Hereditary Pheochromocytoma-Paraganglioma Syndrome

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Inheritance

1

Autosomal dominant HP:0000006

Transmission is autosomal dominant with incomplete, age-dependent penetrance that differs markedly by gene. SDHD-related disease shows a parent-of-origin effect: affected individuals almost always inherit the variant from their father. The mechanism of that effect is not settled — the original SDHD report noted explicitly that the gene showed no evidence of imprinting despite the inheritance pattern predicting it — and is curated here as an open question rather than asserted.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (4 references)

PMID:10657297 SUPPORT Human Clinical

"In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting."

Establishes both that the inheritance pattern of PGL implies a parent-of-origin effect and that the simplest explanation for it was not supported at the gene, which is exactly the caveat this entry records.

PMID:20301715 SUPPORT Other

"Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant."

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.

PMID:20301715 SUPPORT Other

"Pathogenic variants in SDHD, SDHAF2, and possibly MAX demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited"

GeneReviews Genetic Counseling section, stating the parent-of-origin effect as a clinical fact and extending it beyond SDHD to SDHAF2 and possibly MAX. This is the observation whose mechanism remains open in this entry's KNOWLEDGE_GAP discussion — the effect is established, the explanation is not.

+ 1 more reference

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Mechanistic Hypotheses

2

Pseudohypoxic HIF Activation Drives SDHx-Deficient Tumorigenesis

hif_pseudohypoxia_driver CANONICAL

Evidence balance 1 support

The original reading: succinate inhibits the HIF prolyl hydroxylases, HIF is stabilized in normoxia, and the resulting hypoxia programme both transforms the chromaffin or paraganglionic cell and accounts for the striking vascularity of these tumors in the absence of any VHL mutation.

Pathograph links

Succinate-Mediated Dioxygenase Inhibition -> Pseudohypoxic HIF Stabilization in SDH-Deficient Cells Loss of prolyl hydroxylase activity leaves HIF-alpha unhydroxylated and stable in normoxia.

Show evidence (1 reference)

PMID:15652751 SUPPORT In Vitro

"These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations."

The observation on which the pseudohypoxia-driver reading of SDHx tumorigenesis rests.

Hypermethylator Phenotype and Differentiation Block Drives SDHx-Deficient Tumorigenesis

epigenetic_hypermethylation_driver ALTERNATIVE

Evidence balance 1 support

The competing reading: the transforming event is inhibition of the TET and Jumonji demethylases, producing a hypermethylator phenotype that silences neuroendocrine differentiation genes. Its strongest support is that the severity of silencing, not the degree of HIF activation, tracks the clinical severity gradient across SDHx genotypes — epigenetic silencing is most severe in SDHB-mutated tumors, which are also the most likely to metastasize.

Pathograph links

Succinate-Mediated Dioxygenase Inhibition -> Hypermethylator Phenotype and Neuroendocrine Differentiation Block Loss of TET and Jumonji demethylase activity allows DNA and histone methyl marks to accumulate genome-wide.

Show evidence (1 reference)

PMID:23707781 SUPPORT Human Clinical

"Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy."

Ties the epigenetic branch rather than the HIF branch to the clinical severity gradient across genotypes. The source hedges ("potentially explaining"), and this hypothesis is curated as ALTERNATIVE rather than settled.

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Discussions and Knowledge Gaps

1

What mechanism produces the paternal-transmission requirement in SDHD-related paraganglioma, given that the gene itself showed no evidence of imprinting?

KNOWLEDGE GAP OPEN gap_sdhd_parent_of_origin_mechanism

Attached to

pathophysiology#Germline SDHx First-Hit Inactivation

The clinical inheritance pattern of SDHD-related paraganglioma is one of the most striking parent-of-origin effects in cancer genetics, and it directly governs who is offered surveillance in a family. The obvious explanation, genomic imprinting of SDHD, was tested in the original report and not supported. The leading alternative invokes the somatic second hit rather than the germline allele: tumorigenesis requires loss of the entire maternal chromosome 11, so the event is available only when the retained maternal copy is the wild-type one — that is, when the constitutional variant came from the father. The companion `Pheochromocytoma_Paraganglioma` entry (MONDO:0035540) curates that explanation directly, in its "Somatic Loss of Maternal Chromosome 11" node, which now conforms to the second-hit node of the germline two-hit module. This entry keeps the question open rather than restating it as settled, because the evidence quoted here goes only as far as showing that the lost chromosome IS maternal (PMID:11605159) — consistent with the model, but not by itself an account of why the reciprocal event cannot occur. Curators wanting the mechanistic account should follow the cross-reference; curators wanting the clinical rule need only the parent-of-origin observation, which GeneReviews states plainly.

Proposed experiments

Parent-of-origin-resolved allelic analysis of SDHD tumors

parental_allele_resolved_loh_in_sdhd_tumors

Determine, in SDHD paragangliomas from carriers of known transmission parent, which parental chromosome 11 region is lost somatically and whether the pattern differs between paternally and maternally transmitted variants, testing whether the parent-of-origin effect resides in the second hit rather than in germline imprinting.

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Pathophysiology

7

Germline SDHx First-Hit Inactivation

A heterozygous loss-of-function variant in a succinate dehydrogenase subunit gene is present constitutionally. SDHC and SDHD encode the membrane anchors that hold the SDHA/SDHB catalytic core in the inner mitochondrial membrane, so loss of any of the four subunits compromises the same enzyme. The identification of these genes extended tumor predisposition beyond the previously known VHL, NF1 and RET loci to the mitochondrion itself.

SDHB hgnc:10681 ↓ DECREASED

Genetic context SDHB hgnc:10681 variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Constitutional heterozygous inactivating variant in a succinate dehydrogenase subunit gene; SDHB is given as the exemplar because it carries the highest metastatic risk, but SDHA, SDHC, SDHD and SDHAF2 variants act through the same enzyme.

Downstream

Biallelic SDHx Loss and Succinate Dehydrogenase Deficiency A somatic second hit removing the wild-type allele is required before enzyme activity falls far enough for succinate to accumulate.

Show evidence (3 references)

PMID:10657297 SUPPORT Human Clinical

"Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23."

Identifies the first germline succinate dehydrogenase lesion in hereditary paraganglioma families.

PMID:11404820 SUPPORT Human Clinical

"Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma."

Extends the germline first hit to SDHB and to the pheochromocytoma phenotype, establishing the gene family basis of this entry.

PMID:11404820 SUPPORT Human Clinical

"The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane."

Supports the statement that loss of any subunit compromises one shared enzyme, which is why the several PGL loci produce one mechanistic entity.

Biallelic SDHx Loss and Succinate Dehydrogenase Deficiency

In a chromaffin or paraganglionic cell that has inactivated the retained wild-type allele, succinate dehydrogenase activity is lost. This is the handover point from the inherited-predisposition mechanism to the oncometabolite mechanism: the heterozygous carrier cell is not succinate-loaded, and only the biallelic cell reaches the concentrations at which succinate acts as a signalling molecule.

Genetic context SDHB hgnc:10681 variant_origin: GERMLINE_AND_SOMATIC allelic_hit_role: BIALLELIC_INACTIVATION allelic_event: LOSS_OF_HETEROZYGOSITY functional_impact_category: LOSS_OF_FUNCTION

Combined inherited and acquired inactivation leaving the tumor cell without functional succinate dehydrogenase.

succinate dehydrogenase (quinone) activity GO:0008177 ⇓ LOSS OF FUNCTION

Downstream

Succinate Accumulation With the enzyme absent, its substrate accumulates and escapes to the cytosol.

Show evidence (3 references)

PMID:11605159 SUPPORT Human Clinical

"Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes."

Demonstrates the somatic second hit directly, by contrasting tumor with constitutional genotype in an SDHD carrier — and identifies the lost chromosome as the maternal one, which is the observation the parent-of-origin knowledge gap in this entry turns on.

