Mutations In PTPN11 Gene Research Articles

Characteristic Analysis of Adult Acute Myeloid Leukemia Patients with PTPN11 Gene Mutation

To investigate the incidence of PTPN11 gene mutation and its associated gene mutations in adult patients with acute myeloid leukemia (AML), and analyze its clinical characteristics. Second-generation sequencing and Sanger sequencing were used to detect 51 gene mutations, and multiplex-PCR was used to detect 41 fusion genes from 451 newly diagnosed adult AML patients admitted to Affiliated Hospital of Jiangnan University, Changzhou Second People's Hospital, Wuxi People's Hospital and Wuxi Second People's Hospital from January 2017 to July 2022. Among 451 primary adult AML patients, the PTPN11 gene mutation was detected in 34 cases, and the mutation rate was 7.5%. In the 34 patients, 37 PTPN11 alterations were found, which were exclusively missense mutations affecting residues located within the N-SH2 (31 cases) and PTP (6 cases) domains and clustered overwhelmingly in exon 3. The platelet count of PTPN11 mutation patients was 76.5(23.5, 119.0)×109/L, which was significantly higher than 41.0(22.0, 82.5)×109/L of wild-type patients (P < 0.05). While, there were no significant differences in sex, age, peripheral white blood cell count, hemoglobin, and bone marrow blast between PTPN11 mutation and wild-type patients (P >0.05). In FAB subtypes, PTPN11 mutations were mainly distributed in M5, followed by M2 and M4, less frequently in M3 and M6. There was no significant difference in the distribution of FAB subtypes between PTPN11 mutation and wild-type patients (P >0.05). A total of 118 AML patients were detected positive fusion gene, among which patients with PTPN11 mutations had a higher incidence of positive MLL-AF6 than wild-type ones (P < 0.01). 97.1% of 34 patients with PTPN11 mutations were accompanied by other mutations, in descending order, they were respectively NPM1 (38.2%), NRAS (32.4%), FLT3-ITD (32.4%), DNMT3A (32.4%) and KRAS (23.5%), etc . PTPN11 mutation has a certain incidence in AML patients and is clustered overwhelmingly in exon 3. ALL of them are exclusively missense mutations, and most often present in conjunction with NPM1 mutations. FAB typing of PTPN11 mutation is mostly manifested as M5 subtype, which is associated with higher platelet counts.

Noonan syndrome: molecular and clinical findings in individuals with PTPN11 pathogenic variants

Purpose: RASopathies encompass a spectrum of disorders resulting from pathogenic variants in genes associated with the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, critical for cellular functions like proliferation, differentiation and survival. Noonan syndrome (NS), the most prevalent form of RASopathies, presents with a myriad of clinical features including characteristic facial dysmorphisms, congenital heart defects, and developmental delays. Despite its clinical recognition, molecular confirmation remains elusive in a notable percentage of cases. In this study, we aimed to investigate the clinical and molecular profiles of six patients diagnosed with NS, focusing on the role of PTPN11 gene mutations. Materials and methods: Molecular evaluation was performed using PTPN11 gene sequence analysis and whole gene sequencing methods in six patients who were thought to have typical NS phenotypes based on clinical evaluations. Results: Molecular screening in patients identified four different pathogenic variants in the PTPN11 gene. These variants, all heterozygous, were classified as pathogenic according to established criteria. Conclusion: Our findings contribute to understanding the genetic landscape of NS and underscore the significance of molecular analysis in confirming diagnoses.

