Developmental Disorders of the Lymphatics

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Saturday, May 20, 2006

Noonan Syndrome - Part One

Judith E Allanson, MD
Department of Genetics Children's Hospital of Eastern Ottawa

View this article on the GeneTests Web site.Summary

Disease characteristics. Noonan syndrome (NS) is characterized by short stature; congenital heart defect; broad or webbed neck; unusual chest shape with superior pectus carinatum, inferior pectus excavatum, and apparently low-set nipples; developmental delay of variable degree; cryptorchidism; and characteristic facies. Varied coagulation defects and lymphatic dysplasias are frequently observed. Congenital heart disease occurs in 50-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20-50% of individuals. Hypertrophic cardiomyopathy, found in 20-30% of individuals, may be present at birth or appear in infancy or childhood. Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Length at birth is usually normal. Final adult height approaches the lower limit of normal. Mild mental retardation is seen in up to one-third of individuals. Ocular abnormalities, including strabismus, refractive errors, amblyopia, and nystagmus, occur in up to 95% of individuals.

Diagnosis/testing. Diagnosis of NS is made on clinical grounds, by observation of key features. Affected individuals have normal chromosome studies. PTPN11 and KRAS are the only genes known to be associated with Noonan syndrome. Molecular genetic testing identifies mutations in the PTPN11 gene in 50% of affected individuals and is available on a clinical basis. Molecular testing of the KRAS gene is available on a research basis only.

Management. Treatment of cardiovascular anomalies in NS is generally the same as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. The bleeding diathesis in NS can have a variety of causes and the specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Growth velocity increases with growth hormone (GH) treatment. Surveillance includes monitoring of anomalies found in any system, especially cardiovascular abnormalities.

Genetic counseling. NS is inherited in an autosomal dominant manner. Many affected individuals have de novo mutations; however, an affected parent is recognized in 30-75% of families. The risk to the sibs of a proband depends upon the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%).>DiagnosisClinical Diagnosis
Diagnosis of Noonan syndrome (NS) is made on clinical grounds, by observation of key features. Despite a lack of defined diagnostic criteria, the cardinal features of NS are well delineated [
Allanson 1987]:

Short stature
Congenital heart defect
Broad or webbed neck
Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
Apparently low-set nipples
Developmental delay of variable degree
Cryptorchidism in males

Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in the newborn period and middle childhood, and most subtle in the adult [
Allanson et al 1985]. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irides; and eyes that are often wide-spaced, with epicanthal folds and thick or droopy eyelids.


Varied coagulation defects. Coagulation screens such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time often show abnormalities. Specific testing should identify the particular coagulation defect. Laboratory findings include von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.
Lymphatic dysplasias

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Genes. Two genes are known to be associated with Noonan syndrome:

PTPN11mutations are observed in about 50% of individuals with Noonan syndrome.
KRASmutations are observed in about 5-10% of individuals with Noonan syndrome who do not have mutations in PTPN11 [
Schubbert et al 2006].

Other loci. Absence of linkage to 12q in some families from the original report suggested locus heterogeneity. It is unclear whether any of these families may have had KRAS mutations. It is presumed that additional loci may be identified.

Molecular genetic testing: Clinical uses

Confirmatory diagnostic testing
Prenatal diagnosis

Molecular genetic testing: Clinical methods

Sequence analysis. Sequence analysis of all exons of PTPN11 detects missense mutations in about 50% of individuals tested [Tartaglia et al 2001,Tartaglia et al 2002,Jongmans et al 2004].

Molecular genetic testing: Research. Isolation of genomic DNA and direct, bidirectional sequencing of all exons of KRAS detects mutations in 5-10% of individuals with Noonan syndrome who lack mutations in PTPN11 [Schubbert et al 2006].

