Anne Debost-Legrand

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient’s clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

A new case of 8q22.1 microdeletion restricts the critical region for Nablus mask‐like facial syndrome

Microdeletions of 8q21.3–8q22.1 have been identified in all patients with Nablus mask‐like facial syndrome (NMLFS). A recent report of a patient without this specific phenotype presented a 1.6 Mb deletion in this region that partially overlapped with previously reported 8q21.3 microdeletions, thus restricting critical region for this syndrome. We report on another case of an 8q21.3 deletion revealed by array comparative genome hybridization (aCGH) in a 4‐year‐old child with global developmental delay, autism, microcephaly, but without Nablus phenotype. The size of the interstitial deletion was estimated to span 5.2 Mb. By combining the data from previous reports on 8q21.3–8q22.1 deletions and our case, we were able to narrow the critical region of Nablus syndrome to 0.5 Mb. The deleted region includes FAM92A1, which seems to be a potential candidate gene in NMLFS.

Reliability of student midwives’ visual estimate of blood loss in the immediate postpartum period: A cross-sectional study

BACKGROUND In France, postpartum hemorrhage (blood loss≥500mL in the first 24h postpartum) is the leading direct obstetric cause of maternal mortality. In French practice, PPH is mainly diagnosed by a quantitative assessment of blood loss, performed by subjective methods such as visual estimates. Various studies have concluded that visual estimates are imprecise, tend to underestimate blood loss, and thus to delay diagnosis of PPH. OBJECTIVES The principal objective of this study was to assess the accuracy of visual estimates of blood loss by student midwives. The secondary objectives were to study intraobserver agreement of these assessments, to assess the accuracy of visual estimates for threshold values, and to look for a region effect. DESIGN A cross-sectional multicentre study. SETTING All French midwifery schools (n=35). PARTICIPANTS Volunteer French student midwives at their fifth (final) year (n=463). METHODS The online questionnaire contained 16 photographs (8 different, each presented twice) of simulated volumes of blood loss (100, 150, 200, 300, 500, 850, 1000, and 1500mL). A 50-mL reference standard for calibration accompanied each photograph. Only one answer could be selected among the 7 choices offered for each photograph. Comparisons used χ(2) and Kappa tests. RESULTS The participation rate was 48.43% (463/956), and 7.408 visual estimates were collected. Estimates were accurate for 35.34% of the responses. The reproducibility rate for the visual estimates (0.17≤к≤0.48) and for the accurate visual estimates (0.11≤к≤0.55) were moderate for 4 of the 8 volumes (100, 300, 1000, and 1500mL). The percentage of accurate responses was significantly higher for volumes≤300mL than for those ≥500mL (52.94% vs. 17.17%, p<0.0001) and those ≥1000mL (52.94% vs. 18.30%, p<0.0001). The percentage of accurate responses varied between the regions (p=0.042). CONCLUSION Despite the help of a visual aid, both the accuracy and reproducibility of the visual estimates were low.

Prenatal diagnosis of the VACTERL association using routine ultrasound examination.

BACKGROUND The prognosis and early neonatal management of the VACTERL association depend mainly on the severity of malformations ascertained prenatally. METHODS Here we reviewed the spectrum of clinical features observed in cases of VACTERL association ascertained prenatally through ultrasound examination but examined at birth and compared them with cases ascertained postnatally. RESULTS From 1995 to 2011, a total of 19 cases of VACTERL association were observed in our center; 10 were ascertained prenatally and confirmed after birth whereas 9 were ascertained only after birth. The types and frequencies of malformations observed prenatally were as follows: renal malformations (45%), tracheoesophageal fistula (44%), cardiac malformations (20%), vertebral (13%), and limb (11%) defects. Anal atresia was never detected using routine prenatal ultrasound examination. CONCLUSION Further studies of fetuses with the VACTERL association are necessary to better delineate the malformations spectrum observed prenatally to improve the early recognition of the VACTERL association.

Impact of prenatal diagnosis on the outcome of patients with a transposition of great arteries: A 24‐year population‐based study

BACKGROUND Transposition of great arteries (TGA) defined as the combination of concordant atrioventricular and discordant ventriculo-arterial connections is one of the most common congenital heart defects. Prenatal diagnosis of TGA remains difficult. To determine the impact of antenatal diagnosis we evaluated the sensitivity of antenatal detection and the neonatal mortality of TGA considering two study periods and two major types of TGA. METHODS A cross-sectional study was performed. Data were collected from a French population-based birth defect registry. From 1988 to 2012, 94 fetuses with TGA were registered. The study period was subdivided into the 1988 to 1999 period and the 2000 to 2012 period. Two types of TGA were considered: isolated TGA (n = 66) and associated TGA (n = 28). A stratified analysis was performed considering the study periods and the types of TGA. RESULTS Considering the study periods, the sensitivity of prenatal detection of TGA increased significantly (9.8% vs. 51.5%, p = 0.0001). The same trend was found for associated TGA (4.8% vs. 33.3%, p = 0.002) and isolated TGA (21.1% vs. 100%, p < 0.001). A late diagnosis of TGA (7 days after birth) was observed in 13.2% of cases. Neonatal mortality decreased significantly over time for isolated TGA (25.0% vs. 0 p = 0.01). Prenatal diagnosis of both types of TGA did not improve survival. CONCLUSION We demonstrated that prenatal diagnosis and neonatal mortality of TGA varied greatly according to the malformation type and the study period. This could be explained by an improvement in terms of medical management.

False positive morphologic diagnoses at the anomaly scan: marginal or real problem, a population-based cohort study

BackgroundCongenital malformations occur in 3-4% of live births. Their prenatal detection is performed by ultrasound screening. Any announcement about a suspected malformation is a source of stress for the parents, and misdiagnosis during ultrasound screening can lead to expensive and sometimes iatrogenic medical interventions. In this study, we aim to determine the false-positive rate, first overall and then by anatomical system, of ultrasound screening for congenital malformations in the second and third trimesters of pregnancy.MethodsOur sample includes all children born between 1 January, 2006, and 31 December, 2009, in the French region of Auvergne, whose mother had a prenatal ultrasound diagnosis of a congenital malformation during the second or third trimester of pregnancy confirmed by a follow-up ultrasound examination by an expert consultant ultrasonographer. The study included 526 fetuses, divided in 3 groups: false positives, diagnostic misclassifications, and true positives. The rates of false positives and diagnostic misclassifications were calculated for the sample as a whole and then by anatomical system.ResultsOverall, the false-positive rate was 8.8% and the rate of diagnostic misclassification 9.2%. The highest false-positive rates were found for renal and gastrointestinal tract malformations, and the highest diagnostic misclassification rates for cerebral and cardiac malformations. The diagnostic misclassification rate was significantly higher than the false-positive rate for cardiac malformations.ConclusionThe false-positive rate during prenatal ultrasound is not insignificant; these misdiagnoses cause psychological stress for the parents and overmedicalisation of the pregnancy and the child.