RISK FACTORS AND EARLY SIGNS OF CRITICAL CONDITIONS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA ADMITTED TO THE INTENSIVE CARE UNIT

Relevance: Acute lymphoblastic leukemia (ALL) is the most common cancer among children, accounting for nearly a quarter of all childhood cancers.&#x0D; The study aimed to determine the risk factors and signs of critical conditions in children with acute lymphoblastic leukemia admitted to an intensive care unit (ICU).&#x0D; Methods: The approach used was a systematic review. Data was collected from sources published in 2019-2023. Four cohort studies, four retrospective analyses, two literature reviews, one case-control study, and one case study were included in this systematic review.&#x0D; Results: The prognosis in pediatric ALL depends on the initial number of blast cells in the peripheral blood. Patients with B-cell precursor acute lymphoblastic leukemia (BCP ALL) and low blast cell numbers survived better than patients with T-cell acute lymphoblastic leukemia (T-ALL) and low cell count. IL1B and NLRP1 genetic polymorphisms enhanced ALL risk and reduced infectious comorbidity. However, these gene polymorphisms must be confirmed in juvenile leukemia. KRAS, FLT3, NRAS, PTPN11, KMT2D, PTEN, and NOTCH1 gene mutations affected pediatric ALL patient features and treatment results. These mutations demonstrate the relevance of genetic profiling in risk classification and tailored management. Gene variations and availability of effective medication contributed. Pediatric BCP-ALL patients with the PAX5P80R mutation had worse 5-year overall survival, higher white blood cell counts, male preponderance, and more genetic abnormalities. Pediatric BCP-ALL focused on genetic analysis and risk stratification. Children of African American and European American ancestry showed varied incidence, recurrence, and outcome rates for ALL. African American children exhibited lower incidence but greater recurrence rates and poorer prognosis than European American children.&#x0D; Conclusion: Risk factors for these patients’ admission to ICU include comorbidities, infectious diseases, hypoxia, and hemodynamic instability, as well as age and baseline white blood cell count at diagnosis.

Retracted: PTPN11 Gene Mutations and Its Association with the Risk of Congenital Heart Disease.

[This retracts the article DOI: 10.1155/2022/8290779.].

Genomics of next generation sequencing in pediatric B-acute lymphoblastic leukemia and its impact on minimal residual disease

Objective: To describe the gene mutation profile of newly diagnosed pediatric B-acute lymphoblastic leukemia (B-ALL) and analyze its effect on minimal residual disease (MRD). Methods: A total of 506 newly diagnosed B-ALL children treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from September 2018 to July 2021 were enrolled in this retrospective cohort study. The enrolled children were divided into MRD ≥1.00% group and <1.00% group according to MRD results on the 19th day since chemotherapy, and MRD ≥0.01% group and <0.01% group according to MRD results on the 46th day. Clinical characteristics and gene mutations of two groups were compared. Comparisons between groups were performed with chi-square test or Fisher's exact test. Independent risk factors of MRD results on the 19th day and the 46th day were analyzed by Logistic regression model. Results: Among all 506 patients, there were 318 males and 188 females. On the 19th day, there were 114 patients in the MRD ≥1.00% group and 392 patients in the MRD <1.00% group. On the 46th day, there were 76 patients in the MRD ≥0.01% group and 430 patients in the MRD <0.01% group. A total of 187 gene mutations were detected in 487 (96.2%) of 506 children. The most common gene mutations were signal transduction-related KRAS gene mutations in 111 cases (22.8%) and NRAS gene mutations in 99 cases (20.3%). Multivariate analysis showed that PTPN11 (OR=1.92, 95%CI 1.00-3.63), KMT2A (OR=3.51, 95%CI 1.07-11.50) gene mutations and TEL-AML1 (OR=0.48, 95%CI 0.27-0.87), BCR-ABL1 (OR=0.27, 95%CI 0.08-0.92) fusion genes and age >10 years (OR=1.91, 95%CI 1.12-3.24) were independent influencing factors for MRD ≥1.00% on the 19th day. BCORL1 (OR=2.96, 95%CI 1.18-7.44), JAK2 (OR=2.99, 95%CI 1.07-8.42) and JAK3 (OR=4.83, 95%CI 1.50-15.60) gene mutations and TEL-AML1 (OR=0.43, 95%CI 0.21-0.87) fusion gene were independent influencing factors for MRD ≥0.01% on the 46th day. Conclusions: Children with B-ALL are prone to genetic mutations, with abnormalities in the RAS signaling pathway being the most common. Signal transduction related PTPN11, JAK2 and JAK3 gene mutations, epigenetic related KMT2A gene mutation and transcription factor related BCORL1 gene mutation are independent risk factors for MRD.

