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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 362-367
Copyright © 2004 by The Endocrine Society

A Novel Succinate Dehydrogenase Subunit B Gene Mutation, H132P, Causes Familial Malignant Sympathetic Extraadrenal Paragangliomas

Margarete Maier-Woelfle, Michael Brändle, Paul Komminoth, Parvin Saremaslani, Sonja Schmid, Tamara Locher, Philipp U. Heitz, Ina Krull, Renato L. Galeazzi, Christoph Schmid and Aurel Perren

Department of Internal Medicine (M.M.-W., C.S.), Division of Endocrinology and Diabetology, and Institute of Clinical Pathology, Department of Pathology (P.S., S.S., T.L., P.U.H., A.P.), University Hospital Zurich, CH-8091 Zurich, Switzerland; Department of Internal Medicine (M.M.-W., M.B., I.K., R.L.G.), Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland; and Institute of Pathology (P.K.), Kantonsspital Baden, CH-5405 Baden, Switzerland

Address all correspondence and requests for reprints to: Aurel Perren, M.D., Department of Pathology, University Hospital Zurich, Schmelzbergstr 12, CH-8091 Zurich, Switzerland. E-mail: aurel.perren{at}usz.ch.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We report a family with malignant sympathetic paragangliomas (PGL) exhibiting a new type of germline mutation in the succinate dehydrogenase subunit B (SDHB) gene. Two affected brothers, presenting with symptoms at the ages of 25 and 52 yr, suffered from malignant abdominal extraadrenal sympathetic PGL. They died of their disease at ages 43 and 61 yr. Their mother had the same history of signs and symptoms, suggesting a catecholamine-producing tumor at the age of 55 yr. Analysis of the germline DNA from these three patients revealed a novel mutation in exon 4 (H132P) of the SDHB gene. This mutation was absent in 160 control chromosomes. Loss of heterozygosity analysis of the tumors showed a loss of one SDHB allele, and RT-PCR-based expression analysis confirmed the exclusive expression of the mutated allele in both tumors. A review of the published PGL families revealed malignant tumors in seven of 12 well-documented families with SDHB mutation-associated extraadrenal PGL. These findings, as well as findings of the family reported here, suggest a strong causal relationship of SDHB germline mutations with malignant extraadrenal abdominal PGL and imply the necessity of a close follow-up of affected individuals and family members.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PHEOCHROMOCYTOMA (PCC) AND extraadrenal sympathetic paraganglioma (PGL) are phenotypically highly similar tumors of chromaffin cells that may produce and secrete catecholamines. However, possible differences between these tumors have been reported at the molecular level (1). Therefore, we will hereafter classify all extraadrenal tumors as PGL (synonym for sympathetic tumors: extraadrenal PCC; and synonyms for parasympathetic tumors: carotid body tumor and chemodectoma) and strictly reserve the term PCC for tumors of the adrenal medulla. Up to 90% of PCC are noninherited and sporadic, whereas germline mutations in the familial syndromes of multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and neurofibromatosis type 1 (NF1) account for at least 9.5% of PCC (2). More recently, it has been shown that germline mutations of the mitochondrial complex II genes for succinate dehydrogenase subunits B, C, and D (SDHB, SDHC, and SDHD) cause hereditary PGL (3). Although familial adrenal PCCs are caused by mutations of Ret (multiple endocrine neoplasia type 2, OMIM 164761), VHL (VHL, OMIM 193300), or NF1 (NF1, OMIM 162200), familial PGLs are caused by SDHD and rarely SDHC mutations (3, 4, 5), as well as by SDHB mutations (6).

The incidence of malignancy in abdominal extraadrenal PGLs has been reported to range between 14% and 50% (7, 8, 9). However, the evaluation of malignancy in PGLs poses serious problems to the pathologist, and the only reliable criterion for malignancy are metastases, which can occur late in the course of the disease. Therefore, a careful clinical follow up of patients is necessary. Histological characteristics, such as atypia of tumor cells, necrosis, size, weight, and presence of vascular invasion are not reliable criteria of malignancy (10). To date, the occurrence of malignant tumors in a familial setting has not been assessed systematically.

