Noonan syndrome
Encyclopedia
Noonan Syndrome is a relatively common autosomal
dominant congenital disorder
considered to be a type of dwarfism
, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome (and is still sometimes described in this way); however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect
(typically pulmonary valve stenosis
), short stature, learning problems, pectus excavatum
, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. The syndrome
is named after Dr. Jacqueline Noonan
. It is a RASopathy
.
It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome
. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.
The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.
(Type 1) has been noted in some patients with Noonan Syndrome
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin
.
was practicing as a pediatric cardiologist at the University of Iowa
when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature
, webbed neck
, wide spaced eyes, and low-set ears
. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, chromosomes
appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.
Dr. John Opitz, a former student of Dr. Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant congenital disorder
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
considered to be a type of dwarfism
Dwarfism
Dwarfism is short stature resulting from a medical condition. It is sometimes defined as an adult height of less than 4 feet 10 inches , although this definition is problematic because short stature in itself is not a disorder....
, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome (and is still sometimes described in this way); however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect
Congenital heart defect
A congenital heart defect is a defect in the structure of the heart and great vessels which is present at birth. Many types of heart defects exist, most of which either obstruct blood flow in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern. Other...
(typically pulmonary valve stenosis
Pulmonary valve stenosis
Pulmonary valve stenosis is a heart valve disorder in which outflow of blood from the right ventricle of the heart is obstructed at the level of the pulmonic valve. This results in the reduction of flow of blood to the lungs. Valvular pulmonic stenosis accounts for 80% of right ventricular outflow...
), short stature, learning problems, pectus excavatum
Pectus excavatum
Pectus excavatum is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest...
, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. The syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
is named after Dr. Jacqueline Noonan
Jacqueline Noonan
Jacqueline Anne Noonan is a pediatric cardiologist best known for her characterization of a genetic disorder now called Noonan syndrome. She was also the original describer of hypoplastic left heart syndrome.-Biography:...
. It is a RASopathy
RASopathy
The RASopathies are developmental syndromes caused by germline mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinase that control Signal transduction, including:*Capillary malformation-AV malformation syndrome...
.
It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.
Characteristics
Often called a "hidden" condition, the person affected may have no obvious casual signs to the onlooker, but the problems may be many and complex.The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.
Heart
2/3 of patients have one of the following heart defects:- Pulmonary Valvular Stenosis —(50%)
- Septal defects: atrialAtrial septal defectAtrial septal defect is a form of congenital heart defect that enables blood flow between the left and right atria via the interatrial septum. The interatrial septum is the tissue that divides the right and left atria...
—(10%) or ventricularVentricular septal defectA ventricular septal defect is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart.The ventricular septum consists of an inferior muscular and superior membranous portion and is extensively innervated with conducting cardiomyocytes.The membranous...
—(less common) - Heart murmurHeart murmurMurmurs are extra heart sounds that are produced as a result of turbulent blood flow that is sufficient to produce audible noise. Most murmurs can only be heard with the assistance of a stethoscope ....
- CardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
Gastrointestinal system
- Failure to thriveFailure to thriveFailure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
as an infant - Decreased appetite
- Digestive problems
- Frequent or forceful vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- Swallowing difficulties
Lymphatic system
- Posterior cervical hygromaCystic hygromaA cystic hygroma is a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck. This is the most common form of lymphangioma. It contains large cyst like cavities containing watery fluid.Microscopically cystic hygroma...
(webbed neck) - LymphedemaLymphedemaLymphedema , also known as lymphatic obstruction, is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system....
(build-up of body fluid due to poor functioning of the lymphatic system)
Developmental
- Clumsiness
- Poor coordination
- Motor delay
- Mental retardationMental retardationMental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
—(1/3 of patients have mild MR) - Learning disabilities
- Speech and language delays
Musculoskeletal
- Some patients with Noonan Syndrome suffer from severe joint pain or muscle pain often with no identifiable cause
Hematologic
- Easy bruising
- Amegakaryocytic ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet count) - Blood Clotting Disorders
- Von Willebrand diseaseVon Willebrand diseasevon Willebrand disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor , a multimeric protein that is required for...
