Six uneventful pregnancy outcomes in an extended vascular Ehlers-Danlos syndrome family.

Vascular Ehlers-Danlos Syndrome (vEDS) is caused by heterozygous mutations in COL3A1 and is characterized by fragile vasculature and hollow organs, with a high risk of catastrophic events at a young age. During pregnancy and delivery, maternal mortality rates up until 25% have been reported. However, recent pedigree analysis reported a substantial lower pregnancy-related mortality rate of 4.9%. Here, we describe an extended vEDS family with multiple uneventful pregnancy outcomes. In the proband, a 37-year-old woman, DNA-analysis because of an asymptomatic iliac artery dissection revealed a pathogenic mutation in COL3A1 (c.980G>A; p. Gly327Asp). She had had three uneventful vaginal deliveries. At the time of diagnosis, her 33-year-old niece was 25 weeks pregnant. She had had one uneventful vaginal delivery. Targeted DNA-analysis revealed that she was carrier of the COL3A1 mutation. Ultrasound detected an aneurysm in the abdominal aorta with likely a dissection. An uneventful elective cesarean section was performed at a gestational age of 37 weeks. The 40-year-old sister of our proband had had one uneventful vaginal delivery and an active pregnancy wish. Cascade DNA-screening showed her to carry the COL3A1 mutation. Computed Tomography Angiography (CTA) of her aorta revealed a type B dissection with the most proximal entry tear just below the superior mesenteric artery. Pregnancy was therefore discouraged. This familial case illustrates the complexity and challenges of reproductive decision-making in a potentially lethal condition as vEDS, and highlights the importance of a multidisciplinary approach. Moreover, it suggests that previous pregnancy-related risks of vEDS may be overestimated. © 2016 Wiley Periodicals, Inc.

Trends in the utilization of invasive prenatal diagnosis in The Netherlands during 2000-2009.

OBJECTIVE: To analyze trends in the number and type of invasive procedure, reasons for referral, maternal age and chromosomal abnormalities over a 10-year period and correlate the trends to changes in the national prenatal screening policy. METHODS: Data from 10 706 invasive prenatal procedures yielding a full karyotype, performed between 2000 and 2009 were extracted from the cytogenetic database in the central region of The Netherlands. Trends were analyzed. RESULTS: Over a 10-year period, the number of invasive procedures halved and the percentage of chromosomal abnormalities detected, increased from 5.5 to 9.4%. After 2007, however, 5.7% of karyotypes in women over 36 years were found to be abnormal, versus 18.1% in women below 36 years. In 2009, 71.5% of women over 36 are still referred for invasive prenatal diagnosis on the indication advanced maternal age. CONCLUSIONS: Changes in prenatal screening policy significantly increased referral after screening and improved the efficacy of invasive prenatal diagnosis. We show the continuing effect of the different policies applied in the past to women below and above the age of 36. To further improve efficacy of invasive prenatal diagnosis, first trimester combination screening should be actively offered to women of all ages.

Isochromosome 21q is overrepresented among false-negative cell-free DNA prenatal screening results involving Down syndrome.

False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare providers. Understanding the biology behind these results may allow for improved diagnostic follow-up and counseling. In 5 different centers offering cfDNA prenatal screening, 9 false-negative results were documented in 646 confirmed cases of trisomy 21; a false-negative rate of 1.4% (95% CI, 0.7-2.6). False-negative results included 4 cases of classical trisomy 21 and 5 cases with a de novo 21q;21q rearrangement. Two out of five rearrangements had molecular studies and were confirmed as isochromosomes. When combined with reports from the cfDNA screening literature, 8 out of 29 (28%) Down syndrome cases with a false-negative "non-invasive prenatal test" (NIPT) were associated with a 21q;21q rearrangement, compared with 2% reported in live born children with Down syndrome. In our laboratory series, evidence for placental or fetal mosaicism was present in 3 out of 3 true-positive cases involving a 21q;21q rearrangement and was confirmed in one false-negative case where placental material was available for study. Isochromosome 21q rearrangements are thus overrepresented among false-negative cfDNA screening results involving Down syndrome. Postzygotic isochromosome formation leading to placental mosaicism provides a biological cause for the increased prevalence of these rearrangements among false-negative cases. For clinical practice, a low trisomic fraction (z-score or equivalent measure) relative to the fetal fraction suggests placental mosaicism. Care should be taken as these cases may not reflect confined placental mosaicism, but rather full trisomy in the presence of a placenta containing normal cells.