Birt–Hogg–Dubé syndrome

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Birt–Hogg–Dubé syndrome
The characteristic fibrofolliculomas of Birt–Hogg–Dubé syndrome seen on a person's face.
SpecialtyMedical genetics Edit this on Wikidata

Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons

spontaneous pneumothorax
). Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors.

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

tumor suppressor gene that restricts cell growth and division. Versions of FLCN have been found in other animals, including fruit flies, German Shepherds, rats, and mice
. The disease was discovered in 1977, but the connection with FLCN was not elucidated until 2002, after kidney cancer, collapsed lungs, and pulmonary cysts were all definitively connected to BHD.

Birt–Hogg–Dubé syndrome can manifest similarly to other diseases, which must be ruled out when making a diagnosis. These include tuberous sclerosis, which causes skin lesions similar to fibrofolliculomas, and Von Hippel–Lindau disease, which causes hereditary kidney cancers. Once diagnosed, people with BHD are treated preventatively, with monitoring of kidneys and lungs using medical imaging. Fibrofolliculomas can be removed surgically and pneumothorax and kidney cancer are treated according to the normal standard of care. Dermatologic examinations, neck ultrasounds and colonoscopies should be considered as well [1].

Signs and symptoms

Skin

Individual with Birt–Hogg–Dubé syndrome, showing the characteristic facial fibrofolliculomas

Birt–Hogg–Dubé syndrome affects the skin and increases the risk of tumors in the kidneys and lungs. The condition is characterized by multiple noncancerous, dome-shaped tumors of the

psychological distress.[6]

Other tumors can include

acrochordons (skin tags), but may instead be fibrofolliculomas. These lesions are usually found in the armpit, on the eyelids, and in folds of skin.[3] Not all individuals develop the facial tumors; some families with the mutation that causes BHD develop only kidney tumors or spontaneous pneumothorax.[5]

Kidneys

An H&E stain of tissue from a chromophobe renal cell carcinoma, the second-most common cancer associated with BHD

People over 20 years of age with BHD have an increased risk of developing slow-growing

chromophobe renal carcinoma and renal oncocytoma, respectively), kidney cysts, and possibly tumors in other organs and tissues.[2] These tumors often occur in both kidneys and in multiple locations in each kidney.[5] The average number of kidney tumors found in a person with BHD is 5.3, though up to 28 tumors have been found.[7] Hybrid oncocytoma/chromophobe carcinoma, found in 50% of cases,[8] is the most commonly found cancer, followed by chromophobe renal carcinoma, clear cell renal carcinoma, renal oncocytoma, and papillary renal cell carcinoma.[5][8] People over 40 years old and men are more likely to develop kidney tumors, which are diagnosed at a median age of 48.[2][5] Kidney cancer associated with BHD have been diagnosed in people at ages as young as 20.[6]

In general, people with this syndrome are at roughly at seven times the risk of kidney cancer compared to the unaffected population. Estimates of the incidence among people with the disease range from 14 to 34%.

kidney function over time as they grow larger.[8]

Lungs

Along with fibrofolliculomas and kidney tumors, affected individuals frequently develop

lung function is usually normal.[6] More than 83% of people with BHD have cysts, but the syndrome does not cause conditions like progressive chronic obstructive pulmonary disease or generalized respiratory failure,[2] though it does cause emphysema.[4] Spontaneous, sometimes recurrent,[5] pneumothorax occurs far more often and at a younger age with BHD than in the unaffected population. Around 24% of people with the disease have at least one spontaneous pneumothorax, 30 times the occurrence in unaffected people. Though pneumothorax caused by BHD often occurs in middle age, at a median age of 38, 17% of affected people have a spontaneous pneumothorax before turning 40.[2] Pneumothoraces have been seen in people as young as 7 and 16 years of age.[6] Some families have a form of BHD that only affects the lungs.[11]

Other organs

squamous cell carcinoma.[6]

Pathophysiology

Genetics

This diagram shows how autosomal dominant disorders like BHD are passed on. The unaffected parent produces all normal gametes (sperm and egg) and the affected parent produces half mutant gametes and half normal gametes. Because only one copy of the mutation is needed to have an autosomal dominant disease, each offspring has a 50% chance of having the mutation.

