Birt-Hogg-Dube syndrome is an autosomal dominant hereditary cancer and hamartoma syndrome caused by germline loss-of-function variants in FLCN at 17p11.2, which encodes folliculin. It is defined by a triad that spans three unrelated organs — cutaneous follicular hamartomas (fibrofolliculomas), lung cysts with spontaneous pneumothorax, and renal tumors — and the fact that one tumor suppressor produces this particular combination is what makes the syndrome mechanistically interesting. Folliculin is not an enzyme in a proliferation pathway but a component of a nutrient- and energy-sensing network: it binds FNIP1, which in turn binds AMP-activated protein kinase, and folliculin phosphorylation responds to both mTOR and AMPK signalling. Birt-Hogg-Dube therefore belongs with the other hamartoma syndromes whose genes act on the same axis — LKB1/STK11 in Peutz-Jeghers, TSC1/TSC2 in tuberous sclerosis, and PTEN in the PTEN hamartoma tumor syndrome — rather than with the classical cell-cycle tumor suppressors. The renal tumors are characteristically bilateral and multifocal, and their histology is distinctive: renal oncocytoma and chromophobe renal cell carcinoma, and hybrid oncocytic tumors, rather than the clear-cell histology of von Hippel-Lindau disease. Kidney tumor risk and pneumothorax risk both cluster within families, so a positive family history for either feature raises the probability of that feature in a carrier.
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name: Birt-Hogg-Dube Syndrome
creation_date: "2026-08-23T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Hamartoma Syndrome
parents:
- hereditary cancer-predisposing syndrome
disease_term:
preferred_term: Birt-Hogg-Dube syndrome
term:
id: MONDO:0800444
label: Birt-Hogg-Dube syndrome
synonyms:
- BHD
- BHD syndrome
- fibrofolliculomas with trichodiscomas and acrochordons
description: >-
Birt-Hogg-Dube syndrome is an autosomal dominant hereditary cancer and
hamartoma syndrome caused by germline loss-of-function variants in FLCN at
17p11.2, which encodes folliculin. It is defined by a triad that spans three
unrelated organs — cutaneous follicular hamartomas (fibrofolliculomas), lung
cysts with spontaneous pneumothorax, and renal tumors — and the fact that one
tumor suppressor produces this particular combination is what makes the
syndrome mechanistically interesting. Folliculin is not an enzyme in a
proliferation pathway but a component of a nutrient- and energy-sensing
network: it binds FNIP1, which in turn binds AMP-activated protein kinase, and
folliculin phosphorylation responds to both mTOR and AMPK signalling.
Birt-Hogg-Dube therefore belongs with the other hamartoma syndromes whose genes act
on the same axis — LKB1/STK11 in Peutz-Jeghers, TSC1/TSC2 in tuberous
sclerosis, and PTEN in the PTEN hamartoma tumor syndrome — rather than with the
classical cell-cycle tumor suppressors. The renal tumors are characteristically
bilateral and multifocal, and their histology is distinctive: renal oncocytoma
and chromophobe renal cell carcinoma, and hybrid oncocytic tumors, rather than
the clear-cell histology of von Hippel-Lindau disease. Kidney tumor risk and
pneumothorax risk both cluster within families, so a positive family history
for either feature raises the probability of that feature in a carrier.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
expressivity: VARIABLE
description: >-
Birt-Hogg-Dube syndrome is transmitted as an autosomal dominant
predisposition. Expressivity is variable both between and within families: a
minority of mutation-positive families contain individuals with no
histologically confirmed fibrofolliculomas at all, and the probability of
renal tumor or of spontaneous pneumothorax in a carrier depends on whether
that feature has already occurred in the family.
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant
predisposition to the development of follicular hamartomas
(fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney
neoplasms.
explanation: >-
States the autosomal dominant inheritance and the defining multi-organ
phenotype in a series of 50 families.
