Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study.

OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Effect of swim intensity on responses to dynamic apnoea.

The aim of this study was to determine the influence of swim intensity on acute responses to dynamic apnoea. 9 swimmers performed one 50 m front crawl trial in four different conditions: at 400 m velocity (V400) with normal breathing (NB), at V400 in complete apnoea (Ap), at maximal velocity (Vmax) with NB and at Vmax in Ap. Peak heart rate (HRpeak), blood lactate concentration after exercise (Lacpost ex) and Borg rating of perceived exertion (RPE) were measured. Arterial oxygen saturation (SpO2) was monitored with a pulse oximeter at forehead level during and after exercise. In Ap, swimming at V400 induced a significantly lower HRpeak and Lacpost ex than swimming at Vmax whilst RPE and the kinetics of SpO2 were not different at V400 and at Vmax. The minimal value of SpO2 in Ap was reached 10 to 11 s after the end of V400 and Vmax (81.7 ± 10.1% and 84.4 ± 10.6%, respectively). Swimming a 50 m front crawl in Ap resulted in a large decrease in SpO2 which occurred only after the cessation of exercise. The higher duration of apnoea during submaximal exercise could explain why SpO2 and RPE reached the same values as for maximal exercise.​.

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.

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.

Time-course of prednisone effects on hormonal and inflammatory responses at rest and during resistance exercise.

Glucocorticoids are among the most commonly used drugs. They are widely administered for acute and chronic musculoskeletal pain, as well as for several other pain syndromes, although their therapeutic use is sometimes diverted for doping purposes. Their time-course effects on hormonal and inflammatory responses nevertheless remain poorly understood, both at rest and during exercise. We therefore studied the alterations induced by 1 week of prednisone treatment (60 mg daily) in recreationally trained male athletes after 2 days (i. e., acute) and 7 days (i. e., short-term). Hormonal (i. e., DHEA, DHEA-S, aldosterone, and testosterone) and pro- and anti-inflammatory markers (i. e., IL-6, IL-10, and IL-1ß) were investigated at rest and after resistance exercise. A significant decrease in DHEA and DHEA-S (p<0.01) without change in the DHEA/DHEA-S ratio, aldosterone, or testosterone was demonstrated after acute prednisone intake. A significant increment in IL-10 and a significant decrement in IL-6 (p<0.05) were also observed with prednisone both at rest and during exercise, without significant change in IL-1ß. Continued prednisone treatment led to another significant decrease in both DHEA and DHEA-S (p<0.05), whereas no change in the inflammatory markers was observed between days 2 and 7. Our data demonstrate that the anti-inflammatory effects of prednisone were maximal and stable from the beginning of treatment, both in rest and exercise conditions. However, hormonal concentrations continued to decline during short-term intake. Further studies are needed to determine the effects of hormonal time-course alterations with longer glucocorticoid treatment and the clinical consequences.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

The diurnal patterns of cortisol and dehydroepiandrosterone in relation to intense aerobic exercise in recreationally trained soccer players.

Diurnal patterns of cortisol and dehydroepiandrosterone (DHEA) secretion, the two main peripheral secretory products of the hypothalamic-pituitary-adrenal neuroendocrine stress axis, have been well characterized in rest conditions but not in relation to physical exercise. The purpose of this investigation was therefore to determine the effects of an intense 90-min aerobic exercise on the waking diurnal cortisol and DHEA cycles on three separate days [without exercise, with morning exercise (10:00-11:30 h), and with afternoon exercise (14:00-15:30 h)] in nine recreationally trained soccer players. Saliva samples were collected at awakening, 30 min after awakening, and then every 2 h from 08:00 to 22:00 h. A burst of secretory activity was found for cortisol (p < 0.01) but not for DHEA after awakening. Overall, diurnal decline for both adrenal steroids was observed on resting and exercise days under all conditions. However, there was a significant increase in salivary cortisol concentrations on the morning-exercise and afternoon-exercise days at, respectively, 12:00 h (p < 0.05) and 16:00 h (p < 0.01), versus the other trials. This acute response to exercise was not evident for DHEA. The results of this investigation indicate that 90 min of intense aerobic exercise does not affect the circadian pattern of salivary adrenal steroids in recreationally trained athletes over a 16-h waking period, despite a transitory increase in post-exercise cortisol concentration. Further studies are necessary to determine whether these results are applicable to elite athletes or patients with cortisol or DHEA deficiency.

