Georges Audry

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith - Wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental abnormalities, tissue and organ hyperplasia and an increased risk of embryonal tumours (most commonly Wilms tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. Molecular diagnosis of BWS is currently difficult, mostly due to the large spectrum of genetic and epigenetic abnormalities. The other difficulty in managing BWS is the identification of patients at risk of tumour. An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele. A loss of imprinting of the KCNQ1OT gene, associated with the loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 has been described in BWS patients. The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS. The allelic status of the 11p15 region and the methylation status of the KCNQ1OT and H19 genes were investigated in leukocyte DNA from 97 patients referred for BWS and classified into two groups according to clinical data: complete BWS (CBWS) (n=61) and incomplete BWS (IBWS) (n=36). Fifty-eight (60%) patients (39/61 CBWS and 19/36 IBWS) displayed abnormal demethylation of KvDMR1. In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS). Thirteen of the 39 patients with normal methylation of KvDMR1 displayed hypermethylation of the H19 gene. These 13 patients included two siblings with 11p15 trisomy. These results show that analysis of the methylation status of KvDMR1 and the H19 gene in leukocyte DNA is useful in the diagnosis of 11p15-related overgrowth syndromes, resulting in the diagnosis of BWS in more than 70% of investigated patients. We also evaluated clinical and molecular features as prognostic factors for tumour and showed that mosaicism for 11p15 UPD and hypermethylation of the H19 gene in blood cells were associated with an increased risk of tumour.

Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance

Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM). Aim: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis. Results: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors. Conclusion: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

Nephron Sparing Surgery (NSS) for Unilateral Wilms Tumor (UWT): The SIOP 2001 Experience

Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT‐2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non‐infiltrating tumors. Aim: Inventory of the current SIOP NSS‐experience.

Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95.

The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event‐free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP).

Current Concepts in Surgery for Wilms Tumor—The Risk and Function-Adapted Strategy

This article describes the current status of surgical approach to Wilms tumor. Combined multimodal treatment including classical open nephrectomy is still the most recommended and offers excellent survivals. Patients suffering from Wilms tumor as potentially very long-term survivors also need great care of quality of their further life. Nephron-sparing surgery seems an important step in this regard; however, selection of patients is necessary to avoid failures and decreasing survival rate. A new method of describing this kind of procedure developed within the SIOP Renal Tumours Study Group (RTSG) offers an opportunity for further comparisons and assessment. Minimally invasive nephrectomy is not recommended in the treatment of Wilms tumor; however, in experienced hands and correctly selected (rare) cases, minimally invasive nephrectomy may offer the same outcome as the classical open approach. Lymph nodes sampling, essential for reliable staging, appeared rarely correct in children operated by this technique. Any competition with partial nephrectomy should be avoided in favor of the nephron-sparing approach. A small proportion of patients still create surgical difficulties and this is in fact the target group for further surgical reviews. Their prognosis seems at least in part surgeon-dependent. Few clinical factors available preoperatively (tumor side, age, and tumor volume) were detected as influencing potential risk of surgical failures. Once identified, this needs increased attention from the surgical point of view.

Is Nephron Sparing Surgery Justified in Wilms Tumor With Beckwith–Wiedemann Syndrome or Isolated Hemihypertrophy?

Patients with Beckwith–Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome.

Minimally invasive surgery in childhood cancer: a challenging future.

INTRODUCTION Minimally invasive surgery (MIS) has emerged as an alternative to open approach for cancer diagnosis in children ∼20 years ago, but only recently for tumor resection. The purpose of this review is to update the use of MIS in pediatric oncological surgery over the past five years. METHODS The authors conducted a systematic review of papers published between 2009 and 2014 focusing on indications and results of the technique. RESULTS New indications in Wilms tumor, pheochromocytoma, and lung nodules have emerged, thanks to the growing use of MIS in benign urological and thoracic surgery with satisfactory results. Case control studies comparing MIS to open approach have been published for the first time in more classical indications such as neurogenic tumors, while robot-assisted procedure has shown concern in results about its early experience in solid tumors. CONCLUSION MIS is a promising method for removal of thoracic and abdominal malignancies as long as oncological principles are strictly followed. Long-term follow-up is mandatory to further delineate objective indications.

Néphro-urétérectomie polaire pour duplication pyélo-urétérale par voie lombaire postérieure chez le nourrisson

Resume But Etudier l’efficacite et la morbidite de la voie lombaire posterieure (VLP) horizontale dans les nephro-ureterectomies polaires (NUP) pour duplication pyelo-ureterale chez le nourrisson. Materiel et methodes Trente-trois NUP pour duplication pyelo-ureterale ont ete realisees par VLP chez 31nourrissons, âges de 6.7 ± 5.5 mois (1-26) entre Janvier 1994 et Decembre 2005. Resultats La duree operatoire moyenne etait de 121 ± 35 minutes (60-19). Il n’y a pas eu de complication per-operatoire. Les pertes sanguines etaient minimales dans tous les cas ( Conclusion La VLP horizontale a ete une technique sure et reproductible, offrant un benefice esthetique par rapport a la voie classique antero-laterale. Elle peut representer une voie d’abord privilegiee dans la chirurgie ouverte des NUP pour duplication pyelo-ureterale chez le nourrisson, dans une tranche d’âge pour laquelle la videochirurgie reste encore peu evaluee.

Vidéochirurgie chez l’enfant : progrès actuels et perspectives

This review presents the evidence of video-assisted surgery in the pediatric population and discusses future progress in this field. Videosurgery minimizes the cosmetic impact and the pain induced by open procedures and has been in constant development in adults and children. Earlier training of surgeons and residents combined with advances in anesthetics and technology have expanded the use of videosurgery for more complex interventions. Although most feasible surgical procedures have been performed by laparoscopy, the literature has not yet defined it as the gold standard for most interventions, especially because of the lack of evidence for many of them. However, laparoscopy for cholecystectomy is now the preferred approach with excellent postoperative outcomes and few complications. Although no evidence has been demonstrated in children, laparoscopy has been shown to be superior in adults for gastroesophageal reflux disease and splenectomy. Laparoscopic appendectomy remains controversial. Nevertheless, meta-analyses have concluded in moderate but significant advantages in terms of pain, cosmetic considerations, and recovery for the laparoscopic approach. Laparoscopy is now adopted for undescended testes and allows both localization and surgical treatment if necessary. For benign conditions, videosurgery can be an excellent tool for nephrectomy and adrenalectomy. However, laparoscopy remains controversial in pediatric surgical oncology.

Recurrent Intragenic Duplication within the NR5A1 Gene and Severe Proximal Hypospadias

A heterozygous intragenic duplication within the repeated area (CTGCAGCTG)×2 of the NR5A1 gene was found in a 15-year-old 46,XY DSD (disorders/differences of sex development) patient with micropenis and severe proximal hypospadias. This heterozygous duplication has already been described twice in boys with a similar phenotype, whereas a deletion of 3 amino acids at the same position in the protein SF-1 has been described in a 46,XX patient with primary ovarian failure and short stature. These data suggest that this region within the NR5A1 gene has an important role for SF-1 protein function in gonads and is a hotspot for intragenic rearrangements.