Clinical features and prognosis of juvenile myelomonocytic leukemia: an analysis of 63 cases

To investigate the clinical features of juvenile myelomonocytic leukemia (JMML) and their association with prognosis. Clinical and prognosis data were collected from the children with JMML who were admitted from January 2008 to December 2016, and the influencing factors for prognosis were analyzed. A total of 63 children with JMML were included, with a median age of onset of 25 months and a male/female ratio of 3.2∶1. JMML genetic testing was performed for 54 children, and PTPN11 mutation was the most common mutation and was observed in 23 children (43%), among whom 19 had PTPN11 mutation alone and 4 had compound PTPN11 mutation, followed by NRAS mutation observed in 14 children (26%), among whom 12 had NRAS mutation alone and 2 had compound NRAS mutation. The 5-year overall survival (OS) rate was only 22%±10% in these children with JMML. Of the 63 children, 13 (21%) underwent hematopoietic stem cell transplantation (HSCT). The HSCT group had a significantly higher 5-year OS rate than the non-HSCT group (46%±14% vs 29%±7%, P<0.05). There was no significant difference in the 5-year OS rate between the children without PTPN11 gene mutation and those with PTPN11 gene mutation (30%±14% vs 27%±10%, P>0.05). The Cox proportional-hazards regression model analysis showed that platelet count <40×109/L at diagnosis was an influencing factor for 5-year OS rate in children with JMML (P<0.05). The PTPN11 gene was the most common mutant gene in JMML. Platelet count at diagnosis is associated with the prognosis in children with JMML. HSCT can improve the prognosis of children with JMML.

Preliminary investigation of the diagnosis and gene function of deep learning PTPN11 gene mutation syndrome deafness.

Syndromic deafness caused by PTPN11 gene mutation has gradually come into the public's view. In the past, many people did not understand its application mechanism and role and only focused on non-syndromic deafness, so the research on syndromic deafness is not in-depth and there is a large degree of lack of research in this area. In order to let the public know more about the diagnosis and gene function of deafness caused by PTPN11 gene mutation syndrome, this paper used deep learning technology to study the diagnosis and gene function of deafness caused by syndrome with the concept of intelligent medical treatment, and finally drew a feasible conclusion. This paper provided a theoretical and practical basis for the diagnosis of deafness caused by PTPN11 gene mutation syndrome and the study of gene function. This paper made a retrospective analysis of the clinical data of 85 deaf children who visited Hunan Children's Hospital,P.R. China from January 2020 to December 2021. The conclusion were as follows: Children aged 1-6years old had multiple syndrome deafness, while children under 1year old and children aged 6-12years old had relatively low probability of complex deafness; girls were not easy to have comprehensive deafness, but there was no specific basis to prove that the occurrence of comprehensive deafness was necessarily related to gender; the hearing loss of patients with Noonan Syndrome was mainly characterized by moderate and severe damage and abnormal inner ear and auditory nerve; most of the mutation genes in children were located in Exon1 and Exon3, with a total probability of 57.65%. In the course of the experiment, it was found that deep learning was effective in the diagnosis of deafness with PTPN11 gene mutation syndrome. This technology could be applied to medical diagnosis to facilitate the diagnosis and treatment of more patients with deafness with syndrome. Intelligent medical treatment was also becoming a hot topic nowadays. By using this concept to analyze and study the pathological characteristics of deafness caused by PTPN11 gene mutation syndrome, it not only promoted patients to find diseases in time, but also helped doctors to diagnose and treat such diseases, which was of great significance to patients and doctors. The study of PTPN11 gene mutation syndrome deafness was also of great significance in genetics. The analysis of its genes not only enriched the gene pool, but also provided reference for future research.

