16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations.

BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

The transverse musculo-cutaneous gracilis flap for breast reconstruction: How to avoid complications.

BACKGROUND: The transverse musculocutaneous gracilis (TMG) flap has become a common solution for breast reconstruction. However, the safe skin paddle limits are not yet understood. In this study, we attempted to address this issue based on our experiences with inferior and posterior skin paddle extension. METHODS: Forty-four breast reconstructions with TMG flaps performed between November 2010 and January 2014 were analyzed retrospectively. For the first 20 cases, the flap skin paddle was extended 3 cm posteriorly to the middle thigh (group 1). For the next 20 flaps (group 2), the posterior tip was limited to this line, whereas more fat was recruited inferiorly. In the four cases of group 3, the skin flap was extended posteriorly with a second vascular pedicle from the profunda artery perforator (PAP) flap. The weights and the dimensions of the flaps, operating durations, and postoperative complications of the entire series were analyzed. Groups 1 and 2 were statistically compared. RESULTS: Flap complications were statistically more frequent in group 1 compared with group 2 (45 vs. 0%, P = 0.0012); 40% posterior flap tip necrosis was observed in group 1. Conversely, donor site complications were statistically more frequent in group 2 than in group 1 (40 vs. 5%, P = 0.019) with 35% inner thigh dehiscence. In the TMG with extended PAP flap group, the operating duration was 77 min longer compared with the rest of the series with no donor site complications. In one case, limited necrosis occurred at the anterior skin tip. CONCLUSIONS: Harvesting the posterior portion of the TMG up to the middle of the posterior thigh may lead to partial flap necrosis. Extending subcutaneous fat removal under the inferior skin incision may increase the risk of donor site complications. Adding a second vascular pedicle from the PAP flap may improve posterior TMG tip perfusion at the expense of a longer operation.

A pure familial 6q15q21 split duplication associated with obesity and transmitted with partial reduction.

Familial transmission of chromosome 6 duplications is rare. We report on the first observation of a maternally-inherited pure segmental 6q duplication split into two segments, 6q15q16.3 and 6q16.3q21, and associated with obesity. Obesity has previously been correlated to chromosome 6 q-arm deletion but has not yet been assessed in duplications. The aim of this study was to characterize the structure of these intrachromosomal insertional translocations by classic cytogenetic banding, array-CGH, FISH, M-banding and genotyping using microsatellites and SNP array analysis, in a mother and four offspring. The duplicated 6q segments, 9.75 Mb (dup 1) and 7.05 Mb (dup 2) in size in the mother, were inserted distally into two distinct chromosome 6q regions. They were transmitted to four offspring. A son and a daughter inherited the two unbalanced insertions and displayed, like the mother, an abnormal phenotype with facial dysmorphism, intellectual disability, and morbid obesity. Curiously, two daughters with a normal phenotype inherited only the smaller segment, 6q16.3q21. The abnormal phenotype was associated with the larger proximal 6q15q16.3 duplication. We hypothesize a mechanism for this exceptional phenomenon of recurrent reduction and transmission of the duplication during meiosis in a family. We expect the interpretation of our findings to be useful for genetic counseling and for understanding the mechanisms underlying these large segmental 6q duplications and their evolution.

Outcome of alimentary tract duplications operated on by minimally invasive surgery: a retrospective multicenter study by the GECI (Groupe d'Etude en Coeliochirurgie Infantile).

BACKGROUND: Alimentary tract duplications (ATD) are a rare cause of intestinal obstruction in childhood. There are many case reports but few series about laparoscopy or thoracoscopy for ATD. The aim of our study was to report the outcome of minimally invasive surgery (MIS) for ATD. METHODS: This was a retrospective multicenter study from the GECI (Groupe d'Etude en Coeliochirurgie Infantile). We reviewed the charts of 114 patients operated on by MIS for ATD from 1994 to 2009. RESULTS: Sixty-two patients (54 %) had a prenatal diagnosis. Forty-nine patients (43 %) were symptomatic before surgery: 33 of those patients (63 %) with postnatal diagnosis compared to 16 (25 %) with prenatal diagnosis (P < 0.01). In this last group, the median age at onset of symptoms was 16 days (range = 0-972). One hundred and two patients had laparoscopy (esophageal to rectal duplications) and 12 patients had thoracoscopy for esophageal duplications. The mean operative time was 90 min (range = 82-98). There were 32 (28 %) resection anastomoses, 55 (48 %) enucleations, and 27 (24 %) unroofings. The conversion rate was 32 %, and in a multivariate analysis, it was significantly higher, up to 41 % for patients weighing <10 kg (P < 0.01). Ten patients (8 %) had unintentional perioperative opening of the digestive tract during the dissection. Eight patients had nine postoperative complications, including six small bowel obstructions. The median length of hospital stay was 4 days (range = 1-21) without conversion and 6 days (range = 1-27) with conversion (P = 0.01). The median follow-up was 3 months (range = 1-120). Eighteen of the 27 patients who underwent partial surgery had an ultrasound examination during follow-up. Five (18 %) of them had macroscopic residue. CONCLUSION: This study showed that MIS for ATD is feasible with a low rate of complications. Patients with prenatal diagnosis should have prompt surgery to prevent symptoms, despite a high rate of conversion in small infants.

