Noonan Syndrome

Excerpt

Clinical characteristics: Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Diagnosis/testing: The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular genetic testing. Several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals have been identified.

Management: Treatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity. Standard treatment for juvenile myelomonocytic leukemia (JMML) and other malignancies, feeding difficulties, ADHD, behavioral problems, cryptorchidism in males, renal anomalies / hydronephrosis, strabismus, hearing loss, and Chiari malformation.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status in infants and toddlers; monitor for evidence of new neurologic manifestations (chronic headache, neck pain, changes in tone, dizziness, or obstructive sleep apnea); monitor developmental progress; assessment of behavioral issues, as age appropriate; skin examination. Annually in childhood or as clinically indicated: ophthalmology and audiology evaluations.

1. In children age <5 years: if initial cardiac evaluation is normal, at least annual cardiac evaluations until age 5 years.

2. In children age >5 years through adulthood, cardiac evaluation at least every 5 years, or as clinically indicated.

3. Prior to any surgical procedure or in those with clinical bleeding: assessment of bleeding history, CBC with differential, and consideration of measurement of coagulation factors.

4. For those with pathogenic PTPN11 or KRAS variants: consider physical examination with assessment of spleen size & CBC every 3-6 months until age 5 years to assess for concerns about JMML/malignancy.

Agents/circumstances to avoid: Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis.

Pregnancy management: Consider referral to an adult congenital heart program for peripartum evaluation and management; consider a hematology referral if the affected pregnant woman has a history of bleeding abnormalities and/or has not undergone previous screening for coagulopathy.

Genetic counseling: NS is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant NS have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband with autosomal dominant NS depends on the genetic status of the parents: if a parent is affected, the risk is 50%; when the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with autosomal dominant NS has a 50% chance of inheriting the pathogenic variant.

NS caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. The parents of an individual with autosomal recessive NS are typically heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be asymptomatic or have mild features of NS. If both parents are heterozygous for one LZTR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of having one LZTR1 pathogenic variant (which can be associated with mild NS features), and a 25% chance of being unaffected and not a carrier.

Prenatal testing and preimplantation genetic testing are possible if the NS-related pathogenic variant(s) have been identified in an affected family member.