Exploring the Association between PTPN11 Mutations and Diverse Medical Outcomes, including hematological malignancies and neuroblastoma.

By Nucleati Team
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In the realm of genetic research, understanding the implications of specific gene mutations is paramount to unraveling the mysteries of various medical conditions. One such gene of interest is PTPN11, known for its association with a diverse array of outcomes. This blog article aims to shed light on the findings of multiple studies that explore the impact of PTPN11 mutations on medical outcomes. From neuroblastoma to acute myelomonoblastic leukemia, and from Noonan syndrome to myeloproliferative disorders, we delve into the intriguing connections uncovered through case reports and series analyses. The evidence is collected with the help from Nucleati Germline Cancer Evidence Base

Case Reports

Patient/Family Gene/Variation Clinical Characteristics HGVS(es) Citation
Female patient with typical findings of NFNS PTPN11 transversion, 1909A --> G resulting in Gln510Arg and NF1 transversion, 2531A --> G resulting in Leu844Arg Clinical overlap between both syndromes, neurofibromatosis-Noonan syndrome (NFNS) NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile), NM_002834.5(PTPN11):c.1529A>C (p.Gln510Pro), NM_002834.5(PTPN11):c.1529A>G (p.Gln510Arg), NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile), NM_002834.5(PTPN11):c.1530G>C (p.Gln510His) PubMed
A 4-year-old girl with Noonan NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp) The patient had stage 4 neuroblastoma and later developed acute myelomonoblastic leukemia. There is potential association between PTPN11 mutations and leukemogenesis in patients with Noonan syndrome. NM_002834.5(PTPN11):c.922A>G PubMed
NS patient carrying a PTPN11 germline missense mutation PTPN11, p.G60A Short stature, typical craniofacial dysmorphism, skeletal anomalies, congenital heart defects, and predisposition to malignant tumors; neuroblastoma NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala) PubMed
Patient with Noonan syndrome and Hodgkin's lymphoma PTPN11 (1507G > C, Gly503Arg) The patient had Noonan syndrome caused by germ-line mutations in exon 13 of the PTPN11 gene and was diagnosed with Hodgkin's lymphoma. NM_002834.5(PTPN11):c.1507G>C (p.Gly503Arg), NM_002834.5(PTPN11):c.1507G>A (p.Gly503Arg), NM_002834.5(PTPN11):c.1506_1507delinsCC (p.Gly503Arg) PubMed
Fetus with T507K mutation PTPN11 T507K mutation Prenatal presentation with hydrops fetalis, cystic hygroma, and 46, XX karyotype. Autopsy findings reveal testes, male external genitalia, but absent Wolffian ducts.   PubMed
Patient with NSML caused by PTPN11 mutation PTPN11 c.1403C > T (p.Thr468Met) Medulloblastoma associated with NSML NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met) PubMed
Child with Noonan Syndrome PTPN11:c.1507G>C (p.Gly503Arg), PTPN11:c.1507G>A (p.Gly503Arg), PTPN11:c.1506_1507delinsCC (p.Gly503Arg) The child had congenital refractory chylothorax and subcutaneous edema suspected to be secondary to pulmonary lymphangiectasis. The infant died of respiratory failure and anasarca at 80days. The autopsy confirmed lymphatic dysplasia in lungs and mesentery. NM_002834.5(PTPN11):c.1507G>C (p.Gly503Arg), NM_002834.5(PTPN11):c.1507G>A (p.Gly503Arg), NM_002834.5(PTPN11):c.1506_1507delinsCC (p.Gly503Arg) PubMed
6-year-old boy with MCAP phenotype and healthy parents PTPN11 c.1529A>G p.(Gln510Arg) Macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly NM_002834.5(PTPN11):c.1529A>G (p.Gln510Arg) PubMed