PMID:11605159 SUPPORT Human Clinical

"Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was not detected in six sporadic pheochromocytomas."

Confirms at the enzyme level that the tumor cell has lost succinate dehydrogenase function completely, which is the biallelic state this node asserts, and shows the loss is specific to the inherited tumor.

PMID:11404820 SUPPORT Human Clinical

"These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility."

Supports the broader link between loss of this mitochondrial enzyme and tumorigenesis in the lineage. Note this sentence establishes susceptibility, not the biallelic state; the two preceding items carry that claim.

Succinate Accumulation

Succinate builds up as a direct result of succinate dehydrogenase inhibition and moves from the mitochondrion to the cytosol, where it is available to act on 2-oxoglutarate-dependent enzymes. This mitochondrion-to-cytosol step is what converts a metabolic lesion into a signalling lesion.

tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Succinate-Mediated Dioxygenase Inhibition Cytosolic and nuclear succinate competes with 2-oxoglutarate at the shared dioxygenase active site.

Show evidence (1 reference)

PMID:15652751 SUPPORT In Vitro

"Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha."

Establishes succinate accumulation as the consequence of SDH inhibition and its translocation to the cytosol as the signalling step.

Succinate-Mediated Dioxygenase Inhibition

Accumulated succinate inhibits 2-oxoglutarate-dependent dioxygenases, including the HIF prolyl hydroxylases and the histone and DNA demethylases. Because inhibition is at the shared cofactor site it is not selective for one target, which is why a single enzyme deficiency produces simultaneous pseudohypoxic and epigenetic phenotypes in these tumors.

Hypermethylator Phenotype and Differentiation Block Drives SDHx-Deficient Tumorigenesis Pseudohypoxic HIF Activation Drives SDHx-Deficient Tumorigenesis

2-oxoglutarate-dependent dioxygenase activity GO:0016706 ↓ DECREASED

Downstream

Pseudohypoxic HIF Stabilization in SDH-Deficient Cells Loss of prolyl hydroxylase activity leaves HIF-alpha unhydroxylated and stable in normoxia.

Hypermethylator Phenotype and Neuroendocrine Differentiation Block Loss of TET and Jumonji demethylase activity allows DNA and histone methyl marks to accumulate genome-wide.

Show evidence (1 reference)

PMID:23707781 SUPPORT In Vitro

"Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases and established a migratory phenotype reversed by decitabine treatment."

Demonstrates dioxygenase inhibition by succinate in the relevant cell lineage, together with its epigenetic and phenotypic consequences. Evidence source is IN_VITRO (cultured mouse chromaffin cells).

Pseudohypoxic HIF Stabilization in SDH-Deficient Cells

HIF-alpha escapes VHL-dependent degradation and drives the hypoxia transcriptional programme despite adequate oxygen. This is the mechanistic explanation for the striking vascularity of paraganglioma and pheochromocytoma arising without any VHL mutation, and the point at which SDHx disease converges phenotypically on von Hippel-Lindau disease from the opposite direction.

cellular response to decreased oxygen levels GO:0036294 ↑ INCREASED

Downstream

Paraganglioma and Pheochromocytoma Development Constitutive hypoxia-response transcription supports the vascular, metabolically reprogrammed tumor phenotype.

Show evidence (1 reference)

PMID:15652751 SUPPORT In Vitro

"These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations."

Directly supports both the HIF stabilization and its proposed explanation of the vascular phenotype in SDH-mutant tumors.

Hypermethylator Phenotype and Neuroendocrine Differentiation Block

Methylome analysis of a large paraganglioma cohort resolves three stable clusters, and SDHx-mutated tumors form a distinct hypermethylator group in which the genes specifying neuroendocrine differentiation are downregulated. The severity of silencing is genotype-dependent and clinically consequential: it is most marked in SDHB-mutated tumors, which are also the most malignant, which is the strongest available argument that the epigenetic branch — not the pseudohypoxic one — is what determines behaviour.

chromosomal 5-methylcytosine DNA demethylation pathway GO:0141166 ↓ DECREASED demethylation GO:0070988 ↓ DECREASED

Downstream

Paraganglioma and Pheochromocytoma Development Silencing of differentiation programmes locks cells in a progenitor-like, migration-competent state.

Show evidence (2 references)

PMID:23707781 SUPPORT Human Clinical

"SDHx-related tumors displayed a hypermethylator phenotype, associated with downregulation of key genes involved in neuroendocrine differentiation."

Establishes the hypermethylator phenotype and its differentiation consequence in human SDHx paraganglioma.

PMID:23707781 SUPPORT Human Clinical

"Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy."

Ties the severity of the epigenetic branch to the SDHB genotype and to malignant behaviour, which is the genotype-phenotype claim made here. Note the source hedges ("potentially explaining"), and this entry does not assert the link as established.

Paraganglioma and Pheochromocytoma Development

The clinical output: parasympathetic paragangliomas of the head and neck — most characteristically of the carotid body, an oxygen-sensing chemoreceptive organ whose normal physiology also depends on the affected complex — and sympathetic paraganglioma and adrenal pheochromocytoma with catecholamine excess. Tumors are frequently multiple and may be bilateral, and present earlier than their sporadic counterparts. Anatomical distribution and metastatic risk are genotype-dependent, with SDHB carrying the highest risk of malignant behaviour.

Show evidence (2 references)

PMID:10657297 SUPPORT Human Clinical

"Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood."

Defines the characteristic tumor type and site, and names the oxygen-sensing physiology of the carotid body that makes this lineage's vulnerability to a pseudohypoxic lesion notable.

PMID:10657297 SUPPORT Human Clinical

"These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology."

Supports both the tumorigenic role of the mitochondrial lesion and the normal carotid-body function of the affected subunit.

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Pathograph

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Phenotypes

5

Cardiovascular 1

Hypertension HP:0000822

Show evidence (2 references)

PMID:11404820 SUPPORT Human Clinical

"The pheochromocytomas are an important cause of secondary hypertension."

Directly links the tumor to hypertension as its cardinal systemic manifestation.

PMID:20301715 SUPPORT Other

"Symptoms of PGL/PCCs result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety)."

GeneReviews Clinical Characteristics section, giving the full catecholamine symptom complex of which hypertension is one component.

Endocrine 1

Pheochromocytoma HP:0002666

Show evidence (1 reference)

PMID:11404820 SUPPORT Human Clinical

"Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma."

Directly ties pheochromocytoma to germline SDHB variants in affected kindreds, which is what makes it a phenotype of this syndrome rather than merely a cause of hypertension.

Other 3

Paraganglioma HP:0002668

Show evidence (2 references)

PMID:23707781 SUPPORT Human Clinical

"Paragangliomas are neuroendocrine tumors frequently associated with mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes."

Establishes paraganglioma as the defining tumor and names SDHx among its germline causes.

PMID:20301715 SUPPORT Other

"Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory."

GeneReviews Clinical Characteristics section, giving the functional split that determines how a tumor presents — secretory sympathetic lesions with catecholamine symptoms versus silent parasympathetic lesions found as masses.

Head and Neck Paraganglioma Paraganglioma of head and neck HP:0002864

Show evidence (2 references)

PMID:10657297 SUPPORT Human Clinical

"Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood."

Establishes head and neck, and specifically carotid body, as the characteristic sites.

PMID:20301715 SUPPORT Other

"and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory"

GeneReviews Clinical Characteristics section, quantifying that around 95% of head and neck paragangliomas are nonsecretory — which is why they present as painless masses rather than with catecholamine symptoms. The quote starts mid-sentence to avoid the bracketed abbreviation span "[HNPGLs]", which the reference validator strips before matching.

Additional Tumor Spectrum Neoplasm by anatomical site HP:0011793

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma."

