Novel Compound Heterogeneous Mutations in CYB5R3 Gene Leading to Methemoglobinemia (Type I) in a Chinese Boy: Case Report and Relevant Comprehensive Analysis.

INTRODUCTION: Recessive congenital methemoglobinemia (RCM) caused by CYB5R3 deficiency due to the mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (CYB5R) gene is an autosomal recessive inherited disease. Clinically, it can be divided into two types, namely red blood cell affected type (RCM I) and systemically affected type (RCM II). CASE PRESENTATION: A 5-year-old male patient was diagnosed with cyanosis for 5 years. Physical examination showed cyanosis in areas such as the lips, fingers, and toes. Laboratory examination revealed low pulse oxygen saturation (81%) and increased blood methemoglobin (23.6%). Gene testing revealed the compound heterozygous mutations in the CYB5R3 gene, c.149G>A (p.Arg50Gln) and c.331A>G (p.Lys111Glu), respectively originating from his parents. By constructing 3D models of CYB5R3 wild-type and mutant types using SWISS-MODEL software, it was found that the mutation caused significant structural abnormalities in the CYB5R protein. The relationship between CYB5R3 gene mutation sites, amino acid change, enzyme activity, and methemoglobinemia type I and II were listed and analyzed. CONCLUSION: A case of congenital RCM type I caused by compound heterozygous mutations in the CYB5R3 gene was reported, with c.331A>G (p.Lys111Glu) being the newly reported mutation. The homozygosity or heterozygosity of CYB5R3 gene mutations that lead to premature termination, loss of exons, and change in amino acid properties in FAD or NADH binding domains, is positively correlated with the severity (from type I to type II) of methemoglobinemia.

Methemoglobinemia screening and treatment in tank warfare survivors.

INTRODUCTION: Methemoglobinemia, characterized by the conversion of functional hemoglobin to methemoglobin, can significantly impede tissue oxygenation. Prompt diagnosis and treatment of methemoglobinemia are critical to optimizing clinical outcomes. Although the underlying etiology of methemoglobinemia is often attributed to a medication reaction or chemical exposure, its association with battlefield trauma remains underexplored. This case series explores the presence of methemoglobinemia in nine soldiers evacuated from tanks targeted by explosives, shedding new light on screening needs and treatment strategies. CASES DESCRIPTION: Nine combat trauma patients with methemoglobinemia were admitted to Soroka Medical Center over a two-month period. Detailed case descriptions illustrate the diverse presentations and treatment responses. Notably, the administration of methylene blue resulted in rapid methemoglobin reductions and an improvement in oxygenation without any observed side effects. DISCUSSION: This series highlights an unexpected consequence of an explosion within an armored fighting vehicle and the challenges related to standard pulse oximetry interpretation and accuracy in the presence of methemoglobinemia, emphasizing the need for vigilant monitoring and co-oximetry utilization. Additionally, the coexistence of carboxyhemoglobin further warrants attention due to its synergistic and deleterious effects on oxygen delivery. Collaborative efforts with military authorities should aim to explore the underlying mechanisms associated with trauma and methemoglobinemia and optimize battlefield care. CONCLUSION: This case series underscores the significance of methemoglobinemia screening in combat trauma patients, and advocates for systematic co-oximetry utilization and methylene blue availability in combat zones. Early detection and intervention of methemoglobinemia in combat soldiers are often difficult in the context of battlefield injuries but are necessary to mitigate the potentially fatal consequences of this condition.

De Novo Occurrence of Hb Chile [ß28(B10) Leu→Met] in a Korean Boy with Methemoglobinemia.

Hemoglobin (Hb) Chile, a variant of Hb M, is produced by a point mutation of CTG→ATG on codon 29 (legacy codon 28) of the Hb ß locus gene, which results in an amino acid substitution of Leu→Met. It has been identified in two families worldwide and is inherited in an autosomal dominant manner. Here, we report a case of Hb Chile in which a de novo mutation was detected in the proband. A 17-year-old male presented to the outpatient clinic with a pale appearance. There was cyanosis on his lips and fingers. Blood tests indicated the existence of hemolysis, but complete blood counts revealed no anemia. Peripheral arterial oxygen saturation on pulse oximetry was 80% on room air and did not improve with oxygen supplementation. The level of methemoglobin was 15.4%. Targeted next-generation sequencing identified a heterozygous NM_000518.4(HBB):c.85C > A mutation, indicating Hb Chile. The Hb Chile mutation, on the other hand, was not discovered in his parents, implying that it arose as a result of a de novo mutation. This case highlights the necessity of suspecting Hb gene mutations in patients with unexplained chronic methemoglobinemia, even if there is no family history.

