Birt–Hogg–Dube syndrome

Executive Summary

Birt–Hogg–Dube syndrome (BHD) is a human autosomal dominant genetic disorder resulting in a high risk of kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles known as fibrofolliculoma. Fibrofolliculomas are the most prevalent manifestation of BHD among individuals belonging to the age group above 40 years. Around 84% of individuals have pulmonary cysts, while 24% of individuals with BHD will have collapsed lungs, and 14-34% tend to develop kidney tumors. Almost 100 families are globally affected by this syndrome. Women and people of both sexes with late-onset skin complaints have less severe skin phenotypes. The symptom of Birt–Hogg–Dube syndrome is similar to other disorders such as Tuberous sclerosis and Von Hippel–Lindau disease. It is diagnosed if the chances of disease occurrence are found among the individuals. The diagnosis is confirmed by performing genetic testing for a mutation in the FLCN gene that codes for protein folliculin. Also, medical imaging is used to monitor the kidneys and lungs. Surgery is the most common treatment. Skin, lungs, kidneys and other organs such as thyroid nodules are affected by Birt–Hogg–Dube syndrome. Curettage, shave excision, skin resurfacing, or laser ablation have been integrated for surgical removal of fibrofolliculomas. Preventative measures are taken to treat renal and pulmonary symptoms, such as regular CT scans, ultrasounds, or MRIs.

What is Birt–Hogg–Dube syndrome?

Birt–Hogg–Dube syndrome (BHD), also known as Hornstein–Birt–Hogg–Dube syndrome, Hornstein–Knick Enberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons, is a human autosomal dominant genetic disorder that increases the risk of kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles known as fibrofolliculoma ^​1​. Each family’s symptoms are different and can contain any mix of the three signs. Fibrofolliculomas are the most prevalent manifestation of BHD in persons over 40, with over 80% of people with BHD having them on their face and upper trunk. Although pulmonary cysts are widespread (84 per cent), only 24% of persons with BHD will eventually have a collapsed lung (spontaneous pneumothorax) ^​2​. 14–34 per cent of persons with BHD develop kidney tumors, both malignant and benign, and the associated kidney malignancies are frequently rare hybrid tumors.

Birt–Hogg–Dube syndrome can be diagnosed if these disorders occur in a family. However, only a genetic test for a mutation in the FLCN gene, which codes for the protein folliculin, can confirm the diagnosis. It appears to be a tumor suppressor gene that limits cell growth and division, while its function is unknown. FLCN has been discovered in various animals, including fruit flies, German Shepherds, rats, and mice. The condition was found in 1977, but the link to FLCN was not established until 2002, when BHD was firmly linked to kidney cancer, collapsed lungs, and pulmonary cysts.

Birt–Hogg–Dube syndrome has symptoms similar to those of other disorders, which must be checked out before making a diagnosis. Tuberous sclerosis, which causes skin lesions that resemble fibrofolliculomas, and Von Hippel–Lindau disease, which causes hereditary kidney malignancies, are two of these diseases. People with BHD are treated preventatively once diagnosed, with medical imaging used to monitor the kidneys and lungs.

Pneumothorax and kidney cancer are treated according to the standard of care, and fibrofolliculomas can be surgically removed. Skin signs and symptoms

Individuals with Birt–Hogg–Dube syndrome display typical face fibrofolliculomas.

The epidermis is affected by Birt–Hogg–Dube syndrome, which raises the risk of malignancies in the kidneys and lungs. Multiple noncancerous, dome-shaped tumors of the hair follicles (fibrofolliculomas) appear on the face, neck, and, less commonly, the upper chest with this illness. The fibrofolliculomas are usually opaque white or yellowish, with a waxy, smooth feel. Tumors are always observed on and around the nose and on and behind the outer ear. They usually occur in a person’s 20s or 30s and are prevalent in more than 80% of those over 40 who have the condition.

Over time, the tumours grow more extensive and more numerous. Tumours can seem united in plaques, like a comedy with a keratin plug, or comprise epidermoid cysts, depending on the individual. Hyper seborrhea is linked to various facial cancers (abnormally elevated sebum production). The presence of fibrofolliculomas on a person’s face can cause a great deal of mental anguish.

