Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Admission into intensive care unit in preeclampsia: a four-year population-based study in Reunion Island.

INTRODUCTION: Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. The objective of our study was to study risk factors and complications associated with severe preeclampsia requiring intensive care unit (ICU) admission. METHODS: Retrospective comparative study over a period from 1st of January 2015 to 1st of January 2019 in the University's maternity unit of South Reunion (Indian Ocean). Our sampling included all preeclamptic patients who delivered in the Southern part of the island. Patients admitted to intensive care unit (ICU) and those who remained in the maternity unit (controls) were reviewed. RESULTS: Out of 482 preeclampsia cases, 94 women (19.5%) needed a transfer in ICU, of which only 21 (4.3%) needed invasive intensive care. Mean length of stay was 2.4 ± 2.1 days. ICU admission was associated with HELLP syndrome (OR 8.5 [4.9-14.9], p<.001), severe post-partum hemorrhage (OR 5.86 [1.29-26.70], p=.01) and early onset of preeclampsia (<34 weeks gestation), 2.97 [1.9-4.7], p<.001), leading to higher rate of C-section (OR 2.83 [1.67-4.78], p<.001). There were three patients with a history of eclampsia and no case of maternal death was reported. Fetal prognosis was much poorer in maternal ICU admissions than in controls, with outcomes including lower birth weight (1776 vs. 2304 g, p<.001) and higher perinatal morbidity (infant respiratory distress syndrome 3.70 [1.94-7.05], p<.001) and mortality (<.001). CONCLUSIONS: Women needing invasive ICU represented 4.3% of preeclampsia cases. This experience is of interest for lower resource settings such as in countries like Madagascar where very intensive ICU means are very poor, but simpler ICU surveillance is possible. Fetal prognosis was poor though no maternal death was reported. Thus, a multidisciplinary approach of patients with preeclampsia should be encouraged; admission into ICU should be facilitated, as soon as any sign of severity and complications appears.

Discordant malformations in monochorionic twins: a retrospective cohort study in La Reunion Island.

Background: Discordant malformation between monochorionic twins is a rare and unknown phenomenon.Objectives: To estimate the incidence of discordant monochorionic twins and to describe their characteristics.Study design: A retrospective multicenter cohort of pregnancies between 2002 and 2015 in La Reunion Island was analyzed, thanks to a population-based register. Only monochorionic pregnancies were included in order to analyze specifically monozygotic twins. We defined as discordant twin pairs those in which different malformations were identified for each twin and those with only one fetus showing a malformation.Results: During the study period, 203,807 births occurred, including 410 monochorionic twin pairs. Congenital anomalies rate for monochorionic twin pairs was 10.7%. We included 38 monochorionic twin pairs with discordant phenotypes, which represent 9.3% of monochorionic twin pairs and 86.4% of monochorionic twin pairs affected by congenital anomalies. Among them, both twins were affected by different congenital anomalies in 7 pairs (18.4%), and only one twin was affected in 31 pairs (81.6%). We identified 20 congenital heart anomalies (44.4%), 5 brain anomalies (11.1%), 5 genital anomalies (11.1%), 4 axial bones and skull anomalies (8.9%), 4 limb anomalies (8.9%), 4 facial anomalies (8.9%), 3 urological anomalies (6.6%), 2 thoracic anomalies (4.4%), 1 bile duct anomaly (2,2%), 1 abdominal parietal defect (2.2%), and 1 aneuploidy (2.2%). Among them, 3 (6.6%) fetuses had an association of malformations. Among the 45 fetuses with malformations, 37 fetuses (82.2%) were born alive and 21 (46.6%) had postnatal surgery.Conclusions: Despite a supposed identical genome, discordant congenital anomalies in monochorionic twin pregnancies are not exceptional and related to genetic and epigenetic mechanisms. Sonographers and pediatricians should know that in monochorionic twin a pair, the occurrence of discordant phenotypes is high (9.3%).

Recurrent or first preeclampsia in multiparae: A case-control study of singleton pregnancies in Reunion Island.

Recurrent or first preeclampsia in multiparae : a case-control study of singleton pregnancies in Reunion Island Phuong Lien Tran, Pierre-Yves Robillard, Coralie Dumont, Chloé Schweizer, Asma Omarjee, Glorianne Lazaro, Silvia Iacobelli, Malik Boukerrou OBJECTIVE: To compare multiparous women with a first occurrence of preeclampsia and those with recurrent preeclampsia in singleton pregnancies. STUDY DESIGN: a 17.5-year (2001-2018) case-control study conducted in the University's maternity of South Reunion (Indian Ocean), comparing 125 patients with recurrent preeclampsia and 742 patients with a first episode of the disease (controls). Statistical analyses were performed with use of the Student t-test for comparison of continuous data and the Chi-square or Fisher exact test for comparison of categorical variables. RESULTS: There was no difference between the two groups concerning socio-demographic characteristics, post-partum haemorrhage, perinatal mortality rates. Nevertheless, recurrent preeclamptic women had a higher risk to present with prior chronic hypertension (OR 2.05 [1.30-3.23], p = 0.002), and to experience an early onset preeclampsia (< 34 weeks) compared to controls (OR 1.69 [1.15-2.48], p = 0.007). Women with recurrent preeclampsia were more prone to have C-sections (OR 1.63 [1.06-2.51], p = 0.024) mainly because of maternal indications (89.2% vs 76.4%, p = 0.008). Newborns from recurrent preeclampsia were more likely to have very low birthweight < 1500 g (OR 1.79 [1.16-2.77], p = 0.001), while there was no significant difference for gestational ages (34.1 vs 34.7 weeks). CONCLUSION: Recurrent multiparous preeclamptic women presented more severe maternal disease (with a higher rate of early onset preeclampsia). Persistent hypertension in women with a history of preeclampsia is a risk factor for developing recurrent preeclampsia, and these patients should be monitored more closely.

Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome.

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.