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Conditions

Inherited phaeochromocytoma and paraganglioma

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours that arise from the adrenal medulla and the sympathetic or parasympathetic ganglia respectively.

Overview

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours that arise from the adrenal medulla and the sympathetic or parasympathetic ganglia respectively.

It is estimated that up to 30%–40% of phaeochromocytoma and paraganglioma (PPGL) cases are secondary to a constitutional (germline) variant in one of more than 20 reported susceptibility genes. Approximately half of these are attributable to variants in one of the succinate dehydrogenase (SDHx) genes, which encode the different subunits and assembly proteins of the mitochondrial enzyme succinate dehydrogenase.

Hereditary PPGL should be strongly suspected in an individual with multiple, multifocal, recurrent, metastatic or early-onset paraganglioma or phaeochromocytoma and/or a family history of paraganglioma or phaeochromocytoma.

Genes, loci and function

See table 1 for a list of genes in which constitutional (germline) variants are principally associated with PPGL predisposition.

Table 1: Genes in which constitutional (germline) variants are associated with PPGL predisposition

Gene Locus Function
SDHA 5p15.33 Core subunit of SDH
SDHAF2 11q13.1 Mitochondrial assembly factor
SDHB 1p36.13 Core subunit of SDH
SDHC 1q23.3 Integral membrane protein subunit of SDH
SDHD 11q23.1 Integral membrane protein subunit o SDH
MAX 14q23.3 Encodes a leucine zipper-type transcription factor and a member of the MYC/MAX/MXD proteins network
TMEM27 2q11.2 Negative regulator of the mammalian target of rapamycin (mTOR) pathway

A number of other associated genes have been identified, including DLST, MDH2 and SLC25A11, but these account for a very small minority of patients affected by hereditary PPGL. PPGL can also occur as a feature of other genetic tumour predisposition conditions (see below).

Mutational spectrum

Constitutional (germline) inactivating variants in the above listed genes lead to PPGL predisposition. The majority of variants accounting for hereditary PPGL occur in SDHB and SDHD. The clinical features section below provides more details about the expected clinical picture according to genotype.

Some genotype-phenotype correlations have been described – for example, individuals with constitutional (germline) SDHB variants are at higher risk of developing malignant PPGL.

Genomic testing

Constitutional (germline) testing of the hereditary phaeochromocytoma and/or paraganglioma genes is offered as part of the following multigene panels in the National Genomic Test Directory.

  • R223 Inherited phaeochromocytoma and paraganglioma excluding NF1.
    • This involves testing of the individual (proband) affected with cancer (regardless of whether they have a family history) where the individual meets one of the following criteria:
      • phaeochromocytoma at under 60 years of age;
      • any paraganglioma at any age;
      • phaeochromocytoma or paraganglioma with loss of staining for SDH proteins on immunohistochemistry screening;
      • bilateral phaeochromocytoma at any age;
      • phaeochromocytoma and renal cell carcinoma at any age; or
      • phaeochromocytoma or paraganglioma at any age and one or more first-, second- or third-degree relatives with phaeochromocytoma, paraganglioma or renal cell cancer at any age, or a gastrointestinal stromal tumour (GIST).
  • R363 Inherited predisposition to GIST. This should be used if GIST is a prominent cancer type in the family.
    • This involves testing of the affected proband (regardless of whether they have a family history) where the individual meets the following criteria:
      • GIST diagnosed below 50 years of age; or
      • GIST with one or more first-, second- or third-degree relatives with GIST, phaeochromocytoma or paraganglioma.

Clinical features

Table 2 summarises the clinical features seen in PPGL according to genotype.

Table 2: Clinical features of PPGL according to genotype

Gene Proportion of PPGL caused by constitutional (germline) variants Penetrance in non-probands of PPGL Disease pattern (localisation) Multiple PPGL Malignant PPGL Other associated tumours
SDHA Less than 5% Less than 10% Predominantly PGL, though sometimes PCC Less than 5% Rare Wild-type GIST, renal cell carcinoma (RCC), rarely neuroblastoma and pituitary adenoma
SDHAF2 Less than 1% 5% Head and neck PGL 75% Rare Not reported
SDHB 10% 20%–30% Predominantly thoracic and abdominal PPGL, sometimes head and neck PGL 20% Yes – up to 40% Wild-type GIST, RCC, rarely pituitary adenoma
SDHC 1% 10%–25% Head and neck, thoracic PGL 30% Rare Wild-type GIST, rarely RCC
SDHD 9% 40%–50% Predominantly head and neck PGL 66% Rare Wild-type GIST
MAX 1% 30%–50% Predominantly PCC or abdominal PGL 50% Rare Not reported
TMEM127 1%–2% 30%–40% Predominantly PCC Around 33% Rare RCC

Note: Sources for the information in this table can be found in the references section below. Best estimates are based on current literature, and for some of the rarer PPGL predisposition genes, the penetrance may well be lower than the figure quoted. Penetrance estimates in older scientific publications likely represent an overestimation due to selection bias.