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BHDS is characterised by a spectrum of mutations, and clinical
heterogeneity both among and within families.
explanation: >-
Directly supports the variable expressivity asserted here, including
within-family variation.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Each child of an individual with BHDS is at a 50% risk of inheriting the
FLCN pathogenic variant.
explanation: >-
GeneReviews Genetic Counseling section: the transmission risk to
offspring. Evidence source is OTHER because GeneReviews is an
expert-authored review rather than a primary study.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Disease severity can vary significantly even within the same family.
explanation: >-
GeneReviews Clinical Characteristics section, independently supporting the
within-family variable expressivity recorded on this block.
pathophysiology:
- name: Germline FLCN First-Hit Inactivation
conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
description: >-
A heterozygous loss-of-function variant in FLCN at 17p11.2 is present
constitutionally. Most alleles are protein-truncating, and a striking
proportion are insertions or deletions within a hypermutable
mononucleotide C(8) tract, which is why that tract is the first target of
diagnostic sequencing. FLCN transcript is widely expressed — including in
kidney, lung and skin, the three affected organs — so the tissue restriction
of the phenotype is not explained by where the gene is expressed.
role: trigger
biological_scale: MOLECULAR
gene:
preferred_term: FLCN
modifier: DECREASED
term:
id: hgnc:27310
label: FLCN
genetic_context:
gene:
preferred_term: FLCN
term:
id: hgnc:27310
label: FLCN
variant_origin: GERMLINE
allelic_hit_role: FIRST_HIT
allelic_events:
- PATHOGENIC_VARIANT
- FRAMESHIFT_VARIANT
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Constitutional heterozygous FLCN loss of function, predominantly
protein-truncating, with a hotspot in a hypermutable C(8) tract.
evidence:
- reference: PMID:12204536
reference_title: "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Protein-truncating mutations were identified in a novel candidate gene in
a panel of BHD families, with a 44% frequency of insertion/deletion
mutations within a hypermutable C(8) tract.
explanation: >-
Identifies the germline lesion and its mutational hotspot in BHD families,
which is the constitutional first hit this node asserts.
- reference: PMID:12204536
reference_title: "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Tissue expression of the 3.8 kb transcript was widespread, including
kidney, lung, and skin.
explanation: >-
Establishes that FLCN is broadly expressed across the affected organs,
which is the basis for the statement that expression pattern alone does
not explain tissue restriction.
downstream:
- target: Somatic FLCN Second-Hit Inactivation
description: >-
With one allele already inactivated in every cell, a single somatic event
at the FLCN locus becomes the rate-limiting step to folliculin loss.
- name: Somatic FLCN Second-Hit Inactivation
conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
description: >-
A somatic event inactivates the retained wild-type FLCN allele. In BHD
renal tumors the dominant route is not loss of heterozygosity but an
independent intragenic mutation: sequencing 77 renal tumors from 12
carriers found somatic sequence alterations in 53% and loss of
heterozygosity in a further 17%, with most somatic changes producing
frameshifts predicted to truncate the protein. That distribution matters
for interpretation, because a BHD renal tumor without loss of heterozygosity
has usually still completed its second hit, by mutation rather than allele
loss.
role: amplifier
biological_scale: MOLECULAR
genetic_context:
gene:
preferred_term: FLCN
term:
id: hgnc:27310
label: FLCN
variant_origin: SOMATIC
allelic_hit_role: SECOND_HIT
allelic_events:
- FRAMESHIFT_VARIANT
- LOSS_OF_HETEROZYGOSITY
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Acquired inactivation of the retained wild-type FLCN allele in renal
tumor tissue, predominantly by somatic frameshift mutation and less often
by loss of heterozygosity.
evidence:
- reference: PMID:15956655
reference_title: "High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sequence alterations were detected in the majority of renal tumors (41 of
77, 53%), with loss of heterozygosity at the BHD locus in a minority of
additional tumors (14 of 77, 17%).
explanation: >-
Quantifies the somatic second hit in BHD renal tumors and shows that
intragenic mutation rather than allele loss is the dominant route, which
is exactly what this node asserts.
downstream:
- target: Folliculin Loss and FNIP1-AMPK-mTOR Nutrient Sensing Dysregulation
description: >-
Completion of the second hit leaves the renal tumor cell without
functional folliculin.
