Noonan Syndrome (PTPN11)

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Noonan Syndrome (NS), which occurs at an incidence of about 1:1,000 – 1:2,500 live births (1), is characterized by unusual craniofacial features, congenital heart defects, proportionate short stature, cryptorchidism in males, and a range of secondary manifestations (2). Due to the variability of symptoms, clinical diagnosis of NS may be difficult, especially in cases where craniofacial dysmorphies are subtle (3, 4).

In about 50% of cases, NS is associated with autosomal dominant gain-of-function mutations in the gene PTPN11 (5). Genetic testing for mutations in PTPN11 can therefore allow the confirmation of a clinical diagnosis of NS in about half of all patients. In addition, genetic testing may help to establish a more precise disease prognosis, since pulmonary valve stenosis and bleeding diathesis appear to be more common in patients with PTPN11-related NS than in other forms of NS (6, 7).

NS-associated germline mutations in PTPN11 have also been shown to predispose NS patients to juvenile myelomonocytic leukemia (JMML) (8). Since the prognosis of NS-associated JMML is typically much better than that of non-syndromic JMML (9-12), genetic testing for germline mutations in PTPN11 may help to predict the disease course in JMML patients.

Non-Receptor Associated Protein-Tyrosine Phosphatase

The gene PTPN11 codes for a non-receptor associated protein-tyrosine phosphatase (SHP-2), which plays a key role in a number of different signaling cascades controlling developmental processes such as mesodermal patterning, limb development, hematopoietic cell differentiation, and cardiac semilunar valvulogenesis (6). SHP-2 activation is triggered by binding of various growth factors, cytokines, or hormones to their respective cell-surface receptors; in most cases, SHP-2 activity stimulates downstream signaling (e.g., the RAS/MAPK cascade induced by epidermal growth factor), but it can also exert a negative control (e.g., on interferon-stimulated JAK/STAT signaling).

SHP-2 contains an enzymatic phosphatase (PTP) and two regulatory src-homology (SH2) domains. In the basal state, the PTP domain is blocked by the N-terminal SH2 domain (13). Binding of a specific phosphopeptide to the SH2 domains leads to a conformational shift in SHP-2, making the PTP domain accessible to its substrate. The triggering phosphopeptide may be part of a cell-surface receptor or of a separate adapter molecule (14).

About half of all cases of Noonan Syndrome are associated with germline gain-of-function mutations in PTPN11. The gain-of-function mutations in PTPN11 destabilize the inactive basal conformation of SHP-2 by disrupting the interaction between the N-SH2 and phosphatase domains, allowing SHP-2 to exercise its phosphatase activity in the absence of an appropriate upstream triggering event. The mutations are typically missense mutations, although small in–frame deletions have also been reported (15). Gain-of-function mutations have been detected in exons 1 through 3 and exon 4, coding for the N-SH2 and C-SH2 domains, respectively, and exons 7, 8, and 13, coding for the PTP domain; exon 3 and codon 308 in exon 8 appear to form hot-spots for NS-associated mutations.

Noonan-Syndrome Associated JMML
NS-associated germline mutations in PTPN11 lead to an increased risk of juvenile myelomonocytic leukemia (JMML), probably by overstimulating the RAS signal transduction pathway (8). One mutation in particular, a mutation of threonine to isoleucine at position 73 in SHP-2 (Thr73Ile), has been found in several NS patients suffering from JMML (8, 12, 16). Of note, somatic gain-of-function mutations in PTPN11 have been found in 34% of non-syndromic JMML, 10% of childhood myelodysplastic syndrome, and 4% of childhood acute myeloid leukemia and also seem to play a less prominent role in various other cancers (8, 17). Non-syndromic JMML has a much poorer prognosis than NS-associated JMML (9-12), possibly because somatic mutations cause a more pronounced destabilization of the SHP-2 inactive conformation than germline mutations (8, 18).