Inheritance and genomic counselling

  • Constitutional (germline) variants in the hereditary PPGL genes listed above are inherited in an autosomal dominant pattern.
  • First-degree relatives of a carrier of a pathogenic variant in one of these genes are at 50% risk of carrying the familial variant.
  • Due to the parent-of-origin effect, only patients with paternally inherited SDHAF2, SDHD or MAX pathogenic variants require clinical evaluation, biochemical testing and radiological imaging.
  • Penetrance of disease associated with hereditary PPGL increases with age. The risk of developing a tumour in childhood (under 18 years of age), even in those with a constitutional (germline) variant in the PPGL genes, is generally low. A small number of SDHB and SDHD-related paragangliomas have been reported to occur below 10 and 16 years of age respectively. Children with an SDHB variant have a higher risk of developing a metastatic paraganglioma than children with variants in the other SDHx genes. The age at which predictive testing and surveillance is offered for children is tailored to the paediatric risk (see below).
  • Referral to a clinical genetics service should be arranged for newly identified carriers of pathogenic or likely pathogenic variants to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Risk-reducing strategies and management of associated features

Carriers of likely pathogenic or pathogenic variants should have surveillance arranged through a clinical genetics service, endocrinologist or multidisciplinary team clinic, if available. Table 3 lists the recommended surveillance according to genotype (as per UKCGG expert consensus guidelines).

Table 3: Recommended surveillance of affected individuals according to genotype

Gene Recommended surveillance
SDHA
  • Annual clinical review and biochemistry
  • Abdominal imaging* and MRI/CT neck, thorax at baseline and, if normal, every three to five years
SDHAF2**
  • Screening should only be offered to patients who have a paternally inherited SDHAF2 variant
  • Annual clinical review and biochemistry
  • Abdominal imaging* at baseline and, if normal, every three years
  • MRI of neck, thorax at baseline and, if normal, every five years
SDHB
  • Annual clinical review and biochemistry
  • Abdominal imaging* at baseline and, if normal, every 12 to 24 months
  • MRI/CT neck, thorax at baseline and, if normal, every three years
SDHC
  • Annual clinical review and biochemistry
  • Abdominal imaging* and MRI/CT neck, thorax at baseline and, if normal, every three years
SDHD
  • Screening should only be offered to patients who have a paternally inherited SDHD variant
  • Annual clinical review and biochemistry
  • Abdominal imaging* and MRI/CT neck, thorax at baseline and, if normal, every three years
MAX**
  • Screening should only be offered to patients who have a paternally inherited MAX variant
  • Annual clinical review and biochemistry
  • Abdominal imaging* at baseline and, if normal, every three years
  • MRI of neck, thorax at baseline and, if normal, every five years
TMEM127**
  • Annual clinical review and biochemistry
  • Abdominal imaging* at baseline and, if normal, every three years
  • MRI of neck, thorax at baseline and, if normal, every five years

* MRI is the preferred imaging modality because it is radiation sparing, but CT may be required in some instances – for example, if MRI is not tolerated or if MRI cannot be obtained.

** Less information is available about the penetrance of these genes, and surveillance protocols may differ in the future as more information becomes available.

PGL and PCC identified through surveillance should generally be treated in the same way as those in the general population, and will often require a multidisciplinary approach.

  • For all patients with elevated norepinephrine or metanephrine, the recommendation is to offer preoperative pharmaceutical ‘blockade’, regardless of symptoms.
  • Surgery is the preferred therapy for localised, sympathetic PPGL. Treatment of parasympathetic PPGL is more difficult because there is less benefit to be gained from a curative surgical approach, which must be balanced against potentially adverse treatment-related morbidities (such as to the cranial nerves in vagal and jugular PGL). As SDHB-related head and neck PGL are associated with a higher risk of metastatic disease, a more aggressive surgical approach can be discussed in these cases.
  • The patient’s genotype can help predict the risk of bilateral phaeochromocytoma or synchronous tumours (both adrenal and extra adrenal), as well as the malignancy risk, and should be used to inform surgical approaches, long-term surveillance and management strategies at multidisciplinary meetings.
  • Around 10%–20% of patients with PPGL will develop malignant disease, with the highest risk seen in patients with constitutional (germline) pathogenic SDHB variants. After surgical resection, effective treatment options are limited and are aimed at controlling both tumour proliferation and tumour secretion of catecholamines.
  • Other treatment options for localised disease in the head and neck include external beam radiation, stereotactic radiotherapy and watchful waiting.
  • Metastatic disease is currently treated according to guidelines for management of sporadic PCC and PGL.

Family planning implications

The Human Fertilisation & Embryology Authority has approved the use of pre-implantation genetic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis) for couples in whom one parent is a carrier of a likely pathogenic or pathogenic variant in one of the hereditary PPGL genes. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation and natural conception and pregnancy with testing of children later in life.

Other genetic conditions associated with PGLs and PCCs

  • Von Hippel Lindau disease: An autosomal dominant tumour predisposition condition in which approximately 25% of patients develop PPGL, predominantly those with missense variants in the VHL gene.
  • Neurofibromatosis type 1: An autosomal dominant condition caused by loss-of-function variants in the NF1 gene, predominantly characterised by a predisposition to neurofibroma. PPGL occurs in up to 5% of cases (most commonly PCC), often in the patient’s 40s. A proportion of these will be bilateral and metastatic.
  • Multiple endocrine neoplasia type 2 (MEN2): An autosomal dominant condition caused by gain-of-function variants in the RET proto-oncogene. PCC occurs in up to 50% of patients with MEN2A and MEN2B, often in patients’ 30s. Around two thirds of patients develop bilateral disease.
  • Hereditary leiomyomatosis and renal cell cancer: An autosomal dominant condition caused by constitutional (germline) variants in the FH gene, associated with kidney cancer predisposition and cutaneous or uterine leiomyoma. PPGLs are rarely described as a manifestation (less than 1% of cases).

Resources

For clinicians

References:

For patients

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  • Last reviewed: 23/03/2023
  • Next review due: 23/03/2025
  • Authors: Dr Ruth Casey, Dr Claire Forde
  • Reviewers: Dr Fiona Lalloo, Dr Terri McVeigh