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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0780
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3478-3481
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Comprehensive Mutation Scanning of NF1 in Apparently Sporadic Cases of Pheochromocytoma

Birke Bausch1, Ann-Cathrin Koschker1, Martin Fassnacht, Johanna Stoevesandt, Michael M. Hoffmann, Charis Eng, Bruno Allolio and Hartmut P. H. Neumann

Departments of Nephrology (B.B., H.P.H.N.) and Laboratory Medicine (M.M.H.), Albert-Ludwigs-University, D 79106 Freiburg, Germany; Departments of Endocrinology (A.-C.K., M.F., B.A.) and Dermatology (J.S.), Julius-Maximilians-University, D 97070 Würzburg, Germany; Genomic Medicine Institute (C.E.), Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Hartmut P. H. Neumann, M.D., Medizinische Universitätsklinik, Hugstetter Straße 55, D 79106 Freiburg, Germany. E-mail: neumann{at}med1.ukl.uni-freiburg.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Pheochromocytoma is a rare manifestation in patients with neurofibromatosis type 1 (NF 1). The 57-exon susceptibility gene NF1 has so far not been systematically scanned for unexpected germline mutations in individuals with sporadic pheochromocytoma.

Methods: Twenty-seven patients with bilateral adrenal and/or extraadrenal abdominal pheochromocytoma not carrying germline mutations of the genes VHL, RET, SDHB, and SDHD were selected from the European-American pheochromocytoma registry. All 57 exons and flanking intronic regions of the NF1 gene were PCR amplified using newly designed primer pairs to exclude the amplification of pseudogenes. Intragenic mutation scanning was performed using denaturing HPLC and bidirectional direct sequencing.

Results: Of the 27 apparently sporadic cases, one (4%) was found to have a pathogenic germline NF1 mutation, Leu303Arg. Clinical reevaluation of this individual, who had bilateral pheochromocytoma, revealed classic, but very mild, features of NF 1, one cutaneous neurofibroma, axillary freckling, and Lisch nodules of the iris as well as a few café-au-lait spots.

Conclusions: In the absence of germline mutations in VHL, RET, SDHD, and SDHB, patients with pheochromocytoma, especially with bilateral disease, should be checked thoroughly for clinical lesions suggestive of underlying syndromes such as the cutaneous and ophthalmological features characteristic of NF 1.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NEUROFIBROMATOSIS TYPE 1 (NF 1, von Recklinghausen disease) is a clinically characterized disorder. Among the many components that can vary for their presence or absence as well as number and severity even within one family, the cardinal features of NF 1 are cutaneous neurofibromas, café-au-lait spots, axillary or inguinal freckling, and Lisch nodules of the iris. Therefore, the diagnosis is based on operational clinical criteria initially established by the National Institutes of Health Consensus Development Conference in 1988 and revised in 1997 (1, 2). Pheochromocytoma is a rare condition in NF 1 and occurs in about 1% of the patients, which is clearly more than expected by chance (3). A review of the literature performed in 1999 by Walther et al. (4) found that 9.6% of NF 1-associated pheochromocytoma presented as bilateral adrenal tumors and 6% were extraadrenal. Thus, NF 1-related pheochromocytoma show the classic characteristics of a hereditary cause (5, 6, 7).

In 1987, the susceptibility gene, the NF1 gene, was localized to chromosome subband 17q11.2 (8, 9), and in 1990 it was isolated (10). With the isolation of the susceptibility gene, the potential for gene-based diagnosis became a theoretical reality. However, from a practical point of view, routine NF1 mutation scanning was not possible because of the large size of the gene spanning approximately 350 kb genomic DNA with the coding region encompassed by 57 exons, the lack of any mutational hot spots, and the large number of pseudogenes (10, 11). So far, no study exists in which patients with apparently sporadic pheochromocytoma have been subjected to comprehensive germline mutation scanning of the NF1 gene. Because the germline mutation frequency in apparently sporadic pheochromocytoma associated with VHL, RET, SDHB, and SDHD is significant (24%), we sought to determine whether NF1 germline mutations are also germane in the genetic differential diagnosis of apparently sporadic presentations of pheochromocytoma.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The European-American Pheochromocytoma study was formally established in 1995 (6). The study patients presented with symptomatic disease and histologically confirmed adrenal and abdominal or thoracic extraadrenal pheochromocytoma. The molecular genetic classification of these patients is the primary thrust of this group and has been performed for the genes RET (the susceptibility gene for multiple endocrine neoplasia type 2), VHL (the susceptibility gene for von Hippel-Lindau disease), SDHB (the susceptibility gene for paraganglioma syndrome type 4), and SDHD (the susceptibility gene for paraganglioma syndrome type 1) (6, 12). Twenty-seven unrelated patients with multifocal or extraadrenal pheochromocytoma and who were mutation negative for these genes, had a negative family history, and apparently did not meet the clinical criteria for NF 1 were selected for the present study.