GeneReviews Clinical Characteristics section, naming the extra-paraganglial tumor spectrum that surveillance must cover.

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Genetic Associations

7

SDHD

Gene: SDHD hgnc:10683 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:10657297 SUPPORT Human Clinical

"SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS)."

Identifies the gene product of the first-identified paraganglioma susceptibility locus.

SDHB

Gene: SDHB hgnc:10681 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11404820 SUPPORT Human Clinical

"Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma."

The original demonstration of SDHB as a pheochromocytoma-paraganglioma susceptibility gene.

SDHC

Gene: SDHC hgnc:10682 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, which names SDHC among the genes whose germline heterozygous variants establish this diagnosis.

SDHA

Gene: SDHA hgnc:10680 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, which names SDHA among the genes whose germline heterozygous variants establish this diagnosis.

SDHAF2

Gene: SDHAF2 hgnc:26034 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, which names SDHAF2 among the genes whose germline heterozygous variants establish this diagnosis.

MAX

Gene: MAX hgnc:6913 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, which names MAX among the genes whose germline heterozygous variants establish this diagnosis.

TMEM127

Gene: TMEM127 hgnc:26038 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, which names TMEM127 among the genes whose germline heterozygous variants establish this diagnosis.

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Medical Actions

4

Alpha-Adrenergic Blockade Before Resection of a Secretory Tumor

Action: Pharmacotherapy NCIT:C15986

The sequencing here is the safety-critical part of managing a secretory lesion: alpha-adrenergic receptor blockade precedes surgery, because operating on an unblocked catecholamine-secreting tumor risks intraoperative hypertensive crisis. GeneReviews also requires that every head and neck paraganglioma be assessed for catecholamine excess before resection even though ~95% are nonsecretory — a positive result signals a second, secretory primary elsewhere.

Mechanism Target:

INHIBITS Paraganglioma and Pheochromocytoma Development — Alpha blockade does not act on the tumor; it blocks the receptor through which secreted catecholamines produce their systemic effects, making resection of the consequence node survivable.

Show evidence (2 references)

PMID:20301715 SUPPORT Other

"For secretory PGL/PCCs, alpha-adrenergic receptor blockade followed by surgical resection."

GeneReviews Management section, stating both the agent class and the order of operations.

PMID:20301715 SUPPORT Other

"All individuals with HNPGLs should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC."

GeneReviews Management section. Biochemical screening before head and neck surgery serves a diagnostic purpose beyond safety — it can reveal a second tumor, which is the multifocality this syndrome's mechanism predicts.

Genotype-Directed Surgical Management

Action: Surgical Procedure NCIT:C15329

Management is stratified by gene rather than uniform. SDHB-related tumors go to resection because of their metastatic risk, while most head and neck paragangliomas — typically nonsecretory and indolent — may reasonably be observed or irradiated instead. This is the clinical expression of the genotype-severity gradient this entry curates on the epigenetic branch.

Mechanism Target:

INHIBITS Paraganglioma and Pheochromocytoma Development — Resection removes the established tumor; it does not alter the germline lesion, so surveillance for further independent tumors continues.

Show evidence (2 references)

PMID:20301715 SUPPORT Other

"SDHB-related PGL/PCCs are typically treated with surgical resection because of the higher risk for metastatic disease."

GeneReviews Management section, tying the surgical decision directly to the SDHB genotype and its metastatic risk.

PMID:20301715 SUPPORT Other

"In general, most HNPGLs (carotid body, glomus jugulotympanicum, vagal, and jugular paragangliomas) are nonsecretory and may be treated with active observation, surgical resection, or radiation therapy."

GeneReviews Management section, giving the contrasting, less aggressive options for head and neck disease.

Lifelong Biochemical and Imaging Surveillance

Action: Magnetic Resonance Imaging NCIT:C16809

Because independent second hits keep occurring across paraganglial tissue, surveillance is lifelong and combines biochemistry with whole-body imaging. The starting age is gene-dependent, which is why cascade testing precedes surveillance planning.

Mechanism Target:

INHIBITS Paraganglioma and Pheochromocytoma Development — Surveillance shifts detection earlier in the natural history of tumors that second hits initiate; it does not prevent their initiation.

Show evidence (2 references)

PMID:20301715 SUPPORT Other

"Individuals at risk for hereditary PGL/PCC syndromes should have annual clinical assessment for manifestations of PGL/PCCs and GISTs, plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines every two years in childhood and then annually in adults, and whole-body MRI..."

GeneReviews Management section, giving the full surveillance protocol — modality, analyte and interval, with the interval changing between childhood and adulthood.

PMID:20301715 SUPPORT Other

"Age of initiation for screening varies by gene."

GeneReviews Management section. The gene-dependence of the start age is why this entry curates the genotype distinctions in `genetic:` rather than treating SDHx as one undifferentiated cause.

Avoidance of Hypoxic Exposures

Action: Behavioral Counseling NCIT:C181743

An agents-and-circumstances-to-avoid recommendation with a mechanistic rationale specific to this syndrome: the tumors arise through a pseudohypoxic lesion, so genuine hypoxia is a plausible accelerant. GeneReviews is explicit that the supporting data are extremely limited, and this entry does not curate it as established.

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"Hypoxic conditions (e.g., cyanotic heart disease, cigarette smoking) may increase tumor incidence and promote tumor growth, although data are extremely limited."

GeneReviews Agents/Circumstances to Avoid. Quoted with its own caveat intact: the mechanistic rationale is attractive given the pseudohypoxia branch curated upstream, but the evidence is explicitly weak.

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Diagnosis

4

Clinical Features Prompting Hereditary PGL/PCC Evaluation

The features that raise suspicion are precisely those the two-hit mechanism predicts — multiplicity, multifocality, recurrence and early onset — plus family history. A single late-onset sporadic-looking tumor is the situation in which the syndrome is missed.

Clinical Evaluation NCIT:C124351

Results: Multiple, multifocal, recurrent or early-onset disease, or a positive family history, should trigger germline testing.

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"A diagnosis of a hereditary PGL/PCC syndrome is strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma."

GeneReviews Diagnosis/Testing section, giving the clinical selection criteria — which are the clinical signature of the germline two-hit mechanism this entry conforms to.

Germline Molecular Genetic Testing of the PGL/PCC Gene Panel

The diagnosis is established by a germline heterozygous pathogenic variant in one of seven genes. Panel rather than single-gene testing is the norm because the genes are clinically overlapping but differ in metastatic risk, surveillance start age and parent-of-origin behaviour.

Genetic Testing NCIT:C15709

Results: A germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD or TMEM127 establishes the diagnosis and sets the gene-specific surveillance plan.

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing."

GeneReviews Diagnosis/Testing section, naming the confirmatory test and the full gene set that establishes the diagnosis.

Predictive Testing of First-Degree Relatives

Cascade testing both identifies relatives who need lifelong surveillance and releases those who do not from it — a meaningful de-escalation given that surveillance here means biennial whole-body MRI for life.

Genetic Testing NCIT:C15709

Results: Clarifies which first-degree relatives require gene-specific surveillance.

Show evidence (1 reference)

PMID:20301715 SUPPORT Other

"First-degree relatives of an individual with a hereditary PGL/PCC syndrome and a known MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 pathogenic variant should be offered molecular genetic testing to clarify their genetic status to improve diagnostic certainty and reduce the need for costly..."

GeneReviews Evaluation of Relatives at Risk, giving both purposes of cascade testing.

SDHB Immunohistochemistry as a Triage Test for Germline SDHx Testing

SDHB protein is destabilized when any complex II subunit is lost, so loss of SDHB staining reports the whole SDHx arm rather than SDHB alone. Because the second hit removes the wild-type allele in tumor tissue, the tumor itself reports the germline state, and a negative or weak-diffuse stain triages which patients need panel sequencing. It does not replace germline testing.

