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"CHARGE syndrome" (CS) is a multifaceted syndrome associated with a poor prognosis. The prenatal diagnosis remains challenging especially as the fetal anomalies that may evoke suspicion of CS are not comprehensively described., Objective: This study aims to identify the anomalies in MRI with suspected CHARGE syndrome and to propose a possible standardization in the image-based prenatal diagnosis of CS., Methods: This was a retrospective study of 26 fetuses who underwent MRI and had a confirmed diagnosis of CS, as proven by histopathological and/or neonatal examinations and/or the presence of the CHD7 gene mutation., Results: The three most frequent MRI anomalies confirmed at histopathological and/or neonatal examinations were arhinencephaly in 100% (26 of 26), dysplasia of the semicircular canals agenesis (SCA) in 100% (24 of 24), and posterior fossa anomalies in 100% (22 of 22). Our study also revealed short petrous bones with a particular triangular shape in 24 of 24 cases of SCA. Other relevant findings included external ear anomalies in 36% (9 of 25), cleft lip and palate (9 of 9), ventriculomegaly (VMG) (6 of 6), short corpus callosum (3 of 3), and ocular asymmetry in 36.6% (4 of 11)., Conclusion: Our study emphasizes the interest of fetal MRI in the diagnosis of CS with an adapted knowledge of semiology., (© 2019 John Wiley & Sons, Ltd.)

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism., (© 2018 Wiley Periodicals, Inc.)

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm -/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

Objective: To compare the accuracy of magnetic resonance imaging (MRI) and ultrasound (US) to diagnose and characterize congenital obstructive genital abnormalities., Method: Retrospective cohort of 20 fetuses who underwent a fetal MRI following a US diagnosis of obstructive urogenital malformation. We compared MRI and US findings and their correlation with the definitive diagnosis., Result: The correct diagnosis was obtained in 6/20 (30%) cases and 19/20 cases (95%) with US and MRI, respectively. MRI revealed additional information to US in 15/20 cases (75%) and modified the prenatal management in 14 fetuses (70%). The identification rates of the most important anatomical landmarks for the diagnosis, using US and MRI, were compared. Bladder: US 17/20 (85%) vs MRI 20/20 (100%) P = 0.23; vagina: US 6/19 (31.5%) vs MRI 19/19 (100%) P < 10 -4 ; uterus: US 11/19 (57.8%) vs MRI 19/19 (100%) P = 0.003, kidneys: US: 40/40 (100%) MRI: 40/40 (100%) P = 1, ureters: US 14/40 (35%) vs MRI 30/40 (75%) P=0.001, rectum: US 6/20 (30%) MRI 20/20 (100%) P < 10 -4 , and sacrum: US 20/20 (100%) vs MRI 17/20 (85%) P = 0.23., Conclusion: In fetuses with obstructive urogenital malformations, MRI facilitates assessment of major pelvic organs and provides significant information that may alter the prenatal management., (© 2017 John Wiley & Sons, Ltd.)

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

Molecular cytogenetics, particularly array-CGH, opened the way to the « genotype first approach » and for the discovery of new micro rearrangement syndromes. This was the case for the 8q24.3 microdeletion syndrome. Here, we describe the phenotype of a fetus with a 8q24.3 deletion. This rare condition has to be considered as a contiguous genes syndrome because its phenotype is generated by the SCRIB and PUF60 adjacent gene endophenotypes. The fetus presented atrioventricular septal defect and hypoplastic aortic arch, facial dysmorphism, microretrognathia, dysmorphic ears, clinodactyly of the 5th digit on both hands, mild rocker bottom feet and abnormal third sacral vertebra. This fetus is the first case where the endophenotype produced by SCRIB gene is absent. This case is compared with the previous published cases., (© 2015 Wiley Periodicals, Inc.)

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.

Background: Abnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs)., Objective: To determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment., Methods: Between January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry., Results: Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio <0.015 before 28 weeks, and <0.012 after 28 weeks, PH was detected in 15 of the 119 fetuses analyzed (13%). It was significantly associated with CHD with right outflow obstruction, independently of chromosomal abnormalities and associated extracardiac abnormalities (p<0.03). Right outflow obstruction was detected in 60% of the fetuses with CHD and PH, but in only 32% of those with CHD but no PH. In fetuses with right outflow obstruction, no difference was observed between those with PH and those without PH, in terms of the ratio of pulmonary artery diameter to aortic diameter, lung CD31 expression, or lung VEGF expression., Conclusion: CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.

We report on a combination of congenital malformations in a mother and her fetus harboring a heterozygous deletion encompassing the TBX5 and TBX3 genes, which are disease-causing in Holt-Oram and ulnar-mammary syndromes, respectively. This contiguous gene syndrome is reminiscent of Okihiro syndrome and emphasizes the importance of array-CGH as a diagnostic tool in atypical syndromic presentations with intrafamilial variability., (Copyright © 2013 Wiley Periodicals, Inc.)

Disseminated congenital toxoplasmosis mimicking septic shock is unusual. We report a fatal case of disseminated congenital toxoplasmosis that was acquired after a third trimester maternal primary infection. The child had severe pneumonitis, purpura, and hepatitis. After 5 days of treatment, quantitative polymerase chain reaction analysis showed that parasite loads in the serum and in tracheal aspirates had decreased. The child died of refractory hypoxemia. Genotyping revealed a type II strain.

Retinoic acid (RA) is a potent teratogen in all vertebrates when tight homeostatic controls on its endogenous dose, location, or timing are perturbed during early embryogenesis. STRA6 encodes an integral cell-membrane protein that favors RA uptake from soluble retinol-binding protein; its transcription is directly regulated by RA levels. Molecular analysis of STRA6 was undertaken in two human fetuses from consanguineous families we previously described with Matthew-Wood syndrome in a context of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation. The fetuses had either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7 predicting a premature stop codon in STRA6 transcripts. Five other fetuses presenting at least one of the two major signs of clinical anophthalmia or pulmonary hypoplasia with at least one of the two associated signs of diaphragmatic closure defect or cardiopathy had no STRA6 mutations. These findings suggest a molecular basis for the prenatal manifestations of Matthew-Wood syndrome and suggest that phenotypic overlap with other associations may be due to genetic heterogeneity of elements common to the RA- and fibroblast growth factor-signaling cascades.

D-mannoheptulose was recently proposed as a tool to label preferentially insulin-producing cells in the pancreatic gland in the perspective of the non-invasive imaging of the endocrine pancreas. In such a perspective, we have now synthesized 1-deoxy-1-[125I]iodo-D-mannoheptulose ([125I]MH) and examined its uptake by different rat cell types. No phosphorylation of [125I]MH by bovine heart hexokinase could be detected. The apparent distribution space of [125I]MH largely exceeded that of [U-14C]sucrose, considered as an extracellular marker, in erythrocytes, parotid cells, hepatocytes, pancreatic pieces and isolated pancreatic islets. Relative to the mean intracellular distribution space of 3HOH, that of [125I]MH was not significantly different in pancreatic pieces from either normal rats or streptozotocin-induced diabetic animals (STZ rats). In pancreatic islets, the uptake of [125I]MH was decreased at low temperature, but failed to be significantly affected by cytochalasin B. Sixty min after the intravenous injection of [125I]MH, the radioactive content of selected organs displayed the following hierarchy: muscle