Clinical characteristics: Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Diagnosis/testing: The clinical diagnosis of Noonan syndrome with multiple lentigines can be established in a proband with multiple lentigines plus two other cardinal features (cardiac abnormalities; poor linear growth / short stature; pectus deformity; and dysmorphic facial features including widely spaced eyes and ptosis) OR, in the absence of lentigines, three of the other cardinal manifestations plus an affected first-degree relative. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in one of four genes (BRAF, MAP2K1, PTPN11, and RAF1).
Management: Treatment of manifestations: Standard treatment of hypertrophic cardiomyopathy, structural heart defects, eye anomalies / eye movement abnormalities, seizures, cryptorchidism, and developmental issues. Hearing aids may be helpful if hearing loss is present. Growth hormone treatment may be considered for those with short stature, but data on use in NSML are lacking, and growth hormone therapy may be contraindicated in those with hypertrophic cardiomyopathy.
Surveillance: Measurement of growth parameters; cardiac auscultation to assess for new heart murmur; clinical assessment for new neurologic manifestations such as seizures; and monitoring of developmental progress and educational needs at each visit. Annual echocardiogram until age three years and then at ages five years and ten years, or as clinically indicated. Audiology evaluation at least annually in infancy and childhood, or as clinically indicated. Ophthalmology evaluation if eye anomalies or eye movement issues are noted.
Agents/circumstances to avoid: For individuals with hypertrophic cardiomyopathy, treatment with growth hormone must be undertaken with great caution (if at all) to avoid exacerbating a cardiac condition, and certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.
Evaluation of relatives at risk: If the BRAF, MAP2K1, PTPN11, or RAF1 pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives; if the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected a cardiology evaluation with echocardiogram is recommended.
Pregnancy management: For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters.
Genetic counseling: NSML is inherited in an autosomal dominant manner. A proband with NSML may have the disorder as the result of a de novo pathogenic variant; the proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with NSML has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for a pregnancy at increased risk is possible if the pathogenic variant in an affected family member is known.
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