Study reference

Study characteristics

Patient characteristics

Prognostic factor(s)

Follow-up

Outcome measures and effect size

Comments

Abermil et al. 2012

Type of study:

Observation Cohort

Setting: University Medical Center

Country: France

Source of funding: not applicable

Inclusion criteria:

patients with paraganglioma or pheochromocytoma and TMEM127 gene

Exclusion criteria:

No TMEM127 gene

N= 642 patients

Mean age ± SD: 41.6 Range 28-56

Sex: 4 M / 2 F

Describe prognostic factor(s) and method of measurement:

TMEM127 mutation

Endpoint of follow-up:

Not applicable

For how many participants were no complete outcome data available?

N (%): 6

Reasons for incomplete outcome data described?

Other study set-up

Outcome measures and effect size:

six mutations (0.9%) were identified. Three of them at young age at diagnosis, bilateral PCC, or family history. The three others with an apparently sporadic presentation.

Boedeker, 2005

Type of study:

Diagnostic study

Setting: University medical Centre

Country: Germany

Source of funding: None reported

Inclusion criteria: Patients with SDHD mutations.

Exclusion criteria: No SDHD mutation

N= 10

Mean age ± SD: 36 (range 33-46)

Other important characteristics (confounders and effect modifiers):

Describe prognostic factor(s) and method of measurement:

SDHD tumor presence

For how many participants were no complete outcome data available?

N (%): 0

Reasons for incomplete outcome data described?

Not applicable.

Outcome measures and effect size (include 95%CI and p-value if available):

HNPGL presence (100%)

Bordeau et al. 2016

Type of study:

Diagnostiek study

Setting: University medical Centre

Country: France

Source of funding: None reported

Inclusion criteria: Patients with SDHC mutations.

Exclusion criteria: No SDHD mutation

N= 29

Mean age ± SD: 42 (range 23-81)

Other important characteristics (confounders and effect modifiers):

Describe prognostic factor(s) and method of measurement:

SDHC mutation presence

For how many participants were no complete outcome data available?

N (%): 0

Reasons for incomplete outcome data described?

Not applicable.

Outcome measures and effect size (include 95%CI and p-value if available):

Thirteen of 29 patients (44.8%) carried a germline mutation. The same heterozygous nonsense mutation at codon 133 of exon 5 of the SDHC gene (c.397C>T, p.[Arg133Ter]) was found in nine patients, representing 69.2% of the patients having a germline mutation. Seventy percent of these patients had head and neck PGLs. Twenty percent had multiple and 30% had malignant PGLs.

Burnichon et al. 2012

Type of study:

Diagnostiek study

Setting: University medical Centre

Country: France

Source of funding: None reported

Inclusion criteria: Patients with paraganglioma

Exclusion criteria: No parganglioma

N= 1694

Other important characteristics (confounders and effect modifiers): Selected cohort.

Describe prognostic factor(s) and method of measurement:

SDHC mutation presence

MAX related tumor growth

For how many participants were no complete outcome data available?

N (%): 0

Reasons for incomplete outcome data described?

Not applicable.

Outcome measures and effect size (include 95%CI and p-value if available):

Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P <0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine.

Burnichon, 2009

Type of study:

Diagnostiek study

Setting: University medical Centre

Country: France

Source of funding: None reported

Inclusion criteria: Patients with paraganglioma

Exclusion criteria: No parganglioma

N= 445

Other important characteristics (confounders and effect modifiers): Selected cohort.

Describe prognostic factor(s) and method of measurement:

SDHC mutation presence

SDH(x) related tumor growth

For how many participants were no complete outcome data available?

N (%): 0

Reasons for incomplete outcome data described?

Not applicable.

Outcome measures and effect size (include 95%CI and p-value if available):

A large variety of SDH germline mutations were found by direct sequencing in 220 patients and by QMPSF and MLPA in 22 patients (9.1%): 130 in SDHD, 96 in SDHB, and 16 in SDHC. Mutation carriers were younger and more frequently had multiple or malignant paraganglioma than patients without mutations. A head and neck paraganglioma was present in 97.7% of the SDHD and 87.5% of the SDHC mutation carriers, but in only 42.7% of the SDHB carriers. A thoracic-abdominal or pelvic location was present in 63.5% of the SDHB, 16.1% of the SDHD, and in 12.5% of the SDHC mutation carriers. Multiple paragangliomas were diagnosed in 66.9% of the SDHD mutation carriers. A malignant paraganglioma was documented in 37.5% of the SDHB, 3.1% of the SDHD, and none of the SDHC mutation carriers.