PTPN11 Gene Mutations and Its Association with the Risk of Congenital Heart Disease.

Congenital heart disease (CHD) is the most common congenital birth defect, with a prevalence of 8.98‰ of all live births in China. PTPN11 has been known to be closely involved in heart developments. In this research, we carried out whole-exome sequencing in nine CHD families and identified eight rare deleterious missense variants of PTPN11 gene in nine probands by stringently filtering criteria. Sanger sequencing of these probands and their unaffected familiar members revealed that six damaging variants were de novo in seven CHD families. Then, targeted sequencing was used to assess the PTPN11 exon variants in 672 sporadic CHD cases and 399 unrelated controls and identified 7 deleterious missense variants in 8 patients. Fisher's exact test reveals a significant association of PTPN11 variations with CHD (P = 0.0289). We observed the distribution of different subtypes in CHD patients with PTPN11 variants and found atrial septal defect (ASD) is a prominent phenotype (58.8%, 10/17). In vitro functional assays revealed that the predicted PTPN11 variants disturb RAS-mitogen-activated protein kinase signaling activity by influencing the phosphorylation level of pathway proteins and increasing the proliferation and migration abilities of cardiomyocytes to different extents. Our findings demonstrated that PTPN11 variants were associated with increased risk of CHD development and may be served as an important susceptible genetic event for CHD, especially the ASD subphenotype.

The clinical phenotype and gene analysis of syndromic deafness with PTPN11 gene mutation

Objective: To analyze the clinical phenotype and screen the genetic mutations of hereditary deafness in three deaf families to clarify their molecular biology etiology. Methods: From January 2019 to January 2020, three deaf children and family members were collected for medical history, physical examination, audiology evaluation, electrocardiogram and cardiac color Doppler ultrasound, temporal bone CT examination, and peripheral blood DNA was obtained for high-throughput sequencing of deafness genes. Sanger sequencing was performed to verify the variant sites among family members. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomics. Results: The probands in the three families had deafness phenotypes. In family 1, proband had multiple lentigines, special facial features, growth retardation, pectus carinatum, abnormal skin elasticity, cryptorchidism and other manifestations. In family 2, proband had special facial features, growth retardation and abnormal heart, and the proband in family 3 had growth retardation and abnormal electrocardiogram. Genetic testing of three families detected three heterozygous mutations in the PTPN11 gene: c.1391G>C (p.Gly464Ala), c.1510A>G (p.Met504Val), c.1502G>A (p.Arg501Lys). All three sites were missense mutations, and the mutation sites were highly conserved among multiple homologous species. Based on clinical manifestations and genetic test results, proband 1 was diagnosed with multiple lentigines Noonan syndrome, and probands 2 and 3 were diagnosed with Noonan syndrome. Conclusion: Missense mutations in the PTPN11 gene may be the cause of the disease in the three deaf families. This study enriches the clinical phenotype and mutation spectrum of the PTPN11 gene in the Chinese population.

Cochlear Implantation in Noonan Syndrome With and Without Multiple Lentigines: A Case Report and Systematic Review.

To describe outcomes after bilateral cochlear implantation (CI) in a patient with a pathologic PTPN11 variant associated with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML). Additionally, to assess the utility of CI in this specific population based on our outcome and previous reports. Retrospective case report with literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A young boy with various multiorgan abnormalities, speech and language delay, and persistent hearing loss who was found to have a heterozygous PTPN11 gene mutation at age 2. Bilateral tympanostomy tube placement, diagnostic imaging, and eventual staged bilateral CI. Objective audiometric testing and developmental milestone attainment. Bilateral CI was successfully completed over a 2-month period. The patient illustrated significant improvement in objective audiologic measurement. However, he continues to sign as his main form of communication without significant speech progression. Early diagnostic and therapeutic intervention in patients with NS/NSML can help improve long-term audiologic and speech development. Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.

