NORD gratefully acknowledges Amy E. Roberts, MD, Assistant Professor of Medicine, Harvard Medical School and Cardiovascular Genetics, Division of Genetics and Department of Cardiology, Boston Children's Hospital and Judith Allanson, MD, Chief of Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa and Professor of Pediatrics, University of Ottawa, for assistance in the preparation of this report.
Noonan syndrome is a genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes' inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis) and thickening of the ventricular heart muscle (hypertrophic cardiomyopathy). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings.
Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in more than eight genes. The five most commonly involved genes are: PTPN11 (50%), SOS1 (10-13%), RAF1(5%), RIT1 (5%), and KRAS (less than 5%). Fewer individuals have a mutation in NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, SOS2, and LZTR1. Noonan-like disorders are found in association with mutations in SHOC2 and CBL.
Individuals with Noonan syndrome have associated symptoms and physical findings that vary greatly in range and severity from person to person. Some affected individuals have only minor facial abnormalities; others may have the majority of symptoms and findings associated with the disorder, such as distinctive features of the head and facial (craniofacial) area, a broad or webbed neck, short stature, skeletal malformations, congenital heart defects, malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, attention issues, mild intellectual disability, and/or other abnormalities.
Most infants with Noonan syndrome have characteristic craniofacial features. In many cases, the head appears relatively large. Affected infants may have several findings affecting the eyes including widely set eyes (ocular hypertelorism) that are unusually prominent; drooping of the upper eyelids (ptosis) and/or unusually thick, “hooded” eyelids; an eye that turns in or turns out (strabismus); downwardly slanting eyelids (palpebral fissures); skin folds (epicanthal folds) that may cover the eyes’ inner corners; and/or strikingly blue or bluish green colored portions of the eyes (irides).
Many infants with Noonan syndrome also have additional craniofacial features. These may include an unusually deep vertical groove in the middle of the upper lip (philtrum); and/or a small chin. Affected infants may also have a small jaw (micrognathia); crowding of the lower teeth, low-set, posteriorly rotated external ears (pinnae); and/or distinctive abnormalities of the nose including a depressed nasal root, a wide base, and a rounded (bulbous) tip. Affected infants also often have excessive skin in the neck area (nuchal skin) and a low hairline at the back of the neck (low posterior hairline).
The facial features of individuals with Noonan syndrome tend to change in a predictable manner with age. During later childhood, the face may appear relatively coarse and begin to appear more triangular in shape; in addition, the neck lengthens, causing the webbing of the neck (pterygium colli) to appear more pronounced and/or the large, triangular muscles of the upper back and shoulders (trapezius) to appear more prominent. During adolescence, the nasal bridge is thinner and higher, with a “pinched” root and wide base, and the eyes appear less prominent. During older adulthood, characteristic features may include an abnormally high hairline on the forehead; wrinkled, unusually transparent skin; and unusually prominent folds between the nose and the lips (nasolabial folds). In addition, individuals with Noonan syndrome may have wispy scalp hair during infancy that typically becomes more wooly or curly during later childhood or adolescence. Many affected individuals also have distinctive eyebrows that appear highly arched and/or “diamond shaped.”
Many newborns with Noonan syndrome attain normal birth weight. However, in some newborns, the birth weight may be increased due to abnormal accumulations of fluid between layers of tissue under the skin (subcutaneous edema). For example, swelling of the back of the hands and top of the feet (peripheral lymphedema) is common in newborns with Noonan syndrome; in such cases, edema affecting the fingers may result in an increased number of whorls on the fingertips (abnormal dermatoglyphics). Such edema may be due to improper or late development of certain lymph vessels (congenital lymphatic dysplasia).
Some infants with Noonan syndrome may experience feeding problems and fail to grow and gain weight at the expected rate (failure to thrive). In addition, children with the disorder tend to be short for their age, and approximately 20 percent experience delayed bone maturation. Most affected children have a relatively normal growth rate (velocity) before puberty; however, the growth spurt that is typically experienced during puberty may be reduced or absent in some adolescents. Average adult height is approximately five feet, four inches (162.5 cm) in males with Noonan syndrome and approximately five feet (152.7 cm) in females with the disorder. Individuals with the disorder typically reach their adult height by the end of the second decade of life. Growth patterns are influenced by the molecular genetic cause of NS. People with NS harboring mutations in RAF1 and SHOC2 are shorter than other genotypes, whereas those with SOS1 and BRAF mutations have more preserved growth.
