A 35-year-old man presents with multiple skin-colored dome-shaped papules on his face and neck that have been slowly enlarging over the past 5 years. He also reports a recent episode of spontaneous pneumothorax. Genetic testing reveals a pathogenic mutation in the FLCN gene located at the locus marked **B** in the diagram. Which of the following best describes the molecular consequence of this mutation in Birt-Hogg-Dubé syndrome?
A. Biallelic inactivation of the VHL tumor suppressor gene leading to constitutive HIF-1α stabilization and clear cell renal carcinoma
B. Haploinsufficiency of the PTEN gene resulting in unopposed PI3K/AKT pathway activation and hamartoma formation
C. Expansion of trinucleotide repeats in the FMR1 gene causing silencing of fragile X mental retardation protein
D. Loss of folliculin function leading to dysregulated mTORC1 and AMPK signaling, promoting uncontrolled cell proliferation in skin, kidney, and lung tissues
Explanation
Why "Loss of folliculin function leading to dysregulated mTORC1 and AMPK signaling..." is right
The FLCN gene at chromosome 17p11.2 (marked B) encodes the tumor suppressor folliculin. Germline mutations in FLCN cause Birt-Hogg-Dubé syndrome through loss-of-function, which disrupts the normal regulation of mTORC1 and AMPK signaling pathways. This dysregulation drives uncontrolled cell proliferation in the skin (fibrofolliculomas), lungs (cysts with pneumothorax risk), and kidneys (chromophobe RCC and hybrid oncocytic tumors). This is the pathogenic mechanism directly stated in Harrison's 21e and the Menko 2009 consensus definition.
Why each distractor is wrong
Haploinsufficiency of the PTEN gene...: PTEN mutations cause Cowden syndrome with hamartomas and increased breast/thyroid cancer risk, not BHD. The clinical triad (fibrofolliculomas, lung cysts, renal tumors) and the 17p11.2 locus are specific to FLCN, not PTEN.
Expansion of trinucleotide repeats in FMR1...: FMR1 mutations cause Fragile X syndrome with intellectual disability and macro-orchidism, not the cutaneous and pulmonary manifestations of BHD. This mechanism is unrelated to chromosome 17p11.2.
Biallelic inactivation of VHL...: VHL mutations cause von Hippel-Lindau syndrome, which presents with clear cell renal carcinoma (not chromophobe RCC), hemangioblastomas, and pheochromocytomas—not fibrofolliculomas or pneumothorax. VHL is located on chromosome 3p, not 17p11.2.
High-YieldNEET PG
BHD = FLCN at 17p11.2 → dysregulated mTORC1/AMPK → fibrofolliculomas + lung cysts + chromophobe RCC (not clear cell, which is VHL).
