What is Noonan syndrome?

Risk Factors

Up to 75 percent of Noonan syndrome cases are inherited from an affected
parent. It is inherited in an autosomal dominant fashion. Individuals with this
condition have a 50 percent risk in each pregnancy of having a child who has
Noonan syndrome. As with many other single-gene disorders, advanced paternal age
has been associated with de novo (spontaneous) cases.

Etiology and Genetics

Noonan syndrome is caused by a single genetic mutation in one of at least six
known genes. Genetic mutations are typically caused by DNA
replication errors during cell
division. These genetic errors typically occur during
meiosis and result in a mutation in one of the germ cells
(sperm or egg).

Approximately 50 percent of individuals with Noonan syndrome have a genetic
mutation in PTPN11. This gene encodes the protein tyrosine
phosphatase, nonreceptor type 11 (SHP-2). This protein is expressed in all cell
types, and it is important for cellular response to cell adhesion molecules,
cytokines, growth factors, and hormones. It
plays an important role in intercellular signaling, which controls several
developmental processes. It is essential for activation of the
RAS/mitogen-activated protein kinase (MAPK) signaling pathway. This pathway is
important for cellular differentiation and proliferation, as well as for cell
survival and apoptosis.

Mutations in at least five other genes involved in the MAPK cascade are known
to cause Noonan syndrome, including SOS1, KRAS,
BRAF, RAF1, and NRAS.
Cardiofaciocutaneous syndrome (CFC) and Costello syndrome are disorders in the
same clinical spectrum caused by mutations in these genes. SOS1
gene mutations account for 10 to 15 percent of Noonan syndrome cases, and
RAF1 mutations account for 5 to 10 percent.
KRAS mutations account for 2 percent of cases of Noonan
syndrome, and individuals with mutations in this gene typically have a more severe
form of the disorder. Mutations in the BRAF and
NRAS genes account for a very small proportion of people with
Noonan syndrome, and the cause of Noonan syndrome is unknown in approximately 20
percent of cases.

In addition, clinical overlap between Noonan syndrome and neurofibromatosis type
1 has been well described (also referred to as Watson
syndrome). This is due to mutations in the NF1 gene whose protein
product, neurofibromin, is a negative regulator of the Ras-mediated
signal
transduction pathway. LEOPARD syndrome (lentigines,
electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic
stenosis, abnormal genitalia, retarded growth, and deafness) can also be caused by
mutations in PTPN11 and RAF1.

Symptoms

Lymphatic
system abnormalities are common. In the prenatal period a
cystic hygroma (fluid-filled structure, typically at the back of the neck) may be
identified. Lymphatic irregularities can cause a puffy appearance to the hands and
feet. Typically the physical signs of lymphatic dysfunction improve with age. A
structural heart defect is seen in approximately 50 to 80 percent of affected
individuals. The most commonly identified heart defect is pulmonic
stenosis (narrowing of the pulmonary valve), although other
heart defects can be seen.

Most individuals have short stature. Children typically follow a growth curve
that is in the low/low-normal range. About 30 percent of adults with Noonan
syndrome will have a height that falls within the normal range; however, the
majority will have a height that is below average. Individuals often have
characteristic facial features including low set and posteriorly rotated ears,
widely spaced and downslanting eyes, and thick or droopy eyelids. They often have
a sunken chest (pectus excavatum) or a protuding chest (pectus carinatum). A broad
or webbed neck is not uncommon.

Many, although not all, experience some degree of neurocognitive delay. Delays
are generally mild; however, rarely do individuals experience extensive cognitive
disabilities. Other associated medical problems include kidney abnormalities,
delayed puberty, undescended testicles, and potential male fertility problems.
Blood clotting impairments causing excessive bruising or bleeding can occur.
Visual acuity can be affected. Specific mutations in PTPN11 may
cause a predisposition to certain forms of leukemia.

Screening and Diagnosis

Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 births. The
clinical diagnosis is based on observation of the previously mentioned features,
but not every individual will experience all the associated structural or
functional differences. The diagnosis can be confirmed in the majority of
individuals with molecular genetic testing. However, not all
individuals with the clinical diagnosis of Noonan syndrome will have an
identifiable gene mutation.

Individuals in whom the diagnosis is known or suspected should have a thorough
cardiac evaluation. They should also have hearing screening and annual vision
evaluations. Blood clot testing should be performed if clinically warranted or
prior to any surgical procedure. A renal ultrasound is recommended. Growth should
be monitored using specific Noonan syndrome charts.

Treatment and Therapy

There is currently no cure for this condition. However, treatment for individual symptoms is available. This includes cardiac intervention, referral to early intervention services (occupational, speech, and physical therapy), growth hormone therapy, and treatment for specific bleeding impairments.

Prevention and Outcomes

Most individuals with Noonan syndrome who survive the newborn period do very
well and live fulfilling lives with normal life expectancy. Genetic
counseling is important to explain recurrence risks. Prenatal
diagnosis is available if a causative mutation is identified in a family member.

Bibliography

Cassidy, Suzanne
B., and Judith E. Allanson. Management of Genetic
Syndromes. 3rd ed. Hoboken: Wiley, 2010. Print.

Jones, Kenneth
Lyons, Marilyn Crandall Jones, and Miguel del Campo Casanelles.
Smith's Recognizable Patterns of Human Malformation. 7th
ed. Philadelphia: Elsevier, 2013. Print.

Lepri, Francesca Romana, et al. "Diagnosis of
Noonan Syndrome and Related Disorders Using Target Next Generation
Sequencing." BMC Medical Genetics 15.1 (2014): 2–21.
Print.

"Noonan Syndrome." Genetics Home
Reference. National Library of Medicine, Mar. 2011. Web. 5 Aug.
2014.

Nussbaum, Robert
L., Roderick R. McInnes, and Huntington F. Willard. Thompson and
Thompson Genetics in Medicine. 7th ed. Philadelphia: Saunders,
2007. Print.

Prendiville, Terence W., et al.
"Cardiovascular Disease in Noonan Syndrome." Archives of Disease in
Childhood 99.7 (2014): 629–34. Print.

Wei Qiu, et al. "Structural Insights into
Noonan/LEOPARD Syndrome-Related Mutants of Protein-Tyrosine Phosphatase SHP2
(PTPN11)." BMC Structural Biology 14.1 (2014): 1–11.
Print.