Christina Clementson Kockum

22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment

Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.

Paediatric robotic surgery in clinical practice: a cost analysis.

BACKGROUND Since 2006 we have used robotic assistance when performing minimally invasive laparoscopic fundoplications in children. We compared the costs of robotic surgery with the costs for open and laparoscopic surgery to test our hypothesis that the increased costs of the new technology are acceptable. METHOD Costs were calculated using the regional hospital prices for our first 14 fundoplications in children, performed with the aid of the da Vinci Surgical System from Intuitive Surgical. We compared these costs with those of our ten latest fundoplications performed using open and laparoscopic surgery, respectively. There were no differences in the demographic data, work-up or indications for surgery between the three groups of children. RESULTS The mean cost of robotic surgical fundoplications (EUR 9 584) was 7% higher than the mean cost of laparoscopic surgery (EUR 8 982) and 9% lower than the mean costs for open surgical procedures (EUR 10 521). These differences can be explained by the increased cost of robotic instruments (EUR 2 081 per operation). The duration of the operation and the duration of in-hospital stay are comparable to those of laparoscopic surgical interventions. The time required for the operative intervention was considerably longer than for the open surgical procedure; the duration of the in-hospital stay was only half of that of the open surgical procedure. The patients seemed to benefit from the use of robotic instruments with less morphine (as a marker of less postoperative pain) and a shorter hospital stay. CONCLUSION The introduction of robotic assistance into surgical practice involves increased in-hospital costs, mainly because of the cost of the new instruments. This increase in cost can be offset by the shorter hospital stay compared to open surgery. After laparoscopic surgery the hospital stay is about the same as after operations performed with robotic assistance. Cheaper instruments and shorter operating time will make robotic surgery cost efficient in the future. The benefit for the patients is less trauma due to the use of minimally invasive surgery and a shorter hospital stay. Thus, the higher initial costs may be considered worthwhile.

Bladder exstrophy: psychological impact during childhood.

PURPOSE We describe the impact of bladder exstrophy on the behavior, self-esteem and quality of life of children as well as on the parents, and analyze the need for psychological intervention. MATERIALS AND METHODS All 7 boys and 8 girls 3 to 18 years old (median age 11) under treatment at a tertiary pediatric surgery clinic were included in our followup study. Medical and psychological evaluations were performed. Behavior was assessed using the semistructured Höök-Cederblad Child Behavior Interview and the Child Behavior Checklist questionnaire. Self-esteem was assessed by the self-rating I Think I Am questionnaire. Children and parents were interviewed separately. Quality of life was estimated using the Multiattribute Health Status Mark II classification system. RESULTS After repeat operations and hospitalization 10 children were dry, although 9 required catheterization. Four children had some behavioral problems, which were manifest in 2. All but 1 male adolescent had good or very good self-esteem. Quality of life was decreased in most cases due to limited self-care, although emotional problems were few. All mothers had experienced the birth as a traumatic event and 5 parents had had psychiatric symptoms. CONCLUSIONS Self-esteem may be maintained despite multiple operations, urinary leakage and deviant genitalia but the abnormality had a great impact on children and on the lives of the families. Parents and children required individual intervention from a multidisciplinary team during different stages of childhood.

Adolescents with anorectal malfromation: physical outcome, sexual health and quality of life

Abstract Background: The necessity of referring adolescents with anorectal malformation (ARM) from pediatric units to adult care is unclear. The issue requires knowledge about the health of the adolescent. Objective: To examine the physical outcome, sexual health and quality of life (QoL) in adolescents with ARM. Methods: At medical counseling, 24 adolescents with ARM, 15–21 years of age, answered questionnaires about physical outcome according to the Krickenbeck follow-up and QoL according to SF 36 and gastrointestinal quality of life (Giqli). Matched control groups were used; 15 adolescents participated in deep interviews about sexual health and body imaging. Results: Fecal soiling, constipation and gas incontinence were much higher for ARM patients compared with controls (p<0.05). QoL regarding large bowel function was lower for both genders compared with controls (p<0.05). Females scored lower in physically related QoL (p<0.05). Social and sexual adaption to the symptoms was obvious in the deep interviews. Conclusion: Adolescents with ARM have considerable intestinal symptoms, which influence QoL and require adaption in intimate situations. A referral to adult care seems to be important, and continuous cooperation between the pediatric surgeon and adult care is suggested.

