variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

Background: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for variants. In the present study we zoom in on the genotype-phenotype associations of gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy.

Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature.

Background: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy.

Methods: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases.

Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision medicine.

Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the most frequently results from inactivating variants in genes encoding subunits of succinate dehydrogenase.

Clinical decision making in small non-functioning VHL-related incidentalomas.

The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.

Hemangioblastoma and von Hippel-Lindau disease: genetic background, spectrum of disease, and neurosurgical treatment.

Introduction: Hemangioblastomas are rare, histologically benign, highly vascularized tumors of the brain, the spinal cord, and the retina, occurring sporadically or associated with the autosomal dominant inherited von Hippel-Lindau (VHL) disease. Children or adults with VHL disease have one of > 300 known germline mutations of the VHL gene located on chromosome 3. They are prone to develop hemangioblastomas, extremely rarely starting at age 6, rarely at age 12-18, and, typically and almost all, as adults.

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study.

Objective: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.

Growth characteristics and therapeutic decision markers in von Hippel-Lindau disease patients with renal cell carcinoma.

Background: Von Hippel-Lindau (VHL) disease is a multi-systemic hereditary disease associated with several benign and malignant tumor entities, including clear cell renal cell carcinoma (ccRCC). Since ccRCCs grow slowly, nephron sparing surgery is typically performed at a tumor diameter of 3-4 cm before the tumor metastasizes. However, in the case of recurrent disease, repeated surgical intervention can impair renal function.

Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma.

Background: Pathogenic germline variants in subunits of succinate dehydrogenase (, and ) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.

Methods: Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk.

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

Background: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection.

Co-Inheritance of Autosomal Dominant Polycystic Kidney Disease and Naevoid Basal Cell Carcinoma Syndrome: Effects on Renal Progression.

The calcium signalling and hedgehog (HH) signalling pathways operate in the primary cilium. Abnormalities in these pathways cause autosomal dominant polycystic kidney disease (ADPKD) and naevoid basal cell carcinoma syndrome (NBCCS) respectively. Several reports have proposed that hyperactivation of the HH pathway in animal models of polycystic kidney disease affects normal renal development and renal cyst phenotype.

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic ! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations.

Minimally Invasive Surgery (MIS) in Children and Adolescents with Pheochromocytomas and Retroperitoneal Paragangliomas: Experiences in 42 Patients.

Background: Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access.

Max Schottelius: Pioneer in Pheochromocytoma.

First descriptions of diseases attract tremendous interest because they reveal scientific insight even in retrospect. Max Schottelius, the pathologist contributing the first histological description of pheochromocytoma, remains anonymous. We reviewed the description by Schottelius and weighed the report in modern context.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

Importance: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking.

GROWTH RATE OF PARAGANGLIOMAS RELATED TO GERMLINE MUTATIONS OF THE SDHX GENES.

Objective: The purpose was to determine the growth rate of succinate dehydrogenase subunit (SDHx) gene-related paragangliomas based on computed tomography (CT) measurements.

Methods: Twenty-seven patients with SDHx mutations who underwent subsequent CT examinations were enrolled in the study. Tumors were classified as head and neck (HNP), thoracic, or abdominal/pelvic paragangliomas (PGLs).

Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis.

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes.