Birt-Hogg-Dubé syndrome: a large single family cohort

Abstract

BackgroundBirt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function.MethodsThe study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen.ResultsThirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35–7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41–29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results.ConclusionsThis is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden.

Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

“…The multiple pulmonary cysts observed in mutation carriers III-2 and III-3 support this idea. Therefore, it was difficult to calculate the accurate frequency of pulmonary involvement in this family without CT imaging; several previous reports with different sample sizes showed that the number ranges from 70% to 100% (15,(22)(23)(24). Late onset may also play a role in the reported difference in pulmonary involvement.…”

Birt-Hogg-Dubé Syndrome – report of two cases with two new mutations

“…[2][3][4] Changes in the activity of this protein, presumably with still unconfirmed tumor suppressor activity (via mTOR signaling), may favour the appearance of several of these skin malformations, lungs cysts and renal cancer. [2][3][4][5] Fibrofolliculoma and TD, the hallmarks of BHDS, are clinically indistinguishable and usually appear in individuals in their 20s or 30s and present as asymptomatic multiple, smooth, skin-colored or whitish, dome-shaped papules commonly located on the face (mainly on the nose, forehead and cheeks) although they can also appear on the neck and trunk. [1][2][3]5 Several authors point out that FF and TD (and even acrochorda) may actually represent different stages of evolution within one same lesion.…”

“…3 While the age-adjusted risk of pneumothorax is 50 times higher in patients with BHDS than in the general population, lung function is usually normal. 1,[3][4][5][6] Although there is no clear indication for routine CT scanning of the lungs in patients with BHDS, the demonstration of multiple lung cysts strengthens the diagnosis when it is in doubt. Symptomatic patients with lung lesions should have individualized follow-up and all should be reminded of the higher risk of pneumothorax with general anesthesia, during journeys in airplanes or aquatic activities such as diving.…”

“…[1][2][3][4][5][6][7][8][10][11][12] BHDS predisposes to benign hair follicle hamartomas known as fibrofolliculomas (FF) and trichodiscomas (TD), acrochorda; lung disease (bibasilar cysts and, less frequently, pneumothorax); and kidney neoplasms with different histologic presentations. [1][2][3][4][5][6][7][8][10][11][12] The incidence of this syndrome is unknown but it is probably underdiagnosed given its variable penetrance and consequent range of clinical manifestations. 1 We describe two patients with BHDS carrying new FLCN mutations, not previously described in literature, and one of them with a type of adrenal gland tumor associated for the first time to this syndrome.…”

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

“…The data on lung function in BHD are limited to case reports or small series [154, 163, 164]. In 14 patients with baseline data only, the pulmonary function test results were essentially normal with mean spirometric values within the normal range and minimally reduced DLCO [165].…”