Coffin-Siris syndrome (CSS) is a rare AD disorder caused by mutations in genes of BAF chromatin-remodelling complex, characterised by aplasia/hypoplasia of the distal phalanx/nail of the fifth digit, intellectual disability, distinctive facial features, hypotonia, hypertrichosis and sparse scalp hair. Rare prenatal manifestations of CSS have been reported. We describe prenatal manifestations detected in 3 fetuses with CSS. Retrospective review of prenatal and postnatal data of 3 patients referred for fetal anomalies. Fetal anomalies included: increased nuchal translucency (2); early IUGR increasing in severity with pregnancy (3); macrocrania (2); callosal agenesis; cerebellar hypoplasia (3); cardiac anomalies (3); thoracic anomalies (3): lung hypoplasia (3); diaphragmatic agenesis (1); left diaphragmatic hernia (1); Polyhydramnios (3). Distal skeletal anomalies (2): flexion of all toes; adduction of first toes (1); short fifth digits (1); talipes equinovarus (1); scoliosis (1); multicystic dysplastic kidney (1); facial dysmorphism (1). Two families opted for comfort management, and postnatal explorations; both neonates died after a few hours. A pathogenic de novo variant of ARID 1 A was identified for each. Pathological exam was accepted for one and demonstrated evocative facial and digital features. X-rays diagnosed aplasia and hypoplasia of multiple phalanges (including the distal phalanges of fifth digits), 4 tarsal bone ossification centres (1) and 13 pairs of ribs (2). The third neonate with left diaphragmatic hernia is now 11 months old. Postnatal exam confirmed IUGR, microcephaly, and detected incomplete posterior palatal fissure, ungueal hypoplasia of the fifth digits, hypospadias, and inguinal hernia. A pathogenic de novo variant of SMARCA4 (c.2339A > G) was identified. CSS must be included in the differential diagnosis when fetus with IUGR present with midline CNS anomalies, right cardiac cavities predominance, and lung hypoplasia. A careful search for typical fifth digital hypoplasia and facial dysmorphism should be done.

In Québec, the provincial prenatal screening program consists of the integrated first and second trimester maternal biochemical markers with or without nuchal translucency (NT) measurement. However, with the increasing availability of cell free DNA (cfDNA) testing, the Society of Obstetricians and Gynaecologists of Canada stated that cfDNA could be proposed to women who fall in the high-risk category for fetal aneuploidies following integrated screening. In the province of Québec, most of the cfDNA tests are ordered by obstetricians. The aim of this study was to determine the knowledge of generalist obstetricians regarding cfDNA. A survey was sent to the 500 members of the Association of Obstetricians and Gynecologist of Québec. A total of 179 members answered the survey. 139 completed all questions of the survey. 115 (64.25%) are university affiliated and 56 (31.28%) work in a community hospital. 104 (58.10%) have more than ten years of experience. In the event of an increased NT (>4 mm) only 78 (56.12%) would propose an invasive diagnostic procedure whereas 52 (37.41%) would propose cfDNA testing. Faced with positive cfDNA results, 121 (87.05%) would propose amniocentesis. However, 18 (12.95%) would propose chorionic villus sampling. Interestingly, 86 (59.72%) consider the most likely pregnancy outcome to be poor with a positive cfDNA test for a rare autosomal trisomy such as trisomy 16 despite a normal NT and anatomy ultrasound. Most survey responders know the sensitivity of cfDNA for common autosomal disorders. However, the majority does not know how age affects its positive predictive value. Finally, faced with inconclusive results, only 78 (56.12%) would counsel their patient for higher risk of fetal aneuploidy. Although cfDNA is an excellent test and is widely available, our study shows that knowledge about this test amongst obstetricians and gynecologists in Québec is suboptimal. Further education regarding cfDNA is needed before implementing it in a publically-funded universal screening program.

