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Noonan syndrome | |
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Other names | Male Turner syndrome, Noonan–Ehmke syndrome, Turner-like syndrome, Ullrich–Noonan syndrome [1] |
A 12-year-old girl with Noonan syndrome, displaying typical webbed neck and double structural curve with rib deformity. | |
Specialty | Medical genetics, pediatrics |
Symptoms | Mildly unusual facial features, short height, congenital heart disease, bleeding problems, skeletal malformations [1] |
Complications | Leukemia [1] |
Usual onset | Present at birth [2] |
Types | Type 1 to 6 [3] |
Causes | Genetic mutation (autosomal dominant) [1] |
Diagnostic method | Suspected based on symptoms, confirmed with genetic testing [4] [2] |
Differential diagnosis | Cardiofaciocutaneous syndrome, Turner syndrome, Costello syndrome, neurofibromatosis type 1 [2] [3] |
Treatment | Based on the symptoms [3] |
Medication | Growth hormone [3] |
Prognosis | Depends on the severity of heart problems [3] |
Frequency | 1 in 1000 (1 in 2,000 severe disease) [4] |
Named after | Jacqueline Noonan |
Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. [1] Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. [1] Heart problems may include pulmonary valve stenosis. [1] The breast bone may either protrude or be sunken, while the spine may be abnormally curved. [1] Intelligence is often normal. [1] Complications of NS can include leukemia. [1]
A number of genetic mutations can result in Noonan syndrome. [1] The condition may be inherited as an autosomal dominant condition or occur as a new mutation. [3] [1] Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. [1] The diagnosis may be suspected based on symptoms, medical imaging, and blood tests. [2] [4] Confirmation may be achieved with genetic testing. [2]
No cure for NS is known. [5] Treatment is based on the symptoms and underlying problems, and extra support in school may be required. [3] Growth hormone therapy during childhood can increase an affected person's final height. [3] Long-term outcomes typically depend on the severity of heart problems. [3]
An estimated 1 in 1,000 people are mildly affected by NS, while about 1 in 2,000 have a more severe form of the condition. [4] Males appear to be affected more often than females. [2] The condition was named after American pediatric cardiologist Jacqueline Noonan, who described her first case in 1963. [2]
The most common signs leading to the diagnosis of Noonan syndrome are unique facial characteristics and musculoskeletal features. The facial characteristics are most prominent in infancy, becoming less apparent with age in many people with Noonan syndrome. [7]
Some of the characteristic features of Noonan syndrome include a large head with excess skin on the back of the neck, low hairline at the nape of the neck, high hairline at the front of the head, triangular face shape, broad forehead, and a short, webbed neck.
In the eyes, hypertelorism (widely set eyes) is a defining characteristic, present in 95% of people with Noonan syndrome. This may be accompanied by epicanthal folds (extra fold of skin at the inner corner of the eye), ptosis (drooping of the eyelids), proptosis (bulging eyes), strabismus (inward or outward turning of the eyes), nystagmus (jerking movement of the eyes) and refractive visual errors.
The nose may be small, wide, and upturned.
The development of the ears and auditory system may be affected in people with Noonan's syndrome. This can result in low-set ears (in over 90%), backward-rotated ears (over 90%), thick helix (outer rim) of ear (over 90%), incomplete folding of ears, chronic otitis media (ear infections), and hearing loss.
Development of the mouth may also be affected in Noonan syndrome. This can result in deeply grooved philtrum (top lip line) (over 90%), micrognathia (undersized lower jaw), high arched palate, articulation difficulties (teeth don't line up) which can lead to dental problems. Similar to the muscular manifestations above, in the mouth, poor tongue control may be observed.
Skin signs and symptoms in Noonan syndrome include lymphedema (lymph swelling of the extremities), keloid formation, excessive scar formation, hyperkeratosis (overdevelopment of outer skin layer), pigmented nevi (darkly pigmented skin spots), and connective tissue disease.
Abnormalities in the limbs and extremities may occur in Noonan syndrome. This may manifest as bluntly ended fingers, extra padding on fingers and toes, edema of the back of hands and tops of feet, and cubitus valgus (wide carrying angle of the elbows).
