Von Hippel-Lindau Disease and Hereditary Paraganglioma-Phaeochromocytoma Syndromes

Literature and regulatory information updated: 4 October 2026; integration of the French PGL/PHEO PNDS (French National Diagnosis and Care Protocol): 2 November 2026.

Von Hippel-Lindau syndrome (types 1, 2A, 2B and 2C; haemangioblastomas, clear cell renal cell carcinoma, renal and pancreatic cysts, phaeochromocytoma) and hereditary paraganglioma-phaeochromocytoma syndromes associated with SDHB, SDHD, SDHC, SDHA, SDHAF2, TMEM127, MAX and FH — the pseudohypoxia axis in cancer genetics

0. Initial Reference Table

1. Introduction

Von Hippel-Lindau syndrome and hereditary paraganglioma-phaeochromocytoma syndromes share a biological denominator: failure of the cellular oxygen-sensing system and consequent constitutive activation of hypoxia-inducible factors (HIF), a state termed pseudohypoxia in the literature. In VHL, loss of pVHL protein prevents degradation of the HIF alpha subunits; in syndromes associated with succinate dehydrogenase genes (SDHx) and the FH gene, accumulation of succinate or fumarate inhibits the hydroxylases that mark HIF for destruction [3, 6]. This convergence explains the clinical overlap between the two disease families — phaeochromocytoma and paraganglioma occur in both, as does renal cell carcinoma (RCC) — and justifies their study in the same chapter, each with its own rules for diagnosis, surveillance and counselling.

The history of VHL begins in ophthalmology. In 1904, the German ophthalmologist Eugen von Hippel described “retinal angiomatosis”, familial retinal vascular lesions now recognised as retinal haemangioblastomas. In 1926, the Swedish pathologist Arvid Lindau demonstrated that these lesions were associated with cerebellar haemangioblastomas and visceral cysts and tumours, forming a systemic entity. In 1964, Melmon and Rosen reviewed the literature and studied a large family, establishing the eponym “von Hippel-Lindau disease” and its clinical criteria [2, 29]. In 1990, Maher and colleagues published the natural history of the disease in a British cohort, with cumulative probabilities for each manifestation that remain a reference today [30], and in 1991 calculated the birth incidence (1/36 000) and mutation rate [9]. The VHL gene was identified by positional cloning at 3p25 by Latif and colleagues in 1993 [31]. Elucidation of the role of pVHL in oxygen-dependent HIF degradation earned William Kaelin, Peter Ratcliffe and Gregg Semenza the 2019 Nobel Prize in Physiology or Medicine [1] and led, in fewer than three decades, to the first systemic therapy targeting the disease mechanism, belzutifan, approved by the US Food and Drug Administration (FDA) in August 2021 on the basis of the LITESPARK-004 trial [22, 32].

The history of hereditary paragangliomas followed a different path. Carotid body and jugular glomus tumours (“glomus tumours” or chemodectomas) were known to be familial, but their transmission seemed to defy Mendelian rules. In 1989, van der Mey and colleagues analysed 15 Dutch pedigrees and found that familial glomus tumours were transmitted almost exclusively through the paternal line, proposing the genomic imprinting hypothesis [33]. In 2000, Baysal and colleagues identified SDHD, encoding a subunit of mitochondrial complex II, as a hereditary paraganglioma gene [34]; in the same year, Niemann and Müller described variants in SDHC [35] and, in 2001, Astuti and colleagues associated SDHB with familial phaeochromocytoma and paraganglioma [36]. In 2002, Neumann and colleagues demonstrated that 24% (66/271) of patients with non-syndromic phaeochromocytoma and no family history carried germline variants in RET, VHL, SDHD or SDHB — a study that an editorial in the same issue of the New England Journal of Medicine entitled “the death of an axiom”, referring to the rule that 10% were hereditary [8, 37]. These were followed by SDHAF2 (2009) [38], SDHA (2010) [39], TMEM127 (2010) [40], MAX (2011) [41] and FH as a susceptibility gene for metastatic PGL/PHEO (2014) [42]. Today, at least 40% of all phaeochromocytomas and paragangliomas and approximately 30% of apparently sporadic cases are estimated to have a germline variant [8], and guidelines from the Endocrine Society, the American College of Medical Genetics and Genomics and the North American Neuroendocrine Tumor Society recommend genetic testing for all patients with PGL/PHEO [3, 16, 43].

This article addresses VHL as a multisystem syndrome, VHL viewed through its renal and pancreatic cysts — a frequent route to diagnosis — and hereditary paraganglioma-phaeochromocytoma syndromes, described gene by gene, including FH. Allelic and differential entities with the same biological axis (familial erythrocytosis due to biallelic VHL, the mosaic EPAS1 gain-of-function spectrum, mitochondrial complex II deficiency, hereditary leiomyomatosis and FH-related RCC) are addressed where the distinction is clinically relevant.

2. Molecular Genetics and Pathophysiology

2.1 The oxygen sensor: pVHL, prolyl hydroxylases and HIF

Under normoxic conditions, the HIF-1α and HIF-2α subunits (the latter encoded by EPAS1) are hydroxylated at proline residues by oxygen-, iron- and 2-oxoglutarate-dependent prolyl hydroxylases (the PHD enzymes, encoded by EGLN genes). pVHL is the substrate recognition subunit of an E3 ubiquitin ligase complex (with elongins B and C and cullin 2): it binds hydroxylated HIF-α and directs it towards proteasomal degradation. In hypoxia, hydroxylation does not occur, HIF-α accumulates, dimerises with HIF-1β and activates hypoxia-response genes — vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters and platelet-derived growth factors [1, 6]. When pVHL is absent, the cell behaves as if it were permanently hypoxic, even with oxygen available. The resulting tumours — haemangioblastoma and clear cell RCC — are hypervascular and, in RCC, rich in lipids and glycogen, giving them a clear-cell appearance. pVHL also has HIF-independent functions: transcriptional repression with histone deacetylases, oxygen-dependent ubiquitination of the β2-adrenergic receptor, negative regulation of mTORC1 through RPTOR degradation and contributions to cilia formation, senescence and the extracellular matrix [1]. Pathogenic VHL variants also affect vascular branching and maturation through the Notch pathway [1].

2.2 The two-hit model and mosaicism

VHL results from a germline loss-of-function variant associated with a second somatic variant that inactivates the normal allele, in accordance with Knudson's hypothesis [1, 7]. The same mechanism explains sporadic RCC: most sporadic clear cell RCCs have somatic biallelic VHL inactivation through mutation, allelic loss or methylation [7]. In The Cancer Genome Atlas (TCGA) project, which analysed 843 RCCs, loss of the short arm of chromosome 3 was observed in 91% of clear cell RCCs, involving genes also frequently mutated (VHL, PBRM1, BAP1, SETD2); loss of 14q, associated with HIF1A loss, in 45%; and 5q gains in 67% [44]. For this reason, a VHL variant detected only in the tumour has a low probability of germline origin (approximately 1.5% of cases), and ESMO does not recommend confirmatory germline testing in this situation in the absence of other clinical features [44]. Papillary cystadenomas of the epididymis and broad ligament, both of mesonephric origin, are probably a developmental remnant of somatic VHL loss [1]. Approximately 5% of people with VHL are estimated to have somatic mosaicism, and in simplex cases the frequency of parental mosaicism is around 5% [1].

2.3 Variant spectrum in VHL

Most germline variants are inactivating (frameshift, nonsense and deletions of one or more exons); approximately 30% are missense [6]. Sequencing of the coding region, intron 1 and flanking regions detects approximately 85% of pathogenic variants, and targeted deletion and duplication analysis approximately 10%; no variant is identified in approximately 5% of people with a clinical diagnosis [1]. Intron 1 variants may include a cryptic exon (designated E1′) and should be sought in probands without a coding-region variant [1]. Interpretation follows the ClinGen VHL expert panel specifications (version 1.1.0) of the five-class ACMG/AMP classification rules; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. In a Brazilian series of 97 patients with a confirmed variant, 52.6% had missense variants, 22.7% large deletions, 10.3% frameshift, 7.2% splicing, 4.1% nonsense and 3.1% in-frame deletions [45].

2.4 Genotype–phenotype correlations in VHL

Correlations are based mainly on the presence or absence of phaeochromocytoma, because its molecular aetiology appears distinct from that of other lesions [1]. Truncating or missense variants that severely impair pVHL folding (destabilising alpha-helix packing, the interface between alpha and beta domains, binding to elongin C and HIF-1α or hydrophobic core residues) lose HIF regulation and are associated with type 1. Missense variants that partially preserve HIF regulation are associated with type 2; type 2A and 2C variants encode pVHL retaining greater capacity to ubiquitinate HIF-1α in the presence of oxygen than type 2B variants [1]. A complementary hypothesis proposes that mutated pVHL predisposes to phaeochromocytoma by altering the balance of proteins controlling apoptosis of sympathoadrenal precursors during development [1]. Complete or partial VHL deletions extending towards 5′ and including BRK1 (formerly C3orf10) are associated with reduced RCC and phaeochromocytoma risk, a phenotype sometimes designated type 1B [1]; in the Brazilian series by Gomy and colleagues, two type 1 families with large deletions including FANCD2/C3orf10 had no renal lesions [46]. Truncating variants are associated with a higher age-specific incidence of retinal and central nervous system (CNS) haemangioblastomas, RCC and pancreatic neuroendocrine tumours than missense variants or single-amino-acid in-frame deletions [1]. Missense variants appear associated with faster renal growth, greater metastatic risk of pancreatic neuroendocrine tumours between 1.2 and 3.0 cm and, when classified as highly pathogenic by computational models, progression of pancreatic lesions; intragenic deletions are associated with faster haemangioblastoma growth [1]. Nevertheless, GeneReviews emphasises that these patterns are not clear-cut and genotype–phenotype correlations currently have no individual diagnostic or therapeutic value [1]. In the Black Forest, Germany, 14 apparently unrelated families with type 2A VHL share the missense variant NM_000551.4:c.292T>C (p.Tyr98His) — described in the original article, using historical cDNA numbering, as a T>C substitution at nucleotide 505 and Tyr169His at codon 169 — on a common haplotype, also identified in two Pennsylvania families, demonstrating a founder effect associated with the phaeochromocytoma phenotype [47].

2.5 Allelic VHL phenotypes

Familial erythrocytosis type 2 (OMIM #263400) is caused by biallelic VHL variants and is characterised by increased red cell mass, elevated serum erythropoietin and normal haemoglobin oxygen affinity; neither patients nor their heterozygous relatives developed VHL-associated tumours [1]. The paradigmatic example is Chuvash polycythaemia, autosomal recessive and endemic in the middle Volga region (Russia), caused by the homozygous variant NM_000551.4:c.598C>T (p.Arg200Trp), which impairs pVHL interaction with HIF-1α, reduces its degradation and increases expression of target genes such as those for erythropoietin, the GLUT1 glucose transporter, transferrin, the transferrin receptor and VEGF [48]. Some intron 1 variants leading to retention of the cryptic exon also cause this form of erythrocytosis [1]. In ClinVar, c.598C>T has conflicting classifications (VCV000002232), illustrating that pathogenicity is assessed by condition and inheritance model: the variant causes erythrocytosis in homozygosity, and its presence in heterozygosity should not be reported as a diagnosis of von Hippel-Lindau syndrome [48, 49].

2.6 Mitochondrial complex II and SDHx syndromes

Succinate dehydrogenase (SDH) is the only respiratory chain complex whose four subunits are encoded in the nucleus, and participates simultaneously in the tricarboxylic acid cycle and the electron transport chain [50]. The SDHA flavoprotein catalyses oxidation of succinate to fumarate; the SDHB iron–sulphur protein transfers electrons to the ubiquinone pool; SDHC and SDHD are anchoring subunits in the inner mitochondrial membrane; the assembly factors SDHAF1 and SDHAF2 are required for correct assembly, and SDHAF2 is indispensable for SDHA flavination [3, 50]. The five genes SDHA, SDHB, SDHC, SDHD and SDHAF2 (collectively SDHx) are tumour suppressor genes: the second somatic alteration in the tumour may be a chromosomal rearrangement, recombination, single-nucleotide variant or epigenetic change [3]. Complex inactivation leads to succinate accumulation, which competitively inhibits 2-oxoglutarate-dependent dioxygenases — HIF prolyl hydroxylases and histone and DNA demethylases — producing pseudohypoxia and a hypermethylation phenotype [3]. In practical terms, when any component of complex II is completely inactivated, the complex becomes destabilised and the SDHB subunit is degraded; hence loss of SDHB immunohistochemical expression in the tumour indicates SDH deficiency regardless of the affected SDHx gene, and additional SDHA loss points to SDHA [3].

Biallelic variants in the same genes cause an entirely different disease, isolated complex II deficiency, with autosomal recessive inheritance. The presentation is heterogeneous: developmental regression after intercurrent illness, initial hypotonia and spasticity, dilated or hypertrophic cardiomyopathy, ophthalmoplegia, retinopathy, nystagmus, optic atrophy and early-onset leukoencephalopathy; specific magnetic resonance imaging (MRI) patterns in the thalamus and brainstem and white matter succinate accumulation on spectroscopy support the diagnosis, confirmed by complex II activity measured by spectrophotometry [50]. SDHA is the most frequent cause, followed by SDHAF1; SDHB and SDHD have been described in ten and two patients, respectively. Since SDHA is a flavoprotein, riboflavin has been tested in some patients, with neurological improvement in a few [50]. Dilated cardiomyopathy in 15 SDHA homozygotes of Bedouin ancestry, Leigh syndrome due to complex II deficiency and late-onset neurodegeneration with ataxia and optic atrophy (autosomal dominant, SDHA) have also been described [3]. Knowledge of these phenotypes matters in counselling: a couple who are both heterozygous SDHA carriers has a 25% risk of offspring with recessive mitochondrial disease, in addition to each person's own tumour risk.

2.7 Parent-of-origin effect: SDHD, SDHAF2 and MAX

SDHD and SDHAF2 are located on chromosome 11. The most widely accepted explanation for almost exclusive expression after paternal transmission is not classical imprinting of the gene itself, but somatic loss, in the tumour, of the entire maternal chromosome 11: when the variant is inherited from the father, loss of maternal chromosome 11 simultaneously eliminates the normal SDHD allele and tumour suppressor genes with exclusively maternal expression located at 11p15, offering a selective advantage; when the variant is maternal, this combination would require more somatic events [51, 52]. Loss of maternal chromosome 11 is a characteristic event in SDHAF2-, SDHD- and VHL-associated paragangliomas, and less relevant in SDHB-associated tumours [53]. The model also explains exceptions: tumours after maternal SDHD transmission have been described, such as a 26-year-old woman with phaeochromocytoma and a jugular glomus tumour whose variant had been inherited from her mother [52, 54]. In MAX, the number of known carriers is limited, but tumour formation after maternal inheritance has not been observed to date [3].

2.8 TMEM127, MAX, FH and EPAS1

TMEM127 encodes a four-domain transmembrane protein located in early endosomes, the Golgi complex and lysosomes, which negatively regulates mTORC1 signalling; germline loss of function removes this brake in chromaffin tissue [3, 40]. MAX encodes the obligate dimerisation partner of the MYC network: MAX:MYC heterodimers activate transcription at E-box sequences, whereas MAX:MAD dimers repress it; loss of MAX dysregulates this network [3, 41]. Approximately 10% of MAX variants are detected only by deletion and duplication analysis [3]. A recurrent de novo variant, p.Arg60Gln, causes a completely distinct phenotype, polydactyly–macrocephaly syndrome (OMIM #620712), an overgrowth disorder with progressive macrocephaly, postaxial polydactyly, ocular anomalies, global developmental delay and autistic traits, mediated by differential expression of c-Myc targets [55]. The FH gene encodes fumarate hydratase; biallelic loss in the tumour causes fumarate accumulation, which also inhibits 2-oxoglutarate-dependent dioxygenases [56]. Finally, the mosaic EPAS1 gain-of-function spectrum displays the same axis from the opposite side: activating variants in the oxygen-dependent degradation domain of HIF-2α, typically near proline 531, prevent hydroxylation and cause polycythaemia, paragangliomas and somatostatinomas [57, 58].