A Rare Case of Methemoglobinemia after Ifosfamide Infusion in a 3-Year-Old Patient Treated for T-ALL.

Methemoglobinemia is a potentially life-threatening, rare condition in which the oxygen-carrying capacity of hemoglobin is diminished. We present the case of a 3-year-old boy treated for T-cell acute lymphoblastic leukemia (T-ALL) who developed methemoglobinemia (MetHb 57.1%) as a side effect of ifosfamide administration. Due to his critical condition, the patient was transferred to the intensive care unit (ICU). The therapy included methylene blue administration, an exchange transfusion, catecholamine infusion, and steroids. Improving the general condition allowed for continuing chemotherapy without ifosfamide and completion of the HR2 block. Vigilance for methemoglobinemia as a very rare side effect should be widespread when using ifosfamide in the treatment protocols.

Pyrogallol Toxicosis in Horses.

Plants in the maple genus, Acer, and pistachio genus, Pistacia, have been reported to cause acute hemolysis in horses. The cause of hemolysis seems to be metabolism of gallic acids to the potent oxidant pyrogallol by enteric bacteria of the horse. Diagnosis is often tentative and circumstantial. Treatment is symptomatic and supportive and can include detoxification, fluid and electrolyte therapy, supplemental oxygen, and pain control. Corticosteroid and antioxidant therapies do not improve prognosis. Prognosis is guarded to poor but horses that survive 6 days postexposure are expected to recover.

[One case of methemoglobinemia and hemolytic anemia caused by acute nitrogen trifluoride poisoning].

This paper analyzes the pathogenesis, clinical characteristics, treatment measures and prognosis of a case of methemoglobin and hemolytic anemia caused by acute nitrogen trifluoride poisoning. The patient with occupational exposure to nitrogen trifluoride was treated immediately after the onset of illness, methemoglobin was monitored and a comprehensive examination was conducted. After comprehensive analysis, it was considered that acute nitrogen trifluoride poisoning could cause methemoglobinemia, hemolytic anemia and liver injury. The patient was disengaged and given symptomatic treatment such as oxygen therapy, methylene blue, low-dose methylpredrone, vitamin C and reduced glutathione. The prognosis of the patient is good, which provides a reference for the clinical treatment and occupational health examination of nitrogen trifluoride poisoning.

Rasburicase-induced hemolytic anemia and methemoglobinemia: a systematic review of current reports.

Since the FDA's approval of rasburicase use for treatment of tumor lysis syndrome (TLS), multiple cases of rasburicase-induced methemoglobinemia and hemolytic anemia have been reported among patients with G6PD deficiency. This study aims to provide a systematic review of cases reporting such adverse reactions to rasburicase. A literature review of published cases in PubMed, Embase, Cochrane, and Web of Science was conducted. Descriptive studies reporting cases of rasburicase-induced methemoglobinemia and/or hemolytic anemia in English were analyzed and summarized in this study. Forty-three cases, including a case from our institution, were included in this study. Most cases (60.5%) received rasburicase for TLS treatment. Almost all patients (93.8%) were tested for G6PD after rasburicase administration. The median time to symptom onset was 24 h. The median methemoglobin level was 10%, peaking after a median of 24 h. The median hemoglobin nadir was 6.1 g/dL, and most patients (n = 32) required blood transfusion. Out of 39 cases with reported outcomes, 35 patients (89.7%) recovered, while four patients (three females and one male) died. The median time to recovery was 4.5 days while the median time to death was 8 days. Screening for G6PD deficiency among high-risk patients is important but not practical in acutely severe settings. When prior screening for G6PD deficiency is not feasible, close monitoring for methemoglobinemia and hemolytic anemia is recommended. Exchange transfusion is increasingly reported as a potentially successful therapeutic modality. Ascorbic acid may provide limited benefits. Methylene blue should be avoided as it may exacerbate hemolysis among these patients.