Identification of Differentially Expressed Genes and Key Pathways Associated with PTPN11 Mutation in Acute Myeloid Leukemia

PTPN11 is a prominent oncogene in many tumors, which linked with poor prognosis. But the gene expression profile associated with this gene mutation in AML is not yet fully elucidated. So, the current study was intended to explore the key genes and pathways associated with AML with PTPN11 mutation. Using the TCGA database, we investigated the gene expression profile for PTPN11 mutation and wild type. EdgeR, an R platform, was applied to categorize the differentially expressed genes. GO and KEGG enrichment analysis was accomplished using DAVID and GSEA. PPI network is investigated with STRING database and Cytoscape software. A statistical investigation was employed to examine the expression levels of genes and prognostic values. As a result, in total 3268 gene s were differentially expressed. GO, KEGG pathway and GSEA analysis of up and down-regulated genes represented that gene were enriched in apoptosis and metabolic signaling pathways. Furthermore, ten hub genes GAPDH, HSP90AA, MYC, UBB, HSPA4, EP300, CCDS, POLR2A, EFTUD2, RPL11. GAPDH was identified from the PPI network. A statistical investigation revealed that PTPN11 gene mutation associated with AML patients had a shorter median survival time with an increased risk of death compared with those without mutations.

Neurofibromatosis 1-Noonan Syndrome Associated with Pulmonary Stenosis and Hypertrophic Cardiomyopathy

Abstract Neurofibromatosis 1-Noonan syndrome is considered a distinct clinical entity, combining characteristics of both autosomal dominant disorders: neurofibromatosis 1 and Noonan syndrome. We present the case of a 20-year-old patient clinically diagnosed with neurofibromatosis 1-Noonan syndrome, with genetic confirmation-heterozygous mutation of PTPN11 gene and a variant of uncertain significance in NF1 gene (c.2989A&gt;G). Associated congenital heart disease was diagnosed at birth-severe pulmonary valve stenosis and infundibular pulmonary stenosis, surgically corrected at the age of one. At adult age, cardiologic assessment shows severe pulmonary regurgitation post commissurotomy, with residual large pulmonary stenosis and left ventricular apical hypertrophy, suggesting apical hypertrophic cardiomyopathy, confirmed by cardiac magnetic resonance. The patient needs periodical follow-up in order to identify the perfect timing for correction of severe pulmonary regurgitation. As there are no specific genetic therapies for neurofibromatosis 1 or Noonan syndrome, the diagnose and management of associated comorbidities is the main aspect to be taken into considered.

Correlation Analysis of DNA Methylation Level and Clinical Characteristics in JMML Patients

