History and exam

Key diagnostic factors

common

positive family history

In up to 50% of cases NS is inherited as an autosomal dominant disorder.[11][12] Close relatives may have short stature, congenital heart disease, and/or learning difficulties if they harbor the same mutation.

short stature

May be a presenting feature.

Childhood growth tends to follow the third centile, but the pubertal growth spurt is often attenuated or absent.[32]

dysmorphic facial features

Irrespective of the age of the patient, specific facial features are seen.[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@2588169d These include wide-spaced and down-slanting eyes with vivid blue or blue-green irides; low-set, posteriorly rotated ears; an inverted triangular-shaped face with small chin; and a broad or webbed neck.[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@77d21ab6

cryptorchidism

Undescended testes are presenting features in most boys (60% to 69%), and may be associated with delayed puberty.[1]

cardiac anomalies

Pulmonary valve stenosis and/or dysplasia, septal defects, and other less common structural cardiac defects are cardinal features of NS.[30]

Hypertrophic cardiomyopathy may develop in utero, at birth, or in infancy or childhood.

delayed puberty

Males may show delayed puberty.[1][54]

Female puberty is mildly delayed, with mean onset of menarche at 14 years.[30]

easy bruising or bleeding

Easy bruising can be seen, with some patients having a bleeding diathesis: a coagulation factor deficiency, platelet dysfunction, or both.[41][42]

Bleeding diatheses should be considered and, if appropriate, screened for coagulation abnormalities, and if present referred to a hematologist.

uncommon

lymphedema

Less than 20% of cases have a lymphatic abnormality.[29]

Dorsal limb lymphedema may be present at birth, contributing to increased birth weight, and resolving in childhood.

Lymphatic dysplasias, causing limb edema, pulmonary or intestinal lymphangiectasia, and scrotal or penile edema, are less common and may present at any age.

Treatment is challenging, and specialist referral is required.

pigmentary anomalies

Café au lait patches, lentigines, nevi, and keratosis are seen.

sparse or absent eyebrows and lashes

Associated with mutations in SOS1, BRAF, and MAP2K1 genes in most instances.

splenomegaly

Enlargement of the spleen has been observed and may be a feature of myelodysplasia.

Other diagnostic factors

common

abnormalities identified prenatally

During pregnancy, the most common features suggesting a diagnosis of NS 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 (fluid in body cavities).[46][49]

chest deformity

A broad chest with wide-spaced, low nipples and a particular pectus deformity (carinatum superiorly and excavatum inferiorly) is frequently seen.[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@7d2e8a98

developmental delay/learning difficulty

Mild cognitive impairment is found in up to 33% of cases, and IQ ranges from 64 to 127.[29][34]

Specific visual-constructional problems, verbal-performance discrepancy, and language delay or impairment may be present even when IQ is normal.[29][35][36][37][60][39]

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] 

skeletal anomalies

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

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

uncommon

history of renal malformation

Present in up to 10% of cases. Renal malformations may include malformation such as duplex collecting system, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, or unilateral renal ectopia.[50]

Risk factors

strong

family history of NS

In up to 50% of cases, NS is inherited as an autosomal dominant disorder.[11][12]

Close relatives may have short stature, congenital heart disease, and/or learning difficulties if they harbor the same mutation.

weak

advanced paternal age

Advanced paternal age has been identified in a cohort of patients with sporadic NS (with no family history).[28]

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