[Assessment of a post-emergency pathway with early urological regulation]. / Analyse d'un modèle de circuit court post-urgence avec une régulation précoce urologique.

INTRODUCTION: Urological emergencies represent 7 % of the outpatients at the emergency department (ED). We assessed the effect of setting up a post-emergency consultation (CPU) after deferred urological medical regulation. METHODS: All patients admitted to the ED in a university center over the period December 2017 to July 2018 and for whom a CPU was scheduled were included. The regulation concerned the date of CPU and supplementary exams. The main outcome was the ability to provide an efficient response according to a predefined grid of specific solutions. RESULTS: One hundred and twenty-eight patients were included. The median age was 57 years (18-97). Efficacy of the CPU was 76 %. This rate was lower in no-show patients or consulting for rare and complex motives (47 %, n=60). The no-show were not reachable on the first call in 51.6 % of cases, with a similar age and motives distribution to the others. Only 6,9 % (n=128) of all consultants (n=1863) had been referred to the CPU by emergency physicians. The decision was a second consultation in 70 % (48), a new exam in 10 % (7), deferred emergency surgery in 12 % (8) and finally 18 % (12) of no follow-up. CONCLUSION: CPU following early regulation by a urologist provides an effective response in 76 % of situations. Assessment of "no-shows" helped to identify groups at risk. LEVEL OF EVIDENCE: III.

The association of severe encephalopathy and question mark ear is highly suggestive of loss of MEF2C function.

Auriculocondylar syndrome and isolated question mark ear result from dysregulation of the endothelin 1-endothelin receptor type A signaling pathway. Animal models have highlighted the role of the transcription factor MEF2C as an effector of this pathway. We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency.

Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations.

Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.

[Percutaneous nephrolithotomy for kidney stones in elderly patients: Meta-analysis of results and complications]. / Néphrolithotomie percutanée des calculs rénaux des personnes âgées : méta-analyse des résultats et complications.

INTRODUCTION AND OBJECTIVE: Percutaneous nephrolithotomy (PCNL) is the gold standard treatment for kidney stones regardless of age. Elderly patients (EP)≥65years old, in growing numbers, have more comorbidities than the general population, may alter results of PCNL. The aim of this meta-analysis was to compare efficacy and complications of this procedure between EP and young patients (YP). METHODS: Original studies of prospective and historical cohorts, in English or French, presenting PCNL series published on PubMed until 2015 were identified using the keywords percutaneous nephrolithotomy, elderly patients, kidney stones and staghorn calculi. Our analysis focused on therapeutic efficacy, defined by absence of residual fragment or the presence of residual fragments<4mm at 3 postoperative months, and postoperative complications according to patient age: YP<65 years old and EP≥65 years old. Binary qualitative data were analyzed using odds ratio (OR) and quantitative data by estimating the difference of means. RESULTS: In total 397 studies were identified among which 23 were checked and 8 included in the meta-analysis for methodological quality corresponding to 4995 YP and 820 EP. No efficacy difference (OR=0.96; [IC95 %: 0.80; 1.17]; P=0.71), operating time (+1.15min in EP [IC95 %: -2.83; 5.12]; P=0.57) and average length of stay (+0.29 days in EP [IC95 %: -0.14; 0.72]; P=0.19) has been reported. It was a trend to more urinary infections (OR=2.24; [IC95 %: 0.74-6.80]; P=0.16) and a significantly increase of postoperative blood transfusions in EP (OR=1.41; [IC95 %: 1.00-1.97]; P=0.04). CONCLUSIONS: PCNL for kidney stones n EP is effective with a significantly increase the risk of postoperative blood transfusions compared to YP.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

A review of craniofacial disorders caused by spliceosomal defects.

The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.

[RALP: comparison of the oncological and functional outcomes of the intrafascial and the interfascial approaches]. / Résultats carcinologiques et fonctionnels de l'abord interfascial de la prostatectomie robotique comparé avec l'abord intrafascial.

