Noonan Syndrome and Noonan/LEOPARD Syndrome

Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, webbed/broad neck, pectus deformities, cryptorchidism, characteristic facies, coagulation defects and lymphatic dysplasias. 

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Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, webbed/broad neck, pectus deformities, cryptorchidism, characteristic facies, coagulation defects and lymphatic dysplasias. 

Noonan Syndrome is diagnosed in approximately 1-3% of fetuses with an ultrasound finding of cystic hygroma and a normal karyotype.

Four genes are known to cause Noonan Syndrome. Mutations in the PTPN11 gene account for approximately 50% of Noonan Syndrome, SOS1 accounts for 10-13%, RAF1 3-17%, and KRAS 2-5%.

The Ambry SEQUENCE™: Noonan Syndrome starts with PTPN11 Gene Sequence Analysis. If negative, testing reflexes to analysis of SOS1, RAF1 (mutation hotspot exons 7, 12, 14, 17) and KRAS.

For patients whose presentation overlaps with features of the associated disorder LEOPARD Syndrome, the Ambry SEQUENCE™: Noonan/LEOPARD testing includes full Gene Sequence Analysis of PTPN11 and partial RAF1 analysis in the first step, then reflexes to SOS1 and KRAS analysis if negative.

Test options for NS can be customized according to the patient’s needs. Also, please see our separate test information for LEOPARD Syndrome testing under the LEOPARD Syndrome entry in the Test menu.

Disease Name 
Noonan Syndrome
LEOPARD Syndrome
Disease Information 

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, webbed/broad neck, pectus deformities, cryptorchidism, characteristic facies, coagulation defects and lymphatic dysplasias. It occurs in 1/1000 to 1/2500 individuals. Treatment is targeted towards specific complications of the disease and can include early intervention programs for patients with developmental delay, growth hormone therapy, and monitoring of systems, especially for those with cardiac abnormalities. Symptoms lessen with age and most patients do not require special medical care as adults.2

Four genes are known to cause Noonan syndrome. Mutations in any of these genes cause gain-of-function and up-regulation of the Ras-mitogen-activated protein kinase pathway (RAS-MAPK). Mutations in the PTPN11 gene account for approximately 50% of Noonan syndrome, SOS1 accounts for 10-13%, RAF1 3-17%, and KRAS 2-5%.3,4,5,6,7,8,9 At least 50% of these mutations occur de novo, but an affected parent is often recognized in familial cases. There appears to be a predominance of maternal transmittance in familial cases11 and de novo mutations are predominantly paternal in origin.12 Due to the varied penetrance and expressivity of Noonan Syndrome, many adults are diagnosed only after the birth of an obviously affected infant. If parents are clinically unaffected, the recurrence risk is less than 1%; familial (inherited) Noonan syndrome has a 50% recurrence risk.1

Gene % mutation detection Phenotype
PTPN11 50% of NS:
59% familial, 37% sporadic.3  Deletion and duplications are very rare.4
Individuals with mutations in this gene are more likely to have pulmonary valve stenosis, short stature, pectus deformities, easy bruising, characteristic facial appearance and cryptorchidism.Growth hormone therapy does not tend to be as effective in these patients.13
SOS1
10-13%
If PTPN11 negative, 16-20%6,7,1
Mutations in this gene are more frequently associated with ectodermal abnormalities, but normal development and stature.6,7
RAF1 3-17%
If PTPN11 negative, 5-10%8,9,10
95% of patients with mutations in this gene have hypertrophic cardiomyopathy.8,9
KRAS >5%
If PTPN11 negative, 1-2% 5, 10
Patients with mutations in this gene are more likely to have severely affected cognitive function and somatic growth, skin redundancy and  keratinization.2

LEOPARD Syndrome is also caused by mutations in the PTPN11 and RAF1 genes. LEOPARD is an acronym for the main features of the disorder including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness.

Testing Benefits & Indication 

Clinical presentation in Noonan syndrome is highly variable and genetic testing can be a useful tool for diagnosis confirmation. Parental testing should be considered when a mutation has been identified in a patient to determine if mutation is de novo or inherited and for accurate risk assessment. Studies have reported a diagnosis of Noonan syndrome in approximately 1-3% of fetuses with an ultrasound finding of cystic hygroma and a normal karyotype.16 Prenatal diagnosis for Noonan syndrome could be considered for these cases, especially in those with additional abnormalities such as congenital heart defects.16

Test Description 

These Ambry Tests consist of gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-15 of the PTPN11 gene, exons 2-24 of the SOS1 gene, exons 2-17 of the RAF1 gene or exons 7, 12, 14, 17 in SEQUENCE testing, and exons 2-6 of the KRAS gene, plus at least 20 bases into the 5’ and 3’ ends of all introns. Specific mutation analysis for known familial mutations in the PNTP11, SOS1, KRAS or RAF1 genes is also available.

