Information on the following diseases can be found in the Related Disorders section of this report:

• Cardiofaciocutaneous Syndrome
• Turner Syndrome
• Costello Syndrome
• Noonan-Like Multiple Giant Cell Lesion Syndrome
• Neurofibromatosis-Noonan Syndrome
• LEOPARD syndrome

In individuals with Noonan syndrome, associated symptoms and physical findings may vary greatly in range and severity from case to case. Some affected individuals have only minor facial abnormalities; others may have the majority of symptoms and findings associated with the disorder, such as distinctive malformations 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, mild mental retardation, and/or other abnormalities.

Most infants with Noonan syndrome have characteristic craniofacial malformations. In many cases, the head appears relatively large and unusually long, narrow, and pointed at the top (turricephalic). Affected infants may have several abnormalities 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; abnormal deviation of one eye in relation to the other (strabismus); downwardly slanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes' inner corners; and/or strikingly blue or bluish green colored portions of the eyes (irides). Even in those individuals with only mild facial abnormalities ocular hypertelorism, ptosis, and/or epicanthal folds are often present.

In many cases, infants with Noonan syndrome also have additional craniofacial abnormalities. These may include an unusually deep vertical groove in the middle of the upper lip (philtrum); a prominent, protruding upper lip; a highly arched roof of the mouth (palate); and/or a small chin. Affected infants may also have a small jaw (micrognathia); improper positioning of the teeth of the upper jaw in relation to those of the lower jaw (malocclusion); low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head; and/or distinctive abnormalities of the nose including a low nasal bridge, 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 in the back of the head (low posterior hairline).

In individuals with Noonan syndrome, facial features 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 abnormally 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 unusually wooly or curly during later childhood or adolescence. Many affected individuals also have distinctive eyebrows that appear highly arched and/or "diamond shaped."

In many cases, 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 hands and feet (peripheral lymphedema) is common in newborns with Noonan syndrome; in such cases, edema affecting the fingers may result in an increased number of ridges on the fingertips (abnormal dermatoglyphics). Such edema may be due to improper development of certain lymph vessels (congenital lymphatic dyplasia).

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 ages, 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. According to reports in the medical literature, 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.

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 may fail to descend into the scrotum (unilateral or bilateral cryptorchidism) before birth or during the first year of life. As a result, male reproductive cells (spermatozoon) may fail to develop properly within the testes (deficient spermatogenesis), and some affected males may experience inadequate sexual development and associated infertility (sterility). In other cases, 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.) and subsequent fertility. 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 and fertility. In females with the disorder, the acquisition of secondary sexual characteristics (e.g., the appearance of pubic hair, breast development, menstruation) may be delayed or 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 unusually low set. There may also be webbing of the skin under the arms (axillary webbing) that persists into adulthood. In some cases, affected individuals may have additional skeletal malformations including rounded shoulders; outward deviation of the elbows (cubitus valgus); abnormally short, deviated fingers (clinobrachydactyly) with blunt fingertips; and/or front-to-back and/or sideways curvature of the spine (kyphoscoliosis).

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 may vary, depending upon 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 10 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 10 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 cases, of the left ventricular wall (hypertrophic cardiomyopathy). In some rare cases, other congenital heart defects may be present (e.g., ventricular septal defects, patent ductus arteriosus). 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. Males with Noonan syndrome appear to have a higher occurrence of severe cardiac defects than affected females.

Atrial septal defects occur in approximately 10 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 abnormal thinness, 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 10 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.

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). In addition, some affected infants may have malformations of certain lymph vessels (congenital lymphatic dysplasia). Lymph, a bodily fluid that contains certain 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).

Infants with Noonan syndrome may also have additional lymphatic malformations including abnormal masses of widened lymph vessels (lymphangiomas) in certain areas, such as the lungs, the chest wall, and/or the membrane covering the lungs and lining the chest cavity (pleura). In addition, some affected infants may have an abnormal cystic growth consisting of dilated lymph vessels beneath the skin in the neck area (cystic hygroma). 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. In some cases, 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 some 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 abormal bruising and bleeding.

In some cases, 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.

