Germline Mutation ofCBLIs Associated With Moyamoya Disease in a Child With Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Like Disorder

2014 ◽  
Vol 62 (3) ◽  
pp. 542-544 ◽  
Author(s):  
Nobuyuki Hyakuna ◽  
Hideki Muramatsu ◽  
Takeshi Higa ◽  
Yasutsugu Chinen ◽  
Xinan Wang ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Germline Mutation ◽  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myelomonocytic Leukemia

P-155 Persistant thrombocytopenia in Noonan syndrome with juvenile myelomonocytic leukemia: A case report

2013 ◽  
Vol 37 ◽  
pp. S93-S94
Author(s):  
A. Eischen ◽  
C. Paillard ◽  
M. Besse ◽  
A. Spiegel ◽  
P. Lutz ◽  
...  
Keyword(s):  
Case Report ◽  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myelomonocytic Leukemia

scholarly journals Prolonged thrombocytopenia in a neonate with Noonan syndrome: a case report

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052093644
Author(s):  
Meng Li ◽  
Jinghui Zhang ◽  
Nianzheng Sun
Keyword(s):  
Platelet Count ◽  
Case Report ◽  
Noonan Syndrome ◽  
Immune Thrombocytopenia ◽  
Perinatal Asphyxia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Normal Range ◽  
Ptpn11 Gene ◽  
Alloimmune Thrombocytopenia ◽  
Myelomonocytic Leukemia

We report a case of a Chinese neonate who was diagnosed with Noonan syndrome and had persistent, self-limited thrombocytopenia. The neonate was admitted to the Neonatology Department 20 minutes after birth because of respiratory distress. From birth until 2 months of age, platelet values fluctuated between approximately 6 and 30 × 109/L. There was no intracranial hemorrhage. However, the child had a transient hypocalcemic seizure and fever. We excluded thrombocytopenia caused by perinatal asphyxia, immune thrombocytopenia, fetomaternal alloimmune thrombocytopenia, juvenile myelomonocytic leukemia, and chromosome 13, 18, and 21 trisomy syndromes. Despite treatment with anti-infective agents and transfusion of platelets and immunoglobulin, the platelet count did not return to the normal range. Genetic testing confirmed a PTPN11 gene mutation, which led to the diagnosis of Noonan syndrome. At 3 months of age, the platelet count gradually increased without intervention and returned to the normal range by 6 months. We speculate that the thrombocytopenia in this case was closely related to Noonan syndrome.

PTPN11 Mutational Spectrum in Juvenile Myelomonocytic Leukemia and Noonan Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3417-3417 ◽  
Author(s):  
Christian P. Kratz ◽  
Charlotte M. Niemeyer ◽  
Bruce D. Gelb ◽  
Marco Tartaglia ◽  
Mignon L. Loh
Keyword(s):  
Cell Fate ◽  
Noonan Syndrome ◽  
Somatic Mutations ◽  
Heart Defects ◽  
Lymphoblastic Leukemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Acute Monocytic Leukemia ◽  
Missense Mutations ◽  
Ptpn11 Mutation ◽  
Myelomonocytic Leukemia

