Hereditary Thrombocythemia: Clinical Characteristics, Biological Markers and Long-Term Follow-up in 4 Families Observed in a Single Hematologic Pediatric Center

Hereditary thrombocytosis (HT) is an autosomal dominant disorder resulting from mutations involving the thrombopoietin (TPO) gene or its receptor gene, MPL. To date, 4 different mutations in the TPO gene and 2 in the MPL gene have been described. Although the clinical features of HT can resemble those of sporadic essential thrombocytemia (ET), different biological markers characterize the two conditions with different clinical and biological characteristics. The presence of JAK2 ^V617F and MPL^W515L mutations identify familial ET (variable penetrance, clinical features and outcome similar to those of sporadic ET). The absence of JAK2 ^V617F mutations and the presence of MPL^S505A or TPO gene mutations characterize HT (complete predominance, thrombocytosis, no organomegaly and benign clinical course). In our study, we analyzed the clinical and biological features of 17 members of 4 families (fam), diagnosed and followed at the study Institution between 1979 and 2007. The median follow-up is 79 months. Of 49 patients (pts) aged ≤20 years with a diagnosis of ET according to the PVSG or WHO criteria, we have identified 17 pts (M: 8; F: 9; median age 14 years) with HT (34.7%) through a detailed history. Peripheral blood samples were collected after informed consent from 11/17 pts: molecular analysis for the JAK2^V617F, TPO (5′ untranslated region) and MPL (exon 10) gene mutations was performed. In addition, all pts were also evaluated for PRV-1 RNA overespression by qualitative RT-PCR, for endogenous erythroid colony (EECs) growth and all female patients were tested for clonality of hematopoiesis using the HUMARA polymorphism assay and the HUMARA methylation-specific PCR. The table summarizes the features, treatment and follow-up of the pts.

Mild splenomegaly was present in 2 pts (family 4). All pts were negative for JAK2^V617F and TPO gene mutations. All females were polyclonal. In 9 pts of families 1, 2 and 3 studied for MPL mutations, the MPL^S505A mutation was found. No mutations within the TPO or MPL genes were found in the affected members of family 4. Overall, 6 pts received antiaggregant therapy (AT) and 5 pts were treated with hydroxyurea (HU), interferon (IFN), pipobroman (vercite) or anagrelide. No thromboembolic events occurred. To date, 2/11 evaluable pts (family 4) have required treatment because of a persistent high platelet count. Our data suggest that ET in young pts is most frequently a familial form. A detailed history and accurate biological marker studies are needed to identify, characterize and better manage HT.