Materiały źródłowe

• #1 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood

  https://adc.bmj.com/content/107/12/1073

  Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Genetic testing is recommended at the time of clinical diagnosis or suspicion. Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. Early diagnosis would aid clinical management, and optimise developmental and long-term outcomes. Despite the existence of diagnostic guidelines/criteria, diagnosis is difficult in less severely affected individuals for a number of reasons, including both healthcare provider (HCP)-related and patient-related factors. It is proposed that increased awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and possible NS diagnosis, increasing the potential for optimising lifelong patient outcomes.

• #2 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] The diagnosis of NS is primarily based on clinical features aforementioned. Therefore, high clinical suspicion should be a prerequisite for the diagnosis. Mutation analysis of 20 genes (PTPN11, SOS1, RAF1, SHOC2, RIT, KRAS, NRAS, MRAS, BRAF, MEK1, MEK2, CBL, SOS2, SPRY1, LZTR1, A2ML1, RRAS, RRAS2, RASA2, PPP1CB) makes the diagnosis confirmatory in about 80%. […] Management of NS patients is entirely dependent on its individual manifestation. Cautious physical examinations are mandatory to delineate the presence of congenital defects in cardiovascular, genitourinary, skeletal, and other birth defects. […] Gene panel testing offers confirmatory diagnosis in about 80% of patients. RASopathies require multidisciplinary team approach to provide the best medical cares for each particular clinical issue.

• #3 Noonan syndrome – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/diagnosis-treatment/drc-20354428

  A doctor typically diagnoses Noonan syndrome after seeing some key signs. But this can be difficult because some features of the condition are not easily seen and are hard to find. Sometimes Noonan syndrome is not found until adulthood, after a person has a child who is more clearly affected by the condition. Genetic testing can confirm a diagnosis. […] If there’s evidence of heart problems, a cardiologist can find out the type and how serious it is. […] What tests can confirm the diagnosis?

• #4 Noonan syndrome

  https://www.mymlc.com/health-information/diseases-and-conditions/n/noonan-syndrome/

  A diagnosis of Noonan syndrome is usually made after a doctor observes some key signs, but this can be difficult because some features are subtle and hard to identify. Sometimes, Noonan syndrome isn’t diagnosed until adulthood, only after a person has a child who is more obviously affected by the condition. Molecular genetic testing can help confirm a diagnosis. […] If there’s evidence of heart problems, a doctor who specializes in heart conditions (cardiologist) can assess the type and severity.

• #5 Noonan syndrome – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/1193

  Noonan syndrome is a relatively common, autosomal-dominant inherited disorder. […] The syndrome is thought to be caused primarily by gain-of-function (activating) mutations in genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. […] Key diagnostic factors include positive family history, short stature, dysmorphic facial features, cryptorchidism, cardiac anomalies, delayed puberty, easy bruising or bleeding, lymphoedema, pigmentary anomalies, sparse or absent eyebrows and lashes, and splenomegaly. […] Other diagnostic factors include abnormalities identified antenatally, chest deformity, developmental delay/learning difficulty, skeletal anomalies, muscle weakness, and history of renal malformation. […] 1st investigations to order include ECG and echocardiogram. […] Investigations to consider include FBC, coagulation profile, molecular genetic testing, abdominal ultrasound, and renal ultrasound.

• #6 Noonan Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1124/

  Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. […] The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular genetic testing. […] No consensus clinical diagnostic criteria for Noonan syndrome have been published. Diagnostic scoring systems, most recently published in van der Burgt [2007] and embedded in the management guidelines developed by DYSCERNE in the United Kingdom [Noonan Syndrome Guideline Development Group 2010], have been proposed but have not been used extensively in North America.

• #7 Noonan Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947504-overview

  Diagnosis of Noonan syndrome is usually based on characteristic signs. Molecular genetic testing, however, can aid in confirmation. […] The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, down-slanting eyes, webbed neck), congenital heart disease, short stature, and chest deformity. Approximately 25% of individuals with Noonan syndrome have intellectual disability.

• #8 Noonan Syndrome | Noonan Syndrome Awareness Association

  https://noonansyndrome.com.au/noonan-syndrome/

  Diagnosis of Noonan Syndrome can be made clinically and confirmed via genetic testing. […] Noonan syndrome (NS) should be suspected in individuals with the following key features: Characteristic facial features such as: low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; eyes that are often wide-spaced, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis). […] Diagnostic criteria developed by van der Burgt in 1997 is below: Definitive NS: 1 „A” plus one other major sign or two minor signs; 1 „B” plus two major signs or three minor signs. […] Molecular testing approaches can include use of a multi-gene panel, serial single-gene testing, and more comprehensive genomic testing. […] A multi-gene panel is the test of choice for an individual suspected of having Noonan syndrome.

• #9 Noonan Syndrome | Noonan Syndrome Awareness Association

  https://noonansyndrome.com.au/noonan-syndrome/

  Diagnosis of Noonan Syndrome can be made clinically and confirmed via genetic testing. […] Noonan syndrome (NS) should be suspected in individuals with the following key features: Characteristic facial features such as: low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; eyes that are often wide-spaced, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis). […] Diagnostic criteria developed by van der Burgt in 1997 is below: Definitive NS: 1 „A” plus one other major sign or two minor signs; 1 „B” plus two major signs or three minor signs. […] Molecular testing approaches can include use of a multi-gene panel, serial single-gene testing, and more comprehensive genomic testing. […] A multi-gene panel is the test of choice for an individual suspected of having Noonan syndrome.

