PTPN11 gene mutation mediated Noonan syndrome in children with idiopathic short stature / 中华内分泌代谢杂志

Objective:To analyze the genetic etiology of idiopathic short stature(ISS) children, and to investigate the clinical characteristics of Noonan syndrome caused by PTPN11 gene mutation, and the response to recombinant human growth hormone(rhGH) as well.Methods:Genomic DNA was extracted from the peripheral blood of 232 ISS patients, and the genome was detected by whole exon sequencing. The gene variation was analyzed according to the guideline of American College of Medical Genetics and Genomics(ACMG), and clinical baseline data and follow-up data of rhGH treatment were collected from PTPN11 gene pathogenic patients.Results:Among 232 ISS patients, 6 were found to have PTPN11 pathogenic gene variants(c.1507G>C, c. 317A>G, c. 923A>G, c. 922A>G, c. 236A>G, c. 922A>G), diagnosed as Noonan syndrome. Together with 3 cases of Noonan syndrome patients(all PTPN11 gene variation C. 1510A>G) previously diagnosed in our hospital, the clinical characteristics of patients were analyzed. Among the 9 Noonan syndrome patients, 7 were boys and 2 were girls. The average age was 10.2(4.5, 14.7) years old, and their height standard deviation score was -3.06 SD(95% CI -2.29 SD--3.94 SD). Among them, 4 patients received rhGH treatment with an average treatment duration of 2.25(1.5, 3.5) years. After treatment, their height increased by 14.3(8.6, 23.9) cm, and the change in height standard deviation score improved by 0.21 SD(95% CI 0.12 SD-0.27 SD). Conclusion:Noonan syndrome has a wide range of clinical phenotypes. For children with short stature, heart defects and cryptorchidism, the possibility of Noonan syndrome should be considered. PTPN11 is the common pathogenic gene for Noonan syndrome, and genetic testing facilitates the early diagnosis, treatment, and follow-up prognosis of Noonan syndrome patients.

Mutation analysis of the PTPN11 gene in a pedigree with LEOPARD syndrome / 中华皮肤科杂志

Objective:To determine mutations in the PTPN11 gene in a family with LEOPARD syndrome.Methods:Clinical evaluation was carried out in a large pedigree with confirmed LEOPARD syndrome diagnosed in Hwa Mei Hospital, University of Chinese Academy of Sciences. Peripheral blood samples were obtained from 4 patients and 2 unaffected healthy members in the family, as well as 100 unrelated healthy controls. DNA was extracted from the blood samples, and PCR was performed to amplify all exons of the PTPN11 genes, followed by Sanger sequencing.Results:There were 14 members in 3 generations of the family, 6 of whom were affected (3 males and 3 females) , demonstrating an autosomal dominant inheritance pattern. Skin lesions were mainly distributed on the face, trunk and limbs, accompanied by special facial features and cardiovascular system abnormalities. A missense mutation c.1632G>T (p.R558L) in the PTPN11 gene was identified in the 4 patients, which resulted in the substitution of arginine by leucine at amino acid position 558. This mutation had not yet been reported previously. No mutation was detected in the PTPN11 gene in the 2 unaffected family members or 100 healthy controls.Conclusion:The missense mutation c.1632G>T in exon 13 of the PTPN11 gene may be the molecular basis for LEOPARD syndrome in this family.

Caracterización clínica y molecular de niños con síndrome de Noonan y otras RASopatías en Argentina / Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Introducción. Las RASopatías son un conjunto de síndromes fenotípicamente superpuestos causados por mutaciones en genes implicados en la vía RAS/MAPK. La herencia es autosómica dominante, presentan características clínicas comunes, como baja talla, dismorfias craneofaciales, cardiopatia congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1,RAF1, BRAFy HRAS,y comparar las principales características clínicas en pacientes con confirmación molecular. Población y métodos. Se estudiaron niños con diagnóstico clínico de RASopatía evaluados entre agosto de 2013 y febrero de 2017. Resultados. Se identificaron mutaciones en el 71 % (87/122) de los pacientes. El estudio molecular confirmó el diagnóstico en el 73 % de los pacientes con síndrome de Noonan. La mutación más prevalente fue c.922A>G (p.Asn308Asp) en el gen PTPN11. Se detectó una variante no descrita en RAF1, c.1467G>C (p.Leu489Phe). Se confirmó el sindrome cardiofaciocutáneo en el 67 % de los casos con mutaciones en el gen BRAF. El síndrome de Costello y el síndrome de Noonan con múltiples lentigos se confirmaron en todos los casos. Conclusión. La confirmación del diagnóstico clínico permitió un diagnóstico diferencial más preciso. Se determinó la prevalencia de las mutaciones en PTPN11 (el 58 %), SOS1 (el 10 %) y RAF1 (el 5 %) en niños con síndrome de Noonan, en PTPN11 (el 100 %) en el sindrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el sindrome de Costello.

