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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 (PCC) and paragangliomas (PGL) are rare neuroendocrine tumours arising from the adrenal medulla and the sympathetic/parasympathetic ganglia respectively.

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

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

Gene locus and structure

Constitutional variants of specific genes are principally associated with PPGL predisposition. These include a number of genes that encode for subunit of Succinate Dehydrogenase (SDH):

  • SDHA, which encodes a core subunit of SDH.
  • SDHAF2, which encodes a mitochondrial assembly factor.
  • SDHB, which encodes a core subunit of SDH.
  • SDHC, which encodes an integral membrane protein subunit of SDH.
  • SDHD, which encodes an integral membrane protein subunit of SDH.

Other genes in which variants are associated with PPGL susceptibility include:

  • MAX, which encodes a leucine zipper type transcription factor and a member of the MYC/MAX/MXD proteins network; and
  • TMEM27, which encodes a negative regulator of the mTOR pathway.

Note that a number of other candidate PPGL susceptibility genes have been described in the literature, including DLST, MDH2 and SLC25A11 but these account for a small minority of patients affected by hereditary PPGL. Testing of these three genes are not currently recommended (following update of the recommended panel, August 2024), until further data is generated regarding associated penetrance and phenotype.

Table 1: Clinical features seen in hereditary PPGL

Gene name Proportion of PPGL caused by germline variants (see table footnote 1) Penetrance in non-probands of PPGL (see table footnote 2) Disease pattern (localisation) Multiple PPGL (see table footnote 3) Other associated tumours
SDHA less than 5% less than 10% PGL more often than PCC less than 5% Wild type GIST, RCC and, rarely, neuroblastoma and pituitary adenoma
SDHAF2 less than 1% 5% Head and neck PGL 75% Not reported
SDHB 10% 20%–30% Thoracic and abdominal PPGL more common than head and neck PGL 20% Wild type GIST, RCC and, rarely, pituitary adenoma
SDHC 1% 10%–25% Head and neck, thoracic PGL 30% Wild type GIST
SDHD 9% 40%–50% Predominantly head and neck PGL 66% Wild type GIST and, rarely, papillary thyroid cancer
MAX 1% 30%–50% Predominantly PCC or abdominal PGL 50% Not reported
TMEM127 1%–2% 30%–40% Predominantly PCC about 33% RCC

All PGL have metastatic potential, but it is rare for PPGL to metastasise apart from SHDB-associated disease, where metastases are reported in up to 40% cases.

  • Table footnote 1: The proportion of PPGL caused by a germline variant in a particular gene is based on data from Buffet and others (see Resources for clinicians).
  • Table footnote 2: The penetrance of PPGL in non-probands come from estimates in the publications by Andrews and others, Buffet and others, and Toledo and others (see Resources for clinicians). Best estimates are based on current literature, and for some of the rarer PPGL predisposition genes, the penetrance may well be lower than that quoted as penetrance estimates to date may represent an overestimation due to selection bias.
  • Table footnote 3: The multiple PPGL percentages are taken from the publications by Buffet and others and Armaiz-Pena and others (see Resources for clinicians).

Pathogenic variant spectrum

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

Some genotype-phenotype correlations have been described. For example, the phenotype associated with the recurrent variant SDHD: c.242C>T (p.Pro81Leu) is considered distinct from that of other SDHD variants, with risk limited almost exclusively to head and neck PGL. Due to the number of genes associated with hereditary PPGL, not all reported correlations have been listed here.

Disease associations

Rare syndromic causes of PPGL

PPGL can also occur as a feature of other broader cancer predisposition syndromes:

  • Von Hippel Lindau (VHL) disease is an autosomal dominant tumour predisposition condition in which approximately 25% of patients develop PPGL, predominantly those with missense mutations in the VHL gene.
  • Neurofibromatosis type 1 (NF1) is 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 40s. A proportion of these will be bilateral and metastatic.
  • Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant condition called by gain of function mutations in the RET proto-oncogene. PCC occurs in up to 50% of patients with MEN2A and MEN2B. Age of onset is often in the 30s. Around two thirds of patients develop bilateral disease.
  • Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition caused by constitutional FH variants, associated with kidney cancer predisposition and cutaneous/uterine leiomyoma. PPGL are a rarely described manifestation (reported in less than 1% cases).

Genomic testing

Constitutional (germline) testing of the hereditary PPGL genes is offered as part of the following multigene panels in the National Genomic Test Directory, under indication codes:

  • R223 Inherited phaeochromocytoma and paraganglioma excluding NF1. Testing of the affected individual may be offered where the patient fulfils ONE of the following criteria:
    • PCC diagnosed before age 60 years; or
    • PGL (at any age); or
    • PCC/PGL with loss of staining for SDH proteins on immunohistochemistry; or
    • bilateral PCC (at any age); or
    • dual primary PCC AND renal cell carcinoma (at any age); or
    • PCC/PGL (at any age) and at least one first-, second- or third-degree relative with PCC/PGL, renal cell cancer (at any age) or gastrointestinal stromal tumour.
  • R363 Inherited predisposition to GIST. This code should be used where gastrointestinal stromal tumour (GIST) is a prominent cancer type in the family. Testing of an affected individual is recommended if they have one of the following:
    • GIST diagnosed before 50 years of age; or
    • GIST with and at least one first-, second- or third-degree relative with GIST or PPGL.

Genomic counselling

  • First-degree relatives of a carrier of a constitutional pathogenic genetic variant have a 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 a disease associated with hereditary PPGL increases with age. The risk of developing a tumour in children younger than 18 years of age, even in those with a constitutional variant in the PPGL genes, is generally low. A small number of SDHB and SDHD-related PGLs have been reported to occur before age 10 and before age 16 years respectively. Children who carry a constitutional SDHB variant have a higher risk of developing a metastatic PGL than children with constitutional variants in the other SDHx genes. The age at which predictive testing and surveillance is offered for children is tailored to the paediatric risk.
  • Referral to clinical genetics 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

Carriers of pathogenic or likely pathogenic variants should have surveillance arranged through a clinical genetics service, endocrinologist or, if available , an MDT clinic. For abdominal imaging, MRI is the preferred imaging modality as it is radiation sparing. A CT-scan may be required in some instances if MRI is not tolerated or an MRI cannot be obtained.

Recommended surveillance for carriers of constitutional variants in different genes associated with PCC/PGL risk depend on the gene in which the variant has been identified, and may be influenced by personal/family history and parent from which variant has been inherited. Recommended screening for carriers of variants most commonly associated with PGL/PCC risk is outlined here below.

Carriers of pathogenic variants in SDHB

  • an annual clinical review and biochemistry from age 5 years;
  • abdominal imaging (MRI preferred) from age 10 years, and if normal every 12 to 24 months; and
  • MRI/CT neck, thorax from age 10 years, and if normal every 3 years.

Carriers of pathogenic variants in SDHC or paternally inherited pathogenic variants in SDHD

  • an annual clinical review and biochemistry from age 10 years; and
  • abdominal imaging (MRI preferred) and MRI/CT neck, thorax from age 15 years and if normal every 3 years.

Carriers of paternally inherited pathogenic variants in SDHAF2

  • an annual clinical review and biochemistry from age 16.
    • abdominal imaging from age 16–18 years and if normal every 3 years; and
    • MRI of neck, thorax at baseline and if normal every 5 years.

Carriers of pathogenic variants in SDHA

  • Screening in carriers of constitutional pathogenic variants in SDHA depends on the manner in which the variant was ascertained.
  • For patients with a personal or family history of an SDHA-associated tumour (e.g. wild type GIST, PCC/PGL, SDHx-deficient tumour):
    • an annual clinical review and biochemistry; and
    • abdominal imaging and MRI/CT neck, thorax at baseline or from age 15 years and if normal every 3 to 5 years.
  • This screening is not recommended for carriers of constitutional pathogenic variants in SDHA that do not have a personal or family history of SHDA-associated tumours, as the penetrance associated with variants picked up in this scenario is very low.

Carriers of pathogenic variants in TMEM127 or paternally inherited pathogenic variants in MAX

  • an annual clinical review and biochemistry from age 16 years;
  • abdominal imaging (MRI preferred) from age 16–18 years and if normal every 3 years; and
  • MRI of neck, thorax from age 16–18 years and if normal every 5 years.

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

  • For all patients with elevated norepinephrine or metanephrine, the recommendation is to offer a preoperative pharmaceutical ‘blockade’, regardless of symptoms.
  • Surgery is the preferred therapy for localised, sympathetic PPGL. Treatment of parasympathetic PPGL is more difficult, as there is less benefit from a curative surgical approach. This must be balanced against potentially adverse treatment-related morbidities, for example, of the cranial nerves in vagal and jugular PGL. Since SDHB-related head and neck PGL are associated with a higher risk of metastatic disease, it can be discussed whether a more aggressive surgical approach would be preferable.
  • Other treatment options for a localised disease may include external beam radiation or watchful waiting.
  • Metastatic disease is currently treated according to guidelines for management of sporadic PCC and PGL.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genetic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one parent is a carrier of a pathogenic variant or likely pathogenic 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, or natural conception and pregnancy with testing of children later in life.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 18/06/2024
  • Next review due: 18/06/2026
  • Authors: Dr Ruth Casey, Dr Claire Forde
  • Reviewers: Dr Fiona Lalloo, Dr Terri McVeigh