A 9.5-year-old girl Heterozygous somatic mutation in the PTPN11 gene The patient had symptoms such as malaise, fever, massive hepatosplenomegaly, anemia, leukocytosis, monocytosis, thrombocytopenia, and increased hemoglobin. Bone marrow erythroid/myeloid ratio was 40/1 with 7% myeloblast and 5% monocyte suggesting erythroleukemia or juvenile myelomonocytic leukemia (JMML).   PubMed
5-year-old girl with bony lumps on fingers presenting with HME and later developing enchondromas Splice site mutation at the end of exon 11 on the PTPN11 gene Appearance of both exostoses and enchondromas suggested a diagnosis of metachondromatosis. Lesions may spontaneously resolve, making surgical intervention often unnecessary.   PubMed
Child with Noonan syndrome and JMML PTPN11 c.1505C>T (p.Ser502Leu) Child diagnosed with JMML shortly after birth, managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone. NM_002834.5(PTPN11):c.1505C>T (p.Ser502Leu) PubMed
A patient with juvenile myelomonocytic leukemia (JMML) and Lymphoid interstitial pneumonia (LIP) Novel germline mutation of unknown significance in additional sex combs-like-1 (ASXL1) gene and a pathogenic somatic mutation of protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene Patient underwent a matched unrelated bone marrow transplant for JMML with complete resolution of JMML and LIP with no recurrence to date   PubMed
11-year-old Thai boy with Noonan syndrome PTPN11:c.922A>G (p.Asn308Asp) Presented with symptoms related to hydrocephalus secondary to subependymoma in the fourth ventricle NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp) PubMed
Young adult patient with NS Germline PTPN11 and somatic NPM1, IDH1, and BCL6 mutations Fatal AML with 50.5-Mb interstitial deletion of 7q21.11-q33   PubMed
Female premature baby delivered via emergency C-section at 30+1 weeks of GA due to rapidly developing NIHF to a healthy mother. Family history noncontributory. Germline mutation in PTPN11 c.218C>T (p.Thr73Ile) associated with Noonan syndrome, congenital heart defect, persistent thrombocytopenia, and juvenile myelomonocytic leukemia. Noonan syndrome causing NIHF with PTPN11 c.218C>T (p.Thr73Ile) mutation. NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile) PubMed
13-year-old girl with Noonan syndrome and a recurrent mutation in PTPN11 Germline mutation in PTPN11 Patient developed three different types of brain tumors: optic pathway glioma, glioneuronal neoplasm of left temporal lobe, and cerebellar pilocytic astrocytoma.   PubMed
Patient with short stature and osteogenesis imperfecta; peculiar facial features; deafness; history of recurrent fractures De novo variant c.1403C>T (p.Thr468Met) on exon 12 of the PTPN11 gene; compound heterozygous mutation in the SEC24D gene: novel variant c.2609_2610delGA (p.Arg870Thrfs*10) on exon 20 and reported variant c.938G>A (p.Arg313His) on exon 8 Concurrent mutations in PTPN11 and SEC24D induced a phenotype that was significantly different from individual mutations in either PTPN11 or SEC24D gene NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met) PubMed
63-year-old gentleman with composite CLL/SLL and MEITL STAT5B and DNMT3A hotspot mutations closely related to pathogenesis of CLL/SLL and MEITL; BCOR mutation only in CLL/SLL area; likely pathogenic mutations in CLL: SETD2, NOTCH1, SF3B1, and PTPN11, in MEITL: TET2 and ZRSR2; mutations of GATA3, PLCG2, and FAT1 identified in both CLL/SLL and MEITL areas Admitted to hospital due to abdominal pain; diagnosed with CLL/SLL after BM biopsy, BM aspiration, and flow cytometry; diagnosed with MEITL after intestine excision; patient died in 12-month follow-up after surgery   PubMed

