A 16-year-old girl presents with episodic palpitations, sweating, headaches, and paroxysmal hypertension (BP 220/130 mmHg during episodes). On examination, she is noted to have multiple light-brown oval cutaneous macules with smooth borders measuring 1–4 cm scattered over the trunk and limbs, as marked **A** in the diagram. She also has axillary freckling, multiple cutaneous neurofibromas, and a large plexiform neurofibroma over the left thigh. Slit-lamp examination reveals Lisch nodules bilaterally. Plasma free metanephrines are markedly elevated, and imaging confirms a 5-cm right adrenal mass. Which of the following BEST explains the pathophysiologic basis for the multiple cutaneous and systemic manifestations in this patient?

Question

Accepted Answer

D. Loss-of-function mutation in the NF1 gene encoding neurofibromin, a RAS-GTPase-activating protein, leading to unrestrained RAS-MAPK signaling and tumor predisposition. ## Why Loss-of-function mutation in the NF1 gene is correct

The clinical presentation—multiple café-au-lait macules (marked **A**), axillary freckling (Crowe sign), neurofibromas, Lisch nodules, and a pheochromocytoma—fulfills the NIH diagnostic criteria for neurofibromatosis type 1 (NF1). The NF1 gene at 17q11.2 encodes neurofibromin, a RAS-GTPase-activating protein (RAS-GAP) that normally downregulates RAS-MAPK signaling. Loss of neurofibromin function removes this brake on RAS, leading to constitutive RAS-MAPK pathway activation. This unrestrained signaling drives proliferation of neural crest-derived cells (melanocytes forming CALMs, Schwann cells forming neurofibromas) and predisposes to multiple tumors including pheochromocytoma (~3–5% of NF1 patients). NF1 is an autosomal dominant tumor suppressor syndrome with complete penetrance. (Nelson Textbook of Pediatrics 21e; Harrison's 21e)

## Why each distractor is wrong

- **Gain-of-function mutation in GNAS**: This causes McCune-Albright syndrome, characterized by café-au-lait macules with irregular "coast-of-Maine" margins (not smooth "coast-of-California" margins as in this patient), fibrous dysplasia, precocious puberty, and endocrinopathies—NOT neurofibromas or Lisch nodules.
- **Loss-of-function mutation in VHL**: This causes von Hippel-Lindau syndrome, characterized by renal clear-cell carcinoma, hemangioblastomas, pheochromocytoma, and pancreatic cysts—but NOT café-au-lait macules, neurofibromas, or Lisch nodules.
- **Inactivating mutation in RET**: This causes familial medullary thyroid carcinoma and MEN2 syndromes, with pheochromocytoma risk but NO cutaneous neurofibromas, CALMs, or Lisch nodules.

**High-Yield:** NF1 = loss of RAS-GAP → unrestrained RAS-MAPK → neurofibromas + CALMs + Lisch nodules + pheochromocytoma risk; smooth CALM margins distinguish NF1 from McCune-Albright (irregular margins).

[cite: Nelson Textbook of Pediatrics 21e; Harrison's 21e]

Answer

A. Gain-of-function mutation in the GNAS gene encoding the α-subunit of stimulatory G protein, causing constitutive cAMP elevation

Answer

B. Inactivating mutation in the RET proto-oncogene, resulting in impaired tyrosine kinase signaling in neural crest-derived cells

Answer

C. Loss-of-function mutation in the VHL gene encoding the von Hippel-Lindau protein, impairing HIF-1α degradation

Explanation

Why Loss-of-function mutation in the NF1 gene is correct

Why each distractor is wrong

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