INTRODUCTION: Due to its technical ease and greater precision Robotic Assisted Laparoscopic radical Prostatectomy (RALP) allows a better preservation of the neurovascular bundles, thereby improving functional outcomes. The intrafascial dissection has been proposed to allow a more complete preservation of these bundles. However, this technique harbors a high rate of positive surgical margins, justifying another trend: the interfascial approach. To date, there are still few publications directly comparing these 2 techniques and our study is the first to offer a 2-year follow-up. MATERIALS AND METHODS: Our study focused on a two-hundred patients population divided into two consecutive groups. All the patients were continent preoperatively and had a satisfactory IIEF5 score: (1) Group 1 consisted of 100 patients who underwent RALP with the intrafascial approach. They had a mean age of 60.3 years (45-70). The majority of cancers were of the low or moderate risk group of d'Amico. The mean PSA was 7.43ng/ml. Seventy-five patients had a pT2, 24 a pT3 and one patient had a pT4. (2) Group 2 included 100 patients who underwent RALP with the interfascial technique. Patients had a mean age of 61.6±5.96 years (45-72), and their cancers were mostly of the low or moderate risk groups of d'Amico. The mean PSA was 6.3ng/ml. Seventy-four patients had a pT2, 22 a pT3a, and 4 had a pT3b. All patients were evaluated after one and two years of follow-up. RESULT: Rates of positive surgical margins were 45% and 19% respectively for groups 1 and 2 (P<0.0001). The rates of biochemical failure (PSA>0.2ng/ml) at 2 years were 10% and 3%, respectively for groups 1 and 2 (P=0.0447). At 2 years, 2 patients in group 1 and one patient in group 2 were using 2 or more urinary pads. Erection with or without oral medication was maintained in 65 (65%) and 31 (31%) patients respectively for groups 1 and 2 at one year. At 2 years 86 and 65 patients were having spontaneous erection, respectively in groups 1 and 2 (P=0.0006). In addition, 65 and 55 patients were also capable of sexual penetration, respectively in groups 1 and 2 (P=0.0045). CONCLUSION: The intrafascial approach exposed to a very high rate of positive surgical margins while offering only a little benefit in the erectile function preservation at 2 years compared to the interfascial variant. In our series, we did not notice any significant difference between the two techniques concerning the urinary continence. LEVEL OF EVIDENCE: 5.

[Elastography shows promise in testicular cancer detection]. / Apport de l'élastographie en temps réel pour la caractérisation des masses testiculaires.

PURPOSE: Elastography is a novel imaging technology that shows promise in the identification of anatomic structures. The widespread use of ultrasound for screening testicular tumors in patients with cancer risk factors highlights unclassified testicular micronodules. We investigated the ability of elastography to accurately diagnose testicular nodules. MATERIAL: Patients with clinical testicular nodules were assigned to undergo elastography in a prospective study. The imaging was carried out by a single radiologist using a static elastography unit with a 9-14MHz frequency linear transducer, to identify hardness score, loss of architecture of testicular parenchyma, and surrounding effect. When orchidectomy was required, the corresponding specimens were subjected to hematoxylin and eosin staining for histologic correlation. RESULTS: We imaged 34 testicular lesions: 26/34 (76%) malignant tumors and 8/34 (24%) non-tumor lesion including 4 hematomas, 3 orchitis and 1 ischemia. Se, Sp, PPV and NPV of hardness in elastography in differentiating between malignant and benign tissue was found to be 96.2%, 37.5%, 83%, and 75%, respectively. Further, for recognizing cancer, the loss of architecture of the testicular parenchyma detecting in elastography was 92.3%, 75%, 92.3%, and 75%, respectively, and the surrounding effect was 84.6%, 87.5%, 95.6% and 63.6%, respectively. CONCLUSION: Elastography may be a promising tool at diagnosing testicular tumor when the loss of architecture and the surrounding effect were present. Further studies are needed to evaluate whether the utility of elastography is worth pursuing to identify of unclassified testicular micronodules. LEVEL OF EVIDENCE: 3.

Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause.

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.

Corticosteroids in the management of brain-dead potential organ donors: a systematic review.