Immunohistochemistry Staining Method NCIT:C23020

Results: Absent or weak-diffuse cytoplasmic SDHB staining, read against an internal positive control, selects tumors for germline SDHx sequencing; granular cytoplasmic positivity argues against an SDHx cause.

Show evidence (3 references)

PMID:20236688 SUPPORT Human Clinical

"All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining."

Establishes that loss of SDHB staining detects germline variants in SDHB, SDHC and SDHD alike, which is what makes one stain a triage test for the whole arm rather than a test for one gene.

PMID:20236688 SUPPORT Human Clinical

"As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing."

States the triage conclusion and its premise — that an SDHx lesion found in tumor tissue is effectively always constitutional, which is the first-hit architecture this entry curates.

PMID:20236688 SUPPORT Human Clinical

"Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation."

A genotype-staining tendency, not a rule: it is curated as PARTIAL because the study reports it as a trend across 12 mutated tumors and it cannot be used to assign a gene without sequencing.

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Clinical Trials

1

NCT00188019 NOT_APPLICABLE COMPLETED

Completed national study comparing presymptomatic screening methods in asymptomatic SDHx germline variant carriers, addressing the surveillance question that follows directly from the first-hit carrier state.

Target Phenotypes: Paraganglioma HP:0002668 Pheochromocytoma HP:0002666

Show evidence (1 reference)

clinicaltrials:NCT00188019 SUPPORT Human Clinical

"The main objective of our national clinical research project is to test different screening methods to detect presymptomatic tumors in order to establish guidelines for the work-up and the follow-up of SDH mutation carriers."

Registry record for the completed SDHx carrier surveillance study underlying current presymptomatic imaging recommendations.

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Source YAML

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name: Hereditary Pheochromocytoma-Paraganglioma Syndrome
creation_date: "2026-08-23T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Endocrine Neoplasia
parents:
- hereditary cancer-predisposing syndrome
disease_term:
  preferred_term: hereditary pheochromocytoma-paraganglioma
  term:
    id: MONDO:0017366
    label: hereditary pheochromocytoma-paraganglioma
synonyms:
- hereditary paraganglioma-pheochromocytoma syndrome
- SDHx-related paraganglioma-pheochromocytoma
- familial paraganglioma
description: >-
  Hereditary pheochromocytoma-paraganglioma syndrome is a group of autosomal
  dominant cancer predisposition syndromes caused by germline loss-of-function
  variants in the succinate dehydrogenase complex — SDHD (PGL1), SDHAF2 (PGL2),
  SDHC (PGL3), SDHB (PGL4) and SDHA (PGL5) — that predispose to
  catecholamine-secreting adrenal pheochromocytoma and to parasympathetic
  paragangliomas of the head and neck, most characteristically of the carotid
  body. The recognition that a mitochondrial respiratory-chain and TCA-cycle
  enzyme could act as a tumor suppressor was unexpected and reframed the
  relationship between metabolism and cancer. Succinate dehydrogenase sits at the
  junction of the TCA cycle and complex II; when it is lost, succinate
  accumulates and escapes the mitochondrion to act as a signalling molecule in
  the cytosol and nucleus, competitively inhibiting 2-oxoglutarate-dependent
  dioxygenases. Two evidenced consequences follow: inhibition of the HIF prolyl
  hydroxylases stabilizes hypoxia-inducible factor in normoxia, explaining why
  these tumors are strikingly vascular in the absence of any VHL mutation; and
  inhibition of the TET and Jumonji demethylases produces a hypermethylator
  phenotype that silences neuroendocrine differentiation genes. The severity of
  that epigenetic silencing tracks genotype and clinical behaviour — it is most
  marked in SDHB-mutated tumors, which are also the most likely to metastasize,
  and SDHB status is accordingly the single most important determinant of
  surveillance intensity. Genotype also determines anatomical distribution and
  transmission pattern: SDHD disease is dominated by head-and-neck paraganglioma
  and manifests almost exclusively on paternal transmission, while SDHB disease
  carries the highest risk of extra-adrenal abdominal and metastatic tumors.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Transmission is autosomal dominant with incomplete, age-dependent penetrance
    that differs markedly by gene. SDHD-related disease shows a parent-of-origin
    effect: affected individuals almost always inherit the variant from their
    father. The mechanism of that effect is not settled — the original SDHD
    report noted explicitly that the gene showed no evidence of imprinting
    despite the inheritance pattern predicting it — and is curated here as an
    open question rather than asserted.
  evidence:
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to expectations based on the inheritance pattern of PGL, the
      SDHD gene showed no evidence of imprinting.
    explanation: >-
      Establishes both that the inheritance pattern of PGL implies a
      parent-of-origin effect and that the simplest explanation for it was not
      supported at the gene, which is exactly the caveat this entry records.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with a hereditary PGL/PCC syndrome-causing
      pathogenic variant has a 50% chance of inheriting the 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:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathogenic variants in SDHD, SDHAF2, and possibly MAX demonstrate
      parent-of-origin effects and cause disease almost exclusively when they
      are paternally inherited
    explanation: >-
      GeneReviews Genetic Counseling section, stating the parent-of-origin
      effect as a clinical fact and extending it beyond SDHD to SDHAF2 and
      possibly MAX. This is the observation whose mechanism remains open in this
      entry's KNOWLEDGE_GAP discussion — the effect is established, the
      explanation is not.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      an individual who inherits an SDHD or SDHAF2 pathogenic variant from the
      individual's mother is usually not at risk of developing disease –
      however, exceptions occur
    explanation: >-
      GeneReviews Genetic Counseling section. The exception clause matters
      clinically: maternal inheritance lowers risk but does not abolish it, so
      this entry does not curate maternal transmission as protective.
pathophysiology:
- name: Germline SDHx First-Hit Inactivation
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >-
    A heterozygous loss-of-function variant in a succinate dehydrogenase subunit
    gene is present constitutionally. SDHC and SDHD encode the membrane anchors
    that hold the SDHA/SDHB catalytic core in the inner mitochondrial membrane,
    so loss of any of the four subunits compromises the same enzyme. The
    identification of these genes extended tumor predisposition beyond the
    previously known VHL, NF1 and RET loci to the mitochondrion itself.
  role: trigger
  biological_scale: MOLECULAR
  gene:
    preferred_term: SDHB
    modifier: DECREASED
    term:
      id: hgnc:10681
      label: SDHB
  genetic_context:
    gene:
      preferred_term: SDHB
      term:
        id: hgnc:10681
        label: SDHB
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Constitutional heterozygous inactivating variant in a succinate
      dehydrogenase subunit gene; SDHB is given as the exemplar because it
      carries the highest metastatic risk, but SDHA, SDHC, SDHD and SDHAF2
      variants act through the same enzyme.
  evidence:
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of families carrying the PGL1 gene, described here, revealed germ
      line mutations in the SDHD gene on chromosome 11q23.
    explanation: >-
      Identifies the first germline succinate dehydrogenase lesion in hereditary
      paraganglioma families.
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inactivating SDHB mutations were detected in two of the five kindreds with
      familial pheochromocytoma, two of the three kindreds with pheochromocytoma
      and paraganglioma susceptibility, and 1 of the 24 cases of sporadic
      pheochromocytoma.
    explanation: >-
      Extends the germline first hit to SDHB and to the pheochromocytoma
      phenotype, establishing the gene family basis of this entry.
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene products of two components of succinate dehydrogenase, SDHC and
      SDHD, anchor the gene products of two other components, SDHA and SDHB,
      which form the catalytic core, to the inner-mitochondrial membrane.
    explanation: >-
      Supports the statement that loss of any subunit compromises one shared
      enzyme, which is why the several PGL loci produce one mechanistic entity.
  downstream:
  - target: Biallelic SDHx Loss and Succinate Dehydrogenase Deficiency
    description: >-
      A somatic second hit removing the wild-type allele is required before
      enzyme activity falls far enough for succinate to accumulate.