• #10 Noonan Syndrome | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0101/p37.html

  Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. […] Diagnosis can be made on the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. […] The diagnosis of Noonan syndrome should be considered in all fetuses with a normal karyotype and increased nuchal translucency, especially when cardiac anomaly, polyhydramnios, and/or multiple effusions are observed. […] Until recently, diagnosis was made solely on the basis of clinical features, but molecular genetic testing can provide confirmation in 70% of cases. […] A scoring system has been devised to help diagnose patients with the condition. […] The diagnosis of Noonan syndrome depends primarily on the identification of characteristic clinical features.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Noonan-Syndrome-Diagnosis.aspx

  Noonan syndrome is a heterogeneous, but clinically recognizable, multiple congenital anomaly syndrome. Appropriate patient management for Noonan syndrome is vastly dependent on an early and adequate diagnosis. […] The overlapping features observed among related disorders, an absence of clinical features with pathognomonic value, the wide breadth of phenotypes, as well as an overall lack of consensus on diagnostic criteria hamper the diagnosis of Noonan syndrome. […] The diagnosis of Noonan syndrome is first and foremost made clinically by the observation of the condition’s cardinal features. […] Scoring systems can aid significantly in the diagnostic process for Noonan syndrome. […] Due to the high genetic heterogeneity of RASopathies, the standard diagnostic testing protocol should include a multi-step approach using Sanger sequencing. […] If the disease-causing mutation has been recognized in the family, prenatal diagnosis for pregnancies that are at an increased risk of Noonan syndrome may be obtainable through laboratories that offer testing for the gene of interest or custom prenatal testing.

• #12

  https://www.nhs.uk/conditions/noonan-syndrome/diagnosis/

  Noonan syndrome may be suspected if your child has some of the signs and symptoms associated with the condition. […] However, these symptoms can have a number of different causes, so it’s difficult to make a diagnosis based on them alone. […] You may be referred to a genetics specialist for genetic testing. In most cases, Noonan syndrome can be confirmed by a blood test for the various genetic mutations. However, in about 1 in 5 cases no specific mutation can be found, so a negative blood test won’t rule out Noonan syndrome. […] If Noonan syndrome has been confirmed or is strongly suspected, further tests are needed to establish the extent of the symptoms. […] If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition. […] Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition.

• #13 Noonan Syndrome (Leopard Syndrome): Causes & Outlook

  https://my.clevelandclinic.org/health/diseases/17926-noonan-syndrome

  Your healthcare provider may suspect Noonan syndrome after a physical exam and review of your child’s symptoms. Your provider may order genetic tests to confirm a diagnosis and rule out other conditions. […] Genetic testing can find an abnormality in almost 80% of people with Noonan syndrome. For the rest, researchers don’t know the exact cause. […] Noonan syndrome has no cure. But effective treatments can help you and your child manage symptoms. […] Early diagnosis is important for effective treatment and follow-up care.

• #14 Noonan syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/noonan-syndrome/

  Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. […] Most people with Noonan syndrome have some form of critical congenital heart disease. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). […] Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability. […] Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 people. […] Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases.

• #15 FAQs • Genetics & RASopathies • Noonan Syndrome Association

  https://www.noonansyndrome.org.uk/faqs/genetics-rasopathies/

  Noonan syndrome is caused by a fault in one of several genes. The commonest gene involved is called PTPN11 but there have now been around 15 genes discovered which may cause Noonan syndrome or a related disorder. Genetic testing can be used to confirm the diagnosis of Noonan syndrome and also to test for the condition in pregnancy. […] In 2001, this link was narrowed down to a genetic change a mutation in the PTPN11 gene on chromosome 12, present in about half of patients with Noonan syndrome. […] The most common genetic cause of Noonan syndrome is a mutation in a gene called PTPN11. This was discovered in 2001 and, since then, other genes have been linked to the condition. […] In about 510% of cases, the genetic cause of Noonan syndrome is still not known.

• #16 About Noonan Syndrome

  https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome

  The diagnosis of Noonan syndrome is based on the person’s clinical symptoms and signs. The specialist examines the person looking for the specific features of Noonan syndrome. […] Individuals who have Noonan syndrome have normal chromosome studies. Four genes – PTPN11, SOS1, RADF1 and KRAS – are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known.

• #17 Noonan Syndrome | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/noonan-syndrome

  Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes are identified in 70-75 percent of people with Noonan syndrome. However, it is important to remember that not all patients with Noonan syndrome carry a detectable alteration in one of these genes. […] Therefore, the failure to identify an alteration in one of these genes does not exclude the diagnosis of Noonan syndrome.

• #18 Noonan Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1124/

  Noonan syndrome (NS) should be suspected in individuals with the following clinical, laboratory, and family history findings. […] The molecular diagnosis of NS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1 or biallelic pathogenic (or likely pathogenic) variants in LZTR1. […] Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing) depending on the phenotype. […] When the phenotypic findings suggest the diagnosis of Noonan syndrome, molecular genetic testing approaches usually include the use of a multigene panel. […] Serial single-gene testing can be considered if panel testing is not feasible. […] Comprehensive genomic testing, which does not require the clinical to determine which gene is likely involved, may be used.

• #19 Noonan Syndrome: Exploring Karyotypes and Genetic Causes

  https://3billion.io/blog/noonan-syndrome-and-karyotype-genetic-code

  Noonan Syndrome does not have a specific karyotype associated with it. Instead, it is primarily caused by mutations in various specific genes, such as PTPN11, SOS1, RAF1, and others. These mutations occur in specific genes on certain chromosomes and are responsible for the characteristic features and health issues associated with Noonan Syndrome. […] The diagnosis of Noonan Syndrome typically involves a combination of genetic testing and clinical evaluation. […] While karyotype testing can provide valuable information, it may not identify the specific genetic mutations responsible for Noonan Syndrome. To pinpoint the exact genetic cause, more targeted genetic testing is necessary. […] In some cases, whole exome sequencing (WES) or whole genome sequencing (WGS) may be used if initial genetic tests do not identify a mutation. These comprehensive sequencing techniques can analyze the entire exome or genome to identify rare or novel mutations.

• #20 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. […] Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies. […] Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL.

• #21

  https://www.nhs.uk/conditions/noonan-syndrome/diagnosis/

  Noonan syndrome may be suspected if your child has some of the signs and symptoms associated with the condition. […] However, these symptoms can have a number of different causes, so it’s difficult to make a diagnosis based on them alone. […] You may be referred to a genetics specialist for genetic testing. In most cases, Noonan syndrome can be confirmed by a blood test for the various genetic mutations. However, in about 1 in 5 cases no specific mutation can be found, so a negative blood test won’t rule out Noonan syndrome. […] If Noonan syndrome has been confirmed or is strongly suspected, further tests are needed to establish the extent of the symptoms. […] If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition. […] Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition.

