Birt-Hogg-Dubé syndrome initially diagnosed as tuberous sclerosis complex

Pithadia, Deeti J.; Treichel, Alison; Lee, Chyi‐Chia Richard; Cowen, Edward W.; Linehan, W. Marston; Moss, Joel; Darling, Thomas N.

doi:10.1016/j.jdcr.2019.02.009

Cited by 9 publications

(7 citation statements)

References 10 publications

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“…Increased nuclear TFEB is a hallmark of BHD syndrome 24 , which has some clinical similarity to TSC (both diseases are associated with chromophobe/oncocytic RCCs, benign facial skin tumors, and cystic lung disease) 48 , 49 . BHD is caused by mutations in FLCN , a known GAP for RAGC/D 20 – 22 .…”

Section: Discussionmentioning

confidence: 99%

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

et al. 2021

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Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). Transcription factor EB (TFEB), a master regulator of lysosome biogenesis, is negatively regulated by mTORC1 through a RAG GTPase-dependent phosphorylation. Here we show that lysosomal biogenesis is increased in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, kidneys from Tsc2+/− mice, and TSC1/2-deficient cells via a TFEB-dependent mechanism. Interestingly, in TSC1/2-deficient cells, TFEB is hypo-phosphorylated at mTORC1-dependent sites, indicating that mTORC1 is unable to phosphorylate TFEB in the absence of the TSC1/2 complex. Importantly, overexpression of folliculin (FLCN), a GTPase activating protein for RAGC, increases TFEB phosphorylation at the mTORC1 sites in TSC2-deficient cells. Overexpression of constitutively active RAGC is sufficient to relocalize TFEB to the cytoplasm. These findings establish the TSC proteins as critical regulators of lysosomal biogenesis via TFEB and RAGC and identify TFEB as a driver of the proliferation of TSC2-deficient cells.

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Section: Discussionmentioning

confidence: 99%

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

et al. 2021

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“…Perifollicular fibromas [68,[87][88][89], connective tissue nevus [90], multiple angiomatous nodules [91], (angio)lipomas [18], periungual fibromas [92], angiofibromas [68,92,93] and intraoral papules [94] have also been described. The latter three may lead to a wrong diagnosis of tuberous sclerosis complex (TSC) [93], another genetic autosomal dominant disorder characterised by facial angiofibromas, ungual fibromas, kidney angiomyolipomas, retinal hamartomas, cortical tubers, subependymal giant cell astrocytomas and other hamartomatous lesions. In women, TSC is frequently associated with pulmonary LAM, another cystic lung disease characterised by recurrent pneumothorax and progressive destruction of the lung parenchyma.…”

Section: Cutaneous Manifestationsmentioning

confidence: 99%

“…Suspicion of BHD needs histological confirmation if skin lesions are present, which is the case in most families. Only histology can discriminate between fibrofolliculomas, trichodiscomas, perifollicular fibromas [82,88,98] or atypical angiofibromas [84,93], as they are clinically indistinguishable. It is also important to differentiate them from similar lesions such as trichofolliculomas, basaliomas and others.…”

Section: Skin Abnormalitiesmentioning

confidence: 99%

Birt–Hogg–Dubé syndrome

et al. 2020

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Birt–Hogg–Dubé syndrome (BHD) is a rare inherited autosomal dominant disorder caused by germline mutations in the tumour suppressor gene FLCN, encoding the protein folliculin. Its clinical expression typically includes multiple pulmonary cysts, recurrent spontaneous pneumothoraces, cutaneous fibrofolliculomas and renal tumours of various histological types. BHD has no sex predilection and tends to manifest in the third or fourth decade of life. Multiple bilateral pulmonary cysts are found on chest computed tomography in >80% of patients and more than half experience one or more episodes of pneumothorax. A family history of pneumothorax is an important clue, which suggests the diagnosis of BHD. Unlike other cystic lung diseases such as lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis, BHD does not lead to progressive loss of lung function and chronic respiratory insufficiency. Renal tumours affect about 30% of patients during their lifetime, and can be multiple and recurrent. The diagnosis of BHD is based on a combination of genetic, clinical and/or skin histopathological criteria. Management mainly consists of early pleurodesis in the case of pneumothorax, periodic renal imaging for tumour detection, and diagnostic work-up in search of BHD in relatives of the index patient.

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“…The notable cutaneous findings include angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, periungual fibromas, and café-au-lait macules. 1 BHDS—Correct. BHDS is a rare genodermatosis with an AD inactivating mutation of the FLCN gene.…”

mentioning

confidence: 98%

“…The notable cutaneous findings include angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, periungual fibromas, and café-au-lait macules. 1 …”

mentioning

confidence: 99%