Noonan syndrome with multiple lentigines

Abstract

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 (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation 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 percentile for age. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. Diagnosis/testing The diagnosis of NSML is established either by clinical findings or, if clinical findings are insufficient, by identification of a heterozygous pathogenic variant in one of four genes (PTPN11, RAF1, BRAF, and MAP2K1) by molecular genetic testing. At least one additional gene in which mutation is causative is likely to exist. Management Treatment of manifestations: Treatment of cardiovascular anomalies and cryptorchidism is the same as in the general population. Treatment of hearing loss includes hearing aids, enrollment in an educational program for the hearing impaired, and consideration of cochlear implantation. Developmental disability is managed by early intervention programs and individualized education strategies. Prevention of secondary complications: For individuals with hypertrophic cardiomyopathy, certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death. Surveillance: Periodic follow up and often lifelong monitoring may be necessary for any abnormality, especially a cardiovascular abnormality. For hearing loss, twice-yearly examination by a physician familiar with hereditary hearing impairment and repeat audiometry to confirm the stability of the hearing loss are recommended. Routine monitoring of developmental progress and linear growth in childhood and adolescence. 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. Pregnancy management: Affected women with hypertrophic cardiomyopathy or valve dysfunction may be at risk for development or exacerbation of heart failure during pregnancy; cardiac status in these women should be monitored, especially during the second and third trimesters of pregnancy. 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 pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known.