Noonan syndrome with multiple lentigines (LEOPARD syndrome)
NSML; "LEOPARD" syndrome โ Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, Sensorineural Deafness; cardiocutaneous syndrome
Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome) is a rare autosomal dominant cardiocutaneous syndrome within the broader family of RASopathies โ disorders driven by germline mutations of genes encoding components of the Ras-MAPK signalling pathway. The cardinal features are summarised in the historical "LEOPARD" mnemonic โ Lentigines (multiple, small, brown, present from infancy and increasing in number into adulthood), ECG conduction abnormalities, Ocular hypertelorism (and other dysmorphic features), Pulmonary stenosis (and / or hypertrophic cardiomyopathy), Abnormal genitalia, Retardation of growth, Sensorineural Deafness. Most cases are caused by germline mutations of PTPN11 (encoding SHP2) โ the same gene that causes classical Noonan syndrome โ but with distinct activating effects on the kinase. Cancer risk is modestly increased โ neuroblastoma in childhood, juvenile myelomonocytic leukaemia (JMML), Hodgkin lymphoma, melanoma. Recognition by the dermatologist of the multiple lentigines plus characteristic facial features prompts referral for cardiac evaluation, audiometry and clinical genetics.
Genetics
- Autosomal dominant; penetrance high; expressivity variable.
- Underlying genes (RASopathy spectrum):
- PTPN11 (~90%) โ encoding SHP2; specific mutations distinct from classical Noonan syndrome.
- RAF1 โ ~5%.
- BRAF, RIT1, MAP2K1, MAP2K2 โ rare.
- Disease mechanism โ gain-of-function activation of the Ras-MAPK pathway, with overlapping but distinct functional consequences from classical Noonan syndrome.
- Confirm by clinical features plus germline gene-panel testing (RASopathy panel).
Cardinal features (LEOPARD)
- L โ Lentigines:
- Multiple small (1โ5 mm), brown, slightly raised macules / papules.
- Distribution โ face, neck, upper trunk; spare lips and oral mucosa (distinguishing from Peutz-Jeghers and Carney complex).
- Present from infancy; gradually increase in number through life; develop after the cardiac and dysmorphic features so may not be evident in young children.
- Multiple cafรฉ-au-lait macules also present.
- E โ ECG conduction abnormalities โ bundle branch block, QT prolongation, sinus node disease.
- O โ Ocular hypertelorism + ptosis + downslanting palpebral fissures + epicanthus + low-set ears + webbed / short neck (Noonan-like facial dysmorphism).
- P โ Pulmonary stenosis โ particularly valvular; hypertrophic cardiomyopathy in many; principal cause of mortality.
- A โ Abnormal genitalia โ cryptorchidism, hypogonadism (men); delayed puberty.
- R โ Retardation of growth โ short stature.
- S/D โ Sensorineural deafness โ develops in childhood / adolescence; audiometry mandatory.
- Other โ granular cell tumour over-represented (~10ร).
Cancer risk
- Lifetime cancer risk modestly increased (estimated 8-fold increase over general population for any cancer in PTPN11-mutated NSML).
- Childhood:
- Juvenile myelomonocytic leukaemia (JMML) โ particularly in PTPN11 mutation carriers.
- Acute lymphoblastic leukaemia.
- Neuroblastoma.
- Rhabdomyosarcoma.
- Adulthood:
- Cutaneous melanoma โ modest increase.
- Hodgkin lymphoma.
- Granular cell tumour โ substantially over-represented.
- Rare reports of phaeochromocytoma.
Surveillance & management
- Multidisciplinary care โ paediatric cardiology, audiology, endocrinology, dermatology, clinical genetics; lifelong.
- Cardiac surveillance โ echocardiogram at diagnosis and serially; ECG; manage hypertrophic cardiomyopathy with ฮฒ-blockers / disopyramide / surgical myectomy if obstructive.
- Audiology โ assessment at diagnosis and serially; hearing aids as needed.
- Skin โ annual full-skin examination; photoprotection counselling; biopsy any new or changing lesion (melanoma surveillance).
- Cosmetic management of lentigines โ Q-switched lasers (Nd:YAG, ruby, alexandrite); intense pulsed light; topical depigmenting agents (limited efficacy).
- Cancer surveillance โ clinical examination; FBC if symptomatic; biopsy any new lump (granular cell tumour).
- Genetic counselling and cascade testing.
- Differential diagnosis โ Carney complex, Peutz-Jeghers syndrome, classical Noonan syndrome, Cardio-facio-cutaneous syndrome.
References
- Sarkozy A et al. LEOPARD syndrome. Orphanet J Rare Dis; 2008.
- Roberts AE et al. Noonan syndrome. Lancet; 2013.
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