Approach

The diagnosis of NS is typically made clinically. It is a clinically heterogeneous disorder.

A thorough history of the pregnancy, family, and individual, followed by a meticulous physical exam, with particular attention to the features of the head and face, neck, and chest, are usually diagnostic. If NS is suspected, the patient should be investigated for coagulation and cardiac abnormalities, which are common.

Genetic testing may be necessary when the diagnosis is equivocal, or for family reasons (e.g., parental diagnosis, determination of the risk for recurrence, or reproductive planning).

History

Pregnancy and perinatal history

  • Although the birth weight is usually normal, some neonates may have significant subcutaneous edema.

Family history

  • When there is no known history of NS in a close relative, it is important to inquire about relatives with short stature, congenital heart disease, and learning difficulties.

Feeding

  • Feeding difficulties occur in approximately 77% of infants. They include poor sucking with prolonged feeding time, slow feeding with recurrent vomiting, or severe feeding problems requiring tube-feeding for ≥2 weeks.[29][30][31]

  • The feeding difficulties are usually related to hypotonia (low muscle tone) and poor coordination of oral musculature. However, immature gut motility and delayed GI motor development have been documented in some cases.[31]

  • Failure to thrive can occur in up to 40% of neonates. This is self-limited, however, and usually resolves by 18 months of age.[30]

Growth

  • The growth history is important. While birth length is generally normal, childhood growth tends to follow the third centile, with an attenuated or absent pubertal growth spurt.[32]

Puberty

  • Pubertal delay is relatively more common in boys than girls.[33] Inquiry should be made about undescended testes in boys at birth.

Development

  • Mild cognitive impairment is observed in a subset of individuals with NS. IQ typically ranges from 64 to 127.[29][34]

  • About 50% of patients will show mild to moderate clumsiness and coordination problems.

  • There is a 25% likelihood of a learning disability with specific visual-constructional problems, verbal-performance discrepancy, and language delay/impairment.[29][35][36][37]

  • Children with NS have a specific impairment in the global processing of visuospatial information.[38]

  • Adults with NS may experience specific difficulties in information processing, but this rarely has an impact on cognition.[39]

  • Strengths include verbal comprehension, abstract reasoning, and social awareness and judgment.[40] Weaknesses include inability to organize perceptual information, lack of planning abilities, and lack of spatial knowledge.

Increased bruising or bleeding

  • Many patients may report easy bruising.[41] Mild-to-moderate bleeding tendency is not uncommon.[42] Severe hemorrhage has been reported to occur in 3% of cases.

Physical exam

Examination of the head and face may be the most diagnostically important part of the exam, as particular facial characteristics are common, although they change with age.[29][34][Figure caption and citation for the preceding image starts]: Young male with Noonan syndrome, seen at age 3 months (A), 2 years (B), 6 years (C), and 17 years (D)From the collection of Judith E. Allanson [Citation ends].com.bmj.content.model.Caption@72422e9dThe facial features of NS are often subtle, but perhaps most florid in newborns and adolescents. These features are difficult to recognize in adults, and many adults are only diagnosed after the birth of a child with more obvious features.

Head and face

  • The newborn has a tall forehead, wide-spaced and down-slanting eyes, epicanthal folds, a depressed nasal root with upturned nasal tip, a deeply grooved philtrum (depression between nose and lips) with high, wide peaks of the vermilion (resembling a cupid's bow), high-arched palate, small chin, low-set and posteriorly angulated ears with thick helices, and excessive neck skin with low posterior hairline.

  • During infancy, the head seems relatively large, with a tall and prominent forehead. Ptosis or thick, hooded eyelids are characteristic. The nose is short and wide, with a depressed root.

  • In later childhood, the face may appear coarse, hypotonic, or myopathic, as it has rounded features and little expression. Facial shape becomes more triangular with age, as the face lengthens. The patient may have sparse or absent eyebrows and lashes.

  • In the adolescent and young adult, the nose has a narrow and prominent bridge and a wide base. The neck is longer, with accentuated webbing (pterygium colli) or a prominent trapezius muscle.

  • In older adults, unusually prominent nasolabial folds and thin, transparent skin are present.[34] Mean adult head circumference in males is 22.2 inches (56.4 cm), and in females is 21.6 inches (54.9 cm).[30]

  • Hair may be wispy and sparse or curly, thick, and wooly.[34][Figure caption and citation for the preceding image starts]: Female with Noonan syndrome seen at age 4 months (A), 4 years (B), and as an adult (C)From the collection of Judith E. Allanson [Citation ends].com.bmj.content.model.Caption@2a26d96f

Eyes

  • Ocular findings are among the most common features of NS, and observed in up to 95% of cases.

  • They include strabismus (crossed eyes), refractive errors, amblyopia (lazy eye), ptosis, and nystagmus (involuntary eye movement).

  • Anterior segment changes, such as prominent corneal nerves, anterior stromal dystrophy, cataracts, and panuveitis, have been reported.

  • Fundal changes are less frequent, and include optic head drusen, optic disk hypoplasia, colobomas, and myelinated nerves.[29][30][43]

  • The iris is often vivid blue or blue-green, and frequently out of keeping with familial eye color, providing an excellent diagnostic clue.

Musculoskeletal system

  • A particular pectus deformity, with pectus carinatum superiorly and pectus excavatum inferiorly, is noted in 70% to 95% of cases. [Figure caption and citation for the preceding image starts]: Chest demonstrating typical pectus deformity with a marked inferior excavatum and subtle superior carinatumFrom the collection of Judith E. Allanson [Citation ends].com.bmj.content.model.Caption@238a0ce4

  • The thorax is broad, with widely spaced nipples. During childhood, the upper chest appears long; nipples appear low-set, and there is axillary webbing, which persists into adulthood. Shoulders may be rounded, probably because of hypotonic posturing.

