A term infant presented with mild
cyanosis without evidence of
hypoxia. Cardiopulmonary disease,
polycythemia, and
methemoglobinemia were excluded. Standard
hemoglobin electrophoresis, including isoelectric focusing, were normal. However, by reverse-phase C4 HPLC, an abnormal
globin chain was detected. Analysis of tryptic
peptides and amino acid sequence showed that the patient had an amino acid substitution
Phe-->Ser at residue 41(C7) in the G gamma chain. This was confirmed by
DNA sequencing that demonstrated a point mutation at the expected site in exon 2 of the G gamma gene, accounting for the appropriate change in the
codon. This substitution,
hemoglobin F-Cincinnati, alpha 2 gamma 2 41(C7)
Phe-->Ser, not previously described, presumably decreased
oxygen affinity of the
hemoglobin. This substitution is very near the
heme group and the alpha 1 beta 2 interface and, hence, in a crucial area of the
globin chain. Abnormalities of
gamma globin chains tend to be overlooked due to their transient presence and trivial clinical symptomatology, or due to "in utero" selection when physiologically abnormal. Mutant
hemoglobins with altered
oxygen affinity should be included in the differential diagnosis of newborns presenting with
cyanosis, in whom all common causes have been excluded.