We report here a family suffering from malignant abdominal sympathetic PGLs associated with a novel SDHB mutation, and we review the relevant publications dealing with SDHB-, SDHC-, and SDHD-associated familial PGLs with respect to malignant behavior.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We investigated three generations of a family (Fig. 1Go) with two brothers (two of eight members of generation II) suffering from malignant abdominal extraadrenal PGL of the organ of Zuckerkandl. VHL or Ret germline mutations had been excluded. In generation I, members I.1 and I.2 died before our investigations. They did not suffer from symptoms or signs, suggesting a catecholamine-producing tumor. In generation II, five of eight members were examined (II.2, II.4, II.5, II.6, and II.8); the remaining three members (II.1, II.3, and II.7) declined an evaluation for catecholamine-secreting tumors. Until now, only one member of the third generation (III.3) was examined, revealing no clinical signs suggestive of PGL.



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  		FIG. 1. Pedigree of the family.

 
In 1969, at the age of 12 yr, patient II.8 (Fig. 1Go) suffered from episodic headaches, truncal sweating, palpitations, and pallor, suggesting a catecholamine-secreting tumor. At the age of 25 yr, he presented with hypertension (systolic blood pressure > 200 mm Hg, diastolic blood pressure > 110 mm Hg). Urinary excretion of norepinephrine was increased during a hypertensive attack as well as in a 24-h collection. Preoperative abdominal ultrasonography and computed tomography revealed a left-sided abdominal mass. At laparotomy, an extraadrenal paraaortal PGL (8.5 x 5.5 x 3.5 cm) with local lymph node metastasis was removed. Postoperatively, the 24-h urinary excretion of norepinephrine dropped to the normal range. At the age of 42, patient II.8 presented with lower back pain and a new history of episodes of headaches, sweating, and palpitations. The 24-h urinary excretion of norepinephrine was elevated and consistent with recurrent PGL. Magnetic resonance imaging showed lytic lesions within the lumbar vertebra 2. After corporectomy of the lumbar vertebra 2, the 24-h urinary secretion of norepinephrine normalized, but 123I-metaiodobenzylguanidine (MIBG) scintigraphy revealed an increased uptake in the proximal right femur and in the frontal skull. One year later, the metastatic PGL progressed clinically and biochemically. Therapeutic administration of 131I-MIBG was unsuccessful; the only effective treatment was blood pressure control with phenoxybenzamine, with relief from symptoms. The patient died 1 yr after the primary manifestation of bone metastases at the age of 43.

Patient II.4 had a history of a duodenal ulcer at the age of 20 yr and headaches, stress, and palpitations since the age of 45 yr. In 1991, at the age of 52, he presented with attacks of sweating, pallor, weight loss, and psychiatric disorders as episodes of anxiety, nervousness, and panic. Because of the family history of extraadrenal PGL, biochemical and radiological evaluation was initiated and confirmed the diagnosis of an extraadrenal PGL secreting norepinephrine. At laparotomy, an extraadrenal PGL (5.3 x 2.2 x 1.7 cm) was removed. Six years after this operation, intraabdominal and bone metastases (cervical and thoracic spine and in the proximal right femur) were detected. The patient died 3 yr later at the age of 61 yr due to extensive bone metastases that was unresponsive to the 131I-MIBG therapy.

Patient I.3, the aunt of the two brothers, had been successfully operated for a symptomatic, adrenal PCC at the age of 50 yr, without evidence for recurrence during the following 43 yr; she is alive and well.

Patient I.4, the mother of patients II.8 and II.4, showed signs and symptoms consistent with a catecholamine-secreting tumor. Since the age of 55 yr, she presented with episodes of sweating and pallor. She suffered from hypertension resistant to combination therapy with verapamil, furosemide, reserpine, clopamide, and dihydroergocristine and had a high consumption of nonsteroidal antiinflammatory drugs because of forceful attacks of headaches. She died at the age of 67 yr of bleeding duodenal ulcers. Unfortunately, an autopsy has not been performed.

Patient II.6, the 61-yr-old sister of patients II.4 and II.8, is well and does not present any symptoms suggesting PCC besides very rare episodes of headaches. Her blood pressure and the 24-h urinary excretion of norepinephrine, epinephrine, and dopamine are normal.