Off with the blues: Therapeutic plasma exchange in a case of copper sulphate poisoning.

CuSO4 (Copper sulphate) poisoning though rare, is associated with high mortality. It involves multiple organ systems and if not dealt with promptly can lead to death. Supportive care and chelation therapy along with TPE (therapeutic plasma exchange), whole blood exchange or red cell exchange can be employed in management. We report such a case where swift clinical improvement was seen after TPE.

Methemoglobinemia in Hemodialysis Patients due to Acute Chlorine Intoxication: A Case Series Calling Attention on an Old Problem.

INTRODUCTION: Hemodialysis uses municipal water that must be strictly purified and sterilized to be used for that procedure. Large amounts of decontaminants are often used, such as chlorine, and if these compounds are not subsequently removed they can be transferred to the blood of patients causing complications including methemoglobinemia. METHODS: In this case series study, dialysis patients in one unit were evaluated. We reviewed clinical characteristics and laboratory findings obtained on the day when the water supply was disinfected with chlorine, with the aim to quantify methemoglobin concentrations. Our objective was to characterize the clinical presentation and management of patients who presented with methemoglobinemia on a specific index day. We also reviewed reported cases in the literature regarding this underreported complication. RESULTS: Eight patients who presented with chlorine intoxication were evaluated. The methemoglobin concentrations were between 1.3% and 7.9% (reference value 0-1%). We believe this to be caused by water containing 0.78 mg/L of total chlorine. Seven patients presented with cyanosis, 4 with dizziness, 6 with dark brown blood, 4 with dyspnea, and 4 with headache and hemolytic anemia. Subjects were treated with supplemental oxygen, methylene blue, intravenous vitamin C, blood transfusions, and increased doses of erythropoietin. No patient died, and all continued with their usual hemodialysis sessions. CONCLUSION: Acute chlorine intoxication transferred by the water used during hemodialysis sessions can present with methemoglobinemia accompanied by cyanosis, oxygen desaturation, and hemolytic anemia. Chlorine levels should be carefully monitored in the water used for hemodialysis treatment.

The first Chinese with Hb Chile leading to chronic anemia and methemoglobinemia: a case report.

BACKGROUND: Hemoglobin (Hb) Chile [ß28(B10) Leu > Met; HBB: c.85 C > A] is a rare hemoglobin variant caused by a missense mutation in the HBB gene. Only one case of Hb Chile has been reported worldwide so far. It is an unstable hemoglobin, characterized by cyanosis associated with chronic methemoglobinemia and hemolytic anemia induced by sulfonamides or methylene blue. CASE PRESENTATION: A 9-year-3-month-old girl had mild anemia of unknown etiology for more than 6 years. She had a slight pallor without other symptoms or signs. The complete blood count revealed normocytic normochromic anemia with a sometimes-elevated reticulocyte count, and the bone marrow cytology showed marked erythroid hyperplasia, but the tests related to hemolysis were normal. Therefore, the whole exome sequencing was performed and showed a heterozygous mutation for HBB: c.85 C > A. With asymptomatic methemoglobinemia confirmed later, she was eventually diagnosed with Hb Chile. CONCLUSIONS: This is the first report of Hb Chile in China and the second worldwide. This case shows that Hb Chile is clinically heterogeneous and difficult to diagnose and expands our understanding on the clinical and hematological traits of the disease.

Methemoglobinemia Secondary to Babesia Microti Infection: A Novel Case Report.

