Random Dermatology MCQ - LEOPARD syndrome

A 12-year-old boy is evaluated for multiple lentigines on his face and trunk. He has a heart murmur, hypertelorism, and a history of mild developmental delay. An ECG shows conduction abnormalities. His father has similar skin findings and a history of hypertrophic cardiomyopathy. Which of the following is the most likely diagnosis and its underlying genetic defect?

A) LEOPARD syndrome; PTPN11 mutation
B) Neurofibromatosis type 1; NF1 mutation
C) Noonan syndrome; PTPN11 mutation
D) Peutz-Jeghers syndrome; STK11 mutation
E) Carney complex; PRKAR1A mutation

Correct Answer: A) LEOPARD syndrome; PTPN11 mutation

Explanation

This presentation is classic for LEOPARD syndrome, a rare autosomal dominant disorder. LEOPARD is an acronym for its key features.

Key Features of LEOPARD Syndrome (Acronym):

• L - Lentigines: Multiple small, dark brown to black macules, present since childhood, often more numerous on the face, neck, and upper trunk.

• E - ECG abnormalities: Conduction defects (e.g., prolonged PR interval, bundle branch block).

• O - Ocular hypertelorism: Widely spaced eyes.

• P - Pulmonary stenosis: The most common cardiac anomaly, though hypertrophic cardiomyopathy can also occur.

• A - Abnormalities of genitalia (e.g., cryptorchidism).

• R - Retardation of growth: Short stature.

• D - Deafness: Sensorineural deafness.

The case describes lentigines, hypertelorism, developmental delay, ECG abnormalities, and a family history consistent with autosomal dominant inheritance, including cardiac involvement.

Genetic Defect and Pathophysiology:

• Gene: Mutations in the PTPN11 gene on chromosome 12q24.1.

• Mechanism: PTPN11 encodes the protein SHP-2, a non-receptor protein tyrosine phosphatase that is a critical component of several intracellular signal transduction pathways (e.g., RAS/MAPK pathway). The mutations in LEOPARD syndrome are typically loss-of-function, in contrast to the gain-of-function mutations in the same gene that cause Noonan syndrome.

Why Not the Other Options?

• (B) Neurofibromatosis type 1 (NF1): Features café-au-lait macules, axillary freckling, and neurofibromas, not primarily lentigines. Cardiac involvement is not a defining feature.

• (C) Noonan syndrome: Shares the same genetic locus (PTPN11) and many features with LEOPARD syndrome (e.g., short stature, pulmonic stenosis, hypertelorism), but it is characterized by different skin findings (e.g., curly hair, lymphedema) and typically lacks the profuse lentigines that define LEOPARD syndrome.

• (D) Peutz-Jeghers syndrome: Features mucocutaneous melanotic macules (primarily on the lips, oral mucosa, and perioral area) and gastrointestinal hamartomatous polyps.

• (E) Carney complex: Features lentigines (especially on the lips and conjunctiva), cardiac myxomas, and endocrine overactivity, but not the specific constellation of features in the LEOPARD acronym.

Management:

• Multidisciplinary approach: Cardiology (echiocardiogram, ECG), audiology, endocrinology, and genetics.

• Surveillance: Regular cardiac and hearing evaluations.

Prognosis:
Depends on the severity of cardiac involvement. The lentigines are benign but cosmetically concerning.

Note: LEOPARD syndrome is part of the "RASopathies," a group of disorders caused by mutations in genes encoding components of the RAS/MAPK signaling pathway. The presence of multiple lentigines in combination with any cardiac abnormality or dysmorphic facial features should raise suspicion for this syndrome.