The siblings II.2, II.5, and III.3, the daughter of patient II.8, do not show clinical signs of having catecholamine-secreting tumors. The 24-h urinary excretion of norepinephrine, epinephrine, and dopamine is normal in III.3.

Methods

Blood and tumor samples. Peripheral blood for germline DNA analysis was drawn from the family members after obtaining informed consent. A paraffin block from a gastrectomy specimen was the only available source of DNA from patient I.4, the mother with clinical symptoms of a catecholamine-secreting tumor. Paraffin blocks of the tumors of the affected individuals, II.4 and II.8, were obtained from the Pathology Departments of the University Hospital Zurich and Kantonsspital St. Gallen. The samples had been fixed in 4% buffered formalin and embedded in paraffin according to standard protocols.

Controls. Blood samples of 80 unrelated Swiss individuals without endocrine disease were used as normal controls.

Denaturing gradient gel electrophoresis (DGGE)-based mutation analysis. DNA from peripheral blood was extracted using the Purgene kit (GentraSystems, Minneapolis, MN) according to the manufacturer’s instructions. When no blood was available (patients I.4 and II.4), normal tissue was microdissected from 10-µm tissue sections of the paraffin blocks, and the DNA was extracted as previously described (11). The same procedure was applied for the tumor samples.

Primers for PCR have been designed based on GenBank sequences using the Primer 3 software (Whitehead Institute for Biomedical Research, Cambridge, MA) (12), and intron-exon boundaries have been included. PCR using genomic DNA as template was carried out in a 50-µl mixture of 1x PCR buffer (Perkin-Elmer Europe, Rotkreuz, Switzerland) containing 400 ng of template DNA, 200 µM deoxynucleotide triphosphate (Roche Diagnostics, Rotkreuz, Switzerland), 1 µM of each primer and 1 µl of Taq polymerase (Ampli Taq Gold, Perkin-Elmer Europe). A touch-down procedure was used consisting of 5 sec at 95 C, annealing for 60 sec at temperatures decreasing from 60 to 55 C during the first 11 cycles (with 0.5-C decremental steps in cycles two to 11), and ending with an extension step at 72 C for 60 sec. Ten cycles with an annealing temperature of 55 C and 15 cycles with an annealing temperature of 45 C were followed with extension times of 90 sec. After a step of final extension for 10 min at 72 C, heteroduplex formation was induced after 10-min denaturation at 98 C by incubations at 55 C for 30 min and 37 C for 30 min. For DGGE analysis, 10 µl of the PCR product was loaded with 3 µl of Ficoll-based loading buffer onto 10% polyacrylamide gels containing a urea-formamide gradient (available upon request) in 0.5 x Tris acetate-EDTA. The amplicons were electrophoresed at 60 C and 100 V for 16 h. The fragments were visualized using silver staining as described (13). Samples exhibiting additional bands were cycle sequenced. Because only highly fragmented paraffin DNA was available for patient I.4, a PCR spanning codon 132 was designed to yield a small amplification product of 81 bp.

Loss of heterozygosity (LOH) analysis. The genomic DNA obtained from the microdissected tumor samples and adjacent nonneoplastic tissue of patient II.4 and the peripheral blood of patient II.8 were used to amplify the polymorphic markers D1S402 (telomeric) and D1S199 and D1S2644 (centromeric) flanking the SDHB gene. The forward primers were 5' labeled with either 5' hexachloro fluorescein phosphoramidite (HEX) or 5' fluorescein phosphoramidite (6-FAM) fluorescent dyes. Fragment size analysis was performed with the 3100 Genetic Analyzer, Applied Biosystems/Hitachi and Gene-Scan software (Applied Biosystems, Foster City, CA).