For short stature, growth hormone is sometimes combined with IGF-1 (or as an alternative, IGF-1 as a stand-alone) can be used to achieve an increased height/final height quicker. The final adult height of individuals with Noonan syndrome is about 161–167 cm in males and 150–155 cm in females, which approaches the lower limit of normal. [8]
Spinal abnormalities may be present up to 30% of the time and this may require surgery to correct in over 60% of these cases. Other musculoskeletal manifestations in Noonan syndrome are associated with undifferentiated connective-tissue disorders which can be associated with joint contractures (tightness) or joint hypermobility (looseness). Additional factors may present in the form of winging of the scapula, scoliosis, breast bone prominence (pectus carinatum), breast bone depression (pectus excavatum). Muscle abnormalities may present as hypotonia (low muscle tone), which may lead to lordosis (increased hollow in the back) due to poor abdominal muscle tone.
Noonan syndrome is the second most common syndromic cause of congenital heart disease. 50-70% of individuals with NS are born with some form of congenital heart defect, with pulmonary valvular stenosis being the most common (50–60%). [9] Other heart defects include hypertrophic cardiomyopathy (12–35%), ventricular septal defects (5–20%), and atrial septal defects (10–25%). [10] [11] [12]
Restrictive lung function has been reported in some people.
A number of diverse gastrointestinal (GI) symptoms have been associated with Noonan syndrome. These include swallowing difficulties, low gut motility, gastroparesis (delayed gastric emptying), intestinal malrotation, and frequent or forceful vomiting. These digestive issues may lead to decreased appetite, failure to thrive from infancy to puberty (75%), and occasionally the need for a feeding tube.
In some males with Noonan syndrome, testicles do not descend (cryptorchidism).
Lymphatic anomalies including Posterior cervical hygroma (webbed neck) and Lymphedema may present in people with Noonan syndrome.
A number of bleeding disorders have been associated with Noonan syndrome, these include platelet dysfunction, Blood clotting disorders, partial deficiency of factor VIII:C, partial deficiency of factor XI:C, partial deficiency of factor XII:C, and an imbalance of plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (t-PA) activity. It has been associated with Von Willebrand disease, Amegakaryocytic thrombocytopenia (low platelet count), prolonged activated partial thromboplastin time, combined coagulation defects. When present, these Noonan-syndrome accompanying disorders can be associated with a predisposition to bruise easily, or hemorrhage.
Individuals with NS exhibit a broad range of cognitive abilities, typically ranging from mild intellectual disability to completely normal intelligence. Most patients have normal IQ levels (70-120), while around 20% may have cognitive impairment (IQ<70). [13] [14] [15] Occasionally, Chiari malformation (type 1), may occur, which can lead to hydrocephalus. [16] Seizures have also been reported. [17]
Individuals may experience bleeding disorders of various types, often associated with thrombocytopenia, low levels of clotting factors, impaired platelet function, and more. [18] [19]
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. [20]
Individuals with NS have up to a 50% chance of transmitting it to their offspring. However, while 30-75% of cases show a noticeable inheritance from one of the parents, the rest are caused by de-novo genetic mutations occurring for the first time in the affected individual. In such cases, the risk of recurrence is less than 1%, but it still represents a higher risk than in the general population. [21] [22]
The fact that an affected parent is not always identified for children with NS suggests several possibilities:
Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10-13% of cases, and RAF1 or RIT1 - each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15-20% of NS cases remain genetically undiagnosed. [23] [24] [25]
Type | Online Mendelian Inheritance in Man database | Gene | Year found | Locus | % of cases | Description | Refs. |
---|---|---|---|---|---|---|---|
NS1 | 163950 | PTPN11 | 2001 | 12q24.1 | 50% | The PTPN11 gene encodes the protein tyrosine phosphatase SHP-2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the semilunar heart valves. Duplication of the chromosome region containing PTPN11 can also result in NS. | [26] [27] |
NS2 | 605275 | Unknown; autosomal recessive | [28] | ||||
NS3 | 609942 | KRAS | 2006 | 12p12.1 | <5% | [29] | |
NS4 | 610733 | SOS1 | 2006 | 2p22 | 10% | Activating mutations in SOS1 can give rise to NS. SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation mediates NS development. [30] | [31] |
NS5 | 611553 | RAF1 | 2007 | 3p25 | 3–17% | [32] |
Heterozygous mutations in NRAS , HRAS , BRAF , SHOC2 , MAP2K1 , MAP2K2 , and CBL have also been associated with a smaller percentage of NS and related phenotypes. [33]
A condition known as "neurofibromatosis–Noonan syndrome" is associated with neurofibromin. [34]
Diagnosing of NS is based on the clinical symptoms presented by the individual, accompanied by attempts to confirm the diagnosis through molecular genetic tests to identify the specific genetic change leading to the condition. However, despite identification of 14 causative genes, the absence of a known mutation will not exclude the diagnosis, as more, as-yet-undiscovered genes can cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a person has enough of the features to warrant the label. The principal values of making a genetic 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. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, an increase in hypertrophic cardiomyopathy is seen in people with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia exists for a mutation of PTPN11. In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a person has.