A 35-year-old patient, G3P1A1, was referred to our tertiary unit for an abnormal ultrasound at 25 weeks. The fetal ultrasound demonstrated multiples abnormalities, a craniosynostosis with cloverleaf skull aspect, a protrusion of the eye balls and thumbs anomalies. Vertebral anomalies were also present. A fetal magnetic resonance imaging (MRI) confirmed craniosynostosis, facial dysmorphia, thick thumbs, a short trunk, thoraco-abdominal disproportion, and humero-radial synostosis. Pfeiffer syndrome was suspected. An amniocentesis was performed and found a mutation in the FGFR2 gene (c. 1019A>G). The patient opted to terminate the pregnancy at 28 weeks. An X-ray of the fetal skeleton confirmed the ultrasound abnormalities. Pfeiffer syndrome is a form of acrocephalosyndactyly, characterised by variable degrees of bicoronal craniosynostosis, variable hand and foot malformations and various other associated manifestations. The genetic mode of transmission is variable (autosomal dominant or autosomal recessive or X-linked recessive). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

more effective. The fetus can be discovered in time before birth to avoid a series of irreversible pathophysiological changes. Methods: A total of 148 pregnant women who underwent prenatal ultrasound screening in our hospital from December 2016 to May 2018 were selected. 58 patients with fetal thyroid abnormalities were selected in the experimental group, and 90 patients with normal fetal thyroid gland were selected as the control group. Univariate analysis was used to screen out the factors which can enter the model. Statistically significant factors of univariate analysis were included in the regression model for analysis. Logistic regression models were established based on the (above analysis) results and the ultrasound image characteristics of the two groups were compared. Results: Univariate regression analysis showed that there were five factors in the final model, including maternal thyroid dysfunction and thyroid surgery history, goiter, thyroid autoantibodies, history of head and neck radiation, abortion and premature birth history. Logistic regression analysis showed that the mother who with above-mentioned five high-risk factors are the main causes of fetal thyroid dysplasia. Conclusions: The results of the logistic regression analysis showed that the proportion of maternal thyroid dysfunction and thyroid surgery, goiter, thyroid autoantibodies, head and neck radioactivity, abortion and premature birth risk was significantly higher in the experimental group than in the observation group (P < 0.05). Logistic regression analysis showed that the mother who with above-mentioned five high-risk factors lead to fetal thyroid dysplasia.

We present a 30 year-old patient, G3P1A1, refered to our high-risk centre for anomalies on the 20 week ultrasound. She was previously referred to our genetic department because of a fetal nuchal translucency of 6.1mm. Level II anatomy ultrasound demontrated a nuchal translucency of 8,8mm with associated edema. The nasal bone was present. Transcervical chorionic venous sampling was normal for QF-PCR and CGH and Noonan panel was negative. At16 weeks, nuchal fold was thickened and there were minimal pleural effusions. The ribs were noted to be short, the long bones were in the 30th percentile. Fetal echocardiography and TORCH investigations were normal. At the 20 weeks scan, pleural effusions were resolved but edema of the head, lower limbs and dorsal portion of the hands was present. which remained on subsequent ultrasounds. She delivered via Caesarean at 37 weeks because of spontaneous membrane rupture and breech presentation. Postnatal physical exam showed swelling of the neck, head, arms, legs and feet. All genetic evaluations were negative and a diagnosis of congenital lymphoedema was posed. Congenital lymphoedema is a condition present at birth in which lymph collects in tissues and causes swelling. Only a few cases of congenital lymphoedema have been reported. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