Laparoscopic gastropexy for the treatment of gastric volvulus associated with wandering spleen.

A 2.5-year-old boy was referred to the emergency room for a sudden onset of diffuse and increasing abdominal pain with lethargy, abdominal distension, and vomiting, all in the past 24 hours. A plain abdominal X-ray showed gastric distension. Two liters of gastric contents were evacuated by suction. The abdominal sonogram showed an unusual position of the spleen in the left-lower quadrant, with no splenic ischemia. The diagnosis of gastric volvulus associated with a wandering spleen was then evoked. Laparoscopic exploration revealed a nonischemic spleen, absence of normal supporting ligaments for the spleen, and gastric distension with flaccid gastric walls. The spleen was then easily moved in the left-under quadrant. A parietal peritoneal posterolateral incision was made, opposite the large gastric curve, up to the diaphragm (7 cm). This delimitated a sharp demarcation zone between the two edges of the incised peritoneum. The stomach was fixed to the peritoneal incision, covering and anchoring the spleen in a good position. Recovery was uneventful, and an abdominal sonogram performed 4 years after the surgery shows a viable spleen in its correct location. The rarity of gastric volvulus associated with a wandering spleen and its fast clinical improvement with medical treatment often delays the diagnosis and the surgical treatment. Laparoscopy in this case has a dual relevance: diagnosis and therapeutic management (splenectomy or gastropexy). Laparoscopic gastropexy for the treatment of gastric volvulus associated with a wandering spleen is an easy procedure and combines the advantages of all the surgical techniques previously described.

Bilateral simultaneous breast reconstruction with transverse musculocutaneous gracilis flaps.

BACKGROUND: A transverse musculocutaneous gracilis flap provides good autologous reconstruction for small- and medium-sized breasts. Although the procedure is well adapted for bilateral breast reconstruction, no publication has specifically addressed simultaneous bilateral cases. METHODS: From 2010 to 2014, the authors performed seven simultaneous bilateral breast reconstructions using transverse musculocutaneous gracilis flaps. The results with respect to operative data, immediate complications, second-stage reconstruction, and patient satisfaction after >1 year of follow-up were studied retrospectively. RESULTS: The mean operative time was 7 h and 48 min (range, 6-9 h). Three minor complications occurred: two cases of limited flap necrosis and one case of donor-site wound dehiscence. Surgical revision was not required, and there was no flap failure. A second-stage operation was performed in 71% of the patients to improve the aesthetic results and flap volume. On average, 167 cm(3) of fat was injected per breast. After a mean follow-up of 27 months, the satisfaction rate was 86% without significant functional deficits. CONCLUSIONS: A transverse musculocutaneous gracilis flap is an effective and safe option for simultaneous bilateral reconstruction. The operating time is shorter than that for other autologous procedures with similar complication rates and high patient satisfaction levels.

Management of refractory overactive bladder in children by transcutaneous posterior tibial nerve stimulation: A controlled study.

OBJECTIVE: To assess the objective efficacy of transcutaneous posterior tibial nerve stimulation in children presenting with overactive bladder resistant to well conducted treatment. MATERIAL AND METHOD: This was a randomized, double-blind, controlled study on 20 children with OAB. All patients were previously treated with anticholinergic drugs associated with detrusor rehabilitation, diet advice, bladder-voiding hygiene and constipation treatment, with poor clinical results. Patients were randomized into two groups: -Group A: treatment with PTNS (n = 11). -Group B: sham treatment (n = 9). The program lasted 12 consecutive weeks with two 30-minutes sessions a week. Each patient underwent pre-stimulation urodynamic testing to validate bladder overactivity followed by a post-stimulation testing. Pre- and post-stimulation urodynamic parameters were compared in order to objectively evaluate the treatment's efficacy. The patients noted their incontinence episodes for 7 consecutive days in a diary before the beginning of the program, in the middle and at the end of it: this led to computing an incontinence score (score ranged from 0 to 13, from good to poor). The difference between the pre-stimulation and post-stimulation score enabled to express clinical results in terms of poor (less than a 3-point decrease), medium (a 3 to 5-point decrease), good (6 to 8-point decrease), very good (final score ranged between 0 and 3). Children were questioned regarding their impression of being stimulated or not. RESULTS: In Group A, there were five very good clinical results (45%), one medium (10%) and five poor results (45%). In group B, nine very good results (66%) and three poor results (33%) were noted. Regarding urodynamic testing, volume voided during urgency (184 mL to 265 mL), maximal cystomanometry volume (215 mL to 274 mL) and volume at the onset of the first overactive detrusor contraction (ODC) (48 mL to 174 mL) were significantly increased in Group A (p = 0.002, p = 0.024 and p = 0.001) and maximal bladder pressure during ODC had decreased (61 to 46) (p = 0.042). 85% children in group A thought they were being stimulated vs. 70% in group B. CONCLUSION: Even though we noticed urodynamics improvements in group A, which objectively supports the efficacy of TCTPNS, clinical results remained the same between the two groups. In spite of the small size of our sample, this underlines the placebo effect of any type management in this pediatric population. Studying precisely the maximal useful voltage and duration of stimulation should then be relevant in order to yield maximal benefits from this easy-to-use procedure.