Morgagni Hernia Repair in a Small Child Using da Vinci Robotic Instruments - A Case Report

BACKGROUND The recently introduced use of robotic surgery in minimally invasive surgery procedures facilitates several steps in the operative procedure. We report the first case of a robot-assisted laparoscopic repair of a Morgagni hernia using the da Vinci Surgical System from Intuitive Surgical (Sunnyvale, CA, USA) in a 7.8 kg 18-month-old child. METHODS Four trocars were used to gain access to the abdomen. The robot-enhanced instruments were used to close the hernia defect with interrupted, absorbable sutures, using intracorporeal knot tying. RESULTS The operation was completed laparoscopically without a patch. The total setup time for the robotic system was 35 minutes including draping. The operating time at the robotic console was 80 minutes. The child tolerated an oral intake the day after surgery and was discharged home on the third postoperative day. CONCLUSION Robot-assisted laparoscopic Morgagni hernia repair is feasible in small children.

Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder

Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.

Bowel symptoms in children with anorectal malformation: A follow-up with a gender and age perspective.

BACKGROUND Gender specific outcome for children with anorectal malformations (ARM) is rarely reported although it is important for medical care and in parent counseling. PURPOSE To assess bowel function according to the Krickenbeck system in relation to ARM-subtype, gender and age. METHOD All children born with ARM in 1998-2008 and referred to two centers in two different countries were followed up. The bowel function in 50 girls and 71 boys, median age 8 years, was analyzed. RESULTS Among those with a perineal fistula, incontinence occurred in 42% of the females and in 10% of the males (p=0.005) whereas constipation occurred in 62% of the females and 35% of the males (p<0.001). No bowel symptoms differed between the females with perineal and vestibular fistulas (p>0.3 for every symptom). Sacral malformations were associated with incontinence only in males with rectourethral fistulas. Constipation among the males differed between the age groups: 58% versus 26% (p=0.013). Bowel symptoms did not change with age among the females. CONCLUSION Gender differences in outcome for children with ARM must be considered. Males with perineal fistulas had less incontinence and constipation than the females with perineal fistulas. The females with perineal and vestibular fistulas had similar outcomes.

WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish

Bladder exstrophy, a severe congenital urological malformation when a child is born with an open urinary bladder, is the most common form of bladder exstrophy-epispadias complex (BEEC) with an incidence of 1:30,000 children of Caucasian descent. Recent studies suggest that WNT genes may contribute to the etiology of bladder exstrophy. Here, we evaluated WNT-pathway genes in 20 bladder exstrophy patients using massively parallel sequencing. In total 13 variants were identified in WNT3, WNT6, WNT7A, WNT8B, WNT10A, WNT11, WNT16, FZD5, LRP1 and LRP10 genes and predicted as potentially disease causing, of which seven variants were novel. One variant, identified in a patient with a de novo nonsynonymous substitution in WNT3 (p.Cys91Arg), was further evaluated in zebrafish. Knock down of wnt3 in zebrafish showed cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen. Our study suggests that the function of the WNT3 p.Cys91Arg variant was altered, since RNA overexpression of mutant Wnt3 RNA does not result in embryonic lethality as seen with wild-type WNT3 mRNA. Finally, we also mutation screened the WNT3 gene further in 410 DNA samples from BEEC cases and identified one additional mutation c.638G>A (p.Gly213Asp), which was paternally inherited. In aggregate our data support the involvement of WNT-pathway genes in BEEC and suggest that WNT3 in itself is a rare cause of BEEC.

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10−08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10−19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Outcome after Computer-Assisted (Robotic) Nissen Fundoplication in Children Measured as Pre- and Postoperative Acid Reducing and Asthma Medications Use.

PURPOSE This study aims to report the clinical outcome of computer-assisted fundoplication (CAF) in children. METHODS As our center changed policy to using computer-assisted surgery only, a prospectively studied cohort of 40 children underwent CAF, during the period from January 2006 through May 2013. The collected data include patient demographics and postoperative complications as well as medication, 24-hour pH measurements and DeMeester scores before and after surgery. RESULTS In the studied group, the median percentage of the duration of the 24-hour pH < 4 decreased postoperatively from 11 (range, 5-39) to 1% (range, 0-12) (p < 0.001); the DeMeester score decreased from 40 (range, 17-137) to 5 (range, 1-42) (p < 0.001). All 40 patients required antireflux medication before the fundoplication. This number decreased significantly to 8 (20%) after the fundoplication (p < 0.001). Before the fundoplication, 22 children (55%) were using asthma medication and 12 (30%) after the fundoplication (p = 0.04). CONCLUSIONS The CAF significantly reduced the acid reflux from the stomach to the esophagus and the use of antireflux as well as asthma medication during the median observation period of 5 years. The evidence of advantages compared with conventional laparoscopic fundoplication remain to be confirmed.