Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.

PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis.

Hydrops fetalis is a rare disorder associated with significant perinatal complications and a high perinatal mortality of at least 50%. Nonimmune hydrops fetalis (NIHF) is more frequent and results from a wide variety of etiologies. One cause of NIHF is lymphatic malformation 6 (LMPHM6) due to biallelic loss-of-function (LoF) variants in PIEZO1. Most individuals are diagnosed postnatally and only few clinical data are available on fetal presentations. We report six novel biallelic predicted LoF variants in PIEZO1 identified by exome sequencing in six fetuses and one deceased neonate from four unrelated families affected with LMPHM6. During the pregnancy, most cases are revealed by isolated NIHF at second trimester of gestation. At post-mortem examination ascites, pleural effusions and telengectasies can guide the etiological diagnosis. We aim to further describe the perinatal presentation of this condition which could be underdiagnosed.

A Gardos channelopathy associated with nonimmune hydrops and fetal loss.

Dehydrated hereditary stomatocytosis (DHS) (MIM#194380) is a rare autosomal dominant disorder of red blood cell permeability, characterized by a partially or fully compensated nonimmune hemolytic anemia. PIEZO1 is the major gene involved with hundreds of families described, some of which present transient perinatal edema of varying severity. A smaller subset of individuals harbors pathogenic variants in KCNN4, sometimes referred as "Gardos channelopathy." Up to now, only six pathogenic variants in KCNN4 have been reported in 13 unrelated families. Unlike PIEZO1-DHS, neither perinatal edema nor fetal loss has ever been observed linked to KCNN4-DHS. We report the first fetal loss due to non-immune hydrops fetalis related to a pathogenic 28 bp deletion (NM_002250.2: c.1109_1119+17del) in KCNN4. This observation underlies the need for very close monitoring of pregnancies when one parent is affected by DHS regardless of genotype (PIEZO1 or KCNN4).

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

The first two non-Finnish HYLS1 variants: Expanding the phenotypic spectrum of hydrolethalus syndrome.

Hydrolethalus syndrome (HLS) is a rare lethal fetal malformation disorder related to ciliogenesis disruption. This condition is more frequent in Finland where a founder missense variant in the HYLS1 gene was identified. No other HYLS1 variant has hitherto been implicated in HLS. We report two unrelated French fetuses presenting with a phenotype of HLS with brain abnormalities, limbs malformations with pre and postaxial hexadactyly and abnormal genitalia. These two fetuses have compound heterozygous variants in HYLS1. The first allele carries the same Finnish missense variant (NM_145014.2: c.632A > G, p.[Asp211Gly]) in both fetuses and the second allele carries a new missense variant (c.662G > C, p.[Arg221Pro]) in the first fetus, and a new nonsense variant (c.613C > T, p.[Arg205*]) in the second fetus. This is the first report of HYLS1 mutated cases outside Finland. Both cases presented here are consistent with HLS with additional malformations, allowing expansion of the phenotypic presentation previously described.

Cardiac rhabdomyoma with hydrops fetalis: Prenatal management by abdominal drainage.

OBJECTIVE: We described a case of fetal cardiac rhabdomyoma complicated by hydrops. And we discussed our approach during pregnancy. CASE REPORT: A 23-year-old woman primigravida was referred at 29 weeks of gestation (WG) to prenatal unit for a large hyperechogenic intracardiac mass associated with fetal hydrops. An intrauterine peritoneo-amniotic shunt was placed. Complete regression of ascites and pericardial effusions were observed after 34 WG with drain in good position. CONCLUSION: Cardiac rhabdomyoma is the most common prenatal cardiac tumor. These tumors are benign, asymptomatic and spontaneously regress after birth. However, in some cases, these tumors may cause severe obstructions on the fetal heart and need specific treatment.

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-ß4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-ß4 abundance was confirmed with ELISA. Knockout of thymosin-ß4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin ß4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.

A Pilot Study Comparing 2- and 3-dimensional Ultrasound Imaging for Confirmation of Essure Fallopian Tube Pregnancy Prevention Implants.