2.9 Tissue pathophysiology of chromaffin tumours

Chromaffin cells derive from the neural crest. The adrenal medulla and sympathetic nervous system ganglia synthesise and secrete catecholamines; parasympathetic paragangliomas near the aortic arch, in the neck and at the skull base rarely secrete them [8]. The biochemical profile guides aetiological diagnosis: tumours associated with SDHB, SDHC and SDHD mainly produce noradrenaline and normetanephrine (and those associated with SDHB and SDHD are often non-secretory), as do VHL phaeochromocytomas; those associated with MAX, TMEM127 and SDHA have a mixed profile; adrenaline secretion with little noradrenaline excess suggests an adrenal phaeochromocytoma associated with MEN2 [3]. The EPAS1 spectrum produces a noradrenergic profile with very low metanephrine [58].

3. Clinical Spectrum and Manifestations by System

3.1 Von Hippel-Lindau syndrome: overview

VHL predisposes to a wide variety of tumours, particularly cerebellar and spinal cord haemangioblastomas, retinal haemangioblastomas (traditionally called retinal angiomas), RCC, phaeochromocytomas and renal, pancreatic and epididymal cysts [6]. The most frequent initial manifestations are retinal angiomatosis, followed by cerebellar haemangioblastoma, RCC and phaeochromocytoma; the most frequent causes of death are RCC and CNS haemangioblastomas [6]. The mean age at first diagnosis is around 25 years [6]; in a Brazilian cohort of 142 patients from 62 families, mean age at onset was 28.8 years [45]. Expression varies between and within families, even with the same variant [1, 6]. In a Danish study, adult men had more manifestations than women, the risk of new manifestations varied throughout life, and age was the only predictor of the number of organs involved [1].

In the Brazilian cohort, CNS haemangioblastoma was the most frequent manifestation (71%), followed by multiple pancreatic and renal cysts (48.4%), retinal haemangioblastoma (39.8%), RCC (28.9%), phaeochromocytoma (12.5%) and pancreatic neuroendocrine neoplasia (7.8%) [45].

3.2 Central nervous system haemangioblastomas

CNS haemangioblastoma is the prototypical VHL lesion. Approximately 80% develop in the brain and 20% in the spinal cord; multiple synchronous or metachronous tumours are frequent, and some are asymptomatic and discovered only by imaging [1]. In the brain, the vast majority are infratentorial, particularly in the cerebellar hemispheres; the pituitary stalk is the most frequent supratentorial site [1]. Infratentorial tumours cause headache, vomiting, gait abnormalities or ataxia; supratentorial tumours cause symptoms according to location [1]. Spinal haemangioblastomas are usually intradural, cervical or thoracic, may involve the entire spinal cord and, when symptomatic, are associated with cysts or syringomyelia; they present with pain and, with cord compression, sensory and motor deficits [1]. Peripheral nerve haemangiomas are a rare manifestation [1]. Histologically benign, they are a major cause of morbidity and remain the leading cause of death, although survival has improved [1, 6]. Growth is saltatory in 72% (growth periods alternating with quiescent periods), linear in 6% and exponential in 22%; faster growth is associated with male sex, symptomatic tumours, associated cysts and germline intragenic deletions [1]. Approximately 30% of all cerebellar haemangioblastomas occur in VHL, and the younger the patient, the higher the probability of the syndrome [6].

3.3 Retinal haemangioblastomas

Retinal haemangioblastomas are histologically identical to CNS haemangioblastomas, may be the initial manifestation of VHL and may arise in childhood [1]. They are mainly located in the temporal retinal periphery, with feeding and draining vessels directed towards the optic disc; less frequently they arise at the posterior pole (1%) or optic disc (8%) [1]. They may be asymptomatic or present as a visual field defect or loss of acuity due to retinal detachment, exudation or haemorrhage; retinal function tests may be abnormal even with quiescent lesions. Lesion number does not appear to increase with age, but the probability of visual loss increases [1]. Almost all patients with multiple retinal haemangioblastomas have VHL, and a solitary retinal angioma may be sporadic [6]. A clinical and angiographic illustration of retinal haemangioblastomas in a patient with VHL can be viewed in Figure 1 of Alcoreza et al., 2026 [59].

3.4 Kidneys: cysts and clear cell renal cell carcinoma

Multiple bilateral renal cysts are frequent and may be detected from the second decade [1, 6]. Unlike autosomal dominant polycystic kidney disease, the kidneys are not usually enlarged, and associated pancreatic cysts may be present [60]. RCC, specifically the clear cell subtype, develops within a cyst or the surrounding parenchyma, occurs in approximately 70% of patients by 60 years and is a leading cause of mortality [1]. RCC in VHL is frequently multifocal and bilateral, of early onset (detected as early as 16 years) and often, but not always, associated with cysts; the spectrum includes complex cystic lesions with a solid component [6, 7]. VHL is the most frequent cause of hereditary RCC [1]. Overall RCC survival in VHL is associated with tumour size and age [1]. For context, sporadic RCC predominates in males (2:1), typically occurs in the sixth and seventh decades (median approximately 60 years), is clear cell in 70–80% of cases, and only approximately 3% of patients have a family history [7]. The 2022 World Health Organization (WHO) classification introduced a molecular subclassification of RCC with 11 subgroups, including SDH-deficient and FH-deficient RCC, with prognostic and therapeutic implications [44].

3.5 Pancreas: cysts, serous cystadenomas and neuroendocrine tumours

Most pancreatic lesions are simple cysts without malignant potential. They may be numerous, but rarely cause endocrine or exocrine insufficiency; occasionally, pancreatic head cysts cause biliary obstruction [1]. Multiple renal and pancreatic cysts provide a diagnostic clue, but rarely cause significant morbidity [6]. Pancreatic neuroendocrine tumours (pNETs) occur in 5–17% of patients; they are generally not hormonally active and grow slowly, but malignant behaviour occurs, particularly in tumours larger than 2.7 cm, and they have been described from the second decade [1]. pNETs must be distinguished from cysts and serous cystadenomas [1].

3.6 Phaeochromocytoma and paraganglioma in VHL

VHL phaeochromocytoma may be asymptomatic or cause sustained or episodic hypertension. With surveillance, it is identified at younger ages and incidentally in normotensive people; it may be unilateral or bilateral, is often small and multifocal, and is generally benign, although malignant behaviour has been described [1]. Abdominal or thoracic sympathetic paragangliomas also occur and are often non-functioning [1]. In a meta-analysis of 80 studies (4263 patients) by Portuguese authors, the pooled PGL/PHEO frequency in VHL was 19.4% (95% CI 15.9–23.6%), 60.0% in type 2 and, by subtype, 58.2% in 2A, 49.8% in 2B and 84.1% in 2C, with high heterogeneity and risk of bias in all included studies; these frequencies apply to patients with each clinical type and should not be transferred to carriers of a specific variant [61]. Phaeochromocytoma frequency varies greatly between families and defines clinical classification: type 1 without phaeochromocytoma; type 2 with phaeochromocytoma — 2A with low RCC risk, 2B with high RCC risk and 2C with isolated phaeochromocytoma [1, 6]. Haemangioblastomas have arisen in some apparently type 2C families [1].

Sources: [1, 6, 47]

3.7 Endolymphatic sac tumours

Endolymphatic sac tumours (ELSTs) are rare neuroectodermal neoplasms of the petrous temporal bone, arising from inner ear structures and observed in approximately 10–16% of people with VHL [1, 6]. Unilateral or bilateral hearing loss may be the initial syndrome manifestation; onset is typically sudden and loss often severe or profound; vertigo or tinnitus may be the first symptoms. Large ELSTs may involve other cranial nerves, are rarely malignant, and non-VHL-associated ELSTs present with greater hearing loss and volume than VHL-associated lesions [1]. They are frequently confused with Ménière disease [1].

3.8 Epididymal and broad ligament cystadenomas

Papillary epididymal cystadenomas are relatively frequent in men with VHL; they rarely cause problems except when bilateral, when they may cause infertility. The equivalent lesion in women, papillary cystadenoma of the broad ligament, is much less frequent [1].

3.9 Hereditary paraganglioma-phaeochromocytoma syndromes: general presentation

Paragangliomas originate in paraganglia, aggregates of neural crest cells distributed along the paravertebral axis from the skull base to the pelvis and at some visceral sites; phaeochromocytoma is a paraganglioma confined to the adrenal medulla [3]. The 2022 WHO classification of endocrine tumours divides them by location and, directly or indirectly, by secretory status: adrenal paraganglioma (phaeochromocytoma), abdominal sympathetic paraganglioma, head and neck sympathetic paraganglioma and parasympathetic paraganglioma [3]. Since 2017, WHO has replaced “malignant phaeochromocytoma” with “metastatic phaeochromocytoma”: PGL/PHEO are classified as localised or metastatic rather than benign or malignant [3].

Head and neck paragangliomas (HNPGLs) and those of the upper mediastinum are associated with the parasympathetic system, and approximately 95% do not secrete catecholamines; the rare secretory exceptions are a subgroup of carotid body tumours or arise from the cervical sympathetic chain [3]. Most do not metastasise and complications result from mass effect [3]. Carotid body paragangliomas present as painless lateral neck masses, vertically fixed but horizontally mobile, sometimes with a bruit or thrill, and may compress cranial nerves and the sympathetic chain (hoarseness, Horner syndrome); vagal tumours have a similar presentation, with pharyngeal fullness, dysphagia, dysphonia, pain, cough and aspiration; jugulotympanic tumours cause pulsatile tinnitus, hearing loss and lower cranial nerve abnormalities, with a bluish pulsatile mass visible behind the tympanic membrane; jugular tumours may cause dysphagia, hoarseness, dizziness, hearing loss, facial paralysis or pain [3].

Paragangliomas of the lower mediastinum, abdomen and pelvis are associated with the sympathetic system and generally secrete catecholamines; extra-adrenal sympathetic paragangliomas have a higher metastatic risk. The commonest sites are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissue near the origin of the inferior mesenteric artery and aortic bifurcation); a less common site is the bladder wall, where they may cause painless haematuria and paroxysms during micturition [3]. Phaeochromocytomas secrete catecholamines and metastasise less frequently [3].

Symptoms of catecholamine excess are similar in hereditary and sporadic forms: sustained or paroxysmal hypertension, headache, palpitations, arrhythmias, profuse sweating, pallor, apprehension or anxiety, nausea, vomiting, fatigue, sudden changes in glycaemic control and weight loss; paroxysms may be triggered by changes in position, increased intra-abdominal pressure, drugs (e.g. metoclopramide), anaesthetic induction, exercise or micturition [3, 8]. Patients present in four scenarios: symptoms of catecholamine excess, mass effect, an incidental mass on CT or MRI and screening of at-risk relatives [3]. The commonest metastatic sites are bone, lung, liver and lymph nodes; once established, there is no cure, with five-year survival of 50–69%, although some patients live for more than 20 years with sequential targeted treatment [3].

The data compiled by the 2021 French PNDS (French National Diagnosis and Care Protocol) quantify this picture [12]. Phaeochromocytomas and thoracic, abdominal and pelvic paragangliomas are functional in approximately 85% of cases, compared with approximately 10% of head and neck paragangliomas. Hypertension is present in more than 80% of patients—sustained in 50–60% and paroxysmal in approximately 35%—usually with sinus tachycardia; sustained or orthostatic hypotension suggests a dopamine-secreting tumour, and blood pressure may be normal when secretion is low. During paroxysms, headache occurs in 60–90%, sweating in 55–75% and palpitations in 50–70%; the triad has a sensitivity of 91% and a specificity of 94% for functional PGL/PHEO, and pallor due to vasoconstriction usually accompanies the attacks [12]. A clinical score proposed by Geroula and colleagues assigns one point to each of the following findings—body mass index below 25 kg/m², heart rate above 85 per minute, pallor, sweating, palpitations, tremor and nausea—and subtracts one point for obesity; with 3 or more points, the probability of functional PGL/PHEO is 5 to 6 times higher [12]. Non-type 1 diabetes in a person younger than 50 years with a body mass index below 25 kg/m² should prompt a search for the tumour, particularly if adrenergic signs are present. The mean interval between first symptoms and diagnosis is at least 3 years. Other findings are weight loss, constipation (approximately 6%), nausea, vomiting, anxiety and emotional lability; ectopic ACTH secretion, which is rare, causes ACTH-dependent hypercortisolism, and some patients with mild to moderate hypersecretion are asymptomatic [12].

In 10–15% of patients, the first manifestation is an acute cardiovascular complication: mainly Takotsubo-type adrenergic cardiomyopathy, with acute heart failure or cardiogenic shock and normal coronary arteries; more rarely malignant hypertension, hypertrophic obstructive cardiomyopathy, myocardial ischaemia, ventricular or supraventricular arrhythmias, aortic dissection, ischaemic or haemorrhagic stroke, cardiac arrest or sudden death [12]. Colonic pseudo-obstruction (Ogilvie syndrome) with caecal dilatation and risk of perforation, epileptic seizures and, exceptionally, shock with multiorgan failure and hyperthermia have also been described; trauma, anaesthesia, acute stress and certain drugs precipitate these complications [12]. Approximately 5% of adrenal incidentalomas (lesions larger than 10 mm discovered incidentally) are phaeochromocytomas, a proportion that falls to approximately 2 per 1000 when the unenhanced CT attenuation is below 10 HU [12]. Metastases, locoregional recurrence or a new tumour occur in approximately 15% of patients, particularly when there is a genetic predisposition, and the histology of the primary tumour cannot establish benignity, which is the basis for lifelong follow-up [12].

3.10 Other tumours in SDHx syndromes

GIST associated with PGL/PHEO syndromes occur mainly in carriers of SDHA or SDHC variants, but also SDHB and SDHD; they are generally gastric, multifocal in more than 40%, and lack KIT or PDGFRA variants (“wild-type” GIST) [3]. Familial GIST due to KIT and PDGFRA is part of the differential diagnosis. A child with GIST is more likely than an adult to carry a germline variant in a PGL/PHEO susceptibility gene [3]. The GIST–paraganglioma dyad (Carney–Stratakis syndrome) and Carney triad are now mainly historical terms, to be reserved for patients with the phenotype but no germline SDHx variant [3]. Pulmonary chondromas have been described in SDHx carriers [3]. Clear cell RCC is more frequent in SDHB or SDHD carriers [62]. Lifetime RCC risk in SDHB carriers was estimated at 4.7% (versus 1.7% in the general population) in a British study correcting for ascertainment bias [3, 13]; the Oxford Desk Reference gives a lifetime risk of approximately 15%, a figure derived from older proband-focused series [7, 8]. Approximately 5% of patients with features suggesting hereditary RCC have a germline SDHB variant, which may present as non-syndromic familial RCC without PGL/PHEO [7]. Papillary thyroid carcinoma, pituitary adenomas and other neuroendocrine tumours have been described in SDHx carriers, but an increased risk has not been established [3].

3.11 Gene-by-gene distinctions

Source: GeneReviews, tables 1 and 2 (general rules with exceptions) [3]. AD: autosomal dominant; PHEO: phaeochromocytoma; PGL: paraganglioma.

SDHB. Germline SDHB variants are associated with greater morbidity and mortality than variants in the other SDH genes. They are strongly associated with extra-adrenal sympathetic paragangliomas with increased metastatic risk and, less frequently, phaeochromocytomas and parasympathetic paragangliomas [3, 13]. Up to 45% of people with metastatic extra-adrenal paraganglioma have a germline SDHB variant [3]. An SDHB variant is identified in 24–44% of people with thoracic, abdominal or pelvic PGL/PHEO and in 12–20% of people with HNPGL [3]. The Oxford Desk Reference reports a malignancy frequency of approximately 30% [8]. Penetrance at 60 years is 21.8–26.4% in non-probands and 23.9–57.6% when probands are included [3, 13]. There may be no difference in metastatic potential between SDHB-associated and sporadic HNPGL [3].

SDHD. Mainly associated with HNPGL, although extra-adrenal paragangliomas and phaeochromocytomas occur; 75% of carriers have multifocal primary paraganglioma [3, 19]. An SDHD variant is identified in 40–50% of people with HNPGL and approximately 15% of people with thoracic, abdominal or pelvic PGL/PHEO [3]. Penetrance at 60 years in non-probands (paternal transmission) is 43.2% [3]. There are no consistent genotype–phenotype correlations [3]. In a Chinese family with the nonsense variant p.Arg22Ter, the proband, father and two sisters had carotid body tumours, one bilateral, and investigation of the third generation identified a single carrier child [63].