Prenatal features that might lead physicians to consider a diagnosis of Noonan syndrome include cystic hygroma, increased nuchal translucency, pleural effusion, and edema. [35]
While Turner syndrome has similarities with renal anomalies and developmental delay, Turner syndrome is only found in females and often expresses differently. In Turner syndrome, there is a lower incidence of developmental delays, left-sided heart defects are constant and the occurrence of renal abnormalities is much lower. [36]
Other RASopathies
There is no single treatment tailored to alleviate all possible symptoms of NS. Instead, the treatment varies depending on complications but tend to be quite standard, reflecting the treatment of the general population. [36] Management guidelines, divided by systems, including general, developmental, dental, growth and feeding, cardiovascular, audiological, haematological, renal and skeletal, that account for actions to be taken at diagnosis, after diagnosis and if symptomatic, have been published by an American consortium. [35]
Specifically, treatment of cardiovascular complications resemble that of the general population and treatment of bleeding diathesis is guided by the specific factor deficiency or platelet aggregation. [36]
Although a few people with Noonan syndrome have been reported to develop malignant hyperthermia, the gene mutation of diseases known to be associated with malignant hyperthermia is different from that of Noonan syndrome. [44]
The lifespan of people with Noonan's syndrome can be similar to the general population, however, Noonan syndrome can be associated with several health conditions that can contribute to mortality. The greatest contributor to mortality in individuals with Noonan syndrome is complications of cardiovascular disease. [45] [8] Prognosis is therefore largely dependent on the presence or absence of cardiac disease, as well as the type and severity of the disease (if disease is present). [8] Most notably, Noonan syndrome with hypertrophic cardiomyopathy is associated with increased mortality. [45] [8]
Jacqueline Noonan began practicing as a pediatric cardiologist in 1959 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. These characteristics were sometimes seen running in families but were not associated with gross chromosomal abnormalities. In 1961 she joined University of Kentucky’s College of Medicine, where she continued studying the congenital heart disease and other congenital abnormalities. After examining 833 children with the syndrome, in 1963 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". [46] This described nine children who in addition to congenital heart disease had characteristic facial features, chest deformities and short stature.
Dr. John Opitz, a former student of Noonan's, first began to call the condition "Noonan syndrome" when he saw children who looked like those whom Dr. Noonan had described. Noonan produced a paper titled "Hypertelorism with Turner Phenotype" in 1968 where she studied 19 patients who displayed symptoms indicative of Noonan's Syndrome. [47] In 1971, at the Symposium of Cardiovascular defects, the name "Noonan syndrome" became officially recognized.
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.
Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes, a white forelock or patches of light skin. These basic features constitute type 2 of the condition; in type 1, there is also a wider gap between the inner corners of the eyes called telecanthus, or dystopia canthorum. In type 3, which is rare, the arms and hands are also malformed, with permanent finger contractures or fused fingers, while in type 4, the person also has Hirschsprung's disease. There also exist at least two types that can result in central nervous system (CNS) symptoms such as developmental delay and muscle tone abnormalities.
Kabuki syndrome is a rare congenital disorder of genetic origin. It affects multiple parts of the body, with varying symptoms and severity, although the most common is the characteristic facial appearance.