- name: Biallelic SDHx Loss and Succinate Dehydrogenase Deficiency
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  description: >-
    In a chromaffin or paraganglionic cell that has inactivated the retained
    wild-type allele, succinate dehydrogenase activity is lost. This is the
    handover point from the inherited-predisposition mechanism to the
    oncometabolite mechanism: the heterozygous carrier cell is not
    succinate-loaded, and only the biallelic cell reaches the concentrations at
    which succinate acts as a signalling molecule.
  role: central_effector
  biological_scale: CELLULAR
  genetic_context:
    gene:
      preferred_term: SDHB
      term:
        id: hgnc:10681
        label: SDHB
    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 succinate dehydrogenase.
  molecular_functions:
  - preferred_term: succinate dehydrogenase (quinone) activity
    term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:11605159
    reference_title: The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss of heterozygosity was observed for the maternal chromosome 11q21-q25
      within the tumor but not in peripheral leukocytes.
    explanation: >-
      Demonstrates the somatic second hit directly, by contrasting tumor with
      constitutional genotype in an SDHD carrier — and identifies the lost
      chromosome as the maternal one, which is the observation the
      parent-of-origin knowledge gap in this entry turns on.
  - reference: PMID:11605159
    reference_title: The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assessment of the activity of respiratory-chain enzymes showed a complete
      and selective loss of complex II enzymatic activity in the inherited
      pheochromocytoma, that was not detected in six sporadic pheochromocytomas.
    explanation: >-
      Confirms at the enzyme level that the tumor cell has lost succinate
      dehydrogenase function completely, which is the biallelic state this node
      asserts, and shows the loss is specific to the inherited tumor.
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings extend the link between mitochondrial dysfunction and
      tumorigenesis and suggest that germline SDHB mutations are an important
      cause of pheochromocytoma susceptibility.
    explanation: >-
      Supports the broader link between loss of this mitochondrial enzyme and
      tumorigenesis in the lineage. Note this sentence establishes
      susceptibility, not the biallelic state; the two preceding items carry
      that claim.
  downstream:
  - target: Succinate Accumulation
    description: >-
      With the enzyme absent, its substrate accumulates and escapes to the
      cytosol.

- name: Succinate Accumulation
  conforms_to: "oncometabolite_dioxygenase_inhibition#Oncometabolite Accumulation"
  description: >-
    Succinate builds up as a direct result of succinate dehydrogenase inhibition
    and moves from the mitochondrion to the cytosol, where it is available to act
    on 2-oxoglutarate-dependent enzymes. This mitochondrion-to-cytosol step is
    what converts a metabolic lesion into a signalling lesion.
  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:15652751
    reference_title: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we describe a mitochondrion-to-cytosol signaling pathway that links
      mitochondrial dysfunction to oncogenic events: succinate, which
      accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl
      hydroxylases in the cytosol, leading to stabilization and activation of
      HIF-1alpha.
    explanation: >-
      Establishes succinate accumulation as the consequence of SDH inhibition
      and its translocation to the cytosol as the signalling step.
  downstream:
  - target: Succinate-Mediated Dioxygenase Inhibition
    description: >-
      Cytosolic and nuclear succinate competes with 2-oxoglutarate at the shared
      dioxygenase active site.

- name: Succinate-Mediated Dioxygenase Inhibition
  conforms_to: "oncometabolite_dioxygenase_inhibition#Competitive Inhibition of 2-Oxoglutarate-Dependent Dioxygenases"
  description: >-
    Accumulated succinate inhibits 2-oxoglutarate-dependent dioxygenases,
    including the HIF prolyl hydroxylases and the histone and DNA demethylases.
    Because inhibition is at the shared cofactor site it is not selective for one
    target, which is why a single enzyme deficiency produces simultaneous
    pseudohypoxic and epigenetic phenotypes in these tumors.
  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:23707781
    reference_title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA
      hypermethylation by inhibition of 2-OG-dependent histone and DNA
      demethylases and established a migratory phenotype reversed by decitabine
      treatment.
    explanation: >-
      Demonstrates dioxygenase inhibition by succinate in the relevant cell
      lineage, together with its epigenetic and phenotypic consequences.
      Evidence source is IN_VITRO (cultured mouse chromaffin cells).
  downstream:
  - target: Pseudohypoxic HIF Stabilization in SDH-Deficient Cells
    description: >-
      Loss of prolyl hydroxylase activity leaves HIF-alpha unhydroxylated and
      stable in normoxia.
    hypothesis_groups:
    - hif_pseudohypoxia_driver
  - target: Hypermethylator Phenotype and Neuroendocrine Differentiation Block
    description: >-
      Loss of TET and Jumonji demethylase activity allows DNA and histone methyl
      marks to accumulate genome-wide.
    hypothesis_groups:
    - epigenetic_hypermethylation_driver

- name: Pseudohypoxic HIF Stabilization in SDH-Deficient Cells
  conforms_to: "oncometabolite_dioxygenase_inhibition#Pseudohypoxic HIF Stabilization"
  description: >-
    HIF-alpha escapes VHL-dependent degradation and drives the hypoxia
    transcriptional programme despite adequate oxygen. This is the mechanistic
    explanation for the striking vascularity of paraganglioma and
    pheochromocytoma arising without any VHL mutation, and the point at which
    SDHx disease converges phenotypically on von Hippel-Lindau disease from the
    opposite direction.
  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:15652751
    reference_title: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest a mechanistic link between SDH mutations and
      HIF-1alpha induction, providing an explanation for the highly vascular
      tumors that develop in the absence of VHL mutations.
    explanation: >-
      Directly supports both the HIF stabilization and its proposed explanation
      of the vascular phenotype in SDH-mutant tumors.
  downstream:
  - target: Paraganglioma and Pheochromocytoma Development
    description: >-
      Constitutive hypoxia-response transcription supports the vascular,
      metabolically reprogrammed tumor phenotype.

- name: Hypermethylator Phenotype and Neuroendocrine Differentiation Block
  conforms_to: "oncometabolite_dioxygenase_inhibition#Impaired Demethylation and Genome-Wide Hypermethylation"
  description: >-
    Methylome analysis of a large paraganglioma cohort resolves three stable
    clusters, and SDHx-mutated tumors form a distinct hypermethylator group in
    which the genes specifying neuroendocrine differentiation are downregulated.
    The severity of silencing is genotype-dependent and clinically consequential:
    it is most marked in SDHB-mutated tumors, which are also the most malignant,
    which is the strongest available argument that the epigenetic branch — not
    the pseudohypoxic one — is what determines behaviour.
  role: effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: chromosomal 5-methylcytosine DNA demethylation pathway
    term:
      id: GO:0141166
      label: chromosomal 5-methylcytosine DNA demethylation pathway
    modifier: DECREASED
  - preferred_term: demethylation
    term:
      id: GO:0070988
      label: demethylation
    modifier: DECREASED
  evidence:
  - reference: PMID:23707781
    reference_title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SDHx-related tumors displayed a hypermethylator phenotype, associated with
      downregulation of key genes involved in neuroendocrine differentiation.
    explanation: >-
      Establishes the hypermethylator phenotype and its differentiation
      consequence in human SDHx paraganglioma.
  - reference: PMID:23707781
    reference_title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epigenetic silencing was particularly severe in SDHB-mutated tumors,
      potentially explaining their malignancy.
    explanation: >-
      Ties the severity of the epigenetic branch to the SDHB genotype and to
      malignant behaviour, which is the genotype-phenotype claim made here. Note
      the source hedges ("potentially explaining"), and this entry does not
      assert the link as established.
  downstream:
  - target: Paraganglioma and Pheochromocytoma Development
    description: >-
      Silencing of differentiation programmes locks cells in a progenitor-like,
      migration-competent state.