SDHC. Mainly associated with HNPGL; up to approximately 10% of tumours are located in the thoracic cavity [3]. Estimated penetrance at 60 years is 25%, a value that GeneReviews authors consider higher than observed in clinical practice [3, 13].

SDHA. Identified in phaeochromocytomas and sympathetic and parasympathetic paragangliomas [3, 39]. Tumours are usually solitary and metastatic risk is low. Penetrance is 10% at 70 years in non-probands and 50% when probands are included [14]. SDHA has at least four pseudogenes, complicating sequencing interpretation; many laboratories do not perform deletion and duplication analysis for this gene [3].

SDHAF2. Identified in families with HNPGL; the phenotype is poorly characterised because few families have been described. Tumours are multiple in approximately 90%, metastatic risk is low and transmission is paternal [3, 38]. c.232G>A (p.Gly78Arg) is a founder variant in the Dutch population [3].

TMEM127. Mainly associated with phaeochromocytoma (bilateral in approximately 25%), but also HNPGL and extra-adrenal paragangliomas; an association with clear cell RCC has been described [3, 40]. There are no reliable penetrance data [3].

MAX. All described people with MAX-associated PGL/PHEO initially presented with phaeochromocytoma, and some subsequently developed paragangliomas [3]. Tumours are bilateral in approximately 60%, and metastatic risk is approximately 25% [3]. In the study defining the phenotype, germline MAX variants were found in 1.12% of 1694 patients with PGL/PHEO without a variant in other susceptibility genes, age at diagnosis was younger than in cases without a variant, and 10.5% of index cases developed metastases [64]. There are no reliable penetrance data [3].

FH. Heterozygous germline FH variants cause FH tumour predisposition syndrome, historically termed hereditary leiomyomatosis and RCC (HLRCC, Reed syndrome): cutaneous leiomyomas (skin-coloured to light-brown papules or nodules, sometimes painful, from the second to fourth decade), numerous large uterine leiomyomas (mean diagnosis age approximately 30 years) and usually unilateral, solitary, aggressive renal tumours, with a median detection age of approximately 40 years [7, 56]. HLRCC RCC is typically type 2 papillary or collecting duct, may arise early (minimum described age 11 years) and metastasises even with small primary tumours [7, 56]. Phaeochromocytomas and paragangliomas have been described in a small number of families with specific, mainly missense, variants — c.157G>A (p.Glu53Lys), c.220A>T (p.Arg74Ser), c.268-2A>G, c.349G>C (p.Ala117Pro), c.580G>A (p.Ala194Thr), c.700A>G (p.Thr234Ala), c.816_836del21, c.908T>C (p.Leu303Ser), c.986A>G (p.Asn329Ser), c.1142C>T (p.Thr381Ile) and c.1301G>A (p.Cys434Tyr) — whose carriers have a lower likelihood of HLRCC [56]. Castro-Vega and colleagues demonstrated that germline FH variants confer predisposition to PGL/PHEO, with a metastatic profile [42]. The population frequency of heterozygotes for pathogenic FH variants was estimated between 1/2563 and 1/3247 (BRAVO and gnomAD databases), suggesting underdiagnosis [56]. Biallelic variants cause fumarate hydratase deficiency (fumaric aciduria), a severe neonatal encephalopathy [56].

3.12 Pregnancy

In VHL, the French Study Group observed a significantly higher rate of haemangioblastoma complications in women with at least one pregnancy, and another study concluded that pregnancy influences cerebellar haemangioblastoma growth, with an overall complication rate of 17%; conversely, a Danish study observed a reduction in new manifestations during pregnancy and another found no relationship between pregnancy and new haemangioblastomas or growth of tumours and cysts [1]. In PGL/PHEO syndromes, a secretory tumour may mimic pre-eclampsia, but manifests at any stage of pregnancy (pre-eclampsia is more frequent in the second and third trimesters), without weight gain, oedema, proteinuria or thrombocytopenia, and with palpitations, sweating, pallor, orthostatic hypotension, glycosuria and episodic hypertension [3].

According to the French PNDS, PGL/PHEO complicates 1 in 15,000 to 54,000 pregnancies; approximately 70% are phaeochromocytomas, 95% of patients have hypersecretion and half have metanephrines above 10 times the upper limit of the reference range [12]. Hypertension is present in 93%, palpitations in 57%, headache in 50% and sweating in 40%, worsening as pregnancy progresses owing to uterine volume, fetal movements, contractions and abdominal palpation. Paroxysmal hypertension, associated orthostatic hypotension, early onset in gestation, sweating and tachycardia point to a tumour; onset after 20 weeks of gestation, proteinuria, oedema and HELLP syndrome point to gestational hypertension, although proteinuria does not exclude a tumour [12]. Because gestational hypertension and pre-eclampsia affect 3–5% of pregnancies, the diagnosis is frequently delayed or missed: it is made during pregnancy in approximately half of cases (median 24 weeks; range 2 to 38), in the year after delivery in 30% (median 6 weeks), and was already known before pregnancy in 15% [12]. Maternal–fetal complications occur in approximately 15% of pregnancies and all result from catecholamine excess: catecholamines cross the placenta poorly, but maternal surges cause intermittent placental vasoconstriction, hypoxia, growth restriction and fetal death. The main risk factor is diagnosis only after delivery, followed by abdominopelvic location, metanephrines above 10 times normal, non-hereditary forms and the absence of alpha-blockade [12]. Severe maternal complications (myocardial infarction, acute heart failure or pulmonary oedema, stroke, hypertensive crisis, postoperative hypotension, cardiac arrest, severe constipation) fall from up to 20% without diagnosis to approximately 6% with antenatal diagnosis, maternal mortality from up to 30% to 0.5–1%, and miscarriage or intrauterine fetal death from 13% to approximately 5% (median 18 weeks); delivery is preterm in 25% (between 20 and 35 weeks), with a risk of neonatal mortality [12]. These proportions come from retrospective series and reviews, subject to publication bias towards severe cases.

3.13 PGL/PHEO in childhood

Between 10 and 20% of PGL/PHEO are diagnosed before 18 years of age, with an incidence of 0.2–0.5 per million in this age group [12]. Hereditary predisposition is the rule: depending on series size and the test used, 50–80% of children have a germline variant; in a European study of 177 children, the proportion was 56% below 18 years and 70% when the disease presented before 10 years, and in the French series (77 children, 68 tested) it was 77% [12]. VHL is the leading cause of phaeochromocytoma in children, and 10–20% of children with VHL have PGL/PHEO; tumours may arise before 10 years of age, particularly with VHL or SDHB variants, but the mean age at diagnosis in 605 published paediatric cases was 13 years [12]. The frequency of metastases ranges from 10 to 47% across series, with a predominance of SDHB, and in the French series 92% of children with a new tumour site during follow-up carried a variant [12]. Childhood hypertension is due to PGL/PHEO in 0.5–2% of cases, and hypertension is present in 60–90% of paediatric PGL/PHEO; headache accompanies it in almost 70%, and palpitations, sweating, pallor and nausea occur in approximately half. Weight loss, slowing of linear growth, visual disturbances and attention-deficit/hyperactivity presentations have been described [12]. Paediatric tumours are frequently multifocal, bilateral and recurrent, may be metastatic at diagnosis, and essential hypertension is rare at this age; therefore, every child with hypertension undergoes an aetiological work-up that includes measurement of metanephrines [12].

4. Clinical Recognition and Warning Signs

4.1 When to suspect VHL

VHL should be considered, with or without a family history, in the presence of [1]: retinal haemangioblastoma, particularly in a young person; multiple cerebellar or spinal haemangioblastomas, or a single haemangioblastoma diagnosed by 50 years; adrenal or extra-adrenal phaeochromocytoma; RCC diagnosed by 40 years; multiple renal and pancreatic cysts; multiple pNETs; endolymphatic sac tumour; and, less frequently, multiple papillary epididymal or broad ligament cystadenomas. Approximately 30% of cerebellar haemangioblastomas are part of VHL, so all patients with an apparently sporadic cerebellar haemangioblastoma should undergo complete clinical assessment and molecular testing [6]. Multiple retinal haemangioblastomas are practically diagnostic of VHL [6]. Sudden unilateral sensorineural hearing loss attributed to Ménière disease warrants review with MRI of the internal auditory canal when other clues are present [1].

4.2 Clues from renal and pancreatic cysts

The combination of multiple renal and pancreatic cysts is a suspicion criterion and, in the Dutch criteria, counts as a VHL-related manifestation [1]. VHL renal cysts arise from the second decade, coexist with usually normal-sized kidneys and intracystic or parenchymal RCC; numerous pancreatic cysts in a young adult without pancreatitis, renal cysts with a contrast-enhancing solid component and bilateral epididymal cysts in a man with infertility are findings justifying targeted assessment [1, 6, 60]. In a patient with phaeochromocytoma, abdominal MRI performed for diagnosis allows identification of pancreatic cysts and RCC [8].

4.3 When to suspect hereditary PGL/PHEO syndrome

A hereditary syndrome should be suspected in any person with PGL/PHEO, particularly with [3, 16]: multiple tumours (including bilateral adrenal phaeochromocytoma), multifocal (synchronous or metachronous), recurrent, early-onset (before 45 years), extra-adrenal or metastatic tumours; and a family history of PGL/PHEO or relatives with unexplained sudden death. Many people with a hereditary syndrome present with a solitary tumour and no family history [3]. Other warning signs are a growing neck mass, involvement of cranial nerves VII, IX, X and XI, Horner syndrome, pulsatile tinnitus, a palpable abdominal mass and symptoms triggered by micturition (bladder paraganglioma) [3]. A wild-type gastric GIST, particularly in a child, and RCC with loss of SDHB expression are clues outside the chromaffin axis [3, 44].

The French PNDS (French National Diagnosis and Care Protocol), drawing on international recommendations, lists the situations in which a functional PGL/PHEO should be sought: hypertension with adrenergic signs; hypertension diagnosed before 40 years of age; resistant hypertension (office blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic despite triple therapy at effective doses with a renin–angiotensin system blocker, a calcium channel blocker and a thiazide diuretic); hypertension with non-type 1 diabetes before 50 years of age and a body mass index below 25 kg/m²; blood pressure lability on ambulatory blood pressure monitoring; a history of Takotsubo cardiomyopathy; hypertensive crisis or haemodynamic instability during general anaesthesia or after a catecholamine-releasing drug; a predisposing genetic disease; and an adrenal incidentaloma of 10 mm or more, with or without hypertension [12]. Risk factors for metastases or multiple tumours are age below 40 years at diagnosis, extra-adrenal location, a tumour larger than 5 cm, a variant in an SDHx gene, a predominantly noradrenergic (normetanephrine) profile and, possibly, elevated 3-methoxytyramine; in any of these situations whole-body functional imaging is recommended [12]. Among patients with PGL/PHEO, the PNDS estimates that SDHx syndromes account for approximately 20%, VHL for 7%, MEN2 for 6% and NF1 for 3%, which justifies actively looking for the associated lesions of each syndromic form [12].

4.4 Directed physical examination

In assessing a patient with phaeochromocytoma, examination seeks clues to alternative syndromes: marfanoid habitus and mucosal neuromas (MEN2B), a thyroid mass (MEN2), a carotid body tumour (familial paraganglioma), café-au-lait spots, axillary freckles and dermal neurofibromas (NF1), cutaneous leiomyomas (FH) and cerebellar signs — gait, nystagmus, dysmetria and dysdiadochokinesia — secondary to cerebellar haemangioblastoma (VHL) [8]. When VHL is suspected, blood pressure is measured, a careful neurological examination, particularly cerebellar, is performed, and fundoscopy undertaken [6]. In suspected hereditary RCC, skin is examined for fibrofolliculomas (Birt–Hogg–Dubé syndrome) or leiomyomas (HLRCC) [7].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria for VHL

A clinical diagnosis is established in a proband meeting the Dutch or Danish criteria; identification of a heterozygous pathogenic or likely pathogenic germline VHL variant establishes the molecular diagnosis when the clinical presentation is inconclusive [1]. The two proposals differ slightly and were systematised by Wolters and colleagues in the first integrated multidisciplinary clinical pathway for VHL, published in the Netherlands in 2022 [15, 65].

Source: GeneReviews, table 1, adapted from Wolters et al. [1, 65]

The 2022 Danish guideline — developed from international literature, research in the Danish national cohort and patient preferences — reaffirms that VHL can be diagnosed solely by clinical criteria, that surveillance should begin in childhood and include the retina, CNS, inner ear, kidneys, neuroendocrine glands and pancreas, and that treatment should be planned to maximise the probability of cure without unnecessary sequelae, by multidisciplinary teams with systematic recording and collaboration with patient associations [15]. The Danish cohort showed that approximately 25% of people with VHL had a late or missed diagnosis despite meeting international criteria [10].

5.2 Molecular testing in VHL

Options include single-gene testing, a multigene panel and comprehensive genomic testing (exome or genome) [1]. In single-gene testing, sequencing of the coding region, intron 1 and flanking regions is performed first; if no variant is found, targeted deletion and duplication analysis follows (quantitative PCR, long-range PCR, MLPA — multiplex ligation-dependent probe amplification — or a targeted microarray) [1]. A panel including VHL and differential diagnosis genes allows cause identification while limiting findings outside the phenotype [1]. Combined sensitivity is approximately 95% [1]. The Oxford Desk Reference proposes, when suspected, DNA sampling (EDTA) for VHL testing, ophthalmological assessment with direct and indirect fundoscopy, brain and abdominal MRI and 24-hour urinary vanillylmandelic acid or plasma metanephrine measurement [6]. Somatic mosaicism (approximately 5%) should be considered in patients with a suggestive phenotype and negative blood testing [1].

In an isolated haemangioblastoma, isolated retinal angioma or isolated clear cell RCC without a detectable germline variant, test sensitivity allows exclusion of VHL with a high degree of certainty, subject to mosaicism; a younger person, particularly with multiple lesions, is more likely to have a germline variant than an older person with a single lesion [1]. In RCC, ESMO recommends germline testing when diagnosis occurs by 46 years, with bilateral or multifocal tumours, one or more 1st- or 2nd-degree relatives with RCC, manifestations of a known predisposition syndrome or exhaustion of standard treatment options; panels should include BAP1, FH, FLCN, MET, SDHA, SDHAF2, SDHB, SDHC, SDHD, PTEN and VHL, with TSC1/TSC2 according to history [44]. In non-syndromic RCC, the Oxford Desk Reference recommends panels (VHL, MET, FLCN, SDHB, FH, BAP1) and a karyotype to exclude constitutional chromosome 3 translocations [7].

5.3 Biochemical and imaging diagnosis of PGL/PHEO

Measurement of fractionated metanephrines in plasma (free metanephrines) or 24-hour urine is preferable to catecholamines because it is more sensitive [3, 16]. False positives may be reduced by repeating measurement in 24-hour urine when plasma normetanephrine is elevated to less than twice the reference range [3]. Measurement of dopamine or its metabolite 3-methoxytyramine is optional [3]. Plasma chromogranin A is not recommended because it is elevated in many other situations (liver or kidney disease, atrophic gastritis, irritable bowel syndrome, colon cancer, other neuroendocrine tumours) and with proton pump inhibitors [3]. Preanalytical factors cause false positives and false negatives, and all positive results require confirmation [16]. A normal result excludes a functioning tumour at that time, but does not exclude a non-secretory HNPGL or carrier status [3].

Biochemistry according to the French PNDS. The PNDS (French National Diagnosis and Care Protocol) recommends metanephrines exclusively (metanephrine and normetanephrine, free or total), preferably by liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the abandonment of catecholamines and vanillylmandelic acid for diagnosis and follow-up [12]. Plasma free metanephrines have a sensitivity close to 100% and a specificity of approximately 95%; sampling need not coincide with an attack, because tumour production is continuous. Ideal conditions are supine rest for at least 30 minutes, a 12-hour fast and abstention from caffeine and tobacco—from the supine to the sitting position, metanephrine may rise by up to 30% and normetanephrine by up to 27%—; because these conditions are difficult to meet, a first unprepared sample is acceptable, repeated under standardised conditions if the value is raised [12]. In urine, the free or total fraction is measured in a 24-hour collection, with urinary creatinine to confirm that the collection is complete; if this is unreliable, a first morning void expressed as a ratio to creatinine is used. No preservative is added and the sample is not acidified (acidification is proscribed for the free fraction), and collection need not be repeated over several days [12]. A value within the reference range excludes a secreting tumour; a value more than 4 times the upper limit has a high positive predictive value; between 1 and 4 times, physiological, pathological, pharmacological and analytical factors are considered and the standardised plasma sample is repeated or a 24-hour urine collection is performed. No diet is required, except for 3-methoxytyramine, which rises with catecholamine-rich foods (banana, avocado, pineapple, hazelnuts, cereals) [12].