Objective: As a rare, aggressive pediatric myeloproliferative disease, juvenile myelomonocytic leukemia (JMML) encompassed both biological features of myelodysplastic syndrome and myeloproliferative neoplasm. Studies have shown that the methylation level in JMML patients is closely related to prognosis, and patients with high methylation level have poor prognosis. This study aimed to find clinical indicators that were associated with different methylation levels and prognosis.Methods: The clinical information of 24 JMML patients with DNA samples admitted to our center from December 2013 to May 2020 was retrospectively analyzed, and the DNA methylation level of their whole genome was detected.Results: The median age of onset was 14.5 months (0.1-153 months) among the 24 cases, including 17 males and 7 females. At diagnosis, the median WBC count was 27.1×10 9/L (6.2-98.1×10 9/L), and the median platelet count was 38×10 9/L (10-277×10 9/L). Chromosome karyotype abnormalities were found in 12.5% (3/24) of patients. Next-generation sequencing results showed that 79.2% (19/24) patients had at least one Ras pathway-related classical gene mutation, and 41.7% (10/24) patients had two or more somatic mutations. Genomic DNA methylation levels were divided into three groups: 10 cases in the hypomethylation group, 4 cases in the moderate methylation group, and 10 cases in the hypermethylation group. There were significant differences in age, platelets, PTPN11 gene mutation and the number of somatic mutations ≥2 in different methylation groups (P<0.05). The age of hypomethylated group was significantly lower than that of hypermethylated group (P<0.05), and the platelets of hypomethylated group was significantly higher than that of hypermethylated group (P<0.05). Patients ≤12m and platelets＞32×10 9/L had lower DNA methylation level (P<0.0001). The number of patients with PTPN11 gene mutation in the hypomethylated group was significantly lower than that in the hypermethylated group (P<0.05), and the number of patients with ≥2 mutations in the low and medium methylated groups was significantly lower than that in the hypermethylated group (P<0.05). Correlation analysis showed that hypermethylation level was significantly correlated with PTPN11 gene mutation and ≥2 somatic mutations (P<0.001).Conclusions: JMML patients with high methylation level in the DNA genome at diagnosis were older and with lower platelet levels, and hypermethylation were significantly correlated with high-risk prognostic factors such as PTPN11 gene mutation and ≥2 somatic mutations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Decitabine for treatment of children with JMML

Analysis of Gene Mutation and Clinical Characteristics in 19 Children with Juvenile Myelomonocytic Leukemia

To analyze the gene mutations of children with juvenile myelomonocytic leukemia (JMML) and their correlation with clinical characteristics. The genetic mutation results and clinical data of 19 children with JMML in Fujian from January 2015 to December 2018 were collected and analyzed retrospectively. According to the results of gene mutation, they were divided into PTPN11 gene mutation group and non-PTPN11 gene mutation group, and the clinical characteristics and prognosis of children with JMML between two groups were compared. Among the 19 children with JMML, 14 cases were male and 5 cases were female, and male/female ratio was 2.8∶1. The median age at diagnosis was 13(3-48) months, and 14 cases (73.68%) were less than 2 years old. Abdominal distension and pyrexia were the common initial symptoms, and all the children with JMML had splenomegaly. The median white blood cell count was 39.82(4.53-103.4)×109/L，and monocyte count was 4.37(1.04-23.12)×109/L. HbF was higher than the normal high value of the same age in 8 cases (42.11%). All JMML children's Philadelphia chromosome and BCR-ABL1 fusion gene were negative. Among the 19 patients, there were 1 case without any JMML related gene mutation, 7 cases (36.84%) with PTPN11 mutation, 6 cases (31.58%) with K-Ras mutation, 2 cases with NF1 mutation (10.53%), 2 cases with N-Ras mutation (10.53%), and 1 case (5.26%) with NF1 and N-Ras mutations simultaneously. Fifteen patients who only received supporting therapy all died, with a median survival time 9.2 (0.4-58.1) months. Whereas, among the four JMML children who received hematopoietic stem cell transplantation(HSCT), three cases survived and only one case died. Compared with the non-PTPN11 gene mutation group, the proportion of patients with hemoglobin F higher than the normal value of the same age was higher, and the median survival time was shorter in PTPN11 gene mutation group, and the differences were statistically significant (P=0.048 and 0.046, respectively). JMML is more common in male infancy and toddlerhood, and the main gene mutation types are PTPN11 and Ras mutations. Because the JMML children with PTPN11 mutations show particularly rapid disease progression, if there is no timely intervention, most children die in a short period of time. Therefore, early HSCT may improve the prognosis of the children with JMML.

