Noonan Syndrome with Multiple Lentigines

Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome) is an autosomal dominant RASopathy caused mostly by PTPN11 variants that impair SHP2 phosphatase activity, with lentigines, cardiac conduction abnormalities, hypertrophic cardiomyopathy, ocular hypertelorism, pulmonary stenosis, genital anomalies, growth retardation and sensorineural deafness. Cardiomyopathy is the main cause of morbidity.

Pathophysiology. Loss-of-function or dominant negative PTPN11 variants (and rarely RAF1, BRAF or MAP2K1) alter RAS-MAPK and PI3K-AKT signalling. This differs from Noonan syndrome, in which SHP2 activity is increased.

Lentigines appear in childhood and increase in number with age.

Hypertrophic cardiomyopathy occurs in about 70% of patients, and conduction disease raises the risk of arrhythmia.

• Multiple lentigines: flat dark brown macules over face, neck and trunk, sparing mucosa, increasing in number through childhood
• Café-au-lait macules in some
• Hypertrophic cardiomyopathy, pulmonary valve stenosis, conduction abnormalities (long PR, bundle branch block)
• Hypertelorism, ptosis, low set ears, webbed neck and pectus deformity
• Short stature
• Sensorineural hearing loss
• Genital anomalies: cryptorchidism, hypospadias, delayed puberty
• Mild learning difficulty or developmental delay
• Bleeding tendency in some

• Clinical diagnosis: lentigines with cardiac and facial features.
• Genetic testing: a RASopathy panel (PTPN11, RAF1, BRAF, MAP2K1, SOS1 and others) or exome sequencing.
• Echocardiography and ECG at diagnosis, with cardiac MRI if cardiomyopathy is suspected.
• Audiometry.
• Coagulation screen: platelet count, PT, aPTT and factor XI, VIII and IX levels, and von Willebrand tests before surgery.
• Growth and pubertal assessment, and renal ultrasound.

Differential diagnosis.

• Noonan syndrome (similar facies and pulmonary stenosis, but no multiple lentigines)
• Neurofibromatosis type 1 (café-au-lait macules, with Legius syndrome)
• Cardiofaciocutaneous and Costello syndromes
• Peutz-Jeghers syndrome (mucosal lentigines)
• Carney complex
• Xeroderma pigmentosum

• Cardiac surveillance: echocardiography and ECG at diagnosis and every 1 to 2 years (yearly if hypertrophic cardiomyopathy or conduction disease). Holter monitoring when palpitations or syncope occur.
• Hypertrophic cardiomyopathy: propranolol 1 mg/kg daily in two to three divided doses, increasing to 4 mg/kg daily in children (adults propranolol 40 mg twice daily increasing to 160 mg twice daily, or bisoprolol 2.5 to 10 mg daily), with avoidance of dehydration and strenuous isometric exercise. Consider an implantable defibrillator in high risk cases. Surgery or alcohol septal ablation for symptomatic obstruction.
• Pulmonary stenosis: balloon valvuloplasty for a gradient over 50 mmHg or symptoms.
• Hearing: hearing aids or cochlear implant, with audiology every 6 to 12 months.
• Growth: monitor height; growth hormone is generally avoided in patients with hypertrophic cardiomyopathy, and any use needs cardiology agreement.
• Skin: sun protection, and laser for cosmetic lentigines if desired.
• Genital anomalies: orchidopexy, hypospadias repair and pubertal assessment.
• Bleeding risk: check coagulation before surgery and dental extraction. Tranexamic acid 15 to 25 mg/kg orally three times daily (maximum 1 g each dose) can be used for bleeding.
• Development: early intervention and educational support.
• Genetic counselling: 50% chance of transmission from an affected parent.

Special groups.

• Sporting activity: advise against competitive and strenuous sport in patients with hypertrophic cardiomyopathy.

Monitoring. Echocardiography and ECG every 1 to 2 years (yearly with cardiomyopathy or conduction disease), audiology every 6 to 12 months, and growth and pubertal review yearly.

Referral and escalation. Refer to clinical genetics, paediatric or adult cardiology and audiology. Emergency for syncope, chest pain or palpitations with exercise.