Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be considered for all individuals with paragangliomas and/or pheochromocytomas, particularly those with e.g. multifocal, multiple synchronous or metachronous tumors and early onset (age <40y).
Please note: Approximately 25 % of all apparently sporadic carcinomas are the result of germline mutations in the RET, VHL, SDHB or SDHD genes.
Paragangliom-Pheochromocytoma Syndrome Typ PGL1, PGL4 - SDHB, SDHD
Clinical Features
Hereditary Paraganglioma-Pheochromocytoma syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) as well as pheochromocytomas (paragangliomas that are confined to the adrenal medulla).
Clinically, paragangliomas of the sympathetic nervous system lead to catecholamine hypersecretion; paragangliomas of the parasympathic nervous system are non- secreting. Extra-adrenal parasympathetic paragangliomas occur most often on the head and neck and are in approx. 95 % of cases non-secreting. In contrast, extra-adrenal paraganglioma of the sympathetic nervous system are confined to the thorax, abdomen, and pelvis and are typically secreting catecholamines (like most pheochromocytoma) and correlate with an increased risk of malignant development.
Hypersecretion of catecholamines can lead to clinical symptoms such as hypertension, headaches, episodic sweat outbreaks, and palpitations.
Tumor spectrum of hereditary paraganglioma-pheochromocytoma syndromes:
• Parasympathic paragangliomas of the head and neck
(corticoid tumors, vagus and jugular paragangliomas), without secretion.
• Sympathetic paragangliomas of the thorax, abdomen and pelvis, normally hypersecretion of catecholamines.
• Pheochromocytomas and sympathetic, extra-adrenal paragangliomas of the nervous system.
• Renal cell cancer and papillary thyroid cancer.
• Gastrointestinal stromal tumors.
Genetic Information
Hereditary paraganglioma-pheochromocytoma syndromes are caused by germline mutations in the SDHB, SDHC and SDHD genes, which encode three of the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). These three forms of hereditary paraganglioma-pheochromocytoma syndromes can be subdivided into different entities:
• PGL1: SDHD, chromosome 11 (11q23), (Baysal et al 2000)
• PGL3: SDHC, chromosome 1 (1q21), (Niemann & Muller 2000)
• PGL4: SDHB, chromosome 1 (1p36.1) (Astuti et al 2001)
Approximately 70 % of hereditary paragangliomas caused by germline mutations in SDHD are located predominantly in the head and neck, while paragangliomas of the sympathetic nervous system are more frequently caused by mutations in SDHB. Approx. 40 % of patients with a paraganglioma of the head and neck and 10 % of patients with an sympathetic extra-adrenal paraganglioma or pheochromozytoma are carriers of a germline mutation in one of the SDH genes. This indicates an autosomal dominant pattern of inheritance. Furthermore, the SDHD gene (PGL1) underlies an epigenetic imprinting mechanism; the disease is thus primarily caused by a loss of the corresponding paternal gene copy (mutation on the paternal SDHD allele). A loss of the maternal gene copy correlates with a low but not negligible tumor risk (Heutink et al 1992; Baysal et al. 2008).
Diagnostic
Indication
Method
All exons as well as their flanking regions are analysed by direct DNA sequencing.
Deletions and/or duplications of one or more exons in FH are captured using MLPA.
Sample Requirement
2 - 4 ml of EDTA blood
Duration
2 - 3 weeks