Hyperoxia does not accelerate quadriceps muscle deoxygenation kinetics at the onset of heavy exercise cycle.

AIM: The aim of this study was to determine whether an increase in O2 availability induces an alteration of the balance between O2 consumption ((V)O2) and O2 delivery ((Q)O2) at the muscle level. For that, we examined the effect of moderate hyperoxia on muscle deoxygenation kinetics at the onset of heavy-intensity cycling exercise. METHODS: Eight young male adults performed step transitions from 35 W to heavy-intensity exercise corresponding to a power output half-way between the first ventilatory threshold and (V)O2max in normoxia and in hyperoxia (FIO2=0.30). Muscle deoxygenation (HHb) and total hemoglobin (Hbtot) were monitored continuously by near-infrared spectroscopy. HHb data were fit with a mono-exponential model from the onset of exercise up to 90 seconds. RESULTS: Hyperoxia neither altered the delay before the increase in HHb (normoxia: 10.7±1.8 s vs. hyperoxia: 9.5±1.9 s; NS) nor the HHb mean response time (normoxia: 20.6±2.8 s vs. hyperoxia: 19.6±2.3 s; NS). Likewise, Hbtot was not different between normoxia and hyperoxia. CONCLUSION: These results indicate that moderate hyperoxia has no effect on muscle deoxygenation kinetics at the onset of heavy exercise. It suggests that muscle (V)O2 increases at the same rate than O2 delivery when O2 availability is enhanced.

[Does exercise therapy for chronic lower-back pain require daily isokinetic reinforcement of the trunk muscles?]. / Le réentraînement à l'effort de la lombalgie chronique nécessite-t-il un renforcement musculaire isocinétique quotidien du tronc?

OBJECTIVE: The goal of this study was to determine the benefits of a functional retraining programme (with or without daily isokinetic reinforcement of the trunk muscles) in patients with lower-back pain. METHOD: Two groups of 30 patients took part in the study. The control group (CG) underwent a four-week reconditioning program in a day hospital, whereas a second interventional group (IG) additionally performed daily isokinetic training of the trunk muscles. Three evaluations were carried out: before hospitalization (T1), immediately after hospitalization (T2) and three months postrehabilitation (T3). RESULTS: We observed an improvement in each parameter after rehabilitation, regardless of the group. A decrease in the DALLAS scores revealed a reduced impact of lower-back pain on the patients' lives. Pain experienced fell by 24%, analgesic treatment was significantly decreased (CG: -53%; IG: -56%), muscle endurance was improved (quadriceps: +30%, abdominal muscles: +20%, paraspinal muscles: +23%, quadratus lumborum: +33%) and the patients were more supple, as revealed by a decrease in the finger-to-ground distance (at T1, CG: 12.9+/-6.1cm; IG: 13.6+/-5.5 cm at T1; CG: 2.2+/-5.4 cm; IG: 2.8+/-5.1cm at T2). The sole difference for CG and IG at T2 resulted from an improvement in the performance of the trunk extensor muscles, which was significantly greater in the IG (CG: +14%; IG: +20%). Three months after rehabilitation, the benefits were still present for the two groups and, indeed, were even greater for certain parameters. CONCLUSION: Regardless of the protocol, the patients improved in both physical and psychological terms and these improvements were maintained over a short period, at least. Our results confirmed that one functional recovery programme is not superior to another for patients with lower-back pain.

[Adrenal hypoplasia congenita: four new cases in children]. / Hypoplasie congénitale des surrénales : à propos de quatre observations.

