Background:

Head and neck paragangliomas (HNP) are highly vascular tumors of neural crest origin that are benign in the majority of cases. They mayoccur as sporadic as well as hereditary entities [1]. Since the year 2000, the so called ”paraganglioma syndromes” (PGL) have attracted attention. To date, three out of four PGL have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC and PGL 4 by SDHB gene mutations [1]. Patientswith PGL have a high risk for the development of HNP and pheochromocytomas [1]. Von Hippel-Lindau disease (VHL) is characterized byretinal angiomas, haemangioblastomas of the central nervous system, kidney tumors, pancreatic cysts and pheochromocytomas. Only fivecases of VHL patients with HNP have been published in the international medical literature [2-6]. Table 1 gives an overview on tumorsyndromes that are associated with tumors of the paraganglial system.

Head and neck paragangliomas and von Hippel-Lindaudisease

C.C. Boedeker 1, G.J. Ridder 1, W. Maier 1, H.P.H. Neumann 21 Department of Otorhinolaryngology/Head and Neck Surgery2 Department of Nephrology, University of Freiburg, Germany

Contact: Dr. Carsten C. Boedeker, Univ.-HNO-Klinik, Killianstr. 5, D-79106 Freiburg i.Br., Germanyboedeker@hno.ukl.uni-freiburg.de

Methods:In 1983 we founded a registry for VHL patients. Until 2008, 395 index cases could be registered. We systematically reviewed our VHL registry for patients with HNP.Results:Three VHL patients presented with an HNP. The first of those patients (mutation VHL 404 T>A) was diagnosed with a malignantabdominal extra-adrenal pheochromocytoma and lymph node metastases in 1997 at age seven. Two years after resection of the tumor, lymphadenectomy and chemotherapy there was a local recurrence which was resected and radiated. In 2003, there was an adrenalpheochromocytoma (Fig. 1 and 2) and in 2005 the boy was diagnosed with a left sided carotid body tumor (Fig. 3). Both tumors underwentresection. Right now, the disease is stable with a known vertebral bone metastasis (Fig. 4). Another male VHL patient (mutation VHL 404 T>A) presented with a carotid body tumor on the right at age 33. The tumor was completelyresected. So far, no other VHL associated tumors could be detected in this patient. The third patient was diagnosed with a left carotid body tumor at age 33 in the year 2000 (mutation VHL 505 T>C). The tumor underwentcomplete resection. Currently, she has multiple haemangioblastomas of the spinal cord that are followed up by serial MRI.

Discussion:Approximately 33% of all head and neck paragangliomas (HNP) are associated with a hereditary tumor syndrome [1]. Theparaganglioma syndromes 1, 3 and 4 (PGL 1, 3, 4) make up for the vast majority of those tumors [1]. In our international VHL registry, we detected three VHL patients who developed an HNP. The results of our study demonstrate that patients with von Hippel-Lindaudisease seem to have an increased risk for the development of HNP. So far, this rare association has found very little attention in international medical literature [2-6]. The possible occurance of an HNP has to be kept in mind when it comes to molecular geneticcounselling, therapy and follow up of VHL patients. We suggest that all VHL patients should undergo a thorough yearly work up of thehead and neck including an otoscopy, pure tone audiometry, examination of the lower cranial nerves as well as a B mode sonography anda color coded Doppler sonography.

Literature:1) Schiavi F, Boedeker CC, Bausch B et al., Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA 2005; 294: 2057- 20632) Hull MT, Roth LM, Glover JL, Walker PD. Metastatic carotid body paraganglioma in von Hippel-Lindau disease. An electron microscopic study. 1982; 106: 235-2393) Gross DJ, Avishai N, Meiner V et al., Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene. J Clin Endocrinol Metab 1996; 81: 147-1494) Zanelli M, van der Walt JD. Carotid body paraganglioma in von Hippel-Lindau disease: a rare association. Histopathology. 1996; 29: 178-1815) Schimke RN, Collins DL, Rothberg PG. Functioning carotid paraganglioma in the von Hippel-Lindau syndrome. Am J Med Genet 1998; 80: 533-5346) Ercolino T, Becherini L, Valeri A et al., Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline

mutations. Clin Endocrinol 2008; 68: 762-768

Figures 1-4 (from left to right): Male VHL patient (mutation VHL 404 T>A)

Figure 1: Coronar magnetic resonance imaging (MRI) demonstrating a pheochromocytoma of the right adrenal gland (arrow)Figure 2: Axial MRI of the tumor shown in Fig. 1Figure 3: Axial MRI of the neck with a left sided carotid body tumor (Shamblin Class I)Figure 4: Axial MRI revealing a vertebral bone metastasis

Table 1

tumor syndrome gene mutation location paraganglial tumors

MEN 1 MEN 1 11q13 pheochromocytomas

MEN 2 RET 10q11.2 pheochromocytomas

(HNP)

NF 1 NF 1 17q11.2 pheochromocytomas

VHL VHL 3p25 pheochromocytomas

(HNP)

PGL 1 SDHD 11q23 HNP

pheochromocytomas

PGL 2 unknown 11q13 HNP

PGL 3 SDHC 1q21 HNP

(pheochromocytomas)

PGL 4 SDHB 1p36 HNP

pheochromocytomas

MEN: multiple endocrine neoplasia; NF 1: neurofibromatosis type 1; VHL: von Hippel-Lindau;

HNP: head and neck paragangliomas; PGL: paraganglioma syndrome; SDH: succinate

dehydrogenase; q: short arm of a chromosome; p: long arm of a chromosome