Noonan syndrome (NS) is a genetic disorder characterized
by a series of birth defects
dysmorphic facial features, short stature
after birth, webbing of
the neck, caved-in chestbone, cardiovascular
problems such as pulmonic stenosis and hypertrophic
cardiomyopathy, bleeding tendency and,
in boys, testes that do not descend normally into the
scrotum. NS is an autosomal dominant disorder that carries an
elevated risk of developmental and language delay, learning
disability, hearing loss, and mild mental retardation.
The syndrome is relatively common, with an estimated
incidence of 1 in 1,000-2,500 live births. Noonan syndrome is a clinically recognizable and genetically heterogeneous disorder. The common denominator of the various genetic alterations found in patients with Noonan syndrome and related disorders is that they cause dysregulation of RAS-MAPK signaling. Several genes connected to this pathway are associated with NS.
Noonan-like syndrome with loose anagen hair: Patients exhibit consistent features of Noonan syndrome as well as reduced growth with GH deficiency, intellectual delays, hyperactive behavior, dark pigmented skin, eczema, mitral valve or septal cardiac defects and loose thinned hair also known as anagen hair. Macrocephaly and low-set posteriorly rotated ears have also been observed. Mutations in the SHOC2 gene are connected to this condition.
Cardiofaciocutaneous syndrome (CFC) is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe. CFC is considered to be an autosomal dominant condition, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Cardiofaciocutaneous syndrome usually results from new gene mutations and occurs in people with no history of the disorder in their family. In a few reported cases, an affected person has inherited the condition from an affected parent. Mutations in BRAF, MAP2K1, MAP2K2, SHOC2 and KRAS genes have been detected in patients with CFC.
Costello syndrome is an autosomal dominant disorder that affects many parts of the body. This condition is characterized by delayed development and intellectual disability, loose folds of skin, unusually flexible joints, and distinctive facial features including a large mouth. Heart problems are common, including an abnormal heartbeat, structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle. Infants with Costello syndrome may be larger than average at birth, but most have difficulty feeding and grow more slowly than other children. People with this condition have relatively short stature and may have reduced growth hormone levels. Other signs and symptoms of Costello syndrome can include tight Achilles tendons, weak muscle tone , a structural abnormality of the brain called a Chiari I malformation, skeletal abnormalities, dental problems, and problems with vision. Mutations in the HRAS gene cause Costello syndrome.
LEOPARD syndrome is characterized by abnormalities of the skin, heart, inner ears and genitalia. The name LEOPARD is an acronym for the features of this syndrome:
Letigines (dark spots) on the skin, Electrcardiographic conduction defects-abnormal electrical activity of the heart, Ocular hypertelorism-widely spaced eyes, Pulmonary stenosis-obstruction of blood flow from the right ventricle of the heart, Abnormalities of the genitalia, Retarded growth resulting in short stature, Deafness. Mutations in the BRAF, MAP2K1, RAF1 and PTPN11 genes are associated with Leopard syndrome.
Our panel analyzes 16 genes known to be associated with the Noonan spectrum and other related disorders.
Genes: PTPN11, SOS1, KRAS, NRAS, RRAS, HRAS, RAF1, BRAF, MAP2K1, MAP2K2, SOS2, SHOC2, A2ML1, CBL, RIT1, IZTR1
Disorders: Noonan syndrome, Costello syndrome, Leopard syndrome (Noonan syndrome with multiple lentigines), Noonan-Like syndrome with loose anagen hair, CFC syndrome
Purpose: Confirmation of Clinical Diagnosis
Methodology: Next-Generation Sequencing
Test Requisition: Sequencing Requisition
Specimen Requirements: 2-5 mL Blood- Lavender Top Tube
Panel CPT Code: 81442 Cost: $3500.00 (Oklahoma Medicaid requires preauthorization for this test)
Provider can also select specific genes to be analyzed, this will affect pricing and CPT codes used for insurance filing.
Turn-around-time: 5-6 weeks
1. Jamieson CR, van der Burgt I, Brady AF, van Reen M, Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E (1994). "Mapping a gene for Noonan syndrome to the long arm of chromosome 12". Nat. Genet. 8 (4): 357–60
2. Freeman RM, Plutzky J, Neel BG (1992). "Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew". Proc. Natl. Acad. Sci. U.S.A. 89 (23): 11239–43.
3. Tartaglia M, Mehler EL, Goldberg R, et al (2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome". Nat. Genet. 29 (4): 465–8.
4. Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8
5. Van Der Burgt, I.; Brunner, H. (2000). "Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form". American Journal of Medical Genetics 94 (1): 46–51.
6. Schubbert S, Zenker M, Rowe SL, et al (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6
7. Roberts AE, Araki T, Swanson KD, et al (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4
8. Bentires-Alj M, Kontaridis MI, Neel BG (2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5..
9. Razzaque MA, Nishizawa T, Komoike Y, et al (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7
10. Mu, W, et al. "Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing". J Mol Diagn. 2016. 18(6):923-932.