Trichodiscomas (hair disc tumours similar to fibrofolliculomas), angiofibroma, and perifollicular fibromas are other malignancies. Angiofibromas, on the other hand, are more common in tuberous sclerosis. Other skin disorders are seen in persons with Birt–Hogg–Dubé syndrome, in addition to malignancies. Papules can be found on the cheeks (buccal mucosa), tongue, gums, or lips in about 40% of people or families who have the illness. They are white or mucosa-coloured, distinct, tiny, soft, and fibrous tissue covered by thicker epithelium.

Skin collagenomas are also prevalent in some families. Skin lesions that appear to be acrochordons (skin tags) but are fibrofolliculomas are common in persons with BHD. The armpit, eyelids, and skin creases are the most common locations for these lesions. Not everyone with the Birt–Hogg–Dube syndrome mutation develops facial tumours; some families with the gene only have kidney tumours or spontaneous pneumothorax.

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Kidneys

H&E staining of tissue from chromophobe renal cell carcinoma, the second most prevalent malignancy linked to Birt–Hogg–Dubé syndrome.

Slow-growing kidney tumours (chromophobe renal carcinoma and renal oncocytoma, respectively) are more common in those over 20 years old with BHD than kidney cysts and perhaps tumours in other organs and tissues ^​3​. Tumors in both kidneys and various places in each kidney are common. A person with BHD is likely to have 5.3 kidney tumors on average.

The most prevalent cancer is hybrid oncocytoma/chromophobe carcinoma, which is seen in 50% of cases, followed by chromophobe renal carcinoma, clear cell renal carcinoma, renal oncocytoma, and papillary renal cell carcinoma. Kidney tumors are more common in those over 40 and in men, with a median age of diagnosis of 48. BHD has been linked to kidney cancer in people as young as 20.

In general, patients with this syndrome have a seven-fold increased risk of kidney cancer compared to the general population. The condition’s prevalence is estimated to be between 14 and 34 per cent among those who have it. On rare occasions, it’s linked to clear cell renal cell carcinoma and papillary renal cell carcinoma. Renal cell carcinoma develops later in BHD and has a bad prognosis.

Though the tumors associated with Birt–Hogg–Dube syndrome are generally less aggressive, advanced or metastatic kidney cancer has been seen in patients with the disease. As tumours get larger, both benign and malignant tumours can compromise kidney function.

Lungs In addition to fibrofolliculomas and kidney tumors, affected people often develop cysts (blebs or bullae) in the subpleural lung base or intraparenchymal area, which can rupture and create a pneumothorax (abnormal collection of air in the chest cavity), which can lead to lung collapse. Other than the cysts, there are no other symptoms. The function of the lungs is usually expected. Cysts affect more than 83 per cent of persons with Birt–Hogg–Dube syndrome. Despite this, the syndrome does not induce chronic obstructive pulmonary disease (COPD) or generalized respiratory failure. It does, however, cause emphysema.

With BHD, spontaneous, recurrent pneumothorax occurs considerably more frequently and at a younger age than in general. Around 24% of patients with the condition experience at least one spontaneous pneumothorax, which is 30 times higher than the rate in the general population. Though BHD-related pneumothorax is most common in middle age, 17 per cent of those affected suffer a spontaneous pneumothorax before turning 40, at a median age of 38. Pneumothoraxes have been seen in children as young as seven and as old as sixteen. A kind of BHD that solely damages the lungs affects some families.

Organs not listed above

Thyroid nodules have been linked to the Birt–Hogg–Dube phenotype, found in 65 per cent of people with the syndrome and 90 per cent of families. The link between Birt–Hogg–Dube syndrome and thyroid cancer, on the other hand, has not been proven. Other disorders have been linked to the FLCN mutation, but they may or may not be caused by it, or they may not be related at all.

