Atypical haematological presentation in a case of polycythaemia vera with a new variant mutation detected in exon 12: c.1605G>T (p.Met535Ile)

Abstract

<jats:p>One of the major genetic insights into the pathogenesis of polycythaemia vera included the identification of the somatic point gain-of-function mutations in Janus kinase 2 gene—first <jats:italic>JAK2V617F</jats:italic> on exon 14, present in 95%–97% of the cases, and later on exon 12. In the literature, we can find some reported studies where different exon 12 mutations are identified. Unlike patients with <jats:italic>JAK2V617F</jats:italic> mutation in exon 14, the mutation at exon 12 is not usually associated with an increase in the three haematopoietic series (erythrocytosis, leucocytosis and thrombocytosis). It appears to be associated with a distinct syndrome, mostly characterised by isolated and more marked erythrocytosis, independently of the mutational variant. We report here the case of a patient who is <jats:italic>JAK2</jats:italic>exon 12 positive, presenting a novel mutation—c.1605G&gt;T (p.Met535Ile)—associated with c.1612C&gt;T (p.His538Tyr) mutation previously described, evidencing an atypical clinical phenotype.</jats:p>

Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies

“…The fact that exon 12 mutations are more frequently associated with erythrocytosis is consistent with their absence in ET but possible existence in PMF or AML secondary to PV [138]. However, there are exceptions as evidenced in some clinical reports [24]. Despite the phenotypical diversity, the clinical course and outcome seem overlapping between JAK2 V617F and JAK2 exon 12-positive patients, with convergent incidences of thrombosis, myelofibrosis, leukemia, and death [140].…”

“…JAK2 V617F mutational status may have prognostic significance in PV, ET, and PMF [102]. In PV, despite the phenotypic differences, the clinical course seems similar between JAK2 V617F and JAK2 exon 12-positive patients, with similar incidences of thrombosis, myelofibrosis, leukemia, and death [24,140]. JAK2/CALR mutational status did not affect survival in ET [9].…”

“…Unlike JAK2 V617F, which can be detected in any of the PN-MPNs, JAK2 exon 12 mutations are almost exclusive of JAK2 V617F-negative PV patients [24,103]. PV patients who present JAK2 exon 12 mutations, unlike those who are V617F positive, are not commonly homozygous [70,103,124,138].…”

“…Several studies reported various JAK mutations, mostly point mutations, occurring in all members [22][23][24]. JAK2 V617F is one of the most studied mutations affecting JAK family, strongly associated with myeloproliferative neoplasms, which will be discussed in the next section of this chapter, and Hodgkin lymphoma and primary mediastinal B-cell lymphoma [3].…”

“…Although JAK2 V617F and exon 12 mutations express through the same C-terminal tyrosine kinase of JAK2, they originate very different phenotypic outcomes. These patients appear to be associated with a distinct syndrome, with higher hemoglobin concentrations, without concomitant leukocytosis or thrombocytosis (or minimal thrombocytosis), and isolated bone marrow erythroid hyperplasia [124], independently of the mutational variant [24,124,140]. The reasons for these various abnormal phenotypic readouts also remain unclear and are likely to be complex [124,140].…”