De novo alpha 2 hemoglobin gene (HBA2) mutation in a child with hemoglobin M Iwate and symptomatic methemoglobinemia since birth

Abstract

Cyanosis in an apparently healthy newborn baby may be caused by hemoglobin variants associated with the formation of methemoglobin, collectively known as M hemoglobins. They should not be confused with genetic alterations in methemoglobin reductase enzyme systems of red cells since treatment and prognosis are completely different. A newborn male child was noted to be significantly cyanotic at birth and is the basis for this report. Hemoglobin isoelectric focusing, acid and alkaline gel electrophoresis, and HBA/HBB gene sequencing were performed for the child, both parents and a sister. The newborn child was treated with methylene blue in an intensive care unit fearing that he had a defective reductase system and exposure to oxidant drugs or toxins. Newborn hemoglobin screening with high performance liquid chromatography was abnormal on the 10th and 45th days but no conclusive diagnosis was reached. Cyanosis persisted up to four years of age with no other symptoms. Hemoglobin M Iwate [alpha2 87(F8) His>Tyr, HBA2:c.262C>T] was detected. It was not present in the child's presumed mother, father, sister, and brother. The analysis of 15 short tandem repeats in the trio demonstrated a de novo mutation occurrence (p-value < 1 × 10−8). The family was reassured that no further action was necessary and genetic counseling was provided. Methemoglobins should be considered for differential diagnosis of cyanosis in newborns even if no familial cases are detected. Except for cosmetic consequences, the clinical course of patients with hemoglobin M Iwate is unremarkable.

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

“…Since chemical characterizations of Hb M were first reported in the late 1950s and early 1960s by Gerald [6, 7], the rare globin chain variants have been investigated by chromatography, electrophoresis, and gene sequencing [1, 2, 5].…”

“…Hb M caused by a mutation in α-, β-, or γ-globin can lead to spontaneous oxidation of the ferrous ion in the heme and cannot transport or release oxygen in tissues. Hb M disease causes cyanosis that is unresponsive to oxygen therapy [1, 2]. Some variants might need to be considered in the differential diagnosis of central cyanosis in newborns because they cause cyanosis from birth.…”

Hb M-Iwate in an Indian family

“…It was first characterized in the Iwate prefecture of Japan in 1960 where terms like 'black mouth', 'black blood' or 'black child' were used historically to denote the cyanosis in these individuals [2,8,9]. A few case reports have subsequently also been published from Europe [10,11,12], Turkey [13] and Brazil [14]. Hb M-Iwate was previously also christened as Hb M-Oldenburg, M-Kankakee and M-Sendai, all of which after molecular characterization were found to be the same variant [4,15,16].…”

Molecular transduction in receptor-ligand systems by planar electromagnetic fields

“…Elsewhere, it was discovered that mutation of the R671 residue (that modulates the activity of early tryptic fragmentation) alters the conformation of the calcium pumps of SERCA 3 (Corvazier et al, 2009). In the haemoglobin molecule, genetic variants have been reported that cause cyanosis (a diminution in oxygen affinity) when the H58 residue is mutated (a variant known as Hb M Boston) (Nishikura et al, 1975;Viana and Belisário, 2014). Similarly, a further variant known as Hb Hornchurch shows a mutation in the E43 residue, which may be related to diminution in the plate count (thrombocytopenia) (Shi and Wang, 2017).…”