Family History Of Paraganglioma Research Articles

The genetics of paragangliomas: a review

Familial head and neck paragangliomas account for approximately 10% of all head and neck paragangliomas. There are three known genes associated with genetic susceptibility to head and neck paragangliomas: succinate dehydrogenase complex subunit 'D', 'B' and 'C' (SDHD, SDHB and SDHC). The genes most frequently implicated: SDHD and SDHB, also predispose to phaeochromocytoma. SDHD shows a complex inheritance pattern - tumours do not develop if the mutation is inherited from the mother. SDHB mutations are associated with malignant phaeochromocytoma. Patients who present with a family history of paraganglioma or phaeochromocytoma, with multiple tumours, or early onset tumours (<50 years), should be referred for genetic investigation.

Cervical paragangliomas: neurovascular surgical risk and therapeutic management

Paragangliomas of the neck region arise most commonly in the carotid and vagal bodies. The goal of this retrospective study is to evaluate intraoperative vascular and neurological morbidity and to define the therapeutic strategy. During the period 1990-2004, 32 patients with 42 neck paragangliomas were referred to our institution (Head and Neck Service, Otolaryngology Federation, CHU La Timone, Marseilles, France). There were 29 carotid body tumors and 11 vagal body tumors. There were 14 men and 18 women. Forty paragangliomas were surgically excised. Mean age of patients with family history of paragangliomas was 34 years and that of patients without any familial history was 47 years. Only one patient had a malignant paraganglioma. A vascular repair procedure was performed in 10% and always occurred in carotid body tumors including the malignant one. Postoperative hypoglossal nerve deficit was reported in five cases (12.5%). Paralysis of vagus nerve was reported in 11 cases (27.5%), nine of whom were patients with vagal body tumors. Knowledge of number of paragangliomas and their location is of main importance and influences the therapeutic strategy. The goal of this strategy is to avoid major neurovascular morbidity and to optimize treatment of multiple or bilateral tumors. Early management of patients prevents progressive neurological deficit due to an enlarging tumor mass and minimizes neurovascular complications.

Paraganglioma: The role of genetic counselling and radiological screening

Paragangliomas are rare tumours of the autonomic nervous system that occur in both sporadic and hereditary forms. They are usually benign tumours with low mortality, but can cause significant morbidity related to mass effect. Genetic predisposition to develop paraganglioma can occur within known tumour syndromes and familial tumours tend to present at a younger age and at multiple sites compared to sporadic tumours. Tumours should be diagnosed and excised as early as possible, as studies have shown morbidity to be directly related to tumour size. We present a case of a 14-year-old boy with multiple paraganglioma and a strong family history of paraganglioma. He suffered significant morbidity at resection of an extra-adrenal retroperitoneal tumour due to late diagnosis and was later unable to undergo excision of a head and neck paraganglioma due to its size and relation to neurovascular structures in the neck. We review the current literature on suggested genetic counselling (psychological counselling and DNA analysis) and radiological screening guidelines and recommend that genetic counselling should be offered to all patients with a family history of paraganglioma from the age of 5 years. Those positive for paternal paraganglioma locus gene should then undergo regular radiological screening with MRI.

Clinical Characteristics of Pheochromocytoma Patients With Germline Mutations in SDHD

We examined the value of SDHD mutation screening in patients presenting with apparently sporadic and familial pheochromocytoma for the identification of SDHD-related pheochromocytomas. This retrospective study involved 126 patients with adrenal or extra-adrenal pheochromocytomas, including 24 patients with a family history of multiple endocrine neoplasia 2, von Hippel-Lindau disease, neurofibromatosis type 1, or paraganglioma (PGL). Conformation-dependent gel electrophoresis and sequence determination analysis of germline and tumor DNA were used to identify SDHD alterations. The clinical and molecular characteristics of sporadic and hereditary tumors were compared. We reviewed the literature and compared our results with those from previously published studies. Pathogenic germline SDHD mutations were identified in three patients: two (2.0%) of the 102 apparently sporadic pheochromocytoma patients and one patient with a family history of PGL. These patients presented with multifocal disease (two of three multifocal patients) or with a single adrenal tumor (one of 82 patients). In the literature, mutations are mostly found in patients </= 35 years of age or presenting with multifocal or extra-adrenal disease. All patients with an SDHD mutation developed extra-adrenal tumors (pheochromocytomas or PGLs) at presentation or during follow-up. SDHD gene mutations in patients presenting with apparently sporadic adrenal pheochromocytoma are rare. We recommend SDHD mutation screening for patients presenting with a family history of pheochromocytoma or PGL, multiple tumors, isolated adrenal or extra-adrenal pheochromocytomas, and age </= 35 years. Analysis of SDHD can also help to distinguish synchronous primary tumors from abdominal metastases.