- Prolonged activated partial thromboplastin timePartial thromboplastin timeThe partial thromboplastin time or activated partial thromboplastin time is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways...
- Partial deficiency of Factor VIIIFactor VIIIFactor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
:C - Partial deficiency of Factor XIFactor XIFactor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene....
:C - Partial deficiency of Factor XIIFactor XIICoagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...
:C - Combined Coagulation deficiencies
Neurological
Arnold-Chiari MalformationArnold-Chiari malformation
Arnold–Chiari malformation, or often simply Chiari malformation, is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils through the foramen magnum , sometimes causing non-communicating hydrocephalus as a result of obstruction of cerebrospinal fluid outflow...
(Type 1) has been noted in some patients with Noonan Syndrome
Stature and posture
- Short statureShort statureShort stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
- Cervical (neck) spine fusion
- ScoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
- Prominence of breast bone (pectus carinatumPectus carinatumPectus carinatum, , also called pigeon chest, is a deformity of the chest characterized by a protrusion of the sternum and ribs. It is the opposite of pectus excavatum.-Causes:...
) - Depression of breast bone (pectus excavatumPectus excavatumPectus excavatum is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest...
) - Joint contractureContractureA muscle contracture is a permanent shortening of a muscle or joint.. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spastic cerebral palsy....
s or tightness - Joint hyperextensibility or looseness
- Growth retardation
- Winging of the scapulaScapulaIn anatomy, the scapula , omo, or shoulder blade, is the bone that connects the humerus with the clavicle ....
- HypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(low muscle tone)
Head
- Excess skin on the back of the neck
- Low hairline at the nape of the neck
- High hairline at the front of the head
- Large head
- Triangular face shape
- Broad forehead
- Short neck, webbed neck, posterior cervical
- Curly hair
Eyes
- Widely set eyes (hypertelorismHypertelorismHypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
) —(95%) - Drooping of the eyelids (ptosis (eyelid)Ptosis (eyelid)Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
) - Epicanthal foldEpicanthal foldAn epicanthic fold, epicanthal fold, or epicanthus is a skin fold of the upper eyelid, covering the inner corner of the eye....
s (extra fold of skin at the inner corner of the eye) - Proptosis (bulging eyes)
- Refractive visual errors
- Inward or outward turning of the eyes (strabismusStrabismusStrabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
) - Nystagmus - jerking movement of the eyes
Ears and hearing
- Low set ears —(over 90%)
- Backward rotated ears —(over 90%)
- Thick helix of ear (outer rim) —(over 90%)
- Incomplete folding of ears
- Chronic Otitis mediaOtitis mediaOtitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
(ear infections)
Mouth and speech
- Deeply grooved philtrum (top lip line) —(over 90%)
- Micrognathia (undersized lower jaw)
- High Arched palate
- Dental problems
- Articulation Difficulties
- Poor tongue control
Limbs/extremities
- Bluntly ended fingers
- Extra padding on fingers and toes
- EdemaEdemaEdema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
of the back of hands and tops of feet - Cubitus valgusCubitus valgusCubitus valgus is a medical deformity in which the elbows are turned in. A small degree of cubitus valgus is acceptable and occurs in the general population....
(elbow deformity: with abnormal turning-in)
Skin
- Lymphedema (swelling of the extremities)
- Keloids (scar hypertrophy)
- HyperkeratosisHyperkeratosisHyperkeratosis is thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin, and also usually accompanied by an increase also in the granular layer...
- overdevelopment of outer skin layer - Pigmented neviNevusNevus is the medical term for sharply-circumscribed and chronic lesions of the skin. These lesions are commonly named birthmarks and moles. Nevi are benign by definition...
