Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome caused by germline loss-of-function variants in FH at 1q42-q43, encoding the tricarboxylic-acid-cycle enzyme fumarate hydratase. Carriers develop multiple cutaneous leiomyomas and, in women, early and numerous uterine leiomyomas; a subset develop an aggressive type 2 papillary or collecting-duct renal cell carcinoma that metastasizes at small primary size and dominates prognosis. HLRCC is the clearest human example of a metabolic enzyme acting as a classical tumor suppressor: the germline allele is heterozygous, tumors show loss of the wild-type allele, and measured fumarate hydratase activity is very low or absent in tumor tissue. What makes the syndrome mechanistically distinctive is that the oncogenic signal is the accumulated substrate rather than the energetic deficit. Fumarate builds up to concentrations at which it competitively inhibits the 2-oxoglutarate-dependent dioxygenase superfamily — stabilizing hypoxia-inducible factor in normoxia ("pseudohypoxia") and blocking TET- and Jumonji-mediated demethylation — and, uniquely among the oncometabolites, additionally reacts covalently with cysteine thiols, succinating KEAP1 and de-repressing NRF2 antioxidant signalling. The same FH gene has a second, entirely different phenotype in the biallelic state: homozygous or compound heterozygous FH mutation causes recessive fumarate hydratase deficiency, a severe infantile encephalopathy, so the number of damaged alleles inherited determines which of two unrelated diseases results.
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name: Hereditary Leiomyomatosis and Renal Cell Cancer
creation_date: "2026-08-23T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Inborn Error of Metabolism
parents:
- hereditary cancer-predisposing syndrome
disease_term:
preferred_term: hereditary leiomyomatosis and renal cell cancer
term:
id: MONDO:0007888
label: hereditary leiomyomatosis and renal cell cancer
synonyms:
- HLRCC
- multiple cutaneous and uterine leiomyomatosis
- MCUL
- Reed syndrome
description: >-
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal
dominant cancer predisposition syndrome caused by germline loss-of-function
variants in FH at 1q42-q43, encoding the tricarboxylic-acid-cycle enzyme
fumarate hydratase. Carriers develop multiple cutaneous leiomyomas and, in
women, early and numerous uterine leiomyomas; a subset develop an aggressive
type 2 papillary or collecting-duct renal cell carcinoma that metastasizes at
small primary size and dominates prognosis. HLRCC is the clearest human example
of a metabolic enzyme acting as a classical tumor suppressor: the germline
allele is heterozygous, tumors show loss of the wild-type allele, and measured
fumarate hydratase activity is very low or absent in tumor tissue. What makes
the syndrome mechanistically distinctive is that the oncogenic signal is the
accumulated substrate rather than the energetic deficit. Fumarate builds up to
concentrations at which it competitively inhibits the 2-oxoglutarate-dependent
dioxygenase superfamily — stabilizing hypoxia-inducible factor in normoxia
("pseudohypoxia") and blocking TET- and Jumonji-mediated demethylation — and,
uniquely among the oncometabolites, additionally reacts covalently with
cysteine thiols, succinating KEAP1 and de-repressing NRF2 antioxidant
signalling. The same FH gene has a second, entirely different phenotype in the
biallelic state: homozygous or compound heterozygous FH mutation causes
recessive fumarate hydratase deficiency, a severe infantile encephalopathy, so
the number of damaged alleles inherited determines which of two unrelated
diseases results.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
expressivity: VARIABLE
description: >-
HLRCC segregates as an autosomal dominant tumor predisposition. Cutaneous and
uterine leiomyomas are highly penetrant; renal cell carcinoma affects a
minority of carriers but accounts for most of the mortality. The contrast
with the recessive disorder caused by biallelic FH mutation is instructive
and is stated explicitly in the original mapping paper.
