Homozygous haemoglobin constant spring: A need for revision of concept

Abstract

Twenty-two patients with mild haemolytic anaemia and haemoglobin (Hb) Constant Spring (CS) of around 6% were studied because they were suspected of having homozygous Hb CS. Family studies revealed Hb CS trait in both parents of eight patients, supporting that they were homozygous for Hb CS. The other patients were included because they had clinical and haematological features similar to the diagnosed cases of homozygous Hb CS. Heterozygosity and homozygosity for Hb CS are clearly distinguishable in that the former is asymptomatic but the latter is associated with overt haemolytic anaemia, and the levels of Hb CS in the two conditions of less than 1% and around 6%, respectively, do not overlap. The findings in homozygous Hb CS contradict prediction. There are four alpha-structural genes per normal human diploid genome. Hb CS trait is believed to be almost equivalent to alpha-thalassaemia 2 or a loss of one alpha-gene because HB CS, and alpha-variant, is barely or not detectable. Homozygosity for Hb CS has thus been predicted to be equivalent to alpha-thalassaemia 1 or a loss of two genes. The latter is asymptomatic and associated with microcytic-hypochromic red cells. However, Hb CS homozygosity presents with mild overt haemolytic anaemia and normal sized red cells. Pathogenesis associated with Hb CS inheritance is more complex than originally believed. There is a possibility that the unstable alpha CS mRNAs precipitate and aggregate leading to pathology of red cells and to the basophilic stippling appearance, so striking in this syndrome.

Hematologic and biosynthetic studies in homozygous hemoglobin Constant Spring.

“…However, HbCS homozygotes are not phenotypically the same as a4-thalassemia homozygotes. The findings in the HbCS homozygote described here are identical to those previously described (6,8,9 After transcription of the acs-gene (whether this is at a normal or subnormal level is not yet known) there is instability of the acsamRNA, which decreases during erythroid maturation and which is virtually absent from reticulocytes (3,30). The synthesis of C-chains follows the same pattern, decreasing from bone marrow to reticulocytes (2, 31); but once incorporated into a hemoglobin tetramer, the aCs-chains seem to be quite stable in vivo.…”

“…Autohemolysis showed 1.40 and 3.35% lysis after 48 h with and without glucose, respectively. The whole-blood oxygen dissociation curve was shifted left slightly, with an oxygen pressure at 50% Hb saturation of 24.5 mmHg (control 29.0 mmHg) and a 2-3-diphosphoglycerate level of 6.55 mmol/liter.…”

“…These individuals are mildly anemic, with microcytic, hypochromic red cells, but show no other clinical abnormalities or changes in their Hb pattern (7). HbCS homozygotes, in contrast, have a moderate hemolytic anemia with splenomegaly, relatively normal red cell indices, and elevated levels of Hb Barts (y4) (6,8,9). Furthermore, patients with HbH disease with only one a-gene (-a/--) are less anemic and have less HbH than those who are heterozygous for both ao-thalassemia and the HbCS mutation (acs/--) (10, 1 1).…”

“…Both heterozygotes (aa/a a) and homozygotes (a/aaCSa) have been reported to show a/fl globin chain synthesis ratios > 1, rather than the expected deficit of a-chain production (5,6). Furthermore, since the ccs-gene is associated with a very low output of a-globin chains, homozygotes should have the same clinical 1.…”

HbH Disease in Sardinia: Molecular, Hematological and Clinical Aspects

“…In accordance with these findings in South East Asian populations, several studies indicated that the (acsa) haplotype, containing the Constant Spring muta tion in the a 2-gene results in a more severe phenotype than that associated with the (-a) haplotype [25]. Infants with the (acsa/aa) genotype, in fact, produce more Hb Bart's at birth than those with the (-a/aa) genotype, sub jects with the (-/a csa) genotype have a severer form of HbH disease than those with the (-/-a) genotype and fi nally, individuals homozygous for the Constant Spring mutation (a^a/a^a) showed a severer phenotype than the a-carriers [25,26].…”