Source: HAS PNDS, table 4 (indicative values in adults; each laboratory defines its own) [12]. Conversion: 1 ng/mL corresponds to 5.07 nmol/L of metanephrine, 5.46 nmol/L of normetanephrine and 5.98 nmol/L of 3-methoxytyramine.

Metanephrines increase with age; in men, metanephrine and 3-methoxytyramine are approximately 29% and 14% higher, a difference of little clinical relevance. In children, age-specific reference ranges are essential, in plasma and urine, and urine values are expressed as a ratio to creatinine. Pregnancy does not alter catecholamine metabolism or test performance. In hypertension, plasma normetanephrine is approximately 17% higher. In chronic kidney disease, plasma is preferred—with increases of up to 45% in normetanephrine at stage 3 and of up to 100% in normetanephrine and 3-methoxytyramine and 61% in metanephrine on haemodialysis—and urine should not be used [12]. A raised value in the context of acute stress, intensive care admission or after catecholamine administration is repeated at least 10 days later, although imaging may proceed immediately if suspicion is high [12]. Antihypertensive drugs interfere little and need not be stopped. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin–noradrenaline reuptake inhibitors, phenoxybenzamine, sympathomimetics and cocaine raise metanephrines through a pharmacodynamic mechanism, whatever the method, whereas levodopa and a catecholamine-rich diet raise 3-methoxytyramine. With electrochemical detection (LC-ECD), paracetamol, sulfasalazine, midodrine, labetalol, sotalol, buspirone and levodopa cause analytical interference; with LC-MS/MS, interference from ecstasy (MDMA) and methyldopa persists [12]. 3-Methoxytyramine is useful in the rare dopamine-secreting tumours, in head and neck paragangliomas, which may secrete it in isolation, and as a marker of metastatic risk. Unlike GeneReviews, the PNDS considers chromogranin A the most sensitive and specific neuroendocrine marker and useful in the diagnosis and follow-up of non-secreting forms, while noting false elevations in renal failure and with proton pump inhibitors [3, 12]. The clonidine suppression test is no longer performed [12].

CT is often the modality of choice in a symptomatic patient with suggestive biochemistry because of spatial resolution in the chest, abdomen and pelvis; MRI is preferred when radiation must be limited (pregnant women, children) and in lifelong surveillance of asymptomatic carriers [3, 16]. HNPGLs are better characterised by MRI, thoracic paragangliomas by CT and abdominal tumours by either [3]. On MRI, PGL/PHEO have high T2 signal and do not lose signal on in-phase and out-of-phase sequences, distinguishing them from cortical adenomas; on CT they are heterogeneous, with cystic areas, unenhanced density above 10 Hounsfield units, intense enhancement and slow washout [3]. Digital subtraction angiography detects small paragangliomas and is indispensable before preoperative embolisation or carotid occlusion [3]. To characterise a lesion or stage metastatic disease, ⁶⁸Ga-DOTATATE PET-CT is the most sensitive modality for disease expressing somatostatin receptors; ¹²³I-MIBG (metaiodobenzylguanidine) scintigraphy is more specific than CT and MRI, but much less sensitive, and is used mainly to decide whether metastatic disease is treatable with ¹³¹I-MIBG; octreotide scintigraphy has been replaced by ⁶⁸Ga-DOTATATE; ¹⁸F-FDG PET also helps detect metastases [3]. PGL/PHEO biopsy is contraindicated because of the risk of hypertensive crisis, haemorrhage and tumour dissemination, and no reliable histopathological criteria exist to predict metastases [3].

Imaging according to the French PNDS. CT is the first-line morphological examination for thoracic, abdominal and pelvic tumours, with a sensitivity of approximately 90% and a specificity of approximately 75%. The protocol has three phases—unenhanced abdominal (native attenuation), arterial from the lung apices to the pelvis, and portal venous abdominopelvic—with a dose of 15–20 mSv, and non-ionic iodinated contrast is not contraindicated [12]. Imaging may begin with the abdomen and pelvis and be completed with the chest if nothing is found. The typical tumour measures 3–5 cm (median), has an unenhanced attenuation above 10 HU and intense arterial enhancement; MRI is not needed for diagnosis alone, but may be needed for an intracardiac or juxtacardiac paraganglioma (preoperative cardiac MRI) [12]. MRI replaces CT when there is a contraindication to iodinated contrast, renal failure, pregnancy or paediatric age, with thoracic and pelvic acquisition if a paraganglioma is suspected; the protocol includes diffusion, T2, T1 and post-gadolinium T1, and in-phase and opposed-phase sequences help in the adrenal differential diagnosis [12]. In head and neck paragangliomas, MRI is the reference: three-dimensional arterial-phase MR angiography has a sensitivity of 100% and a specificity of 94%, the “salt and pepper” appearance on T2 reflects high-flow vessels, and submillimetre temporal bone CT assesses bone invasion by tympanic tumours [12]. If no lesion is seen on conventional and functional imaging despite raised metanephrines, a diagnosis of PGL/PHEO is excluded and a false positive is sought [12]. In carriers of a genetic predisposition, MRI is the surveillance modality, to limit cumulative radiation and the risk of radiation-induced cancer, with CT reserved for the lungs or when higher spatial resolution is needed [12].

Functional imaging is required for a large phaeochromocytoma or one with a family history, for predominant or exclusive normetanephrine hypersecretion, for a suggestive tumour without raised metanephrines and whenever there are risk factors for metastases or multifocality; it is not indicated for symptoms with normal metanephrines, a situation that calls for differential diagnosis [12]. In head and neck paragangliomas, it reveals multifocal forms, present in more than 40% of SDHx cases. The choice of radiopharmaceutical depends on location and genotype:

Source: HAS PNDS, figure 3 (indicative) [12].

¹⁸F-FDOPA has low physiological adrenal uptake and is not subject to drug interference, which favours it in forms with bilateral adrenal involvement (RET, VHL, NF1, MAX) and in small adrenal lesions with low secretion; it performs less well in retroperitoneal paragangliomas (except in VHL) and in SDHB metastases, where ¹⁸F-FDG and somatostatin analogues are superior [12]. Intense ¹⁸F-FDG uptake does not predict metastases but suggests SDHx. This guidance differs from that of GeneReviews, which presents ⁶⁸Ga-DOTATATE as the most sensitive modality without distinguishing by genotype: in VHL and EPAS1, the PNDS prefers ¹⁸F-FDOPA [3, 12]. In France, only ⁶⁸Ga-DOTATOC had a marketing authorisation in 2021. The effective dose of PET-CT is that of the associated CT (5–20 mSv) plus 0.019 mSv/MBq (¹⁸F-FDG), 0.026 mSv/MBq (¹⁸F-FDOPA) or 0.023 mSv/MBq (⁶⁸Ga-DOTATOC), with 2–3 MBq/kg [12]. Regarding biopsy, the PNDS avoids it because of the risk of catecholamine surge and haemorrhage, but accepts image-guided or endoscopic ultrasound-guided core biopsy, by an experienced radiologist and following retroperitoneal sarcoma methodology, for synchronous metastases or an unresectable tumour, for diagnostic and theranostic purposes; for an atypical adrenal lesion, PGL/PHEO must be excluded before any biopsy [12].

5.4 Genetic testing in PGL/PHEO syndromes

Diagnosis is established in a proband with a personal or family history of PGL/PHEO and a heterozygous pathogenic or likely pathogenic germline variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD or TMEM127 [3]. The test of choice is a multigene panel with deletion and duplication analysis; single-gene testing is reserved for specific situations — SDHB in metastatic phaeochromocytoma or paraganglioma; SDHD in HNPGL [3]. FH and MDH2 are probable susceptibility genes, and EGLN1, EGLN2, EPAS1, KIF1B and KMT2D have been associated with PGL/PHEO with clinical significance still uncertain; the panel should also cover differential diagnosis genes such as RET, VHL and NF1 [3, 8]. Pseudogenes of SDHA (at least four), SDHC (at least five) and SDHD (at least seven) may interfere with sequencing interpretation [3]. Some families with several affected members have no identifiable variant, suggesting variants in regulatory regions or as-yet unknown genes; in these cases, storing proband DNA is recommended [3].

The French PNDS recommends offering testing to all patients with PGL/PHEO, whatever their age or personal and family history, and starting it at diagnosis, without delaying treatment, because the result may take months [12]. It follows the NGSnPPGL group consensus, which requires a minimum of ten genes (VHL, SDHB, SDHD, SDHC, SDHA, RET, NF1, FH, MAX and TMEM127) by next-generation sequencing in an accredited laboratory [12]. In a French study, knowing the result within the first year of follow-up significantly improved the management and clinical course of SDHx and VHL carriers [12]. The frequencies of germline variants among patients with PGL/PHEO and the predisposition profiles presented by the PNDS are:

Source: HAS PNDS, table 2 [12]. Approximately 40% of patients have a germline variant, and more than 30% of apparently sporadic tumours have a somatic variant in the same genes [12]. These frequencies refer to all patients with PGL/PHEO and not to the proportions of each gene among the hereditary forms shown in the table in section 3.11.

Tumour SDHB immunohistochemistry suggests a germline variant when germline testing is inaccessible: SDHB loss occurs when a germline SDHA, SDHB, SDHC or SDHD variant is accompanied by inactivation of the normal allele, and additional SDHA loss points to SDHA [3]. However, evidence is insufficient to recommend its routine use to guide molecular testing: discordant cases exist, VHL variants complicate interpretation and the examination is not widely available [3]. SDHB loss has not been validated for SDHAF2 [3]. In wild-type GIST, SDHA, SDHB, SDHC and SDHD investigation should be performed by tumour immunohistochemistry or germline testing [3].

The PNDS details the pathological assessment [12]. Chromogranin A, INSM1 and synaptophysin confirm neuroendocrine nature; rarefaction of the sustentacular cell network (S100, SOX10) is a criterion of aggressiveness; absence of cytokeratins distinguishes PGL/PHEO from epithelial neuroendocrine tumours. Loss of the granular cytoplasmic (mitochondrial) SDHB pattern indicates an SDHx variant, combined loss of SDHA and SDHB indicates SDHA, and weak diffuse non-granular SDHB staining, seen mainly in SDHD tumours, counts as negative; in difficult cases, the anti-SDHD antibody gives a mirror-image result (positive in SDHx tumours). In VHL, one or more cells with membranous carbonic anhydrase IX staining, sometimes with weaker SDHB, clear cells, capsular vascularisation or intratumoral vessels with their own wall suggest the variant; loss of FH indicates FH. These stains can be reviewed in the review centres of the ENDOCAN network [12]. According to the 2016 WHO classification, there are no validated histological criteria for malignancy in the primary tumour, and metastatic PGL/PHEO is defined by metastases in non-chromaffin tissue; the PASS (below 4) and GAPP (below 3) scores had a negative predictive value of 100% for metastases in a meta-analysis, but neither has achieved consensus [12]. The report should state vascular or capsular invasion, necrosis, mitoses, completeness of excision and the Ki-67 index in the areas of highest proliferation; an SDHB variant, or loss of SDHB on immunohistochemistry, is the main metastatic risk factor, and cryopreservation of tumour tissue from the surgical specimen is recommended [12]. Head and neck paragangliomas account for approximately 20% of paragangliomas, derive mainly from parasympathetic paraganglia, express little chromogranin A and metastasise in 4–6% (compared with 2–50% of abdominopelvic ones); tympanic paragangliomas are always benign, and the TNM classification does not apply to them [12].

5.5 Practical algorithm

Sources: [1, 3, 7, 44]

5.6 Assessment after diagnosis

In VHL, if not already performed, the following are recommended: neurological history and examination with brain and whole-spine MRI; ophthalmological assessment; abdominal ultrasound from 16 years, with suspicious renal, adrenal or pancreatic lesions characterised by CT or MRI; blood pressure and plasma or urinary fractionated metanephrines from 5 years; audiological assessment; MRI of the internal auditory canals between 15 and 20 years or earlier if hearing loss, tinnitus or vertigo occurs; psychosocial assessment; and genetic counselling [1]. In PGL/PHEO syndromes, referral to an experienced specialist is recommended; cross-sectional and functional imaging in patients with symptoms or abnormal biochemistry; clinical assessment, including upper gastrointestinal endoscopy, in children, adolescents and young adults with unexplained gastrointestinal symptoms, bowel obstruction or anaemia; control of hypertension and tachycardia before any therapy; and genetic counselling [3].

5.7 Limitations of genetic tests and report content

What a test does not cover it cannot exclude. In VHL, coding-region sequencing misses deletions of one or more exons or the whole gene (approximately 10% of variants), intron 1 variants including the cryptic exon E1′ and somatic mosaicism (approximately 5%), which may require testing of tumour tissue or more than one tumour [1]. In PGL/PHEO syndromes, SDHA, SDHC and SDHD pseudogenes may generate false positives and false negatives in short-read sequencing; many laboratories do not perform SDHA copy-number analysis; approximately 10% of MAX variants are deletions or duplications; and the SDHB exon 1 deletion, a founder variant in the Iberian Peninsula and frequent in Brazil, is detectable only with MLPA or copy-number analysis [3, 66, 67]. Most EPAS1 variants in the Pacak–Zhuang spectrum are postzygotic and may be absent from blood, so they are sought in the tumour [58]. A negative panel does not exclude disease in a patient with clinical VHL criteria or a family with several affected members, when storing DNA is recommended [1, 3]. Conversely, a variant found only in the tumour — very frequent for VHL in sporadic RCC — has a low probability of germline origin and does not itself establish the syndrome [44], and SDHB loss on immunohistochemistry suggests SDH deficiency but does not replace germline testing [3].

The report should identify the gene, versioned reference transcript, variant in HGVS nomenclature at coding DNA and protein level, zygosity, ACMG/AMP classification — in VHL, according to ClinGen expert panel specifications [1] —, method (sequencing, copy number, introns analysed, read depth) and limitations. MANE Select transcripts to use are: VHL NM_000551.4; SDHB NM_003000.3; SDHD NM_003002.4; SDHC NM_003001.5; SDHA NM_004168.4; SDHAF2 NM_017841.4; TMEM127 NM_017849.4; MAX NM_002382.5; FH NM_000143.4; EPAS1 NM_001430.5 [68]. Older VHL literature uses cDNA numbering offset by 213 nucleotides and 71 codons from current numbering: the Black Forest founder variant, published as “T>C at nucleotide 505, Tyr169His”, is now NM_000551.4:c.292T>C, p.(Tyr98His), classified as pathogenic in ClinVar (VCV000002223) [47, 49]. Likewise, the Chinese family variant described in 10.2 is standardised as NM_003002.4(SDHD):c.64C>T, p.(Arg22Ter) (VCV000006903), and the Dutch SDHAF2 founder variant as NM_017841.4:c.232G>A, p.(Gly78Arg) (VCV000000401), both pathogenic with multiple concordant submissions [49]. When an article uses historical notation, recording both forms is advisable so the variant can be searched in databases and tested in relatives without ambiguity.

A variant of uncertain significance does not become pathogenic because the tumour responds to belzutifan — response reflects HIF-2α dependence, also present in sporadic tumours — or because it is found in one or two affected relatives; in PGL/PHEO syndromes, where penetrance is incomplete and parent-of-origin effects may conceal carriers, partial segregation is even less informative. Family investigation of a VUS is research and contributes to classification only with the weight assigned by ACMG/AMP criteria; relatives' surveillance should not be decided on the basis of a VUS [1, 3].

6. Differential Diagnosis

6.1 Differential diagnosis of VHL

6.2 Differential diagnosis of PGL/PHEO syndromes

Phaeochromocytoma has an incidence of approximately 0.6/100 000/year, and approximately 75% are sporadic; sporadic paraganglioma has an unknown incidence, lower than phaeochromocytoma, but a stronger association with hereditary predisposition [3, 11].