LEOPARD Syndrome and Noonan-Like / Multiple Giant-Cell Lesions Syndrome
LEOPARD syndrome (LS) derives its name from its clinical manifestations, lentigines, EKG anomalies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Noonan-like/multiple giant-cell lesions syndrome (NLS) is characterized by generalized hypomineralization and multiple central giant-cell lesions of bones in the presence of NS-like symptoms. Both LS and NLS are associated with gain-of-function mutations in PTPN11 and have been recognized as clinical variants of NS (8, 19-21). In one patient, an Ala461Thr mutation in SHP-2 consecutively led to the phenotypes of NS, LS, and NLS over the course of 12 years (22).

Gain-of-function mutations in PTPN11 account for most, but not all cases of LS (19-21, 23). While some LS-associated SHP-2 mutations can also lead to NS, the Tyr279Cys and Thr468Met mutations in SHP-2 have only been detected in association with LS.

Of note, cardio-facio-cutaneous (CFC) syndrome, which is characterized by NS-like facial features, often severe mental retardation, hyperkeratotic skin lesions, sparse, curly hair, sparse eyebrows, and heart defects, is not associated with mutations in PTPN11 (24, 25). However, at least one patient with PTPN11-related NS and ectodermal involvement reminiscent of CFC syndrome has been described (4).

Clinical Presentation of Noonan Syndrome

Individuals affected with NS typically present in infancy or childhood, with dysmorphic facial features, a webbed neck with excess nuchal skin, an unusual chest shape, proportionate short stature, cryptorchidism if male, and EKG abnormalities (2, 26). Bleeding diathesis or mild mental retardation may also be present. These and additional symptoms are listed in more detail in the table below.

LS may present very similar to NS in early childhood. The characteristic generalized multiple lentigines typically develop only after 5-6 years of age and are often preceded by café-au-lait spots (20). NLS is characterized by the presence of cyst-like osteolytic lesions, often in the mandible (6, 22).

Diagnosis of Noonan Syndrome

NS is indicated by the presence of characteristic craniofacial features, an unusual chest shape, and detection of a heart murmur. However, facial dysmorphic features become less prominent with age (27) and may be subtle enough to be missed (3, 4). A published diagnostic algorithm (28) based on combinations of major and minor symptoms has been shown to increase the accuracy of NS diagnosis (12).

Diagnosis of LS or NLS is based on the presence of multiple lentigines or osteolytic lesions, respectively, in addition to symptoms typical of NS. LS- or NLS-specific symptoms may not develop until later in childhood, delaying the diagnosis.

Since published studies have established a causal relationship between certain variants of PTPN11 and NS, diagnosis of PTPN11-related NS can be confirmed through genetic testing (5).

Treatment of Noonan Syndrome

Treatment of NS is symptomatic. NS-related heart defects and spine deformities may require surgery, which may be complicated by coagulation defects and malignant hyperthermia. Growth hormone therapy has been shown to increase growth velocity in the first year of treatment, but its effect on adult height is not yet clear (29).

NS-related JMML typically has a relatively good prognosis, often showing spontaneous improvement (9-12).

Genetics of Noonan Syndrome

NS affects males and females in a 2:1 ratio, possibly due to sex-specific developmental effects and selective female fetal lethality (30). NS is genetically heterogeneous and generally shows autosomal dominant inheritance (31), although autosomal recessive inheritance has also been reported (32). In about 50% of cases, NS is dominantly associated with gain-of-function mutations in PTPN11, which show close to 100% penetrance (5, 6).

An affected parent can be identified in 30-75% of NS cases (2, 6, 12). Transmission of NS is mostly maternal, probably because cryptorchidism leads to reduced fertility in males (33). However, sporadic occurrence of NS-associated mutations in PTPN11 seems to be linked to advanced paternal age (30).

Genetic Testing for Noonan Syndrome

The Noonan Syndrome (PTPN11) Evaluation detects mutations in the gene PTPN11 and can confirm or establish a diagnosis of NS in about 50% of cases. In addition, identification of an NS-associated mutation in PTPN11 can aid in establishing a more precise disease prognosis with regard to the type of heart defect and presence of blood disorders. In children with JMML, detection of a germline mutation in PTPN11 typically indicates a relatively good disease prognosis.

How Is Genetic Testing for Noonan Syndrome Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of PTPN11 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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