Adrenal hypoplasia congenita (AHC) is an extremely uncommon disease of early onset. This condition can be lethal in the absence of adapted treatment. Some of these diseases are related to changes in the gene DAX1 that encodes a member of the superfamily of hormone nuclear receptors. It is a transcriptional repressor that is central in the morphogenesis of the adrenals and the gonadic differentiation. Here we report on four cases of X- linked AHC. In the first two familial cases, mutations were identified and mothers were heterozygotes. Abnormally low levels of estriol were evidenced during the pregnancy leading to an early diagnosis and adapted care of the affected male neonates. These children are doing well with a 21-and 20 months follow-up with hormone replacement at the present time. The two last cases corresponded to a contiguous gene syndrome associating AHC to glycerol-kinase deficiency that was revealed respectively at six days and seven years of age by acute adrenal insufficiency.

Effect of oral glucocorticoid intake on autonomic cardiovascular control.

This study analyzed baroreflex sensitivity, heart rate and systolic blood pressure variabilities during an oral 1 week administration of prednisone. This study examined the hypothesis that prednisone might change both systolic blood pressure level and baroreflex sensitivity. Twelve physically active male subjects participated to a double-blind, randomized cross-over study consisting of two 1-week periods of treatment separated by a 4-week drug-free washout period: placebo (PLA) or prednisone (PRED). Trials were performed by each subject four times on the second (D2) and seventh (D7) day of each treatment period. ECG and blood pressure were continuously recorded to compute heart rate variability, systolic blood pressure variability and baroreflex sensitivity components with the smoothed pseudo Wigner Ville distribution and baroreflex analysis. Following D2 prednisone treatment, both HR (PLA: 60.8 ± 10.5 vs. PRED: 65.8 ± 9.1 beats min(-1), p = 0.008) and low frequency component of systolic blood pressure variability (D2: 3.09 ± 0.19 vs. D7: 2.34 ± 0.19, p < 0.041) increased whereas other components did not change. Over 7 days of treatment, LF-SBP amplitude increased (D2: 2.71 ± 0.89 vs. D7: 3.87 ± 0.6 mmHg, p = 0.037). A slight increase in both HR and LF-SBPV were observed suggesting a potential sympathetic cardiovascular stimulus. Although we found a significant effect of the 1-week prednisone treatment on heart rate and low frequency power of systolic blood pressure variability, we reported neither an increase in the systolic blood pressure level nor a decrease in the baroreflex sensitivity. Therefore, the fragility of our results cannot support a deleterious effect of 1-week administration of prednisone on the autonomic cardiovascular control which might be involved in cardiovascular diseases.

Balanced complex chromosomal rearrangements with more than four breakpoints: report of a new case.

Congenital complex chromosomal rearrangement (CCR) compatible with life are rare in man. We report on a new case of apparently balanced CCR in a 30-month-old boy with mental retardation and minor anomalies. This CCR consists in a 3-way reciprocal translocation (2;3;16) and an insertion (6;7), as it was analyzed by different banding and high resolution techniques. It involves 6 breakpoints: 2q11, 13q12, 16p11, 6p21.3, 7q21.3 and 7q35.

Validity of oxygen uptake measurements during exercise under moderate hyperoxia.

PURPOSE: The validity of oxygen uptake in hyperoxia (FIO2 = 30%) measured by an automated system (MedGraphics, CPX/D system) was assessed during the simulation of gas exchanges during exercise with a mechanical system and during submaximal exercise by human subjects. METHODS: The simulation system reproduced a stable and accurate VO2 for 30 min (sim-test). This trial was repeated nine times in normoxia and nine times in hyperoxia. Ten subjects also performed two submaximal exercises (55% of normoxic VO2max) on a cycle ergometer at the same absolute power in normoxia and in hyperoxia (ex-test). RESULTS: There was a significant downward drift of the oxygen fraction measurement in hyperoxia (< or = 0.10% for FIO2 and FEO2) during sim-test, but VO2 measurement remained stable in the two conditions. There was also a downward drift of the oxygen fraction measurement in the two conditions (< or = 0.07% for FIO2) during ex-test. VO2 was significantly higher in hyperoxia (+4.6%), and this result was confirmed using a modified Douglas bag method. CONCLUSIONS: These findings show that the CPX/D system is stable and valid for assessing VO2 in moderate hyperoxia.