(birthmark)
Cause
- manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivityExpressivityExpressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the...
) - a high proportion of cases represent new, sporadic mutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s or - Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
| Type | OMIM | Gene | Description |
|---|---|---|---|
| NS1 | PTPN11 PTPN11 Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ... |
In most of the families with multiple affected members, NS maps to chromosome 12 Chromosome 12 (human) Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 143 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic... q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2. The SHP2 protein is a component of several intracellular signal transduction Signal transduction Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response... pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor Epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR... receptor Receptor (biochemistry) In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism... . The latter pathway is important in the formation of the cardiac semilunar valve Heart valve A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart... s. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome. |
|
| NS2 | unknown (autosomal recessive) | ||
| NS3 | KRAS KRAS GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways... |
Additional mutations in KRAS genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. | |
| NS4 | SOS1 SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes... |
It has recently been shown that activating mutations in SOS1 SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes... also give rise to NS. Shp2 and SOS1 both have roles as positive regulators of the Ras Ras Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells... /MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome. |
|
| NS5 | RAF1 | Additional mutations in RAF1 genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. |
A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin
Neurofibromin
Neurofibromin can refer to one of two different proteins:* Neurofibromin 1* Neurofibromin 2...
.
Diagnosis
Despite identification of four causative genes, the diagnosis of Noonan syndrome is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label indicating association. The patient can be screened for mutations in the PTPN11, SOS1, or KRAS genes, however absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making such a diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates.History
Jacqueline NoonanJacqueline Noonan
Jacqueline Anne Noonan is a pediatric cardiologist best known for her characterization of a genetic disorder now called Noonan syndrome. She was also the original describer of hypoplastic left heart syndrome.-Biography:...
was practicing as a pediatric cardiologist at the University of Iowa
University of Iowa
The University of Iowa is a public state-supported research university located in Iowa City, Iowa, United States. It is the oldest public university in the state. The university is organized into eleven colleges granting undergraduate, graduate, and professional degrees...
when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
, webbed neck
Webbed neck
A webbed neck, or pterygium colli deformity, is a congenital skin fold that runs along the sides of the neck down to the shoulders.There are many variants.-Associated conditions:...
, wide spaced eyes, and low-set ears
Low-set ears
Low-set ears is a term used to describe a depressed positioning of the pinna two or more standard deviations below the population average.It can be associated with conditions such as:* Down's syndrome and Turner Syndrome* Noonan syndrome* Patau syndrome...
. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, chromosomes
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.
Dr. John Opitz, a former student of Dr. Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.
See also
- Turner syndromeTurner syndromeTurner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
— a different disorder which is often confused with Noonan syndrome because of several physical features that they have in common. - Fetal alcohol syndromeFetal alcohol syndromeFetal alcohol syndrome is a pattern of mental and physical defects that can develop in a fetus in association with high levels of alcohol consumption during pregnancy. Current research also implicates other lifestyle choices made by the prospective mother...
— another disorder that is sometimes confused with Noonan syndrome because of some common facial features and mental retardation - Leopard syndromeLeopard syndromeLEOPARD syndrome - is part of a group called Ras/MAPK pathway syndromes - is a rare autosomal dominant, multisystem disease caused by a...
— A related disorder caused by mutations in PTPN11 that are catalytically inactivating. - Cardiofaciocutaneous syndromeCardiofaciocutaneous syndromeCardiofaciocutaneous Syndrome is an extremely rare and serious genetic disorder.It is characterized by the following:*Distinctive facial appearance*Unusually sparse, brittle, curly scalp hair...
— A related disorder which also affects genes encoding elements of the Ras/MAP kinase pathway. - DermatoglyphicsDermatoglyphicsDermatoglyphics is the scientific study of fingerprints. The term was coined by Dr. Harold Cummins, the father of American fingerprint analysis, even though the process of fingerprint identification had already been in use for several hundred years. All primates have ridged skin...