Anne-Marie Guerrot

Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis

Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.

Comparison in Outcomes at Two-Years of Age of Very Preterm Infants Born in 2000, 2005 and 2010

Objective To investigate alteration in 2-year neurological/behavioral outcomes of very preterm infants born in a French level three neonatal intensive care unit. Methods We conducted a prospective, comparative study of very preterm infants born before 33 weeks’ gestation at 5-year intervals in 2000, 2005 and 2010 at Rouen University Hospital. Neonatal mortality/morbidities, ante- and neonatal treatments, and at age 2 years motor, cognitive and behavioral data were collected by standardized questionnaires. Results We included 536 very preterm infants. Follow-up rates at two years old were 78% in 2000, 93% in 2005 and 92% in 2010 respectively. No difference in gestational age, birthweight, neonatal mortality/morbidities was observed except a decrease in low grade subependymal/intraventricular hemorrhages. Care modifications concerned use of antenatal magnesium sulfate, breast-feeding and post-natal corticosteroid therapy. Significant improvement in motor outcome and dramatic decrease in cerebral palsy rates (12% in 2000, 6% in 2005, 1% in 2010, p<0.001) were observed, as were improvements in feeding behavior. Although a non significant difference to better psychosocial behavior was reported, there was no difference in cognitive outcome. Conclusions Improvement in neuromotor outcome and behavior was reported. This could be due to multiple modifications in care: including administration of magnesium sulfate to women at risk of preterm birth, increase in breast-feeding, decrease in low grade subependymal/intraventricular hemorrhages, and decrease in post-natal corticosteroid therapy, all of which require further investigation in other studies. Extended follow-up until school age is mandatory for better detection of cognitive, learning and behavioral disorders.

Évolution de la mortalité, de la morbidité et de la prise en charge des grands prématurés dans un centre de niveau III : comparaison des années 2000, 2005 et 2010

The very preterm birth rate has increased in the past few years. Despite advances in neonatal medicine, neurodevelopmental sequelae have not decreased, despite a perinatal plan published in France in 1994. We conducted an epidemiological comparative survey at Rouen University Hospital in order to analyze morbidity, mortality, and care of very of premature infants by comparing the years 2000, 2005, and 2010. This hospital draws on an area of 17,000 births per year. Our survey was a single-center prospective, descriptive, and comparative study. The three cohorts had the same characteristics and the mortality rate was constant for 11 years. Use of medically assisted procreation and maternal age increased over this period. Chorioamnionitis halved, whereas duration of intrapartum antibiotic therapy increased. Neonatal morbidity was stable for hyaline membrane disease, bronchopulmonary dysplasia, maternofetal or nosocomial infections, and necrotizing enterocolitis. Regarding neurological complications, intraventricular hemorrhages decreased and white matter lesions remained constant. The rate of severe retinopathy remained low. The duration of parenteral nutrition and assisted ventilation, use of postnatal corticosteroids, and length of hospitalization decreased. The breastfeeding rate has increased since 2000 in parallel with postnatal growth restriction : 39% of the premature infants had a weight under the 10th percentile at hospital discharge. Our study allowed us to follow up the changes in neonatal epidemiological characteristics, the mortality and morbidity of extreme premature infants over a period of 11 years and showed few significant changes. Knowledge of medical practices is essential to improve the short- and long-term outcome of premature infants.

Mémoire originalÉvolution de la mortalité, de la morbidité et de la prise en charge des grands prématurés dans un centre de niveau III : comparaison des années 2000, 2005 et 2010Epidemiological study of very preterm infants at Rouen University Hospital: Changes in mortality, morbidity, and care over 11 years

The very preterm birth rate has increased in the past few years. Despite advances in neonatal medicine, neurodevelopmental sequelae have not decreased, despite a perinatal plan published in France in 1994. We conducted an epidemiological comparative survey at Rouen University Hospital in order to analyze morbidity, mortality, and care of very of premature infants by comparing the years 2000, 2005, and 2010. This hospital draws on an area of 17,000 births per year. Our survey was a single-center prospective, descriptive, and comparative study. The three cohorts had the same characteristics and the mortality rate was constant for 11 years. Use of medically assisted procreation and maternal age increased over this period. Chorioamnionitis halved, whereas duration of intrapartum antibiotic therapy increased. Neonatal morbidity was stable for hyaline membrane disease, bronchopulmonary dysplasia, maternofetal or nosocomial infections, and necrotizing enterocolitis. Regarding neurological complications, intraventricular hemorrhages decreased and white matter lesions remained constant. The rate of severe retinopathy remained low. The duration of parenteral nutrition and assisted ventilation, use of postnatal corticosteroids, and length of hospitalization decreased. The breastfeeding rate has increased since 2000 in parallel with postnatal growth restriction : 39% of the premature infants had a weight under the 10th percentile at hospital discharge. Our study allowed us to follow up the changes in neonatal epidemiological characteristics, the mortality and morbidity of extreme premature infants over a period of 11 years and showed few significant changes. Knowledge of medical practices is essential to improve the short- and long-term outcome of premature infants.

Recurrent KIF2A mutations are responsible for classic lissencephaly

Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to −5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that KIF2A mutations represent significant causes of classic lissencephaly with microcephaly.

Compared outcomes of very preterm infants born in 2000 and 2005

Aim:  To compare neonatal and 2‐year outcomes in very premature infants born 5 years apart.

Clinical and pathologic features of Aicardi–Goutières syndrome due to an IFIH1 mutation: A pediatric case report

We describe the case of a young patient with calcifying encephalopathy, born to asymptomatic parents. An extensive hypothesis‐driven etiological assessment was performed and failed to detect the precise etiology during many years. We therefore decided to perform whole exome sequencing of the child–unaffected parents trio. A de novo pathogenic variant in the IFIH1 gene which has recently been shown to cause autosomal dominant forms of Aicardi–Goutières syndrome was identified. This child presented with a severe form with neonatal thrombocytopenia and hepatomegaly, the latter having been detected during late gestation. Although first milestones were uneventful, he progressively lost motor skills from the age of 12 months and developed severe spastic paraplegia. Brain imaging revealed white matter abnormalities and extensive calcifications. He also presented atypical skin lesions, different from chilblains. His medical history was marked by two episodes of acute pancreatitis. We provide herein the results of pathological examination including detailed description of the neuropathological hallmarks. To our knowledge, this the first detailed clinico‐pathological description of a patient with an IFIH1 pathogenic variant.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype–phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad ( ). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory‐bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square‐shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to “MED13L haploinsufficiency syndrome.” Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15–17 and 25–31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.