• #22 Noonan Syndrome Workup: Approach Considerations, Laboratory Studies, Imaging Studies

  https://emedicine.medscape.com/article/947504-workup

  Moreover, before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed. […] If full phenotypic expression is not apparent, karyotyping may be necessary. Mutation analysis may confirm the diagnosis of Noonan syndrome, but failure to identify a germline mutation in any of the associated genes does not rule out the disorder; this entity remains a clinical diagnosis. […] DNA-based testing of the known causative genes, which can be performed via next-generation sequencing, can be considered for confirmation of diagnosis. […] Unless a known mutation is present in a family, negative (ie, normal) test findings do not rule out a diagnosis of Noonan syndrome.

• #23

  https://www.nhs.uk/conditions/noonan-syndrome/diagnosis/

  Noonan syndrome may be suspected if your child has some of the signs and symptoms associated with the condition. […] However, these symptoms can have a number of different causes, so it’s difficult to make a diagnosis based on them alone. […] You may be referred to a genetics specialist for genetic testing. In most cases, Noonan syndrome can be confirmed by a blood test for the various genetic mutations. However, in about 1 in 5 cases no specific mutation can be found, so a negative blood test won’t rule out Noonan syndrome. […] If Noonan syndrome has been confirmed or is strongly suspected, further tests are needed to establish the extent of the symptoms. […] If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition. […] Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition.

• #24

  https://111.wales.nhs.uk/encyclopaedia/n/article/noonansyndrome/

  If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition or if routine ultrasound scans detect possible signs of the condition in your baby. Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition.

• #25 Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review

  https://www.mdpi.com/2077-0383/13/19/5735

  Noonan syndrome is a rare autosomal dominant congenital abnormality associated with a gene defect located on the short arm of chromosome 12. […] Prenatal diagnosis of Noonan syndrome is rare because there are no pathognomonic sonographic signs. […] This study reveals that Noonan syndrome has a relatively specific pattern, which facilitates prenatal molecular genetic diagnosis. Increased nuchal translucency (NT) in the late first trimester and fluid collection in the early second trimester could be warning signs for follow-up, prompting further investigation to detect late-onset features and leading to molecular genetic confirmation. […] Prenatal diagnosis of Noonan syndrome has been made in a very limited number of cases. Typically, sonographic features raise a possibility of the disease, prompting either prenatal molecular diagnosis or postnatal confirmation using a clinical scoring system or genetic tests.

• #26 Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review

  https://www.mdpi.com/2077-0383/13/19/5735

  Several fetal sonographic features can provide diagnostic clues for Noonan syndrome, especially unexplained increased NT, which is associated with Noonan syndrome in 10.5% of cases. […] This series indicated that severe Noonan syndrome in Thai fetuses exhibits a specific pattern of sonographic features that are consistent with those observed in most western studies. […] The most consistent finding in the first trimester was thickened nuchal translucency, accounting for 71.4% of cases, followed by cystic hygroma (16.3%). […] The most common consistent findings in the second/third trimesters was fluid collection in at least one body space, accounting for 59.3% of cases (including hydrops fetalis; 46.2%), followed by cystic hygroma (33.0%), and thickened nuchal fold (26.4%). […] The prenatal natural course of Noonan syndrome can be delineated, extending the phenotype of the disease to prenatal life.

• #27 Noonan Syndrome: Symptoms, Diagnosis, Treatment, and More

  https://www.healthline.com/health/childrens-health/noonan-syndrome

  You may also be able to get a diagnosis during pregnancy. If you suspect that you or your partner carry the gene mutation, your doctor may suggest genetic testing, like amniocentesis or chorionic villus sampling. […] An ultrasound scan can also identify certain signs, like excess amniotic fluid (polyhydramnios) or fluid buildup in other parts of the body. […] What further testing is needed for diagnosis?

• #28 Noonan syndrome – Diagnosis | Health Information from Greenchem Pharmacy

  https://greenchempharmacy.com/nhs_conditions_noonan-syndrome_diagnosis

  If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition, routine ultrasound scans detect possible signs of the condition in your baby, such as polyhydramnios (an excessive amount of amniotic fluid), pleural effusion (fluid in the space around the lungs) or a build-up of fluid in certain other parts of the body. Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition. This can be done using either chorionic villus sampling (where a sample of cells is removed from the placenta) or amniocentesis (where a sample of amniotic fluid is removed). Both of these tests carry around a 0.5 to 1% chance of causing a miscarriage. If your baby is found to have one of the faulty genes, a genetic counsellor will talk to you about what the test result means and what your options are.

• #29 Noonan syndrome – Diagnosis | Health Information from Greenchem Pharmacy

  https://greenchempharmacy.com/nhs_conditions_noonan-syndrome_diagnosis

  If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition, routine ultrasound scans detect possible signs of the condition in your baby, such as polyhydramnios (an excessive amount of amniotic fluid), pleural effusion (fluid in the space around the lungs) or a build-up of fluid in certain other parts of the body. Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition. This can be done using either chorionic villus sampling (where a sample of cells is removed from the placenta) or amniocentesis (where a sample of amniotic fluid is removed). Both of these tests carry around a 0.5 to 1% chance of causing a miscarriage. If your baby is found to have one of the faulty genes, a genetic counsellor will talk to you about what the test result means and what your options are.

• #30 Noonan Syndrome Workup: Approach Considerations, Laboratory Studies, Imaging Studies

  https://emedicine.medscape.com/article/947504-workup

  All patients with Noonan syndrome should be evaluated to determine which disease manifestations they display. A complete physical and neurologic examination should be performed, and a genetics consultation should be sought. In addition, the following assessments should be made at the time of diagnosis: […] Cardiac evaluation – Including echocardiographic and electrocardiographic assessment […] Ophthalmologic and audiologic evaluation […] Coagulation screen […] Renal ultrasonographic examination […] Developmental assessment. […] Before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed. […] A complete blood count (CBC) with platelet count, coagulation profile, and measurement of factor XI level should be obtained at a minimum.