DeAngelis et al. 1987

Type of study: Case report

Setting: University Medical Cetner

Country: ?

Source of funding: ?

Inclusion criteria: Patients suffering NF tumors

Exclusion criteria: No NF mutation

N= 1

Describe prognostic factor(s) and method of measurement:

Neurofibromatosis

Endpoint of follow-up: n.a.

For how many participants were no complete outcome data available?

N (%): 1 (100%)

Outcome measures and effect size (include 95%CI and p-value if available):

A pheochromocytoma, a glomus jugulare tumor, and multiple pulmonary paragangliomas were found in a patient with neurofibromatosis.

Ercolino et al. 2008

Type of study: Case report

Setting: University Medical Cetner

Country: ?

Source of funding: ?

Inclusion criteria: Patients suffering NF tumors

Exclusion criteria: No NF mutation

N= 1

Describe prognostic factor(s) and method of measurement:

Neurofibromatosis

Endpoint of follow-up: n.a.

For how many participants were no complete outcome data available?

N (%): 1 (100%)

Outcome measures and effect size (include 95%CI and p-value if available):

A pheochromocytoma, a glomus jugulare tumor, and multiple pulmonary paragangliomas were found in a patient with neurofibromatosis.

Gross et al. 1996

Type of study: Cohort description

Setting: University Medical Cetner

Country: Israel

Source of funding: ?

Inclusion criteria: Patients suffering VHL disease

Exclusion criteria: No pheo/PGL disease

N= 7

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up: n.a.

For how many participants were no complete outcome data available?

N (%): 1 (100%)

Outcome measures and effect size (include 95%CI and p-value if available):

Seven subjects of generations I and II had pheochromocytoma, in five of seven, the tumors were both adrenal and extaadrenal. One also had a carotid body chemodectoma and one had a malignant adrenal tumor and abdominal paraganglioma. In patients with chemodectoma, a cerebellar hemangioblastomea came manifest. Referring to VHL.

Havekes, 2009

Type of study: Cohort description

Setting: University Medical Cetnter

Country: Netherlands

Source of funding: ?

Inclusion criteria: Patients suffering SDHD related disease

Exclusion criteria: No SDHD mutation

N= 28

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients.

Hensen , 2010

Type of study: Cohort description

Setting: University Medical Cetner

Country: Netherlands

Source of funding: ?

Inclusion criteria: Patients suffering SDHD related disease

Exclusion criteria: No SDHD mutation

N= 243

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

The risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases.

Hensen, 2011

Type of study: Cohort description

Setting: University Medical Cetner

Country: Netherlands

Source of funding: ?

Inclusion criteria: Patients suffering SDHD related disease

Exclusion criteria: No SDHD mutation

N= 236

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate.

Kennedy et al. 1986

Type of study: Case report

Setting: University Medical Cetner

Country: USA

Source of funding: ?

Inclusion criteria: Patients suffering MEN syndrome

Exclusion criteria: Other than MEN ithinl

N= 1

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Carotid body paraganglioma in patiënt with MEN syndrome.

Korpershoek et al. 2011

Type of study: Cohort description

Setting: University Medical Center

Country: Netherlands

Source of funding: ?

Inclusion criteria: Patients suffering SDHA syndrome

Exclusion criteria: Other than SDHA ithinl

N= 6

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations

Kunst et al. 2011

Type of study: Cohort description

Setting: University Medical Center

Country: Netherlands

Source of funding: ?

Inclusion criteria: Patients suffering SDHAF2 syndrome

Exclusion criteria: Other than SDHAF2 syndroma

N= 6

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies.

López-Jiménez et al. 2008

Type of study: Cohort description

Setting: University Medical Center

Country: Spain

Source of funding: ?