Pacak–Zhuang syndrome has been described in approximately 30 people: polycythaemia and PGL/PHEO in 100%, iron deficiency with very low ferritin and vascular malformations in 90–100%, ocular anomalies in approximately 90%, vertebral segmentation anomalies in approximately half and somatostatinoma in approximately 30% [58]. The autosomal dominant germline EPAS1 gain-of-function form causes familial erythrocytosis type 4 without increased tumour risk [58].

For suggestive paroxysmal symptoms, the PNDS (French National Diagnosis and Care Protocol) lists as the main alternative diagnoses panic disorder or generalised anxiety; carcinoid syndrome (flushing, as opposed to the pallor of PGL/PHEO, and diarrhoea, with measurement of 5-hydroxyindoleacetic acid in 24-hour urine if in doubt); ovarian or testicular failure (age, surgery, chemical castration); drugs that cause flushing (corticosteroids, iodinated contrast, some antidepressants, vasodilators, nicotinic acid); cocaine, amphetamines and LSD; and also CNS diseases, mastocytosis, medullary thyroid carcinoma, hyperthyroidism and alcohol consumption [12]. A lateral neck mass raises the possibility of goitre, infectious, inflammatory or metastatic lymphadenopathy (head and neck cancer, thyroid cancer, melanoma), lymphoma, schwannoma, neurofibroma, ganglioneuroma, meningioma, carotid aneurysm and cystic lymphangioma [12]. In the adult extrarenal retroperitoneum, the imaging differential diagnosis includes benign lesions (schwannoma, ganglioneuroma, neurofibroma, lymphangioma, haemangioma, angiomyolipoma, lipoma, myelolipoma, adrenal adenoma, haemangiopericytoma, leiomyoma, desmoid tumour, teratoma, Castleman disease, haematoma, abscess) and malignant lesions (sarcomas, metastatic lymphadenopathy, particularly from renal carcinoma, adrenocortical carcinoma, lymphoma, malignant peripheral nerve sheath tumour, other neuroendocrine tumours, GIST, retroperitoneal carcinomatosis, ganglioneuroblastoma) [12].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no treatment that cures VHL or has been proven to prevent tumour development. Management rests on three pillars: lifelong surveillance in an experienced multidisciplinary centre, intervention directed at each lesion at the time that maximises benefit and minimises functional loss, and HIF-2α-targeted systemic therapy in approved settings [1, 15, 65]. GeneReviews emphasises that there are no guidelines for management of each VHL lesion, so the surgical thresholds described below derive from cohorts and reference centre practice [1]. Improved surveillance has increased life expectancy in people with VHL by more than 16 years since 1990 [1, 70]. In PGL/PHEO syndromes, tumour management resembles that of sporadic tumours, but carriers are more likely to have multiple, multifocal or metastatic tumours [3].

7.2 Belzutifan (Welireg®)

Mechanism and formulation. Belzutifan is an oral HIF-2α inhibitor: it binds HIF-2α and, in hypoxia or with dysfunctional pVHL, blocks the HIF-2α–HIF-1β interaction, reducing transcription of genes associated with cell proliferation, angiogenesis and tumour growth; it thus acts specifically on the biology of cells without functional pVHL [1, 22]. It is available as 40 mg film-coated tablets [22].

Regulatory status. The FDA approved belzutifan on 13 August 2021 for adults with VHL requiring therapy for associated RCC, CNS haemangioblastomas or pNETs not requiring immediate surgery [22, 71]. The current prescribing information (September 2026 revision) also includes advanced clear cell RCC after a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor, adjuvant treatment of RCC with a clear cell component at intermediate-high or high risk in combination with pembrolizumab (approved in June 2026, LITESPARK-022 trial) and, since May 2025, locally advanced, unresectable or metastatic PPGL in adults and paediatric patients aged 12 years or older [22, 71]. On 24 September 2026, the FDA also approved combination with lenvatinib for advanced RCC with a clear cell component after a PD-1/PD-L1 inhibitor (LITESPARK-011 trial), adding a cardiac dysfunction warning for this combination to the prescribing information; the VHL indication, dose and adjustment rules did not change [22, 72]. In the European Union, the European Commission granted conditional marketing authorisation on 12 February 2025 for advanced clear cell RCC and adults with VHL requiring treatment for associated localised RCC, CNS haemangioblastomas or pNETs who cannot undergo surgery or other local treatments; the European Public Assessment Report (EPAR) page consulted in October 2026 does not include a PPGL indication [23]. The medicine is subject to additional monitoring in the European Union [23]. The review published by EMA assessors explains the conditional nature of authorisation: because it is based on a single-arm trial without time-to-event outcomes, the authorisation holder was required to submit final LITESPARK-004 results and efficacy and safety data from at least 64 patients with VHL followed for 24 months or more in a subcohort of study MK-6482-015 (NCT04924075) [73]. According to the holder's August 2026 quarterly SEC report, applications under evaluation in the European Union concern RCC (adjuvant and combination with lenvatinib), not PPGL [74]. Conditional European authorisation does not guarantee marketing, reimbursement or access in each Member State — the holder itself states that availability depends on national reimbursement procedures, handled by INFARMED in Portugal — and FDA or EMA authorisation does not imply ANVISA registration or incorporation into SUS by CONITEC [75].

Efficacy in VHL. The open-label, single-arm phase 2 LITESPARK-004 trial (NCT03401788) included 61 adults with a germline VHL variant and at least one measurable RCC, excluding metastatic disease; median age was 41 years, 84% had type 1 VHL and 77% had previous renal surgery [22, 32]. RCC objective response rate was 49% (all partial responses), with 56% of responses lasting at least 12 months and a median time to response of 8 months [22]. In patients with measurable solid lesions, response was 63% in CNS haemangioblastomas (n=24; one complete response) and 83% in pNETs (n=12; two complete responses), with reduction of peritumoral cysts and syringes [22]. Considering all lesions, the original publication and the update with approximately 2.5 years of follow-up report a 77% response in pancreatic lesions and 30% in CNS haemangioblastomas, a renal disease control rate of 98.4% after 21.8 months, improvement in all 16 evaluable eyes with retinal haemangioblastoma and a marked reduction in the number of required operations [1, 32]. Whether belzutifan prevents new tumours is unknown [1]. The evidence level is that of a single-arm phase 2 study, not a randomised comparison [32]. With longer follow-up, publications from the same trial updated these numbers: at approximately 50 months, RCC objective response by independent review was 67% (95% CI 54–79%; 11% complete responses), with 59% of patients still on treatment at data cut-off [77]; in the 50 patients with evaluable CNS haemangioblastomas (median follow-up 38 months), response was 44% (95% CI 30–59%) when all lesions, including the cystic component, were counted, and 76% (95% CI 55–91%) when only the 25 patients with a measurable solid component were counted [78]; and in pancreatic lesions response was 84% (17 complete responses), and 91% (20 of 22) in pNETs [79]. An analysis with an external control arm, constructed from 244 patients with VHL-associated RCC under active surveillance in a natural history study and adjusted by propensity score, estimated RCC response at 63.9% with belzutifan versus 1.5% without treatment, and a median time to surgery of 51.3 months in controls, not reached with the drug; the authors acknowledge possible residual confounding, and this retrospective analysis does not equate to a randomised trial [80].

Adverse effects and management. In LITESPARK-004, haemoglobin decreased in 93% (grade 3 in 7%), with median onset at 31 days; the commonest reactions (≥25%) were decreased haemoglobin, fatigue, increased creatinine, headache, dizziness, hyperglycaemia and nausea; serious reactions occurred in 15% (anaemia, hypoxia, anaphylactic reaction, retinal detachment and central retinal vein occlusion, one patient each), permanent discontinuation in 3.3%, interruption in 39% and dose reduction in 13% (mainly for fatigue) [22]. Anaemia is related to erythropoietin suppression, with plasma levels falling by an average of approximately 60% after two treatment weeks and gradually returning to baseline after 12 weeks; grade 3 anaemia is more frequent with greater exposure in patients with baseline haemoglobin below 12 g/dL. Haemoglobin is monitored before and periodically during treatment, transfusion is given when indicated, and safety of erythropoiesis-stimulating agents in belzutifan-treated VHL is not established [22]. Oxygen saturation should be measured before and during treatment [22]. In GeneReviews, 33% of patients had grade ≥3 adverse effects and 11.5% discontinued treatment after approximately 2.5 years [1]. Clinical practice reports include a case of retinal haemangioblastoma regression with dose reduction to 80 mg for elevated transaminases [59] and a case of fatal intracranial haemorrhage in a patient with haemangioblastoma treated with belzutifan [81].

Efficacy in PPGL. The international single-arm phase 2 LITESPARK-015 trial (NCT04924075) included 72 patients with locally advanced or metastatic PPGL not amenable to surgery or curative treatment, with controlled blood pressure; none had VHL [22, 24]. With median follow-up of 30.2 months, the confirmed objective response rate was 26% (all partial), disease control 85%, median response duration 20.4 months, median progression-free survival 22.3 months and overall survival at 24 months 76%; 32% of patients receiving antihypertensives reduced the dose of at least one drug by at least 50% for six or more months [24]. Anaemia occurred in 96% (grade 3 in 22%), with serious reactions in 36% and permanent discontinuation in 2.8% [22]. The indication is defined by tumour type, stage and age and does not require a specific genotype [22].

7.3 Other systemic drugs in VHL (off-label)

Pazopanib, a tyrosine kinase inhibitor approved for advanced RCC, has no approved VHL indication. In a single-arm phase 2 trial in 31 people with VHL treated with 800 mg orally once daily for 24 weeks, 42% responded by RECIST criteria, including 52% of RCCs (two complete responses) and 52% of pancreatic lesions, but only 2 of 49 haemangioblastomas; one patient died from CNS haemangioblastoma haemorrhage, and responses were limited to germline variant carriers [1, 82]. Pazopanib may be considered in people with a germline variant and no CNS haemangioblastoma requiring intervention [1]. Sunitinib showed activity in RCC but not haemangioblastomas, and there is no evidence supporting its use in retinal haemangioblastomas [1]. Dovitinib was discontinued in a pilot study because of adverse effects in all six participants [1]. Intravitreal ranibizumab and bevacizumab, long-acting octreotide in an unresectable suprasellar haemangioblastoma, propranolol, thalidomide, immune checkpoint inhibitors and ataluren (in nonsense variants) remain experimental [1].

Extrapolation of evidence and off-label use should be distinguished because they do not coincide. Off-label use is defined by the prescribing information in each jurisdiction, age and lesion type. Belzutifan is indicated in VHL only in adults and only for RCC, CNS haemangioblastomas and pNETs — in the United States when they do not require immediate surgery, in the European Union when local procedures are unsuitable [22, 23]. Therefore, off-label use includes: treatment of a child or adolescent with VHL; treatment directed at retinal haemangioblastomas, although LITESPARK-004 documented improvement in all evaluable eyes as a secondary outcome [32, 83]; and, in the European Union, treatment of advanced PPGL, an indication existing only in American prescribing information (adults and patients aged 12 years or older) [22, 23]. A localised VHL-associated phaeochromocytoma is included in none of the indications, and metastatic PPGL in a person with VHL is covered, in the United States, only by the PPGL indication — based on a trial without patients with VHL, which is extrapolation of evidence rather than off-label use [22, 24]. In pregnancy, the boxed warning for embryofetal toxicity makes use inadvisable in any jurisdiction [22]. Use of pazopanib or sunitinib directed at VHL lesions and sunitinib or lutetium-177 dotatate in PPGL is off-label in both jurisdictions; conversely, an unresectable or metastatic pNET in a person with VHL falls within the general sunitinib and lutetium-177 dotatate indications for pancreatic neuroendocrine tumours, albeit without specific data in this population [1, 3, 84, 85].

7.4 Lesion-directed treatment in VHL

CNS haemangioblastomas. Most can be completely and safely surgically removed [1, 6]. Since they grow at several sites, new lesions arise and growth is unpredictable, many centres defer resection until symptoms appear to avoid unnecessary surgery; others remove symptomatic and asymptomatic lesions early [1, 6]. Intraoperative videoangiography, ultrasound and fluorescein optimise resection and reduce haemorrhage [1]. In spinal haemangioblastomas, preoperative arterial embolisation may be indicated for extensive tumours, minimally invasive approaches are safe in selected cases, and intraoperative neurophysiological monitoring is associated with better neurological outcomes; spinal cord surgery should be performed in a reference centre [1]. Surgical intervention for spinal cord cysts and syringes is recommended [1]. Stereotactic radiosurgery (gamma knife) is useful in small solid or inoperable tumours; it reduces the solid tumour but does not appear to prevent cyst formation. In one series, local control was 96%, 92% and 92% at one, three and five years, with symptomatic improvement in 13 of 16 tumours; in another series of 186 patients, 7% had complications (11 required corticosteroid treatment and one died from refractory peritumoral oedema) [1].

Retinal haemangioblastomas. Most ophthalmologists treat retinal lesions prospectively (but not optic nerve lesions) to prevent blindness [1]. Modalities include laser photocoagulation, cryotherapy, diathermy and xenon, with variable success according to location, size and number; new lesions may arise in the same area years later [1]. Ultra-widefield fluorescein angiography detects more lesions than ophthalmoscopy [1]. Vitreoretinal surgery is indicated for complications (epiretinal membrane, vitreous haemorrhage, tractional or exudative detachment, preretinal fibrosis, proliferative vitreoretinopathy); brachytherapy is an option for larger peripheral lesions and external beam radiotherapy for refractory progression [1]. The ocular surveillance consensus of the International VHL Surveillance Guidelines Consortium, endorsed by the VHL Alliance and American Academy of Ophthalmology, recommends: ocular screening starting within the first 12 months of life and continuing lifelong, every 6–12 months until 30 years and at least annually thereafter; screening before planned pregnancy and every 6–12 months during pregnancy; genetic testing in 1st-degree relatives and any patient with a single or multifocal retinal haemangioblastoma; and immediate treatment of extramacular or extrapapillary lesions [86].

Renal cell carcinoma. The classical strategy is surveillance of small solid tumours and nephron-sparing surgery (limited partial nephrectomy) when the largest reaches 3 cm, repeating the cycle until a new tumour reaches 3 cm; this approach preserves renal function in most, although repeated partial nephrectomies may lead to renal replacement therapy [6, 7]. Image-guided techniques — cryoablation and radiofrequency — are now preferred to resection for small RCCs, particularly below 3 cm, with favourable oncological outcomes; the major complication rate after laparoscopic and percutaneous radiofrequency was 7.3% and 4.3%, respectively [1]. During nephrectomy, the adrenal gland should be preserved to prevent or delay adrenal insufficiency if contralateral phaeochromocytoma arises [1]. Renal transplantation after bilateral nephrectomy is successful, but any related living donor must be tested and excluded if a carrier [1].

Phaeochromocytoma. It should be surgically removed, preferably laparoscopically; active surveillance has been proposed for phaeochromocytomas smaller than 2 cm [1]. Preoperative alpha-adrenergic blockade (with optional beta blockade) for 7–10 days is recommended even in normotensive patients, although debated after a multicentre study showing slightly higher mortality in pretreated patients [1]. Adrenal cortical-sparing surgery is the treatment of choice in children and should be considered in all: it is associated with low recurrence, absence of metastases, rare corticosteroid dependence and unaffected survival; in ten patients with 18 operations, two developed a new ipsilateral adrenal tumour after a median of 7.2 years [1].

The French PNDS (French National Diagnosis and Care Protocol) adds that the cortical-sparing strategy for bilateral phaeochromocytoma is becoming widespread in children, particularly in familial forms, and that a child with VHL and PGL/PHEO should be treated in a reference centre [12].

Pancreas. Pancreatic cysts rarely affect endocrine function and have no malignant behaviour, so they do not require surgery [1]. Resection of a pNET should be strongly considered when metastatic risk is high: size ≥2.5 cm or doubling time below 500 days; missense variant carriers have a higher metastatic rate with pNETs between 1.2 and 3.0 cm [1]. Belzutifan is an approved alternative for pNETs not requiring immediate surgery [22].

Endolymphatic sac tumours. Surgical decisions should address the risk of total deafness; early intervention in small tumours preserves hearing and vestibular function [1]. In 31 patients with 33 resected ELSTs, hearing stabilised or improved in 97% and resection was complete in 91%; complications were cerebrospinal fluid fistula (6%) and transient lower cranial nerve palsy (3%) [1].

Epididymal and broad ligament cystadenomas. Resection is required only if symptomatic or threatening fertility [1].