An association with the folliculin (FLCN) gene was first reported in 2002.

carboxy terminus.[14][3] Very rarely, missense mutations are observed.[6] The mutations in the FLCN gene that cause Birt–Hogg–Dubé syndrome are germline mutations, which means that they occur in every cell of the body and can be passed down to future generations.[15] These mutations are often passed from one generation to the next in an autosomal dominant fashion, but can occur as a new mutation in an individual with no prior family history (a de novo mutation).[16] The children of an affected parent each has a 50% chance of having the disease. BHD has very high penetrance.[5] A correlation between different FLCN genotypes and phenotypes has not been discovered.[16]

Function

FLCN creates a protein, folliculin, that has two

mitochondria.[17] Folliculin interacts with FNIP1 and FNIP2 (FLCN-interacting protein) to form a complex with AMP-activated protein kinase.[8][4] Folliculin's participation in the mTOR pathway may explain the similarity in phenotype between BHD syndrome, Cowden syndrome, tuberous sclerosis, and Peutz–Jeghers syndrome.[3]

Most of the cancer-causing mutations cause the protein to be truncated at the carboxy terminus.

orthologs of folliculin, indicating that it is important to the protein's function.[14]

p arm
of human chromosome 17.

People with BHD are born with one mutated copy of the FLCN gene in each cell.

tumorigenesis differs between the kidney, where loss of FLCN heterozygosity is responsible for cancers, and the skin, where FLCN is strongly expressed in heterozygotes.[6] FLCN has been found to be overexpressed in fibrofolliculoma tissue, and to have very low levels of expression in affected kidneys.[4] Furthermore, the mTOR pathway is shown to be activated in tumor tissue from both humans and mice.[7]

Renal cystogenesis and tumorigenesis in BHD have been shown to be driven by the constitutive activation of TFEB.[18]

Diagnosis

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.[5]

Clinical triad

See also: List of cutaneous neoplasms associated with systemic syndromes

The cutaneous manifestations of BHD were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by

chromophobe, oncocytoma, and oncocytic hybrid tumors) are more commonly seen. Although the original syndrome was discovered on the basis of cutaneous findings, individuals with BHD may only manifest the pulmonary and/or renal findings, without any skin lesions. Though these signs indicate BHD, it is only confirmed with a genetic test for FLCN mutations.[5]

Genetic testing

FLCN mutations are detected by sequencing in 88% of probands with this syndrome. This means that some people with the clinical diagnosis have mutations that are not detectable by current technology, or that mutations in another currently unknown gene could be responsible for a minority of cases. In addition, amplifications and deletions in exonic regions are also tested. 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]

Differential diagnosis

The person in this image has tuberous sclerosis. The skin lesions caused by tuberous sclerosis (angiofibromas) must be distinguished from the characteristic fibrofolliculomas of BHD, which also occur primarily on the face.

BHD can be difficult to diagnose from symptoms alone, because hereditary renal cancers, pneumothorax, and cutaneous tumors occur with other syndromes. Hereditary bilateral, multifocal kidney tumors similar to those seen in BHD can occur with

hereditary papillary renal cancer (papillary renal cell carcinoma), and hereditary leiomyomatosis and renal cell cancer syndrome. They are differentiated with examination of the tumors' histology.[5]

Hereditary recurrent pneumothorax or pulmonary cysts are associated with

alpha1-antitrypsin deficiency, and cystic fibrosis. Nonhereditary recurrent pneumothorax and/or pulmonary cysts can occur with Langerhans cell histiocytosis and lymphangioleiomyomatosis. These conditions are differentiated from BHD through examining the patient history and performing a physical examination.[5] In women suspected to have the disease, ruling out pulmonary or thoracic endometriosis may be necessary.[9]

Though fibrofolliculomas are unique to BHD, they may present with an ambiguous appearance and must be confirmed histologically. Other diseases can mimic the dermatologic manifestations of BHD, including tuberous sclerosis complex,

familial trichoepitheliomas, and multiple endocrine neoplasia type 1.[5] Tuberous sclerosis must be distinguished because both disorders can present with angiofibromas on the face, though they are more common in tuberous sclerosis.[6]

Management

The different manifestations of BHD are controlled in different ways. The fibrofolliculomas can be removed surgically, through

rapamycin may mitigate the effects of FLCN mutations on kidneys and improve renal cancer prognoses because of folliculin's interaction with the mTOR pathway.[6]

Epidemiology

The disorder has been reported in more than 100 families worldwide,

heterogeneous between individuals.[14] Less severe skin phenotypes are seen in women and people of both sexes who have a late onset of skin symptoms.[5]

Patient registry

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.

