Page 1234 - Hematology_ Basic Principles and Practice ( PDFDrive )

1080 Part VII Hematologic Malignancies

VHL mutation or double heterozygosity for CP and other VHL autosomal recessive disorder. Polycythemic patients with PHD2
mutations, have been found. The VHL598C→T mutation has been P317R do not have any evidence of tumors characteristic of the VHL
shown to originate in a single haplotype in the Chuvash patients, as syndrome. Additional mutations in PHD2 have been reported that
well as in whites, Asian Indians, and one African–American indi- lead to erythrocytosis. All of these mutations are germ-line and het-
vidual. Homozygosity of this mutation appears to be the most erozygous, encoding predicted mutant full-length PHD2 proteins. A
common genetic defect leading to congenital polycythemia. The series of HIF-2α gain-of-function mutations have also been reported
mutation originated from a single founder 12,000–51,000 years ago. to lead to familial erythrocytosis. These mutations lead to weakened
This suggests that such wide dissemination from the original founder bonds between PHD2 and HIF-1α, resulting in less hydroxylation
may be associated with some survival advantage for heterozygotes of HIF-1α and subsequent recognition of HIF-1α by VHL. Many
carrying this mutation. Such an advantage might be related to a subtle of these patients present in their twenties, although patients have also
improvement of iron metabolism, erythropoiesis, embryonic devel- been diagnosed in their fifties with erythrocytosis associated with
opment, energy metabolism, or some other yet unknown effect. high EPO levels. All patients have heterozygous mutations, suggest-
VHL mutations are likely the most common cause of congenital ing that one allele is sufficient to cause erythrocytosis. It is not
polycythemias, greatly exceeding the number of patients with hemo- unusual for patients to have a clinical history of thrombotic disorders,
globin chain mutations. In point of fact, in one study of more than but there does not appear to be an increased incidence of cancer.
200 unrelated subjects with apparently congenital polycythemia, none
had a 2,3-BPG deficiency, two had a globin mutation (Hgb Vander-
bilt, and Hemoglobin San Diego), and 12 had EPOR mutations to Neonatal Polycythemia
account for their polycythemia. By contrast, when 50 patients were
examined for the VHL mutation, 22 had VHL mutations, most of Because of the high oxygen affinity of fetal hemoglobin, many neo-
them being the CP VHL mutation, occurring either homozygously or nates have markedly elevated hematocrit levels. Babies with hematocrit
in combination with another VHL mutation. The failure of patients levels over 65% have more neurologic and functional impairments,
with CP to develop VHL syndrome tumors is consistent with the and are more likely to be born to diabetic mothers. Although phle-
concept that dysregulation of H1F-1α and VEGF are not sufficient botomy has been recommended, there is little evidence that it has
to cause tumors. A cluster of patients with clinical features identical to been beneficial for these babies.
