Contributions
Abstract: S433
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:00 - 12:15
Location: Room N101
Background
The THPO-MPL axis plays a central role in platelet biogenesis: it activates the signaling cascade inducing megakaryocytes (MKs) differentiation from progenitor cells and regulates MKs maturation, proplatelet extension, and nascent platelets release into the bloodstream.
Aims
To unravel the molecular basis of ITs and to improve the clinical and laboratory characterization of the new ITs identified.
Methods
Whole exome sequencing (WES) was performed in 86 propositi with an unknown IT. They were part of our case series of 274 consecutive families, 151 of which remained without a definite diagnosis at the end of the diagnostic workup carried out according to the diagnostic algorithm proposed in 2003 by the Italian platelet study group and subsequently updated to include the most recent discovered disorders (Clin Genet 2016;89:141). The investigation was approved by the Institutional Review Board of the IRCCS Policlinico San Matteo Foundation and all patients gave written informed consent.
Results
WES in 86 propositi with unknown IT identified 2 unrelated individuals (family A and B) carrying the heterozygous variant c.91C>T (p. Arg31*), which is expected to result in a mutant protein degradation and THPO haploinsufficiency. In each family the segregation with the disorder was confirmed analyzing one affected relative. Bleeding tendency was absent in all cases. All patients had mild thrombocytopenia; blood film examination did not identify any morphological abnormality of platelets, except for some elements with slightly increased size in patients of family A. In vitro platelet aggregation and surface expression of GPIIb/IIIa and GPIb/IX were investigated in the two patients of Family B and gave normal results. The mild severity of thrombocytopenia and the absence of qualitative platelet defects, at least in the two patients of family B, are consistent with the absence of bleeding tendency in affected subjects.
Conclusion
The p.Arg31* mutation in THPO causes a new autosomal dominant form of mild, non-syndromic thrombocytopenia. This innocuous disorder is relatively rare (1.3% of families of our case series) but it has to be distinguished from the more severe autosomal dominant ITs with normal platelet size deriving from mutations in ETV6, ANKRD26 and RUNX1, since they predispose to the development of hematological malignancies. Because of the similarity of the clinical features and the lack of reliable laboratory markers, we suggest to perform genetic analysis in all subjects with autosomal dominant thrombocytopenia and normal platelet size in order to identify their disorders, define prognosis and organize an appropriate follow-up regimen.
Session topic: 32. Platelets disorders
Keyword(s): Thrombopoietin (TPO), Thrombocytopenia, Inherited platelet disorders
Abstract: S433
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:00 - 12:15
Location: Room N101
Background
The THPO-MPL axis plays a central role in platelet biogenesis: it activates the signaling cascade inducing megakaryocytes (MKs) differentiation from progenitor cells and regulates MKs maturation, proplatelet extension, and nascent platelets release into the bloodstream.
Aims
To unravel the molecular basis of ITs and to improve the clinical and laboratory characterization of the new ITs identified.
Methods
Whole exome sequencing (WES) was performed in 86 propositi with an unknown IT. They were part of our case series of 274 consecutive families, 151 of which remained without a definite diagnosis at the end of the diagnostic workup carried out according to the diagnostic algorithm proposed in 2003 by the Italian platelet study group and subsequently updated to include the most recent discovered disorders (Clin Genet 2016;89:141). The investigation was approved by the Institutional Review Board of the IRCCS Policlinico San Matteo Foundation and all patients gave written informed consent.
Results
WES in 86 propositi with unknown IT identified 2 unrelated individuals (family A and B) carrying the heterozygous variant c.91C>T (p. Arg31*), which is expected to result in a mutant protein degradation and THPO haploinsufficiency. In each family the segregation with the disorder was confirmed analyzing one affected relative. Bleeding tendency was absent in all cases. All patients had mild thrombocytopenia; blood film examination did not identify any morphological abnormality of platelets, except for some elements with slightly increased size in patients of family A. In vitro platelet aggregation and surface expression of GPIIb/IIIa and GPIb/IX were investigated in the two patients of Family B and gave normal results. The mild severity of thrombocytopenia and the absence of qualitative platelet defects, at least in the two patients of family B, are consistent with the absence of bleeding tendency in affected subjects.
Conclusion
The p.Arg31* mutation in THPO causes a new autosomal dominant form of mild, non-syndromic thrombocytopenia. This innocuous disorder is relatively rare (1.3% of families of our case series) but it has to be distinguished from the more severe autosomal dominant ITs with normal platelet size deriving from mutations in ETV6, ANKRD26 and RUNX1, since they predispose to the development of hematological malignancies. Because of the similarity of the clinical features and the lack of reliable laboratory markers, we suggest to perform genetic analysis in all subjects with autosomal dominant thrombocytopenia and normal platelet size in order to identify their disorders, define prognosis and organize an appropriate follow-up regimen.
Session topic: 32. Platelets disorders
Keyword(s): Thrombopoietin (TPO), Thrombocytopenia, Inherited platelet disorders