Case Series

Cohort Setup Outcome HGVS(es) Citation
Patients with Noonan syndrome PTPN11 mutations in human neoplasms Mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp), NM_002834.5(PTPN11):c.206A>T (p.Glu69Val), NM_002834.5(PTPN11):c.205G>A (p.Glu69Lys), NM_002834.5(PTPN11):c.181G>T (p.Asp61Tyr), NM_002834.5(PTPN11):c.173A>G (p.Asn58Ser), NM_002834.5(PTPN11):c.185A>G (p.Tyr62Cys) PubMed
23 cases with B-cell precursor ALL, 44 children with T-lineage ALL, and 69 children with acute myeloid leukemia PTPN11 and other gene mutations PTPN11 mutations were observed in B-cell precursor ALL cases, not among T-lineage ALL cases, and occurred in 4 of 12 cases with acute monocytic leukemia NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly), NM_002834.5(PTPN11):c.844A>G (p.Ile282Val), NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser), NM_002834.5(PTPN11):c.1472C>T (p.Pro491Leu), NM_002834.5(PTPN11):c.226G>C (p.Glu76Gln), NM_002834.5(PTPN11):c.205G>A (p.Glu69Lys), NM_002834.5(PTPN11):c.181G>T (p.Asp61Tyr), NM_002834.5(PTPN11):c.173A>G (p.Asn58Ser) PubMed
A panel of 175 primary human AML samples, including all French-American-British types except M3, and all cytogenetic risk groups Six genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11, and NRAS), and two candidate genes (CCND3 and FES) were analyzed 115 mutations were identified in 97 (55%) patients, including 81 patients (46%) with one mutation, 14 patients (8%) with two mutations, and two patients (1%) with three mutations. Correlation was observed between PTPN11 mutation and 'poor risk' disease. - PubMed
Patients with JMML (n = 69) or NS/MPD (n = 8) PTPN11 mutations identified in blood or bone marrow specimens Genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly), NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp), NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly), NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr), NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys), NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile), NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys), NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly), NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys), NM_002834.5(PTPN11):c.174C>G (p.Asn58Lys), NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala) PubMed
The study investigated the diversity of germline and somatic PTPN11 mutations and delineated their association with Noonan syndrome (NS), LEOPARD syndrome (LS), and leukemia. The report studied the difference in the gene mutations between the two groups (i.e. cases and controls) using genetic and biochemical data, molecular dynamics simulations, and SHP-2 proteins. The results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, the study shows that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity. NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser), NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly), NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp), NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser), NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys), NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp), NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly), NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met), NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr), NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile), NM_002834.5(PTPN11):c.854T>C (p.Phe285Ser) PubMed
Japanese children with acute lymphoblastic leukemia (ALL) Investigated mutations in PTPN11, RAS, and FLT3 using genetic sequencing 6 children with B precursor ALL had exon 3 and 8 missense mutations of PTPN11. 10 patients had RAS mutations and 1 patient had FLT3/ITD mutation. None had simultaneous mutations in PTPN11 and RAS. NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly), NM_002834.5(PTPN11):c.182A>C (p.Asp61Ala), NM_002834.5(PTPN11):c.172A>T (p.Asn58Tyr) PubMed
This study assessed the correlation between phenotype and genotype by analyzing the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with Noonan syndrome. The study aimed to find a correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes. The study found disease-causing mutations in 30 (50.8%) patients located in the PTPN11 (27.1%), SOS1 (16.9%), KRAS (1.7%), and RAF1 (5.1%) genes. Patients with PTPN11 mutations showed higher prevalences of patent ductus arteriosus and thrombocytopenia. NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly), NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser), NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp), NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr), NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala), NM_002834.5(PTPN11):c.184T>A (p.Tyr62Asn), NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp), NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp), NM_002834.5(PTPN11):c.1504T>G (p.Ser502Ala), NM_002834.5(PTPN11):c.1505C>T (p.Ser502Leu), NM_002834.5(PTPN11):c.1510A>G (p.Met504Val) PubMed
