Evaluating low-dose sirolimus for the treatment of PROS

https://doi.org/10.1038/s41436-018-0297-9

Disorders within the PIK3CA-related overgrowth spectrum (PROS) are caused by postzygotic activating variants in the catalytic subunit of phosphatidylinositol-3-kinase (PI3K). Activation of PI3K leads to activation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR), which results in tissue overgrowth. Sirolimus is an mTOR inhibitor, but evidence for its use in the treatment of PROS is limited. In this issue, Parker et al. report a nonrandomized, open-label study that assessed the safety and efficacy of low-dose sirolimus in patients with progressive overgrowth and a mosaic variant in PIK3CA. The study included a 26-week observational run-in period followed by 26 weeks of treatment. Thirty-nine participants were enrolled. The mean age of participants was 16.6 years (range 3–48). Thirty participants completed the study. At affected body sites, the research team observed a 7.2% reduction in mean percent change in total tissue volume (p = 0.04) and a 6.3% reduction in mean percent change of lean tissue volume (p = 0.03) as measured by dual energy X-ray absorptiometry during the treatment period compared with the run-in period. The percent volume change during the run-in period was correlated with the magnitude of treatment effect (p < 0.0001). Quality of life scores did not differ pre- and posttreatment. One or more sirolimus-related adverse events (AEs) occurred in 28 of the 39 participants (72%). Thirteen participants (33%) experienced at least one AE of grade 3 or higher. AEs led to discontinuation of treatment in seven participants (18%). The authors acknowledge that this study was limited by its small size and the phenotypic heterogeneity of participants, and they note the high frequency of AEs. They suggest, however, that treatment with low-dose sirolimus may benefit patients with PROS and that randomized controlled trials are needed. —Raye Alford, News Editor

Postmortem exome sequencing for diagnosis of fetuses with structural anomalies

https://doi.org/10.1038/s41436-018-0298-8

Genetic testing for chromosomal aneuploidies and copy-number variations in fetuses with structural anomalies often fails to reveal a genetic etiology, leaving parents without an explanation for observed anomalies or an estimation of the likelihood of recurrence. Limited evidence suggests that prenatal exome sequencing (ES) can improve diagnostic yield in pregnancies with prenatally identified structural anomalies, but the limitations of phenotyping solely by prenatal ultrasound can complicate the interpretation of sequence variants. In this issue, Quinlan-Jones et al. report the diagnostic yield of ES-based molecular autopsy—the combined use of postmortem genetic testing and autopsy—in fetuses and neonates with prenatally identified structural anomalies that led to fetal demise, neonatal or early infant death, or termination of pregnancy. The research team conducted postmortem ES in 27 proband–parent trios and interpreted genetic variants in the context of prenatal ultrasound and autopsy findings. In 15 of 27 probands, 22 variants identified by ES were reviewed. The variants occurred in 16 different genes and were associated with 17 potential diagnoses. In 10 probands, variants in 9 genes were interpreted as pathogenic or likely pathogenic and contributory to the observed phenotype, resulting in a diagnostic yield of 37%. In 4 probands, the variants occurred de novo. Among consanguineous probands, the diagnostic yield was 50% (3 of 6 cases); among nonconsanguineous probands the yield was 33% (7 of 21 cases). All diagnoses in consanguineous probands involved inherited homozygous variants. Ten variants of uncertain significance were identified, but none were considered related to the observed phenotype. The authors conclude that molecular autopsy has clinical utility for the identification of a genetic etiology in fetuses and neonates with prenatally identified structural anomalies. —Raye Alford, News Editor