In addition, individuals with Noonan syndrome may be at risk for developing malignant hyperthermia, a condition in which exposure to certain anesthetics or muscle relaxants may cause a dangerous, sudden rise in body temperature (hyperthermia), muscle twitching and stiffness, low blood pressure (hypotension), rapid heart beat (tachycardia), irregular heartbeat (cardiac arrhythmia), and/or other symptoms and findings. Without appropriate treatment, life-threatening complications may result. (For more information on this condition, please choose "malignant hyperthermia" as your search term in the Rare Disease Database.)

Up to 35 percent of individuals with Noonan syndrome may also have mild mental retardation. However, many affected individuals have a normal I.Q. (intelligence quotient). According to the medical literature, mental retardation may be more common in affected males. 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 difficulties speaking and/or, in some cases, mild hearing loss.

There is disagreement in the medical literature concerning the potential relationship between Noonan syndrome and Cardiofaciocutaneous syndrome, a disorder that has many similar physical features. Although some researchers indicate that Noonan and Cardiofaciocutaneous syndromes are distinct disorders, others stress that they represent varying manifestations of the same disease entity. (For more information, please see the "Causes" and "Related Disorders" sections of this report below.)
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Noonan syndrome is an autosomal dominant genetic disorder caused be abnormalities (mutations) in four different genes: PTPN11, KRAS, SOS1 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 and RAF1 mutations are observed in 3-17% of those affected. Additional genes associated with Noonan syndrome may be identified in the future.

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 30-75% 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 males and females in equal numbers and is thought to affect approximately one in 1,000 to one in 2,500 newborns. 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 300 cases have been discussed in the medical literature. Such cases include affected individuals from some large multigenerational families (kindreds) as well as isolated cases in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from case to case (variable expressivity), including among affected family members. 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.
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Symptoms of the following disorders may be similar to those of Noonan syndrome. Comparisons may be useful for a differential diagnosis:

Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic disorder, is characterized by a distinctive facial appearance similar to that seen in children with Noonan syndrome. Additional primary characteristics may include unusually sparse, brittle, curly hair; skin abnormalities; heart malformations that are present at birth (congenital heart defects); growth delays; and/or varying degrees of mental retardation. Individuals with cardiofaciocutaneous syndrome typically have distinctive malformations of the craniofacial area including an unusually large head (macrocephaly), a prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); a short, upturned nose with a low nasal bridge; and/or prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated). In most cases, eye abnormalities are also present including downwardly slanting eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), and/or drooping of the upper eyelids (ptosis). In most cases, congenital heart defects are also present, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary valve stenosis) and/or an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). In addition, most individuals with the disorder experience growth delays, mild to severe mental retardation, and abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation).

Cardiofaciocutaneous syndrome has autosomal dominant inheritance. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). A gene responsible for cardiofaciocutaneous syndrome has been located on the long arm of chromosome 12 (12q24). (For more information on this disorder, choose "cardiofaciocutaneous" as your search term in the Rare Disease Database.)

Turner syndrome is a chromosomal disorder that has some similarities to Noonan syndrome. In fact, because some individuals with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.), Noonan syndrome is sometimes referred to as "Male Turner syndrome," "Female Pseudo-Turner syndrome," or "Turner Phenotype with Normal Chromosomes (Karotype)." However, there are many important differences between the two disorders. Noonan syndrome may affect both males and females, and those with the disorder typically have a normal chromosomal makeup (karyotype). However, only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome.

Females with Turner syndrome may have a short, webbed neck with a low hairline; short stature; drooping of the upper eyelids (ptosis) and/or widely spaced eyes (ocular hypertelorism); widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples; congenital heart defects; and/or kidney abnormalities. In almost all cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics fail to develop during puberty, such as the appearance of pubic hair, breast development, and menstruation (primary amenorrhea). Almost all affected females are infertile. Although intellectual abilities are usually normal, some individuals may experience difficulties with visual-spatial relationships (e.g., right-left disorientation). (For more information on Turner syndrome, please choose "Turner" as your search term in the Rare Disease Database.)

Costello syndrome, which is also known as faciocutaneoskeletal syndrome, is a rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral) and nostrils (nares); and/or mild to moderate mental retardation. Newborns with the disorder may have an abnormal accumulation of lymph fluid in tissues throughout the body (generalized lymphedema). In addition, affected infants often have severe feeding and swallowing difficulties and may fail to grow and gain weight at the expected rate (failure to thrive).