patients with CP has been documented on the island of Ischia in the
Bay of Naples, Italy. All of these patients also had the VHL598C→T Drug-Induced Erythrocytosis
mutation. Twelve of the 14 patients were homozygotes, and two The administration of EPO, corticosteroids, or androgens to an
were heterozygotes. The homozygotes had symptoms identical to excessive degree has each been associated with reversible erythrocyto-
patients in Chuvashia with this mutation. Unlike heterozygotes in sis. Androgens have been shown to simulate EPO production and to
Chuvashia, the heterozygotes from Ischia developed erythrocytosis directly affect erythroid progenitor cells. Approximately 5% of
associated with high EPO levels, which raises the possibility that patients receiving long-term testosterone therapy for testosterone-
genetic alterations of additional components of the oxygen-sensing deficiency syndrome develop erythrocytosis. Androgens activate
pathway other than VHL may contribute to the development of HIF-1 and HIF-1-regulated gene expression, leading to increased
erythrocytosis in the Italian patients. The disorder in Ischia has a expression of VEGF and presumably EPO. Rarely, erythrocytosis can
gene frequency even higher than that in Chuvashia, with 14% of the be the presenting manifestation of Cushing syndrome. Blood doping
population estimated to be heterozygotes, which has led to the sug- refers to the use of EPO to increase the RBC mass and enhance
gestion that heterozygotes have a survival advantage, perhaps caused oxygen delivery with the hope of increasing endurance performance
by heterozygosity conferring protection from developing anemia. in athletes. A monitoring of an athlete’s hematologic profile longitu-
The Chuvash mutation has also been shown to have a profound dinally provides some insight into the likelihood of blood doping
effect on the cardiopulmonary system. Patients with CP have signifi- playing a role in the development of erythrocytosis
cant abnormalities of cardiopulmonary physiology, including elevated The development of paradoxical polycythemia in three patients
basal ventilation rates and increased pulmonary vascular tone, with with VHL syndrome and CNS or retinal hemangioblastomas treated
extremely high ventilatory rates and heightened pulmonary vasocon- with a VEGF receptor inhibitor has been reported. The cause of these
striction and heart rates in response to acute hypoxia. These observa- phenomena remains unknown. In addition, reversible paradoxical
tions indicate that the VHL–HIF pathway might also play a central erythrocytosis has been reported with the use of VEGF tyrosine
role in calibrating the pulmonary system to hypoxic challenges. Such kinase inhibitors, including sunitinib, sorafenib, axitinib, pazopanin,
undesirable exaggerated hypoxic responses and the resulting elevated and the anti-VEGF monoclonal antibody bevacizumab, primarily in
pulmonary vascular hypertension may contribute to the morbidity patients with renal cell carcinomas. These patients become symp-
and mortality associated with CP. Increased expression of endothelin-1 tomatic due to fatigue, pruritis, myalgias, headaches, and malignant
has been documented in patients with CP. Endothelin-1 has been hypertension. The cause of the erythrocytosis associated with these
associated with the development of hypoxia-related pulmonary drugs has been attributed to either elevation of EPO levels or sensiti-
hypertension. Endothelin-1 receptor inhibitors might therefore be zation of erythroid cells to EPO. The erythrocytosis in this situation
useful in reversing the associated pulmonary hypertension in these can be controlled with phlebotomy therapy with relief of symptoms.
patients. Treatment strategies for patients with CP have included
phlebotomy, aspirin, and occasionally chemotherapy. Most patients
are treated empirically with phlebotomy therapy, but at present it POLYCYTHEMIA VERA
remains unknown if this approach reduces the incidence of throm-
botic incidences or improves the quality of life. PV is a clonal, chronic, progressive myeloproliferative neoplasm
Additional genetic abnormalities of oxygen sensing have been (MPN) often of insidious onset characterized by an absolute increase
reported that lead to familial polycythemia. A heterozygous C-to-G in RBC mass and often by leukocytosis, thrombocytosis, and spleno-
change at base 950 of the coding sequence of PHD2 (P317R muta- megaly. PV leads to excessive proliferation of erythroid, myeloid, and
tion) was first detected in all three affected family members with this megakaryocytic elements within the BM. Vaquez first described this
syndrome. Hydroxylation of HIF-1 by PHD2 facilitates its interac- clinical entity in 1892, noting the characteristic physical findings. At
tion with VHL, thereby favoring its ubiquitination and degradation the turn of this century, Cabot and Osler independently associated
8
by the proteosome. The failure of PHD2 P317R to bind HIF-1 and the name PV with this clinical disorder.
HIF-2α and promote HIF hydroxylase activity ultimately leads to PV differs from many other hematologic malignancies in that
increased HIF-1 and EPO levels, resulting in the development of prolonged survival is enjoyed by most patients if the excessive produc-
erythrocytosis. The PHD2 P317R mutation is inherited as an auto- tion of RBCs and platelets can be controlled. This prolonged survival,
somal dominant trait in contrast to the CP defect, which is an however, can be punctuated by the development of other syndromes,