Prenatal features in Beckwith-Wiedemann syndrome and indications for prenatal testing.

BACKGROUND: Most cases of Beckwith-Wiedemann spectrum (BWSp) are diagnosed after birth and few studies evaluated the prenatal phenotype; here, we investigate these aspects in a large series of patients with BWSp. METHODS: Eighty-nine patients with BWSp recruited through the BWSp Internal Registry of the Pediatric Genetics Unit of the Regina Margherita Children's Hospital of Torino and through the Italian Association of Patients with BWSp. Data collection was conducted through administration of a personalised questionnaire, interview to patients' parents, review of the clinical records, including prenatal ultrasound (US) and biochemical screening tests, physical examination and review of clinical and molecular data of the patients. RESULTS: Seventeen patients (19.1%) were conceived through assisted reproductive techniques (ART). Twinning occurred in nine pregnancies (three from ART). Pregnancy biochemical screening tests showed increased alpha-fetoprotein (1.52±0.79 multiples of median (MoM), p=0.001), uEstriol (1.37±0.38 MoM, p<0.001) and total human chorionic gonadotrophin (2.14±2.12 MoM, p=0.008) at 15-18 weeks (n=28). Morphology US scan revealed abdominal and head circumferences higher than normal (1.42±1.10 SD scores, p<0.001 and 0.54±0.88, p<0.001, respectively) with normal femur lengths. Sixty-four cases (71.9%%) had a various combination of US findings, including macrosomia (n=32), omphalocele (n=15), enlargement of abdominal organs (n=6), macroglossia (n=11), adrenal cysts/masses (n=2), nephroureteral anomalies (n=11), polyhydramnios (n=28), placental enlargement (n=2) or mesenchymal dysplasia (n=4). CONCLUSION: We propose a clinical scoring system for prenatal molecular investigations defining major, minor and supportive criteria among the several features often observed prenatally in BWSp.

Cell-free DNA screening for fetal aneuploidy using the rolling circle method: A step towards non invasive prenatal testing simplification.

OBJECTIVE: To assess the efficacy of cell-free (cf)DNA screening for aneuploidy using the automated system based on rolling circle replication. METHODS: A prospective study among women referred for invasive prenatal diagnosis between July 2018 and December 2019. The plasma fraction was extracted within 5 days from blood collection, stored at -20°C and cfDNA measured between January and December 2019. RESULTS: A total of 805 women were recruited; 778 with singleton pregnancies and 27 twins. There were 48 Down syndrome, 25 Edwards syndrome and 3 Patau syndrome cases. Overall, the no-call rate was 2.6% (95% confidence interval 1.6%-3.9%) which reduced from 4.7% to 1.1% after relocation of the system (p < 0.002) to ensure a constant ambient temperature below 25°C. In singletons the Down syndrome detection rate (DR) was 100% (93%-100%) and false-positive rate (FPR) 0.14% (0.00%-0.79%). The Edwards syndrome DR was 96% (80%-100%) and FPR 0.78% (0.29%-1.7%). One false-positive had a confined placental trisomy 18 and the remaining five a z-score requiring sample repetition; all the false-positives occurred before system relocation (p < 0.005). Patau syndrome DR and FPR were 67% (9.4%-99%) and 0.26% (0.03%-0.95%). CONCLUSION: The cfDNA rolling circle method yields similar results to other methods provided that room temperature is adequately controlled.

Longitudinal Monitoring of Alpha-Fetoprotein by Dried Blood Spot for Hepatoblastoma Screening in Beckwith⁻Wiedemann Syndrome.

BACKGROUND: Hepatoblastoma screening in the Beckwith⁻Wiedemann spectrum (BWSp) is currently based on measuring a specific serum marker alpha-fetoprotein (αFP) every three months until the fourth birthday. Frequent blood draws can be a burden for patients and their families. METHODS: We have developed a less invasive alternative testing method based on measuring αFPs from dried blood spots (DBS). The method was validated with 259 simultaneous plasma and DBS αFP measurements in 171 children (132 controls and 39 patients with BWSp). RESULTS: The DBS and plasma measurements overlapped across the wide range of αFP concentrations independent of patient age (p < 0.0001), demonstrating the utility of this method for longitudinal monitoring. Occasional differences between measurements by the two techniques fell within standard laboratory error and would not alter clinical management. CONCLUSIONS: This novel method shows consistent overlap with the traditional blood draws, thereby demonstrating its utility for hepatoblastoma screening in this setting and alleviating the burden of frequent blood draws. This also may help increase patient compliance and reduce costs of health care screening. The DBS-based method for the measurement of cancer biomarkers may also be applied to several other chronic diseases with increased risks of αFP-producing liver tumors.