematol 2016;7:108-10. patient with congenital methemoglo- the United Kingdom was reported in 2 17. Ramanamurthy SV. binemia. Anesthesiology2001;95: members of one family.12 Methemoglobinemia: a reappraisal with 1296-7. Upon extensive review of English liter- an Indian perspective. Available from: 3. Barker SJ, Tremper KK, Hyatt J. Effects ature for cases diagnosed as congenital www.apiindia.org/medicine_update_20 Methemoglobinemia duetodeficiency of of methemoglobinemia on pulse oxime- 13/ chap77.pdf. cytochrome b5 reductase, we found 23 try and mixed venous oximetry. 18.Trivedi DJ, Joshiraj B, Bidkar V, Rao R. cases diagnosed as type I (including the Anesthesiology 1989;70:112-7. Methemoglobinemia: living with dor- case reported here). The details of the cases 4. Kern K, Langevin PB, Dunn BM. mantdevil. Indian JClinBiochem are listed in Table 1.10-25 Methemoglobinemia after topical anes- 2017;32:248-50. Seventeen cases (~74%) of type I and 6 thesia with and 19.Gerli GC, Beretta L, Bianchi M, et al. cases (27%) of type II. There is male pre- for a difficult intubation.JClin Anesth Methemoglobinemia; a description of a , 73% versus 26% in females. 2000;12:167-72. case of NADH methemoglobulin reduc- Almost half of reported cases 12 cases 5. Maurtua MA, Emmerling L, Ebrahim tase deficiency. Minerva Med1981; (52%) are Indian, 2 Japanese, 3 English, 2 Z. Anesthetic management of a patient 72:1925-30. Arabic, onecase Spanish and one case with congenital methemoglobinemia. J 20. Kedar P, Warang P, Ghosh K, Colah R. Italian. Clin Anesth 2004;16:455-7. Recessive congenital methemoglobine- For type I, the median calculated age is 6. Fermo E, Bianchi P, Vercellati C, et al. mia due to NADH-cytochrome b5 31 years with cyanosis andshortness of Recessive hereditary methemoglobine- reductase deficiency associated with breath being the most common sign and mia: Two novel mutations in the recurrentearlypregnancy loss (REPL) symptoms. NADH- cytochrome b5 reductase gene. in an Indian family. AnnHematol For type II: Only six cases were report- Blood Cells Mol Dis 2008;41:50-5. 2012;91:1985-6. ed in English literature, all in pediatric age 7. Miller DR. Hemoglobinopathies in chil- 21.Percy MJ, Gillespie MJS,Savage G, et group with median calculated age at pres- dren.Massachusetts: PSG Publishing. al. Familial idiopathic methemoglo- entation is 6 years with neurologic manifes- 1980 binemia revisited:original cases reveal tations andmental retardation are type II 8. Melanie J. Percy1 and Terry R. Lappin. 2 novel mutations in NADH- associated symptoms. Recessive congenital methaemoglobi- cytochrome b5 reductase. Blood The modalities of treatment vary naemia: cytochrome b5 reductase defi- 2002;100:10. between:Methylene blue (MB) alone,MB ciency. Br J Hematol 2008;141:298-308 22. Vives-Corrons JL, Pujades A, Vela E, et with Ascorbic acid or Ascorbic acid alone. 9. Hirono H. Lipids of myelin, white mat- al. Congenital methemoglobin-reduc- Ascorbic acid either aloneor in combina- ter andgraymatter in a case of general- tase (cytochrome b5 reductase) defi- tion with MB was used in seven cases with- ized deficiency of cytochrome b5 ciency associated with mental retarda- in this category with no response in one reductase in congenital methemoglo- tion in aSpanish girl. Acta Haematol case,5 while the other six cases (including binemia with mental retardation.Lipids 1978;59:348-53. our case) responded well. 1980;15:272-5. 23.Yawata Y, D in g L , Tanishima K, 10. LondheyV,KhadilkarK, Gad J, et al. TomodaA.New variantofcytochrome Congenital methaemoglobinaemia: A b5 reductase deficiency (b5Rkurashiki) rare cause of cyanosis in an adult in red cells, platelets, lymphocytes, and Conclusions patient. J Assoc Physicians India cultured fibroblasts with congenital 2014;62:269-71. methemoglobinemia, mental andneuro- Due to lack of systematic epidemiolog- 11.Shonola S, Da-Silva MD. congenital logical retardation, and skeletal anom- ical studies, congenital methemoglobinemia methemoglobinemia: a rare cause of alies. Am JHematol1992;40:299-305 is under diagnosed as it is under investigat- cyanosis in an adult patient. J Assoc 24.Kedar PS1, Nadkarni AH, ed and usually overlooked especially when Physicians India 2014;62:269-71. Phanasgoankar S, et al. Congenital presenting in adulthoodandin absence of 12. Deeny J, Murdock ET, Rogan JJ. methemoglobinemia caused by Hb- obvious acquired agents. Familial idopathic methaemoglobi- MRatnagiri ((beta-63CAT—>TAT, In the present report, we highpoint this naemia. Brit MedJ1943;721. His—>Tyr) in an Indian family. Am J clinically hiddencaseofmethemoglobine- 13 Kitao T, Sugita Y, Yoneyama Y, Hattori Hematol 2005;79:168-70. mia which is misdiagnosed as polycythemia K. Methemoglobin reductase 25. Nellicka S, John A, Abraham V. vera andledto needlessly patient’s expo- (cytochrome b5 reductase) deficiency in Congenital methemoglobinemia Type sure to invasive bonemarrowprocedures congenital methemoglobinemia. Blood 2. A rare case report. Pediatric Oncall and even therapy with Imatinib. 1974;44:879-84. J 2017;14:19.

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