STUDY OBJECTIVE: To show the feasibility of 2-dimensional (2D) ultrasound (US) imaging compared with 3-dimensional (3D) US to identify the location of implants and assess if the classification developed by Simorre et al in 2016 was applicable to the 2 types of US imaging (i.e., 2D and 3D). DESIGN: A prospective study (Canadian Task Force classification II-2). SETTING: The department of obstetrics and gynecology in a teaching hospital. PATIENTS: One hundred fifty patients who had undergone hysteroscopic sterilization with Essure (Bayer Pharma AG Laboratory, Lyon, France) fallopian tube pregnancy prevention implants were invited by letter to participate in the study; 50 replied positively between January and August 2017. INTERVENTIONS: An initial 2D US was performed followed by 3D US reconstruction. The primary end point was to compare the identification of device placement with 2D and 3D US imaging procedures according to this new classification. Secondary considerations were to evaluate the difficulty of attaining images, the quality of implant curvature, the duration of each imaging procedure, and the number of images performed for each technique. MEASUREMENTS AND MAIN RESULTS: Ninety-six percent of tubal implants were observed via 3D US compared with 100% via 2D US. The mean time of 2D US was 14.64 seconds for the right fallopian tube and 15.25 seconds for the left fallopian tube compared with 25.11 seconds for the right and 31.57 seconds for the left fallopian tube in 3D US (p <.01). The mean number of image acquisitions per patient was 1.02 (±0.14 standard deviation) for 2D US compared with 1.37 (±0.64 standard deviation) for 3D US (p <.01). The sonographer had no difficulty performing 2D US in 88% of cases compared with 58% of 3D US cases. CONCLUSIONS: Two-dimensional ultrasound appears to be an acceptable alternative to 3D US. We propose a 2D classification for cross section device localization to facilitate image interpretation.

Perinatal prognosis of pregnancies complicated by placental chronic villitis or intervillositis of unknown etiology and combined lesions: About a series of 178 cases.

INTRODUCTION: The objective of this work was to evaluate and compare perinatal outcomes of pregnancies complicated by placental chronic intervillositis (CIUE) or villitis (CVUE) of unknown etiology and combined lesions. METHODS: Retrospective study of all cases of significant CVUE and CIUE occurring during a 12-year period in a university tertiary hospital center. Multiple pregnancies, infectious and medical termination of pregnancies (TOP) without intra-uterine growth restriction (IUGR) were excluded. RESULTS: 178 placentas were affected (78 cases of CVUE, 24 cases of CIUE and 76 cases of combined lesions involving both villitis and intervillositis) including 12 cases of recurrence. A disorder of fetal growth was found in 73% of cases and we noted 9.5% of cases of abortion. The rate of IUGR appeared to be significantly higher in case of CIUE with a fetal death risk five times higher. These complications seems to be related to more diffuse inflammatory infiltrates (p < 0.05). CVUE was associated with a significant morbidity with 42% of severe IUGR and severe alterations of umbilical artery Doppler in nearly one third of cases. Caesarean section was important (54.8%). Sixty-one percent of newborns were hospitalized and 11.4% in neonatal reanimation. In case of combined lesions, fetal outcomes appeared relatively close to those of CVUE. CVUE could recur in more severe forms or as CIUE with an increased risk for the fetus. Clinicoanatomic correlations were noted. DISCUSSION: Observation of recurrence of CVUE on CIUE or combined lesions and similar phenotypic characteristics of the infiltrates suggest that they could be two different stages of a same disease. CVUE remains a disease to be considered as serious. Association of small lesions of intervillositis does not change the prognosis. The severity of histological lesions and the initial obstetrical accident could be discriminatory to identify patients at risk of serious recurrence. Harmonized classification will be required. CONCLUSIONS: This study confirms the higher morbidity of CIUE compared to CVUE but shows the necessity of monitoring pregnancies following an episode of CVUE, which are still at risk of serious and recurrent complications.

Amniotic fluid biochemistry in isolated polyhydramnios: a series of 464 cases.

OBJECTIVE: To report amniotic fluid biochemistry in a large series of 464 cases of isolated polyhydramnios in order to analyze both the outcome and the benefit of amniotic fluid biochemistry. METHODS: This retrospective cohort (2008-2012) included polyhydramnios cases for which amniotic fluid samples were sent to our laboratory for biochemical analysis (total protein, alpha-fetoprotein and gamma-glutamyl transpeptidase) so as to investigate the etiology. A Bartter index and an esophageal atresia index were defined. Final diagnoses were compared between groups to determine the association between these indices and the frequency and type of adverse outcomes. RESULTS: Among 464 cases of polyhydramnios considered isolated at ultrasound examination, severe fetal diseases were diagnosed in 136 (29.3%): 46 (9.9%) chromosomal anomalies, 28 (6%) Bartter syndrome, 23 (4.95%) other genetic syndromes, 22 (4.75%) swallowing disorders and 17 (3.7%) uro-nephrological disorders. Amniotic fluid biochemistry identified esophageal atresia with 66.6% (10/15) sensitivity and 100% specificity and Bartter syndrome with 85.7% (24/28) sensitivity and 84.2% specificity. CONCLUSION: Isolated polyhydramnios is associated with a high risk of severe fetal diseases. Molecular cytogenetics and amniotic fluid biochemistry are helpful tools.

Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta.

PURPOSE: To evaluate the accuracy of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of placenta accreta and to define the most relevant specific ultrasound and MRI features that may predict placental invasion. MATERIAL AND METHODS: This study was approved by the institutional review board of the French College of Obstetricians and Gynecologists. We retrospectively reviewed the medical records of all patients referred for suspected placenta accreta to two university hospitals from 01/2001 to 05/2012. Our study population included 42 pregnant women who had been investigated by both ultrasonography and MRI. Ultrasound images and MRI were blindly reassessed for each case by 2 raters in order to score features that predict abnormal placental invasion. RESULTS: Sensitivity in the diagnosis of placenta accreta was 100% with ultrasound and 76.9% for MRI (P = 0.03). Specificity was 37.5% with ultrasonography and 50% for MRI (P = 0.6). The features of greatest sensitivity on ultrasonography were intraplacental lacunae and loss of the normal retroplacental clear space. Increased vascularization in the uterine serosa-bladder wall interface and vascularization perpendicular to the uterine wall had the best positive predictive value (92%). At MRI, uterine bulging had the best positive predictive value (85%) and its combination with the presence of dark intraplacental bands on T2-weighted images improved the predictive value to 90%. CONCLUSION: Ultrasound imaging is the mainstay of screening for placenta accreta. MRI appears to be complementary to ultrasonography, especially when there are few ultrasound signs.

Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.

We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations.

Monozygotic triplet pregnancies after single blastocyst transfer: two cases and literature review.

Following IVF, single blastocyst transfer has been thought to reduce the risks of high-order multiple pregnancies. This is a report of two cases of monozygotic triplet pregnancies after single blastocyst transfer and a review of the current concepts of the pathogenesis of multiple monozygotic pregnancies as well as the options for managing these high-risk pregnancies. Both cases were reduced to a twin pregnancy by selective cord coagulation at 15-16 weeks. Whereas one patient had uneventful pregnancy until labour was induced for growth arrest and cord Doppler abnormalities in one twin, the other developed a severe twin-to-twin transfusion syndrome which required fetoscopic laser surgery at 21 weeks. In both cases, healthy twins were delivered by Caesarean section at 34.5 and 34 weeks, respectively. As the predictors of their occurrence are not fully understood, patients should be informed of the risks of monozygotic pregnancies after single blastocyst transfer.

Prenatal sonographic patterns in six cases of Wolf-Hirschhorn (4p-) syndrome.

This multicentric study presents 6 cases of Wolf-Hirschhorn syndrome (deletion of 4p) detected after a sonographic prenatal diagnosis of early intrauterine growth retardation with fetal abnormalities. Standard karyotyping on regular G-banding during pregnancy was normal in half of the cases. Fortunately, the associated sonographic signs of a typical face, cystic cerebral lesions, midline fusion defects and bilateral renal hypoplasia may help to refine specific indications for high-resolution banding and molecular analysis by in situ hybridization.

Prenatal diagnosis of a 'minor' form of Brachmann-de Lange syndrome by three-dimensional sonography and three-dimensional computed tomography.

Brachmann-de Lange syndrome is a congenital disease characterized by severe mental retardation, pre- and postnatal symmetric growth delay, limb defects, visceral anomalies, hirsutism, and a typical face. The authors describe the prenatal sonographic pattern of Brachmann-de Lange syndrome suspected at 20 weeks of gestation, with severe intrauterine growth retardation, facial dysmorphism, cardiac abnormality, and micromelia without the typical defects of the upper limbs. Fetal karyotyping was normal. The diagnosis of a 'minor' form of Brachmann-de Lange syndrome was confirmed at 28 weeks of gestation by using three-dimensional sonography in order to assess precisely the facial dysmorphism and by performing a three-dimensional computed tomography of the upper limbs in order to identify the subtle abnormalities of the radial head and of the first metacarpal bone.