Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8-38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0-5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance.     

PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning

Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.     

Mild variable Noonan syndrome in a family with a novel PTPN11 mutation

Noonan syndrome (OMIM 163950) is a common genetic condition with variable clinical expression and genetic heterogeneity. About half of the cases can be accounted to activating mutations in the PTPN11 gene encoding SHP-2. We report on a family with mild, variable expression of Noonan syndrome in five individuals. Clinical manifestations included short stature, craniofacial anomalies and thorax deformity, but none of the affected family members had a heart defect. Sequencing of the entire coding region of PTPN11 revealed a novel mutation c.1226G-->C in exon 11 predicting the amino acid exchange G409A. This mutation is not located in the previously known mutation clusters. Our observation and the recent report of a mutation affecting a neighbouring residue (T411M) in a family with a variable phenotype suggest that mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations.     

Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation

Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.     

Noonan综合征患者PTPN11基因突变分析

目的 研究中国人Noonan综合征患者非受体型蛋白酪氨酸磷酸酯酶(protein-tyrosine phosphatase,nonreceptor-type 11,PTPN11)基因的突变.方法 收集遗传咨询门诊3例散发的Noonan综合征患者及其无症状父母,外周血提取基因组DNA,PCR产物直接测序法对患者PTPN11基因的全部15个编码区外显子及其邻接的内含子区域进行测序,检出突变后再对其父母的相应外显子区域进行测序,并通过限制性内切酶检测100名无亲缘关系的正常人相应碱基改变以排除多态性,利用网上ClustalW工具分析突变位点所在氨基酸在多个物种中的保守性.结果 在1例患者的第3外显子区域检出一杂合的c.181G＞A碱基取代,导致第61位的天冬氨酸改变为天冬酰胺(p.D61N),在其无症状父母和100名正常个体中无此突变;该位点在多个物种中高度保守.另外2例患者PTPN11基因的编码区未检到突变.结论 p.D61N突变在文献中已有报道,本例患者为新生突变.本研究进一步肯定了 p.D61N为Noonan综合征的致病突变,基因诊断的结果验证了该患者的临床诊断.另外两例Noonan综合征患者可能由其他基因的突变所致,反映了该病的遗传异质性.     

Electrocardiography in Noonan syndrome PTPN11 gene mutation--phenotype characterization

Noonan syndrome is a developmental disorder with distinctive facial features, short stature and cardiac abnormalities. In this cross-sectional study, we evaluated characteristic electrocardiographic (ECG) findings and cardiac abnormalities in 84 patients with Noonan syndrome, 56 (67%) of who were positive for a PTPN11 mutation. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. The ECG showed at least one characteristic finding in 50% of cases including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%) and an abnormal Q wave in 5 (6%) patients with Noonan syndrome. A wide QRS complex was not detected in any of these patients. The characteristic ECG findings of Noonan syndrome patients were not associated with a PTPN11 gene mutation, or with a (specific) cardiac anomaly. We conclude that there are characteristic ECG findings in Noonan syndrome, but the ECG pattern is neither a useful tool for the phenotype characterization of a PTPN11 mutation, nor for the presence or type of cardiac abnormality.     

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

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.     

Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, causes Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than the leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, we generated transgenic fruitflies with GAL4-inducible expression of wild-type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles were lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele caused ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses established that csw(N308D)'s ectopic wing vein phenotype required intact EGF ligand and receptor, and that this transgene interacted genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increased RAS-MAP kinase activation, which was necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.     

PTPN11 gene mutation associated with abnormal gonadal determination

Germline mutations in the PTPN11 gene have been associated with Noonan syndrome (NS) and LEOPARD syndrome. Both germline and somatic mutations in this gene have been reported in association with malignancies. However, the T507K mutation in the PTPN11 gene, has only been reported in malignancies and in a fetus with hydrops fetalis but not in a live patient with NS. We report the autopsy findings in a fetus with the T507K mutation who presented prenatally with hydrops fetalis, cystic hygroma and 46, XX karyotype. On autopsy, the patient was found to have testes, male external genitalia, but absent Wolffian ducts.     

A novel PTPN11 mutation in LEOPARD syndrome

PTPN11 gene mutations are common to both patients with Noonan (NS) and LEOPARD syndrome (LS). So far only two recurrent mutations have been identified in LS patients by different research groups, i.e., Tyr279Cys and Thr468Met. In this work we describe the third PTPN11 mutation that has been found in a single LS patient. The mutation (c.1517A>C) substitutes a proline for a glutamine at amino acid 506 (Gln506Pro) in the phosphatase domain (PTP) of the PTPN11 peptide SHP2. This region is a mutation hotspot. Changes at amino acids 501 to 504 cause NS. Gln506Pro is predicted, by modeling analysis, to seriously disrupt the normal contacts between the regulating N-SH2 and the active PTP domains, leading to hyperactivity of the phosphatase. This report demonstrates that rarer mutations other than Tyr279Cys and Thr468Met can be found in LS patients and the need of screening the whole gene in those negative for the commonest mutations.     

A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia

A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.     

A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome

Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders.