Developmental Disorders of the Lymphatics

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Saturday, May 27, 2006

Noonan Syndrome - Part Two

Genotype-Phenotype Correlations

PTPN11. Analysis of a large cohort of individuals with Noonan syndrome [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with Noonan syndrome caused by PTPN11 abnormalities.

Additional cohort analyses have linked PTPN11 mutations to short stature, pectus deformity, easy bruising, characteristic facial appearance [Zenker et al 2004], and cryptorchidism [Jongmans et al 2004].

The likelihood of developmental delay does not differ in mutation-positive and -negative groups, although individuals with the N308D mutation are said to be more likely to receive normal education [Jongmans et al 2004].

Mutations at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis, and identify a subgroup of individuals with Noonan syndrome at risk for JMML [Niihori et al 2005].

Knowledge of the postreceptor signalling defect causing mild growth hormone resistance in individuals with Noonan syndrome and a PTPN11 mutation [Binder et al 2005] might suggest reduced efficacy of growth hormone treatment in mutation-positive individuals. One published study supports this hypothesis [Ferreira et al 2005].

KRAS. No data are currently available as too few cases have been reported.


Penetrance of Noonan syndrome is difficult to determine because of ascertainment bias and variable expressivity with frequent subtlety of features. Many affected adults are only diagnosed after the birth of a more obviously affected infant.


Anticipation has not been described in Noonan syndrome.


An early term for Noonan syndrome, "male Turner syndrome," implied that the condition would not be found in females.

Ullrich, in 1949, reported a series of affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term Bonnevie-Ullrich syndrome became popular, particularly in Europe.


Noonan syndrome is common, and reported to occur in between one in 1,000 and one in 2,500 persons. Mild expression is likely to be overlooked.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Turner syndrome, found only in females, is differentiated from NS by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.

The Watson syndrome phenotype also overlaps with that of Neurofibromatosis type 1 and the two are now known to be allelic. Like Noonan syndrome, features of Watson syndrome include short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes, such as café au lait patches [
Allanson et al 1991].

Cardiofaciocutaneous (CFC) syndrome and Noonan syndrome have the greatest overlap in features. CFC syndrome has similar cardiac and lymphatic findings [Noonan 2001]. In CFC syndrome, mental deficiency is usually more severe, with a higher likelihood of structural central nervous system anomalies; skin pathology is more florid; gastrointestinal problems are more severe and long lasting; and bleeding diathesis is rare. Facial appearance tends to be more coarse, dolichocephaly and absent eyebrows are more frequently seen, and blue eyes are less commonly seen. CFC syndrome occurs sporadically. PTPN11 mutations were not found in a cohort of 28 affected individuals [Ion et al 2002].

Recently, Rodriguez-Viciana et al (2006) studied 23 individuals with CFC syndrome and demonstrated mutations in three genes in the MAPK pathway. In the majority (18 of 23) a BRAF mutation was found, while more rarely a mutation in MEK1 or MEK2 was found.

Costello syndrome shares features with both NS and CFC [Noonan, personal observations]. Two series of individuals with Costello syndrome have been studied molecularly and no PTPN11 mutation has been identified [Tartaglia, Cotter et al 2003; Troger et al 2003]. Recently, germline mutations occurring exclusively in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [
Aoki et al 2005].

Other. NS should be distinguished from other syndromes with developmental delay, short stature, congenital heart defects, and distinctive facies, especially Williams syndrome, Aarskog syndrome, and in utero exposure to alcohol or primidone.


Evaluations at Initial Diagnosis to Establish the Extent of Disease

At the time of initial diagnosis of NS, a series of evaluations is recommended to appropriately guide medical management:

Complete physical and neurologic examination
Plotting of growth parameters on NS growth charts [
Witt et al 1986]
Cardiologic evaluation with echocardiography and electrocardiography
Ophthalmologic evaluation
Hearing evaluation
Coagulation screen
Renal ultrasound examination with urinalysis if the urinary tract is anomalous
Clinical and radiographic assessment of spine and rib cage
Brain and cervical spine MRI, if neurologic symptoms are present
Multidisciplinary developmental evaluation
Genetics consultation

Treatment of Manifestations

Treatment of cardiovascular anomalies is generally the same as in the general population.

Any developmental disability should be addressed by early intervention programs and individualized education strategies.

The bleeding diathesis in Noonan syndrome can have a variety of causes. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has been successfully used to control bleeding caused by hemophilia, von Willebrand disease, thrombocytopenia, and thrombasthenia. It has also been used in an infant with Noonan syndrome whose platelet count and prothrombin and partial thromboplastin times were normal to control severe post-operative blood loss resulting from gastritis [Tofil et al 2005].

Results of growth hormone (GH) treatment studies from the US, UK and Japan [
Ogawa et al 2004] and aggregated European data are expected shortly. Data show that growth velocity increases with GH treatment, at least over the first three years, with maximum gain in the first year or two. Only a small number of study participants have reached final adult height. In some individuals, bone age appeared to advance disproportionately, but this phenomenon is not unique to treatment of Noonan syndrome. No abnormal impact on ventricular wall size was noted. As a result of these studies, enthusiasm for GH treatment is considerable in the US while in other countries such treatment is not initiated without a documented deficiency of GH (see review of treatment in Allanson 2005). Dutch data [K Noordam, personal communication] suggest a 1.3 standard deviation gain in final height (7 cm), leading endocrinologists in Holland to reserve use of growth hormone for affected individuals whose expected final height would be less than the mean for Noonan syndrome.


If anomalies are found in any system, periodic follow-up should be planned and lifelong monitoring may be necessary, especially of cardiovascular abnormalities.

Agents/Circumstances to Avoid

Aspirin therapy should be avoided.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Noonan syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Many affected individuals have de novo mutations; however, an affected parent is recognized in 30-75% of families [Mendez & Opitz 1985, Allanson 1987]. In simplex cases (i.e., those with no known family history), paternal origin of the mutation has been found universally to date [Tartaglia, Cordeddu et al 2004]. In this cohort, advanced paternal age was observed along with a significant sex-ratio bias favoring transmission to males, which is thus far unexplained.

It is appropriate to evaluate both parents, including a thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and review of photographs of the face at all ages, searching for characteristic features of NS. Molecular genetic testing of parents is available on a clinical basis if the proband has an identified disease-causing mutation.

Sibs of a proband

The risk to the sibs of a proband depends upon the genetic status of the parents.

If a parent is affected or has the disease-causing mutation that was identified in the proband, the risk to the sibs is 50%.

When the parents are clinically unaffected and do not have the disease-causing mutation found in the proband, the risk to the sibs of a proband appears to be low (less than 1%). No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Each child of an individual with NS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

High-risk pregnancy

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for Noonan syndrome caused by a PTPN11 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. No laboratories offering molecular genetic testing for prenatal diagnosis of Noonan syndrome caused by a KRAS mutation are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing.

Ultrasound examination. For pregnancies at 50% risk, high-resolution ultrasound examination is also available. A common prenatal indicator of NS, caused by lymphatic dysfunction or abnormality, is a cystic hygroma, which may be accompanied by scalp edema, polyhydramnios, pleural and pericardial effusions, ascites, and/or frank hydrops fetalis. The presence of these findings should suggest the diagnosis of NS. In addition, a search for a cardiac defect should be made, although a recent study has pointed out how infrequently such a defect will be detected prenatally [Menashe et al 2002].

Low-risk pregnancy. Although the ultrasonographic findings described above suggest the diagnosis of Noonan syndrome in high-risk pregnancies, they are nonspecific and may be associated with cardiovascular defects or other chromosomal and non-chromosomal syndromes.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Table A. Molecular Genetics of Noonan Syndrome
Gene Symbol
Chromosomal Locus
Protein Name

GTPase KRas

Tyrosine-protein phosphatase non-receptor type 11

Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

Table B. OMIM Entries for Noonan Syndrome




Table C. Genomic Databases for Noonan Syndrome

Gene Symbol
Entrez Gene

3845 (MIM No. 190070)


5781 (MIM No. 163950)

For a description of the genomic databases listed, click here.

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