Noonan Syndrome—Certitude Replaces Conjecture

Paul Saenger

Department of Pediatrics, Division of Pediatric Endocrinology, Albert Einstein College of Medicine, Children’s Hospital at Montefiore, Bronx, New York 10467

Address all correspondence and requests for reprints to: Paul Saenger, M.D., Division of Pediatric Endocrinology, Children’s Hospital at Montefiore, 111 East 210th Street, Bronx, New York 10467. E-mail: . PHSAENGER{at}AOL.COM

Noonan syndrome (MIM163950) is an autosomal dominant disorder that is characterized by dysmorphic facial features, proportionate short stature (in about 50% of cases), and heart disease (most commonly valvular pulmonic stenosis and hypertrophic cardiomyopathy). The phenotype also includes webbing of the neck, chest deformities giving a square appearance of the thorax, cryptorchidism, mild mental retardation, and a bleeding diathesis (1).

The syndrome is relatively common, with an estimated incidence of 1:1000–2500 live births. Kobilinsky (2) reported in 1883 a 20-yr-old male with webbing of the neck, incomplete folding of the ears, and low posterior hairline, but no mention was made of other physical findings. The complete syndrome was first described in 1968 by Jacqueline Noonan, a pediatric cardiologist, in Lexington, Kentucky. Her original description was entitled "hypertelorism with Turner phenotype." Ever since then, the syndrome has been called "male Turner," "Turner-like syndrome," and "Noonan syndrome" (3).

Dutch workers mapped first in 1994 the gene for Noonan syndrome to the long-arm of chromosome 12 (4). Having access to large, informative families, the same Dutch groups were also able to further delineate and map more finely the critical region for Noonan syndrome. It also became apparent from family studies that there is marked genetic heterogeneity and evidence for an autosomal recessive form accrued also from studies of informative families (5). This would suggest that there are additional loci responsible for the pathogenesis and the phenotype in Noonan syndrome and diverse genotypes may in fact lead to similar phenotypes. Unlike Turner syndrome, however, the complete lack of an established genotype, associated with a typical phenotypic presentation, hampered clinical assessment of patients with suspected Noonan syndrome considerably.

The break came in 2001 when a multinational group of investigators identified missense mutations in protein-tyrosine-phosphatase, nonreceptor-type II (PTPN11) as a candidate gene for Noonan syndrome because it maps to the critical region on chromosome 12 (12q42 24.1 between DAD12S84 and DAD12S79) and furthermore because its specific gene protein product, SHP-2, is essential in several intracellular signal transduction pathways that control diverse developmental processes. These developmental processes include cardiac valvulogenesis, which is of particular relevance for Noonan syndrome because of its well described right-sided cardiac lesions. SHP-2 is involved in signaling, mediated by the epidermal growth factor receptor during semilunar valvulogenesis (6, 7).

SHP-2 participates also in signaling cascades elicited by a number of growth factors, cytokines and hormones (8, 9, 10). As such, SHP-2 has a role in modulating cellular proliferation, differentiation, and migration (6). SHP-2 clearly has a Janus-faced role in signaling pathways; it can act as either a positive or negative regulator of JAK/STAT and nuclear factor-{kappa}B cascades (11, 12, 13, 14, 15). SHP-2 may act as a phosphatase and as an adapter molecule with docking function, with both functions seemingly relevant to signal transduction.

The international group of investigators found mutations in PTPN11 encoding a protein tyrosine phosphatase SHP-2 in about 50% of patients with Noonan syndrome. The mutations are gain-of-function changes, and this would imply that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity. A thorough understanding of the pathogenesis of Noonan syndrome will require further studies to delineate the perturbations for the individual phenotypic abnormalities. Thus far, SHP-2 mutations can only be used to explain the Noonan specific form of congenital cardiac malformations (6).

Building on the report by Tartaglia et al. (16), Kosaki et al. (17) demonstrate in this issue of The Journal of Clinical Endocrinology and Metabolism PTPN11 mutations in seven Japanese patients with Noonan syndrome. Similar to the previous report, the Japanese investigators, when they analyzed the PTPN11 gene in 21 patients with Noonan syndrome, found different heterozygous missense mutations in 7 cases. However, the important clinical caveat is that the phenotypic features in the mutation-positive and the mutation-negative patients were comparable. There was no phenotypic-genotypic correlation. Similar to patients with Prader-Willi syndrome in which a significant portion of patients do not have the 15p- deletion (18), only about 50% of patients with Noonan syndrome appear to have a mutation to PTPN11. As the Japanese investigators stress again, the observed pleiotropic effects of PTPN11 mutations most likely reflect the diverse role of PTPN11 in regulating multiple signal transduction pathways involving growth factors.

It is important for the clinician to recognize that now, for the first time, a genetic diagnosis can be established in up to 50% of patients with Noonan syndrome. This has important implications for the diagnosis and management of these patients.

In a recent report, Tartaglia et al. (16) show that pulmonic stenosis was more prevalent among the group of subjects with Noonan syndrome who had PTPN11 mutations than it was in the group without them, whereas hypertrophic cardiomyopathy was less prevalent. The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was also identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotype range of disease associated with this gene.

This implies that mutation screening for PTPN11 is necessary for other Noonan syndrome-like conditions, such as, cardio-facio-cutaneous, Leopard, and Noonan/neurofibromatosis syndromes, to elucidate whether those entities are distinct conditions, allelic disorders, or just extreme phenotypes of a single disorder with variable expressivity (19, 20).

Recognizing that the frequency of Noonan syndrome, is very similar, if not, higher than the frequency of Turner syndrome, the reports by Tartaglia (6, 16) and Kosaki et al. (17) in this issue of JCEM present a significant advance in our diagnostic capabilities for patients with this syndrome. Noonan syndrome will now join the list of clinical syndromes in which clinical and phenotypic assessment and expertise will receive firm grounding by mutation analysis and specific genetic diagnoses in many, but not all, cases. This then opens the possibility for large-scale assessment of Noonan patients, evaluation of optimization of therapeutic intervention, and clinical care. For example, we know very little about reproductive function in Noonan syndrome; we also know little about their auxologic characteristics (21). There have been several reports on intervention with GH therapy in patients with short stature and Noonan syndrome, and the robust response equaled that in Turner patients (22, 23, 24).

It would certainly seem reasonable to suggest that similar interventions are being considered in pharmacoepidemiological studies for Noonan syndrome, now that availability of a firm genetic diagnosis replaces conjecture with certitude in most, but not all, cases.

Acknowledgments

Received May 31, 2002.

Accepted May 31, 2002.

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