Diagnosis and characterization of Hb C/Hb Iowa: a rare but easily misidentified compound heterozygous condition

Hb Iowa is a rare hemoglobin (Hb) variant with a Gly --> Ala substitution at position 119 of beta-globin. It was previously reported only in an African American infant who was also heterozygous for Hb S [beta6(A3)Glu --> Val] and her mother (Hb A/Iowa). Here we describe the second report of Hb Iowa, the first in conjunction with Hb C [beta6(A3)Glu --> Lys]. The patient was an African American girl, originally diagnosed as homozygous Hb C during neonatal screening. When seen in our clinic, hematological data for both the child and her mother (Hb C trait) indicated mild anemia with slightly low mean corpuscular volume (MCV) but normal red blood cell (RBC) count. Analysis of blood from the child by capillary isoelectric focusing (cIEF) identified Hb C and an unknown Hb variant with an isoelectric point (pI) intermediate to that of Hbs F and A. The unknown variant was identified as Hb Iowa by DNA sequence analysis of the beta-globin gene (GGC --> GCC). Both reported cases of Hb Iowa indicated that there are no abnormal hematological manifestations associated with this rare Hb variant. In both cases, however, Hb Iowa was mistaken for Hb F during routine neonatal screening by high performance liquid chromatography (HPLC) and/or gel IEF. Neonatal misidentification of Hb Iowa led to misdiagnosis of sickle cell disease and Hb C disease, respectively. In our patient, Hb Iowa was also misidentified as Hb A at 2 years of age by a commercial reference laboratory using cellulose acetate and citrate agar gel electrophoresis. This led to an incorrect diagnosis of Hb C trait. These results show that commonly used analytical methods can easily misidentify Hb Iowa as Hbs F or A in neonates, or older individuals, resulting in incorrect identification of the Hb phenotype. We conclude that the presence of Hb Iowa, or other variants with similar pIs, should be considered in cases where the results of follow-up testing conflict with neonatal diagnosis of sickle cell or Hb C disease, or where clinical presentation does not agree with diagnosis of either homozygous or heterozygous Hb S or Hb C.