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Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The characteristic facies with ptosis and low-set ears, as well as a different cardiac defect from that of Turner syndrome (commonly pulmonary stenosis but also sometimes hypertrophic cardiomyopathy), should allow clinical recognition of this relatively common disorder in either sex. Autosomal dominant inheritance occurs, but the risk to sibs of an isolated case with entirely normal parents is low. Mutations in the gene PTPN11 have been found in about half of those affected. This gene is also involved in the LEOPARD syndrome of lentigines, deafness and pulmonary stenosis. Other genes of the Ras-MAPK pathway can be involved in Noonan syndrome and several disorders caused by mutations in genes in this pathway have overlapping clinical features; they are known collectively as the RASopathies.
Fetal Alcohol Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Margaret P. Adam, H. Eugene Hoyme
Noonan syndrome can also mimic some features of FAS. In particular, patients with Noonan syndrome can have short stature, ptosis, and mild mental retardation. However, these patients can be distinguished from patients with FAS by their other dysmorphic features, which include webbed neck, low posterior hairline, shield chest, cryptorchidism, and pulmonic stenosis. Noonan syndrome is an autosomal dominant condition and approximately 50% of patients with Noonan syndrome have been found to have mutations in the proteintyrosine phosphatase, nonreceptor type 11 (PTPN11) gene on chromosome 12q24.1. This gene encodes a protein that appears to be important in several intracellular signal transduction pathways that control a wide variety of developmental processes (36). Mutation analysis for the PTPN11 gene is now available clinically.
Congenital cardiac anomalies
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Noonan’s syndrome is linked to PTPN11 gene mutations. Extracardiac involvement consists of hypertelorism, ptosis, low-set ears, webbed neck, short stature, variable degrees of mental retardation and cryptorchidism. Cardiac manifestations are dysplastic and stenotic pulmonary valves, atrial septal defects and occasionally hypertrophic cardiomyopathy.
Outcomes of juvenile myelomonocytic leukemia patients after sequential therapy with cytarabine and 6-mercaptopurine
Published in Pediatric Hematology and Oncology, 2020
Abdul Wajid M, Aditya Kumar Gupta, Gargi Das, Debasish Sahoo, Jagdish Prasad Meena, Rachna Seth
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of pediatrics with an incidence of approximately 1.2 per million children per year.1 It is characterized by hypersensitivity of myeloid progenitor cells to granulocyte–macrophage colony-stimulating factor in vitro. JMML patients present with somatic and/or germline mutations in genes of the RAS pathway in approximately 90% and these include, Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11), NRAS, KRAS, neurofibromatosis type 1 (NF1), and Casitas B-lineage Lymphoma (CBL) mutations in leukemic cells.2 Germline NF-1 mutations are seen in 10–15%,2PTPN11 germline mutations are detected in half of patients with Noonan syndrome3 while somatic PTPN11 mutations are found in about 35% of de-novo non syndromic JMML.4 Somatic point mutations in NRAS or KRAS are found in 20– 25% of patients with JMML.5,6 Approximately 35% of JMML patients have karyotype abnormalities most commonly monosomy 7.7 The diagnosis of JMML requires the satisfaction of clinical and laboratory criteria initially proposed by the JMML working group meeting in Geneva, Switzerland in 2006.8 This was later updated to include hyperphosphorylation of STAT5 in place of an elevated white blood cell count.
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
In Noonan syndrome, approximately 50% of cases who present postnatally are found to have mutations in PTPN11 [135,136]. As we carry out increasing amounts of in-utero genetic sequencing, we may find that antenatal presentation correlates more strongly with a different Noonan-causing gene. It is reported that 59% of pregnancies affected by Noonan Syndrome show a consistent pattern of raised nuchal translucency, pleural effusions and nonimmune fetal hydrops, as well as polyhydramnios and cardiac defects [137]. Absence of the ductus venosus has also been observed in approximately 50% of cases [137,138]. It is thought that the lymphatic abnormalities in fetuses with Noonan syndrome result from a disturbance in lymphatic endothelial differentiation due to diminished expression of the lymphatic markers PROX1 and Podoplanin and an increase in the vascular markers VEGF-A and Neuopilin-1 [139]. The fetal hydrops in Noonan syndrome is likely due to lymphatic malformation rather than congenital heart disease.
Targeting SHP2 phosphatase in hematological malignancies
Published in Expert Opinion on Therapeutic Targets, 2022
Rahul Kanumuri, Santhosh Kumar Pasupuleti, Sarah S Burns, Baskar Ramdas, Reuben Kapur
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene [3]. SHP2 is an extensively studied oncogenic tyrosine phosphatase that is associated with various signal transduction pathways, including the activation of the RAS/MAPK, PI3K/AKT, JAK/STAT, PD-1/PD-L1, mTOR, and Hippo pathways [4–7]. Germline mutations in the PTPN11 gene can cause Noonan syndrome (NS), which is an autosomal dominant disorder characterized by undeveloped body parts, and Noonan syndrome with multiple lentigines (NS-ML) [8,9]. In addition, somatic gain-of-function (GOF) mutations in the PTPN11 gene contribute to several hematological malignancies, such as Juvenile myelomonocytic leukemia (JMML), Acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), myelodysplastic syndromes (MDS), and several solid cancers [7,10]. Importantly, infants with NS-based activating PTPN11 mutations can develop JMML or JMML-like myeloproliferative disorders (MPD) [11]. Recent genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and small-molecule screens performed in rhabdoid tumor cell lines revealed a therapeutically relevant dependency between SHP2 and receptor tyrosine kinases (RTKs) [12]. Several SHP2-specific inhibitors are being tested for their therapeutic potential as anti-cancer drugs. In this review, we focus on the functions of SHP2, the diverse effects of its mutations on various signaling pathways, and implications of PTPN11 mutations in the therapeutic management of hematological malignancies.