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Noonan syndrome 2(NS2)

MedGen UID:
344290
Concept ID:
C1854469
Disease or Syndrome
Synonyms: Noonan syndrome autosomal recessive; NS2
 
Gene (location): LZTR1 (22q11.21)
 
Monarch Initiative: MONDO:0011531
OMIM®: 605275

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 descriptions

From OMIM
Noonan syndrome (NS) is a multiple congenital anomalies syndrome characterized by a typical face, congenital heart disease, and short stature (summary by van der Burgt and Brunner, 2000). For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).  http://www.omim.org/entry/605275
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).

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.

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.

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.

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.  https://medlineplus.gov/genetics/condition/noonan-syndrome

Clinical features

From HPO
Leukemia
MedGen UID:
9725
Concept ID:
C0023418
Neoplastic Process
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
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).
Cubitus valgus
MedGen UID:
490152
Concept ID:
C0158465
Acquired Abnormality
Abnormal positioning in which the elbows are turned out.
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.
Mitral stenosis
MedGen UID:
44466
Concept ID:
C0026269
Disease or Syndrome
An abnormal narrowing of the orifice of the mitral valve.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Atrioventricular canal defect
MedGen UID:
235591
Concept ID:
C1389016
Anatomical Abnormality
A defect of the atrioventricular septum of the heart.
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).
Abnormal coronary artery origin
MedGen UID:
868843
Concept ID:
C4023253
Anatomical Abnormality
Isolated abnormalities of the coronary artery origins. This may be in associated with other structural heart malformations but not the patterns of complex structural heart malformations which result in abnormal course of the coronary arteries.
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).
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.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Shield chest
MedGen UID:
322348
Concept ID:
C1834124
Finding
A broad chest.
Relative macrocephaly
MedGen UID:
338607
Concept ID:
C1849075
Congenital Abnormality
A relatively mild degree of macrocephaly in which the head circumference is not above two standard deviations from the mean, but appears dysproportionately large when other factors such as body stature are taken into account.
Abnormal sternum morphology
MedGen UID:
349830
Concept ID:
C1860493
Anatomical Abnormality
An anomaly of the sternum, also known as the breastbone.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
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).
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Underdeveloped supraorbital ridges
MedGen UID:
349384
Concept ID:
C1861869
Congenital Abnormality
Flatness of the supraorbital portion of the frontal bones.
Nevus
MedGen UID:
45074
Concept ID:
C0027960
Neoplastic Process
A nevus is a type of hamartoma that is a circumscribed stable malformation of the skin.
Hyperpigmentation of the skin
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.
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.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Palmoplantar cutis laxa
MedGen UID:
341602
Concept ID:
C1856714
Finding
Loose, wrinkled skin of hands and feet.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Increased nuchal translucency
MedGen UID:
869253
Concept ID:
C4023676
Finding
Nuchal translucency is the sonographic appearance of subcutaneous accumulation of liquid in the back of the fetal neck in the first trimester of pregnancy (11-14 gestational weeks of pregnancy).
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).

Recent clinical studies

Etiology

Yang T, Fan X, Fan Y, Song W, Liu X, Wang J, Chen X
Laryngoscope 2024 Jan;134(1):400-409. Epub 2023 May 31 doi: 10.1002/lary.30799. PMID: 37254944
Yu QX, Zhen L, Lin XM, Wen YJ, Li DZ
Prenat Diagn 2023 Dec;43(13):1662-1665. Epub 2023 Nov 7 doi: 10.1002/pd.6462. PMID: 37936555
Weaver KN, Gripp KW
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):494-500. Epub 2022 Dec 1 doi: 10.1002/ajmg.c.32023. PMID: 36454176
Wang C, Tian Q
Biomed Res Int 2015;2015:342420. Epub 2015 May 17 doi: 10.1155/2015/342420. PMID: 26075230Free PMC Article
Bouchard S, Di Lorenzo M, Youssef S, Simard P, Lapierre JG
J Pediatr Surg 2000 May;35(5):796-800. doi: 10.1053/jpsu.2000.6086. PMID: 10813353

Diagnosis

Yang T, Fan X, Fan Y, Song W, Liu X, Wang J, Chen X
Laryngoscope 2024 Jan;134(1):400-409. Epub 2023 May 31 doi: 10.1002/lary.30799. PMID: 37254944
Yu QX, Zhen L, Lin XM, Wen YJ, Li DZ
Prenat Diagn 2023 Dec;43(13):1662-1665. Epub 2023 Nov 7 doi: 10.1002/pd.6462. PMID: 37936555
Bouchard S, Di Lorenzo M, Youssef S, Simard P, Lapierre JG
J Pediatr Surg 2000 May;35(5):796-800. doi: 10.1053/jpsu.2000.6086. PMID: 10813353

Therapy

Yang T, Fan X, Fan Y, Song W, Liu X, Wang J, Chen X
Laryngoscope 2024 Jan;134(1):400-409. Epub 2023 May 31 doi: 10.1002/lary.30799. PMID: 37254944
Wang C, Tian Q
Biomed Res Int 2015;2015:342420. Epub 2015 May 17 doi: 10.1155/2015/342420. PMID: 26075230Free PMC Article

Prognosis

Bouchard S, Di Lorenzo M, Youssef S, Simard P, Lapierre JG
J Pediatr Surg 2000 May;35(5):796-800. doi: 10.1053/jpsu.2000.6086. PMID: 10813353

Clinical prediction guides

Wang C, Tian Q
Biomed Res Int 2015;2015:342420. Epub 2015 May 17 doi: 10.1155/2015/342420. PMID: 26075230Free PMC Article

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