- name: Folliculin Loss and FNIP1-AMPK-mTOR Nutrient Sensing Dysregulation
conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
description: >-
Folliculin is a tumor-suppressor protein without an assigned catalytic
family; its identified partner FNIP1 binds AMP-activated protein kinase, the
central energy sensor that negatively regulates mTOR. FNIP1 is phosphorylated
by AMPK, and folliculin phosphorylation is reduced by AMPK inhibitors,
diminished by rapamycin and by amino-acid starvation, and increased by FNIP1
overexpression — placing folliculin inside the AMPK and mTOR signalling
network rather than upstream or downstream of it. Loss of folliculin in a
cell that has inactivated both alleles therefore dysregulates nutrient and
energy sensing, which is the mechanistic link between Birt-Hogg-Dube and the
other hamartoma syndromes caused by LKB1, TSC1/2 and PTEN.
role: central_effector
biological_scale: CELLULAR
biological_processes:
- preferred_term: TOR signaling
term:
id: GO:0031929
label: TOR signaling
modifier: ABNORMAL
evidence:
- reference: PMID:15956655
reference_title: "High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These results support a role for BHD as a tumor suppressor gene that
predisposes to the development of renal tumors when both copies are
inactivated.
explanation: >-
Direct evidence that BHD tumorigenesis requires inactivation of both FLCN
copies, which is the biallelic claim this node makes and which the
FNIP1/AMPK evidence below does not itself establish.
- reference: PMID:17028174
reference_title: "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, we report the identification of the FLCN-interacting protein, FNIP1,
and demonstrate its interaction with 5' AMP-activated protein kinase
(AMPK), a key molecule for energy sensing that negatively regulates mTOR
activity.
explanation: >-
Establishes the physical link from folliculin through FNIP1 to AMPK, the
basis for placing this disorder on the nutrient-sensing axis. Evidence
source is IN_VITRO (cell-based interaction and phosphorylation studies).
- reference: PMID:17028174
reference_title: "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its
interacting partner FNIP1 may be involved in energy and/or nutrient
sensing through the AMPK and mTOR signaling pathways.
explanation: >-
The authors' own statement of the pathway assignment. Note the hedged
wording ("may be involved") is preserved here rather than upgraded — the
interaction is demonstrated, the pathway role is inferred.
- reference: PMID:17028174
reference_title: "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The tumor-suppressor proteins encoded by genes responsible for several
other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be
involved in the mammalian target of rapamycin (mTOR) signaling pathway.
explanation: >-
Supports grouping Birt-Hogg-Dube with the other nutrient-sensing hamartoma
syndromes, which is the classification claim made in this entry.
downstream:
- target: Multiorgan Hamartoma and Renal Tumor Development
description: >-
Dysregulated nutrient sensing in folliculin-null cells drives hamartomatous
and neoplastic growth in the affected lineages.
- name: Multiorgan Hamartoma and Renal Tumor Development
conforms_to: "germline_two_hit_tumor_predisposition#Early-Onset, Multifocal, and Bilateral Tumor Spectrum"
description: >-
The clinical output: follicular hamartomas of the skin, cysts in the lung
wall that predispose to spontaneous pneumothorax, and renal neoplasms that
are characteristically bilateral and multifocal. The renal histology is
distinctive and diagnostically useful — oncocytoma and chromophobe renal cell
carcinoma rather than the clear-cell tumors of von Hippel-Lindau disease.
Risk is family-stratified: carriers whose relatives have had kidney cancer,
or spontaneous pneumothorax, are at significantly higher risk of that same
feature, which is what surveillance planning is built on.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:12204536
reference_title: "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Discovery of disease-causing mutations in BHD, a novel kidney cancer gene
associated with renal oncocytoma or chromophobe renal cancer, will
contribute to understanding the role of folliculin in pathways common to
skin, lung, and kidney development.
explanation: >-
Documents the characteristic renal histology and the three-organ
distribution of the phenotype.
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with a germline BHD mutation and family history of kidney cancer
had a statistically significantly increased probability of developing
renal tumours compared to patients without a positive family history (p =
0.0032).
explanation: >-
Quantifies the family-history stratification of renal tumor risk that this
node asserts.
phenotypes:
- category: Dermatologic
name: Fibrofolliculoma
description: >-
Benign follicular hamartoma of the skin, typically multiple and
facial/cervical, and often the first feature to bring a family to attention.