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thus, heterozygous and homozygous or compound heterozygous mutants have
very different clinical phenotypes.
explanation: >-
States the dose-dependent divergence between the dominant tumor
predisposition and the recessive metabolic disease, which is the
inheritance claim made here.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Each child of an individual with FH tumor predisposition syndrome has a
50% chance of inheriting the FH 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:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
It is not possible to precisely predict the likelihood of manifestations,
age of onset, severity and type of features, or rate of disease
progression in offspring who inherit the FH pathogenic variant.
explanation: >-
GeneReviews Genetic Counseling section, and the direct basis for the
VARIABLE expressivity and INCOMPLETE penetrance recorded here — the source
states explicitly that outcome in a carrier is not predictable.
pathophysiology:
- name: Germline FH First-Hit Inactivation
conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
description: >-
A heterozygous loss-of-function variant in FH is present constitutionally.
Leiomyomatosis-associated alleles are predicted to produce absent or
truncated protein, or to substitute or delete highly conserved residues, and
fumarate hydratase activity is already measurably reduced in lymphoblastoid
cells from carriers — so the heterozygous state is not biochemically silent
even though it is clinically a susceptibility rather than a disease.
role: trigger
biological_scale: MOLECULAR
gene:
preferred_term: FH
modifier: DECREASED
term:
id: hgnc:3700
label: FH
genetic_context:
gene:
preferred_term: FH
term:
id: hgnc:3700
label: FH
variant_origin: GERMLINE
allelic_hit_role: FIRST_HIT
allelic_events:
- PATHOGENIC_VARIANT
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Constitutional heterozygous FH loss of function; alleles predict absent or
truncated protein or substitution of highly conserved residues.
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Leiomyomatosis-associated mutations are predicted to result in absent or
truncated protein, or substitutions or deletions of highly conserved amino
acids.
explanation: >-
Characterizes the germline allelic spectrum that constitutes the first hit.
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Activity of fumarate hydratase is reduced in lymphoblastoid cells from
individuals with leiomyomatosis.
explanation: >-
Demonstrates measurable enzyme reduction in the constitutional
heterozygous state, supporting the claim that heterozygosity is not
biochemically silent.
downstream:
- target: Somatic FH Second-Hit Inactivation and Biallelic Loss
description: >-
A somatic event removing the wild-type allele is required before enzyme
activity falls low enough for fumarate to accumulate to signalling
concentrations.
- name: Somatic FH Second-Hit Inactivation and Biallelic Loss
conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
description: >-
Tumors in FH carriers predominantly show functional inactivation of the
retained wild-type allele, and measured fumarate hydratase activity in tumor
tissue is very low or absent — the biallelic state that distinguishes tumor
from surrounding carrier tissue. This is the node at which HLRCC hands over
from the inherited-predisposition mechanism to the oncometabolite mechanism:
only in the biallelic cell does fumarate reach the concentrations at which it
acts as a signalling molecule.
role: central_effector
biological_scale: CELLULAR
genetic_context:
gene:
preferred_term: FH
term:
id: hgnc:3700
label: FH
variant_origin: GERMLINE_AND_SOMATIC
allelic_hit_role: BIALLELIC_INACTIVATION
allelic_events:
- LOSS_OF_HETEROZYGOSITY
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Combined inherited and acquired inactivation leaving the tumor cell without
functional fumarate hydratase.
molecular_functions:
- preferred_term: fumarate hydratase activity
term:
id: GO:0004333
label: fumarate hydratase activity
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:16098467
reference_title: "HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These tumors predominantly exhibit functional inactivation of the
remaining wild-type allele, implicating FH inactivation as a
tumor-promoting event.
explanation: >-
Direct evidence for the second hit and the resulting biallelic state in
human FH-associated renal cancer.
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This enzyme acts as a tumor suppressor in familial leiomyomata, and its
measured activity is very low or absent in tumors from individuals with
leiomyomatosis.
explanation: >-
Confirms near-complete loss of enzyme activity in tumor as opposed to
carrier tissue.
downstream:
- target: Fumarate Accumulation
description: >-
With the enzyme absent, its substrate accumulates to concentrations orders
of magnitude above physiological.