Some males and females with Noonan syndrome may also experience abnormalities in the development of secondary sexual characteristics. In approximately 60 to 75 percent of males with Noonan syndrome, one or both testes fail to descend into the scrotum (unilateral or bilateral cryptorchidism) before birth or during the first year of life. If not corrected surgically, male reproductive cells (spermatozoa) may fail to develop properly within the testes (deficient spermatogenesis), and some affected males may experience infertility (sterility). Other males with Noonan syndrome may experience a delayed yet normal acquisition of secondary sexual characteristics (e.g., increased growth of the testes, scrotum, and penis; appearance of facial and pubic hair; etc.). According to the medical literature, puberty may be delayed an average of two years in such cases. Other males with Noonan syndrome may experience normal pubertal development. Even in the absence of a history of cryptorchidism, adult males appear to have decreased fertility. In females with the disorder, the acquisition of secondary sexual characteristics (e.g., the appearance of pubic hair, breast development, and menstruation) may be mildly delayed but is more often normal. Most females with Noonan syndrome have normal fertility.
In many cases, individuals with Noonan syndrome also have skeletal abnormalities. Approximately 70 percent of affected children have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In addition, the chest may be unusually broad, and the nipples may appear low set. Some affected individuals may have additional skeletal malformations including rounded shoulders; outward deviation of the elbows (cubitus valgus); abnormally short fingers (brachydactyly) with blunt fingertips; and/or front-to-back and/or sideways curvature of the spine (kyphoscoliosis and/or scoliosis respectively). Children with NS have a significantly lower total body bone mineral density when evaluated by DEXA scan putting them at risk for fractures. There is also an increased incidence of serious cervical spine disorders, including cervical stenosis, Arnold-Chiari malformation, and syringomyelia.
Approximately two thirds of infants with Noonan syndrome also have heart (cardiac) abnormalities at birth (congenital heart defects). In about half of such cases, affected infants have obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis). In those with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation. The symptoms resulting from pulmonary stenosis will vary, depending on the severity of the stenosis and any other associated findings. In some severe cases, an affected infant’s heart may begin to enlarge immediately after birth (i.e., upon initiation of breathing in the newborn). In such cases, the heart may be unable to pump blood effectively (heart failure) to the lungs and throughout the body. Associated symptoms and findings may include bluish discoloration of the skin and mucous membranes (cyanosis) due to abnormally low levels of circulating oxygen (hypoxia), breathlessness, swelling of the abdomen, feeding difficulties, and/or other abnormalities. Potentially life-threatening complications may result without appropriate treatment. In less severe cases of pulmonary stenosis, symptoms may not become apparent until later childhood. Such symptoms may include breathlessness, easy fatigability, and/or other abnormalities. In other cases, pulmonary stenosis may be mild and symptoms may not occur (asymptomatic).
In approximately 30 percent of infants with Noonan syndrome, there may be an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Another 20 percent of those with congenital heart defects may have enlargement (hypertrophy) of the partition that separates the left and right ventricles (interventricular septum) and, in some patients, of the left ventricular wall (hypertrophic cardiomyopathy). Less often, other congenital heart defects may be present (e.g., ventricular septal defects, patent ductus arteriosus, atrioventricular canal defect). According to the medical literature, most individuals with Noonan syndrome have a single heart defect. However, some affected individuals may have pulmonary stenosis in combination with either an atrial septal defect or hypertrophic cardiomyopathy, for example.
Atrial septal defects occur in approximately 30 percent of those with Noonan syndrome who have congenital heart defects. In the normal heart, a small opening is present between the two atria (foramen ovale) at birth. Shortly after birth, the atrial septum gradually closes and covers this opening. In infants with atrial septal defects, however, the atrial septum may not close properly or may be malformed during fetal development. As a result, the opening between the atria persists long after it should be closed, causing an increase in the workload on the right side of the heart and associated enlargement of the right ventricle, the right atrium, and the main pulmonary artery. The size, location, and nature of an atrial septal defect and any associated abnormalities determine the severity of symptoms.
Many children with atrial septal defects have no symptoms. However, in some cases, associated symptoms may include poor weight gain, mild growth delays, and an increased susceptibility to repeated respiratory infections (e.g., pneumonia) and bacterial infections of the lining of the heart (endocarditis) and the heart valves. In rare cases, severely affected children may also experience breathlessness, easy fatigability with exercise, heart failure, and/or irregular heartbeats (arrhythmias).
Approximately 20 percent of affected infants with heart defects experience hypertrophic cardiomyopathy. In most cases, such abnormal enlargement (hypertrophy) affects a localized area of the fibrous partition separating the left and right ventricles (anterior interventricular septal hypertrophy); in other cases, the entire septum and the wall of the left ventricle may be affected. Hypertrophic cardiomyopathy may cause reduced cardiac output. Associated symptoms and findings may include fatigue, brief fainting episodes (syncope) during exertion or exercise, and heart failure. Without appropriate treatment, life-threatening complications may result in some cases. Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Rarely, hypertrophic cardiomyopathy can also develop later in life.
