Sickle CellHereditary Persistence of Fetal Hemoglobin

Adult Hb (or in the case of sickle cell anemia Hb S) replaces Hb F as a result of the switch
from - to -globin synthesis that occurs in fetuses. Because of the inhibitory effect of Hb F
on Hb S polymerization and cellular sickling (see Chapter 42), the high fraction of Hb F at
birth masks the expression of SCD until Hb S levels increase to 75% at approximately 6
months of age (see Fig. 40-3). Conditions that preserve elevated levels of Hb F into
adulthood similarly modulate the course of SCD. The compound heterozygous conditions
sickleHPFH (Hb SSHPFH) and sickle cell-thalassemiaHPFH both have higher Hb F
levels and milder clinical courses than are characteristic of sickle cell anemia. Hereditary
persistence of Hb F results from one of several large deletions of the - and -globin genes
that retard the switch from the production of Hb F to adult Hb. A more recently discovered
variety of HPFH is not caused by a deletion but by one of many point mutations that
upregulate the expression of the -globin gene. The clinical expression of deletional and
nondeletional HPFH differs in that the 15% to 35% Hb F in the former is distributed in a
pancellular fashion, the 1% to 5% Hb F in the latter is distributed in a heterocellular fashion,
and certain mild types of nondeletional HPFH express high Hb F levels not in simple heterozygosity but
only in conditions of erythropoietic stress, such as compound heterozygosity with the sickle cell gene. It is
likely that many cases of apparent sickle cell anemia with unexplained elevations of Hb F are the result of
a nondeletion HPFH mutation.
The gene frequency of the deletional HPFH locus is 0.0005 among African Americans, resulting in a
calculated incidence for compound heterozygous sickle celldeletional HPFH of 1/100 that of sickle cell
anemia. Sickle celldeletional HPFH provided the first evidence that Hb F was a potent inhibitor of Hb S
polymerization: individuals with pancellular distribution of 25% Hb F were generally neither anemic nor
affected with vasoocclusive manifestations (see Table 40-10).248 Hb electrophoresis revealed only Hb S, F,
and A2, which resembles sickle cell anemia, sickle cell-thalassemia, and sickle cell-thalassemia.
Notable differences, however, are the pancellular distribution of 15% to 35% Hb F, Hb A2 levels less than
2.5%, and the absence of anemia.249 The generally benign course of sickle celldeletional HPFH is
uncommonly associated with vasoocclusive complication.
http://hmg.oxfordjournals.org/content/18/R2/R216.full