A Rare Culprit of Methemoglobinemia.

Methemoglobinemia is a rare cause of hypoxia and can be a diagnostic challenge early in the disease course. The incidence of medication-induced methemoglobinemia is more common than congenital-related methemoglobinemia. The most common cause of methemoglobinemia is exposure to household detergents, illicit drugs, or medications with nitrate or sulfonamide chemical groups. The 2 main medications accounting for up to 45% of medication-induced cases are dapsone and benzocaine. We report a case of hypoxia and diarrhea with an arterial blood gas (ABG) showing methemoglobinemia at 26%. Infectious and autoimmune workup were negative. Methemoglobinemia level returned to normal level within 2 weeks of hydrochlorothiazide discontinuation, suggesting medication-induced methemoglobinemia at appropriate hypertension dosage. In this case, there was an acute rise in methemoglobin levels following initiation of an hydrochlorothiazide-losartan combination, which improved following the discontinuation of hydrochlorothiazide. Extensive workup ruled out cytochrome b5 reductase (Cb5R) and Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which raised the suspicion of hydrochlorothiazide-induced methemoglobinemia, as it is part of the sulfa drug family.

Heme-bound tyrosine vibrations in hemoglobin M: Resonance Raman, crystallography, and DFT calculation.

Hemoglobins M (Hbs M) are human hemoglobin variants in which either the α or ß subunit contains a ferric heme in the α2ß2 tetramer. Though the ferric subunit cannot bind O2, it regulates O2 affinity of its counterpart ferrous subunit. We have investigated resonance Raman spectra of two Hbs, M Iwate (α87His → tyrosine [Tyr]) and M Boston (α58His → Tyr), having tyrosine as a heme axial ligand at proximal and distal positions, respectively, that exhibit unassigned resonance Raman bands arising from ferric (not ferrous) hemes at 899 and 876 cm-1. Our quantum chemical calculations using density functional theory on Fe-porphyrin models with p-cresol and/or 4-methylimidazole showed that the unassigned bands correspond to the breathing-like modes of Fe3+-bound Tyr and are sensitive to the Fe-O-C(Tyr) angle. Based on the frequencies of the Raman bands, the Fe-O-C(Tyr) angles of Hbs M Iwate and M Boston were predicted to be 153.5° and 129.2°, respectively. Consistent with this prediction, x-ray crystallographic analysis showed that the Fe-O-C(Tyr) angles of Hbs M Iwate and M Boston in the T quaternary structure were 153.6° and 134.6°, respectively. It also showed a similar Fe-O bond length (1.96 and 1.97 Å) and different tilting angles.

A case of congenital methaemoglobinaemia with secondary polycythemia.

Haemoglobin contains iron in a ferrous form. When the iron is oxidized, it is called Methaemoglobin (MetHb). MetHb leads to tissue hypoxia, cyanosis, and secondary polycythemia. Methaemoglobinaemia is acquired or congenital. In this case, a 22-years-old male patient presented with cyanosis, headache, and lack of concentration. Cyanosis was present since birth. His previous investigations showed polycythemia. He was misdiagnosed on multiple occasions and was undergoing venesections for polycythemia. On evaluation at a private clinic, an Oxygen saturation gap was noted between the results of the pulse oximeter and arterial blood gas analyzer. This raised suspicion on the presence of MetHb. He was referred to Armed Forces Institute of Pathology, Rawalpindi for further workup.The sample obtained for MetHb was chocolate brown in colour. Analysis was done via co-oximetry. A high level of MetHb (45.6%) was obtained. All other radiological and haematological investigations were in the normal range. On the basis of history, clinical presentation, and investigations, he was diagnosed as a case of congenital methaemoglobinaemia with secondary polycythemia.

Case Report: Congenital Methaemoglobinaemia Type 1: Benign Cyanosis?

Type 1 congenital methaemoglobinaemia is a rare cause of cyanosis which may manifest in affected individuals during concomitant illness. Treatment indications and aims differ from that of acquired methaemoglobinaemia. Type 1 methaemoglobinaemia is a distinct condition from the type 2 form which has a high mortality rate in infancy. A 25 year old male with known type 1 congential methaemoglobinaemia presented with cyanosis in the context of Influenza A with raised methaemoglobin levels on arterial blood gas analysis. The patient was assessed based on his level of 'functional haemoglobin' with no acute indication for IV methylene blue or ascorbic acid. Consideration could be given to prescription of these on a cosmetic basis for some patient populations.

Baby boy blue and mommy too! A rare case of methaemoglobinaemia presenting simultaneously in a mother-neonate pair.