Molecular genetic analysis

Genomic DNA was extracted from peripheral lymphocytes in 10 ml EDTA-anticoagulated blood according to standard procedures. All 57 exons including the flanking intronic regions were PCR amplified. The 57 primer pairs have been newly designed to avoid the amplification of the 36 known pseudogenes. Mutation scanning was performed by denaturing HPLC using the WAVE analysis system (Transgenomics, Paris, France). Abnormal chromatographic patterns led to bidirectional direct sequencing using a Mega BACE 500 sequencer (Amersham Biosciences, Freiburg, Germany). The detected DNA variants, especially the ones of a missense type, were investigated for pathogenicity by segregating them with the phenotype in families and analyzing whether they were present in 200 healthy, unrelated, and ethnically matched control subjects.

The protocol was approved by the Ethical Committee of the University of Freiburg, and the patients gave written or oral informed consent as per institutional routine.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The median age at diagnosis of the 27 study subjects with apparently sporadic pheochromocytoma was 45 yr (range 6–66). Among these 27, eight (30%) had bilateral adrenal pheochromocytoma, 14 (52%) had multifocal tumors, and 21 (78%) had extraadrenal tumors. Furthermore, two (7%) had malignant pheochromocytoma, defined as neoplasias with distant metastases. The clinical characteristics of the 27 study patients (aged 6–66 yr, eight with bilateral and 14 with multifocal pheochromocytoma) are summarized in Fig. 1Go.


Figure 1
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  		FIG. 1. Venn diagram representing the tumor characteristics of the 27 subjects.

 
Mutation analysis of all 57 coding exons and flanking intronic regions of the NF1 gene in the 27 individuals revealed five different DNA variants. Among these were two different intraexonic missense variants and three different silent variants, at least one found in each patient (data not shown). All but one were classified as polymorphisms because of their presence in the healthy control group and/or did not cause an amino acid substitution. Of note, the NF1 c. 908 T>G nucleotide substitution resulting in the missense mutation Leu303Arg found in one subject was absent in the 200 healthy, unrelated control samples. The Leu303Arg amino acid exchange was therefore classified as a missense mutation. The Human Gene Mutation Database did not cite this newly identified mutation (www.hgmd.cf.ac.uk).

The mutation-positive patient is a 48-yr-old man operated on at the age of 44 yr for benign, bilateral, adrenal pheochromocytoma by endoscopic bilateral adrenalectomy. Preoperative findings included elevation of 24-h urine norepinephrine to 600 µg (normal up to 105), normetanephrines to 2791 µg (normal up to 355), and metanephrines to 1880 µg (normal up to 300). Abdominal computerized tomography (CT) scan (Fig. 2AGo) showed a right adrenal 5.5 x 3.5 x 3 cm tumor and a left adrenal 5 x 3 x 2.7 cm tumor, both of which showed 123I-metaiodobenzylguanidine uptake.


Figure 2
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  		FIG. 2. Findings of the patient identified with the germline NF1 mutation Leu303Arg during this study. A, CT scan: bilateral pheochromocytomas marked with arrows. B, Axillary freckling. C, Café-au-lait spots at the back (arrows). D, Lisch nodules (arrows).

 
Once the mutation analysis revealed the unexpected germline NF1 mutation, the patient was invited to be reevaluated clinically. Again, family history was found to be negative for the diagnostic criteria of NF 1. Both parents are alive without known signs of NF 1. A thorough clinical investigation is pending. The patient has no siblings and no children. Clinical reevaluation disclosed faint bilateral axillary freckling (Fig. 2BGo), three café-au-lait spots on the patient’s back and left upper arm (Fig. 2CGo), a small fibroma of the left breast, and discrete yellow-brownish spots of the iris of both eyes characteristic of Lisch nodules (Fig. 2DGo). Although the patient was seen by several physicians for diagnosis and treatment of bilateral, adrenal pheochromocytomas, the very mild skin and eye lesions characteristic of NF 1 went unrecognized.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
NF 1 is a heritable tumor syndrome with typical lesions of which cutaneous neurofibromas, axillary freckling, café-au-lait spots, and Lisch nodules are the most frequent. Currently these lesions are diagnostic of NF 1 if two of these are present (2) and have until recently been the only physical clues to the diagnosis. Pheochromocytoma has been reported in about 1% of patients with NF 1 (3). Therefore, there are no large series of NF 1 patients with pheochromocytoma originating from a single center. The pathogenesis of pheochromocytoma in NF 1 and the question why only a minority of these subjects develop this tumor type is unknown. A recent review (13) refers to biallelic inactivation of the NF1 gene in a mice model (14) and humans (15) and loss of neurofibromin expression (16, 17). With the discovery of a growing number of pheochromocytoma-predisposing genes, it is possible to assign the molecular etiology for pheochromocytoma.