Psychosocial support. Medical guidelines do not structure psychological support, but research shows a clear need to support people with VHL, their partners and relatives; assessment of psychosocial needs at every visit is recommended [1].

7.5 Treatment of tumours in PGL/PHEO syndromes

Preoperative preparation for secretory tumours. Treatment aims to contain catecholamine effects through adrenergic blockade before surgical removal [3, 16]. Alpha-adrenergic blockade (prazosin or doxazosin) starts at least 7–10 days before surgery to normalise blood pressure and allow volume expansion, with dose adjustment to a low-normal systolic pressure for age; calcium channel blockers (amlodipine, nicardipine) are second-line; a high-sodium diet and liberal fluid intake are recommended; beta blockade starts only after adequate alpha blockade, to control reflex tachycardia, adjusting the dose to a target heart rate of 80 beats per minute [3]. The Endocrine Society guideline provides a titration algorithm [16]. Every patient with HNPGL should be assessed for catecholamine excess before surgery, because its presence suggests a second primary tumour [3].

Preoperative protocol of the French PNDS. The PNDS recommends alpha-blockade for 7–14 days before surgery, with progressive titration according to blood pressure, and extends this reasoning to normotensive tumours, which can also cause intraoperative instability [12]. It acknowledges that there is no randomised placebo-controlled trial (more than 2000 patients would be needed), that retrospective studies are conflicting and that a meta-analysis of 4 studies showed no difference in cardiovascular events, probably because of the low event frequency in experienced centres; the decision to introduce alpha-blockade therefore rests with the expert centre [12]. A randomised trial showed no difference between doxazosin and phenoxybenzamine in the duration of intraoperative hypertension, and 50–70% of patients have at least one systolic pressure peak above 160 mmHg during surgery. Perioperative mortality has fallen from approximately 60% to less than 10% over six decades, mainly through better characterisation and preparation [12]. In France, phenoxybenzamine is not marketed, and prazosin and urapidil (Eupressyl® in France) are used:

Source: HAS PNDS, table 9 (adults) [12]; FDA label [87].

Beta-blockers are never used first-line without prior alpha-blockade, because they may precipitate acute heart failure; they are introduced 3–5 days after the alpha-blocker to control tachycardia, and labetalol, with a predominant beta effect, is not recommended [12]. If hypertension persists, calcium channel blockers or renin–angiotensin system blockers are added; international recommendations also accept calcium channel blockers when symptoms are moderate or when alpha-blockade causes severe orthostatic hypotension. Diuretics without a cardiological indication are stopped because of the risk of hypovolaemia [12]. Hydration and a high-salt diet are added and, usually, 1–2 litres of normal saline over 24 hours before surgery, preferably before the alpha-blocker, with the volume adjusted to cardiac function; cardiological, anaesthetic and surgical assessment in an expert centre is mandatory before operating on a functional tumour [12]. In children and adolescents, the PNDS applies the same preparation with doses adjusted to weight and age, without a specific numerical regimen; because the prazosin label does not establish a paediatric dose, titration starts from the lowest dose and follows blood pressure for age, in a paediatric reference centre [12, 87].

Metirosine. Alpha-methyl-para-tyrosine (metirosine; Demser® in the USA) inhibits tyrosine hydroxylase and reduces catecholamine synthesis, with no antitumour effect, but controls the symptoms of hypersecretion (hypertensive crises, constipation) [12]. In adults, the PNDS specifies 500–4000 mg/day orally (maximum 4000 mg/day) in 1 to 4 doses, adjusted to metanephrines with the aim of reducing them by 50%; the main adverse effect is somnolence, the dose is adjusted in renal impairment (urinary elimination) and, with adult doses above 2 g/day, the risk of urolithiasis increases, so a fluid intake above 2 litres per day is recommended [12]. In France, it was dispensed under a temporary authorisation for use for inoperable or metastatic phaeochromocytoma with marked hypersecretion, and may be combined with alpha-blockade under strict blood pressure control; in other countries it is also used for preoperative preparation, alone or with alpha-blockade [12]. The FDA label, for comparison, specifies for adults and children aged 12 years or older 250 mg orally four times daily, with increases of 250–500 mg per day up to a maximum of 4 g/day in divided doses, usual effective doses of 2–3 g/day, administration for at least 5–7 days before surgery and, in normotensive patients, titration until urinary metanephrines are reduced by at least 50%; it does not establish a dose below 12 years and requires maintenance of intravascular volume during and after surgery [88]. The PNDS contraindicates metirosine in pregnancy, whereas the label only reserves it for clear need, owing to a lack of studies [12, 88].

Hypertensive crisis, orthostatic hypotension and constipation. Many patients have hypertensive crises weekly or several times a week, with tachycardia or arrhythmias. The first step is alpha-blockade (intravenous urapidil or oral prazosin); this is followed by calcium channel blockers, beta-blockers such as esmolol or metoprolol as second line and only after several days of alpha-blockade, nitroprusside as third line, and angiotensin-converting enzyme inhibitors if blood pressure remains high [12]. Orthostatic hypotension is corrected by stopping diuretics and other hypotensive drugs and rehydrating; the patient learns to avoid getting up quickly, alcohol, heat, dehydration and prolonged standing and, when symptoms occur, to sit, squat or lean forward, drink a large glass of water or squeeze a ball hard in the hand; the head of the bed is raised by 10° and class 2 compression stockings may be used. Pharmacological treatment is rarely needed, and midodrine is contraindicated [12]. Constipation is treated with a high-fibre diet, hydration, three meals a day and stimulant laxatives (docusate, bisacodyl, with caution in severe forms because they are painful) or osmotic laxatives (macrogol); marked caecal dilatation may require rescue colonic decompression [12].

Emergency. A patient with PGL/PHEO and an acute cardiovascular complication is treated in intensive care, without emergency surgery, because of the high risk of morbidity and mortality; stabilisation with alpha-blockade comes first [12]. In severe hypotension or shock, adequate volume replacement is given and vasoactive amines are avoided, because circulating catecholamines are already raised; mechanical circulatory support, intra-aortic balloon pump or extracorporeal circulation are alternatives, and excision is considered only after stabilisation [12].

Anaesthesia. The pre-anaesthetic consultation checks blood pressure and rhythm control, correction of chronic volume depletion, cardiac function, blood glucose and electrolytes; it requests, at a minimum, a full blood count, prothrombin time, activated partial thromboplastin time, fibrinogen, electrolytes, creatinine, urea and an electrocardiogram, and an echocardiogram to look for cardiomyopathy, with a cardiology consultation if there is a relevant history or abnormality [12]. There is no indication for routine anxiolytic premedication, and patients with diabetes are warned that their glucose-lowering treatment will be reduced immediately after surgery. Risk factors for haemodynamic instability are raised metanephrines at induction, a large tumour, a mean arterial pressure above 100 mmHg at induction and a deeper postural fall after alpha-blockade [12]. Catecholamine-releasing drugs are avoided—droperidol (dopaminergic blockade), morphine and atracurium (histamine release), ephedrine and ketamine (sympathetic stimulation), atropine and desflurane—and suxamethonium is not recommended; rocuronium and target-controlled total intravenous anaesthesia with propofol and remifentanil are preferred. Magnesium sulfate and dexmedetomidine have favourable but poorly documented reports [12]. For hypertension, rapid-onset, short half-life vasodilators are used—nicardipine or clevidipine, the latter with a half-life of approximately 1 minute—; for tachyarrhythmias, esmolol or landiolol; for hypotension after devascularisation, low-concentration noradrenaline (for example, 10 µg/mL) and, if refractory, vasopressin [12]. The arterial catheter is placed under local anaesthesia before induction, cardiac output may be monitored (for example, by oesophageal Doppler) and blood glucose is closely monitored because of the risk of severe hypoglycaemia after devascularisation [12]. Postoperatively, 3 hours of monitoring in the post-anaesthesia care unit suffices in most cases, with intensive care reserved for severe instability, an intraoperative complication or difficult ventilator weaning; analgesia, electrolytes, blood pressure and blood glucose are monitored, alpha-blockers are stopped, antidiabetic drugs are reduced or stopped and, after bilateral adrenalectomy, hydrocortisone and fludrocortisone are started [12].

Surgical technique. Surgery is never performed as an emergency [12]. Laparoscopic adrenalectomy is the reference technique, by the transperitoneal approach in the lateral decubitus position (the most used) or the retroperitoneal approach (an alternative for small tumours, extensive previous abdominal surgery or bilateral adrenalectomy without repositioning the patient), with no demonstrated differences between the two approaches; in teams performing at least approximately 15 adrenalectomies per year, mortality is almost nil, morbidity 10–15% (mainly minor) and conversion below 3% [12]. Large tumours or those with signs of malignancy are operated on by laparotomy, for R0 excision without capsular rupture, with imaging-guided rather than systematic lymphadenectomy. The main adrenal vein is ligated early, the specimen is extracted in a bag and nephrectomy is not performed unless there is renal invasion; adrenergic surges may occur until the specimen has been completely removed, followed by a fall in blood pressure, which requires continuous communication between surgeon and anaesthetist [12]. In bilateral tumours or those with a predisposition to multiple or recurrent lesions, partial adrenalectomy is considered case by case, informing the patient that it does not guarantee sufficient cortisol secretion; after bilateral adrenalectomy, or partial adrenalectomy with previous contralateral adrenalectomy, perioperative hydrocortisone and fludrocortisone are given and adrenocortical function is assessed in the immediate postoperative period and later; after unilateral adrenalectomy, there is no routine supplementation [12]. For abdominopelvic paragangliomas, the approach depends on size, location, vascular relationships and experience, with laparotomy preferred at the slightest doubt because of the greater risk of malignancy; thoracic paragangliomas are discussed in an expert centre with thoracic or cardiac surgeons [12].

Surgery. Resection, preferably laparoscopic, is the treatment of choice for phaeochromocytoma and may be curative in non-metastatic PGL/PHEO [3]. In SDHB-associated tumours, resection is recommended because of metastatic risk, with greater urgency in extra-adrenal sympathetic paragangliomas [3]. Two to eight weeks after surgery, metanephrines are measured: normal values indicate complete resection; elevated values suggest a second tumour or occult metastases [3]. In bilateral tumours (MAX, TMEM127, VHL), cortical-sparing surgery reduces adrenal insufficiency risk [1, 3].

Head and neck paragangliomas. Options are active surveillance, surgical resection or radiotherapy; active surveillance and radiotherapy are often as advantageous as or more advantageous than surgery, and there is no evidence of increased radiation-induced secondary neoplasms in this population [3]. Choice depends on extent (Shamblin I and II carotid body tumours are good surgical candidates), risks (resection of a vagal paraganglioma almost always causes ipsilateral vagus and recurrent laryngeal nerve loss) and presumed metastatic potential (SDHB-associated tumours may justify a more aggressive approach) [3]. In jugular paragangliomas, small tumours may be removed without complications, but resection of large tumours is associated with cerebrospinal fluid fistula, meningitis, stroke, hearing loss, cranial nerve palsy or death; surveillance with symptom-guided surgery or stereotactic radiosurgery are alternatives [3]. The SDHD-specific consensus addresses management of these multifocal tumours [19].

The PNDS (French National Diagnosis and Care Protocol) organises cervical surgical decision-making using the Shamblin classification for the carotid body (I: small, minimally adherent tumour, easy to resect; II: adherent to or partially surrounding the carotid artery, resectable without vascular injury; III: completely encasing at least one artery and requiring resection of the carotid axis) and the Fisch classification for the temporal bone (A: arising from the tympanic plexus on the promontory, confined to the middle ear; B: tympanic canal with invasion of the hypotympanum and mastoid; C1–C4: jugular bulb with progressive erosion of the carotid canal, reaching the cavernous sinus in C4; De1–De2: extradural intracranial extension of less or more than 2 cm; Di1–Di3: intradural extension, Di3 being inoperable) [12]. Cranial nerves VII to XII and the cervical sympathetic chain are at risk in jugulotympanic tumours, and nerves IX to XII and the sympathetic chain in vagal and carotid tumours, with peripheral facial palsy, sensorineural hearing loss, tinnitus and vertigo, dysphagia, dysphonia, curtain sign, shoulder drop with trapezius wasting, tongue deviation and Horner syndrome [12]. Vagal preservation is unlikely even in small vagal tumours. Some teams reserve surgery for Shamblin I–II carotid tumours and Fisch A–B tympanic tumours and offer exclusive radiotherapy for progressive vagal tumours and for C–D temporal tumours, particularly with an incipient deficit of VII or X, which irradiation can sometimes reverse; the rare secreting head and neck paragangliomas are operated on [12].

Radiotherapy according to the PNDS. External beam radiotherapy is indicated when surgery is contraindicated: an unresectable tumour (jugular or Shamblin III carotid), a foreseeable risk of injury to the mixed cranial nerves or of a vascular procedure, a foreseeable or progressive macroscopic residue, significant progression under surveillance, bilateral head and neck tumours, advanced age or comorbidities, or refusal of surgery [12]. With conventional fractionation, 1.8–2 Gy per fraction is given up to 45–50.4 Gy in 25–28 fractions (5–6 weeks), with intensity modulation and a 5 mm margin around the macroscopic volume; hypofractionated stereotactic irradiation (1 to 5 fractions; 12–20 Gy, most often 14 Gy, margin of 1–3 mm) is reserved for jugular foramen tumours up to 3 cm without mass effect on the brainstem; proton therapy, at equivalent doses, may benefit carriers of multifocal tumours who may need several courses of irradiation, but access is limited and follow-up shorter [12]. Local control (shrinkage, stabilisation or growth of less than 3 mm) exceeds 95%, close to 100% at 5 years, regardless of location, size and technique; clinical stabilisation or improvement is also around 95%, but recovery of neurological deficits is uncertain (0–60% in jugulotympanic tumours), and no randomised trial has compared radiotherapy with surgery or surveillance [12]. Acute effects (mucositis with dysphagia, epithelitis, local alopecia, hearing loss, transient imbalance, transient worsening of cranial nerve deficits) are reversible; late effects include xerostomia, subcutaneous fibrosis and hearing loss, mandibular osteoradionecrosis is no longer described with current techniques, and the risk of a radiation-induced tumour (meningioma or cancer) is approximately 0.28%, to be weighed more heavily in a young patient with an acceptable surgical alternative [12]. In asymptomatic and non-secreting forms, surgery, radiotherapy, active surveillance and targeted radionuclide therapy are discussed at a multidisciplinary meeting; approximately half of paragangliomas progress little, which makes surveillance of small asymptomatic tumours acceptable [12].

Metastatic or unresectable disease. Options include blood pressure control with alpha blockade, surgical debulking, active surveillance of non-progressive non-secretory disease, radiotherapy (particularly for bone lesions), liver-directed therapy, systemic chemotherapy (cyclophosphamide, vincristine and dacarbazine) and radionuclides [3, 43]. ¹³¹I-MIBG therapy is reserved for patients with lesion uptake on MIBG scintigraphy; the high-specific-activity product approved by the FDA for PPGL (Azedra®, iobenguane I-131) is listed in Drugs@FDA as discontinued, so local availability must be checked [3, 71]. Peptide receptor radionuclide therapy with lutetium-177 dotatate (Lutathera®) showed clinical and biochemical responses, but FDA prescribing information is limited to somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours in adults and patients aged 12 years or older, so use in PGL/PHEO is off-label [3, 84]. Belzutifan is approved in the USA for advanced PPGL (section 7.2) [22]. Sunitinib showed a modest increase in progression-free survival; cabozantinib and new alpha-emitting radiopharmaceuticals are under investigation [3].

In France, according to the 2021 PNDS, conventional ¹³¹I-MIBG had a marketing authorisation but was no longer reimbursed, high-specific-activity MIBG was not authorised, and lutetium-177 dotatate could be used off-label after a multidisciplinary meeting, with eligibility determined by ⁶⁸Ga-DOTATOC PET [12]. Somatostatin analogues labelled with ¹⁷⁷Lu or ⁹⁰Y have been evaluated in more than 200 patients, with stabilisation or partial response in more than 80% and symptomatic benefit, and radionuclide therapies require prolonged haematological monitoring because of a 1.5–4% risk of myelodysplastic syndrome or acute myeloid leukaemia in series of gastrointestinal neuroendocrine tumours [12]. In France, management of metastatic disease is referred to the guideline of the national expert centre for rare adrenal cancers (ENDOCAN-COMETE) [12].