  • Cubitus valgus (an increased carrying angle of the forearm) is present in 50% of cases, and short fingers with blunt fingertips are seen in up to one third of cases. Joint hyperextensibility occurs in 30% of cases.[29]

  • Less common skeletal anomalies include talipes equinovarus (clubfoot), joint contractures, scoliosis, and radioulnar synostosis (fusion of radius and ulna).

  • Muscle weakness as measured by grip strength has been documented.[44]

Cardiovascular system

  • Congenital heart defects may occur in up to 75% of cases.[1]

  • The most common anomaly is a dysplastic and/or stenotic pulmonary valve, noted in 50% to 65% of affected children.[30] Congenital structural heart defects and hypertrophic cardiomyopathy may present in the prenatal period, the newborn period, or later in childhood.

Skin

  • Pigmentary changes such as café au lait spots, pigmented nevi, and lentigines may be seen.

  • Adults may show difficulty in growing a beard, due to keratosis pilaris atrophicans faciei (small, scarlike depressions in the face).[45]

Pregnant women

  • During pregnancy, the most common features suggesting a diagnosis are polyhydramnios (excess of amniotic fluid) and cystic hygroma (cystic lymphatic lesion).[29][46][47][48]

  • Other features noted on ultrasound include scalp edema, increased nuchal translucency, pleural or pericardial effusion, ascites, and/or hydrops (abnormal accumulation of fluid in body cavities).[46][49]

Splenomegaly

  • Enlargement of the spleen has been observed and may be a feature of myelodysplasia.[40]

Renal malformations

  • Found in up to 10% of cases, these features include malformations such as duplex collecting system, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, and unilateral renal ectopia.[50]

Diagnostic criteria: scoring systems

Several scoring systems have been devised to help the diagnostic process.[42][51] The most recent scoring system was developed in 1994.[42] In this system, NS is defined as typical facial features plus 1 major or 2 minor clinical characteristics, or suggestive facial features plus 2 major or 3 minor clinical characteristics. However, the typical facial features can be subtle and often require evaluation from an experienced dysmorphologist. Molecular testing for mutations in the genes known to cause NS may be required if the diagnosis is in question.

Major characteristics

  • Cardiac: pulmonary valve stenosis and/or typical ECG

  • Height: <third centile

  • Chest wall: pectus carinatum/excavatum

  • Family history: first-degree relative with definite diagnosis

  • Cognitive impairment, cryptorchidism, lymphatic dysplasia: all 3 present.

Minor characteristics

  • Cardiac: other defects than those described as major characteristics

  • Height: <tenth centile; short stature may be present at birth or postnatal in origin

  • Chest: broad thorax

  • Family: first-degree relative with suggestive diagnosis

  • Cognitive impairment, cryptorchidism, lymphatic dysplasia: any of the 3 present.

Laboratory investigations

Reports have documented multiple types of coagulation defects and bleeding diatheses in NS, and a wide range of clinical presentations.[52] If NS is suspected, the patient should be screened for coagulation abnormalities. Initially, a CBC with platelet count and coagulation profile (i.e., prothrombin time, activated partial thromboplastin time, bleeding time) can be considered.[53]

Males with evidence of pubertal delay should have an evaluation of testicular function as Sertoli cell dysfunction has been described.[54]

Other investigations

ECG and echocardiogram

  • Congenital heart defects are present in up to 75% of cases, so a thorough cardiovascular exam should be performed.[1]

  • An ECG and echocardiogram should identify the features of the most common cardiac anomalies (i.e., dysplastic and/or stenotic pulmonary valve, hypertrophic cardiomyopathy, septal defects, and tetralogy of Fallot).[30][55][56][57]

Molecular genetic testing

  • This may be necessary when the diagnosis is equivocal, or for family reasons (e.g., parental diagnosis, determination of the risk for recurrence, or reproductive planning).

  • Clinical diagnostic testing for the genes in the Ras/MAPK pathway known to cause NS is available. However, a proportion of people with NS will not have a mutation in any of the genes currently known to cause this condition.

  • PTPN11 mutations are found in 50% to 60% of affected individuals.[11][12] SOS1 mutations are found in approximately 10% to 15% of cases.[3][4] RAF1 mutations are found in approximately 5% of cases.[5][6] KRAS mutations are found in approximately 1% of cases.[7][16] Rarely, mutations in other genes (e.g., NRAS, BRAF, or MAP2K1) will be identified.[8][9][10] Mutation "hotspots" are observed in some of these genes.

  • Some laboratories suggest testing in a tiered manner, beginning with the PTPN11 hotspots (serial single gene testing). Other laboratories use a multigene panel that simultaneously tests for all genes known to cause Noonan syndrome.

  • If there are existing genetic test results, do not perform repeat testing unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[58]​

  • In pregnancies complicated by cystic hygroma, increased nuchal translucency, or hydrops, where chromosome analysis is normal, PTPN11 mutations are found in 3% to 11% of cases, depending on the ultrasound finding.[48][59]

Abdominal ultrasound

  • This should be performed if enlargement of the spleen is suspected. Splenomegaly may be a feature of myelodysplasia.[40]

Renal ultrasound

  • This should be performed if renal malformation is suspected (e.g., malformations such as duplex collecting system, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, or unilateral renal ectopia); such malformations may be present in up to 10% of cases.[50]

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