Genetically Related (Allelic) Disorders


LEOPARD syndrome (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) is an autosomal dominant condition with variable expression. It shows significant overlap with Noonan syndrome, in which pigmentary differences such as nevi (25%), café au lait patches (10%), and lentigines (3%) are reported. Recently, mutations in exons 7 and 12 of PTPN11 have been reported in LEOPARD syndrome [Digilio et al 2002,Legius et al 2002]. These reports suggest that Noonan syndrome and LEOPARD syndrome are allelic conditions, or that a particular genotype-phenotype correlation exists with certain mutations in PTPN11 leading to the pigmentary changes observed. It is interesting to note that some families with LEOPARD syndrome show no PTPN11 mutation or linkage to chromosome 12q; thus this condition, like Noonan syndrome, is genetically heterogeneous.

Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) constitutes one-third of childhood cases of myelodysplastic syndrome (MDS) and about 2% of leukemia. Mutations in NRAS, KRAS2, and NF1 have been shown to deregulate the RAS/MAPK pathway leading to JMML in about 40% of cases. Recently, somatic mutations in exons 3 and 13 of PTPN11 have been demonstrated in 34% of a cohort of individuals with JMML [Tartaglia, Niemeyer et al 2003]. Mutations in exon 3 were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-MD, has been shown to be caused by PTPN11 mutations. All of these mutations cause gain of function in tyrosine-protein phosphatase non-receptor type II (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation attributable, in part, to prolonged activation of the RAS/MAPK pathway.

More recently, the spectrum of leukemogenesis associated with PTPN11 mutations has been extended to include childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 8% of B-cell precursor ALL cases, but not among children with T-lineage ALL [Tartaglia, Martinelli et al 2004]. Additionally,
Bentires-Alj and colleagues (2004) have described SHP-2-activating PTPN11 mutations in solid tumors such as breast, lung, and gastric neoplasms, and neuroblastoma.

Noonan-like/multiple giant-cell lesion syndrome is said to be characterized by some cardinal features of Noonan syndrome in association with giant cell lesions of bone and soft tissues (cherubism). PTPN11 mutations have been described in both familial and simplex (i.e., a single occurrence in a family) cases.

Sarkozy et al (2004) reported a girl whose early phenotype was typical of Noonan syndrome, but who, over time, developed the hearing loss and lentigines characteristic of LEOPARD syndrome. Thus, Noonan-like/multiple giant-cell lesion syndrome may be too limited and inaccurate a term; a variety of PTPN11 mutations, some of them programming the phenotype of Noonan syndrome and others the phenotype of LEOPARD syndrome, may also program the development of giant cell lesions.

One family with Noonan-like/multiple giant-cell lesion syndrome has a PTPN11 mutation that has been reported in Noonan syndrome without giant cell lesions [Tartaglia et al 2002]. Thus, additional genetic factors may be necessary for the giant cell proliferation to occur.

KRAS. Mutations in KRAS are rarely associated with cardio-facial-cutaneous syndrome (see Differential Diagnosis).

Clinical Description

Natural History

Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature.

In the neonate, tall forehead, hypertelorism with downslanting palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermillion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.

In infancy, eyes are prominent, with horizontal fissures, hypertelorism, and thickened or ptotic lids. The nose has a depressed root, wide base, and bulbous tip.

In childhood, facial appearance is often lacking in affect or expression, resembling an individual with a myopathy.

By adolescence, facial shape is an inverted triangle, wide at the forehead, tapering to a pointed chin. Eyes are less prominent, and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.

In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.

Cardiovascular. Significant bias in the frequency of congenital heart disease may exist because many clinicians require the presence of cardiac anomalies for diagnosis of NS. The frequency of congenital heart disease is estimated to be between 50% and 80% [Allanson 1987, Patton 1994]. An electrocardiographic abnormality is documented in about 90% of individuals with NS [Sharland, Burch et al 1992], and may be present without concomitant structural defects.

Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 20-50% of affected individuals [Allanson 1987; Sharland, Burch et al 1992; Ishizawa et al 1996]; it may be isolated or associated with other cardiovascular defects.

Hypertrophic cardiomyopathy is found in 20% to 30% of affected individuals [Allanson 1987; Sharland, Burch et al 1992; Patton 1994; Ishizawa et al 1996]. It may present at birth, in infancy, or in childhood.

Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot [Allanson 1987, Ishizawa et al 1996]. Coarctation of the aorta is more common than previously thought [ Digilio et al 1998].

Growth. Birth weight is usually normal, although edema may cause a transient increase [Allanson 1987, Patton 1994]. Infants with NS frequently have feeding difficulties [Sharland, Burch et al 1992]. This period of failure to thrive is self limited, although poor weight gain may persist for up to 18 months.

Length at birth is usually normal. Mean height follows the third centile until puberty, when below-average growth velocity and attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth potential into the 20s is possible [Allanson 1987; Sharland, Burch et al 1992]. Final adult height approaches the lower limit of normal: 161 cm in males and 150-152 cm in females [ Witt et al 1986]. Growth curves have been developed from these cross-sectional retrospective data [ Witt et al 1986]. A recent study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Noonan et al 2003].

Decreased IGF1 and IGF-binding-protein-3, together with low responses to provocation, suggest impaired growth hormone release, or disturbance of the growth hormone/insulin-like growth factor axis, in some affected persons. Mild growth hormone resistance related to a postreceptor signalling defect, which may be partially compensated for by elevated growth hormone secretion, is reported in individuals with Noonan syndrome and a PTPN11 mutation [Binder et al 2005].

Psychomotor development. Early developmental milestones may be delayed, likely as a result, in part, of the combination of joint hyperextensibility and hypotonia.

Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [
Lee et al 2005] and 10% to 15% require special education [Sharland, Burch et al 1992; van der Burgt et al 1999]. Mild mental retardation is observed in up to one-third of individuals [Mendez & Opitz 1985,
Allanson 1987]. Verbal performance is frequently lower than nonverbal performance. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement.

Articulation deficiency is common (72%) but usually responds well to intervention therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies [
Allanson 1987].

No particular syndrome of behavioral disability or psychopathology is observed and self-esteem is comparable to age-related peers [Lee et al 2005].

Ocular. Ocular abnormalities occur in up to 95% of individuals. They include strabismus, refractive errors, amblyopia, and nystagmus. Anterior segment and fundus changes are less frequent [
Lee et al 1992; Sharland, Burch et al 1992].

Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising [Sharland, Patton et al 1992]. About one-third of all individuals with NS have one or more coagulation defects [Witt et al 1988]. The coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences.

Lymphatic. Varied lymphatic abnormalities are described in individuals with NS [
Mendez & Opitz 1985, Witt et al 1987]. They may be localized or widespread, prenatal and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.

Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include transient or persistent cystic hygroma, polyhydramnios and, rarely, hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004, Joo et al 2005].

Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly [George et al 1993].

Male pubertal development and subsequent fertility may be normal, delayed, or inadequate [
Mendez & Opitz 1985; Sharland, Burch et al 1992]. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60% to 80% of males [Patton 1994, personal data].

Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years [
Sharland, Burch et al 1992]. Normal fertility is the rule.

Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardio-facio-cutaneous syndrome (see Differential Diagnosis) [Pierini & Pierini 1979; Sharland, Burch et al 1992].

Scalp hair may be curly, thick, and wooly, or sparse and poor growing with easy breakage.

Café-au-lait spots and lentigines are described in NS more frequently than in the general population [
Allanson 1987; Sharland, Burch et al 1992] (see LEOPARD syndrome discussion in Genetically Related (Allelic) Disorders).


Arnold-Chiari I malformation has been reported several times [Holder-Espinasse & Winter 2003] and the author is aware of at least three other individuals with this anomaly [author, personal observation].

Hepatosplenomegaly is frequent; the cause is unknown [Sharland, Burch et al 1992] but may be related to subclinical myelodysplasia.

Juvenile myelomonocytic leukemia (JMML) is often caused by somatic mutations in PTPN11 (see Genetically Related Disorders) [Tartaglia, Niemeyer et al 2003; Tartaglia, Martinelli et al 2004]. Additionally, individuals with Noonan syndrome and a germline mutation in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course, a finding that may be related to the higher gain-of-function effect of somatic mutations leading to leukemogenesis [Tartaglia et al 2006].

Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].

Complete Article