Absent in a minority of mutation-positive individuals.
phenotype_term:
preferred_term: Fibrofolliculoma
term:
id: HP:0030436
label: Fibrofolliculoma
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant
predisposition to the development of follicular hamartomas
(fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney
neoplasms.
explanation: >-
Names follicular hamartoma (fibrofolliculoma) directly as a defining
feature of the syndrome.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Skin lesions typically appear between the second and fourth decades of
life and typically increase in size and number with age.
explanation: >-
GeneReviews Clinical Characteristics section, giving the onset window and
the progressive accumulation with age — the visible signature of
independent second hits occurring across the skin over time.
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
10% (5/51) of the families had individuals without histologically
confirmed fibrofolliculomas.
explanation: >-
Quantifies the minority of mutation-positive families in which the
cutaneous lesion is not histologically confirmed, which is why this
phenotype carries no frequency band. Marked PARTIAL because it qualifies
rather than supports the association.
- category: Respiratory
name: Pulmonary Cysts
description: >-
Thin-walled lung cysts, typically basal and subpleural, which are the
structural substrate for pneumothorax.
phenotype_term:
preferred_term: Pulmonary cyst
term:
id: HP:0032445
label: Pulmonary cyst
evidence:
- reference: PMID:17028174
reference_title: "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign
tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by
germ-line mutations in the BHD(FLCN) gene
explanation: >-
Names lung cysts directly as a defining feature of the syndrome, rather
than leaving the cystic lesion to be inferred from a pneumothorax
statement.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Lung cysts are mainly in the basal lung regions; most individuals are
asymptomatic but at high risk for spontaneous pneumothorax.
explanation: >-
GeneReviews Clinical Characteristics section, giving the basal
distribution and the key clinical asymmetry: the cysts themselves are
usually silent, but they carry a high pneumothorax risk.
- category: Respiratory
name: Spontaneous Pneumothorax
description: >-
Recurrent spontaneous pneumothorax arising from rupture of the
characteristic lung cysts; risk is strongly stratified by family history.
phenotype_term:
preferred_term: Spontaneous pneumothorax
term:
id: HP:0002108
label: Spontaneous pneumothorax
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Similarly, patients with a BHD germline mutation and family history of
spontaneous pneumothorax had a significantly increased greater probability
of having spontaneous pneumothorax than BHDS patients without a family
history of spontaneous pneumothorax (p = 0.011).
explanation: >-
Establishes spontaneous pneumothorax as a BHD feature and quantifies its
familial clustering.
- category: Renal
name: Renal Neoplasm
description: >-
Bilateral, multifocal renal tumors; oncocytoma, chromophobe renal cell
carcinoma and hybrid oncocytic tumors predominate.
phenotype_term:
preferred_term: Renal neoplasm
term:
id: HP:0009726
label: Renal neoplasm
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of 44 families ascertained on the basis of skin lesions, 18 (41%) had
kidney tumours.
explanation: >-
Quantifies renal tumor occurrence in families ascertained through the
cutaneous phenotype.
- category: Renal
name: Renal Oncocytoma
description: >-
Characteristic benign renal tumor of Birt-Hogg-Dube; bilateral multifocal
oncocytoma is a strong pointer to the diagnosis.
phenotype_term:
preferred_term: Renal oncocytoma
term:
id: HP:0011798
label: Renal oncocytoma
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report the first germline missense mutation in BHD c.1978A>G (K508R) in
a patient who presented with bilateral multifocal renal oncocytomas.
explanation: >-
Documents bilateral multifocal renal oncocytoma as a presenting phenotype
in a mutation-confirmed carrier — the multifocality predicted by the
two-hit mechanism.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The most common renal tumors are a hybrid of oncocytoma and chromophobe
histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and
oncocytoma are also common.
explanation: >-
GeneReviews Clinical Characteristics section, giving the full renal
histological spectrum. Note it includes clear cell carcinoma, so the
oncocytic/chromophobe predominance is a tendency rather than an absolute
discriminator from von Hippel-Lindau disease.
genetic:
- name: FLCN
gene_term:
preferred_term: FLCN
term:
id: hgnc:27310
label: FLCN
relationship_type: CAUSATIVE
notes: >-
FLCN at 17p11.2 encodes folliculin. Germline loss-of-function variants,
predominantly protein-truncating, cause Birt-Hogg-Dube syndrome; the
mutation detection rate in clinically defined families is high.
evidence:
- reference: PMID:18234728
reference_title: "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The BHD mutation detection rate was 88% (51/58).
explanation: >-
Quantifies diagnostic yield of FLCN sequencing in clinically ascertained
BHD families.
