Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis

Abstract

Familial and acquired erythrocytosis and thrombocytosis are characterized by myeloid lineage hyperproliferation, which is either single or multi‐lineage in origin. The single lineage disorders exhibit Mendelian inheritance with polyclonal hematopoiesis and often arise from a single genetic defect. In contrast, the multi‐lineage disorders exhibit complex patterns of inheritance with multi‐genetic origins and clonal hematopoiesis. They have the potential to acquire JAK2 somatic mutations, but this is not the primary event. Identification of the disease‐causing genes will enable better classification of familial and acquired erythrocytosis and thrombocytosis. Furthermore, it will provide an insight into the mechanisms regulating myeloid cell proliferation. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.

Clinical utility gene card for: Hereditary thrombocythemia

“…11,20,22,23 Sporadic ET but not hereditary thrombocythemia with MPL codon W515 mutations have not been described so far. 13 Adult and elderly patients, but not children with MPL S505N-positive THCYT2, have frequently developed myelofibrosis.…”

“…20,21 1.9 If applicable, prevalence in the ethnic group of investigated person The exact overall prevalence is not known, but likely o1:100.000. 20,21 In principle, individuals from any ethnic group can develop THCYT/hereditary ET.…”

“…9 Autosomal-dominant THCYT1, non-MPL P106L THCYT2 and THCYT3: 100% in heterozygously and homozygously mutated cases. 20,21 2.6 Negative clinical predictive value (probability of not developing the disease if the test is negative) Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.…”

“…2 Autosomal-dominant THCYT1, non-MPL P106L THCYT2 and THCYT3, risk to develop the disease: 50% if one parent is a heterozygous patient and the other parent is not, 75% if both parents are heterozygous patients, 100% if one parent is a heterozygous patient and one parent is a homozygous patient, 100% if both parents are homozygous patients. 20 …”

“…Hereditary thrombocythemia can be primary or secondary: 20,21 A primary thrombocythemia in terms of THCYT2 and THCYT3 occurs when there is an intrinsic defect in the megakaryocytic cells in the bone marrow (MPL and/or JAK2 mutations). In these cases, THPO levels will be normal (which would be inappropriate for a raised platelet count) or below normal.…”