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Noonan syndrome 9(NS9)

MedGen UID:
896352
Concept ID:
C4225282
Disease or Syndrome
Synonym: NS9
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SOS2 (14q21.3)
 
Monarch Initiative: MONDO:0014691
OMIM®: 616559

Definition

Noonan syndrome is an autosomal dominant disorder characterized by short stature, craniofacial dysmorphism, short and/or webbed neck, cardiac abnormalities, cryptorchidism, and coagulation defects (summary by Yamamoto et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950). [from OMIM]

Additional descriptions

From MedlinePlus Genetics
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.\n\nSome 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.\n\nNoonan 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.\n\nAdolescent 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.\n\nA 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.\n\nMost 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.\n\nIndividuals 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).\n\nBetween 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.\n\nPeople 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.\n\nNoonan 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.  https://medlineplus.gov/genetics/condition/noonan-syndrome
From MedlinePlus Genetics
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.\n\nNoonan 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.\n\nNoonan 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.\n\nAdolescent 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.\n\nA 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.\n\nMost 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.\n\nIndividuals 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).\n\nBetween 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.\n\nPeople 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.\n\nNoonan 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.  https://medlineplus.gov/genetics/condition/noonan-syndrome

Clinical features

From HPO
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).
Coarctation of aorta
MedGen UID:
1617
Concept ID:
C0003492
Congenital Abnormality
Congenital narrowing of a segment of the aorta. Signs and symptoms include hypertension, muscle weakness, shortness of breath, headaches and leg cramps.
Abnormality of the cardiac septa
MedGen UID:
6752
Concept ID:
C0018816
Congenital Abnormality
An anomaly of the intra-atrial or intraventricular septum.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
Narrowing of the opening between the pulmonary artery and the right ventricle, usually at the level of the valve leaflets.
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).
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.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
A congenital, usually bilateral, thick web-like fold of skin that extends from the acromion to the mastoid process. This deformity is associated with Turner Syndrome and Noonan Syndrome.
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.
Sparse and thin eyebrow
MedGen UID:
924309
Concept ID:
C4282407
Finding
Decreased density/number and/or decreased diameter of eyebrow hairs.
Keratosis pilaris
MedGen UID:
82664
Concept ID:
C0263383
Disease or Syndrome
Keratosis pilaris atrophicans (KPA) represents a group of rare genodermatoses characterized by perifollicular keratosis and inflammation that progresses to atrophy and scarring of the facial skin. Keratosis pilaris of extensor surfaces of limbs is a common associated finding. Affected individuals may present with features that overlap between 3 subtypes, keratosis pilaris atrophicans faciei (KPAF), keratosis follicularis spinulosa decalvans (KFSD), and atrophoderma vermiculata (AVA; see 209700) (summary by Klar et al., 2015).
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Sparse and thin eyebrow
MedGen UID:
924309
Concept ID:
C4282407
Finding
Decreased density/number and/or decreased diameter of eyebrow hairs.
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 (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Recent clinical studies

Etiology

Briggs B, Savla D, Ramchandar N, Dimmock D, Le D, Thornburg CD
J Pediatr 2020 May;220:154-158.e6. Epub 2020 Feb 25 doi: 10.1016/j.jpeds.2020.01.048. PMID: 32111381
Biko DM, Reisen B, Otero HJ, Ravishankar C, Victoria T, Glatz AC, Rome JJ, Dori Y
Pediatr Radiol 2019 May;49(5):586-592. Epub 2019 Jan 6 doi: 10.1007/s00247-018-04337-6. PMID: 30613845
Hemmati P, Dearani JA, Daly RC, King KS, Ammash NM, Cetta F, Schaff HV
Semin Thorac Cardiovasc Surg 2019 Autumn;31(3):507-513. Epub 2018 Dec 18 doi: 10.1053/j.semtcvs.2018.12.004. PMID: 30576779
Harms FL, Alawi M, Amor DJ, Tan TY, Cuturilo G, Lissewski C, Brinkmann J, Schanze D, Kutsche K, Zenker M
Am J Med Genet A 2018 Feb;176(2):470-476. Epub 2017 Dec 22 doi: 10.1002/ajmg.a.38569. PMID: 29271604
Colquitt JL, Noonan JA
Congenit Heart Dis 2014 Mar-Apr;9(2):144-50. Epub 2013 Jun 10 doi: 10.1111/chd.12102. PMID: 23750712

