Abstract

The occurrence of multiple globin abnormalities in one individual is not very rare, particularly in populations where hemoglobinopathies are common. In most cases, this is of genetic interest and may pose a diagnostic challenge due to the interaction of the products of mutant α and β globin genes and the presence of hybrid hemoglobins. Co-inheritance of α globin variants with sickle cell disease (Hb SS or SC) could have an effect on the disease phenotype particularly when the variant in question has altered functional properties (decreased or increased oxygen affinity) or stability. We report a patient with Hb SC disease with co-inheritance of the α chain variant, Hb Chicago (α136Leu→Met), and deletional α thalassemia (−α3.7) in trans to the Hb Chicago mutation. The patient is a 3-year old African-American male referred to the Pediatric Sickle Cell Clinic from the local Health Department. He is the product of an uneventful term pregnancy and a normal labor. He presented with seizures at age 3 weeks and underwent a neurologic evaluation which failed to reveal any abnormality. His subsequent course was uneventful without further seizures after 1 year of age and no hospitalizations. Physical exam was unremarkable with normal growth. A CBC showed Hb of 11.3 g/dl, Hct 35.2%, MCV 64.8 fl, MCH 20.8, MCHC 32.1, RDW 18.4%, retic count of 1.7% (absolute retic count of 92,480). Cation exchange HPLC revealed a Hb F of 6.8%, A2 3.3%, Hb S 33.1% and Hb C 30.0%. Both Hb S and Hb C peaks were followed by an additional peak of 13.2% (Hb SX) and 13.6% (Hb CX) respectively suggesting the presence of an α chain variant. The total quantity of Hb S was 46.3% (Hb S+Hb SX) and that of Hb C was 43.6% (Hb C+ Hb CX), whereas Hb X amounted to 26.8%. A reversed phase HPLC confirmed the presence of an α chain variant, which eluted earlier than normal α chains; αX constituted 37.5% of the total α chains. Sequencing of the β-globin gene confirmed the presence of Hb S (GAG→GTG) and Hb C (GAG→AAG) mutations in codon 6. A PCR for α globin deletions confirmed heterozygosity for the -α3.7 deletion. α globin sequencing revealed an apparent homozygosity for a CTG→ATG (Leu→Met) substitution of the codon 136 in α2 globin gene; this “apparent” homozygosity is due to the -α3.7 deletion in trans. Family studies showed that the patient’s mother had Hb C trait with heterozygous α-thalassemia; the father was not available. The paternal grandmother had normal α-globin gene numbers, with heterozygous Hb Chicago, which was quantitated at 20.7%. Thus, the patient’s genotype was ascertained as βSC;-α/αChicagoα. Hb Chicago has been reported in conjunction with Hb SS but not with Hb SC disease. The co-inheritance of the α-chain variant, Hb G-Philadelphia (α68Asn→Lys) and Hb SC disease, has been reported by Lawrence et al (

Blood
90
:
2819
–25,
1997
); this combination resulted in the acceleration of Hb C crystal formation and decreased Hb S polymerization with a resultant mild sickling disorder. α136 is a heme contact; the Leu→Met substitution in Hb Chicago does not alter the functional properties or the stability of the molecule and is not associated with any hematologic abnormalities in heterozygous carriers. This residue is not involved in intermolecular contacts of deoxy Hb S and hence is not expected to alter the kinetics of deoxy Hb S polymerization. The significance of this observation is the accurate diagnosis of the complex Hb phenotype and ascertainment of its lack of interaction with the sickling or crystallization process.

Author notes

Disclosure: No relevant conflicts of interest to declare.