Hereditary Thrombocythemia: Clinical Characteristics, Biological Markers and Long-Term Follow-up in 4 Families Observed in a Single Hematologic Pediatric Center
Authors: Giona Fiorina , Amendola Angela , Teofili Luciana , Palumbo Giovanna , Mancini Francesca , Nunes Vittorio , Rea Massimiliano , Martini Maurizio , Foa Robert 
Published: April 2020

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 MPLW515L 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 MPLS505A 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 JAK2V617F, 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.

Sex/Age at diagnosis (yrs) Plts at diagnosis (× 109/l) JAK2 V617F PRV-1 EECs Clonality MPL mutation Treatment Follow-up (FU) Plts (× 109/l) FU Duration (mo) *N.T.=Not tested Fam 1 M/18 900 neg neg neg - MPLS505A NO PLT≤1,000 &gt;330 M/88/12 1,459 neg neg neg - MPLS505A AT PLT≤500 &gt;79 F/20 934 N.T.* N.T. N.T. N.T. N.T. AT; Anagrelide-&gt; Vercite -&gt;HU-&gt;IFN PLT≤500 Lost to FU 184 Fam 2 M/18 700 neg pos neg - MPLS505A AT HUà stop C hepatitis PLT≤1,000 &gt;228 M/114/12 783 neg neg neg - MPLS505A NO PLT&lt;1,000 &gt;39 F/165/12 963 neg pos pos Poly MPLS505A NO PLT≤1,500 &gt;129 F/173/12 695 neg pos neg Poly MPLS505A NO PLT≤1,000 &gt;39 F/92/12 1,230 N.T. N.T. N.T. N.T. N.T. NO PLT≤1,000 Lost to FU 47 F/14 932 N.T. N.T. N.T. N.T. N.T. NO PLT≤1,000 Lost to FU 42 Fam 3 F/149/12 1,060 neg pos pos Poly MPLS505A AT 1 pregnancy PLT≤1,000 &gt;229 M/03/12 1,528 neg pos pos - MPLS505A NO PLT ≤1,500 &gt;44 F/1010/12 611 neg pos neg Poly MPLS505A NO PLT&lt;1,000 &gt;131 M/103/12 759 N.T. N.T. N.T. N.T. N.T. NO PLT&lt;1,000 Lost to FU 49 M/14 2,950 N.T. N.T. N.T. N.T. N.T. Verciteà HU PLT&lt;1,000 Lost to FU 72 F/38/12 1,430 N.T. N.T. N.T. N.T. N.T. NO PLT&lt;1,000 Lost to FU 36 Fam 4 M/1911/12 690 neg pos pos - No mutation AT HUàAnagrelide Previous splenectomy PLT&lt;1,000 &gt;86 F/178/12 1,118 neg neg neg Poly No mutation AT, HU-&gt;Anagrelide-&gt;IFN PLT&lt;1,000 &gt;144

Mild splenomegaly was present in 2 pts (family 4). All pts were negative for JAK2V617F and TPO gene mutations. All females were polyclonal. In 9 pts of families 1, 2 and 3 studied for MPL mutations, the MPLS505A 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.