Introduction. RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. Objective. To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. Results. Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. Conclusion. The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 % ), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.

A Rare Case of Left Ventricular Noncompaction in LEOPARD Syndrome

No abstract available.

Four cases of PTPN11 associated RASopathies:Analysis of the correlation between gene mutation and clinical phenotype / 中华内分泌代谢杂志

PTPN11 is the most common mutation gene of RAS disease, which is located in the upstream of RAS/MAPK pathway and participates in signal transduction. Because the molecular mechanism of RAS's disease involves the same pathway, it may present a certain commonality in clinic, but the different genotypes with PTPN11 mutation may also express different phenotypes. Therefore, it is not easy to identify and diagnose this disease early in clinic. The present article aims to analyze the correlation between the clinical phenotype and genotype of 4 patients with RAS disease.

Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome

PURPOSE: Noonan syndrome (NS) is characterized by short stature, heart anomalies, developmental delays, dysmorphic features, cryptorchidism, and coagulation defects. Several studies reported the short-term effects of recombinant human growth hormone (rhGH) treatment on the improvement of height. This study was performed to evaluate the long-term efficacy of rhGH in children with NS in Korea. METHODS: This study included 15 prepubertal NS children who received rhGH subcutaneously at a dose of 50-75 µg/kg/day for 6 days a week for at least >3 years. Preand posttreatment data, such as height, weight, bone age, insulin-like growth factor 1 (IGF-1), and IGF binding protein 3 (IGFBP-3) levels, were collected every 6 months. RESULTS: Chronologic age and bone age at the start of treatment were 7.97±1.81 and 5.09±2.12 years, respectively. Height standard deviation score (SDS) was increased from -2.64±0.64 to -1.54±1.24 years after 3 years (P<0.001). Serum IGF-1 SDS levels were elevated from -1.28±1.03 to -0.10±0.94 (P<0.001). Height SDS was more increased in subjects without PTPN11 mutations compared to those with mutations after 3 years (P=0.012). However, the other parameters, including bone age, IGF-1 SDS, and IGFBP-3 SDS, were not significantly different between patients with and without PTPN11 mutations. CONCLUSION: Although this study included a relatively small number of patients, long-term rhGH therapy in NS patients was safe and effective at improving height, growth velocity, and serum IGF-1 levels, in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Patients with PTPN11 mutations demonstrated a decreased response to rhGH therapy compared to those without mutations.

Metachondromatosis: Clinical and radiological diagnosis and differential diagnosis / Metacondromatosis: diagnóstico clínico, radiológico y diagnóstico diferencial

The clinical case of a 9-year-old patient derived from Orthopedics to the Institute of Genetics at Universidad Nacional de Colombia due to a longstanding medical history of multiple bony outgrowths that required surgical management without etiologic diagnosis is presented in this paper. A possible diagnosis of metachondromatosis is suggested based on the clinical course, the family history, and the findings of the biopsy and regular growth parameters. On the other hand, differential diagnoses were compared taking into account the most common enchondromatosis type, based on data obtained during physical examination, radiological signs and other variables. This comparison was grounded on the review of existing literature on this type of entities.

En el presente artículo se presenta el caso clínico de una paciente de 9 años de edad remitida al Instituto de Genética de la Universidad Nacional de Colombia desde el servicio de Ortopedia por cuadro clínico de larga data, consistente en múltiples excrecencias óseas que han requerido manejo quirúrgico sin diagnóstico etiológico. Se Plantea la posibilidad de metacondromatosis como diagnóstico, basándose en el curso clínico, la historia familiar, los hallazgos en biopsia y los parámetros normales de crecimiento; también se compararon los diagnósticos diferenciales dentro de las encondromatosis más frecuentes teniendo en cuenta datos tomados del examen físico, signos radiológicos y otras variables, esta comparación se basó en la revisión bibliográfica de la literatura existente actualmente sobre este tipo de entidades.

