Noonan syndrome
Noonan syndrome is a genetic disorder resulting from mutations in specific genes, primarily affecting the RAS/MAPK signaling pathway. This condition is characterized by a variety of clinical features, including distinctive facial dysmorphisms, short stature, congenital heart defects, and lymphatic system abnormalities. Common heart issues include pulmonic stenosis, and up to 80% of individuals may present with structural heart defects. Neurocognitive delays are also frequently observed, though they are typically mild.
The syndrome is inherited in an autosomal dominant pattern, meaning that an affected parent has a 50% chance of passing the condition to their offspring. Genetic testing can confirm a diagnosis, but not all individuals will have detectable mutations. Early diagnosis and intervention, including cardiac care and therapies for developmental support, can improve outcomes. Despite the challenges, individuals with Noonan syndrome often lead fulfilling lives with a normal life expectancy, emphasizing the importance of supportive care and genetic counseling for affected families.
Noonan syndrome
ALSO KNOWN AS:Male Turner syndrome; female pseudo-Turner syndrome; Turner's phenotype with normal karyotype
DEFINITION: Noonan syndrome is a genetic disorder caused by a germline mutation in one of the following genes: MRAS, SPRED2, RRAS2, PTPN11, CBL, SOS1, KRAS, RAF1, NRAS, RIT1, LZTR1, RASA2, or SOS2. Clinical features include facial dysmorphisms, short stature, cardiac defects, neurocognitive delays, lymphatic abnormalities, and hematologic complications.
Risk Factors
Up to 75 percent of Noonan syndrome cases are inherited from an affected parent. It is inherited in an autosomal dominant fashion. Individuals with this condition have a 50 percent risk in each pregnancy of having a child who has Noonan syndrome. As with many other single-gene disorders, advanced paternal age has been associated with de novo (spontaneous) cases.
![Noonan syndrome. A 12-year-old female with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity. By Konstantinos C Soultanis, Alexandros H Payatakes, Vasilios T Chouliaras, Georgios C Mandellos, Nikolaos E Pyrovolou, Fani M Pliarchopoulou and Panayotis N Soucacos [CC-BY-2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons 94416614-89447.jpg](https://imageserver.ebscohost.com/img/embimages/ers/sp/embedded/94416614-89447.jpg?ephost1=dGJyMNHX8kSepq84xNvgOLCmsE2epq5Srqa4SK6WxWXS)
![Noonan1883. The oldest known case of Noonan syndrome, described in 1883 by Kobylinski. By see above [Public domain], via Wikimedia Commons 94416614-89448.jpg](https://imageserver.ebscohost.com/img/embimages/ers/sp/embedded/94416614-89448.jpg?ephost1=dGJyMNHX8kSepq84xNvgOLCmsE2epq5Srqa4SK6WxWXS)
Etiology and Genetics
Noonan syndrome is caused by a single genetic mutation in one of at least thirteen known genes. Genetic mutations are typically caused by DNA replication errors during cell division. These genetic errors typically occur during meiosis and result in a mutation in one of the germ cells (sperm or egg).
Approximately 50 percent of individuals with Noonan syndrome have a genetic mutation in PTPN11. This gene encodes the protein tyrosine phosphatase, nonreceptor type 11 (SHP-2). This protein is expressed in all cell types, and it is important for cellular response to cell adhesion molecules, cytokines, growth factors, and hormones. It plays an important role in intercellular signaling, which controls several developmental processes. It is essential for activation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. This pathway is important for cellular differentiation and proliferation, as well as for cell survival and apoptosis.
Mutations in at least five other genes involved in the MAPK cascade are known to cause Noonan syndrome, including SOS1 (10 to 13 percent), KRAS, BRAF, RAF1, and NRAS. Cardiofaciocutaneous syndrome (CFC) and Costello syndrome are disorders in the same clinical spectrum caused by mutations in these genes. SOS1 gene mutations account for 10 to 13 percent of Noonan syndrome cases, and RAF1 mutations account for 5 to 10 percent. KRAS mutations account for 2 percent of cases of Noonan syndrome, and individuals with mutations in this gene typically have a more severe form of the disorder. Mutations in the other genes account for a very small proportion of people with Noonan syndrome.