- name: Fumarate Accumulation
conforms_to: "oncometabolite_dioxygenase_inhibition#Oncometabolite Accumulation"
description: >-
Fumarate, the substrate of the missing enzyme, accumulates within the
FH-null cell. It is a structural analogue of 2-oxoglutarate and, at these
concentrations, competes with it; it is also an electrophile that reacts with
cysteine thiols. Both properties are exploited downstream, and they are
chemically independent of each other.
role: amplifier
biological_scale: MOLECULAR
biological_processes:
- preferred_term: tricarboxylic acid cycle
term:
id: GO:0006099
label: tricarboxylic acid cycle
modifier: DECREASED
evidence:
- reference: PMID:16098467
reference_title: "HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We demonstrate that FH inhibition, together with elevated intracellular
fumarate, coincides with HIF upregulation.
explanation: >-
Establishes elevated intracellular fumarate as the consequence of enzyme
loss and links it to the downstream signalling readout.
downstream:
- target: Fumarate-Mediated Dioxygenase Inhibition
description: >-
Accumulated fumarate competes with 2-oxoglutarate at the active site of
the dioxygenase superfamily.
- target: KEAP1 Succination and NRF2 Activation
description: >-
Fumarate additionally succinates cysteine residues, a covalent
modification unrelated to its competitive inhibition.
- name: Fumarate-Mediated Dioxygenase Inhibition
conforms_to: "oncometabolite_dioxygenase_inhibition#Competitive Inhibition of 2-Oxoglutarate-Dependent Dioxygenases"
description: >-
Fumarate acts as a competitive inhibitor of the HIF prolyl hydroxylases and,
by the same active-site competition, of other 2-oxoglutarate-dependent
dioxygenases including the TET 5-methylcytosine hydroxylases and Jumonji
histone demethylases. This is the rate-limiting signalling step of the
oncometabolite mechanism in HLRCC.
role: central_effector
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: 2-oxoglutarate-dependent dioxygenase activity
term:
id: GO:0016706
label: 2-oxoglutarate-dependent dioxygenase activity
modifier: DECREASED
evidence:
- reference: PMID:16098467
reference_title: "HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Further, we show that fumarate acts as a competitive inhibitor of HPH.
explanation: >-
The direct biochemical demonstration of competitive inhibition that
defines this node.
downstream:
- target: Pseudohypoxic HIF Stabilization in FH-Null Cells
description: >-
Loss of prolyl hydroxylation prevents VHL-dependent degradation of
HIF-alpha under normal oxygen tension.
hypothesis_groups:
- hif_pseudohypoxia_driver
- name: Pseudohypoxic HIF Stabilization in FH-Null Cells
conforms_to: "oncometabolite_dioxygenase_inhibition#Pseudohypoxic HIF Stabilization"
description: >-
Unhydroxylated HIF-alpha escapes VHL recognition and accumulates in normoxia,
driving the hypoxia transcriptional programme. HIF overexpression correlates
with biallelic FH loss in human renal cancer. Whether this is the
transforming event or an accompanying marker is genuinely unsettled, and this
entry curates it as one of two competing readings rather than as the
mechanism.
role: effector
biological_scale: CELLULAR
biological_processes:
- preferred_term: cellular response to decreased oxygen levels
term:
id: GO:0036294
label: cellular response to decreased oxygen levels
modifier: INCREASED
evidence:
- reference: PMID:16098467
reference_title: "HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with hemizygous germline fumarate hydratase (FH) mutations are
predisposed to renal cancer.
explanation: >-
Anchors the pseudohypoxia observation to the human renal cancer
predisposition this entry describes.
downstream:
- target: Leiomyomatosis and Aggressive Renal Cell Carcinoma
description: >-
Constitutive hypoxia-response transcription supports the vascular and
metabolic phenotype of the resulting tumors.
- name: KEAP1 Succination and NRF2 Activation
conforms_to: "oncometabolite_dioxygenase_inhibition#KEAP1 Succination and NRF2 Antioxidant Pathway Activation"
description: >-
Fumarate covalently modifies cysteine residues on KEAP1 to form
S-(2-succinyl)cysteine, abrogating KEAP1's ability to repress NRF2 and
leaving the antioxidant transcriptional programme constitutively active.