Ambry SEQUENCE: Noonan Syndrome starts with the PTPN11 gene sequence analysis which detects 50% of the mutations in Noonan Syndrome. If negative, testing is reflex to analysis of SOS1, RAF1 (exons 7, 12, 14, 17) and KRAS genes. These can also be ordered separately for those patients who have been tested for PTPN11 gene mutations in the past but not for the SOS1, RAF1, or KRAS genes.

For patients suspected to have Noonan Syndrome, or the associated disorder LEOPARD Syndrome, the Ambry SEQUENCE: Noonan/LEOPARD starts with full gene analysis for the PTPN11 gene and the major mutation hotspots of the RAF1 gene (exons 7, 12, 14 and 17). This portion of the test has a detection rate of 53-67% for Noonan syndrome. If negative, this test automatically reflexes to sequence analysis of the SOS1 and KRAS genes. Sequence analysis for each gene can also be ordered individually or in any combination.

Mutation Detection Rate 

Mutations in the PTPN11 gene account for approximately 50% of Noonan syndrome, SOS1 accounts for 10-13%, RAF1 3-17%, and KRAS 2-5%.3,4,5,6,7,8,9 Gene sequence analysis can detect 99% of mutations in these genes.

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA (purple-top) tube (first choice) or ACD (yellow-top) tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.  
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

Billing Codes 
Test Code Technique
2280 PTPN11 Gene Sequence Analysis
2284 Step 1 Only (PTPN11)
2300 SOS1-Related Noonan Disorders
2320 RAF1 Gene Sequence Analysis
2340 KRAS Gene Sequence Analysis
8400 Ambry SEQUENCE: Noonan Reflex Option (PTPN11, SOS1, RAF1, KRAS)
8402 Ambry SEQUENCE: Noonan Concurrent (PTPN11, SOS1, RAF1, KRAS)
8420 Step 2 Only (SOS1, Partial RAF1, KRAS)
8460 LEOPARD Syndrome (PTPN11, partial RAF1)

 

Turnaround Time 
Technique Days
PTPN11 Gene Sequence Analysis 10-21
Step 1 Only (PTPN11) 10-21
SOS1-Related Noonan Disorders 10-21
RAF1 Gene Sequence Analysis 10-21
KRAS Gene Sequence Analysis 10-21
Ambry SEQUENCE: Noonan Reflex Option (PTPN11, SOS1, RAF1, KRAS) 10-42
Ambry SEQUENCE: Noonan Concurrent (PTPN11, SOS1, RAF1, KRAS) 10-28
Step 2 Only (SOS1, Partial RAF1, KRAS) 10-28
LEOPARD Syndrome (PTPN11, partial RAF1) 10-28

 

Specialty 
Genes 
References 

1. Mendez HM & Opitz JM. Noonan syndrome: a review. Am J Med Genet.1985;21(3):493-506. [PMID: 3895929]

2. Van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007; 2:4. [PMID: 17222357]

3. Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70(6):1555-63. [PMID: 11992261]

4. Tartalgia M, Mehler El, Goldberg R et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465-468. [PMID: 11704759]

5. Schubbert S, Zenker M, Rowe SL et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331-336. [PMID: 16474405]

6. Tartaglia M , Pennacchio LA, Zhao C et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:75-79. [PMID: 17143282]

7. Roberts AE, Araki T, Swanson KD et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70-74. [PMID: 17143285]

8. Pandit B, Sarkozy A, Pennacchio LA et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:1007-1012. [PMID: 17143282]

9. Razzaque MA, Nishizawa T, Komoike Y et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013-1017. [PMID: 17603482]

10. Ko JM, Kim JM, Kim GH et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. [PMID: 19020799]

11. Allanson JE. Noonan syndrome. J Med Genet. 1987;24(1):9-13. [PMID: 3543368]

12. Tartaglia M, Cordeddu V, Chang H et al. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Med Genet. 2004;75(3):492-497. [PMID: 15248152]

13. Limal JM, Parfait B, Cabrol S et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006;91(1):300-306. [PMID: 16263833]

14. Schubbert S, Zenker M, Rowe SL et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38:331-336. [PMID: 16474405]

15. Schlüter G, Steckel M, Schiffmann H et al. Prenatal DNA diagnosis of Noonan syndrome in a fetus with massive hygroma colli, pleural effusion and ascites. Prenat Diagn. 2005;25(7):574-576. [PMID: 16032767]

16. Lee KA, Williams B, Roza K et al. PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet. 2009;75(2):190-194. [PMID: 18759865]