Inclusion criteria: Patients suffering SDHAF2 syndrome

Exclusion criteria: Other than SDHAF2 syndroma

N= 6

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

A new mutation (c.256–257insTTT) affecting the SDHC gene in a 60‐year‐old‐patient with a single head and neck paraganglioma, and without familial antecedents of the disease. Control population analyses did not detect this variant but revealed a novel SDHC polymorphism that exhibited a frequency of 0·3% (3/1020).

Millar et al. 2014

Type of study: Case report

Setting: University Medical Center

Country: Canada

Source of funding: ?

Inclusion criteria: Patients suffering SDHC syndrome

Exclusion criteria: Other than SDHC ithinl

N=1

Describe prognostic factor(s) and method of measurement:

Mutation ithinl

Endpoint of follow-up: n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

We report the first case of a functional cardiac paraganglioma associated with an intronic frameshift SDHC gene mutation.

Neumann et al. 2009

Type of study: Cohort ithinling

Setting: University Medical Center

Country: Germany

Source of funding:?

Inclusion criteria: Patients suffering SDHD/B

Exclusion criteria: Not suffering SDHD/B

N=598

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5).

Neumann et al. 2011

Type of study: Cohort ithinling

Setting: University Medical Center

Country: Germany

Source of funding:?

Inclusion criteria: Patients suffering TMEM127

Exclusion criteria: Not suffering TMEM127 mutation

N=48

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor.

Neumann, 2004

Type of study: Cohort ithinling

Setting: University Medical Center

Country: Germany

Source of funding:?

Inclusion criteria: Patients suffering SDHD/B

Exclusion criteria: Not suffering SDHD/B

N=49

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

A total of 49 (12%) of 417 registrants carried SDHB or SDHD mutations.

In addition, 28 SDHB and 23 SDHD mutation carriers were newly detected among relatives of these carriers. Comparison of 53 SDHB and 47 SDHD total mutation carriers showed similar ages at diagnosis but differences in penetrance and of tumor manifestations. Head and neck paragangliomas (10/32 vs 27/34, respectively, P_.001) and multifocal (9/32 vs 25/34, respectively, P_.001) tumors were more frequent in carriers of SDHD mutations. In contrast, SDHB mutation carriers have an increased frequency of malignant disease (11/32 vs 0/34, P_.001). Renal cell cancer was observed in 2 SDHB mutation carriers and papillary thyroid cancer in 1 SDHB mutation carrier and 1 SDHD mutation carrier.

Niemeijer et al. 2017

Type of study: Cohort ithinling

Setting: University Medical Center

Country: Netherlands

Source of funding:?

Inclusion criteria: Patients suffering SDHB

Exclusion criteria: Not suffering SDHB

N=194

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0-36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423 + 1G > A).

Peczkowska et al. 2008

Type of study: Case Report

Setting: University Medical Center

Country: Germany

Source of funding:?

Inclusion criteria: Patients suffering SDHC

Exclusion criteria: Not suffering SDHC

N=1

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Right adrenal pheochromocytoma and left adrenal incidentaloma, as part of a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa).

Persu et al. 2008

Type of study: Cohort description

Setting: University Medical Center

Country:

Source of funding:?

Inclusion criteria: Patients suffering SDHD/B

Exclusion criteria: Not suffering SDHD/B

N=1

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Fifty-six unrelated patients were included (36 head and neck paragangliomas, including six familial cases and 30 sporadic cases; 18 abdominal pheochromocytoma/paraganglioma and two paraganglioma of the cauda equina). The overall prevalence of mutations was 41% (n = 23 including 19 head and neck paragangliomas and four abdominal pheochromocytoma/paraganglioma), mainly due to SDH mutations. While SDHD mutations were found in all patients with familial head and neck paragangliomas, in sporadic cases, the prevalence of SDHB mutations (n = 8, 27%) was twice that of SDHD mutations (n = 4, 13%). Patients harbouring SDHB mutations had unilateral late-onset head and neck tumours without evidence of recurrence or malignancy.

Ricketts, 2010

Type of study: Cohort description

Setting: University Medical Center

Country:

Source of funding:?