Mouse genetics places this branch outside the HIF axis: Fh1-associated renal
cyst formation is HIF-independent, and deleting Hif-1alpha exacerbated rather
than prevented cysts. This is a model-derived claim and is marked as such.
role: adaptive_escape
biological_scale: MOLECULAR
biological_processes:
- preferred_term: cellular response to oxidative stress
term:
id: GO:0034599
label: cellular response to oxidative stress
modifier: INCREASED
evidence:
- reference: PMID:22014577
reference_title: "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mechanistic analysis revealed that fumarate modifies cysteine residues
within the Kelch-like ECH-associated protein 1 (KEAP1), abrogating its
ability to repress the Nuclear factor (erythroid-derived 2)-like 2
(Nrf2)-mediated antioxidant response pathway, suggesting a role for Nrf2
dysregulation in FH-associated cysts and tumors.
explanation: >-
Establishes the succination branch and its NRF2 output in an Fh1-deficient
mouse. Evidence source is MODEL_ORGANISM; the human equivalence is an open
question recorded in this entry's discussions.
downstream:
- target: Leiomyomatosis and Aggressive Renal Cell Carcinoma
description: >-
Constitutive antioxidant signalling supports survival of FH-null cells.
hypothesis_groups:
- nrf2_succination_driver
- name: Leiomyomatosis and Aggressive Renal Cell Carcinoma
conforms_to: "germline_two_hit_tumor_predisposition#Early-Onset, Multifocal, and Bilateral Tumor Spectrum"
description: >-
The clinical output: multiple cutaneous leiomyomas, early and numerous
uterine leiomyomas often leading to hysterectomy in the third or fourth
decade, and — in a minority of carriers — a type 2 papillary or
collecting-duct renal cell carcinoma notable for metastasizing while the
primary is still small. The multiplicity of the leiomyomas is the signature
of independent second hits across a primed tissue; the renal tumor is rarer
because fewer renal cells complete the second hit, but it determines
prognosis.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We previously mapped a gene that predisposes to multiple fibroids,
cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43
(refs 4-6).
explanation: >-
Defines the three-component tumor spectrum of the syndrome as originally
mapped.
- reference: PMID:22014577
reference_title: "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited
cancer syndrome in which affected individuals are at risk of developing
benign cutaneous and uterine leiomyomas, renal cysts, and aggressive
collecting duct and Type 2 papillary renal cell carcinomas (pRCC)
explanation: >-
Documents the renal histology and its aggressiveness. Evidence source is
OTHER because this sentence is the paper's introductory characterization of
the syndrome rather than its own experimental result.
phenotypes:
- category: Dermatologic
name: Multiple Cutaneous Leiomyomas
description: >-
Multiple firm skin-coloured to brown papules and nodules arising from arrector
pili smooth muscle, often painful and frequently the first sign of the
syndrome.
phenotype_term:
preferred_term: Multiple cutaneous leiomyomas
term:
id: HP:0007437
label: Multiple cutaneous leiomyomas
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We previously mapped a gene that predisposes to multiple fibroids,
cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43
(refs 4-6).
explanation: >-
Names multiple cutaneous leiomyomata as a defining component of the
mapped phenotype.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Cutaneous leiomyomata appear as skin-colored to light brown papules or
nodules distributed across the trunk and extremities and occasionally on
the face, and are usually noted in the second to fourth decades of life,
increasing in size and number with age.
explanation: >-
GeneReviews Clinical Characteristics section, giving the appearance,
distribution and onset window of the cutaneous lesion, and its progressive
accumulation with age — the visible signature of independent second hits
across the skin over time.
- category: Reproductive
name: Uterine Leiomyoma
description: >-
Uterine fibroids that are numerous, symptomatic and of early onset relative
to sporadic fibroids, commonly leading to myomectomy or hysterectomy in young
adulthood.
phenotype_term:
preferred_term: Uterine leiomyoma
term:
id: HP:0000131
label: Uterine leiomyoma
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We previously mapped a gene that predisposes to multiple fibroids,
cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43
(refs 4-6).
explanation: >-
Names multiple uterine fibroids as part of the inherited predisposition
mapped to the FH locus. The sentence used previously here described
sporadic fibroids in general and said nothing about the syndrome.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Uterine leiomyomata tend to be numerous and large; mean age at diagnosis
is ~30 years, with most females experiencing irregular or heavy
menstruation and pelvic pain.
explanation: >-
GeneReviews Clinical Characteristics section, giving the mean age at
diagnosis and the symptom burden — the reason many carriers reach
myomectomy or hysterectomy in early adulthood.