In addition, clinical overlap between Noonan syndrome and neurofibromatosis type 1 has been well described (also referred to as Watson syndrome). This is due to mutations in the NF1 gene, whose protein product, neurofibromin, is a negative regulator of the Ras-mediated signal transduction pathway. LEOPARD syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarded growth, and deafness) can also be caused by mutations in PTPN11 and RAF1.
Symptoms
Lymphatic system abnormalities are common. In the prenatal period, a cystic hygroma (a fluid-filled structure, typically at the back of the neck) may be identified. Lymphatic irregularities can cause a puffy appearance to the hands and feet. Typically, the physical signs of lymphatic dysfunction improve with age. A structural heart defect is seen in approximately 50 to 80 percent of affected individuals. The most commonly identified heart defect is pulmonic stenosis (narrowing of the pulmonary valve), although other heart defects can be seen.
Most individuals have short stature. Children typically follow a growth curve that is in the low/low-normal range. About 30 percent of adults with Noonan syndrome will have a height that falls within the normal range; however, the majority will have a height that is below average. Individuals often have characteristic facial features, including low-set and posteriorly rotated ears, widely spaced and downslanting eyes, and thick or droopy eyelids. They often have a sunken chest (pectus excavatum) or a protuding chest (pectus carinatum). A broad or webbed neck is not uncommon.
Many, although not all, experience some degree of neurocognitive delay. Delays are generally mild; however, individuals rarely experience extensive cognitive disabilities. Other associated medical problems include kidney abnormalities, delayed puberty, undescended testicles, and potential male fertility problems. Blood clotting impairments causing excessive bruising or bleeding can occur. Visual acuity can be affected. Specific mutations in PTPN11 may cause a predisposition to certain forms of leukemia.
Screening and Diagnosis
Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 births. The clinical diagnosis is based on observation of the previously mentioned features, but not every individual will experience all the associated structural or functional differences. Noonan syndrome is sometimes diagnosed at a later age in females because many young males with the condition present with cryptorchidism, or undescended testicles. The diagnosis can be confirmed in the majority of individuals with molecular genetic testing. However, not all individuals with the clinical diagnosis of Noonan syndrome will have an identifiable gene mutation.
Individuals in whom the diagnosis is known or suspected should have a thorough cardiac evaluation. They should also have hearing screenings and annual vision evaluations. Blood clot testing should be performed if clinically warranted or prior to any surgical procedure. A renal ultrasound is recommended. Growth should be monitored using specific Noonan syndrome charts.
Treatment and Therapy
There is currently no cure for this condition. However, treatment for individual symptoms is available. This includes cardiac intervention, referral to early intervention services (occupational, speech, and physical therapy), growth hormone therapy, and treatment for specific bleeding impairments.
Prevention and Outcomes
Most individuals with Noonan syndrome who survive the newborn period do very well and live fulfilling lives with normal life expectancy. Genetic counseling is important to explain recurrence risks. Prenatal diagnosis is available if a causative mutation is identified in a family member.
Bibliography
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Lepri, Francesca Romana, et al. "Diagnosis of Noonan Syndrome and Related Disorders Using Target Next Generation Sequencing." BMC Medical Genetics 15.1 (2014): 2–21. Print.
"Noonan Syndrome." Genetic and Rare Diseases Information Center, 8 Nov. 2021, rarediseases.info.nih.gov/diseases/10955/noonan-syndrome. Accessed 6 Sept. 2024.
"Noonan Syndrome." Genetics Home Reference. National Library of Medicine, Mar. 2011. Web. 5 Aug. 2014.
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Prendiville, Terence W., et al. "Cardiovascular Disease in Noonan Syndrome." Archives of Disease in Childhood 99.7 (2014): 629–34. Print.
Wei Qiu, et al. "Structural Insights into Noonan/LEOPARD Syndrome-Related Mutants of Protein-Tyrosine Phosphatase SHP2 (PTPN11)." BMC Structural Biology 14.1 (2014): 1–11. Print.