Noonan/LEOPARD Syndrome

Please Note: We are no longer able to offer diagnostic testing for the PTPN11 gene due to patent restrictions enforced by U.S. Patent 7,335,469.

Clinical characteristics:

• Noonan syndrome
  • Heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis
  • Facial dysmorphology
  • Short stature
  • Chest wall deformities
  • Developmental delay
• LEOPARD syndrome
  • Acronym for multiple lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness
  • Lentigines may or may not be present
  • Heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis
  • Cryptorchidism
  • Postnatal growth retardation
  • Mild facial dysmorphology
  • Mild mental retardation
• Noonan-like syndrome with loose anagen hair
  • features of Noonan syndrome
  • actively growing hair that is easy to pluck, sparse, thin, and slow-growing

Inheritance pattern:  Autosomal dominant

What this test can tell us:
Testing can be performed in tiers, moving to the next tier only if the preceding test is negative. Testing can also be performed concurrently or in any order requested. The following strategy is suggested for Noonan syndrome testing: Tier 2 is suggested if an individual has findings suggestive of LEOPARD syndrome; Tier 4 is suggested if an individual has loose anagen hair.

Tier 1: Sequencing of the entire coding region of SOS1

Tier 2: Sequencing of exons 7, 14 and 17 of RAF1

Tier 3: Sequencing of the entire coding region of KRAS

Tier 4: Sequencing of part of exon 2 for reported mutation in SHOC2

Sequencing tests will detect point mutations, small deletions, and small insertions in the regions of the genes that are analyzed. It will not detect a partial or whole gene deletion or duplication.

For Noonan syndrome, mutations are detected in:

• SOS1 in about 10% of affected individuals
• Exon 7, 14, or 17 of RAF1 in 3% to 17% of affected individuals
• KRAS in less than 5% of affected individuals
• Exon 2 of SHOC2 in individuals with Noonan-like syndrome with loose anagen hair

For LEOPARD syndrome, mutations are detected in:

• Exon 7, 14, or 17 of RAF1 in about 3% of affected individuals

A negative test does not completely rule out a diagnosis of Noonan syndrome or LEOPARD syndrome, since mutations in these five genes do not account for 100% of cases. Clinical overlap is seen between Noonan syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome. Tests for Costello syndrome and CFC syndrome are also available in our laboratory and can be requested if clinically indicated.

Sample requirements: Draw one or two 4-cc tubes of blood in EDTA/purple-top tube (minimum of 2-3 cc for infants due to large number of assays).

Turn-around time: 7 – 10 days for each gene; about 3 weeks for all 4 tiers

CPT codes and cost:

Tier 1:   83891 x 1    83898 x 18    83904 x 42     83912 x 1     $1,500

Tier 2:   83891 x 1    83898 x 4      83904 x 8      83912 x 1      $250

Tier 3:   83891 x 1    83898 x 6      83904 x 14    83912 x 1      $350

Tier 4:   83891 x 1    83893 x1       83904 x 2      83912 x 1      $150

Noonan/LEOPARD Syndrome Testing Packet

Additional Resources

• GeneReview for Noonan syndrome
• GeneReview for LEOPARD syndrome
• OMIM Entries