11 metachondromatosis (MC) families with single-linked interval Linkage analysis, targeted array, and parallel sequencing Heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, lesions in patients with MC appear to arise following a "second hit," MC may be locus heterogeneous, and PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp), NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met), NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr), NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile), NM_002834.5(PTPN11):c.409_413del (p.Val137fs), NM_002834.5(PTPN11):c.458_463delinsAAGAACACAGGGGAGAGCA (p.Thr153fs), NM_002834.5(PTPN11):c.1516C>T (p.Gln506Ter), NM_002834.5(PTPN11):c.353_354del (p.Ser118fs), NM_002834.5(PTPN11):c.1315del (p.Leu439fs), NM_002834.5(PTPN11):c.295A>T (p.Lys99Ter), NM_002834.5(PTPN11):c.643-2A>C PubMed
297 Dutch NS patients with a PTPN11 mutation (mean age 18 years) Estimation of cancer risk and spectrum in patients with NS carrying a PTPN11 mutation; investigation of whether specific PTPN11 mutations result in an increased malignancy risk 12 patients with NS developed a malignancy, 3.5-fold increased risk of developing cancer compared to the general population (23% cumulative risk up to age 55 years), hematological malignancies occurred most frequently, no correlation was found between specific PTPN11 mutations and cancer occurrence NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp), NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp), NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys), NM_002834.5(PTPN11):c.172A>C (p.Asn58His), NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala), NM_002834.5(PTPN11):c.184T>A (p.Tyr62Asn), NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp), NM_002834.5(PTPN11):c.844A>G (p.Ile282Val), NM_002834.5(PTPN11):c.846C>G (p.Ile282Met), NM_002834.5(PTPN11):c.925A>G (p.Ile309Val), NM_002834.5(PTPN11):c.1507G>A (p.Gly503Arg) PubMed
Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. The study focused on the identification of MPD features in a large cohort of patients with a germline PTPN11 mutation. Patients with a p.Thr73Ile mutation had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. JMML represents the first cause of death in PTPN11-associated NS. NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly), NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly), NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met), NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile), NM_002834.5(PTPN11):c.227A>T (p.Glu76Val), NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly), NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr), NM_002834.5(PTPN11):c.172A>C (p.Asn58His), NM_002834.5(PTPN11):c.181G>C (p.Asp61His), NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn), NM_002834.5(PTPN11):c.211T>C (p.Phe71Leu) PubMed
Adult patients with AML Screening for PTPN11 mutations using targeted next-generation sequencing PTPN11 mutations associated with lower complete response rates and shorter overall survival   PubMed
Twelve pediatric patients diagnosed with therapy-related myeloid neoplasm (t-MN) since 2006 - Thrombocytopenia was present in all patients at t-MN diagnoses; 25% of patients had genetic predisposition NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr) PubMed
74 PTPN11 mutation-positive AML patients treated at a single institution Examined prevalence of PTPN11 mutations using targeted next-generation sequencing technology, analyzed clinical characteristics, prognostic impact, and association with other mutations PTPN11 mutations co-occurred more commonly with DNMT3A, NPM1, and FLT3 internal tandem duplication mutations. Compared with PTPN11 wild-type (WT) patients, PTPN11 mutation-positive AML patients presented with higher white blood cell (WBC) and platelet (PLT) counts. PTPN11 mutations had an adverse effect on overall survival (OS) (62.5%) and a negative prognostic effect on event-free survival (EFS) (50%). - PubMed


The studies discussed in this article present compelling evidence linking PTPN11 mutations to a broad spectrum of medical outcomes. From hematological malignancies to developmental anomalies, the presence of these mutations appears to play a significant role in disease pathogenesis and clinical manifestations. Understanding these associations opens up new avenues for diagnosis, treatment, and genetic counseling, potentially paving the way for personalized interventions and improved patient outcomes.


This comprehensive analysis explores the impact of PTPN11 mutations on diverse medical outcomes, drawing insights from case reports and series analyses. The studies reveal intriguing connections between PTPN11 mutations and conditions such as neuroblastoma, acute myelomonoblastic leukemia, Noonan syndrome, myeloproliferative disorders, and more. The findings emphasize the importance of genetic research in unraveling the underlying mechanisms of various diseases, providing valuable insights for clinicians, researchers, and genetic counselors alike.