• #31 Noonan syndrome – Diagnosis | Health Information from Greenchem Pharmacy

  https://greenchempharmacy.com/nhs_conditions_noonan-syndrome_diagnosis

  Noonan syndrome may be suspected if your child has some of the signs and symptoms associated with the condition. These include: distinctive facial features, short stature (restricted growth), a mild learning disability, undescended testicles, lymphoedema, heart problems, a family history of Noonan syndrome. However, these symptoms can have a number of different causes, so it’s difficult to make a diagnosis based on them alone. You may be referred to a genetics specialist for genetic testing. In most cases, Noonan syndrome can be confirmed by a blood test for the various genetic mutations. However, in about 1 in 5 cases no specific mutation can be found, so a negative blood test won’t rule out Noonan syndrome. […] If Noonan syndrome has been confirmed or is strongly suspected, further tests are needed to establish the extent of the symptoms. These tests may include: an electrocardiogram (ECG) where electrodes (small, metallic discs placed on the skin) measure the electrical activity of the heart, an echocardiogram an ultrasound scan of the heart, an educational assessment, blood tests to check how well the blood clots, eye tests to check for problems such as squints or blurred vision, hearing tests to check for problems such as hearing loss caused by a middle ear infection or damage to the cells or nerves inside the ear. Some of these tests may need to be repeated regularly after the diagnosis, to monitor the symptoms.

• #32 Noonan Syndrome: Symptoms, Diagnosis, Treatment, and More

  https://www.healthline.com/health/childrens-health/noonan-syndrome

  Noonan syndrome is a genetic condition that affects around 1 in every 1,0002,500 people. The signs and symptoms can vary greatly from person to person, so this condition may be underdiagnosed or even misdiagnosed. […] Since signs and symptoms can vary greatly from person to person, some babies may be diagnosed at birth while others may not be diagnosed until later in life. […] At birth, your child’s doctor may observe certain physical signs, facial features, for instance, or congenital heart issues. From there, diagnosis can be confirmed via a blood test to look for genetic mutations. […] A negative blood test doesn’t always mean that a child doesn’t have Noonan syndrome, though. In 1 out of 5 cases, no genetic mutation is found. […] As your child grows, other tests may be ordered to look at specific health issues. They include: heart tests, like electrocardiogram or echocardiogram, blood tests to assess clotting factors, eye tests and hearing tests, educational assessments to assess developmental delays.

• #33 Noonan Syndrome | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/noonan-syndrome

  The diagnosis of Noonan syndrome is often made on clinical grounds, based on the presence of specific features, including: […] In addition to these clinical findings, coagulation (blood clotting) defects may be present in patients with Noonan syndrome. Coagulation screening tests such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time may show abnormalities. […] Therefore, individuals should meet with a genetics specialist with experience in the diagnosis and management of Noonan syndrome in order to confirm the diagnosis and coordinate medical management. […] To confirm on a molecular level that an individual has Noonan syndrome, he or she can undergo the process of genetic testing. Genetic testing usually involves the collection of a sample of blood, from which the white blood cells are isolated and used as a source of DNA.

• #34 Noonan Syndrome Workup: Approach Considerations, Laboratory Studies, Imaging Studies

  https://emedicine.medscape.com/article/947504-workup

  All patients with Noonan syndrome should be evaluated to determine which disease manifestations they display. A complete physical and neurologic examination should be performed, and a genetics consultation should be sought. In addition, the following assessments should be made at the time of diagnosis: […] Cardiac evaluation – Including echocardiographic and electrocardiographic assessment […] Ophthalmologic and audiologic evaluation […] Coagulation screen […] Renal ultrasonographic examination […] Developmental assessment. […] Before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed. […] A complete blood count (CBC) with platelet count, coagulation profile, and measurement of factor XI level should be obtained at a minimum.

• #35 Noonan Syndrome Workup: Approach Considerations, Laboratory Studies, Imaging Studies

  https://emedicine.medscape.com/article/947504-workup

  Moreover, before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed. […] If full phenotypic expression is not apparent, karyotyping may be necessary. Mutation analysis may confirm the diagnosis of Noonan syndrome, but failure to identify a germline mutation in any of the associated genes does not rule out the disorder; this entity remains a clinical diagnosis. […] DNA-based testing of the known causative genes, which can be performed via next-generation sequencing, can be considered for confirmation of diagnosis. […] Unless a known mutation is present in a family, negative (ie, normal) test findings do not rule out a diagnosis of Noonan syndrome.

• #36 Noonan syndrome differential diagnosis – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_differential_diagnosis

  Noonan syndrome can be considered in any patient with congenital cardiac anomalies although 3 important syndromes can resemble the Noonan phenotype particularly LEOPARD syndrome, Costello syndrome, and Turner syndrome in girls. […] Although Turner syndrome has been genetically and clinically delineated and can be differentiated from Noonan’s syndrome, initially, Noonan’s was considered a form of Turner syndrome that can affect males due to the marked overlap between the 2 disorders. […] In females with any difficulty in differentiating the syndromes clinically due to the variable expression, karyotype and genetic analysis are helpful.

• #37 Noonan Syndrome: Exploring Karyotypes and Genetic Causes

  https://3billion.io/blog/noonan-syndrome-and-karyotype-genetic-code

  Noonan Syndrome does not have a specific karyotype associated with it. Instead, it is primarily caused by mutations in various specific genes, such as PTPN11, SOS1, RAF1, and others. These mutations occur in specific genes on certain chromosomes and are responsible for the characteristic features and health issues associated with Noonan Syndrome. […] The diagnosis of Noonan Syndrome typically involves a combination of genetic testing and clinical evaluation. […] While karyotype testing can provide valuable information, it may not identify the specific genetic mutations responsible for Noonan Syndrome. To pinpoint the exact genetic cause, more targeted genetic testing is necessary. […] In some cases, whole exome sequencing (WES) or whole genome sequencing (WGS) may be used if initial genetic tests do not identify a mutation. These comprehensive sequencing techniques can analyze the entire exome or genome to identify rare or novel mutations.

