Familial paragangliomas

Abstract

Paragangliomas are rare tumours of the autonomic nervous system and occur in sporadic and hereditary forms. They are usually benign and have a low mortality. However, they cause significant morbidity related to their mass effect. Genetic predisposition can occur within the familial tumour syndromes multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) and neurofibromatosis type 1 (NF-1), or be due to mutations in genes specific to the development of paraganglioma only. Compared to sporadic forms, familial paragangliomas tend to present at a younger age and at multiple sites. Tumours should be diagnosed and resected as early as possible, as it has been shown that morbidity is related to tumour size. This article gives an overview of the current literature on the origin of the different forms of paragangliomas, DNA diagnosis, as well as biochemical and radiological screening guidelines.

Figure 1

Paragangliomas classified according to their origin and location Paragangliomas have their origin in cells derived from the embryological neuroectoderm. There are 4 types of paragangliomas (according to Kleinsasser O. Arch. Klin. Exp. Ohren, Nasen, Kehlkopfheilkunde, 1064; 184: 214-25 and Glenner GG, Grimley PM, Atlas of tumor Pathology 1974; p. 18). 1. Branchiomeric group: In the region of the embryological branchiomeres (jugulotympanic ganglion, carotid body, laryngeal ganglia, subclavian ganglion, aorticopulmonary ganglion). There is a close relationship with blood vessels. 2. Intravagal group: In the region of the parasympathetic nerves (jugular ganglion, nodose ganglion). They have their origin within the perineurium. 3. Aortosympathetic group: In the region of the sympathetic nerves of the aorta. 4. Visceral autonomic group: in the nervous system of the heart, digestive tract, liver hilus, and bladder.

Figure 2

Cells obtain their energy from their environment by oxidation of carbohydrates, proteins and triglycerides to CO₂ and H₂O. The energy from these macronutrients is transformed into ATP in 4 different stages. Stage 1 - hydrolysis of macromolecules into monosaccharides, fatty acids, amino acids. Stage 2 - oxidation into Acetyl Co A. Stage 3 - Acetyl Co A oxidation into Tricarboxylic acid (TCA) cycle → Co₂. Stage 4 - reduction NAD → NADH, FAD → FADH₂, phosphorylation ATP H₂O and ATP.

Figure 3

Imaginary example of a family with hereditary paragangliomas and genomic imprinting. The pedigree has four generations (I-IV). Expression of the disease skips one or two generations. In these generations, the genetic predisposition is present. In the first generation (I) the mother (I 2) is a carrier of the paraganglioma disease gene and has expression of the disease. Her daughter (II 1) inherited the mutated paraganglioma gene, but will not develop paragangliomas. She will transfer the mutated paraganglioma gene to two of her children (daughter III 2 and son III 4). These children will not develop the disease, but pass the predisposition to the next generation. The granddaughter of (II 1) IV 1 has the predisposition but no expression, whereas the grandson IV 3 and granddaughter IV 4 have both the predisposition and expression of the disease. The son (II 4) of I 2 has also inherited the disease gene from his mother, but will not have symptoms. His son (III 5) is a paraganglioma carrier and will have complaints just the same as his sister III 7. His children (IV 6 and 7) have predisposition for paragangliomas and will have the disease. The son and daughter (IV 8 and 9) of III 7 do inherit the mutated paraganglioma gene from their mother, but will not have symptoms.