Four-week low-glycemic index breakfast with a modest amount of soluble fibers in type 2 diabetic men.

Low-glycemic index diets are associated with a wide range of benefits when followed on a chronic basis. The chronic effects, however, of the substitution of 1 meal per day are not well known in diabetic subjects. Therefore, we aimed to evaluate whether the chronic use of a low-glycemic index breakfast (low-GIB) rich in low-GI carbohydrates and a modest amount of soluble fibers could have an effect on lipemia at a subsequent lunch, and improve glucose and lipid metabolism in men with type 2 diabetes. A total of 13 men with type 2 diabetes were randomly allocated in a double-blind cross-over design to a 4-week daily intake of a low-GI versus a high-GI breakfast separated by a 15-day washout interval. The low-GI breakfast was composed of whole grain bread and muesli containing 3 g beta-glucan from oats. Low-GIB induced lower postprandial plasma glucose peaks than the high-GIB at the beginning (baseline, P <.001) and after the 4-week intake (P <.001). The incremental area under the plasma glucose curve was also lower (P <.001, P <.01, baseline, and 4 weeks, respectively). There was no effect on fasting plasma glucose, insulin, fructosamine, or glycosylated hemoglobin (HbA(1c)). Fasting plasma cholesterol, as well as the incremental area under the cholesterol curve, were lower (P <.03, P <.02) after the 4-week low-GIB period than after the high-GIB period. Apolipoprotein B (apo B) was also decreased by the 4-week low-GIB. There was no effect of the low-GI breakfast on triacylglycerol excursions or glucose and insulin responses at the second meal. The high-GIB, however, tended to decrease the amount of mRNA of leptin in abdominal adipose tissue, but had no effect on peroxisome proliferator-activated receptor gamma (PPARgamma) and cholesterylester transfer protein (CETP) mRNA amounts. In conclusion, the intake of a low-GI breakfast containing a modest amount (3 g) of beta-glucan for 4 weeks allowed good glycemic control and induced low plasma cholesterol levels in men with type 2 diabetes. The decrease in plasma cholesterol associated with low-GI breakfast intake may reduce the risk of developing cardiovascular complications in subjects with type 2 diabetes.

Botulinum toxin injections in the management of non-neurogenic overactive bladders in children.

INTRODUCTION: Non-neurogenic detrusor overactivity in children leads to varying degrees of functional impairments (urinary urgency, pollakiuria, urge incontinence, nocturia). Botulinum toxin has shown its effectiveness in the management of detrusor overactivity in neurological patients. OBJECTIVES: To evaluate the relevance of intravesical Botulinum toxin injections for the treatment of non-neurogenic overactive bladders in children. These pediatric patients were resistant to all the usual therapeutics (e.g. bladder/bowel rehabilitation, anticholinergic drugs, management of diet/hygiene habits and constipation, percutaneous posterior tibial nerve stimulation). MATERIALS AND METHODS: 8 children (mean age: 12.5years), 5 girls, 3 boys with daytime and/or nighttime incontinence and non-neurogenic detrusor overactivity validated by urodynamic testing. Urodynamic testing was conducted before the injections as well as 6weeks and 1year post injections. We used Dysport® 8 Speywood Units/kg injected via cystoscopy into 25 different sites. RESULTS: We noted improvements without any complaints during bladder voiding for all patients, in 6 patients the overactivity disappeared after 1 injection. Compliance was improved early-on in half the cases and at 1year for all cases (from 12% to 61%, p=0.01). Noninhibited contractions decreased constantly in both frequency and intensity. Clinical symptoms improved: mean of 7.75 daytime urinary incontinence episodes (IE) per week before the injection vs. 3 after the procedure (p=0.04). For nighttime IE the improvement was even more noticeable with 7.38 nighttime IE episodes per week before the injection vs. 2.06 after the procedure (p=0,02). CONCLUSION: Intradetrusor Botulinum toxin injections are a potential therapeutic option for the management of non-neurogenic detrusor overactivity in children resistant to the usual treatments.

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.

Cleft palate and bilateral congenital cataract: a familial observation: a new syndrome?

We report a family with a rare association of congenital bilateral cataract and cleft palate that has not to our knowledge been previously reported. The lineage has unveiled abnormalities over four generations affecting 21 people with congenital bilateral cataract, with or without cleft palate. The transmission seems autosomal dominant. Four brothers and sisters presented with this defect, and a fifth sister is healthy. The mother has facial dimorphism, congenital bilateral cataract, submucous cleft palate, clinodactyly, and scoliosis. The propositus' karyotype was normal. Array comparative genomic hybridisation (CGH) analysis showed an interstitial amplification in Xp21.1, found in the mother, in all the affected siblings but one, and in the healthy girl. Thisl association is not rare and has been reported in over 50 syndromes but rarely in familial observations. Based on the genetic-clinical discordance we wonder about the deleterious impact of the Xp21.1 amplification that might be a copy number polymorphism.