- name: Paraganglioma and Pheochromocytoma Development
  conforms_to: "germline_two_hit_tumor_predisposition#Early-Onset, Multifocal, and Bilateral Tumor Spectrum"
  description: >-
    The clinical output: parasympathetic paragangliomas of the head and neck —
    most characteristically of the carotid body, an oxygen-sensing chemoreceptive
    organ whose normal physiology also depends on the affected complex — and
    sympathetic paraganglioma and adrenal pheochromocytoma with catecholamine
    excess. Tumors are frequently multiple and may be bilateral, and present
    earlier than their sporadic counterparts. Anatomical distribution and
    metastatic risk are genotype-dependent, with SDHB carrying the highest risk
    of malignant behaviour.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary paraganglioma (PGL) is characterized by the development of
      benign, vascularized tumors in the head and neck. The most common tumor
      site is the carotid body (CB), a chemoreceptive organ that senses oxygen
      levels in the blood.
    explanation: >-
      Defines the characteristic tumor type and site, and names the oxygen-sensing
      physiology of the carotid body that makes this lineage's vulnerability to a
      pseudohypoxic lesion notable.
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that mitochondria play an important role in the
      pathogenesis of certain tumors and that cybS plays a role in normal CB
      physiology.
    explanation: >-
      Supports both the tumorigenic role of the mitochondrial lesion and the
      normal carotid-body function of the affected subunit.
phenotypes:
- category: Endocrine
  name: Pheochromocytoma
  description: >-
    Catecholamine-secreting tumor of adrenal medullary chromaffin cells; may be
    bilateral, and is a recognized cause of secondary hypertension.
  phenotype_term:
    preferred_term: Pheochromocytoma
    term:
      id: HP:0002666
      label: Pheochromocytoma
  evidence:
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inactivating SDHB mutations were detected in two of the five kindreds with
      familial pheochromocytoma, two of the three kindreds with pheochromocytoma
      and paraganglioma susceptibility, and 1 of the 24 cases of sporadic
      pheochromocytoma.
    explanation: >-
      Directly ties pheochromocytoma to germline SDHB variants in affected
      kindreds, which is what makes it a phenotype of this syndrome rather than
      merely a cause of hypertension.
- category: Neoplastic
  name: Paraganglioma
  description: >-
    Tumor of extra-adrenal paraganglia; in SDHD-related disease predominantly
    parasympathetic and located in the head and neck, in SDHB-related disease
    more often sympathetic, abdominal and metastatic.
  phenotype_term:
    preferred_term: Paraganglioma
    term:
      id: HP:0002668
      label: Paraganglioma
  evidence:
  - reference: PMID:23707781
    reference_title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paragangliomas are neuroendocrine tumors frequently associated with
      mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes.
    explanation: >-
      Establishes paraganglioma as the defining tumor and names SDHx among its
      germline causes.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sympathetic paragangliomas cause catecholamine excess; parasympathetic
      paragangliomas are most often nonsecretory.
    explanation: >-
      GeneReviews Clinical Characteristics section, giving the functional split
      that determines how a tumor presents — secretory sympathetic lesions with
      catecholamine symptoms versus silent parasympathetic lesions found as
      masses.
- category: Neoplastic
  name: Head and Neck Paraganglioma
  description: >-
    Carotid body, jugulotympanic and vagal paragangliomas — the characteristic
    presentation of SDHD-related disease, typically non-secretory and presenting
    as a painless neck mass or with cranial nerve compression.
  phenotype_term:
    preferred_term: Paraganglioma of head and neck
    term:
      id: HP:0002864
      label: Paraganglioma of head and neck
  evidence:
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary paraganglioma (PGL) is characterized by the development of
      benign, vascularized tumors in the head and neck. The most common tumor
      site is the carotid body (CB), a chemoreceptive organ that senses oxygen
      levels in the blood.
    explanation: >-
      Establishes head and neck, and specifically carotid body, as the
      characteristic sites.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      and sometimes in the upper mediastinum; approximately 95% of such tumors
      are nonsecretory
    explanation: >-
      GeneReviews Clinical Characteristics section, quantifying that around 95%
      of head and neck paragangliomas are nonsecretory — which is why they
      present as painless masses rather than with catecholamine symptoms. The
      quote starts mid-sentence to avoid the bracketed abbreviation span
      "[HNPGLs]", which the reference validator strips before matching.
- category: Cardiovascular
  name: Hypertension
  description: >-
    Secondary hypertension driven by catecholamine excess from a secretory
    pheochromocytoma or sympathetic paraganglioma.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pheochromocytomas are an important cause of secondary hypertension.
    explanation: >-
      Directly links the tumor to hypertension as its cardinal systemic
      manifestation.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of PGL/PCCs result from either mass effects or catecholamine
      hypersecretion (e.g., sustained or paroxysmal elevations in blood
      pressure, headache, episodic profuse sweating, forceful palpitations,
      pallor, and apprehension or anxiety).
    explanation: >-
      GeneReviews Clinical Characteristics section, giving the full
      catecholamine symptom complex of which hypertension is one component.
- category: Neoplastic
  name: Additional Tumor Spectrum
  description: >-
    Beyond paraganglioma and pheochromocytoma, SDHx carriers develop
    gastrointestinal stromal tumors, pulmonary chondromas and clear cell renal
    cell carcinoma. The GIST/chondroma combination is the overlap with
    Carney-Stratakis syndrome and the Carney triad, which is why unexplained
    anaemia or gastrointestinal symptoms in a carrier prompt endoscopy.
  phenotype_term:
    preferred_term: Neoplasm by anatomical site
    term:
      id: HP:0011793
      label: Neoplasm by anatomical site
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional tumors reported in individuals with hereditary PGL/PCC
      syndromes include gastrointestinal stromal tumors (GISTs), pulmonary
      chondromas, and clear cell renal cell carcinoma.
    explanation: >-
      GeneReviews Clinical Characteristics section, naming the extra-paraganglial
      tumor spectrum that surveillance must cover.
genetic:
- name: SDHD
  gene_term:
    preferred_term: SDHD
    term:
      id: hgnc:10683
      label: SDHD
  relationship_type: CAUSATIVE
  notes: >-
    SDHD at 11q23 (PGL1) encodes the small subunit of cytochrome b in
    succinate-ubiquinone oxidoreductase. Germline loss-of-function variants cause
    predominantly head-and-neck paraganglioma, with disease manifesting almost
    exclusively after paternal transmission.
  evidence:
  - reference: PMID:10657297
    reference_title: "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SDHD encodes a mitochondrial respiratory chain protein-the small subunit
      of cytochrome b in succinate-ubiquinone oxidoreductase (cybS).
    explanation: >-
      Identifies the gene product of the first-identified paraganglioma
      susceptibility locus.
- name: SDHB
  gene_term:
    preferred_term: SDHB
    term:
      id: hgnc:10681
      label: SDHB
  relationship_type: CAUSATIVE
  notes: >-
    SDHB (PGL4) encodes an iron-sulfur subunit of the succinate dehydrogenase
    catalytic core. Germline loss-of-function variants confer the highest risk of
    extra-adrenal and metastatic disease within this syndrome group.
  evidence:
  - reference: PMID:11404820
    reference_title: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inactivating SDHB mutations were detected in two of the five kindreds with
      familial pheochromocytoma, two of the three kindreds with pheochromocytoma
      and paraganglioma susceptibility, and 1 of the 24 cases of sporadic
      pheochromocytoma.
    explanation: >-
      The original demonstration of SDHB as a pheochromocytoma-paraganglioma
      susceptibility gene.
- name: SDHC
  gene_term:
    preferred_term: SDHC
    term:
      id: hgnc:10682
      label: SDHC
  relationship_type: CAUSATIVE
  notes: >-
    SDHC (PGL3) encodes a membrane-anchor subunit of succinate dehydrogenase; germline loss-of-function variants predispose predominantly to head and neck paraganglioma.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, which names SDHC among the genes
      whose germline heterozygous variants establish this diagnosis.
- name: SDHA
  gene_term:
    preferred_term: SDHA
    term:
      id: hgnc:10680
      label: SDHA
  relationship_type: CAUSATIVE
  notes: >-