BACKGROUND: Tick-borne illnesses and methemoglobinemia have not been known to occur together in humans. Few cases have been documented in various animals of methemoglobinemia secondary to tick-borne infections. CASE REPORT: A 49-year-old man with no significant medical history presented to the emergency department from an urgent care with hypoxia saturating in the mid 80s. He also reported a pruritic rash on his back and right shoulder as well as both of his lower extremities. The rash had been present for 4 days. The patient was tachycardic and hypoxic at 90% but denied shortness of breath. He had cyanosis of the lips and fingertips and multiple erythematous, raised, ovoid lesions on the right shoulder and left lower extremity. Methemoglobin levels were elevated at 26%. He was treated with methylene blue, supplemental oxygen, and empiric doxycycline with improvement in his oxygenation. A tick-borne illness panel later tested positive for Babesia microti infection. His skin lesions resolved with the above described treatment. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Both tick-borne illnesses and methemoglobinemia are typically easily treatable with proper antimicrobial coverage and methylene blue, respectively. The current literature is bare regarding concurrent tick-borne illnesses, specifically babesiosis, and methemoglobinemia. Without knowledge and documentation of a potential link between the two conditions, hypoxia, if found to be due to methemoglobinemia, may be treated adequately, but a potentially life-threatening tick-borne illness may continue to cause damage and disease to the patient if not tested for, identified, and treated.

Hereditary Congenital Methemoglobinemia Diagnosed at the Age of 79 Years: A Case Report.

Background: Cardiopulmonary disorders are the most common cause of central cyanosis, and methemoglobinemia is often overlooked in the differential diagnosis of patients with central cyanosis. In most cases, methemoglobinemia is acquired and hereditary congenital methemoglobinemia is rare. Only a few case reports of congenital methemoglobinemia can be found in PubMed. To date, only four cases of congenital methemoglobinemia diagnosed after the age of 50 years have been reported. Case Presentation: A 79-year-old Japanese woman presented at our hospital with the chief complaints of dyspnea and cyanosis. She exhibited cyanosis of the lips and extremities, and her SpO2 was 80%, with oxygen administration at 5 L/min. Blood gas analysis revealed a PaO2 of 325.4 mmHg and methemoglobin level of 36.9%. The SpO2 and PaO2 values were dissociated, and methemoglobin levels were markedly elevated. Genetic analysis revealed a nonsynonymous variant in the gene encoding nicotinamide adenine dinucleotide cytochrome (NADH) B5 reductase 3 (CYB5R3), and the patient was diagnosed with congenital methemoglobinemia. Conclusions: It is important to consider methemoglobinemia in the differential diagnosis of patients with central cyanosis. At 79 years of age, our patient represents the oldest patient with this diagnosis. This report indicates that it is crucial to consider the possibility of methemoglobinemia regardless of the patient's age.

Suicidal sodium nitrite intoxication: a case report focusing on the postmortem findings and toxicological analyses-review of the literature.

Sodium nitrite (NaNO2) is an inorganic compound that is commonly used as a preservative (E250) in the fish and meat industry. When ingested, sodium nitrite will lead to methemoglobinemia, hypotension, and arrhythmias. An increasing trend in the use of sodium nitrite as a suicide agent has been reported. In Belgium however it remains a rare phenomenon. The ingestion of sodium nitrite is not always apparent from the death scene investigation, especially in cases of covert administration or accidental ingestion. Hence, the forensic pathologist must be aware of this trend and the postmortem changes related to the ingestion of sodium nitrite to effectively identify these cases and determine the cause and manner of death. We describe a case of fatal self-poisoning following the oral ingestion of sodium nitrite with suicidal intent. Postmortem investigations showed signs of methemoglobinemia, such as a gray-brown discoloration of lividity and a chocolate brown discoloration of the blood. Postmortem toxicological investigation revealed methemoglobinemia (35%) in cardiac blood, hypernatremia (159.6 mmol/L) in vitreous humor, and the presence of nitrite in gastric contents (1.15 g/L) and, for the first time in a forensic case, in serum (38 µg/mL). A review of the existing literature regarding cases of sodium nitrite intoxications was performed to correlate these findings.

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia.

