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Noonan syndrome 5(NS5)

MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Synonyms: NS5; RAF1 gene related Noonan syndrome; RAF1-Related Noonan Syndrome
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): RAF1 (3p25.2)
OMIM®: 611553

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 description

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

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.
Craniofacial Abnormalities
MedGen UID:
91281
Concept ID:
C0376634
Congenital Abnormality
Craniofacial is a medical term that relates to the bones of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft lip and palate, are among the most common of all birth defects. Others are very rare. Most of them affect how a person's face or head looks. These conditions may also affect other parts of the body. Treatment depends on the type of problem. Plastic and reconstructive surgery may help the person's appearance.

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, van Nierop J, Draaisma JM, van der Burgt I, Kunst H, Croonen EA, Admiraal RJ
Int J Pediatr Otorhinolaryngol 2015 Jun;79(6):874-8. Epub 2015 Apr 1 doi: 10.1016/j.ijporl.2015.03.021. PMID: 25862627
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
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

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
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
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

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
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. PMID: 25503994
Choi JH, Lee BH, Jung CW, Kim YM, Jin HY, Kim JM, Kim GH, Hwang JS, Yang SW, Lee J, Yoo HW
Horm Res Paediatr 2012;77(6):388-93. doi: 10.1159/000339677. PMID: 22777296
Moos D, Droitcourt C, Rancherevince D, Marec Berard P, Skowron F
Pediatr Dermatol 2012 Sep-Oct;29(5):665-6. Epub 2012 Feb 14 doi: 10.1111/j.1525-1470.2011.01641.x. PMID: 22329457
Noordam K
Horm Res 2007;68 Suppl 5:24-7. Epub 2007 Dec 10 doi: 10.1159/000110468. PMID: 18174700

Prognosis

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
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
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

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
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
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

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
Lee CK, Chang BS, Hong YM, Yang SW, Lee CS, Seo JB
J Bone Joint Surg Am 2001 Oct;83-A(10):1495-502. PMID: 11679599

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