Methaemoglobinaemia occurs when there is >1% methaemoglobin in erythrocytes. In an infant, they can present either congenitally or in an acquired form. We present a rare case of methaemoglobinaemia presenting simultaneously in a mother and infant pair. The mother and infant were discharged well on Day-4 post-delivery with both mother and baby recording oxygen saturation levels of 100%. On Day-7, during a routine clinic visit, they were incidentally found to be centrally cyanosed. There were no other abnormalities. On investigation, the methaemoglobin levels were elevated in the infant (23.9%) and mother (14.3%). Treatment with ascorbic acid normalised mother's methaemoglobin levels; but baby's levels remained high until the administration of oral methylene blue. Both baby and mother remained well and pink at last follow-up at 2 years 8 months of age. This case illustrates difficulties in ascertaining the cause of methaemoglobinaemia. Postdelivery, the mother-neonate pair were pink, and their haemoglobin electrophoresis were normal, hence it was unlikely to be congenital methaemoglobinaemia. The team could not identify any triggering factors for acquired methaemoglobinaemia. There was also the uncertainty of the necessity to treat the baby. This is because treatment is not without harmful effects and despite the high methaemoglobin levels, the infant was otherwise well. Only a single published paper recommended that high methaemoglobin levels must be treated, and the recommendation was not supported by evidence. Lessons learnt from our case are that neonates with methaemoglobinaemia can be safely treated with oral methylene blue, but more research is needed on the benefitrisk profile of treatment.

Interpreting sulfhemoglobin and methemoglobin in patients with cyanosis: An overview of patients with M-hemoglobin variants.

INTRODUCTION: Methemoglobin (MetHb) and sulfhemoglobin (SHb) measurements are useful in the evaluation of cyanosis. When one or both values are elevated, additional analysis is important to establish the etiology of the disorder. Methemoglobinemia occurs from acquired or hereditary causes with diverse treatment considerations, while true sulfhemoglobinemia is only acquired and treatment is restricted to toxin removal. Some toxic exposures can result in a dual increase in MetHb and SHb. Hereditary conditions, such as M-Hemoglobin variants (M-Hbs), can result in increased MetHb and/or SHb values but are clinically compensated and do not require treatment if they are cyanotic but otherwise clinically well. METHODS: Herein, we report 53 hemoglobin variant cases that have associated MetHb and SHb levels measured by an adapted Evelyn-Malloy laboratory assay method. RESULTS: Our data indicate M-Hbs cause variable patterns of MetHb and SHb elevation in a fairly reproducible pattern for the particular variant. In particular, α globin chain M-Hbs can mimic acquired sulfhemoglobinemia due to an isolated increased SHb value. CONCLUSION: If the patient appears clinically well other than cyanosis, M-Hbs should be considered early in the evaluation process to differentiate from acquired conditions to avoid unnecessary testing and treatment regimens and prompt genetic counseling.

First Observation of HbM-Saskatoon at the Origin of Neonatal Cyanosis in a Tunisian Baby.

Several causes are known to be at the origin of neonatal cyanosis among them methemoglobinemia is by inheritance of an hemoglobin (Hb) M variant. This is a rare condition never been reported in Tunisia so far. Here, we report a Tunisian newborn with refractory cyanosis since birth. As cardiac and respiratory diseases were ruled out, methemoglobinemia was suspected. Hematological parameters, concentration of methemoglobin, capillary electrophoresis, and amplification sequencing of the HBB gene were performed. Computational analysis was achieved by different in silico tools to investigate the mutation effect. The diagnosis was established by a raised MetHb, confirmed by the presence HbM-Saskatoon [Beta63 (E7) His>Tyr] by capillary electrophoresis and molecular analysis. The identified mutation occurred as a de novo mutation. In silico analysis confirmed the pathogenicity of the mutation. To our knowledge, this is the first time that this mutation has been reported in the Tunisian population. In view of its low incidence rate, clinicians might misdiagnose cyanosis caused by HbM, which can lead to inappropriate treatment and clinical complications. An up-to-date literature review of HbM disease is presented in this study.

The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia.

Hemoglobin M (HbM) is a group of abnormal hemoglobin variants that form methemoglobin, which leads to cyanosis and hemolytic anemia. HbM-Milwaukee-2 is a rare variant caused by the point mutation CAC>TAC on codon 93 of the hemoglobin subunit beta (HBB) gene, resulting in the replacement of histidine by tyrosine. We here report the first Korean family with HbM-Milwaukee-2, whose diagnosis was confirmed by gene sequencing. A high index of suspicion for this rare Hb variant is necessary in a patient presenting with cyanosis since childhood, along with methemoglobinemia and a family history of cyanosis.

Hereditary methemoglobinemia caused by Hb M-Hyde Park (Hb M-Akita) (HBB:c.277C > T; p.His93Tyr).

Healthy human blood contains only a trace amount of methemoglobin (Hb M), less than 1%. In Hb M iron is present in the oxidized ferric state (Fe3+) not in the reduced ferrous form (Fe2+) and this reduces the ability of hemoglobin to bind oxygen. The described rare hemoglobin variant Hb M­Hyde Park (also known as Hb M-Akita) results from the substitution of amino acid tyrosine by histidine at position 93 of the beta-globin chain of hemoglobin. The rare Hb variant Hb M­Hyde Park (Hb M­Akita) is mainly inherited autosomal dominant and causes methemoglobinemia. Due to the low frequency of inherited Hb M variants, the diagnosis is challenging. Here, we here report on a family with Hb M­Hyde Park (Hb M­Akita) whose members demonstrated Hb M > 10%, but were, asymptomatic except for chronic cyanosis. Due to human mobility and migration other hemogobin variants, such as beta-thalassemia minor have spread to Austria . A genetic combination of two different hemoglobin variants may result in severe anemia. Genetic counseling for patients with hemoglobin variants, including Hb M­Hyde Park (Hb M­Akita) and beta-thalassemia minor, is essential.