- reference: PMID:12204536
reference_title: "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The full-length BHD sequence predicted a novel protein, folliculin, that
was highly conserved across species.
explanation: >-
Identifies the gene product and its evolutionary conservation.
treatments:
- name: Renal Surveillance and Nephron-Sparing Surgery
notes: >-
Curated under `treatments:` as a management intervention, not as a claim
that imaging or biochemistry is itself therapeutic. In a two-hit
predisposition syndrome the second hit cannot be prevented, so the only
available lever is stage at detection: surveillance is the intervention
that converts an unavoidable tumor into a resectable one. Where a
`target_mechanisms` link is present it points at the clinical-outcome node
for that reason, and never at an upstream mechanistic node.
description: >-
The renal arm dominates management. Tumors under 3 cm are watched rather
than resected, and larger ones are removed nephron-sparingly where possible
— a deliberately conservative approach that only makes sense because the
tumors are typically indolent oncocytic lesions and because bilateral,
multifocal disease means renal tissue must be preserved for future
operations. This is the opposite of the wide-margin policy used in HLRCC,
where the renal tumor metastasizes while small.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Nephrectomy
term:
id: NCIT:C15284
label: Nephrectomy
target_mechanisms:
- target: Multiorgan Hamartoma and Renal Tumor Development
treatment_effect: INHIBITS
description: >-
Surveillance and nephron-sparing resection act on the consequence node by
removing established tumors while preserving tissue for the further
independent tumors the two-hit mechanism predicts.
evidence:
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Renal tumors less than 3.0 cm in diameter can be monitored with imaging;
when possible, nephron-sparing surgery is the treatment of choice for
larger renal tumors, depending on their size and location.
explanation: >-
GeneReviews Management section, giving the size threshold for observation
versus surgery and the nephron-sparing preference.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Annual abdominal/pelvic MRI to assess for renal lesions beginning at age
20 years or earlier in those with a family history of renal tumors before
age 30 years
explanation: >-
GeneReviews Management section, giving the surveillance modality, interval
and start age, including the family-history-dependent earlier start.
- name: Pneumothorax Management and Risk-Activity Counselling
description: >-
Pneumothoraces are treated conventionally, with surgery considered for
recurrence. The distinctive part is anticipatory counselling: carriers are
advised about activities involving ambient pressure change, because the
underlying cysts are permanent and the risk is lifelong.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Behavioral Counseling
term:
id: NCIT:C181743
label: Behavioral Counseling
evidence:
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Pneumothoraces are treated as in the general population; consider surgical
intervention for recurrent pneumothoraces.
explanation: >-
GeneReviews Management section on treating the acute event and the
threshold for surgical intervention.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
discuss activities that might increase pneumothorax risk (e.g., working as
a pilot, flying in unpressurized aircraft, diving)
explanation: >-
GeneReviews Management section, giving the specific activities that
warrant counselling in a carrier.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Agents/circumstances to avoid: Cigarette smoking, high ambient pressures,
and radiation exposure.
explanation: >-
GeneReviews Agents/Circumstances to Avoid, covering all three exposures
relevant across the pulmonary and renal arms of the syndrome.
- name: Treatment of Cutaneous Fibrofolliculomas
description: >-
Surgical and laser treatment of fibrofolliculomas is cosmetic and
temporary — the lesions recur, which is expected given that the skin
continues to accumulate independently initiated lesions with age.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Therapeutic Procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Surgical and laser treatment can lead to temporary improvement of
fibrofolliculomas, but lesions often recur.
explanation: >-
GeneReviews Management section. The recurrence caveat is quoted because it
is the clinically important half of the statement.
diagnosis:
- name: Clinical Diagnostic Criteria for Birt-Hogg-Dube Syndrome
description: >-
A clinical diagnosis can be made without genetic testing: one major
criterion (more than five fibrofolliculomas or trichodiscomas, at least one
histologically confirmed) or two minor criteria drawn from the pulmonary,
renal and family-history features.
