Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD)
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A child with multiple café-au-lait macules and dark lentigines covering the trunk has hypertrophic cardiomyopathy on echo, mild hypertelorism, and sensorineural deafness. Pulmonary stenosis was suspected but echo shows obstructive HCM instead.
AD; mostly PTPN11 (~85%, but catalytically inactive (loss-of-function) variants of SHP2 phosphatase activity, distinct from Noonan's gain-of-function mutations), with RAF1 and BRAF in a minority. Same RAS-MAPK pathway as Noonan, opposite mutation effect on PTPN11.
- Lentigines: multiple, dark, scattered (not photoexposed-only)
- ECG conduction abnormalities
- Ocular hypertelorism
- Pulmonary stenosis (less common than Noonan; HCM more common)
- Abnormal genitalia (cryptorchidism)
- Retardation of growth (short stature)
- Deafness (sensorineural)
Hypertrophic cardiomyopathy in NSML is frequent and clinically dominant, distinct from Noonan, where pulmonary stenosis is the headline cardiac finding.
Clinical (lentigines + cardiac findings + facial features) plus PTPN11/RAF1/BRAF sequencing. Café-au-lait macules can mimic NF1; lentigines are the differentiating feature (sharper, darker, no neurofibromas).
- Noonan syndrome: same pathway, similar facies, but pulmonary stenosis dominates and lentigines are absent.
- NF1: café-au-lait + neurofibromas + Lisch nodules; lentigines NSML are histologically different.
- Carney complex: lentigines + cardiac myxomas + endocrine tumors.
- Cardiology surveillance with serial echo (HCM progression)
- Audiology (sensorineural hearing loss in ~25%)
- Growth monitoring; growth hormone considered case-by-case
- Genetic counseling: autosomal dominant, ~50% recurrence
LEOPARD spots map to the seven cardinal features above. The animal is hard to forget; remember the modern name (NSML) is preferred because the legacy acronym is phasing out of clinical use.