Diagnosis

Delehaye C, Della Corte M, Ranucci G, Prestipino E, De Brasi D, Varone A
Eur J Med Genet 2021 Sep;64(9):104284. Epub 2021 Jul 7 doi: 10.1016/j.ejmg.2021.104284. PMID: 34242782
Li M, Zhang J, Sun N
J Int Med Res 2020 Aug;48(8):300060520936445. doi: 10.1177/0300060520936445. PMID: 32867556Free PMC Article
Briggs B, Savla D, Ramchandar N, Dimmock D, Le D, Thornburg CD
J Pediatr 2020 May;220:154-158.e6. Epub 2020 Feb 25 doi: 10.1016/j.jpeds.2020.01.048. PMID: 32111381
Harms FL, Alawi M, Amor DJ, Tan TY, Cuturilo G, Lissewski C, Brinkmann J, Schanze D, Kutsche K, Zenker M
Am J Med Genet A 2018 Feb;176(2):470-476. Epub 2017 Dec 22 doi: 10.1002/ajmg.a.38569. PMID: 29271604
Colquitt JL, Noonan JA
Congenit Heart Dis 2014 Mar-Apr;9(2):144-50. Epub 2013 Jun 10 doi: 10.1111/chd.12102. PMID: 23750712

Therapy

Delehaye C, Della Corte M, Ranucci G, Prestipino E, De Brasi D, Varone A
Eur J Med Genet 2021 Sep;64(9):104284. Epub 2021 Jul 7 doi: 10.1016/j.ejmg.2021.104284. PMID: 34242782
Malaquias AC, Noronha RM, Souza TTO, Homma TK, Funari MFA, Yamamoto GL, Silva FV, Moraes MB, Honjo RS, Kim CA, Nesi-França S, Carvalho JAR, Quedas EPS, Bertola DR, Jorge AAL
Horm Res Paediatr 2019;91(4):252-261. Epub 2019 May 27 doi: 10.1159/000500264. PMID: 31132774
Romano AA
Pediatr Endocrinol Rev 2019 May;16(Suppl 2):459-464. doi: 10.17458/per.vol16.2019.r.growthhormonenoonan. PMID: 31115197
Hemmati P, Dearani JA, Daly RC, King KS, Ammash NM, Cetta F, Schaff HV
Semin Thorac Cardiovasc Surg 2019 Autumn;31(3):507-513. Epub 2018 Dec 18 doi: 10.1053/j.semtcvs.2018.12.004. PMID: 30576779
Hatemi AC, Gursoy M, Tongut A, Bicakhan B, Guzeltas A, Cetin G, Kansiz E
Tex Heart Inst J 2010;37(1):99-101. PMID: 20200638Free PMC Article

Prognosis

Petrin Z, Soffer B, Daniels SJ
Cardiol Young 2019 Sep;29(9):1214-1216. Epub 2019 Aug 5 doi: 10.1017/S1047951119001720. PMID: 31378211
Artoni A, Selicorni A, Passamonti SM, Lecchi A, Bucciarelli P, Cerutti M, Cianci P, Gianniello F, Martinelli I
Pediatrics 2014 May;133(5):e1299-304. doi: 10.1542/peds.2013-3251. PMID: 24753526
Arvaniti A, Samakouri M, Keskeridou F, Veletza S
Eur Eat Disord Rev 2014 Jan;22(1):83-5. Epub 2013 Sep 24 doi: 10.1002/erv.2261. PMID: 24089313
Colquitt JL, Noonan JA
Congenit Heart Dis 2014 Mar-Apr;9(2):144-50. Epub 2013 Jun 10 doi: 10.1111/chd.12102. PMID: 23750712
Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y
Am J Hum Genet 2013 Jul 11;93(1):173-80. Epub 2013 Jun 20 doi: 10.1016/j.ajhg.2013.05.021. PMID: 23791108Free PMC Article

Clinical prediction guides

Eichhorn C, Voges I, Daubeney PEF
J Med Case Rep 2019 Jun 15;13(1):194. doi: 10.1186/s13256-019-2096-6. PMID: 31208451Free PMC Article
Malaquias AC, Noronha RM, Souza TTO, Homma TK, Funari MFA, Yamamoto GL, Silva FV, Moraes MB, Honjo RS, Kim CA, Nesi-França S, Carvalho JAR, Quedas EPS, Bertola DR, Jorge AAL
Horm Res Paediatr 2019;91(4):252-261. Epub 2019 May 27 doi: 10.1159/000500264. PMID: 31132774
Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA
Genet Med 2019 Feb;21(2):417-425. Epub 2018 Jun 15 doi: 10.1038/s41436-018-0062-0. PMID: 29907801
Croonen EA, Essink M, van der Burgt I, Draaisma JM, Noordam C, Nijhuis-van der Sanden MWG
Am J Med Genet A 2017 Sep;173(9):2335-2345. Epub 2017 Jun 19 doi: 10.1002/ajmg.a.38322. PMID: 28627718
Baldassarre G, Mussa A, Carli D, Molinatto C, Ferrero GB
Am J Med Genet A 2017 Mar;173(3):692-698. doi: 10.1002/ajmg.a.38086. PMID: 28211980

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