Inclusion criteria: Patients suffering SDHD/B

Exclusion criteria: Not suffering SDHD/B

N=358

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype–phenotype correlations were detected for SDHB mutations. Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH‐associated HNPGL and pheochromocytoma.

Rijken et al. 2016

Type of study: Cohort description

Setting: University Medical Center

Country: Netherlands

Source of funding:?

Inclusion criteria: Patients suffering SDHB

Exclusion criteria: Not suffering SDHDB

N= 153

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early‐onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB‐linked disease and is important in the ithinling of SDHB‐linked patients. Risk estimates should preferably be based on the specific mutation involved.

Rijken et al. 2017

Type of study: Cohort description

Setting: University Medical Center

Country: Netherlands

Source of funding:?

Inclusion criteria: Patients suffering SDHB

Exclusion criteria: Not suffering SDHDB

N= 195

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Schiavi et al. 2005

Type of study: Cohort description

Setting: University Medical Center

Country: Collaboration

Source of funding:?

Inclusion criteria: Patients suffering SDHC

Exclusion criteria: Not suffering SDHDC

N= 195

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

The prevalence of SDHC carriers was 4% in HNP but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42) mutation carriers and with 90 patients with sporadic HNPs. Location, number of tumors, malignancy, and age were different: more carotid body tumors were found in SDHC (13/22 [59%]) than in sporadic HNPs (29/90 [32%], P = .03), as well as fewer instances of multiple tumors in SDHC (2/22) than in SDHD (24/42; P<.001), 0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age at diagnosis in SDHC than in sporadic HNPs (45 vs 52 years; P = .03).

Van Hulsteijn, 2012

Type of study: Cohort description

Setting: University Medical Center

Country: Netherlands

Source of funding:?

Inclusion criteria: Patients suffering SDHB

Exclusion criteria: Not suffering SDHDB

N= 47

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Mean follow-up was 3.6 ± 3.6 years. Twenty-seven persons (57 %) carried the SDHB c.423+1 G>A mutation and seven persons (15 %) the SDHB c.201-4429_287-933del (exon 3 deletion) mutation. No differences were found in the clinical phenotype of carriers of these two specific SDHB mutations. By end of follow-up, 49 % of SDHB mutation carriers displayed no biochemical or radiological evidence of manifest disease, i.e. they were unaffected carriers. Three persons (6 %) had been diagnosed with a pheochromocytoma (PCC), four with a sympathetic PGL (sPGL) (9 %), 18 with a HNPGL (38 %), and two persons (4 %) had developed a malignant paraganglioma, i.e. metastatic disease. In conclusion, the two main Dutch SDHB founder mutations do not differ in clinical expression and result in a relatively mild phenotype. Over one-third of SDHB mutation carriers develop HNPGL, with sPGL/PCC in only 15 % and malignancy in only 4 %.

Zbuk et al. 2007

Type of study: Case Report

Setting: University Medical Center

Country: USA

Source of funding:?

Inclusion criteria: Patients suffering SDHC

Exclusion criteria: Not suffering SDHDC

N= 1

Describe prognostic factor(s) and method of measurement:

Mutation analysis

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

• 37 year old female, papillary thyroid cancer, and withinyears paraganglioma of left carotid body.
•  

Zinnamosca et al. 2011

Type of study: cohort description

Setting: University Medical Center

Country: Italy

Source of funding:?

Inclusion criteria: Patients suffering NF1

Exclusion criteria: Not suffering nf1

N= 48

Describe prognostic factor(s) and method of measurement:

Mutation analysis; screening for PGL presence.

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

In NF1 patients, 11 (29.3%) had arterial hypertension, 7 (14.6%) had a PHEO. Four (57%) NF1 patients with PHEO were symptomatic at the diagnosis. In PHEO-NF1 patients, we revealed a lower BMI and WC values with respect to NF1 patients without PHEO and normal subjects (NSs) (p < 0.05), respectively. The nocturnal non-dipping pattern at the ABPM was present in 40.4% of NF1 patients, and in particular this phenomenon was present in PHEO-NF1 patients (71.4%). Left ventricular mass index and intima media thickness were significantly higher in NF1 patients as compared to NS (p < 0.05), particularly in NF1-PHEO patients (p < 0.05).