Background and Objective: Mutations in the CYB5R3 gene cause reduced NADH-dependent cytochrome b5 reductase enzyme function and consequently lead to recessive congenital methemoglobinemia (RCM). RCM exists as RCM type I (RCM1) and RCM type II (RCM2). RCM1 leads to higher methemoglobin levels causing only cyanosis, while in RCM2, neurological complications are also present along with cyanosis. Materials and Methods: In the current study, a consanguineous Pakistani family with three individuals showing clinical manifestations of cyanosis, chest pain radiating to the left arm, dyspnea, orthopnea, and hemoptysis was studied. Following clinical assessment, a search for the causative gene was performed using whole exome sequencing (WES) and Sanger sequencing. Various variant effect prediction tools and ACMG criteria were applied to interpret the pathogenicity of the prioritized variants. Molecular dynamic simulation studies of wild and mutant systems were performed to determine the stability of the mutant CYB5R3 protein. Results: Data analysis of WES revealed a novel homozygous missense variant NM_001171660.2: c.670A > T: NP_001165131.1: p.(Ile224Phe) in exon 8 of the CYB5R3 gene located on chromosome 22q13.2. Sanger sequencing validated the segregation of the identified variant with the disease phenotype within the family. Bioinformatics prediction tools and ACMG guidelines predicted the identified variant p.(Ile224Phe) as disease-causing and likely pathogenic, respectively. Molecular dynamics study revealed that the variant p.(Ile224Phe) in the CYB5R3 resides in the NADH domain of the protein, the aberrant function of which is detrimental. Conclusions: The present study expanded the variant spectrum of the CYB5R3 gene. This will facilitate genetic counselling of the same and other similar families carrying mutations in the CYB5R3 gene.

Preclusion of methemoglobinemia caused by nitrate drugs in diabetics and nondiabetics: Possible role of Vitamin C.

The drugs containing nitrates like isosorbide dinitrate, isosorbide mononitrate and glyceryl trinitrate, etc., trigger the oxidation of hemoglobin which is manifested in the pathological disorder named methemoglobinemia. It was considered interesting to investigate the preventive roles of vitamin C towards the toxic effects of nitrate containing drugs used for the treatment of angina. The aim is to find whether these drugs need to be administered with special care to diabetic patients who are more prone to develop methemoglobinemia. Vitamin C (500 mg/day) was administered orally to reduce the methemoglobin (metHb) level in both the diabetic and nondiabetic patients consuming nitrate containing drugs regularly, keeping diabetic and nondiabetic patients not on nitrate drugs as control. Concentration of metHb and hemoglobin A (HbA) was estimated spectrophotometrically assuming the molar extinction coefficient values of metHb as 3.78 mM--1 cm--1 at 630 nm and HbA as 125,000 M --1 cm --1 at 415 nm. MetHb level was found to be lower after the treatment with vitamin C for 30 consecutive days than that before the trial with statistically significant two tailed p value. Additionally, fasting insulin level was also found to decrease after 4 weeks of consumption of vitamin C with moderate lowering of fasting serum glucose level as well, indicating a higher insulin sensitivity for the treated patients.

Understanding the EKG changes in methemoglobinemia.

Methemoglobin is a form of hemoglobin that has been oxidized, changing its heme iron configuration from the ferrous to the ferric state. Unlike normal hemoglobin, methemoglobin does not bind oxygen and as a result, cannot deliver oxygen to the tissues. At the presentation in the emergency department, an electrocardiogram (EKG) is usually performed as a reflex for patients admitted for shortness of breath to rule out acute coronary syndrome. Very limited data is available on EKG abnormalities in patients with methemoglobinemia. In this study, we retrospectively analyzed the pattern of EKG changes in patients with methemoglobinemia.

Acquired methemoglobinemia: A systematic review of reported cases.

INTRODUCTION: Acquired methemoglobinemia may cause cyanosis and tissue ischemia unresponsive to oxygen supplementation. METHODS: We performed a literature search to identify cases of acquired methemoglobinemia published between 1980 and 2020. Clinical, diagnostic, and treatment details were extracted from eligible cases. RESULTS: A total of 76 reports involving 87 cases were analyzed. The median age at presentation was 32.5 with male to female ratio of 1.6. Cyanosis and SpO2 <90 % were reported in 82 % and 60 % of cases, respectively. Dapsone or cocaine-based anesthetics were causative in 52 % of cases; most anesthetic-related cases occurred in the peri-procedural setting. Methylene blue (MB) and red cell transfusion were given in 71 % and 10 % of cases, respectively. Compared to MB untreated patients, MB treated patients were more likely to be cyanotic (91.9 % vs 54.2 %), had higher proportions (%) and levels (g/dL) of methemoglobin (MetHb) - 33.2 % vs 15.3 % and 3.1 g/dL vs 1.2 g/dL, respectively. We found that among cyanotic cases, the median MetHb level was 3.0 g/dL (0.4-12.3 g/dL) with 74 % of values ≥ 1.5 g/dL. An SaO2:SpO2 ratio of >1 was not universally present, but always coincided with an [SaO2-SpO2] delta value greater than zero. CONCLUSIONS: Cyanosis and hypoxemia were not universal findings of acquired methemoglobinemia in our series. In addition, not all patients had cyanosis at MetHb ≥ 1.5 g/dL or an SaO2:SpO2 ratio of >1. All those with an SaO2:SpO2 >1 did, however, have a delta value greater than zero - a finding not previously reported which we feel holds diagnostic value.

