It can cause susceptibility to kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles, called fibrofolliculomas.

Pulmonary cysts are equally common (84%) and 24% of people with BHD eventually experience a collapsed lung (spontaneous pneumothorax).

Any of these conditions that occurs in a family can indicate a diagnosis of Birt–Hogg–Dubé syndrome, though it is only confirmed by a genetic test for a mutation in the FLCN gene, which codes for the protein folliculin.

Versions of FLCN have been found in other animals, including fruit flies, German Shepherds, rats, and mice.

The condition is characterized by multiple noncancerous, dome-shaped tumors of the hair follicles (fibrofolliculomas), particularly on the face, neck, and more rarely, the upper chest.

[5] Tumors differ between individuals; they may appear merged in plaques, look similar to a comedo with a plug of keratin, or include epidermoid cysts.

About 40% of people or families with the disease have papules in their mouths, which can be located on the cheeks (buccal mucosa), tongue, gums, or lips.

[9] Though the types of tumors typically associated with BHD are considered less aggressive, cases of advanced or metastatic kidney cancer have been observed in people with the syndrome.

Mutations in the FLCN gene may interfere with the ability of folliculin to restrain cell growth and division, leading to the formation of noncancerous and cancerous tumors.

Recent studies suggest that folliculin accomplishes this function through its involvement with cellular metabolism, possibly through modulation of the mTOR (mammalian target of rapamycin) pathway and/or oxidative phosphorylation in mitochondria.

The lysine at this position is found to be conserved between invertebrate and vertebrate orthologs of folliculin, indicating that it is important to the protein's function.

[18] BHD can be suggested by clinical findings but is definitively diagnosed by molecular genetic testing to detect mutations in the FLCN gene.

The classical clinical triad includes benign growths of the hair follicles, pulmonary cysts and spontaneous pneumothorax, and bilateral, multifocal renal tumors.

Genetic testing can be useful to confirm the clinical diagnosis and to provide a means of determining other at-risk individuals in a family even if they have not yet developed BHD symptoms.

[5][6] BHD can be difficult to diagnose from symptoms alone, because hereditary renal cancers, pneumothorax, and cutaneous tumors occur with other syndromes.

Other diseases can mimic the dermatologic manifestations of BHD, including tuberous sclerosis complex, Cowden syndrome, familial trichoepitheliomas, and multiple endocrine neoplasia type 1.

The fibrofolliculomas can be removed surgically, through curettage, shave excision, skin resurfacing, or laser ablation; this is not a permanent solution, though, as the tumors often recur.

[19] The renal and pulmonary symptoms are generally managed preventatively: CT scans, ultrasounds, or MRIs of the kidneys are recommended regularly, and family members are advised not to smoke.

[2] However, surgical interventions such as video assisted thoracoscopy (VATS) and mechanical or chemical pleurodesis should be considered in case of recurrent pneumothorax.

[20] MRIs are the preferred method for surveillance of the kidneys in people with BHD because they do not carry the same risk of radiation complications as CT scans, and are more sensitive than ultrasounds.

[5] Knockout mouse studies have shown that administration of rapamycin may mitigate the effects of FLCN mutations on kidneys and improve renal cancer prognoses because of folliculin's interaction with the mTOR pathway.

[5] Birt-Hogg-Dubé Syndrome patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry.

This is a privacy-protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

[3] The first case of BHD with the systemic symptoms was described by Hornstein and Knickenberg and found in two siblings and their father, all of whom exhibited colon polyps and the characteristic fibrofolliculomas.

[5] Birt, Hogg, and Dubé examined a family with a hereditary thyroid cancer, and discovered that many of the members had fibrofolliculomas, trichodiscomas, and acrochordons, which became defined as the classical symptoms of the eponymous disease.

[26][27][28] Genes related to FLCN and diseases similar to BHD have been found in dogs, fruit flies, rats, and mice.

In German Shepherd dogs, missense mutations in the canine ortholog of FLCN cause a similar phenotype to human BHD—kidney cancers (in this case, multifocal renal cystadenocarcinoma) and skin tumors (nodular dermatofibrosis).

They had a similar pattern of tumorigenesis to human BHD in that the skin lesions were heterozygous for the FLCN mutation, and the renal tumors were likely caused by loss of heterozygosity.

They have a mutation in the FLCN homolog that produces a truncated protein, though they do not develop the cutaneous or pulmonary symptoms seen in humans.

[6] Knockout mice have been created for a kidney-cancer causing mutation of BHD; heterozygotes develop kidney cysts and tumors that lead to renal failure within three weeks of birth.