Noonan - CFC Syndrome, NS, Rasopathies
Noonan syndrome (NS) is a rare autosomal dominant disease characterized by short stature, characteristic facies, congenital heart defect, and developmental delay. NS is one of the most common birth defects, with an estimated incidence of 1 in 1,000 to 1 in 2,500 births 1.
Noonan syndrome belongs to the group of diseases called “RASopathies” e.g. disorders of development characterized by broad clinical and geneticc heterogeneity. RASopathies are caused by germline mutations in those genes that encode RAS family of proteins, e.g. mitogen-activated protein kinases, protein that control signal transduction, participate in development and tumorigenesis, and they include the following conditions (among others):
- Noonan syndrome (NS)
- Cardiofaciocutaneous syndrome (CFC syndrome)
- Noonan syndrome with multiple lentigines, also known as LEOPARD syndrome (LS)
- Costello syndrome (CS)
- Neurofibromatosis type 1 (NF1)
- Legious Syndrome (NF-1 like)
- Autoimmune lymphoproliferative syndrome (ALPS)
Noonan syndrome (NS) is characterized by characteristic facial features and short stature, specific cardiological features and other signs and symptoms. In many cases those affected with NS prenatal features could be diagnosed based on common perinatal findings, such as lymphatic dysplasia, polyhydramnios, cystic hygroma, renal and/or cardiac anomalies, and others 2. Newborn infants with NS usually have feeding problems resulting in poor growth and delayed bone growth. Finally, more than 50% of all affected females and 40% of affected males have an adult height that is below the third centile 3.
Major clinical features, suggestive of a clinical diagnosis of Noonan syndrome, include the following:
Characteristic facies including:
- Triangular-shaped face
- Down-slanting palpebral fissures
- Ptosis (drooping of the upper eyelid)
- Strabismus (48%) (“crossed eyes”) 4
- Amblyopia (33%) (“lazy eye” e.g. reduced vision in one eye) 4
- Refractive errors (61%)4
- Hypertelorism (unusual distance between eyes)
- Low-set ears with thickened helices
- High nasal bridge
- Short, webbed neck
Ocular features frequently observed in NS-patients include the following: Hypertelorism and eyelid abnormalities, amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, abnormal stereopsis, and posterior embryotoxon 4.
Auditory features include progressive high-frequency sensorineural hearing loss, in many cases as high as 50% 5. Early monitoring of hearing quality is important for young NS-patients in order to prevent speech abnormalities. Chest/back abnormalities are common in NS-patients in a form of pectus carinatum and/or excavatum and scoliosis.
Cardiac defects occur in up to 80% of Noonan syndrome patients 1, 6, including pulmonary stenosis, dysplastic pulmonary valve, hypertrophic cardiomyopathy, atrial and ventricular septal defects, and others.
Skin findings observed in Noonan patients include:
- Prominent pads of fingers and toes (67%) 1
- Follicular keratosis of the face and extensor surfaces (14%)1
- Multiple lentigines (3%)1
Neurologic findings include the following:
- Seizure disorder (13%)1
- Unexplained peripheral neuropathy (infrequent) 1
Further signs and symptoms of Noonan syndrome include hepatosplenomegaly, genitourinary features, renal anomalies and skeletal features 1, 6. Joint laxity is present in more than half of patients as well as talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures 1, 6.
Affected individuals clinically diagnosed with Noonan syndrome have normal chromosome studies. However, molecular genetic testing has identified a pathogenic variant in several genes that are now proven to be associated with Noonan syndrome. These genes are included in CENTOGENE´s Noonan - CFC syndrome panel (BRAF, CBL, HRAS, KAT6B, KRAS, LZTR1, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RASA2, RIT1, SHOC2, SOS1, SOS2, SPRED1; see Table).
Mutations in PTPN11 are identified in approximately 50% of affected individuals 21. About 16-20% of individuals with a clinical diagnosis of NS who do not have an identified PTPN11 pathogenic variant are found to have an SOS1 pathogenic variant 21, 25. Furthermore, the frequency of NS-causing mutations in the SOS1 gene is about 13% 21, in the RAF1 and RIT1 genes about 5% each 22, and in the KRAS gene fewer than 5% 14, 15.
The KRAS-related NS phenotype tends to be atypical, with severe intellectual disability, and unusual feature of craniosynostosis in rare cases. Only few individuals with an NRAS pathogenic variant have been reported with a NS phenotype. The clinical features appear to be typical with no particular or distinctive phenotype observed.
Other genes in which mutations have been reported to cause Noonan syndrome in less than 1% of cases include NRAS, BRAF, KAT6B, MAP2K1, MAP2K2, NF1, and others (Table).
The differential diagnosis of Noonan - CFC syndrome-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Other RASopathies including Costello syndrome, Craniofaciocutaneous syndrome, LEOPARD syndrome, Neurofibromatosis type 1, SPRED1 spectrum
- Chromosomal abnormalities including X-/XY mosaicism, Turner syndrome
- Fetal hydantoin syndrome
- Other syndromes with developmental delay, short stature and cardiac defects (with other overlapping symptoms): Williams syndrome, Aarskog syndrome, in utero alcohol/primidone intoxication, and others
To confirm/establish the diagnosis, we offer Noonan - CFC syndrome panel sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels that are designed for the molecular diagnostics of related conditions/phenotypes. Thus, CENTOGENE offers the following testing strategy for Noonan - CFC syndrome panel gene testing:
Step 1: Noonan - CFC syndrome panel sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter for all the genes included in the Noonan - CFC syndrome panel.
Step 2: Deletion/duplication analysis/mutational scanning of selected Noonan - CFC syndrome panel genes (NF1, SPRED1).
Step 3: If no mutation is identified after analysis with the Noonan - CFC syndrome panel, we can offer whole exome sequencing, based on NGS technology.
The following patients should be tested using CENTOGENE´s Noonan - CFC syndrome panel:
- Newborns affected with characteristic NS-facial features, short stature, congenital heart defects, etc. and with a positive family history for NS-symptoms
- Newborns/infants without a positive family history for NS, but with specific clinical findings
- Genetic testing (using CENTOGENE´s Noonan syndrome panel) is useful to confirm the diagnosis and identify the disease causing mutations within a family, regardless of intensity of clinical features, in order to allow for carrier testing and prenatal diagnosis.
Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected of having Noonan syndrome and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the Noonan syndrome and related disorders, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.