    SDHA (PGL5) encodes the flavoprotein catalytic subunit. Heterozygous germline variants predispose to paraganglioma; biallelic SDHA variants instead cause a mitochondrial encephalomyopathy, the same dose-dependent divergence seen at FH.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, which names SDHA among the genes
      whose germline heterozygous variants establish this diagnosis.
- name: SDHAF2
  gene_term:
    preferred_term: SDHAF2
    term:
      id: hgnc:26034
      label: SDHAF2
  relationship_type: CAUSATIVE
  notes: >-
    SDHAF2 (PGL2) encodes an assembly factor required to flavinate SDHA rather than a subunit of the complex itself. Like SDHD it shows a paternal parent-of-origin effect.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, which names SDHAF2 among the genes
      whose germline heterozygous variants establish this diagnosis.
- name: MAX
  gene_term:
    preferred_term: MAX
    term:
      id: hgnc:6913
      label: MAX
  relationship_type: CAUSATIVE
  notes: >-
    MAX is not a succinate dehydrogenase component; it encodes a MYC-network transcription factor and reaches the same phenotype by a different route, which is why it sits outside this entry's oncometabolite pathophysiology chain.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, which names MAX among the genes
      whose germline heterozygous variants establish this diagnosis.
- name: TMEM127
  gene_term:
    preferred_term: TMEM127
    term:
      id: hgnc:26038
      label: TMEM127
  relationship_type: CAUSATIVE
  notes: >-
    TMEM127 is likewise outside the succinate dehydrogenase complex, acting on mTOR signalling, and is included here because GeneReviews lists it among the genes whose testing establishes the diagnosis.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, which names TMEM127 among the genes
      whose germline heterozygous variants establish this diagnosis.
discussions:
- discussion_id: gap_sdhd_parent_of_origin_mechanism
  prompt: >-
    What mechanism produces the paternal-transmission requirement in
    SDHD-related paraganglioma, given that the gene itself showed no evidence of
    imprinting?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Germline SDHx First-Hit Inactivation
  rationale: >-
    The clinical inheritance pattern of SDHD-related paraganglioma is one of the
    most striking parent-of-origin effects in cancer genetics, and it directly
    governs who is offered surveillance in a family. The obvious explanation,
    genomic imprinting of SDHD, was tested in the original report and not
    supported. The leading alternative invokes the somatic second hit rather
    than the germline allele: tumorigenesis requires loss of the entire maternal
    chromosome 11, so the event is available only when the retained maternal
    copy is the wild-type one — that is, when the constitutional variant came
    from the father. The companion `Pheochromocytoma_Paraganglioma` entry
    (MONDO:0035540) curates that explanation directly, in its "Somatic Loss of
    Maternal Chromosome 11" node, which now conforms to the second-hit node of
    the germline two-hit module. This entry keeps the question open rather than
    restating it as settled, because the evidence quoted here goes only as far
    as showing that the lost chromosome IS maternal (PMID:11605159) — consistent
    with the model, but not by itself an account of why the reciprocal event
    cannot occur. Curators wanting the mechanistic account should follow the
    cross-reference; curators wanting the clinical rule need only the
    parent-of-origin observation, which GeneReviews states plainly.
  proposed_experiments:
  - experiment_id: parental_allele_resolved_loh_in_sdhd_tumors
    name: Parent-of-origin-resolved allelic analysis of SDHD tumors
    description: >-
      Determine, in SDHD paragangliomas from carriers of known transmission
      parent, which parental chromosome 11 region is lost somatically and
      whether the pattern differs between paternally and maternally transmitted
      variants, testing whether the parent-of-origin effect resides in the
      second hit rather than in germline imprinting.
treatments:
- name: Alpha-Adrenergic Blockade Before Resection of a Secretory Tumor
  description: >-
    The sequencing here is the safety-critical part of managing a secretory
    lesion: alpha-adrenergic receptor blockade precedes surgery, because
    operating on an unblocked catecholamine-secreting tumor risks
    intraoperative hypertensive crisis. GeneReviews also requires that every
    head and neck paraganglioma be assessed for catecholamine excess before
    resection even though ~95% are nonsecretory — a positive result signals a
    second, secretory primary elsewhere.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Paraganglioma and Pheochromocytoma Development
    treatment_effect: INHIBITS
    description: >-
      Alpha blockade does not act on the tumor; it blocks the receptor
      through which secreted catecholamines produce their systemic effects,
      making resection of the consequence node survivable.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For secretory PGL/PCCs, alpha-adrenergic receptor blockade followed by
      surgical resection.
    explanation: >-
      GeneReviews Management section, stating both the agent class and the
      order of operations.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      All individuals with HNPGLs should be evaluated for catecholamine excess
      before surgical resection, which, if present, can suggest an additional
      primary PGL/PCC.
    explanation: >-
      GeneReviews Management section. Biochemical screening before head and
      neck surgery serves a diagnostic purpose beyond safety — it can reveal a
      second tumor, which is the multifocality this syndrome's mechanism
      predicts.
- name: Genotype-Directed Surgical Management
  description: >-
    Management is stratified by gene rather than uniform. SDHB-related tumors
    go to resection because of their metastatic risk, while most head and neck
    paragangliomas — typically nonsecretory and indolent — may reasonably be
    observed or irradiated instead. This is the clinical expression of the
    genotype-severity gradient this entry curates on the epigenetic branch.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Paraganglioma and Pheochromocytoma Development
    treatment_effect: INHIBITS
    description: >-
      Resection removes the established tumor; it does not alter the germline
      lesion, so surveillance for further independent tumors continues.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SDHB-related PGL/PCCs are typically treated with surgical resection
      because of the higher risk for metastatic disease.
    explanation: >-
      GeneReviews Management section, tying the surgical decision directly to
      the SDHB genotype and its metastatic risk.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In general, most HNPGLs (carotid body, glomus jugulotympanicum, vagal,
      and jugular paragangliomas) are nonsecretory and may be treated with
      active observation, surgical resection, or radiation therapy.
    explanation: >-
      GeneReviews Management section, giving the contrasting, less aggressive
      options for head and neck disease.
- name: Lifelong Biochemical and Imaging Surveillance
  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 independent second hits keep occurring across paraganglial tissue,
    surveillance is lifelong and combines biochemistry with whole-body imaging.
    The starting age is gene-dependent, which is why cascade testing precedes
    surveillance planning.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  target_mechanisms:
  - target: Paraganglioma and Pheochromocytoma Development
    treatment_effect: INHIBITS
    description: >-
      Surveillance shifts detection earlier in the natural history of tumors
      that second hits initiate; it does not prevent their initiation.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals at risk for hereditary PGL/PCC syndromes should have annual
      clinical assessment for manifestations of PGL/PCCs and GISTs, plasma-free
      fractionated metanephrines or 24-hour urine fractionated metanephrines
      every two years in childhood and then annually in adults, and whole-body
      MRI every two to three years.
    explanation: >-
      GeneReviews Management section, giving the full surveillance protocol —
      modality, analyte and interval, with the interval changing between
      childhood and adulthood.
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Age of initiation for screening varies by gene.
    explanation: >-
      GeneReviews Management section. The gene-dependence of the start age is
      why this entry curates the genotype distinctions in `genetic:` rather
      than treating SDHx as one undifferentiated cause.
- name: Avoidance of Hypoxic Exposures
  description: >-
    An agents-and-circumstances-to-avoid recommendation with a mechanistic
    rationale specific to this syndrome: the tumors arise through a
    pseudohypoxic lesion, so genuine hypoxia is a plausible accelerant.
    GeneReviews is explicit that the supporting data are extremely limited, and