- category: Renal
name: Papillary Renal Cell Carcinoma
description: >-
Type 2 papillary (or collecting-duct) renal cell carcinoma; typically
unilateral and solitary but biologically aggressive, with a propensity to
metastasize at small size that governs surveillance and surgical policy.
phenotype_term:
preferred_term: Papillary renal cell carcinoma
term:
id: HP:0006766
label: Papillary renal cell carcinoma
evidence:
- reference: PMID:22014577
reference_title: "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited
cancer syndrome in which affected individuals are at risk of developing
benign cutaneous and uterine leiomyomas, renal cysts, and aggressive
collecting duct and Type 2 papillary renal cell carcinomas (pRCC)
explanation: >-
Specifies the renal histological subtypes seen in HLRCC. Evidence source
is OTHER because this is the paper's background characterization.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Renal tumors are usually unilateral, solitary, and aggressive. They are
associated with poor survival due to clinical aggressiveness and
propensity to metastasize despite small primary tumor size. The median age
of detection is approximately 40 years.
explanation: >-
GeneReviews Clinical Characteristics section. This is the clinically
decisive sentence of the entry: unlike the multifocal cutaneous and
uterine lesions, the renal tumor is usually solitary yet metastasizes
while small, which is why surveillance is imaging-based and annual rather
than triggered by symptoms.
genetic:
- name: FH
gene_term:
preferred_term: FH
term:
id: hgnc:3700
label: FH
relationship_type: CAUSATIVE
notes: >-
FH at 1q42.3-q43 encodes fumarate hydratase. Heterozygous germline
loss-of-function variants cause HLRCC; biallelic germline variants instead
cause the recessive metabolic disease fumarate hydratase deficiency.
evidence:
- reference: PMID:11865300
reference_title: "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in FH also occur in the recessive condition fumarate hydratase
deficiency, and some parents of people with this condition are susceptible
to leiomyomata.
explanation: >-
Documents the allelic relationship between the dominant tumor syndrome and
the recessive metabolic disease at the same locus.
discussions:
- discussion_id: hlrcc_human_model_fidelity_of_nrf2_branch
prompt: >-
Does the HIF-independent, KEAP1-succination/NRF2 mechanism established in
Fh1-deficient mouse kidney account for tumorigenesis in human HLRCC, where
HIF overexpression is the observed correlate of biallelic FH loss?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#KEAP1 Succination and NRF2 Activation
- pathophysiology#Pseudohypoxic HIF Stabilization in FH-Null Cells
rationale: >-
The two branches point in different therapeutic directions and the evidence
for them is of different kinds. The human evidence is observational — HIF
overexpression correlates with biallelic FH loss in human renal cancer — and
supports the pseudohypoxia reading. The evidence that removes HIF from the
causal path is genetic but murine: Fh1-associated cyst formation proceeds
without HIF, and deleting Hif-1alpha made cysts worse. Neither result
settles the human case, and a correlation in human tumors cannot
discriminate driver from marker. Curators should not present either branch
as the established human mechanism, and should keep the model-derived claim
tagged MODEL_ORGANISM.
proposed_experiments:
- experiment_id: succination_versus_hif_in_human_hlrcc_tumors
name: Succination burden versus HIF target output in matched human HLRCC tumors
description: >-
Quantify S-(2-succinyl)cysteine burden, NRF2 target-gene output and HIF
target-gene output in the same human HLRCC renal tumors and matched
leiomyomas, testing whether one branch tracks tumor grade and behaviour
while the other does not.