History

The syndrome was first well described in 1977,[21] by three Canadian physicians, Arthur R. Birt, Georgina R. Hogg, and William J. Dubé. The earliest case of possible BHD in the medical literature was published by Burnier and Rejsek in 1927,[22] who described a case of perifollicular fibromas on a 56-year-old woman's face. Trichodiscomas were first described in 1974 by H. S. Zackheim and H. Pinkus, but were not associated with BHD until Birt, Hogg, and Dubé.[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.[23] Though the siblings did not have renal or pulmonary symptoms, their father had cysts in his lungs and kidneys.[3] Hornstein-Knickenberg syndrome is a now-deprecated name for the inherited fibrofolliculomas inherent to BHD.[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. The first case of spontaneous pneumothorax associated with BHD was discovered in 1986;

colorectal polyps and neoplasms, but this has been disproven.[2] The BHD Foundation supports research into the syndrome and holds regular symposia in BHD and related disorders for researchers, clinicians, and family members.[24][25][26]

Other animals

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

uterine leiomyomas.[3]

A homolog of FLCN called DBHD has been discovered in the common fruit fly, Drosophila melanogaster.[27][3] Decrease expression of the DBHD results in loss of male germline stem cells (GSC), which suggest that DBHD is required for male GSC maintenance in the fly testis.[28] Further, DBHD regulates GSC maintenance downstream or in parallel of the JAK/STAT and Dpp signal-transduction pathways, which suggest that BHD regulates tumorigenesis by controlling stem cells in human {[29] Singh et al. 2006}

A line of rats with hereditary kidney cancer were developed by Japanese researchers. 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. Heterozygotes have renal abnormalities seen very early in life that develop into clear-cell and hybrid tumors, significantly shortening the animals' lifespans; they also are prone to endometrial and salivary gland clear-cell hyperplasia as well as rhabdomyolysis. Homozygotes do not survive to birth.[3] When a wild-type FLCN gene was added, the phenotype was rescued.[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. In these mice, the mTOR pathway was inappropriately activated, indicating that the mouse homolog of FLCN plays a regulatory role in this pathway. Rapamycin partially rescued the phenotype by regulating mTOR. Homozygotes die in utero.[3]

References

Citations

  1. ^ a b c Genetics Home Reference.
  2. ^ a b c d e f g h i j k l m n o Andrews 2011.
  3. ^ a b c d e f g h i j k l m n o p Reese et al. 2009.
  4. ^ a b c d e f Palmirotta et al. 2010.
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Toro 2008.
  6. ^ a b c d e f g h i j k l m n o p q r Menko et al. 2009.
  7. ^ a b Chan-Smutko 2012, p. 345.
  8. ^ a b c d e f g Coleman & Russo 2009, p. 482.
  9. ^ a b Furuya & Nakatani 2012.
  10. ^ Grant, Babar & Griffin 2009, p. 442.
  11. ^ Devine & Garcia 2012, p. 4.
  12. ^ Coleman & Russo 2009, p. 481.
  13. ^ Nickerson et al. 2002.
  14. ^ a b c d e Toro et al. 2008.
  15. ^ "Rare Lung Diseases Disorder Definitions". www1.rarediseasesnetwork.org. Retrieved 13 November 2021.
  16. ^ a b Maher 2011.
  17. ^ Sudarshan et al. 2013.
  18. S2CID 220289684
    .
  19. ^ Ayo et al. 2007.
  20. ^ Verine et al. 2010.
  21. ^ Birt, Hogg & Dubé 1977.
  22. ^ Riegert-Johnson.
  23. ^ Kniffin 2012.
  24. ^ BHD Foundation.
  25. ^ National Organization for Rare Disorders.
  26. ^ Genetics Home Reference: Educational Resources.
  27. ^ Liu et al. 2013.
  28. ^ Singh SR, Zhen W, Zheng Z, Wang H, Oh SW, Liu W, Zbar B, Schmidt LS, Hou SX. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene. 2006 Sep 28;25(44):5933-41.
  29. ^ Singh SR, Zhen W, Zheng Z, Wang H, Oh SW, Liu W, Zbar B, Schmidt LS, Hou SX. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene. 2006 Sep 28;25(44):5933-41

Bibliography

External links

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