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Noonan syndrome 3(NS3)

MedGen UID:
349931
Concept ID:
C1860991
Disease or Syndrome
Synonyms: KRAS gene related Noonan syndrome; KRAS-Related Noonan Syndrome; NS3
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
892334
Concept ID:
CN000007
Functional Concept
Source: HPO
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): KRAS (12p12.1)
OMIM®: 609942

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:
Judith E Allanson  |  Amy E Roberts   view full author information

Additional descriptions

From OMIM
Noonan syndrome is an autosomal dominant dysmorphic syndrome characterized primarily by dysmorphic facial features, cardiac abnormalities, and short stature, among other features (summary by Shah et al., 1999). For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950), which is caused by mutations in the PTPN11 gene (176876). Approximately 50% of cases of Noonan syndrome are caused by mutations in PTPN11.  http://www.omim.org/entry/609942
From GHR
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.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.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.  https://ghr.nlm.nih.gov/condition/noonan-syndrome

Clinical features

Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Juvenile myelomonocytic leukemia
MedGen UID:
506693
Concept ID:
CN167935
Finding
Juvenile myelomonocytic leukemia (JMML) is a lethal myeloproliferative disease of young childhood characterized clinically by overproduction of myelomonocytic cells and by the in vitro phenotype of hematopoietic progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Anatomical Abnormality
Developmental abnormalities in any portion of the VENTRICULAR SEPTUM resulting in abnormal communications between the two lower chambers of the heart. Classification of ventricular septal defects is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect.
Atrial septal aneurysm
MedGen UID:
488911
Concept ID:
C0521533
Disease or Syndrome
A bulging of the interatrial septum towards one side. IN adults, atrial septal aneurysm can be defined as a protrusion of the aneurysm of >10 mm beyond the plane of the atrial septum as measured by transesophageal echocardiography.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Height greater than two standard deviations below the mean of the appropriate reference population for the age and sex of the individual.
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.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Juvenile myelomonocytic leukemia
MedGen UID:
506693
Concept ID:
CN167935
Finding
Juvenile myelomonocytic leukemia (JMML) is a lethal myeloproliferative disease of young childhood characterized clinically by overproduction of myelomonocytic cells and by the in vitro phenotype of hematopoietic progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor.
Juvenile myelomonocytic leukemia
MedGen UID:
506693
Concept ID:
CN167935
Finding
Juvenile myelomonocytic leukemia (JMML) is a lethal myeloproliferative disease of young childhood characterized clinically by overproduction of myelomonocytic cells and by the in vitro phenotype of hematopoietic progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor.
Sagittal craniosynostosis
MedGen UID:
140921
Concept ID:
C0432123
Congenital Abnormality
A kind of craniosynostosis affecting the sagittal suture.
Frontal bossing
MedGen UID:
505049
Concept ID:
CN001816
Finding
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
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.
Sagittal craniosynostosis
MedGen UID:
140921
Concept ID:
C0432123
Congenital Abnormality
A kind of craniosynostosis affecting the sagittal suture.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Frontal bossing
MedGen UID:
505049
Concept ID:
CN001816
Finding
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.

Professional guidelines

PubMed

Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA
Pediatrics 2010 Oct;126(4):746-59. Epub 2010 Sep 27 doi: 10.1542/peds.2009-3207. PMID: 20876176

Recent clinical studies

Etiology

Niemczyk J, Equit M, Borggrefe-Moussavian S, Curfs L, von Gontard A
J Pediatr Urol 2015 Aug;11(4):201.e1-5. Epub 2015 Jun 18 doi: 10.1016/j.jpurol.2015.06.002. PMID: 26143485
Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR
J Med Genet 2015 Jun;52(6):413-21. Epub 2015 Mar 20 doi: 10.1136/jmedgenet-2015-103018. PMID: 25795793
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
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
Gripp KW, Zand DJ, Demmer L, Anderson CE, Dobyns WB, Zackai EH, Denenberg E, Jenny K, Stabley DL, Sol-Church K
Am J Med Genet A 2013 Oct;161A(10):2420-30. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36098. PMID: 23918763Free PMC Article

Diagnosis

El Bouchikhi I, Samri I, Iraqui Houssaini M, Trhanint S, Bouguenouch L, Sayel H, Hida M, Atmani S, Ouldim K
Turk J Med Sci 2015;45(2):306-12. PMID: 26084119
Loddo I, Romano C, Cutrupi MC, Sciveres M, Riva S, Salpietro A, Ferraù V, Gallizzi R, Briuglia S
Eur J Med Genet 2015 Mar;58(3):188-90. Epub 2015 Jan 13 doi: 10.1016/j.ejmg.2014.12.013. PMID: 25595571
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
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
Gripp KW, Zand DJ, Demmer L, Anderson CE, Dobyns WB, Zackai EH, Denenberg E, Jenny K, Stabley DL, Sol-Church K
Am J Med Genet A 2013 Oct;161A(10):2420-30. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36098. PMID: 23918763Free PMC Article

Therapy

Zavras N, Meazza C, Pilotta A, Gertosio C, Pagani S, Tinelli C, Bozzola M
Ital J Pediatr 2015 Oct 6;41:71. doi: 10.1186/s13052-015-0183-x. PMID: 26444854Free PMC Article
Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. PMID: 25721697
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
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
Tofil NM, Winkler MK, Watts RG, Noonan J
Pediatr Crit Care Med 2005 May;6(3):352-4. doi: 10.1097/01.PCC.0000160656.71424.D1. PMID: 15857538

Prognosis

Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, Pouvreau N, Pereira S, Baumann C, Contet A, Sirvent N, Méchinaud F, Guellec I, Adjaoud D, Paillard C, Alberti C, Zenker M, Chomienne C, Bertrand Y, Baruchel A, Verloes A, Cavé H
J Med Genet 2014 Oct;51(10):689-97. Epub 2014 Aug 5 doi: 10.1136/jmedgenet-2014-102611. PMID: 25097206
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
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
Gripp KW, Zand DJ, Demmer L, Anderson CE, Dobyns WB, Zackai EH, Denenberg E, Jenny K, Stabley DL, Sol-Church K
Am J Med Genet A 2013 Oct;161A(10):2420-30. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36098. PMID: 23918763Free PMC Article

Clinical prediction guides

Niemczyk J, Equit M, Borggrefe-Moussavian S, Curfs L, von Gontard A
J Pediatr Urol 2015 Aug;11(4):201.e1-5. Epub 2015 Jun 18 doi: 10.1016/j.jpurol.2015.06.002. PMID: 26143485
Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. PMID: 25721697
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, Pouvreau N, Pereira S, Baumann C, Contet A, Sirvent N, Méchinaud F, Guellec I, Adjaoud D, Paillard C, Alberti C, Zenker M, Chomienne C, Bertrand Y, Baruchel A, Verloes A, Cavé H
J Med Genet 2014 Oct;51(10):689-97. Epub 2014 Aug 5 doi: 10.1136/jmedgenet-2014-102611. PMID: 25097206
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

Recent systematic reviews

Lissewski C, Kant SG, Stark Z, Schanze I, Zenker M
Am J Med Genet A 2015 Nov;167A(11):2685-90. Epub 2015 May 14 doi: 10.1002/ajmg.a.37155. PMID: 25974318
Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. PMID: 25721697

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