A 3-year-old boy is brought to see his pediatrician for a health maintenance visit. During the exam, the pediatrician notes that the child’s face lacks expression, has a short neck with excessive skin, a low hairline, low set ears, and a short broad nose (Figure 226-1). The child is appropriate for weight but his height is well below the third percentile. An audible systolic ejection murmur is heard. The pediatrician refers the child to a pediatric cardiologist who makes the diagnosis of pulmonic stenosis from physical exam and echocardiogram. Based on these findings, the pediatrician and cardiologist make a clinical diagnosis of Noonan syndrome, which is confirmed by genetic testing. A multidisciplinary approach to the child’s care is planned.

Noonan syndrome is an autosomal dominant, variably expressed, multisystem disorder characterized by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS–MAPK pathway, leading to pathway dysregulation.

Male Turner syndrome.

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  First described by Jacqueline Noonan, who reported nine patients with pulmonary stenosis, short stature, chest deformities, and mild developmental delay.^1,2

  
  
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  Estimated prevalence is 1 in 1000 to 2500.²

  
  
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  Although this syndrome was first described in males who had the Turner syndrome phenotype, it is now recognized in females as well.

  
  
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  Autosomal dominant condition with complete penetrance but variable expressivity.

  
  
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  Congenital heart disease present in 80 to 90 percent of patients.

  
  
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  After trisomy 21, Noonan syndrome is the second most common syndromic cause of congenital heart disease.

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  Autosomal dominant inheritance.

  
  
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  Eight genes in the RAS–MAPK signaling pathway cause Noonan syndrome or closely related conditions (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, and CBL).

  
  
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  The RAS–MAPK pathway is a well-studied, widely important signal transduction pathway through which extracellular ligands—such as some growth factors, cytokines, and hormones—stimulate cell proliferation, differentiation, survival, and metabolism.

  
  
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  Noonan syndrome has been linked to the chromosomal band 12q24.1 and PTPN11, which encodes the protein SHP2. Because SHP2 has essential roles in signal transduction pathways that control several developmental processes, including cardiac semilunar valvulogenesis, PTPN11 was deemed an excellent candidate gene.

  
  
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  Studies suggest that 50 percent of cases of Noonan syndrome are caused by missense, gain of-function mutations in PTPN11.^3,4

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  Autosomal dominant and the risk for having an affected child is 50 percent.

Diagnosis is made from the key clinical features and genetic testing.

Clinical Features

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  Facial features, especially early in life, most often lead to the clinical diagnosis of Noonan syndrome. Wide-spaced and prominent eyes, epicanthal folds, ptosis, and down-slanting palpebral fissures are common. Other features include hypertelorism (widely spaced eyes), low set posteriorly rotated ears, distinctive upper lip, short neck with excessive skin, and low posterior hairline (Figure 226-1).²

  
  
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  During adolescence, the face shape becomes an inverted triangle, wide at the forehead and tapered to a pointed chin. The eyes become less prominent, the neck is longer, and there is accentuation of skin webbing or prominence of the trapezius muscle (Figures 226-2 and 226-3).

  
  
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  Multiple cardiovascular conditions occur in Noonan syndrome. The most common are pulmonary stenosis (often with dysplastic valves; 50 to 60%), hypertrophic cardiomyopathy (20%), and secundum atrial septal defect (6 to 10%).^5,6,7

  
  
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  Short stature is present in 50 to 75 percent of patients, who may have growth hormone deficiency, neurosecretory dysfunction, and growth hormone resistance. Mean age at puberty is delayed compared to general population.⁸

  
  
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  Most infants with Noonan syndrome have feeding difficulties that can lead to failure to thrive. Poor suck, prolonged feeding time, or recurrent vomiting have been reported and about 25 percent of infants need to be fed by tube for 2 weeks or longer. Gastroesophageal reflux is also common.^6,8

  
  
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  Up to 80 percent of boys diagnosed with Noonan syndrome have unilateral or bilateral cryptorchidism. Male gonadal dysfunction has been reported and is suggested to be caused by primary Sertoli cell dysfunction rather than cryptorchidism.

  
  
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  An estimated 30 percent of children have a spinal deformity with surgical correction recommended in two thirds of cases. Chest deformity (superior pectus carinatum and inferior pectus excavatum), widely spaced nipples, cubitus valgus, and genu valgum have also been reported.

  
  
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  Though several hematological abnormalities, including transient monocytosis, thrombocytopenia, and myeloproliferative disorders, have been seen, the most common hematologic disorders are abnormalities of bleeding caused by coagulation defects. Hematological cancers, including juvenile myelomonocytic leukemia, acute myelogenous leukemia, and B-cell acute lymphoblastic leukemia have been reported.

  
  
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  Lymphatic abnormalities, most commonly peripheral lymphedema, are present in less than 20 percent of individuals but can cause substantial morbidity. Peripheral lymphedema can occur in infants and resolves in the first few years of life or it can develop in adolescence or adulthood.

  
  
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  In most affected individuals, intelligence is within the normal range, with intelligence quotient generally varying between 70 and 120.

  
  
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  Roughly 10 percent of affected individuals have auditory deficits in the low frequency range caused by sensorineural hearing loss and 25 percent have deficits in the high frequency range. Inner ear structural abnormalities, including temporal bone abnormalities, have been reported.

  
  
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  Language impairments are more common in patients with the disease than in the general population and, when present, are associated with a high risk of reading and spelling difficulties.

  
  
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  Up to 95 percent of affected individuals will have at least one characteristic eye finding including strabismus, refractive errors, amblyopia, or nystagmus. 2/3 of patients develop anterior chamber abnormalities including cataracts. Fundal changes, including optic head drusen, optic disk hypoplasia, colobomas, and myelinated nerves, occur in 20 percent of patients.

  
  
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  Abnormal pigmentation can occur, including multiple pigmented nevi, café-au-lait spots, and lentigines. Keratosis pilaris of the upper arms and face is common and can impede hair and eyebrow growth. Hair is often thick and curly, although thin, sparse hair has also been reported.