Exon sequencing of the alpha-2-globin gene for the differential diagnosis of central cyanosis in newborns: a case report.

BACKGROUND: Cyanosis is usually associated with serious conditions requiring urgent treatment in the neonatal intensive care unit (NICU). Hemoglobin M (Hb M) disease is one type of congenital methemoglobinemia characterized by cyanosis. Among these variants, α-globin chain mutations such as Hb M Boston present cyanosis from birth while other variants usually manifest later in life. CASE PRESENTATION: We report a case of a male newborn with cyanosis apparent since birth. Surprisingly, his respiratory and hemodynamic status including normal arterial blood oxygen saturation was stable, but oxygen saturation on pulse oximetry did not increase after 100% supplemental oxygen was started. In addition to routine pulmonary and cardiologic evaluation, further evaluation for dyshemoglobin was conducted; α2-globin gene sequencing showed a single-point variant causing Hb M Boston. Methemoglobin (MetHb) level estimated by co-oximetry was normal. After a 14-day stay in the NICU, the patient remained respiratory and hemodynamically stable without supplemental oxygen except for cyanosis. CONCLUSIONS: Hb M disease is a benign disease and does not require any treatment whereas acquired methemoglobinemia is a potentially fatal condition. Neonatologists should be aware that low oxygenation status on pulse oximetry in the face of normal arterial blood saturation values might indicate the possibility of Hb M disease in early neonatal cyanosis, irrespective of MetHb value.

Heterogeneity between Two α Subunits of α2ß2 Human Hemoglobin and O2 Binding Properties: Raman, 1H Nuclear Magnetic Resonance, and Terahertz Spectra.

Following a previous detailed investigation of the ß subunit of α2ß2 human adult hemoglobin (Hb A), this study focuses on the α subunit by using three natural valency hybrid α(Fe2+-deoxy/O2)ß(Fe3+) hemoglobin M (Hb M) in which O2 cannot bind to the ß subunit: Hb M Hyde Park (ß92His → Tyr), Hb M Saskatoon (ß63His → Tyr), and Hb M Milwaukee (ß67Val → Glu). In contrast with the ß subunit that exhibited a clear correlation between O2 affinity and Fe2+-His stretching frequencies, the Fe2+-His stretching mode of the α subunit gave two Raman bands only in the T quaternary structure. This means the presence of two tertiary structures in α subunits of the α2ß2 tetramer with T structure, and the two structures seemed to be nondynamical as judged from terahertz absorption spectra in the 5-30 cm-1 region of Hb M Milwaukee, α(Fe2+-deoxy)ß(Fe3+). This kind of heterogeneity of α subunits was noticed in the reported spectra of a metal hybrid Hb A like α(Fe2+-deoxy)ß(Co2+) and, therefore, seems to be universal among α subunits of Hb A. Unexpectedly, the two Fe-His frequencies were hardly changed with a large alteration of O2 affinity by pH change, suggesting no correlation of frequency with O2 affinity for the α subunit. Instead, a new Fe2+-His band corresponding to the R quaternary structure appeared at a higher frequency and was intensified as the O2 affinity increased. The high-frequency counterpart was also observed for a partially O2-bound form, α(Fe2+-deoxy)α(Fe2+-O2)ß(Fe3+)ß(Fe3+), of the present Hb M, consistent with our previous finding that binding of O2 to one α subunit of T structure α2ß2 tetramer changes the other α subunit to the R structure.

Diagnosis of a rare fetal haemoglobinopathy in the age of next-generation sequencing.

Neonatal cyanosis resulting from a fetal methaemoglobin variant is rare. Most such variants are only described in a few published case reports. We present the case of a newborn with unexplained persistent cyanosis, ultimately determined to have a γ-chain mutation causing Hb FM-Fort Ripley. This neonatal haemoglobinopathy can be challenging to diagnose, as significant oxygen desaturation may result from barely detectable levels of the mutant haemoglobin and co-oximetry studies may show a falsely normal methaemoglobin level. Our analysis of the infant's haemoglobin included high-performance liquid chromatography, cellulose acetate electrophoresis and citrate agar electrophoresis, which showed trace amounts of a suspected variant. Ultimately, the diagnosis was made through a novel application of next-generation sequencing (NGS). NGS-based diagnostic approaches are becoming increasingly available to clinicians, and our case provides a framework and evidence for the utilisation of such testing paradigms in the diagnosis of a rare cause of neonatal cyanosis.