Random Dermatology MCQ - Neurofibromatosis Type 1

A 10-year-old boy presents with multiple café-au-lait macules and freckling in the axillary and inguinal regions. His mother has similar skin findings and a history of bilateral acoustic neuromas. Which of the following is the most likely diagnosis and its associated genetic defect?

A) Neurofibromatosis type 2; NF2 (merlin) mutation
B) Neurofibromatosis type 1; NF1 (neurofibromin) mutation
C) McCune-Albright syndrome; GNAS1 mutation
D) Legius syndrome; SPRED1 mutation
E) Tuberous sclerosis; TSC1 or TSC2 mutation

Correct Answer: B) Neurofibromatosis type 1; NF1 (neurofibromin) mutation

Explanation

This presentation is classic for Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease. The history in the mother is misleading; bilateral acoustic neuromas are the hallmark of NF2, not NF1. This tests attention to detail—the patient's findings are pure NF1.

Key Diagnostic Criteria for NF1 (NIH Consensus Conference):

Two or more of the following are required for diagnosis:

1. Six or more café-au-lait macules (>5 mm in prepubertal, >15 mm in postpubertal individuals).

2. Axillary or inguinal freckling (Crowe's sign).

3. Two or more neurofibromas of any type or one plexiform neurofibroma.

4. Optic glioma.

5. Two or more Lisch nodules (iris hamartomas).

6. A distinctive osseous lesion (e.g., sphenoid wing dysplasia).

7. A first-degree relative with NF1.

This patient meets criteria 1, 2, and 7.

Genetic Defect and Pathophysiology:

• Gene: Mutations in the NF1 gene on chromosome 17q11.2.

• Protein: The NF1 gene encodes neurofibromin, a large protein that functions as a GTPase-Activating Protein (GAP) for the RAS oncoprotein.

• Mechanism: Loss of neurofibromin leads to constitutive activation of the RAS/MAPK signaling pathway, promoting cell proliferation and tumorigenesis. This explains the development of benign tumors (neurofibromas) and the increased risk of malignant peripheral nerve sheath tumors (MPNST).

Why Not the Other Options?

• (A) Neurofibromatosis type 2 (NF2): Characterized by bilateral vestibular schwannomas (acoustic neuromas), meningiomas, and ependymomas. Skin findings are much less prominent (fewer café-au-lait macules, no axillary freckling). Caused by mutations in the NF2 gene (merlin/schwannomin).

• (C) McCune-Albright syndrome: Features café-au-lait macules that are typically large, unilateral, and have a "coast of Maine" border. Associated with polyostotic fibrous dysplasia and precocious puberty. Caused by postzygotic GNAS1 mutations.

• (D) Legius syndrome: Can mimic NF1 with café-au-lait macules and axillary freckling, but Lisch nodules, neurofibromas, and optic gliomas are absent. Caused by SPRED1 mutations, which also dysregulate the RAS/MAPK pathway.

• (E) Tuberous sclerosis: Features hypomelanotic macules (ash-leaf spots), facial angiofibromas, shagreen patches, and seizures, not café-au-lait macules.

Management:

• Multidisciplinary care: Annual ophthalmologic exams, blood pressure monitoring, neurologic and developmental assessments.

• MRI for symptomatic or progressive lesions.

• Genetic counseling.

Prognosis:
Variable. Most have a normal life expectancy, but complications include learning disabilities, plexiform neurofibromas, optic gliomas, and MPNST risk.

Note: The combination of café-au-lait macules and axillary/inguinal freckling is highly specific for NF1. While the mother's history of "acoustic neuromas" is a distractor for NF2, the patient's own findings fulfill the criteria for NF1. It is possible the mother was misdiagnosed or has a rare overlap.