Mutation analysis of the PTPN11 gene in a family with LEOPARD syndrome / 中华皮肤科杂志

Objective To detect mutations in the PTPN11 gene in a family with LEOPARD syndrome (LS).Methods Clinical data were collected from a 7-year-old boy patient with LS.Peripheral blood was obtained from the patient,both of his parents,and 50 healthy controls.All the exons and their flanking sequences of the PTPN11 gene were amplified by PCR followed by direct DNA sequencing.Results A heterozygous missense mutation c.836A ＞ G,which resulted in a substitution of TAT by TGT at codon 279,was found in exon 7 of the PTPN11 gene in the patient.No mutation was detected in the unaffected parents or healthy controls.Conclusion The missense mutation c.836A ＞ G may be the cause of the phenotype of LS in this family.

Regulatory effect of protein tyrosine phosphatase non-receptor type on the cardiac Kv11.1 (HERG) potas-sium channel / 医学研究生学报

Objective Cardiac HERG potassium channel currents can cause long QT syndrome .The function of the cardiac HERG potassium channel is regulated by tyrosine kinase and phosphatase , and protein tyrosine phosphatase non-receptor type 11 ( PTPN11) negatively regulates the HERG potassium channel .This study aimed to investigate the effect of PTPN 11 on the electrophysio-logical characteristics of the HERG channel . Methods The plasmids of pcDNA3.1-PTPN11-EGFP were constructed by PCR technique and transfected or cotransfected with the pcDNA 3.1-PTPN11-EGFP plasmid into HEK293 cells using Lipofectamine 2000.The patch clamp technique was employed to record the HERG channel currents in the control group ( HEK293 cells transfected with pcDNA3.0-HERG-EGFP), PTPN11 overexpression group (pcDNA3.0-HERG and pcDNA3.1-PTPN6-EGFP cotransfected HEK293 cells), and PTPN11 overexpression with PAO group . Results The pcDNA3.1-PTPN11-EGFP plasmid was successfully constructed .Green fluorescence was observed in the HEK293 cells transfected with pcDNA3.0-HERG-EG-FP or cotransfected with pcDNA3.0-HERG and pcDNA3.1-PTPN11.The maximum densities of pulse and tail currents were significantly decreased in the PTPN11 overexpression group as compared with the control ([31.85 ±5.54] vs [45.92 ±3.18] pApF, P<0.05;[73.82 ±11.31] vs [108.43 ±7.98] pApF, P<0.05) but markedly in-creased in the PTPN11 overexpression with PAO group ([48.08 ±4.32] pApF;[120.06 ±8.02] pApF) (P<0.05).The time con-stant of deactivation was significantly higher in the PTPN 11 overexpression group than in the control ([622.16 ±46.49] vs [440.70 ± 49.49] ms, P<0.05). Conclusion The overexpression of PTPN11 decreases HERG potassium channel currents , which can be re-versed by PAO.This finding provides a theoretical basis for the application of certain regulatory enzymes in the HERG channel as a treat -ment of long QT syndrome .

Síndrome de Noonan / Noonan syndrome

El Síndrome de Noonan fue descrito por Noonan y Ehmke en 1963. La incidencia se ha estimado en 1 de 1000 y 1 de 2500 nacimientos vivos.1 El gen se encuentra localizado en el cromosoma 12q22 y se hereda en forma autosómica dominante y tiene una expresividad muy variable. La principal característica incluye estatura baja, defectos cardiacos, dismorfismo facial entre otros. Estatura La severidad de los síntomas varían mucho en estos pacientes. Lo que no siempre es fácil hacer el diagnóstico en los primeros años, y muchas veces son subdiagnosticados, condición que nos motivo a revisar el caso.

Noonan Syndrome is a relative common autosomic dominant congenital disorder, with an incidence between 1:1,000 and 1:2,500 children worldwide. The gen is in 12q22 chromosome. The principal features include short stature, typical facial dysmorphology and congenital heart disease, among others. The range and severity of features can vary greatly in patients with NS, therefore, establishing a diagnose is difficult. The syndrome is not always identified at an early age, and many times misdiagnosed.

PTK2 and PTPN11 expression in myelodysplastic syndromes

OBJECTIVE: The aim of this study was to evaluate the expression of protein tyrosine kinase 2 and protein tyrosine phosphatase non-receptor type 11, which respectively encode focal adhesion kinase protein and src homology 2 domain-containing protein-tyrosine phosphatase 2, in hematopoietic cells from patients with myelodysplastic syndromes. METHODS: Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions were analyzed by quantitative polymerase chain reaction in bone marrow cells from patients with myelodysplastic syndromes and healthy donors. RESULTS: Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions did not significantly differ between normal cells and myelodysplastic cells. CONCLUSIONS: Our data suggest that despite the relevance of focal adhesion kinase and src homology 2 domain-containing protein-tyrosine phosphatase 2 in hematopoietic disorders, their mRNA expression do not significantly differ between total bone marrow cells from patients with myelodysplastic syndromes and healthy donors. .

