title: A de novo T73I mutation in PTPN11 in a neonate with severe and prolonged congenital thrombocytopenia and Noonan syndrome.
abstract: We observed a neonate with severe congenital thrombocytopenia and features of Noonan syndrome where evaluations were negative for immune-mediated thrombocytopenia, congenital infections, and Fanconi anemia. The marrow findings and a significantly elevated plasma thrombopoietin (Tpo) level were consistent with congenital amegakaryocytic thrombocytopenia; we sought a genetic mutation that could explain this phenotype. No mutations were identified in c-MPL (the Tpo receptor gene). Microarray analysis of peripheral blood did not reveal an abnormality. DNA sequencing of the PTPN11 gene showed a heterozygous C>T nucleotide substitution in exon 3 (c.218C>T) predicted to result in a threonine-to-isoleucine change at residue 73 (T73I). A 6-week trial of eltrombopag (an agonist of the Tpo receptor) failed to increase the platelet count. We propose this specific PTPN11 mutation results in abnormalities of the protein product SHP-2, which, because of its role in signal transduction, results in severe congenital thrombocytopenia refractory to c-MPL agonists.
authors: Department of Women and Newborns, Intermountain Healthcare,University of Utah School of Medicine, Salt Lake City, Utah 84403, USA. rdchris4@ihc.com
authors: Robert D
authors: RD
authors: Christensen
authors: Hassan M
authors: HM
authors: Yaish
authors: Eyby L
authors: EL
authors: Leon
authors: Martha C
authors: MC
authors: Sola-Visner
authors: Pankaj B
authors: PB
authors: Agrawal
mesh_terms: D000328:Adult; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000502:physiology; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000151:congenital* / Q000235:genetics* / Q000628:therapy; D013926:Thrombopoietin / Q000097:blood
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11