Spectrum of Mutations in PTPN11 in Russian Cohort.

Noonan syndrome is a group of diseases with a similar clinical picture, consisting of 16 diseases caused by mutations in 15 genes. According to the literature, approximately half of all cases are attributed to Noonan syndrome type 1, NSML, caused by mutations in the PTPN11 gene. We analyzed 456 unrelated probands using a gene panel NGS, and in 206 cases, the cause of the disease was identified. Approximately half of the cases (107) were caused by variants in the PTPN11 gene, including three previously undescribed variants, one of which was classified as VOUS, and the other two as LP causative complex alleles. Frequent variants of the PTPN11 gene characteristics for Russian patients were identified, accounting for more than 38% (c.922A>G p.Asn308Asp, c.417G>C p.Glu139Asp, c.1403C>T p.Thr468Met) of all cases with mutations in the PTPN11 gene. A comparative characterization of frequent variants of the PTPN11 gene in different populations is shown. The most common features of Noonan syndrome in the studied sample were facial dysmorphisms and cardiovascular system abnormalities. A lower representation of patients with growth delay was observed compared to previously described samples.

High frequency of hotspot mutation in PTPN11 gene among Moroccan patients with Noonan syndrome.

Noonan syndrome (NS; OMIM 163950) is an autosomal dominant RASopathy with variable clinical expression and genetic heterogeneity. Clinical manifestations include characteristic facial features, short stature, and cardiac anomalies. Variants in protein-tyrosine phosphatase, non-receptor-type 11 (PTPN11), encoding SHP-2, account for about half of NS patients, SOS1 in approximately 13%, RAF1 in 10%, and RIT1 each in 9%. Other genes have been reported to cause NS in less than 5% of cases including SHOC2, RASA2, LZTR1, SPRED2, SOS2, CBL, KRAS, NRAS, MRAS, PRAS, BRAF, PPP1CB, A2ML1, MAP2K1, and CDC42. Several additional genes associated with a Noonan syndrome-like phenotype have been identified. Clinical presentation and variants in patients with Noonan syndrome are this study's objectives. We performed Sanger sequencing of PTPN11 hotspot (exons 3, 8, and 13). We report molecular analysis of 61 patients with NS phenotype belonging to 58 families. We screened for hotspot variants (exons 3, 8, and 13) in PTPN11 gene by Sanger sequencing. Twenty-seven patients were carrying heterozygous pathogenic variants of PTPN11 gene with a similar frequency (41.4%) compared to the literature. Our findings expand the variant spectrum of Moroccan patients with NS phenotype in whom the analysis of hotspot variants showed a high frequency of exons 3 and 8. This screening test allowed us to establish a molecular diagnosis in almost half of the patients with a good benefit-cost ratio, with appropriate management and genetic counseling.

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 1-6 years old had multiple syndrome deafness, while children under 1 year old and children aged 6-12 years 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.

Refractory thrombocytopenia could be a rare initial presentation of Noonan syndrome in newborn infants: a case report and literature review.

BACKGROUND: Noonan syndrome (NS) is a relatively rare inherited disease. Typical clinical presentation is important for the diagnosis of NS. But the initial presentation of NS could be significant variant individually which results in the difficult of working diagnosis. Here we report a rare neonatal case of NS who presented with refractory thrombocytopenia as the initial manifestation. CASE PRESENTATION: This was a preterm infant with refractory thrombocytopenia of unknown origin transferred from obstetric hospital at 6 weeks of age. During hospitalization, typical phenotypes of NS in addition to thrombocytopenia were observed, such as typical facial characteristics, short stature, atrial septal defect, cryptochidism, coagulation defect and chylothorax. Genetic testing showed a pathogenic variant at exon 2 of the PTPN11 gene with c.124A > G (p.T42A). Respiratory distress was deteriorated with progressive chylothorax. Chest tube was inserted for continuous draining. Chemical pleurodesis with erythromycin was tried twice, but barely effective. Finally, parents decided to withdraw medical care and the patient died. CONCLUSIONS: Thrombocytopenia could be the first symptom of Noonan syndrome. After ruling out other common causes of thrombocytopenia, NS should be considered as the working diagnosis.

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.

Allosteric Inhibitors of SHP2: An Updated Patent Review (2015-2020).