treatments:
- name: Systemic Therapy for FH-Deficient Renal Cell Carcinoma
description: >-
The renal tumor is the arm that determines prognosis, and it is managed
differently from sporadic renal cell carcinoma. Beyond surgery, GeneReviews
names two systemic combinations as potentially beneficial: erlotinib plus
bevacizumab, and cabozantinib plus nivolumab. The erlotinib/bevacizumab
pairing is mechanistically coherent with this entry's pathophysiology — an
anti-VEGF antibody targeting the pseudohypoxic, HIF-driven angiogenic output
of the FH-null cell, combined with EGFR blockade. Note the source's own
hedging ("may be beneficial"); this is not curated as established efficacy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: erlotinib
term:
id: NCIT:C65530
label: Erlotinib
- preferred_term: bevacizumab
term:
id: NCIT:C2039
label: Bevacizumab
target_mechanisms:
- target: Pseudohypoxic HIF Stabilization in FH-Null Cells
treatment_effect: INHIBITS
description: >-
Bevacizumab neutralizes VEGF, the principal angiogenic output of the
stabilized HIF complex, acting downstream of the untreatable metabolic
lesion rather than on it. This targets the pseudohypoxia branch
specifically and is therefore contingent on that branch being the driver —
an open question recorded in this entry's mechanistic_hypotheses.
evidence:
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In addition, treatment with erlotinib plus bevacizumab or cabozantinib
plus nivolumab may be beneficial for kidney tumors.
explanation: >-
GeneReviews Management section, naming both systemic combinations. The
hedged "may be beneficial" is preserved rather than upgraded.
- name: Renal Surveillance and 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: >-
Because the renal tumor metastasizes at small size, surveillance is annual
thin-slice MRI from childhood rather than symptom-triggered imaging, and
surgery uses wide margins. Referral to a surgeon familiar with the syndrome
is specified, reflecting that nephron-sparing norms for sporadic renal
tumors do not transfer here.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Nephrectomy
term:
id: NCIT:C15284
label: Nephrectomy
target_mechanisms:
- target: Leiomyomatosis and Aggressive Renal Cell Carcinoma
treatment_effect: INHIBITS
description: >-
Surveillance and wide-margin resection act on the consequence node by
detecting and removing the renal tumor before dissemination; they do not
alter the germline lesion or prevent further second hits.
evidence:
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
annual MRI with 1- to 3-mm slices through the kidneys from age eight
years; prompt follow up for suspicious renal lesions
explanation: >-
GeneReviews Management section, giving the surveillance modality, slice
thickness and starting age. The unusually early start and fine slices
follow directly from the tumor metastasizing while small.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Total or partial nephrectomy with wide margins may be carefully considered
in some settings.
explanation: >-
GeneReviews Management section on the surgical approach. The wide-margin
qualifier distinguishes this from standard nephron-sparing surgery for
sporadic renal tumors.
- name: Symptomatic Management of Cutaneous and Uterine Leiomyomas
description: >-
The benign lesions are treated for symptom burden rather than cancer risk:
cutaneous leiomyomas by excision or ablation with pharmacological options
for the characteristic pain, and uterine fibroids medically or surgically.
GeneReviews attaches an important caveat to fibroid surgery — histology must
distinguish atypical smooth muscle neoplasm from leiomyosarcoma.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Therapeutic Procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Treatment of cutaneous leiomyomas can include surgical excision, carbon
dioxide laser, cryotherapy, or electrodessication.
explanation: >-
GeneReviews Management section, listing the cutaneous treatment options.
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
histologic examination to differentiate between atypical smooth muscle
neoplasm and leiomyosarcoma should be performed in those undergoing
surgery
explanation: >-
GeneReviews Management section. This is a safety caveat rather than a
treatment: fibroid surgery in an FH carrier must not assume the lesion is
benign.
diagnosis:
- name: Molecular Genetic Testing for Heterozygous FH Variants
description: >-
The diagnosis is established by identifying a heterozygous germline FH
pathogenic variant. The zygosity in that sentence is load-bearing: a
heterozygous variant establishes this tumor predisposition syndrome, whereas
biallelic FH variants cause the recessive metabolic disease fumarate
hydratase deficiency, which is a different disorder with a different
GeneReviews chapter.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
results: >-
A heterozygous germline pathogenic FH variant establishes the diagnosis and
makes at-risk relatives eligible for predictive testing and early renal
surveillance.
evidence:
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Diagnosis of FH tumor predisposition syndrome is established in a proband
with a heterozygous pathogenic variant in FH identified by molecular
genetic testing.
explanation: >-
GeneReviews Diagnosis/Testing section, stating the confirmatory test and
the heterozygous zygosity that separates this syndrome from recessive
fumarate hydratase deficiency.