A Challenging Diagnosis of Acute Myeloid Leukemia with Myelodysplasia Related Changes in the Setting of Ayurvedic Supplements and B12 Deficiency

Abstract Introduction/Objective Bone marrow findings of myelodysplastic changes can be associated with vitamin or mineral deficiencies (B12, folic acid or copper), infections, inflammatory disorders, exposure to toxins, heavy metals, zinc excess, recent radio- or chemotherapy, or myeloid neoplasms including myelodysplasia (MDS) and acute myeloid leukemia (AML). We present a case of a 32 year old Indian woman who presented with fatigue and weakness. She has a history of vitamin B12 deficiency and has been taking Ayurvedic supplements. This clinical history is very important because studies have shown that vitamin B12 deficiency has led to incorrect diagnoses of AML and/or MDS. Additionally, Ayurvedic supplements can contain a variety of heavy metals which can contribute to myelodysplastic changes. Results A complete blood count and peripheral smear analysis showed pancytopenia with rare blasts. A bone marrow core biopsy with ancillary testing was performed to evaluate for a hematologic malignancy. Vitamin B12 testing and heavy metal analysis was necessary to reach a final diagnosis. Flow cytometric analysis of the marrow identified 19.5% CD34 positive myeloblasts. The aspirate and core are hypercellular with increased blasts (17% on aspirate and 20-25% on core biopsy) with trilineage dyspoiesis. AML panel by fluorescence in situ hybridization showed no abnormalities. Heavy metal analysis shows no increase in lead, cadmium, mercury and arsenic levels. Recent vitamin B12 tests show results within normal range secondary to successful replacement. Ultimately, chromosome analysis identifies t(3;12)(q26,p13) involving ETV6/MECOM characteristic of a very poor prognosis in MDS or AML. Molecular AML panel identified BCOR and PTPN11 gene mutations which are associated with more aggressive disease and a poor prognosis in myeloid neoplasms. Conclusion This case had multiple possible causes of myelodysplastic changes and it was necessary to exclude these factors before yielding the final diagnosis of Acute Myeloid Leukemia with myelodysplastic related changes which demonstrated a rare translocation t(3;12) ETV6/MECOM which has a poor prognosis.

Mutation and Phenotypic Spectrum of Patients With RASopathies

To examine the common and specific clinical features, mutation spectrum and genotype-phenotype correlation in Noonan syndrome and related RASopathies. Records of 30 patients with clinical diagnosis of Noonan syndrome and related RASopathies presenting over a six-year period at a Tertiary care Medical Genetics centre were reviewed. Detailed clinical phenotype evaluation and genetic testing (PTPN11 sequencing or next generation sequencing) was done. The genetic results were used to classify the patients. Noonan syndrome was confirmed in 22 patients, 5 had cardiofaciocutaneous syndrome and 3 had Noonan syndrome like disorder with loose anagen hair. The molecular diagnosis was confirmed in 27 patients. Mutations in PTPN11 gene were confirmed in 57.8 % patients. Developmental delay, cardiac defects, ectodermal abnormalities and coarse face was the predominant phenotype. Noonan syndrome like disorder with loose anagen hair was clinically identifiable by the sparse, slow growing hair and caused by one recurrent SHOC2, c.4A>G mutation. Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.

Orodental, Facial and Clinical Features of Mutation-Positive Noonan Syndrome: A Monocentric Study.

To evaluate orodental, facial, clinical and molecular characteristics of the patients with Noonan Syndrome (NS). The orodental, clinical and molecular characteristics of 29 mutation-positive patients with NS were recorded. Orodental examination was performed in 17 patients. All exons and exonintron boundries of PTPN11 and SOS1 genes were analyzed by Sanger sequencing. A total of 29 patients with NS from 27 unrelated families were included in the study. Seventeen patients were examined by a specialist in oral medicine. The most common orodental findings were high-arched palate (n=13), gingivitis (n=6) and severe caries (n=6). Anterior open bite, posterior cross bite, Class II malocclusion, hypodontia, prognathism (maxillary or mandibular), macroglossia and gingival hyperplasia were also detected. Thirteen different mutations were observed in PTPN11 gene and exon 3 was the hotspot region. Hypodontia was detected in two patients who had the same mutation in PTPN11 gene, c.181G>A, p.D61N. This study indicated a high prevalance of orodental problems including high-arched palate, severe dental caries and gingivitis in patients with mutation-positive NS. The mutation in PTPN11 gene, c.181G>A, p.D61N, may be associated with hypodontia in patients with NS.