Srchomology-2-domain-containing PTP 2 (SHP2) is a nonreceptor phosphatase encoded by the PTPN11 gene. Over expression of SHP2 is associated with various human diseases, such as Noonan syndrome, LEOPARD syndrome, and cancers. To overcome the shortcomings of existing orthosteric inhibitors, novel inhibitors targeting the allosteric site of SHP2 with high selectivity and low toxicity are under development. This paper reviews allosteric inhibitors of SHP2 published in patents from 2015 to 2020. The molecules are classified according to the chemical structure of the central core. SHP2 has long been considered as an 'undruggable' protein. Fortunately, a critical breakthrough was made by researchers from Novartis AG Ltd., who identified SHP099 as a highly potent, selective, soluble, and orally bioavailable SHP2 allosteric inhibitor. Currently, there are several allosteric inhibitors of SHP2 in clinical development. However, drug resistance is still a major challenge. The combination of SHP2 allosteric inhibitors and immunotherapy drugs or molecular targeted drugs is emerging as a promising therapeutic strategy against drug resistance.

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.

SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling.

Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby exerting essential developmental functions. This phosphatase also deploys proto-oncogenic functions and specific inhibitors have recently been developed. With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied. The function of this phosphatase downstream of cytokines important for lymphocytes is less understood, though multiple lines of evidence suggest its importance. In addition, SHP-2 has been proposed to mediate the suppressive effects of inhibitory receptors (IRs) that sustain a dysfunctional state in anticancer T cells. Molecules involved in IR signaling are of potential pharmaceutical interest as blockade of these inhibitory circuits leads to remarkable clinical benefit. Here, we discuss the dichotomy in the functions ascribed to SHP-2 downstream of cytokine receptors and IRs, with a focus on T and NK lymphocytes. Further, we highlight the importance of broadening our understanding of SHP-2's relevance in lymphocytes, an essential step to inform on side effects and unanticipated benefits of its therapeutic blockade.

[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.

Noonan syndrome: Severe phenotype and PTPN11 mutations.

INTRODUCTION AND OBJECTIVE: Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. PATIENTS AND METHODS: We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. RESULTS: Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. DISCUSSION: These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations.

Gain-of-function mutation in PTPN11 in histiocytic sarcomas of Bernese Mountain Dogs.

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm of dendritic cell origin that is common in certain breeds of dogs. High prevalence of fatal, disseminated HS has been described in Bernese Mountain Dogs (BMDs). Support for genetic predisposition to develop HS has been presented in several studies, but to date, causative genetic events have not been reported. In addition, no driver mutations have been identified in tumours. Recently, E76K gain-of-function mutation in SHP2 encoded by the PTPN11 gene has been described in human histiocytic malignancies. In our study, we identified the PTPN11E76K in HS of BMDs. Amplification of exon 3 of the PTPN11 gene followed by Sanger sequencing was used to detect the mutation and estimate the prevalence in HS from 30 BMDs, 13 Golden Retrievers and 10 other dog breeds. The overall prevalence of PTPN11E76K in HS of BMDs was 36.67% compared with 8.69% in other breeds. No mutation was identified in normal tissues from 10 BMDs with HS that carried the mutation and 12 control dogs with no neoplastic disease, including 6 BMDs. Increased immunoreactivity for AKT, phosphorylated ERK1/2 and phosphorylated AKT in a small subset of BMDs with PTPN11E76K suggests that a gain-of-function might be mediated by the ERK and AKT pathways. These data suggest PTPN11E76K as an important driver mutation of HS in BMDs. This information may not only aid in unravelling the tumourigenic events associated with HS in BMDs, but also help in identifying more promising therapeutic strategies.

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.

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.

Phenotypical diversity of patients with LEOPARD syndrome carrying the worldwide recurrent p.Tyr279Cys PTPN11 mutation.

LEOPARD syndrome (LS, OMIM 151100) is a rare monogenic disorder. The name is an acronym of its major features such as multiple lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth and sensorineural deafness. LS develops due to mutations in the protein-tyrosine phosphatase nonreceptor-type 11, PTPN11. Here, we have investigated a 51-year-old Hungarian male patient affected by LS. Direct sequencing of the PTPN11 gene revealed a worldwide recurrent missense mutation (c.836A/G; p.Tyr279Cys), which has been previously identified in 47 LS patients. Comparison of the clinical phenotypes of our patient and the ones reported in the literature demonstrates great phenotypic diversity despite the same genotype.

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 café-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.

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.