diagnosis_term:
preferred_term: Clinical Evaluation
term:
id: NCIT:C124351
label: Clinical Evaluation
results: >-
One major or two minor criteria establish the clinical diagnosis and
prompt confirmatory FLCN testing.
evidence:
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The clinical diagnosis of BHDS is established in a proband with either one
major criteria (>5 fibrofolliculomas/trichodiscomas; one histologically
confirmed) or two minor criteria
explanation: >-
GeneReviews Diagnosis/Testing section, giving the major and minor criteria
structure of the clinical diagnosis.
- name: Molecular Genetic Testing for FLCN
description: >-
A germline heterozygous FLCN pathogenic variant establishes the molecular
diagnosis. Cascade testing then serves both directions: starting renal
surveillance in carriers and releasing non-carriers from lifelong imaging.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
results: >-
A heterozygous germline pathogenic FLCN variant confirms the diagnosis and
determines which relatives need renal surveillance.
evidence:
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The molecular diagnosis is established in a proband with any suggestive
findings and a germline heterozygous pathogenic variant in FLCN identified
by molecular genetic testing.
explanation: >-
GeneReviews Diagnosis/Testing section, stating the confirmatory molecular
test.
- reference: PMID:20301695
reference_title: "Birt-Hogg-Dubé Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Molecular genetic testing for the family-specific FLCN pathogenic variant
for early identification of at-risk family members improves diagnostic
certainty and reduces costly screening procedures in at-risk relatives who
have not inherited the family-specific pathogenic variant.
explanation: >-
GeneReviews Evaluation of Relatives at Risk, giving both purposes of
cascade testing.
prevalence:
- population: General population
measure_type: POINT_PREVALENCE
prevalence_class: BELOW_1_IN_1000000
rate_per_100000: 0.2
notes: >-
Estimated 2 cases per million, normalised to 0.2 per 100,000. Treat as an
order-of-magnitude estimate rather than a measured rate: Birt-Hogg-Dube is
substantially underdiagnosed because its commonest features — skin papules
and asymptomatic lung cysts — rarely prompt genetic evaluation on their own,
so ascertainment-based estimates are expected to run low. The same source
reports a local founder cluster, which illustrates how far the figure can
depart from the general-population estimate in a specific ancestry group.
evidence:
- reference: PMID:35907578
reference_title: "Birt-Hogg-Dubé syndrome: Another mTOR phenomenon."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Although its prevalence in the general population has been estimated at 2
cases per million, BHDS has been detected in a few patients from the
nearby Portuguese-lineage quarter of the city of Newark, a disproportionate
prevalence possibly explained by the founder effect.
explanation: >-
Source for the general-population estimate, quoted together with the
founder-effect cluster that qualifies it. Evidence source is OTHER because
this is a review article rather than a primary epidemiological study.
references:
- reference: PMID:20301695
title: "Birt-Hogg-Dubé Syndrome."
tags:
- GeneReviews
clinical_trials:
- name: NCT02504892
phase: PHASE_II
status: TERMINATED
description: >-
Terminated phase II study of the mTOR inhibitor everolimus in
BHD-associated kidney cancer, testing the therapeutic prediction that
follows from FLCN loss releasing mTOR signaling.
target_phenotypes:
- preferred_term: Renal neoplasm
term:
id: HP:0009726
label: Renal neoplasm
- preferred_term: Renal oncocytoma
term:
id: HP:0011798
label: Renal oncocytoma
evidence:
- reference: clinicaltrials:NCT02504892
reference_title: Phase 2 Study of Everolimus Therapy in Patients With Birt-Hogg-Dube Syndrome (BHD)-Associated Kidney Cancer or Sporadic Chromophobe Renal Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To see if everolimus is safe and effective in people with Birt-Hogg-Dube Syndrome (BHD)-associated kidney cancer or sporadic (nonfamilial) chromophobe renal cancer.
explanation: >-
Registry record documenting the mTOR-directed interventional trial in
BHD-associated renal tumors. The trial terminated, so it establishes that
the hypothesis was tested clinically, not that everolimus is effective.