Expression analysis. RNA was extracted from microdissected 10-µm paraffin sections of tumor tissue using a commercial kit (RNeasy Mini Kit; Qiagen, Basel, Switzerland) according to the manufacturer’s recommendation. After removal of remaining DNA by DNase digestion (DNAfree-Kit; Ambion, Austin, TX), 1 µg of RNA was reverse transcribed using oligo-p(dt) primers and the First Strand cDNA Synthesis Kit (Roche Diagnostics). To assure that only cDNA and not genomic DNA could be amplified, primers for RT-PCR were designed to span intron 4 and to yield a small product of 78 bp. This PCR product was then gel purified on 1% agarose gels, extracted from the agarose using the QIAEX II Extraction Kit (Qiagen), and cycle sequenced.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
DNA analysis was performed in eight of the 15 family members. DGGE analysis of the germline DNA revealed a polymorphism in exon 2 of the SDHD gene in five family members (II.4, II.5, II.6, II.8, and III.3) and a new germline variant in exon 4 of the SDHB gene in four family members (I.4, II.4, II.6, and II.8) (Fig. 1Go). Three of the members (I.4, II.4, and II.8) had classic clinical symptoms of a catecholamine-secreting tumor, and two of them (II.4 and II.8) had histologically proven malignant sympathetic PGL (Fig. 1Go). In patient I.3, who had a history of adrenal PCC, DGGE analysis of the germline DNA excluded the polymorphism in exon 2 of the SDHD gene and the new variant in exon 4 of the SDHB gene.

Sequencing of the exon 4 variant of the SDHB gene showed a nucleotide exchange a>c in codon 132, resulting in an amino acid change H132P (Fig. 2Go, top). This variant was absent in all 160 control chromosomes examined but present in both affected individuals (II.4 and II.8), as well as in their mother (I.4). No DGGE variants were detected in the SDHC gene.



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  		FIG. 2. Top, SDHB exon 4 sequence analysis of the genomic DNA reveals the H132P mutation in a heterozygous form in both affected brothers as well as their mother. Middle, LOH analysis using microsatellite markers; D1S402 is not informative in patient II.4, D1S199 shows loss of one allele in the tumors of patients II.4 and II.8 (arrow). Bottom, SDHB exon 4 sequence analysis of cDNA reverse transcribed from tumor tissue RNA. Control cDNA shows the wild-type sequence, and tumors of patients II.4 and II.8 show exclusive expression of the allele carrying the H132P mutation. No, Nonneoplastic tissue; Tu, tumor tissue.

 
One of the microsatellite markers (D1S199) showed two distinct products and was informative for the brothers (II.4 and II.8). In both of their tumors, the larger allele of the D1S199 was lost, whereas the allele of 90 bp was retained (Fig. 2Go, middle). The marker D1S2644 was not informative, and D1S402 could not be amplified in the tumor tissues because of its large size of 230 bp.

RT-PCR of parts of exons 4 and 5 of the SDHB gene showed loss of the wild-type allele in both tumors, resulting in sole expression of the allele carrying the a>c transition, indicating that H132P is not a polymorphism but a true germline mutation (Fig. 2Go, bottom).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We identified a nucleotide exchange a>c in codon 132 of the SDHB gene, resulting in an exchange of the neutral hydrophilic histidine by a hydrophobic proline in the germline DNA of two brothers (patients II.4 and II.8) who suffered from metastasizing extraadrenal sympathetic PGL. The same nucleotide exchange was present in the germline DNA of their mother (patient I.4), who suffered from the same disease, and of the sister (patient II.6), who does not present clear-cut signs of the disease. This variant was absent in 160 control chromosomes, arguing against a polymorphism. This histidine residue is conserved among human, rat, Drosophila, and yeast, and the glycine at the corresponding residue of the Escherichia coli homolog is also a neutral hydrophilic amino acid.

According to the two-hit hypothesis of Knudson et al. (14), both alleles of a tumor suppressor gene are impaired in familial tumors. PGLs occurring in families with SDHD germline mutations (PGL1, OMIM 168000) have been shown to have an allelic loss of the 11q23 region (4). The status of the second allele in tumors of patients with SDHB germline mutations has also been assessed. Although Young et al. (15) showed LOH of the flanking microsatellite marker D1S507, sequencing of the mutated codon 242 in exon 7 suggested the retention of the wild-type allele. This result could suggest (15) that other tumor suppressor genes on 1p35–36 are involved. Alternatively, a partial loss of the SDHB wild-type allele may have occurred. Gimenez-Roqueplo et al. (16) have shown LOH in tumor tissue of a SDHB-associated PCC. This tumor was malignant and showed extensive local invasion into the vena cava and right auricle to such an extent that a distinction of an adrenal PCC from a juxtaadrenal sympathetic PGL becomes difficult. These authors also showed the functional consequence of a complete loss of malonate-sensitive cytochrome c activity.