Some infants with Noonan syndrome may also have malformations of certain blood vessels, such as the presence of abnormal passages (fistulas) involving the arteries that supply blood to heart muscle (coronary arteries). The coronary arteries may also be dilated (ectatic) and/or curved (tortuous) in contour. In addition, some affected infants may have malformations of certain lymph vessels (congenital lymphatic dysplasia). Lymph, a bodily fluid that contains white blood cells (lymphocytes), fats, and proteins, accumulates outside blood vessels in spaces between cells in tissues and flows back into the bloodstream via lymph vessels. In some infants with Noonan syndrome, lymphatic system malformations may include underdevelopment (hypoplasia) of certain channels within lymph tissue through which lymph enters lymph vessels; abnormal widening (dilatation) of lymph vessels within the lungs (pulmonary lymphangiectasis); and/or widening (dilatation) of intestinal lymph vessels (intestinal lymphangiectasis), particularly the vessels that transport chyle, the milky fluid that is absorbed from food during digestion. Intestinal lymphangiectasis may result in loss of protein during intestinal absorption (protein-losing enteropathy), abnormally low levels of certain circulating white blood cells (lymphopenia), and loose, foul smelling stools that contain an excessive amount of fat (steatorrhea). During the teenage years, some individuals with Noonan syndrome develop swelling of the lower extremities (lymphedema).
In utero, some affected infants may have an abnormal cystic swelling beneath the skin in the neck area (cystic hygroma). There may, in addition, may more amniotic fluid around the baby than usual (polyhydramnios). Due to lymphatic system malformations and associated obstruction of normal lymph flow into the bloodstream, affected infants may have an abnormal accumulation of lymph fluid in certain tissues (lymphedema). In some cases, edema may affect tissues and cavities throughout the body (hydrops fetalis).
Approximately 20 to 33 percent of individuals with Noonan syndrome also have various blood clotting defects (coagulation factor deficiencies), low levels of circulating platelets in the blood (thrombocytopenia), and/or improper function of blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Affected individuals may have low levels of certain substances in the blood (coagulation factors) that are essential in the normal blood clotting process, a complex process that is necessary to stop bleeding (hemostatis). In individuals with Noonan syndrome, such deficiencies may include low levels of coagulation factor XI and/or, in some cases, factors XII and/or VIII. Some affected individuals may have von Willebrand disease; an inherited condition characterized by deficiency of coagulation factor VIII, prolonged bleeding time, and impaired adhesion of platelets. In addition, in rare cases, affected individuals’ urine may have an abnormally “fishy” smell (trimethylaminuria), a finding that may be associated with platelet dysfunction. Due to coagulation factor deficiencies, platelet dysfunction, and/or thrombocytopenia, affected individuals may have a history of abnormal and easy bruising and bleeding. They should avoid aspirin-containing medications.
Some individuals with Noonan syndrome may also abnormal skin discolorations. In approximately one quarter of affected individuals, pigmented moles (nevi) may be present. In rare cases, there may be pale tan or light brown patches (café-au-lait spots) and/or black, darkish tan or brown “freckle-like” spots (lentigines) on the skin.
Up to 35 percent of individuals with Noonan syndrome may also have mild intellectual disability. However, many affected individuals have a normal I.Q. (intelligence quotient). In addition, affected individuals may experience abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation), learning disabilities, and language delays that may potentially be due to hypotonia, difficulties speaking and/or, in some individuals, mild hearing loss. Inattention and challenges with executive functioning have also been reported. A lowered speed of information processing and relatively intact functioning in other cognitive domains characterizes the cognitive profile of many adults with NS.
Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in several different genes, the main ones being: PTPN11, KRAS, SOS1 RIT1 and RAF1. PTPN11 mutations have been found in approximately 50% of affected individuals; KRAS mutations have been found in fewer than 5% of those affected; SOS1 mutations have been seen in approximately 13% of people with Noonan syndrome; RIT1 mutations have been seen in approximately 5% of people with Noonan syndrome, and RAF1 mutations are observed in 5% of those affected. Additional genes associated with Noonan syndrome have been identified in fewer cases: NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, SOS2, and LZTR1. Two conditions with overlap are newly described in association with mutations in SHOC2 and CBL.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Approximately 50% of affected individuals have an affected parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Noonan syndrome appears to affect more males than females and is thought to affect approximately one in 1,000 to one in 2,500 people. However, other reports indicate that the disorder may affect more than one in 1,000 newborns in the general population. Since Noonan syndrome was originally reported in 1883 (O. Kobylinski) and more thoroughly described in 1963 (J.A. Noonan and D.A. Ehmke), more than 500 patients shave been discussed in the medical literature. Because Noonan syndrome is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
In some cases, Noonan syndrome may be suspected before birth (prenatally) based upon results of fetal ultrasonography, a specializing imaging technique in which sound waves are used to create an image of the developing fetus. A diagnosis of Noonan syndrome may be considered due to abnormal maternal serum triple screen, detection of excessive amniotic fluid surrounding the fetus within the amniotic sac (polyhydramnios), the presence of an abnormal cystic swelling consisting of dilated lymph vessels in the neck area (cystic hygroma), a structural heart difference, other fetal anomalies, and confirmation of a normal chromosomal makeup (karyotype). However, in many cases, Noonan syndrome is diagnosed at birth or early infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests.
It is important to note that, in some cases, individuals who have only minor, subtle characteristics associated with Noonan syndrome may not receive a diagnosis. Physicians who specialize in diagnosing and treating heart abnormalities (cardiologists) should suspect the possibility of Noonan syndrome in any individuals who have congenital pulmonary valve stenosis. Because Noonan syndrome may be difficult to confirm in such cases (particularly if there is no family history of the disorder), Noonan syndrome should be strongly considered as a possible diagnosis in any individuals with pulmonary valve stenosis and certain eye abnormalities typically found even in the more mild cases (e.g., ptosis, epicanthal folds, ocular hypertelorism). In addition, in such cases, all immediate (first-degree) relatives should be examined for mild facial abnormalities and cardiac defects potentially occurring in association with Noonan syndrome.
In many individuals with the disorder, certain advanced imaging techniques and laboratory tests may be used to detect, confirm, and/or characterize specific abnormalities that may be associated with Noonan syndrome.
Congenital heart defects that occur in association with Noonan syndrome may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. Clinical examination may include a physician’s evaluation of heart and lung sounds through use of a stethoscope. In mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.
Specialized cardiac tests may include electrocardiography (EKG), echocardiography, and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns (e.g., left axis deviation, left anterior hemiblock, deep S wave). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart.
This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. In addition, physicians may also closely evaluate respiratory (ventilatory) capabilities since associated heart defects may result in inadequate blood supply to the lungs and breathlessness.
Specialized blood tests may be performed to detect potential coagulation factor deficiencies and/or platelet dysfunction.
Molecular genetic testing for mutations in the associated genes is available to confirm the diagnosis and for prenatal diagnosis.
The treatment of Noonan syndrome is directed toward the specific complications that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), physicians who diagnose and treat disorders of the blood and blood-forming tissues (hematologists), physicians who diagnose and treat disorders of growth (endocrinologists) and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
In some individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, any surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms. Cardiac, arteriovenous, and/or lymphatic malformations that may be present must be taken into consideration during decisions concerning surgical procedures. For example, during certain types of surgery performed on lymphangiomas, there is an increased risk that chyle may escape from the largest lymph channel in the body (thoracic duct) into the cavity between the neck and the diaphragm (thoracic cavity), potentially causing life-threatening complications (chylothorax).
For those who also have thrombocytopenia, platelet dysfunction, and/or coagulation factor deficiencies, physicians, dentists, and/or other health care workers may recommend certain preventive measures before or take certain supportive measures during surgery to prevent, lower the risk of, or control abnormal bleeding.
Respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, affected individuals with certain heart defects may be given medication prior to any surgical procedures, including dental procedures, such as tooth extractions.
In affected males with cryptorchidism, surgery should be performed to move undescended testes into the scrotum and attach them in a fixed position (orchiopexy). Such surgery is typically performed between 12 and 24 months of age to help prevent the risk of associated infertility.
In addition, appropriate supportive measures may be used in affected individuals with lymphedema.
Early intervention may be important in helping children with Noonan syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, speech therapy, physical therapy, and other medical, social, and/or vocational services. The short stature in patients with Noonan syndrome can be treated with growth hormone which has been shown to improve final adult height.
Genetic counseling is recommended for affected individuals and their families. As mentioned earlier, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be associated with Noonan syndrome. Other treatment for the disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about Noonan syndrome:
Amy E. Roberts, MD
Assistant Professor of Medicine
Harvard Medical School
Division of Genetics, Department of Medicine and Department of Cardiology
Boston Children’s Hospital
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Osio D, Dahlgren J, Wikland KA, et al. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr. 2005;94:1232-7.
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