Clinical and Genetic Characteristics of Patients with Neurofibromatosis Type 1 and Pheochromocytoma
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《新英格兰医药杂志》
To the Editor: Pheochromocytoma occurs in approximately 1 percent of patients with neurofibromatosis type 1.1 Accordingly, germ-line mutations in the NF1 gene — the susceptibility gene for neurofibromatosis type 1 — are assumed to be one of the heritable causes of pheochromocytoma.2
Given the previous lack of relevant molecular data, we established and analyzed a registry for patients with neurofibromatosis type 1 and pheochromocytoma in collaboration with colleagues from 20 centers in Germany, other European countries, and the United States. We compared the findings for patients with neurofibromatosis type 1 with those for patients with other pheochromocytoma-related syndromes, including von Hippel–Lindau disease (susceptibility gene, VHL), multiple endocrine neoplasia type 2 (MEN-2; susceptibility gene, RET), paraganglioma syndrome 1 (susceptibility gene, SDHD), and paraganglioma syndrome 4 (susceptibility gene, SDHB).
Patients with neurofibromatosis type 1 and pheochromocytoma were added to those in our previously described pheochromocytoma registry,3,4 which was updated to July 1, 2005. The entire registry, counting the patients with neurofibromatosis type 1, includes 565 patients with adrenal, extraadrenal–abdominal, and extraadrenal–thoracic pheochromocytoma. This registry is continually updated; cases from Germany and central Poland may best be considered population-based, whereas the cases (approximately 10 percent) from other countries are not. The registry includes 15 patients with conditions related to neurofibromatosis type 1, and data on 10 additional patients with neurofibromatosis type 1 were contributed specifically for this study. Only symptomatic index patients were included, and relatives were excluded in order to avoid a founder effect.
Screening for a mutation of the NF1 gene was performed in two steps. For intraexonic mutations, we designed new primer pairs to exclude coamplifications of the 36 pseudogenes that are already known to be involved when the NF1 gene is screened for mutations. Analyses were performed with the use of denaturing high-performance liquid chromatography (DHPLC) (WAVE analysis system, Transgenomics). Samples displaying abnormal chromatographic patterns on DHPLC were subjected to direct sequencing with the use of a MegaBACE500 DNA sequencing machine (Amersham Biosciences). In addition, large deletions were sought by quantitative real-time polymerase chain reaction with SYBR Green I detection (SYBR Green PCR Master Mix, Qiagen), as previously described.5
Not counting the 10 cases that were contributed specifically for the study, the prevalence of NF1 carriers in our registry was 3 percent (15 of 565). Ninety-two percent of the 25 patients with neurofibromatosis type 1 had germ-line mutations. The spectrum of observed mutations included missense, stop-codon, splice-site, microdeletion, and microinsertion mutations, as well as a large deletion of 57 exons. Relevant clinical findings are shown in Table 1. The 25 patients with neurofibromatosis type 1 were compared with 31 patients with MEN-2, 75 with von Hippel–Lindau disease, 21 with paraganglioma syndrome 1, 33 with paraganglioma syndrome 4 mutations, and 380 with sporadic disease pheochromocytoma. The characteristics of patients with pheochromocytoma related to neurofibromatosis type 1 were similar to those of patients with sporadic pheochromocytoma. There were significant differences in the age at diagnosis between the group with von Hippel–Lindau disease and the group with paraganglioma syndrome 1; in the extent of multifocal tumors in the group with MEN-2, the group with von Hippel–Lindau disease, and the group with paraganglioma syndrome 1; and in the extent of extraadrenal tumors in the group with MEN-2, the group with von Hippel–Lindau disease, the group with paraganglioma syndrome 1, and the group with paraganglioma syndrome 4.
Table 1. Demographic, Clinical, and Genetic Features of Patients with One of the Five Syndromes Associated with Pheochromocytoma.
Patients with neurofibromatosis type 1 had a relatively high (but not significant) prevalence of malignant disease (12 percent), second only to that among patients with paraganglioma syndrome 4 who had a germ-line mutation in the SDHB gene (24 percent). Taken together, 33 percent of all symptomatic patients with pheochromocytoma in the registry carried germ-line mutations in one of the five genes, including NF1.
Birke Bausch, M.D.
Wiktor Borozdin, Ph.D.
Hartmut P.H. Neumann, M.D.
University of Freiburg
79106 Freiburg, Germany
neumann@med1.ukl.uni-freiburg.de
for the European-American Pheochromocytoma Study Group
Dr. Neumann is supported by a grant (NE 571/5-3) from the Deutsche Forschungsgemeinschaft, a grant (70-3313-ne1) from the Deutsche Krebshilfe, and a grant (LSHC-CT-2005-518200) from the European Union.
References
Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305:1617-1627.
Dluhy RG. Pheochromocytoma -- death of an axiom. N Engl J Med 2002;346:1486-1488.
Luijten M, Wang Y, Smith BT, et al. Mechanism of spreading of the highly related neurofibromatosis type 1 (NF1) pseudogenes on chromosomes 2, 14 and 22. Eur J Hum Genet 2000;8:209-214.
Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943-951.
Borozdin W, Boehm D, Leipoldt M, et al. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet 2004;41:e113-e113.
Given the previous lack of relevant molecular data, we established and analyzed a registry for patients with neurofibromatosis type 1 and pheochromocytoma in collaboration with colleagues from 20 centers in Germany, other European countries, and the United States. We compared the findings for patients with neurofibromatosis type 1 with those for patients with other pheochromocytoma-related syndromes, including von Hippel–Lindau disease (susceptibility gene, VHL), multiple endocrine neoplasia type 2 (MEN-2; susceptibility gene, RET), paraganglioma syndrome 1 (susceptibility gene, SDHD), and paraganglioma syndrome 4 (susceptibility gene, SDHB).
Patients with neurofibromatosis type 1 and pheochromocytoma were added to those in our previously described pheochromocytoma registry,3,4 which was updated to July 1, 2005. The entire registry, counting the patients with neurofibromatosis type 1, includes 565 patients with adrenal, extraadrenal–abdominal, and extraadrenal–thoracic pheochromocytoma. This registry is continually updated; cases from Germany and central Poland may best be considered population-based, whereas the cases (approximately 10 percent) from other countries are not. The registry includes 15 patients with conditions related to neurofibromatosis type 1, and data on 10 additional patients with neurofibromatosis type 1 were contributed specifically for this study. Only symptomatic index patients were included, and relatives were excluded in order to avoid a founder effect.
Screening for a mutation of the NF1 gene was performed in two steps. For intraexonic mutations, we designed new primer pairs to exclude coamplifications of the 36 pseudogenes that are already known to be involved when the NF1 gene is screened for mutations. Analyses were performed with the use of denaturing high-performance liquid chromatography (DHPLC) (WAVE analysis system, Transgenomics). Samples displaying abnormal chromatographic patterns on DHPLC were subjected to direct sequencing with the use of a MegaBACE500 DNA sequencing machine (Amersham Biosciences). In addition, large deletions were sought by quantitative real-time polymerase chain reaction with SYBR Green I detection (SYBR Green PCR Master Mix, Qiagen), as previously described.5
Not counting the 10 cases that were contributed specifically for the study, the prevalence of NF1 carriers in our registry was 3 percent (15 of 565). Ninety-two percent of the 25 patients with neurofibromatosis type 1 had germ-line mutations. The spectrum of observed mutations included missense, stop-codon, splice-site, microdeletion, and microinsertion mutations, as well as a large deletion of 57 exons. Relevant clinical findings are shown in Table 1. The 25 patients with neurofibromatosis type 1 were compared with 31 patients with MEN-2, 75 with von Hippel–Lindau disease, 21 with paraganglioma syndrome 1, 33 with paraganglioma syndrome 4 mutations, and 380 with sporadic disease pheochromocytoma. The characteristics of patients with pheochromocytoma related to neurofibromatosis type 1 were similar to those of patients with sporadic pheochromocytoma. There were significant differences in the age at diagnosis between the group with von Hippel–Lindau disease and the group with paraganglioma syndrome 1; in the extent of multifocal tumors in the group with MEN-2, the group with von Hippel–Lindau disease, and the group with paraganglioma syndrome 1; and in the extent of extraadrenal tumors in the group with MEN-2, the group with von Hippel–Lindau disease, the group with paraganglioma syndrome 1, and the group with paraganglioma syndrome 4.
Table 1. Demographic, Clinical, and Genetic Features of Patients with One of the Five Syndromes Associated with Pheochromocytoma.
Patients with neurofibromatosis type 1 had a relatively high (but not significant) prevalence of malignant disease (12 percent), second only to that among patients with paraganglioma syndrome 4 who had a germ-line mutation in the SDHB gene (24 percent). Taken together, 33 percent of all symptomatic patients with pheochromocytoma in the registry carried germ-line mutations in one of the five genes, including NF1.
Birke Bausch, M.D.
Wiktor Borozdin, Ph.D.
Hartmut P.H. Neumann, M.D.
University of Freiburg
79106 Freiburg, Germany
neumann@med1.ukl.uni-freiburg.de
for the European-American Pheochromocytoma Study Group
Dr. Neumann is supported by a grant (NE 571/5-3) from the Deutsche Forschungsgemeinschaft, a grant (70-3313-ne1) from the Deutsche Krebshilfe, and a grant (LSHC-CT-2005-518200) from the European Union.
References
Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305:1617-1627.
Dluhy RG. Pheochromocytoma -- death of an axiom. N Engl J Med 2002;346:1486-1488.
Luijten M, Wang Y, Smith BT, et al. Mechanism of spreading of the highly related neurofibromatosis type 1 (NF1) pseudogenes on chromosomes 2, 14 and 22. Eur J Hum Genet 2000;8:209-214.
Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943-951.
Borozdin W, Boehm D, Leipoldt M, et al. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet 2004;41:e113-e113.