PTPN11 and the deafness

Summary PTPN11 gene encodes tyrosine phosphatase SHP-2 which locates on chromosome 12（12q24.1）, expresses in most embryonic and adult tissues, and plays pivotal roles in cell proliferation, differentiation, survival and cell death. SHP-2 apparently participates in signaling events downstream of RAS-MAPK and JAK/STAT. Diseases related to PTPN11 gene mutations include the Noonan syndrome（NS） and the NS with Multiple Lentigines（NSML）. Both NS and NSML contain the phenotypes of deafness, craniofacial anomalies, short stature, congenital heart defects, skin disorders, ophthalmologic abnormalities and cancer predisposition.

Endocrine Complications of Noonan Syndrome beyond Short Stature.

Noonan syndrome (NS) is a diagnosis that is made clinically based on features including typical facies, congenital heart defects, short stature and developmental delay. Approximately 50% of the patients have identified mutations in the PTPN11 gene, and a smaller percentage of mutations have been reported in other genes such as SOS1, RAF1 and RIT1 Despite normal birth length, patients typically reach adult height below normal. Other than growth, endocrine complications of NS are not as commonly reported. These include possible pathology in thyroid function, pubertal development and bone metabolism. Some investigators have looked to see if genetic mutations in these patients could pose a risk for future endocrinopathies. This chapter reviews reports on endocrine dysfunction other than growth in patients with NS. The information is meant to enhance awareness in those providers who care for these patients to the possibility of other existing endocrinopathies. Most importantly, it supports and highlights the endocrinologist's role in the care of patients with NS.

Clinical and genetic analyses of juvenile myelomonocytic leukemia

To study the clinical and genetic features of juvenile myelomonocytic leukemia (JMML) and the association between genotype and prognosis. Methods The clinical data of 15 children who were diagnosed with JMML were collected. Next-generation sequencing was used to detect common gene mutations of JMML. The male/female ratio was 6.5:1, and the age of onset was 19 months (range 2-67 months). Of the 15 children, 11 (73%) experienced disease onset before the age of 4 years, with abdominal distension and pyrexia as initial symptoms. All children had hepatosplenomegaly and superficial lymphadenectasis, with a number of peripheral blood mononuclear cells of >1.0×109/L and a percentage of juvenile cells of 1%-7% in peripheral blood smear. The percentage of bone marrow blasts + juvenile cells was <20%, and the percentage of monoblasts + promonocytes was 1%-10%. Of the 15 children, 10 (67%) had a higher level of hemoglobin F than the normal level at the corresponding age, with the highest level of 62.5%. All 15 children had the absence of Philadelphia chromosome, and one child had chromosome 7 deletion. All 15 children had a negative result of BCR/ABL fusion gene detection. PTPN11 gene mutation was found in 5 children (33%), NF1 mutation in 4 children (27%), CBL mutation in 3 children (20%), and RAS mutation in 3 children (20%). No children received regular chemotherapy, and one child underwent hematopoietic stem cell transplantation. The median follow-up time of 15 children was 18 months (range 1-48 months). Among the 15 children, 8 died (among whom 4 had PTPN11 gene mutation, 3 had NF1 mutation, and 1 had RAS mutation) and 7 survived. The children with PTPN11 mutation had the worst prognosis and the highest mortality rate, and those with CBL or NRAS mutation had a relatively good prognosis. The level of hemoglobin F was negatively correlated with survival time (rs=-7.21, P=0.002). In children with JMML, the type of gene mutation is associated with prognosis. The children with PTPN11 mutation often have a poor prognosis, and those with CBL or NRAS mutation have a relatively good prognosis.