Summary Current guidelines recommend the administration of hormonal combination therapy including immunosuppressive doses of corticosteroids to donors with low left ventricular ejection fractions and to consider hormonal therapy administration to all donors. However, these recommendations are largely based on observational data. The aim of this systematic review (SR) was to assess the clinical efficacy and safety of corticosteroids in brain-dead potential organ donors. MEDLINE and EMBASE were searched from the earliest accessible date up to March 2013 with a qualified librarian. Studies comparing the effects of any corticosteroid with those of placebo, standard treatment, or another active comparator were sought. Two independent reviewers evaluated each citation retrieved and selected studies independently and in duplicate. A third independent reviewer resolved any disagreement. Outcomes included donor haemodynamics and oxygenation, organ procurement, recipient survival, and graft survival. This review included 11 randomized controlled trials (RCTs) and 14 observational studies. The majority used methylprednisolone and often combined it with other hormonal therapies. Ten out of the 11 RCTs yielded neutral results. However, in observational studies, use of corticosteroids generally resulted in improved donor haemodynamics and oxygenation status, increased organ procurement, and improved recipient and graft survival. Overall quality of included studies was poor, as most of them presented high risks of confounding. This SR highlights the low quality and conflicting evidence supporting the routine use of corticosteroids in the management of organ donors. A large trial evaluating the effect of corticosteroids on outcomes such as organ recovery and graft survival is warranted.

[Management of the bladder cuff removal by open excision versus transurethral resection of the ureteral orifice after laparoscopic radical nephroureterectomy in upper urinary tract--urothelial carcinoma]. / Évaluation des différentes techniques d'excision de la collerette vésicale lors des néphro-urétérectomies laparoscopiques pour la prise en charge des carcinomes urothéliaux de la voie excrétrice supérieure.

OBJECTIVES: To assess treatment-related complication outcomes in the management of the bladder cuff removal by open excision (OE) or transurethral resection of the ureteral orifice (TURUO) after laparoscopic radical nephroureterectomy (LNU) in upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: We did a retrospective study involving patients having UUT-UC who underwent LNU from 2004 to 2012 in two references center. Flexible ureteroscopy was carried out for multiple biopsies. Patients were assigned to one of two different surgical groups consisting of LNU with OE versus TURUO for the bladder cuff removal. Perioperative characteristics, complication related treatment and oncological outcomes were collected during the follow-up. RESULTS: Overall, 29 patients underwent LNU over-time including 16 using LNU with OE and 13 LNU with TURUO. LNU+OE were older (66.5 years [48-87] [P<0.01]). Operative time was shorter (180 min vs. 240 min [P=0.01]) with a longer hospital stay (7 days vs. 5 days [P<0.01]) than TURUO technic. No difference in the complication rate was reported. LNU +OE was associated with higher grade (81.3% vs. 38.5% [P=0.026]) and more invasive tumor (37.5% vs. 24.1% [P=0.03]). Regardless the technic, the cancer-specific survival rate was 63.7 years without significant differences between technics. CONCLUSION: TURUO was shorter in hospital stay but had a longer operative time with no impact on the treatment-related complication. Oncological control not highlighted any difference between technics however longer follow up is expected for recommendations.

[Ipsilateral dual kidney transplantation: a monocentric experience about 15 cases and literature review]. / Bi-transplantation rénale par abord ipsilatéral: expérience d'un centre à propos de 15 patients opérés consécutivement et revue de la littérature.

OBJECTIVE: Our study aimed to support the viability of the concept of Ipsilateral Dual Kidney Transplantation (DKT) by presenting our initial experience and proposing a review of the literature in this subject. METHODS: Fifteen ipsilateral DKT were performed at Nice University Hospital between August 2010 and March 2012. We have described our skin incision preferences, the vascular anastomoses, and the uretero-vesical reimplantation. We have analyzed the operative duration, the cold ischemia time (CIT) of both transplants, the blood transfusion volume, the intraoperative and postoperative complications, the time to diuresis recovery, the hospital stay, and the kinetics of the creatinine clearance until the third postoperative month. We have compared our results with those of the literature. RESULTS: The average CIT of the first transplant (T1) was 17.5 ± 3.3 hours, and that of the second (T2) was 18.4 ± 3.3 hours. The mean operating time was 234 ± 67 minutes. Patients received an average of 2 units of blood during surgery [0-4] and 1.8 units in the postoperative period [0-15]. The complications rate was 26.7% and included an intraoperative T2 artery thrombosis and 3 postoperative complications consistent with a hematoma, a T2 ureteric necrosis and a T2 venous thrombosis. Two transplants were lost (6.7%) and one death (6.7%) was reported on day 40. The average length of hospital stay was 20.9 ± 7.8 days. The mean creatinine clearance values were 12.6 mL/min at D2, 35.6 mL/min at D7, 44.9 mL/min on discharge, and 48.2 mL/min at D90. CONCLUSION: Our results supported the viability of the dual kidney transplantation concept. Furthermore the ipsilateral approach shortened the procedure and limited the surgical trauma by preserving the contralateral iliac fossa, without compromising renal function recovery or increasing morbidity.