Pediatric extraadrenal paraganglioma

Background: Pediatric paraganglioma is rare and extraadrenal paraganglioma has not been characterized in children. Methods: The authors reviewed the medical records and pathology samples of children with extraadrenal paraganglioma treated at our institution between December 1978 and September 2000. Clinical presentation, treatment, and outcome were evaluated. Results: Eight patients (median age, 11.4 years) were identified, 4 were boys and none had a family history of paraganglioma or associated syndromes. Primary tumors arose in the retroperitoneum (n = 3), carotid body (n = 2), jugulotympanic ganglion (n = 1), cervical-paraspinal region (n = 1), and lung (n = 1). Extraadrenal paraganglioma had not been suspected at presentation in any patient. Of 5 patients who underwent gross total resection at the time of diagnosis, 4 remain disease free, 1 had microscopic residual tumor and died of disease. Three patients had initially unresectable disease, 2 are disease free after neoadjuvant therapy and delayed surgery, and 1 has persistent disease after tumor embolization and radiotherapy. Conclusions: Pediatric extraadrenal paraganglioma occurs most commonly in the retroperitoneum and head and neck, and the diagnosis usually is not suspected at the time of presentation. Surgery is the mainstay of treatment, and outcome is good after gross total resection. Neoadjuvant therapy can facilitate complete resection of initially unresectable tumors.

Germline SDHD mutation in paraganglioma of the spinal cord.

Hereditary paraganglioma of the head and neck is associated with germline mutations in the SDHD gene, which encodes a mitochondrial respiratory chain protein. Paragangliomas of the central nervous system are very rare, occur almost exclusively in the cauda equina of the spinal cord and are considered non-familial. In the present study, we screened 22 apparently sporadic paragangliomas of the cauda equina for SDHD mutations. One spinal paraganglioma and similar cerebellar tumours that developed 22 years later in the same patient contained a missense mutation at codon 12 (GGT-->AGT, Gly-->Ser) and a silent mutation at codon 68 (AGC-->AGT, Ser-->Ser). There was no family history of paragangliomas but DNA from white blood cells of this patient showed the same sequence alterations, indicating the presence of a germline mutation. All other cases of spinal paraganglioma had the wild-type SDHD sequence, except one case with a silent mutation at codon 68 (AGC-->AGT, Ser-->Ser). This is the first observation indicating that inherited SDHD mutations may occasionally cause the development of paragangliomas in the central nervous system.

Carotid Body Paragangliomas: A Clinicopathologic and DNA Analysis of 13 Tumors

The clinical and pathological features of 13 carotid body paragangliomas from 12 patients were examined and correlated with the DNA ploidy pattern as determined by image analysis. These tumors occurred in 7 women and 5 men aged 19 to 62 years (average, 42 years). All presented with a slowly enlarging, usually asymptomatic mass of 2 weeks' to 25 years' duration. Two patients were related and had a family history of paragangliomas. The tumors ranged from 2 to 6 cm. All contained scattered chief cells with pleomorphic nuclei, two exhibited mitoses, and three showed perineural and three vascular invasion. Follow-up was available in all 12 patients and ranged from 15 months to 28 years (average, 7.3 years). None of the tumors recurred locally, but one did metastasize to a single cervical lymph node that was apparent at the time of diagnosis. Of 13 carotid body paragangliomas examined for DNA, 4 were diploid, 3 diploid-tetraploid, 3 tetraploid, 2 aneuploid, and 1 polyploid. The only malignant tumor was polyploid. From these observations, we conclude that abnormalities in DNA content of carotid body paragangliomas are common and that tumor ploidy cannot be used to assess malignant potential. We also found no apparent relationship among nuclear pleomorphism, mitotic activity, perineural invasion, or vascular invasion and clinical behavior. Perineural and vascular invasion, however, were observed only in tumors with abnormal DNA histograms.