Noonan syndrome is a heterogeneous, but clinically recognizable, multiple congenital anomaly syndrome. In approximately 50% of cases the condition can be attributed to missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the protein SHP-2. Appropriate patient management is vastly dependent on an early and adequate diagnosis.

The overlapping features observed among related disorders, an absence of clinical features with pathognomonic value, the wide breadth of phenotypes and lack of consensus on diagnostic criteria hamper the diagnosis of Noonan syndrome. The use of molecular diagnostic tools is a way to overcome the weakness of subjective clinical criteria, and can be a highly informative prognostic tool in our arsenal.

Diagnosing the condition

Diagnosis of Noonan syndrome is first and foremost made clinically by the observation of cardinal features. They are well delineated and include short stature, congenital heart defect, variable degree of developmental delay, unusual chest shape with pectus carinatum and pectus excavatum, cryptorchidism in males, as well as characteristic facial features.

The facial appearance of Noonan syndrome changes considerably with age, with most striking appearances in the newborn period and early childhood, and most subtle in the adult years. Characteristic features that are found regardless of age include low-set ears with posterior rotation and thickened helix, eyes that are often wide-spaced with vivid blue or blue-green irises, and broad or webbed neck.

Electrocardiograms (ECG) in individuals with Noonan syndrome usually exhibit wide QRS complexes with a predominantly negative pattern in the left precordial leads. Left axis deviation, small R waves in the left precordial leads and giant Q waves are also characteristic findings. Still, ECG pattern is not a useful tool for the phenotype characterization or differentiation of specific cardiac abnormalities.

Growth hormone levels are in the normal range, while somatomedin levels can be elevated in some instances. Increased follicle stimulating hormone and luteinizing hormone levels are present in prepubertal boys, while decrease of semen quality has been demonstrated in adults, suggesting a failure of spermatogenesis in individuals with testicular maldescent.

Coagulation screens such as bleeding time, platelet count, prothrombin time and activated partial thromboplastin time may show certain abnormalities. The use of specific test will enable identification of the particular coagulation defect, such as thrombocytopenia, von Willebrand disease, various coagulation factor defects and platelet dysfunction.

Scoring systems can aid significantly in the diagnostic process. The most recent one that is still used today is developed in 1994, and it is based on family history, height, as well as features such as facial, cardiac, chest wall and other anomalies (Table 1).

Differential diagnosis

The main differential diagnostic consideration is Turner syndrome. Turner syndrome, which is found only in females, is differentiated from Noonan syndrome by demonstration of a sex chromosome abnormality on cytogenetic studies. Furthermore, the phenotype of Turner syndrome is quite different when one considers face, development, heart and kidneys.

Then there is a group of distinct syndromes with partially overlapping phenotypes with mutations in genes of the RAS-MAPK pathway. These include Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and LEOPARD syndrome (the acronym stands for multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness).

Genetic testing

Due to high genetic heterogeneity of RASopathies, the standard diagnostic testing protocol should include a multi-step approach, using Sanger sequencing. The selection of the genes to screen on a first diagnostic level depends on the frequency of their association with this disorder and their association with a distinct phenotype.

If the disease-causing mutation has been recognized in the family, prenatal diagnosis for pregnancies at increased risk may be obtainable through laboratories offering testing for the gene of interest or custom prenatal testing. Although the ultrasonographic findings can suggest the diagnosis of Noonan syndrome in high-risk pregnancies, they are considered nonspecific and may be related to cardiovascular defects or other chromosomal and non-chromosomal syndromes.

Table 1. Scoring system for Noonan syndrome. Definite Noonan syndrome: "A" plus one other major sign or two minor signs; 1 "B" plus two major signs or three minor signs. Source: van der Burgt I. Noonan syndrome. Orphanet Journal of Rare Diseases 2007;2:4.