Other tumours. Localised GIST is treated by resection, particularly if bleeding, obstructing, larger than 2 cm or growing; tyrosine kinase inhibitors are used as adjuvants or in metastatic disease, but SDH-deficient GISTs are largely resistant [3]. Pulmonary chondromas are monitored unless causing bronchial compression [3]. Clear cell RCC is treated by early surgery, with partial nephrectomy for a solitary early-stage tumour [3]. In FH-associated RCC, conversely, active surveillance, cryoablation and radiofrequency are inappropriate: immediate resection with wide margins, regardless of size, by a urological surgeon experienced in the syndrome is recommended [7, 56].

7.6 Surveillance in VHL

The internationally accepted VHL Alliance protocol was reproduced by GeneReviews and applies to people with VHL and 1st-degree relatives without genetic testing [1]. In 2023, the International VHL Surveillance Guidelines Consortium and VHL Alliance published an updated consensus statement [17], and Denmark and the Netherlands have national guidelines [15, 65].

Sources: GeneReviews, table 5 [1]; ocular consensus [86]

The 2021 French PGL/PHEO PNDS (French National Diagnosis and Care Protocol) proposes its own schedule for VHL, with surveillance starting at 5 years of age, annual fundoscopy and abdominal ultrasonography in childhood, and alternating abdominal ultrasonography and MRI in adulthood; the schedule and the divergences are given in sections 11.3 and 7.12 [12].

ELST presents as a mass in the posterior wall of the petrous temporal bone and may be missed on conventional MRI; the best method of detection is unknown [1]. The older protocol described in the Oxford Desk Reference — annual blood pressure and ophthalmoscopy from 5 years, annual renal imaging (MRI or ultrasound) from 16 years, annual urinary vanillylmandelic acid or plasma metanephrines from 11 years and brain MRI every 3 years from 15 years — illustrates the evolution towards earlier biochemical testing, inclusion of the spine and inner ear and a longer abdominal imaging interval [6]. In several centres, CNS lesions are removed only when symptomatic, which should be explained to patients [6]. Adherence is a real problem: in Brazil, 60% of patients with an attending physician did not report regular examination intervals [45]; in Denmark adherence was low, and in the Netherlands 64% of patients had received information only partially consistent with national guidance [1].

7.7 Surveillance in PGL/PHEO syndromes

There are no clear data on starting age, the best method or ideal frequency, but surveillance of all at-risk people is reasonable, adapting the strategy to gene and penetrance; gene-specific recommendations are based on limited data [3, 18].

Sources: GeneReviews, table 8 [3]; GeneReviews FH [56]; Amar 2021 [18]; Taïeb 2023 [19]; Hanson 2023 [20]; AACR [21, 89]

The range of starting ages results from different consensus statements (paediatric AACR and 2021 international consensus), and a person-centred decision is recommended [3]. PET-CT has limited data as a screening test, as opposed to characterisation of suspicious lesions, and entails costs and radiation [3]. The 2025 AACR update reviews the 2017 paediatric recommendations and records that several groups have proposed alternative and divergent regimens [21].

The French PNDS schedule for SDHB, SDHA, SDHC and SDHD (starting at 6–10 years in SDHB and at 10–15 years in the others; initial adult assessment with cervical and abdominopelvic MRI and functional imaging) is given in section 11.3 [12].

7.8 Agents and circumstances to avoid

In VHL, tobacco (a renal cancer risk factor), industrial chemicals and toxins affecting involved organs and contact sports when adrenal or pancreatic lesions are present should be avoided [1]. In PGL/PHEO syndromes, smoking and other activities predisposing to chronic lung disease should be discouraged; there is limited evidence of higher penetrance at high altitude or with chronic hypoxia exposure, insufficient to support recommendations [3]. Drugs such as metoclopramide, anaesthetic induction and increased intra-abdominal pressure may trigger paroxysms in patients with a secretory tumour [3].

The PNDS (French National Diagnosis and Care Protocol) lists the drugs to avoid before surgery because they may trigger an adrenergic crisis [12]: beta-blockers, particularly non-cardioselective ones, including eye drops (timolol, carteolol, betaxolol, levobunolol); monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors with or without noradrenergic action, and mianserin; peripheral (metoclopramide, alizapride, metopimazine, domperidone) and central (benzamides, butyrophenones, phenothiazines, atypical antipsychotics, veralipride) dopamine antagonists; sympathomimetics (nasal decongestants, oral pseudoephedrine, methylphenidate, salbutamol, terbutaline, isoprenaline and resuscitation amines); high-dose corticosteroids; betahistine; ACTH, CRH, angiotensin II and glucagon tests; histamine-releasing neuromuscular blockers and opioids; hyperosmolar iodinated contrast media (with non-ionic agents, the risk is almost nil); cyclophosphamide, vincristine and dacarbazine; levodopa; and midodrine. Most patients with phaeochromocytoma undergo the overnight dexamethasone suppression test without complications during the work-up of an adrenal mass, and hydrocortisone supplementation should not be stopped: only high-dose glucocorticoids are avoided [12]. The patient should be aware of these risk situations, in order to avoid them and to inform other professionals [12].

7.9 Assessment of at-risk relatives

The American Society of Clinical Oncology classifies VHL as a Group 1 disease, in which genetic testing is part of standard management for at-risk relatives [1]. If the familial variant is known, molecular testing identifies carriers early and spares non-carriers surveillance; if it is unknown or a relative declines testing, surveillance continues [1]. When the affected relative is unavailable, a negative result in an at-risk relative does not completely exclude VHL [1]. In PGL/PHEO syndromes, predictive testing should be offered to at-risk relatives, including children and adolescents, because surveillance begins in childhood for all genes; in maternal transmission of SDHD, SDHAF2 (and possibly MAX), testing may be deferred until 18 years for autonomous decision-making, maintaining family-history-based risk assessment [3]. If the familial variant is unknown, surveillance may be considered in families with more than one affected member [3].

7.10 Management during pregnancy

In VHL, there is no consensus on pregnancy surveillance; phaeochromocytoma and cerebellar haemangioblastoma surveillance may be intensified before conception and during pregnancy in a specialised centre, and VHL active surveillance guidelines recommend cerebellar MRI without contrast at four months of pregnancy [1]. In PGL/PHEO syndromes, every woman should be assessed for a secretory tumour before planned pregnancy or as soon as pregnancy is recognised, using plasma or urinary metanephrines; repetition in the second trimester and before delivery should be considered [3]. MRI without gadolinium is first-line for localisation; CT and radioisotope studies should be avoided [3]. A retrospective multicentre study showed better maternal and fetal outcomes with alpha-adrenergic blockade, without an advantage of second-trimester surgery over medical treatment; after 24 weeks, surgery may need to wait until fetal maturity (approximately 34 weeks), sometimes with elective caesarean section and open surgery, and successful vaginal delivery has been described only with adequate alpha blockade [3]. Belzutifan should be avoided during pregnancy because of the boxed warning for embryofetal toxicity; in rats it caused embryofetal lethality, reduced fetal weight and skeletal malformations at exposures equal to or greater than 0.2 times human exposure at the recommended dose [22].

The French PNDS (French National Diagnosis and Care Protocol) recommends management in an expert centre and in a level III maternity unit [12]. For imaging, abdominal ultrasonography is first-line in the 1st and 2nd trimesters (mean lesion size approximately 5 cm, but the examination is operator-dependent and has false negatives); if it is negative or the situation warrants it, and after a multidisciplinary decision (radiologist, physician, obstetrician, paediatrician) with the patient, MRI without gadolinium is performed, up to 3 tesla, starting with the adrenal glands and then extending, or chest–abdomen–pelvis CT with iodinated contrast at an optimised dose—in which case the paediatrician should be informed because of the risk of neonatal thyroid dysfunction. In the 3rd trimester, the strategy is the same, with easier access to cross-sectional imaging; nuclear imaging is contraindicated throughout pregnancy [12]. Alpha-blockade, in the same way as outside pregnancy, significantly reduces maternal–fetal complications, with no fetotoxicity described and placental transfer of 10–20%; rehydration and, if necessary, methyldopa or nicardipine are added, with a target office blood pressure of 130–140 mmHg systolic and 80–90 mmHg diastolic; metirosine is contraindicated [12]. Surgery during pregnancy does not appear to reduce complications: approximately 70% of patients are operated on within 2 months after delivery and approximately 20% during pregnancy, preferably in the 2nd trimester and ideally before 24 weeks, after alpha-blockade and by an experienced team; with a diagnosis in the 1st or 2nd trimester, surgery during pregnancy is usual, and in the 3rd trimester excision is performed during caesarean section or postpartum, which allows conventional and nuclear imaging to be completed and uterine involution to be awaited for laparoscopy [12]. When the diagnosis is made during pregnancy, caesarean section is performed in approximately 85% if there are signs or marked hypersecretion, but vaginal delivery is possible with good medical control. A present PGL/PHEO is a temporary contraindication to pregnancy (with exceptions for metastatic forms or non-secreting head and neck tumours, with the agreement of the expert centre), carriers of hereditary forms should undergo clinical, biochemical and imaging assessment before conception, and breastfeeding is permitted with a non-secreting tumour [12].

7.11 Comparative regulatory status and trial interpretation

The table summarises the position in the United States and European Union on 4 October 2026, distinguishing the medicine's initial authorisation date from the date and scope of the indication relevant to this article.

Sources: FDA prescribing information and records (openFDA, Drugs@FDA) and EMA medicines dataset, accessed on 4 October 2026 [22, 23, 71, 72, 84, 85, 90].

Interpretation of these data requires an explicit hierarchy. Belzutifan indications in VHL rest on a single single-arm phase 2 trial, published in a peer-reviewed journal and updated in successive publications; the American PPGL indication rests on another single-arm trial; the December 2024 CHMP opinion was a recommendation, and authorisation existed only with the February 2025 European Commission decision; information on applications under evaluation comes from the holder's SEC documents rather than regulatory decisions [22–24, 32, 73, 74].

These results do not allow treatments to be ranked. Belzutifan response rates in VHL and PPGL come from different populations and cannot be compared with each other or with pazopanib's 52% renal responses, obtained in another centre with different follow-up and patient selection [24, 32, 82]. The difference between haemangioblastoma figures (44% versus 76%) shows how the same trial can produce distinct results depending on whether the tumour is measured with or without the associated cyst — an aspect with clinical consequences, because the cyst is often the cause of symptoms [78]. In a single-arm trial, objective response is an intermediate outcome; comparison with an external natural history control suggests a real effect, but does not replace randomisation [80]. FIRSTMAPPP is, to date, the only randomised trial in metastatic PPGL: it achieved the primary outcome defined by the Simon design, but with 90% confidence intervals, in a phase 2 trial, and an absolute difference of 17 percentage points in the proportion of patients without progression at 12 months — meaning that approximately two-thirds of treated patients progressed in the first year [91]. None of these trials measured overall survival as the primary outcome, and none tested prevention of new tumours in asymptomatic carriers.

7.12 Divergences between the French PNDS and the other guidelines cited

The age divergences mainly reflect choices about the start of surveillance, not new penetrance data; the PNDS values were set in 2021, before the 2024 ocular consensus and the 2025 AACR paediatric update [12, 21, 86].

8. Reproductive Options and Family Counselling

8.1 VHL

VHL is autosomal dominant and each child of an affected person has a 50% risk of inheriting the variant; clinical severity cannot be predicted because expression varies greatly within the same family [1, 6]. Approximately 80% of probands have an affected parent and approximately 20% have a de novo variant, in themselves or as a postzygotic event in an apparently unaffected mosaic parent [1]. In an apparently isolated proband with a molecular diagnosis, parents are tested; without a molecular diagnosis, at least ophthalmological screening and abdominal ultrasound are offered to both parents [1]. An apparently negative family history is confirmed only when molecular testing demonstrates that neither parent has the variant, because disease may have been unrecognised, the parent may have died before symptom onset or may have late onset [1]. If the variant is not detected in either parent's leucocytes, sibling risk is slightly above the population risk because of possible germline mosaicism, estimated at approximately 5% in simplex cases [1]. If parents have not been tested but are clinically unaffected and at least 35 years old, sibling risk appears low, although not zero [1].

Predictive testing is possible when the familial variant is known and is usually performed before surveillance begins (for example, between 2 and 5 years) [6]. Since ophthalmological screening begins in the first year and certainly before 5 years, molecular testing may be considered in young children; many parents wish to know their children's genetic status before starting examinations, to avoid unnecessary procedures in a non-carrier child [1]. Educational preparation of the child and parents, a plan for communicating results and materials such as the VHL Alliance VHL Kids Handbook are recommended [1]. Prenatal diagnosis by chorionic villus sampling at 11 weeks is technically possible, although infrequently requested [6], and preimplantation genetic testing is an alternative [1]. The ideal time to discuss risk and these options is before pregnancy; preconception counselling should include possible male infertility due to epididymal cystadenomas [1]. In probands without a molecular diagnosis, storing DNA is recommended [1].

8.2 PGL/PHEO syndromes

Inheritance is autosomal dominant and most probands inherited the variant; de novo variants are rare and their proportion is unknown [3]. Age-dependent penetrance, variable expressivity and parent-of-origin effects mean that many carriers appear to be isolated cases; a negative family history is accepted only after parental assessment or testing [3]. If the variant is detected in neither parent, sibling risk is estimated at 1% because of the theoretical possibility of germline mosaicism [3].

Sources: [3, 8, 52, 54]

Applying the SDHD rule to an SDHB family would incorrectly reassure half of it, because the parent-of-origin effect does not apply to SDHB [3]. Since surveillance begins in childhood for all genes, predictive testing is offered to children and adolescents, with prior education, the opportunity for assent from older children and a results communication plan [3]. In people with a known syndrome, screening for sympathetic PGL/PHEO before conception is ideal; at minimum, it should be performed during pregnancy [3]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known, and perspectives on their use vary among professionals and families [3]. Two heterozygous carriers of variants in SDHA, SDHB or SDHD have a 25% risk in each pregnancy of offspring with recessive mitochondrial complex II deficiency [3, 50]; a couple carrying FH has a 25% risk of fumarate hydratase deficiency [56].

In France, the PNDS (French National Diagnosis and Care Protocol) places testing within the framework of article 16-10 of the Civil Code and the good practice rules of the Agence de la biomédecine and the HAS: a dedicated consultation, prior information adapted to the person's maturity and understanding, express written consent and prescription by a geneticist, by a genetic counsellor under the responsibility of a medical geneticist or by a non-geneticist physician able to interpret the result and working with a clinical genetics team [12]. The laboratory must be authorised by the Regional Health Agency and accredited, the result is validated by a professional approved by the Agence de la biomédecine and is communicated by the prescriber, at a further consultation, with a written document; the list of authorised laboratories for rare neuroendocrine tumours is maintained by the TENgen network [12]. Before testing, the prescriber informs the patient of the obligation to inform potentially affected relatives if a variant is found, explains the risks of silence and plans this communication in writing; if the patient refuses, decree no. 2013-527 applies [12]. Presymptomatic testing of a relative is carried out at an individual consultation within a multidisciplinary team; in a minor, it is possible with parental agreement when a positive result would lead to immediate preventive or curative measures. The minimum age depends on the gene, the age of the earliest lesion described and the mode of transmission, with maternal imprinting in SDHD and SDHAF2 [12]:

Source: HAS PNDS, table 3 [12]. The same PNDS also defines the ages for MEN2 and the surveillance of MEN2 and NF1. These ages are later than those in GeneReviews for VHL and for SDHA, SDHC and SDHD (section 7.12). The PNDS does not address prenatal diagnosis or preimplantation genetic testing, which in France follow the specific legal framework for those procedures.

9. Special Considerations: Population Diversity and Epidemiology

9.1 Epidemiology of VHL

VHL occurs in all studied populations. In East Anglia (United Kingdom), Maher and colleagues estimated in 1991 a heterozygote prevalence of 1.89/100 000 (1/53 000) and birth incidence of 2.73/100 000 (1/36 000), with a direct mutation rate of 4.4 × 10⁻⁶ per gene per generation and reproductive fitness of 0.83 [9]. The Danish national study, based on all known carriers, estimated a prevalence of 1/46 900 (2.13/100 000) and birth incidence of 1/27 300 (3.66/100 000) [10]. Orphanet records validated point prevalence values of 1.1/100 000 and birth prevalence of 2.3/100 000 in the United Kingdom, in addition to the Danish values [4]. The difference between birth incidence and prevalence and the proportion of missed diagnoses in Denmark (approximately 25%) indicate that prevalence values underestimate disease [10].