• #38 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  To detect these mutations, an additional screening level is required with a second panel of genes, which again should be guided by clinical geneticist. […] In these latter cases the molecular diagnosis requires a longer time before identifying the pathogenic mutation. […] Here we report our personal experience on the use of targeted Next Generation Sequencing (NGS) for diagnosis of RASopathies. […] Our study suggests that this protocol can be easily used as a standard diagnostic tool to identify disease-causing mutations, with a straightforward workflow from genomic DNA up to genomic variants identification. […] The absence of any false negative and false positive results and the possibility to have an easy and accurate data analysis make this approach a good diagnostic tool. […] This study demonstrates that NGS can be successfully applied to the molecular testing of RASopathies with a remarkable gain of time and less cost, while maintaining the high quality of the results. […] Taken all together, these data highlight the usefulness of a molecular characterization that lead to an early diagnosis especially for patients with mild, nonspecific or atypical features and might direct to a more appropriate genetic counselling and clinical management.

• #39 Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review

  https://www.mdpi.com/2077-0383/13/19/5735

  Based on this review, lymphatic disorders are typical prenatal features of Noonan syndrome, expressed with varying degrees of severity, ranging from simple thickened NT or cystic hygroma in the first trimester to fluid collection in various body spaces and eventually hydrops fetalis. […] Clinical implication: Prenatal diagnosis is important for counseling the couples and offering choices for management and decision-making. […] A comprehensive scoring system for the diagnosis of Noonan syndrome should include the prenatal phenotype; this might be important for diagnosis, especially in the settings where molecular diagnosis is not available. […] The differential diagnosis for fetal Noonan syndrome may include a variety of genetic and syndromic disorders with overlapping prenatal features, including Turner syndrome, Cardiofaciocutaneous syndrome, Costello syndrome, and others.

• #40 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] The diagnosis of NS is primarily based on clinical features aforementioned. Therefore, high clinical suspicion should be a prerequisite for the diagnosis. Mutation analysis of 20 genes (PTPN11, SOS1, RAF1, SHOC2, RIT, KRAS, NRAS, MRAS, BRAF, MEK1, MEK2, CBL, SOS2, SPRY1, LZTR1, A2ML1, RRAS, RRAS2, RASA2, PPP1CB) makes the diagnosis confirmatory in about 80%. […] Management of NS patients is entirely dependent on its individual manifestation. Cautious physical examinations are mandatory to delineate the presence of congenital defects in cardiovascular, genitourinary, skeletal, and other birth defects. […] Gene panel testing offers confirmatory diagnosis in about 80% of patients. RASopathies require multidisciplinary team approach to provide the best medical cares for each particular clinical issue.

• #41

  https://knightdxlabs.ohsu.edu/home/test-details?id=Noonan%20and%20Other%20Related%20Disorders

  Mutations in genes within the Ras/mitogen activated protein kinase (MAPK) pathway are associated with a set of genetic syndromes, collectively called RASopathies. Noonan syndrome and the other RASopathies are autosomal dominant conditions with prevalence between 1:1000 and 1:2500 individuals. This next-generation sequencing test is designed to detect mutations in the coding regions of the 13 genes associated with these conditions. […] Clinical presentation consistent with Noonan syndrome or other RASopathy. […] Confirmation of clinical diagnosis. […] Next generation sequencing using Illumina NextSeq 500/550. […] A Bayesian model was validated clinically in our lab. The model can detect copy changes at a resolution of three (3) or more probe targets (exons) for deletions and duplications in genes that do not have pseudogenes, and is not designed to detect low-level mosaicism or balanced alterations.

• #42 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood

  https://adc.bmj.com/content/107/12/1073

  Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Genetic testing is recommended at the time of clinical diagnosis or suspicion. Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. Early diagnosis would aid clinical management, and optimise developmental and long-term outcomes. Despite the existence of diagnostic guidelines/criteria, diagnosis is difficult in less severely affected individuals for a number of reasons, including both healthcare provider (HCP)-related and patient-related factors. It is proposed that increased awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and possible NS diagnosis, increasing the potential for optimising lifelong patient outcomes.

• #43 Noonan syndrome: Causes, symptoms, and management

  https://www.medicalnewstoday.com/articles/179200

  A doctor will diagnose Noonan syndrome based on key signs and symptoms. Diagnosis can often be difficult because of the subtlety of some of the features associated with the condition. […] In some cases, the disorder isnt diagnosed until someone with Noonan syndrome has a child with more obvious signs and symptoms. A diagnosis can be confirmed through molecular genetic testing. […] The earlier Noonan syndrome is diagnosed, the earlier treatment and prevention strategies can be implemented, leading to better outcomes for patients.

• #44 Noonan syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422

  How the face looks is one key feature that leads to a diagnosis of Noonan syndrome. […] If you suspect you or your child may have this condition, see your primary care professional or your child’s pediatrician. You may be referred to a specialist in genetics or a specialist in heart problems or another type of doctor, depending on the symptoms. […] If Noonan syndrome is detected early, it’s possible that proper and ongoing care may lessen complications such as heart disease.

• #45

  https://journals.lww.com/md-cases/fulltext/2022/04000/an_early_diagnostic_case_of_noonan_syndrome_with.4.aspx

  In the present case, the diagnosis was suggested by clinical and paraclinical characteristic elements: typical facial dysmorphic syndrome, in addition to 2 other major criteria and 1 minor criterion (short height, pulmonary stenosis, and broad thorax). […] This case study presents some elements. First, early diagnosis was made at the age of 3 months in the presence of congenital pulmonary valve stenosis (although published cases usually present an average diagnosis age of 9 years). […] The evolution of patients with Noonan syndrome is good, and their lifespan is comparable to that of the general population; however, they require frequent follow-up and close monitoring by multidisciplinary teams. […] In conclusion, Noonan syndrome presents large clinical variability, with emphasis on the importance of early diagnosis, especially in cases with early manifestations.

• #46 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood

  https://adc.bmj.com/content/107/12/1073

  Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Genetic testing is recommended at the time of clinical diagnosis or suspicion. Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. Early diagnosis would aid clinical management, and optimise developmental and long-term outcomes. Despite the existence of diagnostic guidelines/criteria, diagnosis is difficult in less severely affected individuals for a number of reasons, including both healthcare provider (HCP)-related and patient-related factors. It is proposed that increased awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and possible NS diagnosis, increasing the potential for optimising lifelong patient outcomes.