We present the case of a 33-year-old patient, G2P1, referred to our centre for a dichorionic-diamniotic twin pregnancy. She is now for a Crohn disease treated with Imuran. The first trimester ultrasound at 12 5/7 weeks showed a nuchal translucency for BB1 of 1,4mm associated with a microretrognathia. BB2 was normal with a nuchal translucency of 1,2mm. Four weeks later, an early morphology ultrasound was made demonstrating a severe retrognathia for BB1 and an estimated fetal weight below the third percentile. Moreover, the axis of the heart was deviated and they noted anomalies of both hands. BB2 showed no anomaly. Selective termination of pregnancy was decided by the couple and performed at 17 weeks of pregnancy without complication. An amniocentesis was performed and confirmed a Nager syndrome with an heterozygote mutation c.1A > G in the SF3B4 gene. The patient had a vaginal delivery at 40 weeks with no complication. Nager syndrome is a rare condition that mainly affects the development of the face, hands and arms. Its also called Nager acro-facial dysostose. The mode of transmission is autosomal dominant and the prevalence is unknown. Few cases of Nager syndrome have been reported. We presented a rare and early diagnosis of Nager syndrome and his management in dichorionic twins. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Microcephalic osteodysplastic primordial dwarfism type 1, also known as Taybi-Linder syndrome, is a rare and severe genetic condition characterised by intrauterine growth retardation, microcephaly, skeletal dysplasia and brain anomalies. It is inherited in an autosomal recessive manner and is caused by mutations in the RNU4ATAC gene. Fifty cases are reported in the literature and no clear genotype-phenotype correlation has been observed. Most cases reported were diagnosed postnatally, with few cases diagnosed prenatally. We report four fetuses from two unrelated families with RNU4ATAC mutations. We provide antenatal features and postnatal autopsy descriptions. This series shows the variable phenotypic pattern, even within cases occurring in the same family and affected by the same mutation. We also report two features for the first time in cases of MOPD type 1: hallux valgus and cerebral infundibular hamartoma. From the first family, fetus 1 had IUGR (-2SD), severe skeletal anomalies (platyspondyly, brachydactyly and lack of ossification centres) and unilateral ventriculomegaly, without microcephaly (-1SD). Fetus 2 (sibling of fetus 1) had severe IUGR (-2.8SD) and severe microcephaly (- 3.1SD) with few skeletal anomalies. From the second family, fetus 3 had severe IUGR (-2.4SD), severe microcephaly (-3.5SD), hypoplastic corpus callosum and abnormal gyration. This fetus also demonstrated atypical features such as hallux valgus and a cerebral infundibular hamartoma. Fetus 4 (sibling of fetus 3) was diagnosed by antenatal molecular diagnosis and the pregnancy was surgically terminated at 17 weeks without contributive pathological examination. In conclusion, mutations in the RNU4ATAC gene can be confirmed by antenatal molecular diagnosis. Our series shows that the phenotypic expression can be very heterogeneous even with the same mutation within the same family.

Silver–Russell syndrome is characterised by severe intrauterine growth restriction. Postnatal phenotype is highly variable, and associates poor growth, short stature, specific dysmorphism with triangular shaped face and broad forehead, body asymmetry and rarely other anomalies. Children are at significant risk for developmental delay and learning disabilities. Around 60% are due to hypomethylation of the IGF2/H19 in 11p15 and 10 % are associated with maternal uniparental disomy of chromosome 7; 30% remain unexplained. Recently, 2 women were referred to our prenatal diagnosis centre for early intrauterine growth restriction. Both women were first seen at 21 weeks of gestation with a fetal weight < 5th percentile. Abdomen circumference showed a difference of 2 weeks with the 50th percentile, femur length 1 week, while head circumference was appropriate for gestational age. Uterine arteries had normal flow patterns. Both patients underwent amniocentesis which showed normal aCGH, and congenital infection was ruled out. For both, follow-up only showed borderline amniotic fluid, and persistent stable growth restriction of the abdomen with preserved cephalic circumference. The first patient gave birth at 37 weeks to a male neonate with a weight of 2010 grams. The second patient gave birth at 38 weeks to a female neonate weighing 1710 grams. They required hospitalisation for 13 and 18 days respectively. After birth, both children presented with hypoglycemia, failure to thrive, body asymmetry, and evocative facial dysmorphism. Analyses confirmed hypomethylation of the H19 region in 11p15.5 for both. Now that Silver–Russell syndrome's phenotype and management are well described (international consensus statement published in 2017), our cases stress the importance of considering this diagnosis prenatally. This would allow appropriate counselling to parents and early postnatal specific management, including adequate nutrition and consideration for growth hormone therapy.

