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Noonan syndrome 7(NS7)

MedGen UID:
462320
Concept ID:
C3150970
Disease or Syndrome
Synonyms: BRAF-Related Noonan Syndrome; Noonan Syndrome; NS7
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): BRAF (7q34)
OMIM®: 613706

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 a developmental disorder characterized by reduced postnatal growth, dysmorphic facial features, cardiac defects, and variable cognitive defects (summary by Sarkozy et al., 2009).  http://www.omim.org/entry/613706
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:
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).
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.
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) or just below the pulmonary valve (infundibular stenosis).
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.
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.
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.
Thickened helices
MedGen UID:
325240
Concept ID:
C1837732
Finding
Increased thickness of the helix of the ear.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28)
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
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).
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Prominent forehead
MedGen UID:
401234
Concept ID:
C1867446
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
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.

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

van Trier DC, Vos AM, Draaijer RW, van der Burgt I, Draaisma JM, Cruysberg JR
Ophthalmology 2016 Oct;123(10):2137-46. Epub 2016 Aug 9 doi: 10.1016/j.ophtha.2016.06.061. PMID: 27521173
Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI
Brain Behav 2016 Jul;6(7):e00479. Epub 2016 May 3 doi: 10.1002/brb3.479. PMID: 27247851Free PMC Article
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
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P
Hormones (Athens) 2013 Jan-Mar;12(1):86-92. PMID: 23624134

Diagnosis

van Trier DC, Vos AM, Draaijer RW, van der Burgt I, Draaisma JM, Cruysberg JR
Ophthalmology 2016 Oct;123(10):2137-46. Epub 2016 Aug 9 doi: 10.1016/j.ophtha.2016.06.061. PMID: 27521173
Nemcikova M, Vejvalkova S, Fencl F, Sukova M, Krepelova A
Eur J Pediatr 2016 Apr;175(4):587-92. Epub 2015 Oct 31 doi: 10.1007/s00431-015-2658-6. PMID: 26518681
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
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P
Hormones (Athens) 2013 Jan-Mar;12(1):86-92. PMID: 23624134

Therapy

Gupta M, Choudhri OA, Feroze AH, Do HM, Grant GA, Steinberg GK
J Clin Neurosci 2016 Jun;28:107-11. Epub 2016 Jan 6 doi: 10.1016/j.jocn.2015.11.017. PMID: 26778511
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
Romano AA, Dana K, Bakker B, Davis DA, Hunold JJ, Jacobs J, Lippe B
J Clin Endocrinol Metab 2009 Jul;94(7):2338-44. Epub 2009 Apr 28 doi: 10.1210/jc.2008-2094. PMID: 19401366
Noordam C, Peer PG, Francois I, De Schepper J, van den Burgt I, Otten BJ
Eur J Endocrinol 2008 Sep;159(3):203-8. Epub 2008 Jun 18 doi: 10.1530/EJE-08-0413. PMID: 18562489
Binder G, Neuer K, Ranke MB, Wittekindt NE
J Clin Endocrinol Metab 2005 Sep;90(9):5377-81. Epub 2005 Jun 28 doi: 10.1210/jc.2005-0995. PMID: 15985475

Prognosis

Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI
Brain Behav 2016 Jul;6(7):e00479. Epub 2016 May 3 doi: 10.1002/brb3.479. PMID: 27247851Free PMC Article
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
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
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P
Hormones (Athens) 2013 Jan-Mar;12(1):86-92. PMID: 23624134

Clinical prediction guides

Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI
Brain Behav 2016 Jul;6(7):e00479. Epub 2016 May 3 doi: 10.1002/brb3.479. PMID: 27247851Free PMC Article
Nemcikova M, Vejvalkova S, Fencl F, Sukova M, Krepelova A
Eur J Pediatr 2016 Apr;175(4):587-92. Epub 2015 Oct 31 doi: 10.1007/s00431-015-2658-6. PMID: 26518681
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
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
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P
Hormones (Athens) 2013 Jan-Mar;12(1):86-92. PMID: 23624134

Recent systematic reviews

Schütte P, Möricke A, Zimmermann M, Bleckmann K, Reismüller B, Attarbaschi A, Mann G, Bodmer N, Niggli F, Schrappe M, Stanulla M, Kratz CP
Eur J Med Genet 2016 Mar;59(3):143-51. Epub 2015 Dec 28 doi: 10.1016/j.ejmg.2015.12.008. PMID: 26732628
Bader-Meunier B, Cavé H, Jeremiah N, Magerus A, Lanzarotti N, Rieux-Laucat F, Cormier-Daire V
Semin Arthritis Rheum 2013 Oct;43(2):217-9. Epub 2013 Jun 17 doi: 10.1016/j.semarthrit.2013.04.009. PMID: 23786871

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