Kater, Cláudio E.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

AbstractObjectiveDescribe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects.Design, Setting and ParticipantsA prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital.MethodsCollect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography‐mass spectrometry (LC‐MS): pregnenolone, 17‐OH pregnenolone, 17‐OH progesterone, 11‐deoxycorticosterone, 11‐deoxyortisol, 21‐deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone.ResultsMean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143–665) nmol/L,(p < .0001), unilateral 268 ± 89 3.2 (range 98–507) nmol/L (p < .019) compared to controls 207 ± 100 (range 72–502) nmol/L. ACTH stimulation showed significantly higher levels in bilateral and unilateral cases compared to controls. After dexamethasone, mean serum cortisol levels suppressed in bilaterals 89 ± 69 (range 30–3) nmol/L (p < .0001), 58 ± 52 (range 16–323) nmol/L in unilateral (p < .01) compared to 26 ± 9 (range 7–46) nmol/L in controls. Mean baseline serum corticosterone was higher in bilateral 9.3 ± 4.8 (range 2.4–18.4) nmol/L (p < .005) and unilateral 7.3 ± 5.7 (range 0.1–30.3) nmol/L (p < .01) compared to controls 4.2 ± 2.4 (range 1.1–10.2) nmol/L, after ACTH stimulation significantly increased to higher levels in bilateral (p < .0002) and unilateral cases (p < .044) compared to controls. After dexamethasone, mean levels were 2.5 ± 2.6 (range 0.5–12.5) nmol/L in bilateral (p < .0006), 1.5 ± 1.6 (range 0.3–9.3) nmol/L in unilateral (p < .09) and 0.75 ± 0.46 (range 0.1–2.1) nmol/L in controls. Mean baseline serum 11‐deoxycorticosterone (DOC) was higher in bilaterals 0.32 ± 0.23 (range 0.08–1.1) nmol/L (p < .03) compared to controls 0.15 ± 0.21 (range 0.08–1.1) nmol/L. ACTH stimulation increased levels to 3.27 ± 1.72 (range 0.5–7.4) nmol/L in bilateral cases compared to controls 1.369 ± 1.53 (range 0.1–7.1) nmol/L (p < .0001). Dexamethasone decreased levels to baseline (p ns). There were significant differences in serum 21‐deoxycortisol (p < .0002) and serum pregnenolone (p < .004) only after ACTH stimulation.ConclusionsThere is increased activity in several steroid biosynthesis pathways and higher steroid levels in bilateral compared to unilateral cases and evidence of hypercortisolism in 30% unilateral and 62% of bilateral incidentalomas.