Characteristic craniofacial abnormalities associated with the disorder may include an unusually large head (macrocephaly) and wide forehead; a large, depressed nasal bridge; abnormally wide nostrils; vertical skin folds (epicanthal folds) that may cover the eyes' inner corners; low-set ears with large, thick lobes; and/or unusually thick lips. Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. In addition, some affected individuals may also have congenital heart defects. Most cases of Costello syndrome occur sporadically, with no family history of the disorder. Such cases are thought to represent new dominant gene mutations. (For more information on this disorder, choose "Costello" as your search term in the Rare Disease Database.)

Noonan-like multiple giant cell lesion syndrome is a rare disorder that may be characterized by abnormal changes (lesions) involving certain large cells (giant cells) within bone and soft tissue of the jaw; the appearance of multiple, small black or dark brown "freckle-like" spots on the skin (lentigines); obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis); and/or short stature. Additional characteristics may include widely spaced eyes (ocular hypertelorism); abnormally prominent, improperly positioned ears; webbing of the neck (pterygium colli); and/or abnormal deviation of the elbows (cubitus valgus).

Noonan-like multiple giant cell lesion syndrome is also associated with PPTN11 gene mutations.

Neurofibromatosis-Noonan syndrome is characterized by the occurrence of neurofibromatosis type I in association with manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness, and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears, and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). According to the medical literature, it is unclear whether Neurofibromatosis-Noonan syndrome is a rare variant of Noonan syndrome, is due to the chance occurrence of both disorders in the same individuals, represents a rare variant of neurofibromatosis type I, or represents a new disease entity.

LEOPARD syndrome is an extremely rare inherited disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from case to case.

LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the hear); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some individuals with LEOPARD syndrome may also exhibit mild mental retardation, speech difficulties, and/or, in some cases, additional physical abnormalities. LEOPARD syndrome is an autosomal dominant genetic disorder caused by an abnormality (change) in one of two genes: PTPN11 or RAF1.

Diagnosis
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 detection of excessive amniotic fluid surrounding the fetus within the amniotic sac (hydramnios), the presence of an abnormal cystic growth consisting of dilated lymph vessels in the neck area (cystic hygroma), 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. According to the medical literature, physicians who specialize in diagnosing and treating heart abnormalities (cardiologists) should suspect the possibility of Noonan syndrome in any individuals who experience 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), reports suggest that 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. Specialized x-ray studies such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) may help confirm the presence and/or extent of certain craniofacial and/or other skeletal malformations. During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of certain structures.

Congenital heart defects that may 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 x-ray studies, electrocardiography (EKG), echocardiography, and/or cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart and/or malformation of certain heart structures. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns (e.g., 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 any potential coagulation factor deficiencies and/or platelet dysfunction.

Molecular genetic testing for the PTPN11, KRAS, SOS1 and RAF1 genes is available to confirm the diagnosis and for prenatal diagnosis.

Treatment
The treatment of Noonan syndrome is directed toward the specific symptoms 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), 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).

Some individuals with Noonan syndrome may be at risk for malignant hyperthermia when exposed to certain anesthetics or muscle relaxants. This risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning potential surgery and use of particular anesthetics. This risk must be also taken into consideration by primary care physicians when prescribing certain medications. 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.

In addition, 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, such as atrial septal defects, may be given medication prior to any surgical procedures, including dental procedures, such as tooth extractions.

In some affected males with cryptorchidism, surgery may be performed to move undescended testes into the scrotum and attach them in a fixed position (orchiopexy). Such surgery is typically performed before the age of five years to help prevent the risk of associated infertility.

In addition, appropriate supportive measures may be used in affected individuals with lymphedema. In some cases, cystic hygromas and/or other lymphatic malformations (e.g., lymphangiomas) may be surgically removed.

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 syndorme can be treated with Norditropin (Somatropin) which has been approved by the FDA and is manufactured by Novo Nordisk Inc.

Genetic counseling will be of benefit for affected individuals and their families. In addition, 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.

