Endocrine Abstracts

Familial pheochromocytoma is inherited as a component of one of 5 pheochromocytoma – related syndromes such as von Hippel-Lindau disease, multiple endocrine neoplasia type 2 and the paraganglioma syndromes type 1 and type 4.

Neurofibromatosis type 1 is often cited as the fifth of these syndromes but a clinical-genetic characterisation does not exist. 0.1 to 5.7% of patients with neurofibromatosis type 1 have pheochromocytoma. The NF1 gene as the susceptibility gene for neurofibromatosis type 1 is considered to be one of the largest genes in the human. Mutation detection is a considerable challenge because of the large size of the gene, the lack of any mutational clustering and the presence of 36 pseudogenes.

The background of this study was a registry of 24 patients with neurofibromatosis type 1 and pheochromocytoma. The search for intra-exonic mutations and exon-specific deletions was performed for all 57 exons of the NF1 gene. An inactivation of the NF1 wildtype allele in tumor tissue was tested by loss of heterozygosity analysis.

22 of the 24 patients showed germline mutations of the NF1 gene. The mutation hit rate was 92%. A loss of the wildtype allele was found in 67% of the paired lymphocytes and tumor samples. Patients showed an average age at diagnosis of 42 years. All NF1 – related pheochromocytomas were adrenal.

The wildtype inactivation found in 67% of the pheochromocytomas suggests the causative role of NF 1 in these tumors. Pheochromocytoma as a classic tumor of neural crest derived origin is therefore a true component of neurofibromatosis type 1. The mutation rate was 92%. 78% of the detected mutations were germline point mutations 14% of them were large deletions affecting one single exon or almost the entire gene.