Abermil et al. 2012

Type of study: cohort description

Setting: University Medical Center

Country: France

Source of funding:?

Inclusion criteria: Patients suffering pheochromocytoma

Exclusion criteria: Not suffering PGL/Pheo’s

N= 642

Describe prognostic factor(s) and method of measurement:

Mutation analysis; TMEM127

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

In our cohort six mutations (0.9%) were identified. Three of them (p.Ala47Asp, p.Gln64HisfsX18, p.Tyr164X) were found in patients exhibiting clinical criteria for a hereditary disease (young age at diagnosis, bilateral PCC, or family history). The three others (p.Gln157X, p.Val68SerfsX13, p.Val90Met) were detected in patients with an apparently sporadic presentation. No mutation was found among patients with PGL, and no large chromosomal rearrangement spanning the TMEM127 gene was detected.

Bayley et al. 2010

Type of study: cohort description

Setting: University Medical Center

Country: France

Source of funding:Dutch cancer Society; European Union 6^th Framework program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer

Inclusion criteria: Patients suffering pheochromocytoma

Exclusion criteria: Not suffering PGL/Pheo’s

N= 642

Describe prognostic factor(s) and method of measurement:

Mutation analysis; TMEM127

Endpoint of follow-up:

n.a.

Outcome measures and effect size (include 95%CI and p-value if available):

Analysis of germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred.

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Abermil et al. 2012

Unlikely

Likely

Unlikely

Unlikely

Bayley et al. 2010

Unlkely

Likely

Unlikely

Unlikely

Boedeker et al. 2005

Likely

Unlikely

Unlikely

Likely

Bourdeau et al. 2012

Unlikely

Likely

Unlikely

Unlikely

Burnichon et al. 2009

Unlikely

Unlikely

Unlikely

Unlikely

Burnichon et al. 2009

Likely

Likely

Likely

Unlikely

Burnichon et al. 2012

Unlikely

Likely

Unlikely

Unlikely

DeAngelis et al. 1987

Unlikely

Likely

Unlikely

Unlikely

Ercolino et al. 2008

Unlikely

Likely

Likely

Likely

Gross et al. 1996

Likely

Likely

Likely

Likely

Havekes et al. 2009

Likely

Unlikely

Unlikely

Unlikely

Hensen et al. 2010

Unlikely

Unlikely

Unlikely

Unlikely

Hensen et al. 2011

Unlikely

Likely

Unlikely

Unlikely

Kennedy et al. 1986

Unlikely

Likely

Unlikely

Unlikely

Korpershoek et al. 2011

Unlikely

Likely

Unlikely

Unlikely

Kunst et al. 2011

Unlikely

Likely

Unlikely

Unlikely

Lopez-Jimenez et al. 2007

Unlikely

Likely

Unlikely

Unlikely

Millar et al. 2014

Likely

Likely

Unlikely

Unlikely

Neumann et al. 2004

Unlikely

Unlikely

Unlikely

Unlikely

Neumann et al. 2009

Unlikely

Unlikely

Likely

Unlikely

Neumann et al. 2011

Unlikely

Unlikely

Unlikely

Unlikely

Niemeijer et al. 2017

Unlikely

Unlikely

Unlikely

Unlikely

Peckowska et al. 2007

Unlikely

Likely

Unlikely

Unlikely

Ricketts et al. 2010

Unlikely

Likely

Likely

Unlikely

Ricketts et al. 2010

Unlikely

Likely

Unlikely

Unlikely

Rijken et al. 2016

Unlikely

Unlikely

Unlikely

Unlikely

Rijken et al. 2017

Unlikely

Unlikely

Unlikely

Unlikely

Schiavi et al. 2005

Likely

Likely

Unlikely

Likely

Van Hulsteijn et al. 2012

Unlikely

Unlikely

Unlikely

Unlikely

Van Hulsteijn et al. 2014

Unlikely

Unlikely

Unlikely

Unlikely

Zbuk et al. 2007

Unlikely

Likely

Unlikely

Unlikely

Zinnamosca et al. 2011

Unlikely

Unlikely

Unlikely

Unlikely