Artificially produced human growth hormone (growth hormone recombinant [hGHr]) has been used to treat some individuals with Noonan syndrome who are affected by short stature. Growth hormone, a natural hormone produced by the pituitary gland, stimulates normal body development and growth. (The pituitary gland is the hormone-producing gland at the base of the brain.) Some studies have demonstrated that treatment with daily injections of recombinant human growth hormone in some children with Noonan syndrome prior to puberty may significantly increase growth rate (height velocity) and final adult height. However, other studies have suggested that, since such treatment may induce puberty earlier than otherwise expected in individuals with Noonan syndrome, such therapy may not be effective in increasing final adult height. Further studies are needed to determine the long-term safety and effectiveness of recombinant human growth hormone in the treatment of individuals with Noonan syndrome who are affected by short stature.

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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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OCCURRANCE OF MYELOPROLIFERATIVE DISORDER IN PATIENTS WITH NOONAN SYNDROME. B. Bader-Meunier et al.; J Pediatr (Jun 1997; 130(6)). Pp. 885-89. Comment in: J Pediatr (Jun 1997; 130(6)). Pp. 857-59.

GROWTH HORMONE THERAPY IN PRE-PUBERTAL CHILDREN WITH NOONAN SYNDROME: FIRST YEAR GROWTH RESPONSE AND COMPARISON WITH TURNER SYNDROME. J. DeSchepper et al.; Acta Pediatr (Sep 1997; 86(9)). Pp. 943-46.

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NOONAN SYNDROME: COAGULATION AND CLINICAL ASPECTS. A.A. Massarano et al.; Acta Pediatr (Oct 1996; 85(10)). Pp. 1181-85.

GROWTH HORMONE TREATMENT IN NOONAN SYNDROME. T. Tanaka; Acta Pediatr Jpn (Feb 1996; 38(1)). Pp. 99-101.

HYPERTROPHIC CARDIOMYOPATHY IN NOONAN SYNDROME. T. Nishikawa et al.; Acta Paediatr Jpn (Feb 1996; 38(1)). Pp. 91-98.

DILATED CARDIOMYOPATHY IN NOONAN'S SYNDROME. C.M. Yu et al.; Int J Cardiol (Sep 1996; 56(1)). Pp. 83-85.

ARE CARDIO-FACIO-CUTANEOUS SYNDROME AND NOONAN SYNDROME DISTINCT? A CASES OF CFC OFFSPRING OF A MOTHER WITH NOONAN SYNDROME. L.G. Leichtman; Clin Dysmorphol (Jan 1996; 5(1)). Pp. 61-64.

CARDIOVASCULAR ABNORMALITIES IN NOONAN SYNDROME: THE CLINICAL FINDINGS AND TREATMENTS. A. Ishizawa et al.; Acta Paediatr Jpn (Feb 1996; 38(1)). Pp. 84-90.

NOONAN SYNDROME AND ITS RELATED DISORDERS. Y. Fukushima; Acta Paediatr Jpn (Feb 1996; 38(1)). Pp. 102-04.

GROWTH HORMONE TREATMENT IN NOONAN SYNDROME: THE NATIONAL COOPERATIVE GROWTH STUDY EXPERIENCE. A.A. Romano et al.; J Pediatr (May 1996; 128(5 Pt 2)). Pp. S18-21.

CLASSICAL NOONAN SYNDROME IS NOT ASSOCIATED WITH DELETIONS OF 22Q11. N.H. Robin et al.; Am J Med Genet (Mar 13 1995; 56(1)). Pp. 94-96.

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BEHAVIOURAL ASPECTS AND PSYCHIATRIC FINDINGS IN NOONAN'S SYNDROME. A. Wood et al.; Arch Dis Child (Feb 1995; 72(2)). Pp. 153-55.

MAPPING A GENE FOR NOONAN SYNDROME TO THE LONG ARM OF CHROMOSOME 12. C.R. Jamieson et al.; Nat Genet (Dec 1994; 8(4)). Pp. 357-60.

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NOONAN SYNDROME: GROWTH AND CLINICAL MANIFESTATIONS IN 144 CASES. M.B. Ranke et al.; Eur J Pediatr (1988; 148). Pp. 220-27.

NOONAN SYNDROME. J.E. Allanson; J Med Genet (1987; 24). Pp. 9-13.

A NOONAN-LIKE SHORT STATURE SYNDROME WITH SPARSE HAIR. M. Baraitser et al.; J Med Genet (1986; 23). Pp. 161-64.

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INTERNET:
Allanson JE (Updated 9/6/07). Noonan Syndrome. In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washinton, Seattle. 1997-2007. Available at http://www.genetests.org. Accessed 9/07.