Hemoglobin H Hydrops Fetalis Associated with Homozygous Hemoglobin Constant Spring. Case Report.

Abstract

While Barts hydrops is predicted when all 4 α globin genes are absent or non functional, hydrops has rarely been described with a hemoglobin H (Hb H) genotype. Hb H disease has a varied hematologic phenotype ranging from asymptomatic to transfusion dependant. The severest clinical expression is non immune hydrops and may result in fetal demise. The commonest form of Hb H disease is deletional-type. This occurs when there is deletion of α2 and α1 genes in cis and deletion of either α2 or α1 in trans. The less frequent type, but clinically more severe, is non-deletional. This is usually due to a mutation in either α2 or α1 in cis and a deletion of both α2 and α1 in trans. There are rare reports of non-deletional Hb H due to homozygous α2 mutations without any α1 deletions or mutations. Heretofore, there have been no reports of hydrops with homozygous hemoglobin Constant Spring (Hb CS). A 31-year-old Laotian woman presented at 22 weeks with polyhydramnios. Besides this, the pregnancy was uneventful for the mother. On ultrasound the fetus had a pericardial effusion and signs of congestive heart failure. The hematological and genotypic parameters of the parents and fetus are outlined in table 1. Intrauterine transfusions were performed at 22 and 29 weeks. A male infant was born vaginally at 36 weeks gestation weighing 2.3 kg. The hemoglobin was 15.9 g/dL and bilirubin was 8.4mg/dL. There was no evidence of maternofetal alloimmunization. G6PD screen was negative. By 4 weeks post-partum, the bilirubin had decreased to 0.9 mg/dL but the hemoglobin had progressively fallen to 6.9 g/dL, requiring transfusion. He had two additional transfusions at 6 and 8 weeks of life but has subsequently maintained a hemoglobin above 10 g/dL and has steadily gained weight. As in this patient, the genotypes of the other reported cases of Hb H hydrops are usually associated with a thalassemia intermedia phenotype. Thus the α globin genotypes alone do not explain why hydrops occurs. This suggests that there may be unknown genetic and/or acquired modifiers contributing to the severity of Hb H disease that results in hydrops as in this fetus with homozygous Hb CS.[Table 1]MotherFatherFetus at 22 weeksHemoglobin g/dL10.012.55.2MCV fL86.381.8143.8MCH pg26.525.6.846.4RDW %16.713.621.4Reticulocyte %9.9ND19.0NRBC/100WBC104756Hemoglobin Fractions by HPLCHb A73.3%97.8%3.4%Hb F0.8%0.0%77.7%Hb A20.9%2.1%0.0%Barts0.0%0.0%17.7%Hb Constant Spring2.8%0.1%1.2%HbE 22.2%0.0%0.0%αGlobin Gene Dosage Assay by Linear PCR444αGlobin Gene Deletions by PCR - 3.7, - 4.2, _SEA, - 20.5, _MED,_FIL,_THAINone detectedNone detectedNone detectedα2 Globin Gene Sequencingα-2CS/α-2CSα-2CS/WTα-2CS/α-2CSα1 Globin Gene SequencingWT/WTWT/WTWT/WTβGlobin Gene SequencingHeterozygous Hb EWT/WTWT/WT E