In this report, we describe a novel germline mutation in the SDHB gene, mutations of which are known to cause the heritable PG syndrome PGL4. In this syndrome, patients are at significantly increased risk of developing head and neck and sympathetic PG and, occasionally, pheochromocytomas.
gene is located on chromosome 1p36-1p35 and contains eight exons and a total open reading frame of 756 nucleotides. The gene codes for the iron sulfur protein in the succinate-ubiquinone oxidoreductase of the succinate dehydrogenase enzyme complex.2
Mutations in this gene are autosomal dominant, and estimates of their penetrance vary widely (8–55% at age 40 and 30–100% at age 80).3
In a combined pheochromocytoma and paraganglioma registry in Europe, 5% of registrants had one of 15 different germline mutations in SDHB
, most of them missense mutations.4
A mutation in SDHB
tends to cause fewer head and neck PG than SDHD
mutations, though malignant tumors and additional extraparaganglial malignancies such as renal cell carcinoma and possibly thyroid papillary carcinoma are more common in those with SDHB
Furthermore, gastrointestinal stromal tumors may occur in association with PG due to SDHB, SDHD
, or SDHC
mutations (also known as the Carney-Stratakis dyad). Thus, a patient with a known SDHB
mutation deserves full body screening for other tumors or malignancies.
Mutations in the SDH
gene family are hypothesized to cause PG syndromes via two putative mechanisms: the first is by disrupting normal apoptotic pathways in paraganglionic cells – SDH activity is required for the proapoptotic activity of the prolyl hydroxylase EglN3, which is feedback inhibited by succinate.2
With a poorly-functioning SDH enzyme complex, the accumulation of succinate inhibits EglN3, leading to cellular escape from apoptosis. The second mechanism is the dysregulation of hypoxia-induced factors (HIF), which produces a cellular response similar to that of hypoxia, stimulating paraganglial hypertrophy and hyperfunction. Mutations of SDH result in the inhibition of HIF-1 prolyl hydroxylase, which leads to stabilization of HIF-1 cofactor that can enter the nucleus and stimulate gene transcription5
The mutation described in this report is a cytosine-to-guanine mutation at nucleotide 331 that changes the amino acid from leucine to valine at amino acid position 111 in exon 4 (Leu111Val). This mutation has not been described previously in the literature or the SDHB
At the time of this drafting, the database contains 24 other mutations in SDHB
that contributed to carotid body PG, though most of those patients had other PG or pheochromocytomas as well. Because this patient presented with bilateral PG of the carotid body, we presume she has an underlying genetic susceptibility to PG, and we speculate that the Leu111Val mutation of SDHB
is pathogenic. However, it is possible that Leu111Val could be a rare but benign polymorphism not associated with PG risk, and the real disease-causing mutation is not able to be identified with current techniques. Further molecular analysis will be necessary to determine the oncogenic impact of this mutation.
Due to the rarity of PG and their hereditary syndromes, optimal therapy is challenging to determine, particularly among those with multiple or bilateral tumors.7
Earlier identification of disease could improve outcomes. Therefore, genetic screening is crucial in patients at risk of PG syndromes to identify those who merit enrollment in an appropriate imaging-based screening program. We suggest that patients with features suggesting a heritable PG syndrome undergo screening for mutations in SDHD, SDHB
, and SDHC
. The most recently described genes responsible for PG syndrome, SDHAF2, TMEM127
, and KIF1B
should also be considered if the more common mutations are absent and as genetic testing becomes available. However, counseling patients will be challenging due to the paucity of data regarding mutation detection rates, the possibility of variants of uncertain significance and unknown disease penetrance associated with these genes. It has been argued that patients with seemingly sporadic disease may also benefit from genetic testing, though clinical judgment based on presentation and family history is likely a superior method from a cost-benefit point of view.8
In general, patients with an apparently sporadic single tumor who have a young-onset (age of diagnosis less than 40 years) or malignant disease are good candidates for genetic testing. Due to the substantial differences in allele frequencies seen in the literature, it is important to be aware of the local genetic variability in order to best decide on screening parameters in the clinician’s place of practice. Further research with population-linked data on allelic frequencies will elucidate the appropriate specific genetic screening that should be performed on patients with suspected familial PG syndromes.