• #47 Families living with Noonan Syndrome call for more social support and medical awareness | News and events | Loughborough University

  https://www.lboro.ac.uk/news-events/news/2024/february/noonan-syndrome-awareness-report-families-impact/

  A survey of more than 60 families living with Noonan Syndrome has highlighted the need for more social support and medical awareness. […] One of the key survey findings is that there is a lack of awareness of the rare genetic condition even among medical professionals, which can lead to difficulties in accessing care. […] Despite increasing medical research, very often medical professionals involved in families care don’t know much about Noonan Syndrome, if anything at all, she said. […] Families have told us of experiences of poor support from professionals in their lives, lack of understanding about the realities of living with Noonan Syndrome, and difficulties in accessing care. […] In addition to finding families struggle with a lack of awareness of the condition, another significant theme emerged from the survey responses: the social and emotional impacts of living with Noonan Syndrome are overlooked for both individuals and carers.

• #48 Noonan Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532269/

  Noonan syndrome is typically a genetically inherited disorder with heterogeneous phenotypic manifestations that can change with age. […] Diagnostic criteria have been developed to aid in the diagnosis of Noonan syndrome. […] Noonan syndrome is typically a clinical diagnosis. […] Molecular genetic testing can be done to confirm the diagnosis. […] Noonan syndrome remains a clinical diagnosis. […] The diagnosis and management of Noonan syndrome require an interprofessional team that includes a geneticist, pediatrician, primary care provider, ENT surgeon, audiologist, ophthalmologist, and cardiologist.

• #49 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] The diagnosis of NS is primarily based on clinical features aforementioned. Therefore, high clinical suspicion should be a prerequisite for the diagnosis. Mutation analysis of 20 genes (PTPN11, SOS1, RAF1, SHOC2, RIT, KRAS, NRAS, MRAS, BRAF, MEK1, MEK2, CBL, SOS2, SPRY1, LZTR1, A2ML1, RRAS, RRAS2, RASA2, PPP1CB) makes the diagnosis confirmatory in about 80%. […] Management of NS patients is entirely dependent on its individual manifestation. Cautious physical examinations are mandatory to delineate the presence of congenital defects in cardiovascular, genitourinary, skeletal, and other birth defects. […] Gene panel testing offers confirmatory diagnosis in about 80% of patients. RASopathies require multidisciplinary team approach to provide the best medical cares for each particular clinical issue.

• #50 Noonan Syndrome: Diagnosis & Treatment | NewYork-Presbyterian

  https://www.nyp.org/pediatrics/noonan-syndrome/treatment

  Knowing the symptoms of Noonan syndrome is important for an accurate diagnosis and early treatment. Pediatricians at NewYork-Presbyterian have experience in recognizing the varied and sometimes subtle symptoms of Noonan syndrome. Schedule an appointment for a consultation for expert pediatric care and referral to our pediatric cardiology and endocrinology specialists.

• #51

  https://journals.lww.com/md-cases/fulltext/2022/04000/an_early_diagnostic_case_of_noonan_syndrome_with.4.aspx

  Noonan syndrome is a genetic disorder with variable clinical manifestations that affects different systems. […] Therefore, a systematic and thorough evaluation according to the guidelines for the assessment and management of Noonan syndrome is needed. […] Echocardiography showed severe pulmonary valve stenosis, mild pulmonary regurgitation, a 6.5 mm ostium secundum atrial septal defect, and a persistent ductus arteriosus. […] The diagnosis was initially suggested by the characteristic unique clinical events associated with cardiac involvement and confirmed later through genetic molecular testing. […] The initial diagnosis of Noonan syndrome was initially made through clinical assessment and later reinforced by genetic molecular testing. […] An early and precise diagnosis of Noonan syndrome is important because each patient requires a personalized evaluation and treatment protocol.

• #52 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. […] Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies. […] Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL.

• #53 Genetic Test Improves Noonan Syndrome Diagnosis – molecular-diagnostics – Labmedica.com

  https://www.labmedica.com/molecular-diagnostics/articles/294741532/genetic-test-improves-noonan-syndrome-diagnosis.html

  A new one-step test provides large-scale parallel screening of all 12 genes associated with Noonan disorders in one panel. […] Correctly identifying the disorder is essential to ensure that appropriate care and monitoring is provided and to preclude unnecessary investigations. […] Currently genetic testing of suspected Noonan cases is carried out on a gradual basis by testing for one disorder or gene and then another until a mutation is identified to confirm the diagnosis. […] Molecular testing has simplified the process of making a diagnosis. […] A positive test result will provide a definite diagnosis of the syndrome in question as the mutation spectrum has been well defined and no cases of nonpenetrance have been identified. […] Importantly, as a positive result will also determine which disorder is applicable, medical interventions appropriate for that specific disorder can be highlighted more quickly.

• #54 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  All expected variants in patients belonging to the validation set have been identified by targeted NGS providing a detection rate of 100%. […] Here we show how molecular testing of RASopathies by targeted NGS could allow an early and accurate diagnosis for all enrolled patients, enabling a prompt diagnosis especially for those patients with mild, non-specific or atypical features, in whom the detection of the causative mutation usually requires prolonged diagnostic timings when using standard routine. […] Nowadays, due to high genetic heterogeneity of these disorders, which affect genes that all together span about 30 kb of genomic DNA, the standard diagnostic testing protocol requires a multi-step approach, using Sanger sequencing. […] By using this approach, the causative mutations can be identified in most of the cases.

• #55 (PDF) Diagnosis of Noonan syndrome and related disorders using target next generation sequencing

  https://www.academia.edu/19174720/Diagnosis_of_Noonan_syndrome_and_related_disorders_using_target_next_generation_sequencing

  Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. […] Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies. […] Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL.

• #56 (PDF) Diagnosis of Noonan syndrome and related disorders using target next generation sequencing

  https://www.academia.edu/19174720/Diagnosis_of_Noonan_syndrome_and_related_disorders_using_target_next_generation_sequencing

  All expected variants in patients belonging to the validation set have been identified by targeted NGS providing a detection rate of 100%. […] The molecular diagnosis was confirmed in 27 patients. […] Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.