Multinodular goitre, medullary thyroid carcinoma, parotid oncocytoma, colonic polyposis, connective tissue nevus, lipomas, angiolipomas, parathyroid adenomas, flecked chorioretinopathy, neurothekeoma, meningiomas, facial angiofibromas, trichoblastoma, cutaneous focal mucinosis, cutaneous leiomyoma,

Pathophysiology

Genetics

The diseased parent produces half mutant and half normal gametes, while the unaffected parent produces all normal (sperm and egg). Because an autosomal dominant disease requires only one copy of the mutation, each offspring has a 50% chance of mutating.

In 2002, a link to the folliculin (FLCN) gene was discovered for the first time. This 14-exon gene is found on chromosome 17’s short arm and features a cytosine-rich region in exon 11 that is particularly sensitive to mutation. In 53 per cent of BHD-affected families, the insertion or deletion of a cytosine residue is the most prevalent change in this location. There is no discernible difference in the symptoms reported by families with an insertion versus those who have a deletion at that site. Still, mutations in FLCN linked to Birt–Hogg–Dubé syndrome are diverse, and most are nonsense or frameshift mutations that result in early carboxy-terminus truncation of the protein product. Missense mutations are incredibly uncommon. Birt-Hogg-Dubé syndrome is caused by germline mutations in the FLCN gene, which means they occur in every body cell and can be handed down to future generations ^​4​. The disease has a 50% probability of infecting the offspring of an infected parent. The penetration of BHD is high. There hasn’t been any evidence of a link between distinct FLCN genotypes and phenotypes.

Function

FLCN produces two isoforms of the protein folliculin. It is highly expressed in the epidermis, distal nephrons, and type I pneumocytes and appears to operate as a tumor suppressor. The parotid gland, brain, breast, pancreas, prostate, and ovaries have all been discovered to contain it. Tumor suppressors stop cells from dividing and developing too quickly or uncontrolled. The ability of folliculin to control cell growth and division may be harmed by mutations in the FLCN gene, resulting in noncancerous and cancerous tumors. Recent research suggests that folliculin achieves this function by interfering with cellular metabolism, presumably by modulating the mTOR (mammalian target of rapamycin) pathway and mitochondrial oxidative phosphorylation.

Folliculin forms a complex with AMP-activated protein kinase by interacting with FNIP1 and FNIP2 (FLCN-interacting proteins). Folliculin’s role in the mTOR pathway could explain why BHD syndrome, Cowden syndrome, tuberous sclerosis, and Peutz–Jeghers disease have comparable phenotypes. The carboxy terminus of the protein is shortened in the majority of cancer-causing mutations. Folliculin’s C-terminal end has been discovered to be the domain through which it interacts with FNIP1, hence, the mTOR pathway. FLCN is highly conserved in vertebrates, with many vertebrate species having very similar FLCN. A missense mutation affects the 508th amino acid, typically lysine, in persons with BHD. The lysine at this position is conserved in both invertebrate and vertebrate folliculin orthologs, implying that it is required for the protein’s function.

The FLCN gene, which is found on the p arm of human chromosome 17, encodes folliculin. Each cell with Birt–Hogg–Dubé syndrome cell has one mutant copy of the FLCN gene. The fibrofolliculomas and pulmonary cysts are caused by haploinsufficiency or having just one functioning copy of the FLCN gene. One copy of the gene, on the other hand, is sufficient to keep kidney cells in check. Random mutations may inactivate the normal copy of the gene in a subpopulation of cells during a person’s lifespan. When this happens, the cells lose their ability to control their growth because they no longer have functional copies of the FLCN gene. This loss of heterozygosity is a typical cancer mechanism, and it is frequently observed in BHD-related kidney malignancies.

The molecular genetic faults in renal tumours in persons with BHD are distinct from chromophobe renal cell carcinoma and renal oncocytoma, two other kidney malignancies with similar molecular congenital disabilities. The kidney, where the loss of FLCN heterozygosity causes malignancies, and the epidermis, where FLCN is prominently expressed in heterozygotes, are two different types of BHD-associated carcinogenesis. FLCN is overexpressed in fibrofolliculoma tissue and expressed at extremely low levels in the affected kidneys. Furthermore, the mTOR pathway is active in human and mouse tumour tissue. In BHD, TFEB activity is constant, promoting renal cystogenesis and tumorigenesis.

