Birt–Hogg–Dubé syndrome and intracranial vascular pathologies

Abstract

Birt-Hogg-Dubé syndrome, first described in 1977, is a rare autosomal dominant condition that commonly presents with skin lesions, including fibrofolliculomas and trichodiscomas; pulmonary cysts; spontaneous pneumothoraces; and renal cancer. We present the only known cases of intracranial vascular pathologies in patients with Birt-Hogg-Dubé syndrome. We present three cases (three female; age range 18-50) of intracranial vascular lesions in Birt-Hogg-Dubé patients, including two aneurysms and one arteriovenous malformation, and review one previously reported case of carotid aplasia. Due to the rarity of Birt-Hogg-Dubé syndrome and significant variations in its clinical presentation, it is difficult to assess whether or not Birt-Hogg-Dubé patients are predisposed to intracranial vascular pathologies. We hypothesize that increased transcription of hypoxia-inducible factor 1-alpha, resulting from a mutated form of the protein folliculin transcribed by the Birt-Hogg-Dubé gene, may be associated with vascular pathogenesis in Birt-Hogg-Dubé patients and thus provide a possible molecular basis for a link between these two conditions.

Birt-Hogg-Dube syndrome accompanied by pulmonary arteriovenous malformation

“…Association of pulmonary arteriovenous malformation with BHD syndrome has not been previously reported; therefore, the relationship is unknown. Kapoor et al hypothesize that mutated FLCN may affect hypoxia-inducible factor 1-alpha (HIF-1α) activation and implicate in vascular malformation on intracranial vascular pathology (6). Clarification of the relationship between pulmonary arteriovenous malformation and BHD syndrome is anticipated through the accumulation of more BHD syndrome cases.…”

A Case of Birt-Hogg-Dubé Syndrome and Multiple Intracranial Aneurysms

“…So far, these cases include two patients with intracranial aneurysms, one with an arteriovenous malformation (AVM) and one with carotid aplasia [2]. There is a hypothesized link between the BHD gene mutation and vascular pathology, although this is yet to be proven definitively [3][4][5]. Here we describe a case of a patient with BHD syndrome and multiple intracranial aneurysms.…”

Genetically diagnosed Birt–Hogg–Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report

“…However, the range of tumours associated with mutations in a particular gene may expand as more cases are uncovered through research or clinical testing. Recently it has been proposed that intracranial vascular pathologies may also form part of this condition following the report of three BHD patients with a saccular aneurysm, an arteriovenous malformation and a carotid artery aneurysm [1]. …”

“…One consequence of upregulation of the mTOR pathway is increased HIF1-α activity [4], which has been observed in a patient derived renal tumour cell line null for FLCN gene product [5]. It has therefore been proposed (given the role of HIF1-α in angiogenesis) as a mechanism leading to an elevated risk of intracranial vascular pathology in patients harbouring FLCN mutations [1]. …”

“…Genetic investigations revealed constitutional mutations in FLCN , associated with Birt–Hogg–Dubé syndrome (BHD) and CCM2 , associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al in Fam Cancer 14:595–597, 10.1007/s10689-015-9807-y, 2015) but it is not yet clear whether they represent a genuine part of that conditions’ phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available.…”