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

Management of LEOPARD Syndrome

LEOPARD syndrome requires a systematic, multidisciplinary surveillance approach focused on early detection and management of cardiac complications—particularly hypertrophic cardiomyopathy—which represents the primary mortality risk, alongside monitoring for conduction abnormalities, growth retardation, hearing loss, and developmental delays. 1, 2

Diagnostic Confirmation

• Molecular genetic testing should be performed on blood samples to identify heterozygous missense mutations in PTPN11 gene (exons 7,12, or 13), which are detected in approximately 85% of cases. 2
• If PTPN11 testing is negative, screen for RAF1 gene mutations, which account for some PTPN11-negative cases. 2
• Parental testing should be conducted to determine if the mutation is inherited or de novo, as this affects recurrence risk counseling (50% if parent affected, low if de novo). 2
• In infants under 12 months without characteristic lentigines, clinical diagnosis can be suspected based on three cardinal features: characteristic facial dysmorphism (hypertelorism, downslanting palpebral fissures, ptosis, dysmorphic ears), hypertrophic cardiomyopathy (87% of cases), and café-au-lait spots (75% of cases). 3

Cardiac Surveillance and Management

Annual cardiac evaluation is mandatory given that hypertrophic cardiomyopathy—predominantly affecting the left ventricle—represents the most significant morbidity and mortality risk. 1, 2

Initial Cardiac Assessment

• Baseline echocardiography and 12-lead ECG should be performed at diagnosis to assess for hypertrophic cardiomyopathy, pulmonary stenosis, and conduction abnormalities. 1
• Determine cardiac arch sidedness on initial imaging. 1
• ECG abnormalities are common and include conduction defects, which may be present even without structural heart disease. 2, 4

Ongoing Cardiac Monitoring

• Annual echocardiography is required to monitor for development or progression of ventricular hypertrophy throughout childhood and adolescence. 2
• Annual ECG screening is necessary to detect progressive conduction abnormalities, arrhythmias, and dilated aortic root. 1
• Periodic ECG screening is particularly important in patients receiving antiepileptic or neuropsychiatric medications, or those with hypocalcemia or thyroid disease, as these conditions increase arrhythmia risk. 1
• Ambulatory ECG monitoring should be performed to assess for non-sustained ventricular tachycardia and paroxysmal supraventricular arrhythmias, which inform sudden cardiac death risk stratification. 1

Hypertrophic Cardiomyopathy Management

• Careful risk assessment for sudden cardiac death is essential, with prophylactic measures (including ICD consideration) in high-risk patients based on established risk stratification models. 2
• Restriction from competitive sports and strenuous physical activity is recommended for patients with hypertrophic cardiomyopathy. 1
• Cardiac magnetic resonance imaging may be indicated to assess myocardial fibrosis and scar burden when echocardiography is inadequate. 1

Critical Pitfall

• Any invasive dental or surgical procedure requires antibiotic prophylaxis against infective endocarditis in patients with cardiac abnormalities. 5

Growth and Endocrine Monitoring

• Serial growth parameters (weight, height, head circumference) should be plotted at each visit, as stature is typically below the 25th percentile. 2
• Evaluate for delayed puberty and cryptorchidism in males, which are common features. 2, 4
• Consider growth hormone studies if growth retardation is significant. 1

Auditory Assessment

• Annual audiologic evaluation with audiometry and tympanometry is required from diagnosis through adulthood to detect and manage sensorineural deafness, which can be progressive. 2, 4
• Early detection of hearing loss allows for timely intervention with hearing aids or other assistive devices to optimize language development. 2

Ophthalmologic Evaluation

• Baseline ophthalmologic examination should assess for ocular hypertelorism, palpebral ptosis, and other structural abnormalities. 1, 2
• Periodic vision screening is appropriate, though severe visual impairment is uncommon. 1

Developmental and Neuropsychological Support

• Comprehensive developmental assessment should evaluate gross motor, fine motor, speech/language, and cognitive domains, as mild developmental delay, hypotonia, and learning difficulties occur in a subset of patients. 2, 4
• Neuropsychological evaluation should be performed upon school entry to establish baseline cognitive function and guide educational planning, including individualized education plans if needed. 2
• Physical therapy is indicated for hypotonia and motor delays. 2
• Speech and language therapy should be provided for oral-motor dysfunction and communication difficulties. 2

Dermatologic Monitoring

• Multiple lentigines typically appear by age 4-5 years and increase throughout puberty, though they may be present at birth in some cases. 2, 6
• Lentigines distribution varies widely—they may concentrate on the face and upper trunk, or predominantly in joint areas and lower extremities. 6
• Café-au-lait spots are present in approximately 75% of cases and can aid early diagnosis before lentigines develop. 3
• The rapid growth of lentigines during early childhood (ages 2-5 years) is a key diagnostic clue that should prompt consideration of LEOPARD syndrome. 6

Genetic Counseling

• Families should receive counseling regarding autosomal dominant inheritance with full penetrance and variable expressivity. 2
• If one parent is affected, recurrence risk is 50% for each pregnancy. 2
• Prenatal diagnosis via DNA testing on chorionic villi or amniotic fluid samples can be offered, particularly if severe cardiac hypertrophy is detected on fetal ultrasound. 2

Long-Term Prognosis

• With the exception of ventricular hypertrophy requiring ongoing surveillance, adults with LEOPARD syndrome do not require special medical care beyond routine health maintenance, and long-term prognosis is generally favorable. 2
• The primary determinant of long-term outcomes is the severity of cardiac involvement and adequacy of sudden death risk management. 2

Multidisciplinary Coordination

• Annual follow-up with a geneticist or clinician experienced with RASopathies is recommended for ongoing management coordination and updates on natural history. 1, 2
• Care coordination should involve cardiology, audiology, endocrinology, developmental pediatrics, and genetics at minimum. 1, 2