Abstract Somatic, heterozygous missense mutations in the PTPN11 proto-oncogene encoding SHP-2 are identified in 35% of patients with juvenile myelomonocytic leukemia (JMML). Other non-syndromic hematologic malignancies in which somatic PTPN11 mutations have been detected are pediatric myelodysplastic syndrome, acute monocytic leukemia (FAB-M5 AML) and common or B-cell precursor acute lymphoblastic leukemia. Germline PTPN11 mutations are found in 50% of patients with Noonan syndrome (NS), an autosomal dominant disorder characterized by facial anomalies, short stature and congenital heart defects. Infants with NS are predisposed to developing JMML (NS/JMML); however, the course of NS/JMML tends to be milder and self-resolving. JMML that is not associated with NS have a poor prognosis and are currently being treated with intensive regimens such stem cell transplantation. Differentiating JMML from NS/JMML is of critical clinical relevance and also provides interesting questions about the pathogenesis of these diseases. To that end, we have compared the spectrum of mutations in patients with isolated JMML, NS/JMML and NS alone. The assembly of all known published and unpublished germline and somatic exon 3 and 13 PTPN11 mutations detected in ours and other laboratories (78 pts with PTPN11 mutation positive isolated JMML; 18 pts with PTPN11 mutation positive NS/JMML) reveal that the identity of the affected residues or the type of substitution differ between NS and JMML, even though the resulting molecular defects appear to be functionally similar. In NS defects in exons 4, 7 and 8 account for approximately one-half of cases. On the contrary, mutations affecting these exons are rarely identified in JMML. A few germline NS-causative mutations affect the same residues of SHP-2 that are also altered by somatic mutations in non-syndromic JMML. In almost all of the cases, the germline and somatic mutations affecting identical residues differ with respect to the amino acid substitution. There are 2 major hot spots: 7 out of 18 patients (39%) with NS/JMML carry the T73I substitution. In isolated JMML the E76K mutation is detected most often (18 out of 78 patients (23%)). We describe 2 novel JMML mutations (E76M, G503V) and 2 novel NS/JMML mutations (R598W, S502A). Six mutations associated with isolated NS are also observed in NS/JMML. These findings imply the presence of a germline mutation needs to be excluded in all mutation positive neonates with presumed isolated JMML. In addition, our findings raise a number of research questions: First, are somatic PTPN11 mutations alone sufficient to initate leukemia and what are the molecular factors influencing the consequences of a PTPN11 mutation in hematopoietic cells? Second, do identical mutations have different consequences on cell fate of hematopoetic cells depending on whether they occur as germline or somatic events? Do some patients with isolated NS and PTPN11 mutation develop transient myeloproliferation of hematopoetic cells which may be subtle and unrecognised?

scholarly journals Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

2017 ◽  
Vol 25 (4) ◽  
pp. 509-511 ◽  
Author(s):  
Heather Mason-Suares ◽  
Diana Toledo ◽  
Jean Gekas ◽  
Katherine A Lafferty ◽  
Naomi Meeks ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myelomonocytic Leukemia

Noonan syndrome and juvenile myelomonocytic leukemia: Different diseases caused by deregulation of identical pathways

2006 ◽  
Vol 30 ◽  
pp. S2
Author(s):  
C.P. Kratz ◽  
S. Schubbert ◽  
M. Zenker ◽  
S. Böll ◽  
G. Bollag ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia in a 16-Year-Old With Noonan Syndrome

2012 ◽  
Vol 34 (7) ◽  
pp. 569-572 ◽  
Author(s):  
Michael Vincent Ortiz ◽  
Suzanne Skoda-Smith ◽  
Katherine A. Rauen ◽  
Robert W. Allan ◽  
William Birdsall Slayton
Keyword(s):  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myelomonocytic Leukemia

scholarly journals Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome

2020 ◽  
Author(s):  
Maja Solman ◽  
Sasja Blokzijl-Franke ◽  
Chuan Yan ◽  
Qiqi Yang ◽  
Sarah M. Kamel ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Developmentally Regulated ◽  
Hematopoietic Stem ◽  
Activating Mutations ◽  
Stem And Progenitor Cells ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Myelomonocytic Leukemia

SummaryThe RASopathy Noonan syndrome (NS) is a frequent developmental disorder predominantly caused by activating mutations in the phosphatase SHP2. Among other features, NS children are predisposed to develop juvenile myelomonocytic leukemia (JMML). We developed a zebrafish mutant line carrying the NS-patient associated mutation Shp2-D61G. Shp2D61G zebrafish recapitulate major NS traits, including a JMML-like phenotype originating from defective hematopoietic stem and progenitor cells (HSPCs). Single cell RNA sequencing of mutant HSPCs revealed expansion of monocyte/macrophage progenitor cells associated with developmentally regulated cytokine production and elevated inflammation. Importantly, an anti-inflammatory agent rescued the JMML-like phenotype. Our results reveal a role for developmentally-induced inflammation in genesis of NS/JMML blood phenotypes and suggest anti-inflammatory drugs as potential new therapies.

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