    this entry does not curate it as established.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Behavioral Counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypoxic conditions (e.g., cyanotic heart disease, cigarette smoking) may
      increase tumor incidence and promote tumor growth, although data are
      extremely limited.
    explanation: >-
      GeneReviews Agents/Circumstances to Avoid. Quoted with its own caveat
      intact: the mechanistic rationale is attractive given the pseudohypoxia
      branch curated upstream, but the evidence is explicitly weak.
diagnosis:
- name: Clinical Features Prompting Hereditary PGL/PCC Evaluation
  description: >-
    The features that raise suspicion are precisely those the two-hit mechanism
    predicts — multiplicity, multifocality, recurrence and early onset — plus
    family history. A single late-onset sporadic-looking tumor is the situation
    in which the syndrome is missed.
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Multiple, multifocal, recurrent or early-onset disease, or a positive family
    history, should trigger germline testing.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A diagnosis of a hereditary PGL/PCC syndrome is strongly suspected in an
      individual with multiple, multifocal, recurrent, or early-onset
      paraganglioma or pheochromocytoma and/or a family history of paraganglioma
      or pheochromocytoma.
    explanation: >-
      GeneReviews Diagnosis/Testing section, giving the clinical selection
      criteria — which are the clinical signature of the germline two-hit
      mechanism this entry conforms to.
- name: Germline Molecular Genetic Testing of the PGL/PCC Gene Panel
  description: >-
    The diagnosis is established by a germline heterozygous pathogenic variant
    in one of seven genes. Panel rather than single-gene testing is the norm
    because the genes are clinically overlapping but differ in metastatic risk,
    surveillance start age and parent-of-origin behaviour.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB,
    SDHC, SDHD or TMEM127 establishes the diagnosis and sets the
    gene-specific surveillance plan.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis is established in a proband with a personal or family
      history of paraganglioma or pheochromocytoma and a germline heterozygous
      pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, naming the confirmatory test and
      the full gene set that establishes the diagnosis.
- name: Predictive Testing of First-Degree Relatives
  description: >-
    Cascade testing both identifies relatives who need lifelong surveillance and
    releases those who do not from it — a meaningful de-escalation given that
    surveillance here means biennial whole-body MRI for life.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Clarifies which first-degree relatives require gene-specific surveillance.
  evidence:
  - reference: PMID:20301715
    reference_title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      First-degree relatives of an individual with a hereditary PGL/PCC syndrome
      and a known MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 pathogenic
      variant should be offered molecular genetic testing to clarify their
      genetic status to improve diagnostic certainty and reduce the need for
      costly screening procedures in those who have not inherited the pathogenic
      variant.
    explanation: >-
      GeneReviews Evaluation of Relatives at Risk, giving both purposes of
      cascade testing.
- name: SDHB Immunohistochemistry as a Triage Test for Germline SDHx Testing
  description: >-
    SDHB protein is destabilized when any complex II subunit is lost, so loss of
    SDHB staining reports the whole SDHx arm rather than SDHB alone. Because the
    second hit removes the wild-type allele in tumor tissue, the tumor itself
    reports the germline state, and a negative or weak-diffuse stain triages
    which patients need panel sequencing. It does not replace germline testing.
  diagnosis_term:
    preferred_term: Immunohistochemistry Staining Method
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  results: >-
    Absent or weak-diffuse cytoplasmic SDHB staining, read against an internal
    positive control, selects tumors for germline SDHx sequencing; granular
    cytoplasmic positivity argues against an SDHx cause.
  evidence:
  - reference: PMID:20236688
    reference_title: Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse
      or negative staining.
    explanation: >-
      Establishes that loss of SDHB staining detects germline variants in SDHB,
      SDHC and SDHD alike, which is what makes one stain a triage test for the
      whole arm rather than a test for one gene.
  - reference: PMID:20236688
    reference_title: Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As SDH mutations are virtually always germline, we conclude that
      approximately 15% of all pheochromocytomas or paragangliomas are
      associated with germline SDH mutation and that immunohistochemistry can be
      used to triage genetic testing.
    explanation: >-
      States the triage conclusion and its premise — that an SDHx lesion found
      in tumor tissue is effectively always constitutional, which is the
      first-hit architecture this entry curates.
  - reference: PMID:20236688
    reference_title: Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Completely absent staining is more commonly found with SDHB mutation,
      whereas weak diffuse staining often occurs with SDHD mutation.
    explanation: >-
      A genotype-staining tendency, not a rule: it is curated as PARTIAL because
      the study reports it as a trend across 12 mutated tumors and it cannot be
      used to assign a gene without sequencing.
mechanistic_hypotheses:
- hypothesis_group_id: hif_pseudohypoxia_driver
  hypothesis_label: Pseudohypoxic HIF Activation Drives SDHx-Deficient Tumorigenesis
  status: CANONICAL
  description: >-
    The original reading: succinate inhibits the HIF prolyl hydroxylases, HIF is
    stabilized in normoxia, and the resulting hypoxia programme both transforms
    the chromaffin or paraganglionic cell and accounts for the striking
    vascularity of these tumors in the absence of any VHL mutation.
  evidence:
  - reference: PMID:15652751
    reference_title: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest a mechanistic link between SDH mutations and
      HIF-1alpha induction, providing an explanation for the highly vascular
      tumors that develop in the absence of VHL mutations.
    explanation: >-
      The observation on which the pseudohypoxia-driver reading of SDHx
      tumorigenesis rests.
- hypothesis_group_id: epigenetic_hypermethylation_driver
  hypothesis_label: Hypermethylator Phenotype and Differentiation Block Drives SDHx-Deficient Tumorigenesis
  status: ALTERNATIVE
  description: >-
    The competing reading: the transforming event is inhibition of the TET and
    Jumonji demethylases, producing a hypermethylator phenotype that silences
    neuroendocrine differentiation genes. Its strongest support is that the
    severity of silencing, not the degree of HIF activation, tracks the clinical
    severity gradient across SDHx genotypes — epigenetic silencing is most severe
    in SDHB-mutated tumors, which are also the most likely to metastasize.
  evidence:
  - reference: PMID:23707781
    reference_title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epigenetic silencing was particularly severe in SDHB-mutated tumors,
      potentially explaining their malignancy.
    explanation: >-
      Ties the epigenetic branch rather than the HIF branch to the clinical
      severity gradient across genotypes. The source hedges ("potentially
      explaining"), and this hypothesis is curated as ALTERNATIVE rather than
      settled.
references:
- reference: PMID:20301715
  title: "Hereditary Paraganglioma-Pheochromocytoma Syndromes."
  tags:
  - GeneReviews
clinical_trials:
- name: NCT00188019
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed national study comparing presymptomatic screening methods in
    asymptomatic SDHx germline variant carriers, addressing the surveillance
    question that follows directly from the first-hit carrier state.
  target_phenotypes:
  - preferred_term: Paraganglioma
    term:
      id: HP:0002668
      label: Paraganglioma
  - preferred_term: Pheochromocytoma
    term:
      id: HP:0002666
      label: Pheochromocytoma
  evidence:
  - reference: clinicaltrials:NCT00188019
    reference_title: "Evaluation Des méthodes de dépistage du Paragangliome héréditaire Chez Les Sujets prédisposés génétiquement"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main objective of our national clinical research project is to test different screening methods to detect presymptomatic tumors in order to establish guidelines for the work-up and the follow-up of SDH mutation carriers.
    explanation: >-
      Registry record for the completed SDHx carrier surveillance study
      underlying current presymptomatic imaging recommendations.

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PMID:20301715

Hereditary Paraganglioma-Pheochromocytoma Syndromes.

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Hereditary Pheochromocytoma-Paraganglioma Syndrome

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