157: Noonan Syndrome and Related Disorders

Key Points

• Disease summary:

  • 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

  • Incidence: 1:1000-1:2500

  • Disease genes: PTPN11(41%), SOS1(11%), RAF1(5%), BRAF(1%), KRAS(1%), NRAS(<1%), SHOC2(2%)

• Hereditary basis:

  • Autosomal dominant, de novo mutation; complete penetrance, variable phenotype

• Differential diagnosis:

  • 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

Diagnostic Criteria

• 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

Clinical Characteristics

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 ...