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 in the function of the protein SHP-2. Appropriate patient management for Noonan syndrome 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, as well as an overall lack of consensus on diagnostic criteria hamper the diagnosis of Noonan syndrome. The use of molecular diagnostic tools is one way to overcome the weaknesses associated with subjective clinical criteria and can be a highly informative prognostic tool in our arsenal.
Olivia: 2015 CMN Miracle Child
Characteristics of Noonan syndrome
The diagnosis of Noonan syndrome is first and foremost made clinically by the observation of the condition's cardinal features. Common characteristics of Noonan syndrome include:
- Short stature
- Congenital heart defect
- Variable degree of developmental delay
- Unusual chest shape with pectus carinatum and pectus excavatum
- Cryptorchidism in males
- Characteristic facial features.
The facial appearance of Noonan syndrome changes considerably with age, with its most striking appearances identified in the newborn period and early childhood. Comparatively, more subtle facial appearances are present in the adult years.
Some of the characteristic features that are found in patients with Noonan syndrome, 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
- 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, as well as giant Q waves are also characteristic findings. Still, observing the ECG patterns alone is not a useful tool for the phenotype characterization or differentiation of specific cardiac abnormalities.
Growth hormone levels are in the normal range in individuals with Noonan syndrome, whereas somatomedin levels can be elevated in some instances. More specifically, an increase in both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are often identified in prepubertal boys. Additionally, a reduction in semen quality has been demonstrated in adults, suggesting a failure of spermatogenesis in individuals with testicular male descent.
Coagulation screens such as bleeding time, platelet count, prothrombin time, and activated partial thromboplastin time may show certain abnormalities. The use of specific tests will enable the 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 for Noonan syndrome. The most recent scoring system that remains in use today was originally developed in 1994. To this end, the scoring system is based on family history, height, as well as specific features of the condition 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 in cytogenetic studies. Furthermore, the phenotype of Turner syndrome is quite different when one considers the face, development, heart, and kidneys of these patients.
There is also 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 the 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 the 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 that are at an increased risk of Noonan syndrome may be obtainable through laboratories that offer 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.
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Feature
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A = Major
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B = Minor
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Facial
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Typical dysmorphology of the face
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Suggestive dysmorphology of the face
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Chest wall
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Pectus carinatum/excavatum
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Broad thorax
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Cardiac
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Hypertrophic obstructive cardiomyopathy, pulmonary valve stenosis, or ECG abnormalities typical for Noonan syndrome
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Other cardiac defects
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Height
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Less than the third percentile according to age
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Less than the tenth percentile according to age
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Family history
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First degree relative with definite Noonan syndrome
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First degree relative with suggestive Noonan syndrome
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Other
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Mental retardation, lymphatic dysplasia, cryptorchidism
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One of mental retardation, lymphatic dysplasia, cryptorchidism
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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.
References
Further Reading