- name: Predictive Testing of At-Risk Relatives
description: >-
Cascade testing is framed by GeneReviews as serving two purposes: starting
surveillance early in carriers, and sparing non-carriers the cost and burden
of lifelong renal imaging.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
results: >-
Identifies which at-risk relatives require early renal surveillance and
which can be discharged from it.
evidence:
- reference: PMID:20301430
reference_title: "FH Tumor Predisposition Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
It is appropriate to clarify the genetic status of apparently
asymptomatic at-risk relatives of an affected individual by molecular
genetic testing for the familial FH pathogenic variant in order to
identify as early as possible those who would benefit from early
surveillance and treatment and to reduce costly screening procedures in
those who have not inherited the pathogenic variant.
explanation: >-
GeneReviews Evaluation of Relatives at Risk, giving both the case for
cascade testing and the de-escalation rationale for non-carriers.
mechanistic_hypotheses:
- hypothesis_group_id: hif_pseudohypoxia_driver
hypothesis_label: Pseudohypoxic HIF Activation Drives FH-Deficient Tumorigenesis
status: CANONICAL
description: >-
The long-standing reading of HLRCC: competitive inhibition of the HIF prolyl
hydroxylases by accumulated fumarate stabilizes HIF in normoxia, and the
resulting constitutive hypoxia programme is what transforms the FH-null
cell. The human evidence for this arm is observational — HIF overexpression
correlates with biallelic FH loss in HLRCC-associated renal cancer.
evidence:
- reference: PMID:16098467
reference_title: "HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We demonstrate that FH inhibition, together with elevated intracellular
fumarate, coincides with HIF upregulation.
explanation: >-
The human tumor observation on which the pseudohypoxia-driver reading of
HLRCC rests.
- hypothesis_group_id: nrf2_succination_driver
hypothesis_label: KEAP1 Succination and NRF2 Dysregulation Drives FH-Deficient Tumorigenesis
status: ALTERNATIVE
description: >-
The competing reading, specific to the fumarate lesion: the transforming
event is covalent succination of KEAP1 and consequent constitutive NRF2
antioxidant signalling, not HIF stabilization. Mouse genetics is the
strongest evidence and it removes HIF from the causal path — Fh1-associated
renal cyst formation proceeds without HIF, and deleting Hif-1alpha made
cysts worse rather than better. This entry does not adjudicate between the
two readings; see the HUMAN_MODEL_MISMATCH discussion below.
evidence:
- reference: PMID:22014577
reference_title: "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Using a mouse model, we provide genetic evidence that Fh1-associated cyst
formation is Hif independent, as is striking upregulation of antioxidant
signaling pathways revealed by gene expression profiling.
explanation: >-
Genetic evidence placing cyst formation outside the HIF axis, which is
what makes this an alternative to rather than a complement of the
pseudohypoxia reading. Evidence source is MODEL_ORGANISM.
references:
- reference: PMID:20301430
title: "FH Tumor Predisposition Syndrome."
tags:
- GeneReviews
clinical_trials:
- name: NCT02495103
phase: PHASE_II
status: TERMINATED
description: >-
Terminated phase I/II trial of vandetanib plus metformin in HLRCC-associated
and SDH-associated kidney cancer, pairing the two oncometabolite-driven
renal cancer syndromes in one metabolic-therapy arm.
target_phenotypes:
- preferred_term: Papillary renal cell carcinoma
term:
id: HP:0006766
label: Papillary renal cell carcinoma
evidence:
- reference: clinicaltrials:NCT02495103
reference_title: Phase I/II Trial of Vandetanib in Combination With Metformin in Subjects With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
For Phase II, people 18 and over with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC), succinate dehydrogenase renal cell carcinoma (SDH-RCC), or advanced papillary renal cell carcinoma not related to a hereditary syndrome
explanation: >-
Registry record defining an HLRCC-specific phase II cohort. The trial
terminated, so it evidences that the combination was studied in HLRCC, not
that it is efficacious.