In the tumors of the patients presented here, the sequencing results provided evidence for LOH of the SDHB locus, because only the mutant cytosine was amplified from the tumor DNA (Fig. 2Go, top). In addition, using the flanking microsatellite marker D1S199, we showed allelic loss centromeric of SDHB in both tumors. Furthermore, the same allele of 90 bp of the microsatellite marker D1S199 was retained, whereas the alleles of 98 bp (patient II.4) and 92 bp (patient II.8) were lost in the tumors. Expression analysis was performed to demonstrate the loss of the wild-type allele. Sequencing of the RT-PCR products showed expression of the H132P variant but not of the wild-type sequence in both tumors. Thus, we have shown that in the tumors one allele carries the H132P variant in presence of the loss of the wild-type allele. We conclude that this variant represents a true germline mutation. Intriguingly, patient I.3 who had a sympathetic tumor did not carry this germline variant. However, the phenotype was different; she suffered from a clinically benign adrenal PCC, and we consider it a sporadic tumor.

Studies on SDHB and SDHD mutation-associated PGLs reveal an emerging genotype-phenotype correlation. Baysal (17) noted that families with SDHD mutations most often exhibit cervical parasympathetic PGLs but rarely suffer from abdominal sympathetic PGLs. In contrast, the phenotype of 25 (89%) of 28 independent germline SDHB mutation-associated tumors was characterized by abdominal, mostly sympathetic extraadrenal PGLs (Table 1Go). Abdominal extraadrenal PGLs are known to be the most aggressive PGLs of the sympathoadrenal neuroendocrine system, with an incidence of malignancy of 15% (7) to 50% (9).


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  		TABLE 1. Summary of reported SDHB mutations and associated phenotype

 
To date, 24 different SDHB mutations have been described in 28 unrelated individuals or families (3, 5, 6, 15, 16, 18), including the present report (Table 1Go). Based on the studies with detailed clinical information, an additional phenotype-genotype correlation emerges. Ten (90%) of 12 SDHB-associated families were characterized by the exclusive occurrence of extraadrenal sympathetic PGLs (6, 15, 18), including the family reported here. Only one tumor was reported to have occurred in the adrenal gland (16), and one family was reported to suffer from both extraadrenal PGLs and a PCC (18). It is important to realize that seven (58%) of 12 of these well-documented families carrying SDHB germline mutations exhibited a malignant phenotype (Table 1Go). Interestingly, the clinical course of one patient reported by Young et al. (15) with a 30-yr survival of a malignant catecholamine-secreting tumor resembles the family reported here. Patient II.8 died 18 yr after the diagnosis of a malignant extraadrenal PGL, and patient II.4 retrospectively most probably suffered from this disease for 16 yr. Unfortunately, most multicenter studies consist of groups of patients and include neither follow-up data nor the precise location of the tumors or a malignant phenotype. To our knowledge, no PGL family with SDHD mutation was reported to harbor malignant tumors.

Although Ret, NF1, and VHL are genes that primarily cause adrenal PCCs, the SDHB gene appears to cause extraadrenal PGLs with a high rate of malignant behavior. Therefore, SDHB mutation analysis should be recommended for patients presenting with familial extraadrenal PGLs. Identification of a SDHB mutation may then warrant a close follow up of affected patients and of germline mutation-carrying children.


   Acknowledgments
 
We thank Dr. R. Schmid, Pathology, St. Gallen, Switzerland, for providing tissue blocks.


   Footnotes
 
This work was supported by Swiss Cancer League Grant SKL-997-02-2000 and Swiss National Science Foundation Grant 31-618845.00.

Abbreviations: DGGE, Denaturing gradient gel electrophoresis; LOH, loss of heterozygosity; MIBG, metaiodobenzylguanidine; NF1, neurofibromatosis type 1; PCC, pheochromocytoma; PGL, paraganglioma; SDHB, succinate dehydrogenase subunit B; SDHC, succinate dehydrogenase subunit C; SDHD, succinate dehydrogenase subunit D; VHL, von Hippel-Lindau.

Received August 1, 2003.

Accepted September 29, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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