BHD is diagnosed by molecular genetic testing to discover mutations in the FLCN gene, which can be suggested by clinical findings but is identified by molecular genetic testing to detect mutations in the FLCN gene. Hair follicle benign growths, pulmonary cysts and spontaneous pneumothorax, and bilateral, multifocal kidney tumours make up the traditional clinical triad.

Triad of clinical symptoms

Initially, fibrofolliculomas (abnormal hair follicle growths), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, typically observed on the face), and acrochordons were used to define the cutaneous symptoms of Birt–Hogg–Dubé syndrome (skin tags). Histology confirms the cutaneous symptoms. Most people with BHD (89%) have several cysts in both lungs, and 24% have had one or more pneumothorax events. A chest CT scan can reveal the cysts. Renal tumors can take the form of several types of renal cell carcinoma; however, some pathological subtypes (such as chromophobe, oncocytoma, and oncocytic hybrid tumors) are more common. Even though the original condition was diagnosed based on cutaneous data, people with BHD can have pulmonary and renal symptoms without skin abnormalities. Though these symptoms suggest BHD, only a genetic test for FLCN mutations can prove it.

Testing for genetic mutations

FLCN mutations are found in 88 percent of probands with this condition when DNA is sequenced. This suggests that some persons with clinical diagnoses have mutations that aren’t detectable by present technology. Changes in a previously unknown gene could be to blame in a few cases. Amplification and deletions in exonic areas are also investigated. Even if they have not yet experienced Birt–Hogg–Dubé syndrome symptoms, genetic testing can help confirm the clinical diagnosis and identify other at-risk persons in a family.

Differential Diagnosis 

Tuberous sclerosis affects the subject in this photograph. Tuberous sclerosis skin lesions (angiofibromas) must be separated from BHD’s distinctive fibrofolliculomas, primarily found on the face.

Because hereditary kidney malignancies, pneumothorax, and cutaneous tumors occur with other diseases, BHD can be difficult to identify based on symptoms alone. Von Hippel–Lindau disease (clear cell renal cell carcinoma), hereditary papillary renal cancer (papillary renal cell carcinoma), hereditary leiomyomatosis, and renal cell cancer syndrome can all cause bilateral, multifocal kidney disease tumors identical to those found in BHD. They can be distinguished by looking at the histology of the tumors.

Marfan disease, Ehlers–Danlos syndrome, tuberous sclerosis complex, alpha1-antitrypsin deficiency, and cystic fibrosis are linked to hereditary recurrent pneumothorax or pulmonary cysts.

Langerhans cell histiocytosis and lymphangioleiomyomatosis can cause nonhereditary recurrent pneumothorax and pulmonary cysts. These conditions are distinguished from BHD by reviewing the patient’s medical history and physical examination. It may be required to rule out pulmonary or thoracic endometriosis in women suspected of having the illness.

Even though fibrofolliculomas are peculiar to Birt–Hogg–Dubé syndrome, their appearance might be unclear and must be validated histologically. Tuberous sclerosis complex, Cowden syndrome, familial trichoepitheliomas, and multiple endocrine neoplasia type 1 can all mimic the dermatologic signs of BHD. Tuberous sclerosis and angiofibroma on the face can occur in both illnesses, while angiofibroma is more common in tuberous sclerosis.

Management

The varied symptoms of BHD are managed in a variety of methods. Curettage, shave excision, skin resurfacing, or laser ablation can be used to remove fibrofolliculomas surgically; however, this is not a permanent solution because the tumors frequently reappear. Preventative measures are taken to treat renal and pulmonary symptoms: regular CT scans, ultrasounds, or MRIs of the kidneys are indicated, and family members are encouraged not to smoke ^​5​. Because MRIs do not have the same radiation risks as CT scans and are more sensitive than ultrasounds, they are the preferred tool for monitoring the kidneys in persons with Birt–Hogg–Dubé syndrome. Nonsmokers have more severe lung symptoms than smokers with Birt–Hogg–Dubé. Though nephrectomy is sometimes necessary, in situations of BHD, kidney tumors are frequently eliminated without removing the entire kidney in partial nephrectomy. According to knockout mice experiments, the use of rapamycin may attenuate the effects of FLCN mutations on the kidneys.

