Genetics of Familial Paragangliomas
Genetics of familial paragangliomas: Past, present, and future

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Phenotype

Human genetics research explores how variations at the genetic level (i.e., cause) affect variations at the phenotypic level (i.e, effect) and relies heavily on the phenotype description, which is obtained by clinical and laboratory assessment. The phenotype of paraganglioma refers to the presence of tumors derived from paraganglionic tissue (i.e., the extra-adrenal chromaffin cell system).32 Paraganglioma tumors generally are classified on the basis of their anatomic location and common

Characterization of Hereditary Paraganglioma Pedigrees

The first step in the genetic analysis of paraganglioma tumors includes identification of families and characterization of genetic transmission patterns. The familial nature of paraganglioma tumors has been known for more than half a century. In 1933, Chase19 described two sisters with carotid body tumors, and Goekoop26 described familial jugular body tumors. Carotid body tumors were seen in members of three successive generations, transmitted in an autosomal-dominant pattern of inheritance.5,

Genetic Mapping of PGL Loci

Identification of genes responsible for hereditary paraganglioma began with the genetic mapping of the susceptibility genes to specific chromosomal regions. The mapping was performed by genetic linkage analysis. Linkage analysis determined which chromosomal region cosegregated with PGL in affected individuals in pedigrees using polymorphic DNA markers. This chromosomal region then was evaluated physically to identify the responsible gene. In a large Dutch pedigree with hereditary paraganglioma,

Physical Mapping of the New PGL1 Critical Region

Identification of the PGL1 gene required physical localization of candidate genes to the genetic interval defined by the genetic recombination events. First, the author's group built a complete overlapping clone set (contig) spanning the whole critical region (Baysal et al, unpublished results). This high-resolution clone contig not only helped them to fine-map neighboring genes and short segments of expressed DNA sequences that can be amplified by PCR (ESTs) but also provided them with the

Genetic Mimicry of the Response of the Carotid Body to Chronic Hypoxic Stimulation

The oxygen-sensing role of the carotid body was implicated in paraganglioma tumor development under certain conditions. Humans and other mammals, including cattle, dogs, rabbits, and guinea pigs living at high altitudes have heavier and larger carotid bodies and an increased incidence of carotid body tumors than those living at sea level.2, 3, 24, 62 Histologic analyses showed hyperplasia–anaplasia of the carotid body chemoreceptor cells, which presumably resulted from sustained stimulation by

Identification of the Role of cybS in Cellular Oxygen Sensing

The extreme phenotypic similarity between the hereditary paraganglioma tumors and the carotid body tumors arising from chronic hypoxic stimulation suggests that the cybS protein is associated closely with the hypoxic responsiveness of the paraganglionic system. It has been postulated that hypoxic stimulation activates a transcription factor, hypoxia-inducible factor 1.66 The activated hypoxia-inducible factor 1 stimulates the synthesis of erythropoietin, which increases red cell mass; vascular

Summary

Genetic studies of familial paragangliomas and the appreciation of chronic hypoxic stimulation as a potential tumorigenic factor have affected the understanding of the pathogenesis of these rare tumors. These investigative studies show that once the presence of any underlying chronic hypoxic condition is excluded, genetic defects are major causative factors in head and neck paragangliomas (Table 1). The familial basis of these tumors has been established firmly with the identification of at

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  • Cited by (35)

    • Carney's triad with paraganglioma

      2016, British Journal of Oral and Maxillofacial Surgery
    • Chromosomal changes in sporadic and familial head and neck paragangliomas

      2009, Otolaryngology - Head and Neck Surgery
      Citation Excerpt :

      The distribution of clinicopathologic and mutational features in our series of 24 cases (Tables 1 and 3) closely paralleled those described in larger series.1 It is estimated that the familial incidence of head and neck PGLs is approximately 10 percent.3 If such a history is present, there is a 78 percent to 87 percent possibility of multiple tumors.10

    • Current concepts for the surgical management of carotid body tumor

      2006, American Journal of Surgery
      Citation Excerpt :

      Significantly, germline mutations in the paraganglioma (PGL) susceptibility genes may occur spontaneously and provoke heritable CBT in the absence of a family history. These tumors are genetically heterogeneous and have been mapped to at least 4 different chromosomal loci [18]. Each of the 4 types seen in CBT has a dominant mode of inheritance with possible age- and hypoxia-related penetrance.

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    The research in the author's laboratory is supported by a Competitive Medical Research Fund from the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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