Taking advantage of our population-based registry of symptomatic apparently sporadic pheochromocytoma presentations, we found that 24% actually were due to germline mutations in one of RET, VHL, SDHB, and SDHD (6). However, despite this high frequency of germline mutations (i.e. heritable cause) among apparently sporadic cases, there always remained those without these mutations but showing signs of heredity, such as bilateral or multifocal disease, early onset, and an extraadrenal tumor location. In addition to the syndromes associated with these genes, it is well known that pheochromocytoma is a component, albeit uncommon, of NF 1 (3). One extensive literature survey includes 148 patients with NF 1-associated pheochromocytoma (4). These patients showed predominantly adrenal tumors (94%). Only 6% displayed extraadrenal pheochromocytoma; 16% of the patients had multiple tumors. In this study, when we examined 27 apparently sporadic pheochromocytoma cases without germline mutations in any of these four genes, we found one of 27 (4%) of the patients with an NF1 germline mutation. In our study group of 27 were eight with bilateral disease. Therefore, we note that one of eight patients (13%) with bilateral adrenal pheochromocytoma carried an unexpected germline NF1 mutation. Surprisingly, clinical reevaluation disclosed minor, but characteristic, lesions typical for NF 1. These were so mild that they were previously overlooked, although several physicians had seen the patient for the diagnosis and surgical treatment of his two tumors. Why seven of eight patients with bilateral adrenal pheochromocytoma, a striking feature for inherited conditions, did not show any germline mutation is difficult to answer and is most likely pointing to new, so-far-unidentified susceptibility genes (18). Another explanation may be incomplete sensitivity of the mutation detection technologies used. To miss seven of eight would be highly unusual, given that we used denaturing HPLC followed by sequencing, both considered highly sensitive (>95%) techniques. However, like all PCR-based technologies, they do not detect large deletions.

For any neoplasia, determining whether it is sporadic or hereditary is vital because of the implications for the patient himself/herself and for his/her whole family. Assigning a specific gene as the hereditary predisposing gene is equally important because mutations in different genes that predispose to a single type of neoplasia may carry with it predisposition to other cancers or other risks. For example, if a germline mutation in RET is found in an individual with pheochromocytoma, then that individual is at very high risk for developing medullary thyroid cancer and hyperparathyroidism (19, 20). In contrast, germline mutations in SDHB predispose to not only pheochromocytoma and paraganglioma but also possibly increased risk of malignant disease and renal cell carcinoma at a young age (12). Therefore, if an individual with pheochromocytoma has not been found to have germline mutations in VHL, RET, SDHB, and SDHD, then a thorough physical examination looking for even subtle signs of NF 1 would be warranted. This would help avoid unnecessary searching for large deletions and rearrangements in SDHB and SDHD, which have been described in individuals presenting with pheochromocytoma who are mutation negative for VHL, RET, SDHB, and SDHD by PCR-based techniques (21).

In summary, we have demonstrated that a germline mutation of the NF1 gene can be unexpectedly found in a candidate group of patients with bilateral or extraadrenal pheochromocytoma. However, careful clinical investigations for skin and eye lesions typically found in NF 1 patients can avoid the enormous costs caused by molecular genetic analyses of the series of pheochromocytoma susceptibility genes. The importance of identifying NF 1 patients amongst those presenting with pheochromocytoma is underscored by the fact that many of the presenting clinical features of this neoplasia are similar between NF 1 and sporadic cases, except for an increased risk of malignant disease in NF 1 and multifocality. We have systematically and comprehensively compared the clinical features of these two groups of pheochromocytoma in our extended registry, of which the presently reported patients are a part (22).


   Acknowledgments
 
We thank Dr. Handwerker (Karlstadt, Germany) for the CT images and the Department of Nuclear Medicine of the Julius-Maximilians-University of Würzburg for the 123I-metaiodobenzylguanidine images. We are grateful to Dr. Beyer (Oberhausen, Germany), Dr. Brauckhoff (Halle, Germany), Dr. Fottner (Mainz, Germany), Dr. Januszewicz and Dr. Peçzkowska (Warsaw, Poland), Dr. Birkenfeld (Berlin, Germany), Dr. MacGregor (London, UK), Dr. Opocher (Padova, Italy), Dr. Petersenn (Essen, Germany), Dr. Schmid (Munich, Germany), and Dr. Walz (Essen, Germany) for their continued collaboration.


   Footnotes
 
This work was supported by Grants 70-3313-Ne 1 from the Deutsche Krebshilfe (German Cancer Foundation) (to H.P.H.N.) and NE 571/5-3 from the Deutsche Forschungsgemeinschaft (German Research Foundation). C.E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is funded by the National Institutes of Health (R01HD39058).

First Published Online June 20, 2006

1 B.B and A.-C.K. contributed equally to the work. Back

Abbreviations: CT, Computerized tomography; NF 1, neurofibromatosis type 1.

Received April 10, 2006.

Accepted June 13, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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