Near-fatal pediatric methemoglobinemia secondary to intentional sodium nitrite ingestion.

Methemoglobinemia is the result of inappropriate oxidation of hemoglobin iron groups, leading to a failure of oxygen transport and delivery, resulting in a clinical state of refractory hypoxia. Methemoglobin levels above 70% are often considered fatal. Acquired methemoglobinemia can be caused by a variety of substances, including sodium nitrite, a commercially available food preservative and color fixative. This report describes a patient presenting with a methemoglobin level of 83% secondary to intentional sodium nitrite ingestion. The methemoglobin level recorded is amongst some of the highest found in surviving patients.

A rare combination of methemoglobinemia and carboxyhemoglobinemia in pesticide poisoning.

Dyshemoglobinemias are disorders in which the haemoglobin is functionally altered and prevented from carrying oxygen. They include carboxyhemoglobin, methemoglobin, and sulfhemoglobin. This increase in abnormal haemoglobin has reduced oxygen binding capacity, which leads to decrease in total oxygen content in the blood causing anaemic-hypoxia. The anaemic-hypoxia which is present in these disorders are refractory to the oxygen supplementation and cause many systemic and life threatening complications.Many cases are reported in literature with either of haemoglobin. It is very rare to have two abnormal haemoglobin levels in the same patient. Here we discuss an uncommon case which presented to our tertiary care hospital after consuming pesticide with suicidal intention. The patient was very pale, had peripheral cyanosis,tachypnea and tachycardia and dizziness on presentation. The SpO2 of 85% was our clue to suspect methemoglobinemia which was confirmed along with carboxyhemoglobinemia on arterial blood gas saving result. Despite that patient being very unstable, she was successfully managed with 100% oxygen through High flow nasal cannula (HFNC), methylene blue and blood transfusion. The patient's signs and symptoms gradually reduced in a few days and got discharged after 2 weeks without any neurological and cardiorespiratory sequelae. An early suspicion and personalized emergency management was the key to success. As in all fields of Medicine, Emergency Medicine is also witnessing a change towards precision and personalized Medicine practice.

Local anesthetic systemic toxicity in the pediatric patient.

Lidocaine and prilocaine are local anesthetics, a class of medications which are frequently used in clinical medicine to minimize pain in a variety of procedures. They are commonly found in over-the-counter products such as topical anesthetic creams advertised to relieve localized muscle and joint pain. While safe and well-tolerated when used appropriately, an overdose of these anesthetics increases the risk for local anesthetic systemic toxicity (LAST), which in severe cases can present with seizures, cardiac dysrhythmias, and ultimately cardiovascular collapse. The reduced muscle mass of pediatric patients puts them at an increased risk of LAST due to the depot effect of the systemically absorbed anesthetic. Methemoglobinemia may also be associated with local anesthetic toxicity. Our case involves a previously healthy 15-month-old female who presented to one of our networks' emergency departments in status epilepticus following an accidental ingestion of a tube of 2.5% lidocaine/2.5% prilocaine cream. Her seizure activity was initially resistant to intraosseous benzodiazepine administration, but ultimately resolved following administration of lipid emulsion and sodium bicarbonate. Additionally, the patient had refractory hypoxia on the monitor which resolved shortly after administration of methylene blue. After stabilization, the patient was transferred to the Pediatric ICU and ultimately made a complete recovery. LAST is a life-threatening presentation which requires early recognition by clinicians, as well as an understanding of the appropriate treatment modalities. We review the assessment and management of LAST, with special focus on the pediatric patient.