What is the recommended management approach for a patient with LEOPARD (Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormalities of the genitals, Retardation of growth, and sensorineural Deafness) syndrome?

Management of LEOPARD Syndrome

Patients with LEOPARD syndrome require systematic multidisciplinary surveillance focused on cardiac monitoring (particularly for hypertrophic cardiomyopathy), annual hearing assessments, and management of associated congenital anomalies, with cardiac involvement being the primary determinant of morbidity and mortality. 1, 2

Cardiac Management - The Critical Priority

Hypertrophic cardiomyopathy (HCM) is the most life-threatening manifestation and requires annual cardiac evaluation with ECG and echocardiography. 1, 2, 3

• HCM occurs in approximately 87% of molecularly confirmed LEOPARD syndrome patients and often precedes the appearance of lentigines, making it the earliest detectable feature 3, 4
• Cardiac evaluation should include assessment for left ventricular outflow tract obstruction, septal hypertrophy, and progressive ventricular hypertrophy 3
• Risk stratification for sudden cardiac death is essential, with prophylactic measures (including ICD consideration) in high-risk patients 2
• Pulmonary stenosis, when present, requires monitoring according to standard congenital heart disease protocols 1
• ECG abnormalities (conduction defects) are common and necessitate ongoing surveillance for arrhythmias 1, 2

Antibiotic prophylaxis is mandatory before any invasive dental or surgical procedures due to cardiac involvement. 5

Audiologic Surveillance

Annual hearing evaluations are required from diagnosis through adulthood due to progressive sensorineural deafness. 1, 2

• Sensorineural hearing loss is a key distinguishing feature from Noonan syndrome 1
• Early intervention with hearing aids when indicated improves developmental outcomes 2

Growth and Developmental Monitoring

Growth parameters should be tracked regularly, as stature typically falls below the 25th percentile. 2, 4

• Monitor for delayed puberty and abnormal genitalia (particularly cryptorchidism in males) requiring endocrinology and urology consultation 2, 4
• Assess for mild developmental delay, hypotonia, and learning difficulties with early intervention services as needed 2, 4
• Neurodevelopmental screening is appropriate given the association with intellectual disability in some cases 1

Ophthalmologic Assessment

Baseline ophthalmologic evaluation should address ocular hypertelorism, ptosis, and refractive errors. 4

• Ptosis may require surgical correction if visually significant 4
• Regular follow-up for amblyopia prevention 4

Dermatologic Features

Multiple lentigines typically appear by age 4-5 years and increase through puberty, requiring no specific treatment but serving as diagnostic markers. 2, 4

• Café-au-lait spots are present in approximately 75% of cases and help distinguish from other RASopathies 4
• These cutaneous findings are cosmetic rather than medically significant 2

Genetic Counseling and Molecular Diagnosis

Molecular testing for PTPN11 mutations (exons 7,12,13) confirms diagnosis in approximately 85% of cases, with RAF1 mutations accounting for some PTPN11-negative patients. 2, 4

• Autosomal dominant inheritance with 50% recurrence risk when a parent is affected 2
• Prenatal diagnosis is available for families with known mutations, particularly when severe cardiac hypertrophy is detected on fetal ultrasound 2, 4
• Mutation analysis distinguishes LEOPARD syndrome from overlapping conditions including Noonan syndrome and Neurofibromatosis type 1-Noonan syndrome 2, 4

Diagnostic Pitfalls

The diagnosis is challenging in infancy because lentigines are typically absent at birth—the clinical triad of characteristic facial features (hypertelorism, ptosis, downslanting palpebral fissures), hypertrophic cardiomyopathy, and café-au-lait spots should prompt molecular testing. 4

• Do not wait for lentigines to appear before pursuing diagnosis, as cardiac complications may develop early 3, 4
• A cardiac murmur may be the only clinical finding on routine examination, making thorough cardiovascular assessment essential in any patient with suggestive facial features 3

Long-Term Prognosis

With appropriate cardiac monitoring and management, long-term prognosis is generally favorable, with ventricular hypertrophy being the primary exception requiring lifelong surveillance. 2

• Adults with LEOPARD syndrome do not require special medical care beyond cardiac follow-up if other anomalies have been addressed 2
• The key to optimal outcomes is early recognition, particularly of cardiac involvement, before complications develop 3, 4