9.2 Founder effects and population variants

In the Black Forest, 14 German families with type 2A VHL share p.Tyr98His on a common haplotype, also observed in Pennsylvania families [47]. In the middle Volga region (Chuvashia), homozygosity for VHL p.Arg200Trp causes endemic Chuvash polycythaemia without VHL tumours [1, 48]; congenital erythrocytosis due to VHL variants is endemic in several subpopulations [1]. In PGL/PHEO syndromes, SDHAF2 c.232G>A (p.Gly78Arg) is a founder variant in the Netherlands [3]. In Brazil, in a cohort of 155 index PGL/PHEO cases at the Hospital das Clínicas of the University of São Paulo, 14.2% had pathogenic or likely pathogenic SDHB variants, and complete SDHB exon 1 deletion was the most frequent defect (8 of 22 carriers, 36%); haplotype and breakpoint analysis (15,678 bp deletion) demonstrated a common origin with the deletion described in the Iberian Peninsula, a founder effect relevant to Brazilian and Portuguese laboratories, which should include deletion and duplication analysis [66]. In Portugal, SDHB exon 1 deletion was described as a founder variant in patients with paraganglioma [67]; a 2024 review estimates that it represents 26–37% of pathogenic SDHx alleles in Portuguese patients with PGL/PHEO, also occurs in northern Spain and accounts for approximately 36% of SDHB variants in Brazil and approximately 90% in Colombia [92]. In the largest Portuguese series of patients with an SDHx variant (30 patients at the Instituto Português de Oncologia in Lisbon, diagnosed between 1986 and 2016; mean age 36.8 years), SDHB exon 1 and SDHD exon 4 deletions were the most frequent genetic findings; SDHC and SDHD carriers tended to have solitary and multiple head and neck paragangliomas, respectively, SDHB carriers had a higher risk of metastatic disease, and peptide receptor radionuclide therapy and ¹³¹I-MIBG were ineffective in this series [93]. These proportions describe reference centre patients, not population carrier frequency. In a series of 115 patients at the Federal University of São Paulo, pathogenic germline variants were found in RET (38.3%), VHL (21.3%), SDHB and NF1 (17% each) and MAX, SDHD, TMEM127 and TP53 (2.1% each), a distribution with greater RET representation than European series [94]. Brazilian VHL has had a national registry since 2023 (VHLBR, 142 patients from 62 families), with predominance of missense variants (52.6%) and large deletions (22.7%) [45], and an earlier series identified a type 2B-associated splicing variant not previously described in the germline [46].

9.3 Altitude, hypoxia and environment

There is limited evidence that penetrance of PGL/PHEO syndromes may be greater in people living at high altitude or chronically exposed to hypoxia, as in cyanotic heart disease or smoking, but insufficient to support recommendations [3]. This observation is relevant to Andean and other high-altitude populations, for which no gene-specific penetrance studies were found in the consulted sources.

9.4 Trial representativeness and data gaps

Populations in pivotal belzutifan trials were predominantly White: 90% in LITESPARK-004 (3.3% Black or African American, 1.6% Asian) and 93% in LITESPARK-015 (4.2% Black or African American, 1.4% Asian, 6% Hispanic or Latino) [22]. No population prevalence data for VHL or PGL/PHEO syndromes were found in the consulted sources for Africa, the Middle East, South Asia or Southeast Asia, nor gene-specific penetrance estimates outside European and North American cohorts. For Portugal, no population prevalence studies of VHL or hereditary PGL/PHEO syndromes were found. The closest data are from a study in the catchment area of the Braga Local Health Unit (2004–2024), identifying 85 patients with PGL/PHEO and estimating a mean annual incidence of 5.3 cases per million between 2012 and 2024, with an increasing trend; of the 61 patients tested, 20 had familial disease, diagnosed earlier (mean age 43.4 years), and metastatic disease occurred only in familial cases [95]. This incidence concerns all PGL/PHEO in one region, not hereditary syndromes, and the proportion of familial cases depends on who was tested. A Portuguese group also proposed standardised surveillance protocols for hereditary RCC syndromes, including VHL and FH-associated RCC [96]. The incidence of hereditary PGL/PHEO syndromes is not precisely known in any region; Orphanet gives a worldwide annual incidence of 1–9 per 1,000,000 (a value not yet validated) [3, 5].

In France, the PNDS (French National Diagnosis and Care Protocol) estimates the incidence of PGL/PHEO at 0.57 per 100,000 person-years (0.46 for phaeochromocytoma and 0.11 for paraganglioma), a prevalence of 0.1–0.6% among patients with hypertension and an autosomal dominant familial form in approximately 40% of patients [12]. The incidence cited comes from the international literature and not from a French registry, but it is of the same order of magnitude as that estimated in Braga (5.3 per million per year). In the French paediatric series, 77% of the children tested had a germline variant, and 92% of those who developed a new tumour site during follow-up were carriers [12].

10. Illustrative Clinical Case

10.1 VHL with retinal haemangioblastomas treated with belzutifan (published case)

A 49-year-old woman with VHL was referred by urology for ophthalmological assessment. She had a history of RCC, an aspirated pancreatic cyst and multiple cerebellar haemangioblastomas treated by resection and gamma knife radiosurgery; twenty years previously, a retinal haemangioblastoma in the left eye had been treated with laser photocoagulation, after which the patient was lost to follow-up [59]. At examination, she reported intermittent floaters; corrected visual acuity was 20/20 in both eyes. The left fundus showed a nasal yellow-orange nodular lesion of 0.138 mm², with prominent feeding vessels and laser scars, and a new peripheral inferotemporal lesion of 0.113 mm² with exudation; fluorescein angiography revealed early hyperfluorescence with late leakage, and indocyanine green angiography persistent hypercyanescent lesions (Figure 1; Figure 2) [59]. Cryotherapy had been planned, but because the urology team had started belzutifan 120 mg daily for slow growth of a right renal mass, close observation was chosen, reserving local therapy as rescue [59]. At two months, the patient had elevated transaminases (ALT 230 IU/L; AST 103 IU/L), so the dose was reduced to 80 mg daily; retinal lesions decreased to 0.082 mm² and 0.083 mm², and at four and six months reduced perfusion was observed, with feeding vessels reduced to ghost vessels, lesions of 0.082 mm² and 0.071 mm² and acuity of 20/16 (Figure 3) [59]. Renal MRI showed reduced volume of the left cystic lesion and partial response of the right solid lesion, without metastases [59].

Teaching points. The case illustrates the multisystem and lifelong nature of VHL (CNS, retina, kidney and pancreas in the same patient), the risk of loss to follow-up after treatment of an initial lesion, the ability of a single systemic drug to act on several lesions simultaneously — consistent with improvement in all evaluable eyes in LITESPARK-004 [32] — and the need to monitor adverse effects and adjust the dose according to prescribing information [22]. It also recalls that local ablation remains the reference treatment for extramacular retinal lesions and that deferring local treatment requires close ophthalmological surveillance [86].

10.2 Family with carotid body paragangliomas due to an SDHD variant (published case)

In a Chinese family of 15 members across three generations, a 31-year-old man (II-4) was diagnosed with a left parotid tumour and right carotid body tumour; his father and eldest sister had right carotid body tumours and his third sister had bilateral tumours [63]. Exome sequencing, confirmed by Sanger sequencing, identified the nonsense SDHD variant c.64C>T (p.Arg22Ter) in the proband and three affected relatives. Counselling of the third generation identified only one carrier child (III-4), the daughter of the third sister [63].

Teaching points. The pattern — often bilateral or multifocal head and neck tumours in several siblings of an affected father — is typical of SDHD with paternal transmission [3]. The carrier child inherited the variant from her mother; according to the model of somatic loss of maternal chromosome 11, her tumour risk is usually low, but not zero, and predictive testing in these situations may be deferred until 18 years; later, if this person is male and transmits the variant, carrier children will have high risk; if female, carrier children will generally have low risk [3, 51, 54]. In paternal-line carriers, surveillance includes annual clinical assessment from 6–15 years, metanephrines and whole-body MRI every 2 or 3 years, remembering that SDHD tumours are often non-secretory and normal biochemistry does not remove the need for imaging [3, 19]. Before any carotid surgery, catecholamine excess must be excluded, as it would indicate a second primary [3].

11. Prognosis and Long-Term Follow-Up

11.1 VHL

The most frequent causes of death are RCC and CNS haemangioblastomas [6]; haemangioblastomas remain the leading cause of death, although survival has improved [1]. Life expectancy has increased by more than 16 years since 1990 with improved surveillance guidelines [1, 70]. RCC survival is associated with tumour size and age [1]. Morbidity accumulates over time: visual loss, neurological deficits after CNS or spinal cord surgery, hearing loss due to ELST, renal insufficiency after repeated nephrectomies and adrenal insufficiency after adrenalectomies, justifying organ-sparing strategies (nephron-sparing surgery, percutaneous ablation, cortical-sparing adrenalectomy) and, where applicable, systemic belzutifan therapy [1, 6]. Follow-up is lifelong, in a multidisciplinary centre, with care coordination and psychosocial support [1, 65]. In the European Union, VHL and hereditary PGL/PHEO syndrome fall within ERN GENTURIS (thematic group 4), and genetic endocrine tumour syndromes within Endo-ERN, whose providers may be consulted for referral and discussion of complex cases; metastatic disease may also be discussed at EURACAN centres [26–28]. ClinGen classifies VHL as strongly actionable in adults and moderately actionable in children, without making paediatric surveillance optional, as it begins in the first year of life [1, 25].

11.2 PGL/PHEO syndromes

Non-metastatic PGL/PHEO may be cured by surgery; once metastases are established, there is no cure and five-year survival is 50–69%, although some patients live for more than 20 years with sequential treatment [3]. SDHB is the gene with the worst prognosis because of metastatic risk of 24–58% [3, 13]; SDHD has multifocal but indolent disease, with metastatic risk below 5% [3]. Since primary tumour histopathology does not reliably predict metastasis, postoperative follow-up is lifelong, with postoperative metanephrines at 2–8 weeks and periodic biochemical and imaging surveillance [3, 16]. In LITESPARK-015, overall survival at 24 months with belzutifan in advanced disease was 76% [24]. ClinGen classifies PGL1–5 syndromes and phaeochromocytoma as strongly actionable in adults and SDHA as moderately actionable, without a paediatric assertion [25]. In FH tumour predisposition syndrome, prognosis depends on RCC stage, justifying renal MRI surveillance from childhood [56].

11.3 Follow-up according to the French PNDS

The PNDS (French National Diagnosis and Care Protocol) considers long-term follow-up indispensable after any PGL/PHEO, because excision may be incomplete, another tumour or metastases may be present, some patients are not operated on (excessive surgical risk or non-secreting paraganglioma under surveillance) and, even in remission, a risk of local or metastatic recurrence or of a new tumour persists [12]. In a systematic review, recurrence was 1 per 100 person-years, and a retrospective cohort estimated approximately 2 per 100 person-years; the data support follow-up during the first 10 years, after which studies include few patients, and most centres maintain lifelong follow-up [12]. No study has compared hormonal or imaging strategies or different intervals. The patient is informed, at the first postoperative assessment, that the metastatic risk persists and that the genetic test result, often still pending, may change follow-up [12]. Criteria for a high risk of malignancy are a variant in SDHB (or, more rarely, in FH or SLC25A11), positive markers 3–6 months after surgery, extra-adrenal location outside the head and neck and a size greater than 5 cm in the specimen; in these patients, surveillance is decided at a multidisciplinary meeting, for example with MRI at 5 years after a phaeochromocytoma larger than 5 cm [12]. In patients with a tumour present or metastases, the frequency depends on metanephrines, location and size, and is decided at a multidisciplinary meeting. In syndromic forms, or where there are sequelae, medical and psychosocial support may be offered [12].

Source: HAS PNDS, chapter XIV and table 12 [12]. The PNDS does not set schedules for SDHAF2, TMEM127, MAX and FH, which follow the table in section 7.7.

Organisation of care in France. The PNDS directs diagnostic confirmation and management to the reference centre for rare adrenal diseases—coordinating site at Cochin Hospital and constituent site at the hypertension unit of the Georges Pompidou European Hospital, in Paris—and to the 31 competence centres accredited in September 2021, distributed across the country, including Réunion, and linked within the FIRENDO rare endocrine diseases network (filière) [12]. Metastatic disease is referred to the national expert centre for rare adrenal cancers (ENDOCAN-COMETE), pathology review to the centres of the ENDOCAN network and genetic testing to the laboratories of the TENgen network [12]. The PNDS serves as a reference for the attending physician for the care protocol and for the application for exemption from patient co-payment as a long-term condition not on the official list (ALD hors liste), and notes that plasma free metanephrines were not included in the nomenclature of laboratory procedures in 2021 (cost of approximately 40 euros to the patient) [12]. Transition from paediatric to adult services is organised with transition consultations and multidisciplinary meetings in the reference and competence centres, and the associations VHL France and Association Surrénales support the communication of the diagnosis, publicise the centres and the therapeutic education workshops and reinforce continuity of annual follow-up in an expert centre [12]. This national network coexists with ERN GENTURIS and Endo-ERN, which French centres can call on for complex cases [26, 27].

12. Summary and Final Considerations

Von Hippel-Lindau syndrome and hereditary paraganglioma-phaeochromocytoma syndromes are clinical expressions of the same failure: the cell's inability to recognise that it has sufficient oxygen. In VHL, biallelic VHL loss stabilises HIF and produces retinal and CNS haemangioblastomas, clear cell RCC, renal and pancreatic cysts, pNETs, phaeochromocytomas, ELSTs and epididymal and broad ligament cystadenomas, with penetrance approaching 100% at 65 years. Classification into types 1, 2A, 2B and 2C organises phaeochromocytoma and RCC risk, but does not replace complete surveillance of each patient. Diagnosis rests on Danish or Dutch criteria and VHL testing with intron 1 and deletion analysis, remembering mosaicism. Surveillance according to the VHL Alliance protocol — retina from the first year, metanephrines from 5 years, craniospinal MRI from 11 and abdominal MRI from 15 years, audiology and inner ear MRI — and organ-sparing treatment have increased life expectancy by more than 16 years. Belzutifan (Welireg®), 120 mg once daily, inaugurated systemic therapy targeting the mechanism, with responses in the kidney, pancreas, CNS and retina, at the cost of anaemia, hypoxia and embryofetal toxicity requiring monitoring; evidence continues to come from a single-arm trial, explaining the conditional nature of European authorisation and the more restrictive European prescribing criterion.

In PGL/PHEO syndromes, the rule is to test all patients because 35–40% of tumours are hereditary and many carriers appear to be isolated cases. Each gene has its own profile: SDHB with sympathetic paragangliomas and the highest metastatic risk; SDHD and SDHAF2 with multifocal head and neck paragangliomas and almost exclusive expression after paternal transmission; SDHC and SDHA with low penetrance, which in incidental SDHA findings argues against surveillance; TMEM127 and MAX with often bilateral phaeochromocytomas; FH with aggressive RCC and PGL/PHEO in specific variants. Surveillance using metanephrines and whole-body MRI starts in childhood, preoperative preparation with alpha-adrenergic blockade is mandatory in secretory tumours, and counselling must integrate parent-of-origin effects, recessive risks of mitochondrial disease and founder effects such as the Iberian SDHB exon 1 deletion in Brazil. Therapy for metastatic disease is evolving with belzutifan approved in the USA (but not the European Union) for advanced PPGL, sunitinib, the only drug with benefit in a randomised trial but without a PPGL indication, and radiopharmaceuticals still off-label, in a field where data gaps outside Europe and North America remain relevant.

The 2021 French PNDS (French National Diagnosis and Care Protocol) adds a preoperative protocol with doses of prazosin, urapidil and metirosine, rules for anaesthesia and surgical technique, the choice of radiopharmaceutical by genotype (¹⁸F-FDOPA in VHL), the particularities of pregnancy and paediatric age, and a surveillance schedule that starts later than the North American one for VHL and for SDHA, SDHC and SDHD; in these divergences, the ocular start in the first year of life, from the specific 2024 consensus, remains the reference [12].

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