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Noonan syndrome 1(NS1)

MedGen UID:
1638960
Concept ID:
C4551602
Disease or Syndrome
Synonyms: Female pseudo-Turner syndrome; NS1; PTPN11-Related Noonan Syndrome; Turner phenotype with normal karyotype; Turner Syndrome, Male
 
Genes (locations): BRAF (7q34); MAP2K1 (15q22.31); PTPN11 (12q24.13)
 
Monarch Initiative: MONDO:0008104
OMIM®: 163950

Disease characteristics

Excerpted from the GeneReview: Noonan Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population. [from GeneReviews]
Authors:
Amy E Roberts   view full author information

Additional description

From MedlinePlus Genetics
Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms.

People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward. Affected individuals may have a high arch in the roof of the mouth (high-arched palate), poor teeth alignment, and a small lower jaw (micrognathia). Many children with Noonan syndrome have a short neck, and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck.

Between 50 and 70 percent of individuals with Noonan syndrome have short stature. At birth, they are usually a normal length and weight, but growth slows over time. Abnormal levels of growth hormone, a protein that is necessary for the normal growth of the body's bones and tissues, may contribute to the slow growth.

Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).

Most people with Noonan syndrome have some form of critical congenital heart disease. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). Some have hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle.

A variety of bleeding disorders have been associated with Noonan syndrome. Some affected individuals have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery. Rarely, women with Noonan syndrome who have a bleeding disorder have excessive bleeding during menstruation (menorrhagia) or childbirth.

Noonan syndrome is one of a group of related conditions, collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines.

Adolescent males with Noonan syndrome typically experience delayed puberty. They go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt that results in shortened stature. Most males with Noonan syndrome have undescended testes (cryptorchidism), which may contribute to infertility (inability to father a child) later in life. Females with Noonan syndrome can experience delayed puberty but most have normal puberty and fertility.

Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability. Some affected individuals have vision or hearing problems. Affected infants may have feeding problems, which typically get better by age 1 or 2 years. Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (lymphedema), which can go away on its own. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia). It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers.  https://medlineplus.gov/genetics/condition/noonan-syndrome

Clinical features

From HPO
Neurofibrosarcoma
MedGen UID:
104927
Concept ID:
C0206729
Neoplastic Process
A form of malignant cancer of the connective tissue surrounding nerves. Given its origin and behavior, it is classified as a sarcoma.
Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Male infertility
MedGen UID:
5796
Concept ID:
C0021364
Disease or Syndrome
The inability of the male to effect fertilization of an ovum after a specified period of unprotected intercourse. Male sterility is permanent infertility.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Cubitus valgus
MedGen UID:
490152
Concept ID:
C0158465
Acquired Abnormality
Abnormal positioning in which the elbows are turned out.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Coarctation of aorta
MedGen UID:
1617
Concept ID:
C0003492
Congenital Abnormality
Coarctation of the aorta is a narrowing or constriction of a segment of the aorta.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Failure to thrive in infancy
MedGen UID:
358083
Concept ID:
C1867873
Finding
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Factor XII deficiency disease
MedGen UID:
8772
Concept ID:
C0015526
Disease or Syndrome
Hereditary factor XII deficiency is clinically asymptomatic but results in prolonged activated partial thromboplastin time (APTT). Typically, homozygous or compound heterozygous carriers exhibit almost no (less than 1%) factor XII activity as compared with normal individuals, whereas heterozygotes display intermediate activity. Most of these individuals also lack immunologically detectable factor XII and are referred to as cross-reacting material (CRM)-negative (summary by Kondo et al., 1999).
Amegakaryocytic thrombocytopenia
MedGen UID:
97985
Concept ID:
C0398639
Disease or Syndrome
Thrombocytopenia related to lack of or severe reduction in the count of megakaryocytes.
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects.
Reduced factor XIII activity
MedGen UID:
870254
Concept ID:
C4024692
Finding
Decreased activity of coagulation factor XIII (also known as fibrin stabilizing factor). Activated Factor XIII cross-links fibrin polymers solidifying the clot.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Synovitis
MedGen UID:
21051
Concept ID:
C0039103
Disease or Syndrome
Inflammation of a synovial membrane.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Shield chest
MedGen UID:
322348
Concept ID:
C1834124
Finding
A broad chest.
Abnormal sternum morphology
MedGen UID:
349830
Concept ID:
C1860493
Anatomical Abnormality
An anomaly of the sternum, also known as the breastbone.
Superior pectus carinatum
MedGen UID:
351219
Concept ID:
C1864795
Finding
Pectus carinatum affecting primarily the superior part of the sternum.
Pectus excavatum of inferior sternum
MedGen UID:
400614
Concept ID:
C1864796
Finding
Pectus excavatum (defect of the chest wall characterized by depression of the sternum) affecting primarily the inferior region of the sternum.
Chylothorax
MedGen UID:
40305
Concept ID:
C0008733
Disease or Syndrome
Accumulation of excessive amounts of lymphatic fluid (chyle) in the pleural cavity.
Lymphedema
MedGen UID:
6155
Concept ID:
C0024236
Disease or Syndrome
Localized fluid retention and tissue swelling caused by a compromised lymphatic system.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Cystic hygroma
MedGen UID:
60195
Concept ID:
C0206620
Neoplastic Process
A cystic lymphatic lesion of the neck.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
High, narrow palate
MedGen UID:
324787
Concept ID:
C1837404
Finding
The presence of a high and narrow palate.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children.
Wooly hair
MedGen UID:
87469
Concept ID:
C0343073
Finding
The term wooly hair refers to an abnormal variant of hair that is fine, with tightly coiled curls, and often hypopigmented. Optical microscopy may reveal the presence of tight spirals and a clear diameter reduction as compared with normal hair. Electron microscopy may show flat, oval hair shafts with reduced transversal diameter.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Hypogonadism
MedGen UID:
5711
Concept ID:
C0020619
Disease or Syndrome
A decreased functionality of the gonad.
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.

Professional guidelines

PubMed

Pellegrinelli JM, Kohler A, Kohler M, Weingertner AS, Favre R
Prenat Diagn 2012 May;32(5):467-71. Epub 2012 Apr 13 doi: 10.1002/pd.3840. PMID: 22499187

Recent clinical studies

Etiology

Pellegrinelli JM, Kohler A, Kohler M, Weingertner AS, Favre R
Prenat Diagn 2012 May;32(5):467-71. Epub 2012 Apr 13 doi: 10.1002/pd.3840. PMID: 22499187
Masura J, Burch M, Deanfield JE, Sullivan ID
J Am Coll Cardiol 1993 Jan;21(1):132-6. doi: 10.1016/0735-1097(93)90727-i. PMID: 8417053

Diagnosis

Pellegrinelli JM, Kohler A, Kohler M, Weingertner AS, Favre R
Prenat Diagn 2012 May;32(5):467-71. Epub 2012 Apr 13 doi: 10.1002/pd.3840. PMID: 22499187

Prognosis

Masura J, Burch M, Deanfield JE, Sullivan ID
J Am Coll Cardiol 1993 Jan;21(1):132-6. doi: 10.1016/0735-1097(93)90727-i. PMID: 8417053

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