Noonan syndrome is the “prototype” of a spectrum of clinical entities that during the last few years was found to be caused by mutations in various genes along the RAS-MAPK pathway. This pathway is well known for its role in cancer. There is a strong correlation between the clinical phenotype and the genetic defect, which so far is unique to this disease entity.
Features: congenital heart disease (especially pulmonary stenosis), hypertrophic cardiomyopathy, facial dysmorphia, webbed neck, lymphedema, short stature, mild developmental delay, delayed onset of puberty, cryptorchidism, male infertility, bleeding disorders, malignancies, malrotation, hepatosplenomegaly, renal anomalies, ophthalmologic and dermatologic problems to a variable degree
Disease genes: PTPN11(41%), SOS1(11%), RAF1(5%), BRAF(1%), KRAS(1%), NRAS(<1%), SHOC2(2%)
Autosomal dominant, de novo mutation; complete penetrance, variable phenotype
Noonan syndrome with multiple lentigines: formerly known as LEOPARD syndrome with major features including lentigines, echocardiogram (ECG) conduction anomalies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, same cardiac defects as Noonan syndrome, but higher prevalence of hypertrophic cardiomyopathy
Cardiofaciocutaneous syndrome: more severe variant of Noonan syndrome with more coarse facial features, hyperkeratotic skin, curly hair and sparse eyebrows and eyelashes, severe developmental delay, hypotonia, seizures, structural brain anomalies
Costello syndrome: more severe variant of Noonan syndrome with prenatal overgrowth and postnatal growth delay, more coarse facial features, benign cutaneous papillomata, and 15% childhood incidence of solid tumors (rhabdomyosarcoma, neuroblastoma, bladder carcinoma)
Neurofibromatosis-Noonan syndrome: features of both neurofibromatosis type 1 and Noonan syndrome
Legius syndrome: axillary freckling, café-au-lait spots, macrocephaly, and facial dysmorphism resembling Noonan syndrome
Diagnostic Criteria and Clinical Characteristics
Diagnosis is made by clinical examination.
Van der Burgt et al. developed a scoring system to aid in the clinical diagnosis of Noonan syndrome (Table 157-1):
Typical facial features plus one major or two minor criteria
Suggestive facial features plus two major or three minor criteria
Pulmonary stenosis, hypertrophic obstructive cardiomyopathy, and/or typical ECG changes
Other cardiac defect
First-degree relative with confirmed NS
First-degree relative with possible NS
Mental retardation, cryptorchidism, and lymphatic dysplasia
Mental retardation, cryptorchidism, or lymphatic dysplasia
Noonan syndrome (OMIM 163950) was first described by Jacqueline Noonan in 1968. She noticed a recurring pattern of defects in patients with pulmonary stenosis, dysmorphic facial features with hypertelorism, ptosis and low-set ears, webbed neck, and chest deformities. Several male patients also had cryptorchidism. Because the phenotype resembled that of Turner syndrome, it was previously called “male Turner syndrome.” Noonan syndrome is inherited in an autosomal dominant pattern or caused by spontaneous mutations of genes along the RAS-MAPK pathway, most commonly PTPN11. Noonan syndrome is the most common syndrome associated with congenital heart disease with an estimated incidence of 1 in 1000 to 2500 live births. One study demonstrated 1% prevalence among patients with congenital heart disease which again has an incidence of approximately 1% of all live births.
Since Noonan syndrome was first described a number of other cardiac and noncardiac features have been identified (Table 157-2). Cardiac involvement is reported in 80% to 90% of patients with Noonan syndrome. While hypertrophic cardiomyopathy and valvar pulmonary stenosis are the most well-known defects in Noonan syndrome, other forms of congenital heart disease occur not uncommonly. The largest study included 136 Noonan syndrome patients with heart disease and showed the following defects: pulmonary stenosis (39%), partial atrioventricular canal defect (15%), hypertrophic cardiomyopathy (10%), aortic coarctation (9%), atrial septal defect (8%), anomalies of the mitral valve (6%), and tetralogy of Fallot (4%). While echocardiography of newborns will detect congenital heart disease, hypertrophic cardiomyopathy may develop during infancy or later in life. Thus periodic cardiology follow-up is recommended for all Noonan syndrome patients throughout life.
