Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE).

International audienceHoloprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype-phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case

New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases.

International audienceBACKGROUND: Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon. METHODS: A large European series of 645 HPE probands (and 699 relatives), consisting of 51% fetuses and 49% liveborn children, is reported. RESULTS: Mutations in the four main genes involved in HPE (SHH, ZIC2, SIX3, TGIF) were identified in 25% of cases. The SHH, SIX3, and TGIF mutations were inherited in more than 70% of these cases, whereas 70% of the mutations in ZIC2 occurred de novo. Moreover, rearrangements were detected in 22% of the 260 patients screened by array comparative genomic hybridisation. 15 probands had two mutations providing additional support for the 'multiple-hit process' in HPE. There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. The most severe HPE types were associated with SIX3 and ZIC2 mutations, whereas microforms were associated with SHH mutations. The study focused on the associated brain malformations, including neuronal migration defects, which predominated in individuals with ZIC2 mutations, and neural tube defects, which were frequently associated with ZIC2 (rachischisis) and TGIF mutations. Extracraniofacial features were observed in 27% of the individuals in this series (up to 40% of those with ZIC2 mutations) and a significant correlation was found between renal/urinary defects and mutations of SHH and ZIC2. CONCLUSIONS: An algorithm is proposed based on these new phenotype-genotype correlations, to facilitate molecular analysis and genetic counselling for HPE

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma

International audienceBackgroundOne of the major challenges in managing allergic bronchopulmonary aspergillosis (ABPA) remains consistent and reproducible assessment of response to treatment.Research questionWhat are the most relevant changes in computed tomography (CT-scan) parameters over time for assessing response to treatment?Study Design and MethodsIn this ancillary study of a randomized clinical trial (NEBULAMB), asthmatic patients with available CT-scan and without exacerbation during a 4-month ABPA exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT-scan parameters were assessed by systematic analyses of CT-scan findings at initiation (M0) and end of treatment (M4). CT-scans were assessed by two radiologists blinded to the clinical data. Radiological parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiological response. Agreement between radiological changes, clinical and immunologic responses was likewise investigated.ResultsAmong the 139 originally randomized patients, 132 were included. We identified 5 CT-scan parameters showing significant changes at M4: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities and bronchial wall thickening (P<0.05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical or immunologic and radiological responses, assessed as an overall response, or considering each of the parameters (Cohen’s κ, -0.01 to 0.24).InterpretationChanges in extent and density of mucoid impactions, centrilobular micronodules, consolidation/ground-glass opacities and thickening of the bronchial walls were found to be the most relevant CT-scan parameters to assess radiological response to treatment. A clinical, immunologic and radiological multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment

Rapid Improvement after Starting Elexacaftor–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease

International audienceRationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended