Geva et al. (2004) described a girl of Puerto Rican descent who presented with symptomatic sickle cell disease exacerbated by mild hypoxemia, despite a newborn screening diagnosis of sickle cell trait. The child was found to be heterozygous for mutations in the HBB gene: the sickle cell mutation glu6 to val (G6V; 141900.0243), and a neutral leu68-to-phe (L68F; 141900.0524) mutation. Analysis of the patient's hemoglobin demonstrated that the doubly mutant protein, which the authors called hemoglobin Jamaica Plain (Hb JP) for Jamaica Plain, Massachusetts, had severely reduced oxygen affinity, especially in the presence of 2,3-diphosphoglycerate. Structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at an ambient partial pressure of oxygen. The patient's sickle cell disease was exacerbated by intercurrent respiratory infection, and she developed splenomegaly. The splenomegaly and anemia were recurrent. At the age of 19 months, during her first airplane trip, the child became acutely ill, with her spleen reaching the pelvic brim, as reported by a physician on board. After landing, she was hospitalized and found to have a hematocrit of 18%. Packed red cells were transfused; the hematocrit then rose to 28% with resolution of symptoms and a decrease in splenomegaly. Because of the apparent splenic sequestration crisis, a splenectomy was performed when she was 2 years old. Since that time, she had been asymptomatic and required no transfusions in the previous 24 months. In a commentary on the work of Geva et al. (2004), Benz (2004) noted that by itself, the L68F mutation is known as hemoglobin Rockford, a member of a class of 'low affinity hemoglobins' with reduced affinity for oxygen. These hemoglobins cause few symptoms, if any. When the L68F and G6V mutations coexist in the same beta-globin molecule, the L68F mutation causes Hb JP to desaturate easily and therefore to sickle more readily than ordinarily occurs with Hb S (G6V).