Epidemiology

The condition is inherited in an autosomal dominant form and recorded in more than 100 families globally; however other sources claim up to 400 families. Because of the wide range of symptoms, it is underdiagnosed. Individuals have a different patterns of mutations and a different range of symptoms. Women and people of both sexes with late-onset skin complaints have less severe skin phenotypes.

a patient database

Patients, relatives, and caregivers with Birt–Hogg–Dubé syndrome is urged to join the NIH Rare Lung Diseases Consortium Contact Registry. Individuals interested in the latest scientific news, trials, and treatments relating to uncommon lung disorders can access this privacy-protected site.

History

Arthur R. Birt, Georgina R. Hogg, and William J. Dubé, three Canadian physicians, initially defined the illness in 1977. In 1927, Burnier and Rejsek recorded a case of perifollicular fibromas on a 56-year-old woman’s face, which was the first example of suspected BHD in the medical literature. H. S. Zackheim and H. Pinkus first described trichodiscomas in 1974, but Birt, Hogg, and Dubé were the first to link them to BHD. Hornstein and Knickenberg described the first BHD case with systemic symptoms, which involved two siblings and their father. Colon polyps and fibrofolliculomas were all present in each of them. Their father had cysts in his lungs and kidneys, despite the siblings’ lack of renal or pulmonary symptoms. Hornstein-Knickenberg syndrome is a term that is no longer used to describe inherited fibrofolliculomas that are a part of BHD.

When Birt, Hogg, and Dubé looked at a family with hereditary thyroid cancer, they noticed that many members had fibrofolliculomas, trichodiscomas, and acrochordons, which became known as the characteristic symptoms of the condition. In 1986, the first incidence of spontaneous pneumothorax linked to BHD was discovered; in 1993, the first case of kidney cancer was detected; and in 1999, the presence of lung cysts in BHD patients was established. Colorectal polyps and neoplasms were initially assumed to be more common in people with BHD. However, this has now been disproven. The BHD Foundation funds research into the syndrome and hosts quarterly symposia for researchers, physicians, and family members interested in BHD and related illnesses.

Other Animals

In dogs, fruit flies, rats, and mice, genes associated with FLCN and disorders similar to Birt–Hogg–Dubé syndrome have been discovered. Missense mutations in the canine ortholog of FLCN produce kidney malignancies (in this case, multifocal renal cystadenocarcinoma) and skin tumours in German Shepherd dogs, analogous to human BHD (nodular dermatofibroma). They displayed a tumorigenesis pattern that was identical to human BHD. The skin lesions were heterozygous for the FLCN mutation, and loss of heterozygosity was most likely the cause of the kidney malignancies. Uterine leiomyomas are also common in female German Shepherds with the FLCN mutation.

In the common fruit fly, Drosophila melanogaster, a homolog of FLCN termed DBHD, has been found. The loss of male germline stem cells (GSC) occurs when DBHD expression is reduced, suggesting that DBHD is essential for male GSC maintenance in the fly testis.

Furthermore, DBHD affects GSC maintenance downstream or parallel to the JAK/STAT and Dpp signaling pathways, implying that BHD governs cancer in humans via managing stem cells.

Japanese researchers developed a strain of rats with hereditary kidney cancer. They have a shortened protein due to a mutation in the FLCN homolog, but they do not experience the cutaneous or pulmonary symptoms that humans do. Heterozygotes exhibit kidney abnormalities that develop into clear-cell and hybrid tumors early in life, drastically reducing the animals’ lifespans; they’re also prone to endometrial and salivary gland clear-cell hyperplasia, as well as rhabdomyolysis. Homozygotes do not live until they are born. The phenotype was restored when a wild-type FLCN gene was introduced.

A kidney cancer-causing BHD mutation has been knocked out in mice; heterozygotes develop kidney cysts and tumors that lead to renal failure within three weeks of birth. The mTOR pathway was incorrectly active in these animals, demonstrating that the mouse equivalent of FLCN regulates this pathway. By controlling mTOR, rapamycin was able to reverse the phenotype partially. In utero, homozygotes die.

References