[Salvage HIFU after radiotherapy and salvage radiotherapy after HIFU in locally recurrent prostate cancer: Retrospective analysis of morbidity]. / Traitements de rattrapage par HIFU après radiothérapie première et par radiothérapie après HIFU première dans la récidive locale du cancer de prostate: analyse rétrospective de la toxicité

OBJECTIVES: To evaluate the toxicity of therapeutic sequences High Intensity Focused Ultrasound (HIFU)-salvage radiotherapy (HIFU-RT) or radiotherapy-salvage HIFU (RT-HIFU) in case of locally recurrent prostate cancer. MATERIALS AND METHODS: Nineteen patients had a local recurrence of prostate cancer. Among them, 10 patients were treated by HIFU-RT and 9 patients by RT- HIFU (4 by external beam radiotherapy [EBR] and 5 by brachytherapy [BRACHY]). Urinary side effects were assessed using CTCAE v4. RESULTS: At the time of the initial management, the median age was 66.5 years (53-72), the median PSA was 10.8ng/mL (3.4-50) and the median initial Gleason score was 6.3 (5-8). Median follow-up after salvage treatment was 46.3 months (2-108). Thirty percent of the patients in the HIFU-RT group and 33.3 % of the patients in the RT-HIFU group, all belonging to the sub-group BRACHY-HIFU, had urinary complication greater than or equal to grade 2. Among all the patients, only 1 had grade 1 gastrointestinal toxicity. CONCLUSION: BRACHY-HIFU sequence seems to be purveyor of many significant urinary side effects. A larger database is needed to confirm this conclusion.

A retrospective study on the prognostic factors and success, survival, and failure outcomes of treated endodontic-periodontal lesions.

OBJECTIVES: The objective of this retrospective study was to determine possible prognostic factors of endodontic-periodontal lesions and to compare success, survival, and failure outcomes of treated endodontic-periodontal lesions across different treatment modalities, demographic variables, and anatomical tooth variations. MATERIALS AND METHODS: Data was collected from patient records in the patient management system (Salud, Titanium Solutions) from the Griffith University Dental Clinic between January 2008 and December 2021. The search strategy used the terms "endodontic periodontal lesion," "periodontal endodontic lesion," "endo perio lesion," "perio endo lesion," and "EPL." The 88 cases which met inclusion and exclusion criteria were analyzed. RESULTS: The overall success rate was 46.6%, with 21.6% of teeth surviving and 31.8% of teeth failing. Bone loss extending to the apical third (OR = 0.3, 95% CI [0.104, 0.866]), and probing depths of 5-7 mm (OR = 0.147, 95% CI [0.034, 0.633]) and 8-10 mm (OR = 0.126, 95% CI [0.029, 0.542]) were associated with a statistically significant lower odds of success (p < .05). A history of no periodontal disease (OR = 7.705, 95% CI [1.603, 37.037]) was associated with a statistically significant higher odds of success (p < .05). CONCLUSION: Practitioners should be aware of bone loss to the apical third, deep probing depths, and a history of periodontal disease as possible prognostic factors that can affect the success rate when treating endodontic-periodontal lesions. Further research with more stringent control over operator factors should be done to investigate these variables.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).

Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.

SOX10 mutations in patients with Waardenburg-Hirschsprung disease.

Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.