Influence of training on NIRS muscle oxygen saturation during submaximal exercise.

PURPOSE: Endurance training improves the oxygen delivery and muscle metabolism. Muscle oxygen saturation measured by near infrared spectroscopy (IR-SO(2)), which is primarily influenced by the local delivery/demand balance, should thus be modified by training. We examined this effect by determining the influence of change in blood lactate and muscle capillary density with training on IR-SO(2) in seven healthy young subjects. METHODS: Two submaximal exercise tests at 50% (Ex1) and 80% pretraining VO(2max) (Ex2) were performed before and after a 4-wk endurance-training program. RESULTS: VO(2max) increased only slightly (+8%, NS) with training but the training effect was confirmed by the increased capillary density (+31%, P < 0.01) and citrate synthase activity (50%, P < 0.01), determined from muscle biopsy samples. Before training, blood lactate increased during the first 5 min of Ex1 and then remained constant (3.8 +/- 0.5 mmol x L(-1), P < 0.01), whereas it increased continuously during Ex2 (8.9 +/- 1.8 mmol x L(-1), P < 0.001). After training, lactate decreased significantly and remained constant during the two bouts of exercise (2.0 +/- 0.4 and 3.7 +/- 1.2 at the end of Ex1 and Ex2, respectively, both P < 0.001). During Ex1, IR-SO(2) dropped initially at the onset of exercise and recovered progressively without reaching the resting level. Training did not change this pattern of IR-SO(2). During Ex2, IR-SO(2) decreased progressively during the 15 min of exercise (P < 0.05); IR-SO2 kept constant after the initial drop after training. We found a significant relationship (r = 0.42, P = 0.03) between blood lactate and IR-SO(2) at the end of both bouts of exercise; this relationship was closer before training. By contrast, IR-SO(2) or IR-BV was not related to the capillary density. CONCLUSION: The training-induced adaptation in blood lactate influences IR-SO(2) during mild- to hard-intensity exercise. Thus, NIRS could be used as a noninvasive monitoring of training-induced adaptations.

Age-associated alteration of muscle oxygenation measured by near infrared spectroscopy during exercise.

The influence of ageing on the capacity to increase muscle oxygen delivery during exercise is unclear. This was investigated by comparing the evolution of Near InfraRed Spectroscopy (NIRS) in 10 old (67 +/- 5 years, Old group) and 13 young subjects (27 +/- 4 years, Young group), during a progressive maximal exercise. The NIRS probe was placed on the vastus lateralis; muscle oxygen saturation - IR-SmO(2) - values were expressed on a scale using an arterial occlusion as the lower reference point and the subsequent reactive hyperaemia as the upper reference point. Resting IR-SmO( 2) was found to be significantly lower in the Old as co mpared to the Young group. During exercise, VO(2) increased similarly as a function of the workload whereas IR-SmO(2) decreased faster in old subjects than in young ones. Conversely, when expressed at the same percentage of VO( 2max), IR-SmO(2) followed a similar evolution in both groups from rest to maximal exercise (27.3 +/- 16.7 vs 24.3 +/- 12.9% decrease, in Old and Young group, respectively, NS). Thus, the initial difference remained constant between the two groups. During recovery, the time to recover the signal variation was not different between the two groups. We concluded that Old subjects demonstrate a systematic lower muscle oxygen saturation than Young ones. This difference could be explained by an age related decrease in muscle blood flow limiting O(2) supply.

[Prenatal Bartter's syndrome. Report of two cases]. / Le syndrome de Bartter anténatal. A propos de deux cas.

