Two patients with paraganglioma (one of whom also had somatostatinoma) were found to have mutations in HIF2A that altered HIF-2α turnover and led to excess erythropoietin production and polycythemia. Hypoxia-inducible factors, originally described by Wang et al., 1 are transcription factors that respond to changes in tissue oxygen concentration. These highly conserved proteins are composed of α and β subunits. The HIF-β subunit is constitutively expressed, whereas the α subunits are inducible by hypoxia and are associated with aggressive, treatment-refractory tumors. 2 , 3 Under normoxic conditions, HIF-1α, HIF-2α, and HIF-3α are hydroxylated on specific prolyl residues, allowing for recognition by the von Hippel–Lindau (VHL) tumor-suppressor protein, ubiquitination, and rapid degradation through the proteasome. 4 Under hypoxic conditions, prolyl hydroxylation of HIF-α proteins is reduced, resulting in their stabilization and, in turn, transcription . . .
To the Editor: Zhuang et al. (Sept. 6 issue) 1 report HIF2A somatic mutations in two patients with paraganglioma. In a recent transcriptome analysis of a large number of pheochromocytomas and paragangliomas, we identified 16 sporadic tumors with a transcription signature similar to that of VHL- mutated tumors. 2 There was somatic inactivation of VHL in 11 of the tumors; the genetic defect in the other 5 tumors remained unexplained. We sequenced HIF2A in these tumors and identified a c.1591C→T heterozygous mutation in a pheochromocytoma resected from a 24-year-old woman. This mutation undoubtedly promoted HIF-2α stabilization, since it affected the prolyl hydroxylase . . .
Objective To quantify sonographic placental echogenicity in twin anemia-polycythemia sequence (TAPS) and to correlate it with middle cerebral artery peak systolic velocity (MCA-PSV) measurements. Methods We performed a retrospective search for consecutive TAPS cases between 16 and 36 weeks of gestation (MCA-PSV > 1.5 multiples of the median (MoM) in the anemic donor and < 1.0 MoM in the polycythemic recipient) in our database of monochorionic twin gestations from January 2007 until December 2016. In cases for which ultrasound images showing the donor's and the recipient's part of the placenta were available, echogenicity for both twins was quantified by image processing. MCA-PSV Doppler values of both fetuses were correlated to their respective placental echogenicity. Placental thickness of both twins was also measured. Results Of 756 cases with MCA-PSV measurements identified from the database, 36 (4.8%) had TAPS; of these, 23 had TAPS combined with twin-twin transfusion syndrome and 13 showed isolated TAPS. Placental echogenicity could be quantified in 28 pregnancies. Mean +/- SD placental echogenicity of donor twins was significantly higher than that of recipients (138.7 +/- 22.8 vs 77.9 +/- 37.0; P < 0.0001). Furthermore, a significant positive correlation was found between placental echogenicity and MCA-PSV MoM (R=0.67, P < 0.0001). Mean placental thickness of donor twins (n = 20) was significantly higher than that of recipients (49.3 mm +/- 13.4 vs 25.4 mm +/- 10.1; P < 0.0001). Conclusions Echogenicity of the placental share in recipient and donor twins with TAPS correlates with MCA-PSV values. Quantification of sonographic placental echogenicity may help to determine the severity of TAPS in monochorionic twins. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd.
Background. The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. Methods. We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. Results. The 7%–10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. Conclusions. Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C>T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit alpha(HIF1alpha). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1alpha reducing the rate of degradation of HIF1alpha and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).
Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.
Objective Twin anemia-polycythemia sequence (TAPS) can occur as a unique disease or as a complication of twin-twin transfusion syndrome (TTTS). Middle cerebral artery (MCA) Doppler studies are not currently part of the routine evaluation of monochorionic twins since they are not used in the Quintero staging system. As such, the true incidence of TAPS is unknown. We aimed to compare the characteristics and outcomes of twin pregnancies with TTTS complicated by spontaneous anemia-polycythemia vs those with TTTS alone. Methods This was a secondary analysis of data collected prospectively from a cohort of 156 consecutive patients undergoing fetoscopic laser surgery for TTTS, between October 2011 and August 2014. TAPS was defined as discordance in the preoperative MCA peak systolic velocity (PSV), with one twin fetus having MCA-PSV = 1.5MoM. Maternal demographics as well as preoperative, operative and postoperative variables were analyzed. Results Included in the final analysis were 133 patients with complete records: 11 cases with TTTS with anemia-polycythemia and 122 cases with TTTS alone. There was no difference in maternal body mass index, gestational age (GA) at procedure, rate of preterm prelabor rupture of membranes or GA at delivery between the two groups. Patients with TTTS and anemia-polycythemia were more likely to be older (P = 0.03) and parous (P = 0.04) and had a significantly lower number of placental anastomoses (P = 0.01). The dual live-birth rate was similar for both groups (P = 0.76). Conclusion Cases of TTTS with anemia-polycythemia were more likely to be found in parous and older women and were characterized by fewer vascular anastomoses. TTTS with anemia-polycythemia was not associated with worse perinatal outcome after laser therapy. Copyright (C) 2015 ISUOG. Published by John Wiley & Sons Ltd.