Estudio clínico y molecular del síndrome de Noonan / Clinical and molecular study of the Noonan syndrome

El síndrome de Noonan es una entidad autosómica dominante relativamente común, clínicamente variable y genéticamente heterogénea, caracterizado por reducción del crecimiento postnatal, dismorfismo facial distintivo, alteraciones cardíacas y déficit cognitivo variable. El gen PTPN11 se encuentra localizado en el brazo largo del cromosoma 12 y es el principal responsable de los casos clínicamente diagnosticados de esta entidad. Se reporta el caso de un lactante mayor masculino, de 18 meses de edad, evaluado de forma multidisciplinaria con diagnóstico clínico y molecular de síndrome de Noonan, con la mutación en sentido errado del gen PTPN11, G503R (c.1507 G>A). Se discutieron los diversos hallazgos clínicos y las alteraciones genéticas asociadas con esta mutación.

Noonan syndrome is a relatively common autosomal dominant entity, clinically variable and genetically heterogeneous; characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. The PTPN11 gene is located on the long arm of chromosome 12 and is primarily responsible for the clinically diagnosed cases of this entity. We report the case of a 18 month-old boy, evaluated in a multidisciplinary way, with clinic and molecular diagnosis of Noonan syndrome, with the missense mutation in PTPN11 gene, G503R (c.1507 G>A). Several clinical features and the genetic alterations associated with this mutation are discussed.

LEOPARD Syndrome with PTPN11 Gene Mutation Showing Six Cardinal Symptoms of LEOPARD

LEOPARD multiple congenital anomaly syndrome inherited in an autosomal dominant manner. LEOPARD is an acronym for Lentigines, Eletrocardiographic conduction defects, Ocular hypertelorism, Pulmonary valve stenosis, Abnormalities of the genitalia, Retardation of growth, and Deafness. Clinical diagnosis is primarily based on multiple lentigines, typical facial features, and the presence of hypertrophic cardiomyopathy and/or cafe-au-lait macules. We report a typical case of LEOPARD syndrome with PTPN11 gene mutation associated with lentigines, electrocardiograph abnormality, ocular hypertelorism, pulmonary valve stenosis, growth retardation, and sensorineural hearing loss.

Familial Noonan Syndrome Confirmed by PTPN11 Gene Test / 대한소아내분비학회지

Noonan syndrome is characterized by short stature, mental retardation, typical facial morphology, webbed neck and congenital heart disease. Noonan syndrome can be inherited in an autosomal dominant manner but all Korean patients with Noonan syndrome have been reported as sporadic cases thus far. In approximately 50-60% of cases, the disease is caused by mutation in the PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) gene on chromosome 12, encoding SHP-2 (Src homology protein-tyrosine phosphatase-2). We have experienced a boy and his father with typical clinical features of Noonan syndrome in whom Asn58Asp mutation of the PTPN11 gene were identified. To the best of our knowledge, this is the first report of genetically confirmed familial Noonan syndrome in Korea.

Mutational Analysis of PTPN11 Gene in Noonan Syndrome / 대한소아내분비학회지

PURPOSE: Noonan syndrome (NS), congenital malformation syndrome characterized by distinct facial anomalies, short stature and variable congenital heart defects, is thought to be caused by mutations of the gene for PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11). The aim of this study is to know the type and detection rate of mutations of PTPN11 in NS. METHODS: This study consisted of 17 NS patients (11 males and 6 females). All of the NS patients met the diagnostic criteria proposed by van der Burgt et al. The leukocyte genomic DNA of each patients was amplified by PCR for 7 exons, where the mutations had been reported so far, out of 15 exons of PTPN11 gene. And the PCR products were subjected to direct sequencing from both directions. RESULTS: All 17 NS patients were sporadic cases. Heterozygous PTPN11 mutations were identified in 3 of the 17 patients (17.6%, all males). All mutations were known missense mutations. They consist of two D61N in exon 3 and one S502T in exon 13. CONCLUSION: This study showed 17.6% (3/17) of detection rate of PTPN11 gene mutation in NS. This is smaller than that of previous reports. The further study with larger number of cases will be needed to analyse type of mutation and genotype-phenotype correlation.