• #57 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  To detect these mutations, an additional screening level is required with a second panel of genes, which again should be guided by clinical geneticist. […] In these latter cases the molecular diagnosis requires a longer time before identifying the pathogenic mutation. […] Here we report our personal experience on the use of targeted Next Generation Sequencing (NGS) for diagnosis of RASopathies. […] Our study suggests that this protocol can be easily used as a standard diagnostic tool to identify disease-causing mutations, with a straightforward workflow from genomic DNA up to genomic variants identification. […] The absence of any false negative and false positive results and the possibility to have an easy and accurate data analysis make this approach a good diagnostic tool. […] This study demonstrates that NGS can be successfully applied to the molecular testing of RASopathies with a remarkable gain of time and less cost, while maintaining the high quality of the results. […] Taken all together, these data highlight the usefulness of a molecular characterization that lead to an early diagnosis especially for patients with mild, nonspecific or atypical features and might direct to a more appropriate genetic counselling and clinical management.

• #58 Noonan Syndrome Genetic Testing | Panel | Ambry Genetics

  https://www.ambrygen.com/providers/genetic-testing/83/exome-and-general-genetics/noonannext

  Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage. […] Knowing if your patient has Noonan syndrome can help you guide your medical management recommendations. Key benefits include: […] Clarify diagnosis and future risk of congenital heart disease […] Confirm diagnosis and identify inherited mutation following a sudden death with autopsy findings […] The NoonanNext test is designed and validated to be capable of detecting 99% of described mutations in the gene represented on the test (analytical sensitivity). […] NoonanNext is a comprehensive analysis of 18 genes associated with Noonan syndrome and related disorders.

• #59 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. […] Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies. […] Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL.

• #60 About Noonan Syndrome

  https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome

  The diagnosis of Noonan syndrome is based on the person’s clinical symptoms and signs. The specialist examines the person looking for the specific features of Noonan syndrome. […] Individuals who have Noonan syndrome have normal chromosome studies. Four genes – PTPN11, SOS1, RADF1 and KRAS – are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known.

• #61 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] The diagnosis of NS is primarily based on clinical features aforementioned. Therefore, high clinical suspicion should be a prerequisite for the diagnosis. Mutation analysis of 20 genes (PTPN11, SOS1, RAF1, SHOC2, RIT, KRAS, NRAS, MRAS, BRAF, MEK1, MEK2, CBL, SOS2, SPRY1, LZTR1, A2ML1, RRAS, RRAS2, RASA2, PPP1CB) makes the diagnosis confirmatory in about 80%. […] Management of NS patients is entirely dependent on its individual manifestation. Cautious physical examinations are mandatory to delineate the presence of congenital defects in cardiovascular, genitourinary, skeletal, and other birth defects. […] Gene panel testing offers confirmatory diagnosis in about 80% of patients. RASopathies require multidisciplinary team approach to provide the best medical cares for each particular clinical issue.

• #62 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Noonan-Syndrome-Diagnosis.aspx

  Noonan syndrome is a heterogeneous, but clinically recognizable, multiple congenital anomaly syndrome. Appropriate patient management for Noonan syndrome is vastly dependent on an early and adequate diagnosis. […] The overlapping features observed among related disorders, an absence of clinical features with pathognomonic value, the wide breadth of phenotypes, as well as an overall lack of consensus on diagnostic criteria hamper the diagnosis of Noonan syndrome. […] The diagnosis of Noonan syndrome is first and foremost made clinically by the observation of the condition’s cardinal features. […] Scoring systems can aid significantly in the diagnostic process for Noonan syndrome. […] Due to the high genetic heterogeneity of RASopathies, the standard diagnostic testing protocol should include a multi-step approach using Sanger sequencing. […] If the disease-causing mutation has been recognized in the family, prenatal diagnosis for pregnancies that are at an increased risk of Noonan syndrome may be obtainable through laboratories that offer testing for the gene of interest or custom prenatal testing.

• #63 Families living with Noonan Syndrome call for more social support and medical awareness | News and events | Loughborough University

  https://www.lboro.ac.uk/news-events/news/2024/february/noonan-syndrome-awareness-report-families-impact/

  A survey of more than 60 families living with Noonan Syndrome has highlighted the need for more social support and medical awareness. […] One of the key survey findings is that there is a lack of awareness of the rare genetic condition even among medical professionals, which can lead to difficulties in accessing care. […] Despite increasing medical research, very often medical professionals involved in families care don’t know much about Noonan Syndrome, if anything at all, she said. […] Families have told us of experiences of poor support from professionals in their lives, lack of understanding about the realities of living with Noonan Syndrome, and difficulties in accessing care. […] In addition to finding families struggle with a lack of awareness of the condition, another significant theme emerged from the survey responses: the social and emotional impacts of living with Noonan Syndrome are overlooked for both individuals and carers.

• #64 Families living with Noonan Syndrome call for more social support and medical awareness | News and events | Loughborough University

  https://www.lboro.ac.uk/news-events/news/2024/february/noonan-syndrome-awareness-report-families-impact/

  Dr Coveney and the Noonan Syndrome Association are calling for greater Noonan Syndrome awareness, especially among medical professionals. […] The majority of parent carers in our study were not able to find paid employment that fits around their caring responsibilities, which can lead to financial pressures and stress. […] The couple discovered at 26 weeks pregnant, after a prenatal screening test, that one of their twins, Matilda, had Noonan Syndrome. […] They say the lack of awareness among medical professionals has been challenging, especially at the point of diagnosis. […] We learnt all we did about the condition from looking things up on the internet; we found, and still find, we are the ones having to explain what Noonan Syndrome is to medical professionals. […] Andrea worries her daughter and other people with the same gene mutation will never get a diagnosis as she believes there is a hesitancy to fund studies into rare genetic diseases. […] The research from Loughborough University highlights difficulties we all face, whether its Noonan Syndrome or a different rare genetic condition.

• #65 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood

  https://adc.bmj.com/content/107/12/1073

  Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Genetic testing is recommended at the time of clinical diagnosis or suspicion. Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. Early diagnosis would aid clinical management, and optimise developmental and long-term outcomes. Despite the existence of diagnostic guidelines/criteria, diagnosis is difficult in less severely affected individuals for a number of reasons, including both healthcare provider (HCP)-related and patient-related factors. It is proposed that increased awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and possible NS diagnosis, increasing the potential for optimising lifelong patient outcomes.

