Hematological findings in Noonan syndrome

Bertola, Débora Romeo; Carneiro, Jorge David Aivazoglou; D'Ámico, Elbio Antônio; Kim, Chong; Albano, Lilian Maria José; Sugayama, Sofia Mizuho Miura; Gonzalez, Claudette Hajaj

doi:10.1590/s0041-87812003000100002

Cited by 37 publications

(22 citation statements)

References 11 publications

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“…They are also at risk of developing transient myeloproliferative syndromes in the neonatal period and coagulopathies. [28][29][30][31] They do not, however, appear to be at an increased risk of developing AML. While some of the same codons are affected in both NS and AML, many are different.…”

Section: Resultsmentioning

confidence: 97%

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group

et al. 2004

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The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21 ras (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-AmericanBritish (FAB) morphology M5 AML (P ¼ 0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML. Leukemia (2004) [2][3][4] Uncovering other mutations that perturb the RTK/Ras signaling pathways could further illuminate the biology of AML, provide new independent prognostic markers, and/or identify new therapeutic targets.The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to Ras and other signaling molecules. 5 Germline mutations in PTPN11 are a major cause of Noonan syndrome (NS). 6,7 Children with NS are at increased risk of developing juvenile myelomonocytic leukemia (JMML), a relentless myeloproliferative disorder characterized by overproduction of myelomonocytic cells that infiltrate spleen, liver, and skin, among other organs. [8][9][10] Most children with JMML are boys. [8][9][10] We and others have recently reported that up to 35% of patients with JMML harbor missense PTPN11 mutations, which are largely exclusive of RAS and NF1 alterations. 11,12 All of these mutations are predicted to activate SHP-2 phosphatase activity by disrupting the inhibitory interaction between the N-SH2 and PTP domains of the protein. Although the biochemical data are inconclusive, genetic studies suggest that the hyperactive PTPN11 mutations found in JMML contribute to leukemia growth by deregulating the Ras pathway. 11,12 Based on the existence of NRAS and KRAS mutations in AML and JMML, we reasoned that mutations in PTPN11 might also occur in both diseases. To address this question, we screened a well-characterized cohort of AML specimens from children enrolled on Children's Cancer Group (CCG) clinical trials 2941 and 2961 for mutations in PTPN11 and correlated these data with clinical and molecular data. Materials and methods Patients and therapyBone marrow specimens from 298 patients with de novo AML registered on protocols CCG 2941 and 2961 were included in this study. A total of 278 specimens had adequate DNA for analysis. The diagnosis of AML...

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Section: Resultsmentioning

confidence: 97%

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group

et al. 2004

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“…Easy bruising and bleeding problems have been reported in up to 55% of patients. Coagulation studies reveal prolonged bleeding time, factor VIII, XI and XII deficiencies, thrombocytopenia and platelet function defects [8][9][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, typical facial dysmorphisms, congenital heart defects and other anomalies [8][9][10] such as bleeding problems which have been reported in up to 55% of patients [8][9][10][11][12][13][14]. NS is a clinical diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Duodenal Hematoma and Pancreatitis Complicating Endoscopic Intestinal Biopsy in a Boy with Noonan Syndrome

Leva

Macchini²,

Cesare³

et al. 2012

J Trauma Treatment

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“…Furthermore, some case reports have documented NS patients with important bleeding problems, and even the rare abnormality of FXIII deficiency [Sgouros et al, 2004;Tofil et al, 2005;Staudt et al, 2005]. To date, it has been widely held that NS patients are at risk for abnormal bleeding and should be tested for bleeding abnormalities [Singer et al, 1997;Bertola et al, 2003]. Musante et al [2002] studied genotype and phenotype in 96 NS patients with PTPN11 mutations.…”

Section: Discussionmentioning

confidence: 99%

Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations

Derbent

Öncel

Tokel

et al. 2010

American J of Med Genetics Pt A

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Reports on Noonan syndrome (NS) have documented multiple types of coagulation defects and bleeding diathesis, and a wide range of clinical presentations. Early studies suggested that a large proportion of NS patients have coagulation defects, whereas more recent reports indicate low rates of coagulopathy. The aim of this study was to evaluate phenotypic characteristics, PTPN11 gene mutations, and hematological and coagulation parameters in 30 clinically diagnosed cases of NS. One of the NS patients had a history of easy bruising; however, his hematological and coagulation tests were normal. None of the other patients had clinical coagulation problems. In the NS group, values for platelet count, activity of factors XI, XII, and protein C were significantly lower than the corresponding means for the control group. However, the results of coagulation tests in the NS group were diagnostically inconclusive and only one patient had clinical signs of coagulopathy. Interestingly, two NS patients had low protein C activity. One of these children had an A1517C mutation and transient myelodysplasia. The other patient had a C1528G mutation in exon 13 that has not been reported previously. Neither of these individuals experienced a thrombotic event or any complication during approximately 3 years of follow-up. For all patients clinically diagnosed with NS, a thorough history of coagulation issues should be taken and first-line coagulation testing should be done to evaluate for bleeding diathesis. However, if these assessments reveal nothing abnormal, complications related to coagulation are unlikely and extensive testing is unnecessary.

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Hematological findings in Noonan syndrome

Cited by 37 publications

References 11 publications

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group

Duodenal Hematoma and Pancreatitis Complicating Endoscopic Intestinal Biopsy in a Boy with Noonan Syndrome

Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations

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