A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular disease. Signs and symptoms depend on the specific type of defect. Symptoms can vary from none to life-threatening. When present, symptoms are variable and may include rapid breathing, bluish skin (cyanosis), poor weight gain, and feeling tired. CHD does not cause chest pain. Most congenital heart defects are not associated with other diseases. A complication of CHD is heart failure.
Wolf–Hirschhorn syndrome (WHS) is a chromosomal deletion syndrome resulting from a partial deletion on the short arm of chromosome 4 [del(4)(p16.3)]. Features include a distinct craniofacial phenotype and intellectual disability.
Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969. Children with Alagille syndrome live to the age of 18 in about 90% of the cases.
Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate (CL/P), and cleft palate only (CPO). The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve CL/P. VWS is distinct from other clefting syndromes due to the combination of cleft lip and palate (CLP) and CPO within the same family. Other features frequently associated with VWS include hypodontia in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities, syndactyly of the hands, polythelia, ankyloglossia, and adhesions between the upper and lower gum pads.
CHARGE syndrome is a rare syndrome caused by a genetic disorder. First described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of coloboma of the eye, heart defects, atresia of the nasal choanae, restricted growth or development, genital or urinary abnormalities, and ear abnormalities and deafness. These features are no longer used in making a diagnosis of CHARGE syndrome, but the name remains. About two thirds of cases are due to a CHD7 mutation. CHARGE syndrome occurs only in 0.1–1.2 per 10,000 live births; as of 2009, it was the leading cause of congenital deafblindness in the US.
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Barakat syndrome is a rare disease characterized by hypoparathyroidism, sensorineural deafness and renal disease, and hence also known as HDR syndrome. It is an autosomal dominant condition with incomplete penetrance and variable expressivity that was first described by Amin J. Barakat et al. in 1977.
Simpson–Golabi–Behmel syndrome (SGBS) is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with SGBS which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.
Mowat–Wilson syndrome is a rare genetic disorder that was clinically delineated by David R. Mowat and Meredith J. Wilson in 1998. The condition affects both males and females, has been described in various countries and ethnic groups around the world, and occurs in approximately 1 in 50,000–100,000 births.
Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, is a rare autosomal dominant, multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known; however, research is ongoing. It is a RASopathy.
3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.
The RASopathies are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Common features include intellectual disability, congenital heart defects, skin abnormalities, and craniofacial abnormalities.
Floating–Harbor syndrome, also known as Pelletier–Leisti syndrome, is a rare disease with fewer than 50 cases described in the literature. It is usually diagnosed in early childhood and is characterized by the triad of proportionate short stature with delayed bone age, characteristic facial appearance, and delayed speech development. Although its cause is unknown, it is thought to result from genetic mutation, and diagnosis is established by the presence of a heterozygous SRCAP mutation in those with clinical findings of FHS.
L1 syndrome is a group of mild to severe X-linked recessive disorders that share a common genetic basis. The spectrum of L1 syndrome disorders includes X-linked complicated corpus callosum dysgenesis, spastic paraplegia 1, MASA syndrome, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). It is also called L1CAM syndrome and CRASH syndrome, an acronym for its primary clinical features: corpus callosum hypoplasia, retardation, adducted thumbs, spasticity, and hydrocephalus.
XK aprosencephaly is an extremely rare congenital disorder characterized by the absence of the embryonic forebrain. Because the prosencephalon gives way to the cerebral cortex, survival with aprosencephaly is not possible outside utero. The external symptoms are similar to holoprosencephaly, a related disorder, including a smaller than normal head (microcephaly), small eyeballs (microphthalmia), a small mouth (microstomia), anal atresia, and abnormalities of the external genitalia, radius, nostrils, and pharynx (throat).
Waardenburg syndrome type 1 is a congenital disorder that caused by a mutation in the PAX3 gene that results in abnormal development in the neural crest during early development. Type 1 results in early graying and white forelock and a notable distance between the eyes, noted as dystopia canthorum. Common symptoms of the disease also includes non-progressive hearing loss in majority of patients with type 1. Patients can display complete or partial heterochromia and hypoplastic blue irides and congenital leukemia.
Meacham syndrome is a rare genetic disorder which is characterized by lung, diaphragmatic and genitourinary anomalies.