Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1

SummaryBackground: Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. Objective: Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. Materials & methods: The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. Conclusions: This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.

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Rothmund–Thomson syndrome type 1 caused by biallelic ANAPC1 gene mutations

Skin Health and Disease ◽

10.1002/ski2.12 ◽

2021 ◽

Author(s):

B. Zirn ◽

U. Bernbeck ◽

K. Alt ◽

F. Oeffner ◽

A. Gerhardinger ◽

...

Keyword(s):

Gene Mutations ◽

Syndrome Type ◽

Rothmund Thomson Syndrome

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Simpson-Golabi-Behmel Syndrome Type 1 and Hepatoblastoma in a Patient With a Novel Exon 2-4 Duplication of theGPC3Gene

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.35738 ◽

2013 ◽

Vol 161 (5) ◽

pp. 1091-1095 ◽

Cited By ~ 16

Author(s):

María Elena Mateos ◽

Katrin Beyer ◽

Eduardo López-Laso ◽

Juan López Siles ◽

Juan Luis Pérez-Navero ◽

...

Keyword(s):

Syndrome Type ◽

Exon 2 ◽

Novel Exon

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Faculty Opinions recommendation of The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14266035.15778169 ◽

2012 ◽

Author(s):

Adrian Daly

Keyword(s):

Syndrome Type ◽

Clinical Expression ◽

Paraganglioma Syndrome

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Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1

Acta Endocrinologica ◽

10.1530/eje-08-0328 ◽

2008 ◽

Vol 159 (5) ◽

pp. 633-639 ◽

Cited By ~ 22

Author(s):

Katarina Trebušak Podkrajšek ◽

Tatjana Milenković ◽

Roelof J Odink ◽

Hedi L Claasen-van der Grinten ◽

Nina Bratanič ◽

...

Keyword(s):

Mutation Detection ◽

Gene Mutations ◽

Chronic Otitis Media ◽

Silent Mutation ◽

Atypical Presentation ◽

Syndrome Type ◽

Autoimmune Regulator ◽

Autoimmune Polyglandular Syndrome ◽

Autoimmune Polyglandular Syndrome Type

ObjectiveAutoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.DesignAIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.MethodsSequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.ResultsSeven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.ConclusionsAIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.

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Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Acta Endocrinologica ◽

10.1530/eje-14-0130 ◽

2014 ◽

Vol 171 (3) ◽

pp. 335-342 ◽

Cited By ~ 14

Author(s):

Viviane C Longuini ◽

Delmar M Lourenço ◽

Tomoko Sekiya ◽

Osorio Meirelles ◽

Tatiana D Goncalves ◽

...

Keyword(s):

Multiple Testing ◽

Complex Disease ◽

Gene Mutations ◽

Germline Mutations ◽

Suppressor Gene ◽

Multiple Testing Correction ◽

Men1 Syndrome ◽

Disease Modifier ◽

Variable Clinical Presentation

ObjectiveTo date, no evidence of robust genotype–phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.DesignAs the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.MethodsGenotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.ResultsThere were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013–5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88–16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.ConclusionsOur study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.

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Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01585-6 ◽

2021 ◽

Author(s):

S. Garelli ◽

M. Dalla Costa ◽

C. Sabbadin ◽

S. Barollo ◽

B. Rubin ◽

...

Keyword(s):

Gene Mutations ◽

Premature Menopause ◽

Chronic Mucocutaneous Candidiasis ◽

Syndrome Type ◽

Inherited Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Polyendocrine Syndrome ◽

Autoimmune Conditions

Abstract Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

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Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study

Endocrine Connections ◽

10.1530/ec-17-0022 ◽

2017 ◽

Vol 6 (5) ◽

pp. 289-296 ◽

Cited By ~ 8

Author(s):

Ghazala Zaidi ◽

Vijayalakshmi Bhatia ◽

Saroj K Sahoo ◽

Aditya Narayan Sarangi ◽

Niharika Bharti ◽

...

Keyword(s):

Clinical Features ◽

Genetic Heterogeneity ◽

Clinical Manifestations ◽

Gene Mutations ◽

Young Age ◽

Clinical Aspects ◽

Syndrome Type ◽

Autoimmune Polyendocrine Syndrome ◽

Organ Specific

Objective Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years. Methods Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

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Distinct Clinical Phenotype and Immunoreactivity in Japanese Siblings with Autoimmune Polyglandular Syndrome Type 1 (APS-1) Associated with Compound Heterozygous Novel AIRE Gene Mutations

Clinical Immunology ◽

10.1006/clim.2002.5208 ◽

2002 ◽

Vol 103 (3) ◽

pp. 277-283 ◽

Cited By ~ 29

Author(s):

Kazuhiko Kogawa ◽

Jun Kudoh ◽

Seiho Nagafuchi ◽

Shouichi Ohga ◽

Hitoshi Katsuta ◽

...

Keyword(s):

Clinical Phenotype ◽

Gene Mutations ◽

Compound Heterozygous ◽

Syndrome Type ◽

Autoimmune Polyglandular Syndrome ◽

Aire Gene ◽

Autoimmune Polyglandular Syndrome Type

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SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1043 ◽

2011 ◽

Vol 96 (9) ◽

pp. E1472-E1476 ◽

Cited By ~ 182

Author(s):

Esther Korpershoek ◽

Judith Favier ◽

José Gaal ◽

Nelly Burnichon ◽

Bram van Gessel ◽

...

Keyword(s):

Sequence Analysis ◽

The Netherlands ◽

Succinate Dehydrogenase ◽

Missense Mutation ◽

Medical Center ◽

Gene Mutations ◽

Germline Mutations ◽

Wild Type ◽

Erasmus Medical ◽

Paraganglioma Syndrome

Abstract Context: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. Objective: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. Setting: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). Methods: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: 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. Conclusions: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.

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