Chondrodysplasia punctata (CDP) is an etiologically heterogeneous condition and has been associated with genetic causes and teratogenic exposures (maternal vitamin K deficiency or warfarin…). Some types of chondrodysplasia punctata can be associated with peroxisomal disorders, and these cases are often associated with a more severe prognosis. Few cases of chondrodysplasia punctate associated with lupus and auto-immune diseases have been reported. We report a case of chondrodysplasia punctata in a 30 years-old G2P1 affected by systemic lupus erythematosus with positive anti-SSA and antiphospholipid antibodies. Her previous pregnancy was complicated by pre-eclampsia and HELLP syndrome at 34 weeks. She was followed in our high-risk centre because of her condition. Her prenatal screening was high risk for T21 (1/8) with normal nuchal translucency. At 19 weeks, a hypoplastic nasal bone with hypoplastic mid-face (like Binder syndrome) was discovered with precocious ossification of talus evoking stippled epiphyses and bilateral pyelectasis in a male fetus. An amniocentesis was performed for CGH-array and peroximal analysis: results were normal. The baby was delivered by Caesarean section at term. We concluded a diagnosis of chondrodysplasia punctata due to systemic lupus erythematosus. Ro/SSA antibodies have been considered in the physiopathologic mechanism. Thus, in addition to cardiac evaluation, fetal ultrasound with specific search for mid-face hypoplasia, rhizomely, and stipples epiphyses should be realised. Amniocentesis may be discussed to eliminate a chondrodysplasia punctate associated with peroxisomal disorders.

Failed visualisation of the fetal nasal bone is strongly associated with aneuploidies (T21, 13, and 18). It may also rarely be observed in euploid fetuses, mostly of Afro-Caribbean and Asian ethnicities. Absent nasal bone can be the presenting sign for cleidocranial dysplasia. Case report: A 42-year-old pregnant woman was referred at 24 weeks for an absent nasal bone (Fig 1). In addition to this finding, the fontanelles were large with wide sutures (Fig 2), the brain parenchyma was unusually clearly visible, and the clavicles were hypoplastic (Fig 3). Fetal growth was normal. The child's father had two children from a previous relationship who had missing clavicles. The diagnosis of cleidocranial dysplasia was made and confirmed by amniocentesis with detection of RUNX2 gene mutation. Discussion: Cleidocranial dysplasia is an autosomal dominant skeletal dysplasia characterised by abnormal bone and dental development with normal cognitive function. 80% of cases are caused by a mutation in the RUNX2 gene. Prenatal genetic testing for this mutation is available. The prenatal sonographic diagnosis is primarily based on clavicular hypoplasia or aplasia and insufficient ossification of the cranium. In the few published cases, there are occasional references to the absence of the nasal bone, yet in most cases this is retrospective. Absent nasal bone may help to establish the prenatal diagnosis. Prenatal diagnosis is important, since the abnormal ossification of the skull and chest may expose the fetal brain and lungs to potential damage during natural birth. In conclusion, in absence of fetal nasal bone and low risk for fetal aneuploidies or if aneuploidies are excluded, consider cleidocranial dysplasia and check the clavicles.

The Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive disorder characterised by a pre- and postnatal overgrowth. A mutation on the GPC3 gene has been found in the majority of cases described. Organomegaly, facial dysmorphism, skeletal malformations, tumor predisposition and intellectual disability have also been described. A 29-year old mother was referred to our tertiary care centre at 22 weeks for a marked polyhydramnios, bilateral fetal renal dilation and echogenic bowels in a male fetus. An ultrasound was repeated at 24 weeks revealing a fetal macrosomia (>97th percentile) with severe polyhydramnios (>97th percentile), right renal pyelectasis and right foot anomaly. After genetic counselling, the patient declined diagnostic procedure. The amniotic fluid index was monitored weekly and at 28 weeks, an amnioreduction was performed for threatened preterm labour secondary to the severe polyhydramnios. An aCGH was realised on the amniotic fluid obtained from the amnioreduction. This analysis revealed a duplication of the exon 7 in the GPC3 gene. Postnatal examination of the boy was concordant with the diagnosis of SGBS (facial dysmorphism, nephromegaly, diasthasis recti, vertebral anomalies). Functional studies are ongoing to confirm the pathological effect of this variation. A 32 weeks premature preterm rupture of membrane preceded the vaginal delivery at 33 + 1 weeks of a 2,400 g healthy baby boy. The postnatal examination of the newborn was concordant with the diagnosis of SGBS. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The clubfoot congenital with or without deficiency of the long bones and/or mirror image polydactyly (CCF) syndrome is a rare genetic condition. We report the case of a 30-year-old patient referred to our tertiary care centre for elevated AFP (2.56 MoM) in the second trimester. Many fetal anomalies were noticed at the 18th-week ultrasound, mainly affecting the heart and lower limbs which were in jackknife position. A single 10th percentile bone was found in each leg. Both feet were totally inverted and hyperflexed in relation to the leg. There was an abnormal position of the great cardiac vessels and a possible IVC. The CGH analysis revealed a 46XY fetus with interstitial deletion on chromosome 5 (5 q31. 1q32). The PITX1 gene mutation on this chromosome is associated with CCF. After medical termination of pregnancy at 19 weeks, an autopsy revealed tibial agenesia with peroneal incurvation, preaxial polydactyly of the left foot, craniofacial dysmorphism with microcephaly, cleft palate and visceral anomalies (microcolon and renal hypoplasia). CCF is an autosomal dominant syndrome with incomplete penetrance. An increased prevalence is found in males and in fetuses exposed to maternal smoking. Clubfoot can be isolated or associated with other anomalies, as seen on this case. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

We report a case of PMD presenting clinically as a hydatidiform mole. Ultrasonography at 15 weeks showed a thick, cystic placenta. Interruption at 16 + 5 weeks confirmed the placentamegaly with vesicle formation. Stromal cells of abnormal villi were negative for P57. The placental karyotype was 46,XX. The fetus had hemihypertrophy and marked adrenal nucleocytomegaly but was otherwise grossly normal. This association was suggestive of a Beckwith-Wiedemann syndrome with PMD. The etiology of PMD is not well established, but can occur in androgenic/biparental mosaicism. PMD is associated with BWS (23–25%). PMD is often associated with a bad fetal outcome, including fetal growth restriction and intra uterine fetal death. It has also been associated with adverse maternal outcomes such as pre-eclampsia, persistent gestational trophoblastic disease and in some cases, maternal death. BWS is generally caused by epigenetic alterations of either the maternal or paternal 11p15.5, perturbing the expression of IGF2 (growth factor)/H19 (growth suppressor)/P57, which would explain the proliferative nature of the fetus with BWS and explain the increased childhood risk of tumors in BWS. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

A 20-year old G1 patient was referred early in pregnancy for genetics counselling at our tertiary care centre. The patient presented with developmental and mental retardation and microcephaly that had been attributed to perinatal asphyxia while her partner suffered from autism spectrum disorder. A 19-week ultrasound of the fetus showed asymmetrical cerebellum with hypoplasia of the right hemisphere and hyperechogenic germinal matrix. On a 23-week MRI left germinal matrix hemorrhage with secondary substance loss and hypoplasia of the right cerebellar hemisphere were noted. TORCH and alloimmune thrombocytopenia screening was negative. Karyotype and array CGH were normal. The fetus tested negative for tuberous sclerosis. A mutation of undetermined significance of the COL4A1 gene was identified. MRI of the mother's brain showed lesions similar to those found in the fetus, with a small right cerebellar hemisphere and diffuse white matter loss. She tested positive for the mutation identified in her fetus. A Caesarean section was performed at 37 weeks to minimise the risk of intracranial bleeding. COL4A1 mutation is a rare autosomal dominant disorder associated with porencephaly, intracerebral and retinal hemorrhage. This is, to our knowledge, the first reported case of a clinically affected mother diagnosed through the prenatal diagnosis of her offspring.