• #66

  https://www.nhs.uk/conditions/noonan-syndrome/diagnosis/

  Noonan syndrome may be suspected if your child has some of the signs and symptoms associated with the condition. […] However, these symptoms can have a number of different causes, so it’s difficult to make a diagnosis based on them alone. […] You may be referred to a genetics specialist for genetic testing. In most cases, Noonan syndrome can be confirmed by a blood test for the various genetic mutations. However, in about 1 in 5 cases no specific mutation can be found, so a negative blood test won’t rule out Noonan syndrome. […] If Noonan syndrome has been confirmed or is strongly suspected, further tests are needed to establish the extent of the symptoms. […] If you’re pregnant, it may be possible to test your unborn baby for Noonan syndrome if: you, your partner or a close family member has been found to carry one of the faulty genes associated with the condition. […] Testing for Noonan syndrome during pregnancy involves collecting a sample of your baby’s DNA and checking it for any of the faulty genes associated with the condition.

• #67 Noonan syndrome – UpToDate

  https://www.uptodate.com/contents/noonan-syndrome

  Noonan syndrome (NS) is a common autosomal-dominant condition that is associated with short stature and congenital heart disease (CHD), most often pulmonic stenosis. […] This topic reviews the epidemiology, genetics, pathophysiology, clinical manifestations, diagnosis, and management of NS. […] DIAGNOSIS Clinical assessment, Genetic testing, Prenatal testing. […] Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes may be involved. […] A number of candidate genes for NS have been identified using high-throughput technologies such as exome sequencing and are awaiting further evaluation before their role in NS can be confirmed.

• #68 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] The diagnosis of NS is primarily based on clinical features aforementioned. Therefore, high clinical suspicion should be a prerequisite for the diagnosis. Mutation analysis of 20 genes (PTPN11, SOS1, RAF1, SHOC2, RIT, KRAS, NRAS, MRAS, BRAF, MEK1, MEK2, CBL, SOS2, SPRY1, LZTR1, A2ML1, RRAS, RRAS2, RASA2, PPP1CB) makes the diagnosis confirmatory in about 80%. […] Management of NS patients is entirely dependent on its individual manifestation. Cautious physical examinations are mandatory to delineate the presence of congenital defects in cardiovascular, genitourinary, skeletal, and other birth defects. […] Gene panel testing offers confirmatory diagnosis in about 80% of patients. RASopathies require multidisciplinary team approach to provide the best medical cares for each particular clinical issue.

• #69 Noonan Syndrome | Noonan Syndrome Awareness Association

  https://noonansyndrome.com.au/noonan-syndrome/

  Diagnosis of Noonan Syndrome can be made clinically and confirmed via genetic testing. […] Noonan syndrome (NS) should be suspected in individuals with the following key features: Characteristic facial features such as: low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; eyes that are often wide-spaced, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis). […] Diagnostic criteria developed by van der Burgt in 1997 is below: Definitive NS: 1 „A” plus one other major sign or two minor signs; 1 „B” plus two major signs or three minor signs. […] Molecular testing approaches can include use of a multi-gene panel, serial single-gene testing, and more comprehensive genomic testing. […] A multi-gene panel is the test of choice for an individual suspected of having Noonan syndrome.

• #70

  https://journals.lww.com/md-cases/fulltext/2022/04000/an_early_diagnostic_case_of_noonan_syndrome_with.4.aspx

  Noonan syndrome is a genetic disorder with variable clinical manifestations that affects different systems. […] Therefore, a systematic and thorough evaluation according to the guidelines for the assessment and management of Noonan syndrome is needed. […] Echocardiography showed severe pulmonary valve stenosis, mild pulmonary regurgitation, a 6.5 mm ostium secundum atrial septal defect, and a persistent ductus arteriosus. […] The diagnosis was initially suggested by the characteristic unique clinical events associated with cardiac involvement and confirmed later through genetic molecular testing. […] The initial diagnosis of Noonan syndrome was initially made through clinical assessment and later reinforced by genetic molecular testing. […] An early and precise diagnosis of Noonan syndrome is important because each patient requires a personalized evaluation and treatment protocol.

• #71 Noonan Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532269/

  Noonan syndrome is typically a genetically inherited disorder with heterogeneous phenotypic manifestations that can change with age. […] Diagnostic criteria have been developed to aid in the diagnosis of Noonan syndrome. […] Noonan syndrome is typically a clinical diagnosis. […] Molecular genetic testing can be done to confirm the diagnosis. […] Noonan syndrome remains a clinical diagnosis. […] The diagnosis and management of Noonan syndrome require an interprofessional team that includes a geneticist, pediatrician, primary care provider, ENT surgeon, audiologist, ophthalmologist, and cardiologist.

• #72 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood

  https://adc.bmj.com/content/107/12/1073

  Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Genetic testing is recommended at the time of clinical diagnosis or suspicion. Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. Early diagnosis would aid clinical management, and optimise developmental and long-term outcomes. Despite the existence of diagnostic guidelines/criteria, diagnosis is difficult in less severely affected individuals for a number of reasons, including both healthcare provider (HCP)-related and patient-related factors. It is proposed that increased awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and possible NS diagnosis, increasing the potential for optimising lifelong patient outcomes.

• #73 Diagnosis of Noonan syndrome and related disorders using target next generation sequencing | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-15-14

  To detect these mutations, an additional screening level is required with a second panel of genes, which again should be guided by clinical geneticist. […] In these latter cases the molecular diagnosis requires a longer time before identifying the pathogenic mutation. […] Here we report our personal experience on the use of targeted Next Generation Sequencing (NGS) for diagnosis of RASopathies. […] Our study suggests that this protocol can be easily used as a standard diagnostic tool to identify disease-causing mutations, with a straightforward workflow from genomic DNA up to genomic variants identification. […] The absence of any false negative and false positive results and the possibility to have an easy and accurate data analysis make this approach a good diagnostic tool. […] This study demonstrates that NGS can be successfully applied to the molecular testing of RASopathies with a remarkable gain of time and less cost, while maintaining the high quality of the results. […] Taken all together, these data highlight the usefulness of a molecular characterization that lead to an early diagnosis especially for patients with mild, nonspecific or atypical features and might direct to a more appropriate genetic counselling and clinical management.

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