Pulmonary stenosis (39%), partial atrioventricular canal defect (15%), hypertrophic cardiomyopathy (10%), aortic coarctation (9%), atrial septal defect (8%), anomalies of the mitral valve (6%) and tetralogy of Fallot (4%). ECG anomalies include wide QRS complex, negative pattern in left precordial leads, left axis deviation, giant Q waves
Hypertelorism, downslanting palpebral fissures with high-arched eyebrows, epicanthal folds, ptosis, low-set and/or posteriorly rotated ears, a full upper lip, depressed nasal root with a wide nasal base, high forehead. Phenotype often mild in adults
Short and/or webbed neck
Normal prenatal growth, postnatal growth delay involving height and weight (50%) but not cranial growth, feeding problems during infancy (76%), mean adult height 162.5 cm in males and 152.7 cm in females (<THIRD p="" percentile)
Pectuscarinatus superiorly and pectus excavatum inferiorly most common; thoracic scoliosis (10%), talipes equinovarus, joint contractures, radioulnar synostosis, and cervical spine fusion less common
Hypotonia, mild-to-moderate developmental delays (20% require special education), attention deficit disorder, Chiari malformation
Splenomegaly, hepatosplenomegaly, malrotation (rare), choledochal cyst (rare)
Pyeloureteric stenosis with or without hydronephrosis
Cryptorchidism, male infertility, delayed onset of puberty by 2 years
Moderate-severe bleeding diathesis, may resolve with age
Juvenile myelomonocytic leukemia (JMML) and acute lymphoblastic leukemia (ALL) although still rare. Spontaneous resolution of JMML common unlike in nonsyndromic patients. Hepatosplenomegaly of unknown origin may be due to subclinical myelodysplasia
Neonatal lymphedema, lymphangiectasia of lungs (chylothorax) or gastrointestinal tract (protein-losing enteropathy), peripheral lymphedema
Strabismus, refractive errors, amblyopia, and nystagmus, visuomotor integration
Conductive hearing loss
Extra prominence on the pads of all fingers and toes most common (67%), less common are curly and thick (29%) or sparse hair (11%), follicular keratosis (14%), café-au-lait spots, multiple lentigines (>100 in 3%)
High-arched palate most common, less frequent dental malocclusion (50%-67%), articulation difficulties (72%), micrognathia (33%-43%)
Noncardiac clinical manifestations can be categorized into the following organ systems: dysmorphism, skeletal/growth, gastrointestinal, genitourinary, hematologic/oncologic, neurologic/developmental, lymphatic, and ectodermal.
Facial features include hypertelorism, downslanting palpebral fissures with high-arched eyebrows, epicanthal folds, ptosis, low-set and/or posteriorly rotated ears, a full upper lip, depressed nasal root with a wide nasal base, and a high forehead. Webbing of the neck occurs in only 23% of cases. In adults, facial dysmorphism is often mild and may pose diagnostic difficulties. While a child’s face may appear coarse and myopathic with prominent eyes and a short neck, the face becomes more triangular with less prominent eyes and a more normal-looking neck during adolescence.
Birth length and weight are typically normal, but postnatal growth delay involving height and weight affects about 50%. Cranial growth is spared. Feeding problems occur in 76% of patients during infancy, requiring tube feeding in 24%. In most patients, feeding difficulties resolve by around age 18 months. Onset of puberty and bone maturity is delayed by approximately 2 years. Mean adult height is 162.5 cm in males and 152.7 cm in females, which are below the third percentile. Noonan syndrome-specific growth data and charts are available, (www.norditropin.com/). Abnormal growth hormone (GH) secretion and decreased sensitivity to GH have been described in Noonan syndrome. While the effect on adult height is not as strong as in idiopathic GH deficiency, GH treatment of Noonan syndrome patients still significantly improves final compared to predicted adult height (10.9 cm for males, 9.2 cm for females). Duration of prepubertal GH therapy was an important predictor of growth. In children with hypertrophic cardiomyopathy, however, and those carrying certain RAF1 mutations, GH therapy should not be initiated due to its known effect on cardiac muscle mass.
Skeletal features include pectus carinatum superiorly and pectus excavatum inferiorly in 95% of the patients. Thoracic scoliosis, talipes equinovarus, joint contractures, radioulnar synostosis, and cervical spine fusion are less common.
The only gastrointestinal anomalies described are unexplained (hepato) splenomegaly (50%) which may be due to subclinical myelodysplasia, and rarely malrotation. Regarding the genitourinary system, cryptorchidism occurs in 70% of males and infertility may be associated with it. Renal anomalies, primarily pyeloureteric stenosis with or without hydronephrosis, occur in 10% of patients.
Mild-to-moderate bleeding diathesis is a common problem in Noonan syndrome. Mildly abnormal bleeding (ie, easy bruising with raised bruises >5 cm in diameter occurring over the whole body after minor trauma) is reported in 34% of the patients. Moderately abnormal bleeding (ie, major bruising after surgery or postoperative bleeding lasting >24 h) occurs in 21%. However, severe hemorrhage requiring an emergent blood transfusion happens in only 3%. The etiology is variable and may be a combination of clotting factor or platelet deficiencies, and/or abnormal platelet function. These reports are in concordance with abnormalities found in the intrinsic coagulation cascade in 50% of Noonan syndrome patients. Hematologic evaluation prior to major surgical procedures is generally recommended.