Antenatal Bartter Syndrome (ABS) is a rare autosomic recessive tubulopathy characterized by idiopathic hydramnios, fetal polyuria and elevated levels of amniotic chloride. It is related to mutations affecting several transporters in the loop of Henle e.g. the Na-K-2Cl cotransporter, the chloride channel CLC-NKB and the potassium channel ROMK. We report two cases of ABS in siblings born to consanguineous parents (first cousins). The first pregnancy showed hydramnios of unknown etiology at week 23. Two amnio drains were performed at weeks 26 and 27. The baby was born in week 29 and developed polyuria with hyponatremia, hypokalemia and hyperaldosteronism. After eliminating diabetes insipidus and adrenal insufficiency, ABS was diagnosed. The baby was treated with 0.5 mg/kg/d indomethacine, which controlled the polyuria and the hydroelectrolytic disorder. The second pregnancy showed idiopathic hydramnios at week 24. The elevated amniotic chloride level (above 112 mmole/l) led to the antenatal diagnosis of ABS. The mother was treated with 1 mg/kg/d indomethacine until week 31 in order to stabilize the hydramnios. Two amnio drains at weeks 31 and 33 allowed the pregnancy to be prolonged until week 34. A genetic study of the family showed homozygosity of the NKCC2 gene marker suggesting its implication in the disease.

[First-trimester cystic hygroma: prenatal diagnosis and fetal outcome]. / Hygroma kystique découvert à l'échographie obstétricale du 1er trimestre : caractéristiques échographiques, caryotypiques et devenir de la grossesse.

OBJECTIVES: To describe the ultrasonographic (US) and fetal karyotyping data of fetuses with cystic hygroma diagnosed in the first trimester. PATIENTS & METHODS: Maternal and fetal data of 69 consecutive fetal cystic hygroma were analysed between 2002 and 2009. RESULTS: The mean size of the cystic hygroma was 6.3 mm ± 2.4 mm. US abnormalities were present in 54% of cases (37/69) (essentially hydrops fetalis in 45%), with an unfavourable prognosis (P=0.006). Chromosomal abnormalities were present in 53% of cases (36/68) (including 44% of Down syndrome). The rate of unfavourable outcome of pregnancy was 71% of cases (49/69) and was associated with the oldest mothers (P=0.011). In the chromosomally normal pregnancies, there were 59% (19/32) fetus with no apparently abnormalities. Among these 19 children, 13 have been followed up until an average age of 5 years and a half, the infant development was strictly normal. DISCUSSION AND CONCLUSION: The current results suggest to look for the poor prognosis data: nuchal thickness superior to 6 to 6,5 mm, presence of a hydrops fetalis and/or US abnormalities, fetal karyotyping and/or US evolution of cystic hygroma.

Therapeutic glucocorticoid administration alters the diurnal pattern of dehydroepiandrosterone.

Significant alteration in hypothalamic-pituitary-adrenal function has been demonstrated in patients after short-term glucocorticoid therapy, but its impact on the circadian rhythm of steroid hormones has never been investigated. This study examined the effects of short-term prednisone administration on the diurnal patterns of dehydroepiandrosterone (DHEA) and testosterone. Saliva samples were collected from 11 healthy, physically active, male volunteers for DHEA and testosterone analysis, as follows: every 4 h from 0800 to 2000 h on 2 control days without medication, and after 1 week of oral therapeutic prednisone treatment (60 mg daily) (days 0-3). Overall, a diurnal decline in the two steroid hormones was observed on the control days. After short-term glucocorticoid administration, DHEA concentrations were significantly decreased with a complete disappearance of the DHEA diurnal pattern, which lasted 2 days post-treatment. No glucocorticoid effect was observed for testosterone. The results indicate that short-term prednisone treatment affects the circadian pattern of saliva DHEA but not testosterone in healthy active volunteers. Further studies are necessary to determine whether this alteration in DHEA circadian pattern has clinical consequences in patients with chronic glucocorticoid therapy.