Assessment of Involuntary PFM Contractions in Comparison with Existing Literature and IUGA/ICS Terminology Reports.

INTRODUCTION AND HYPOTHESIS: Involuntary pelvic floor muscle (PFM) contractions are thought to occur during an increase in intra-abdominal pressure (IAP). Although no studies have assessed their presence in women with normal pelvic floor (PF) function, existing literature links the absence of involuntary PFM contractions to various PF dysfunctions. This study rectifies this lacuna by evaluating involuntary PFM contractions during IAP in healthy nulliparous women with no PF dysfunction, using visual observation and vaginal palpation. Results were compared with the literature and the IUGA/ICS Terminology Reports. METHODS: Nulliparous (n=149) women performed three sets of three maximal coughs. Visual observation and vaginal palpation were conducted in the standing and supine positions. The women were not instructed to contract their PFMs. Occurrence rates were calculated for each assessment method and position; differences between positions were analyzed using the Chi-squared test. RESULTS: Rates of occurrence of involuntary PFM contraction were low across both assessments and positions (5-17%). Significant differences were found between standing (5%) and supine (15%) positions for visual observation, but not vaginal palpation (15%, 17% respectively). Occurrence rates also differed compared with the literature and terminology reports. CONCLUSIONS: Contrary to clinical expectations, rates of occurrence of involuntary PFM contraction among our cohort of nulliparous women were extremely low. Digital palpation results showed high agreement with the terminology reports, but only partial agreement was observed for the visual observation results. Our study underscores the need for more research aimed at defining normal involuntary PF functions, a review of our understanding of involuntary PFM contractions, and better standardized guidelines for involuntary PFM assessment methods.

Pelvic floor muscle rehabilitation for genitourinary syndrome of menopause: why, how and when?

Genitourinary syndrome of menopause (GSM) is caused by chronic deprivation of estrogen and other sex steroids during the postmenopausal period, which leads to changes in the vulvovaginal tissues. These changes cause bothersome symptoms, such as vaginal dryness, pruritus, dyspareunia, increased daytime urinary frequency, urgency and urinary incontinence, which have considerable negative effects on women's quality of life and sexual function. Recent studies have investigated a novel treatment approach for GSM. Pelvic floor muscle (PFM) rehabilitation, a low-cost conservative management with no side-effects, has been studied alone or in combination with other treatment modalities to reduce the signs and symptoms of GSM. The aim of this article is to discuss why PFM rehabilitation could be useful for women with GSM, how it may help improve signs and symptoms of GSM and when this treatment should be recommended.

Pelvic floor muscle training: mechanisms of action for the improvement of genitourinary syndrome of menopause.

Objective: This study aims to investigate the mechanism of action of pelvic floor muscle training (PFMT) for the improvement of the signs and symptoms of genitourinary syndrome of menopause (GSM) in postmenopausal women with GSM and urinary incontinence (UI).Methods: Twenty-nine women were included in the secondary analysis of a single-arm feasibility study. Using color Doppler ultrasound, the peak systolic velocity, time-averaged maximum velocity, and pulsatility index of the internal pudendal and dorsal clitoral arteries were measured at rest and after a pelvic floor muscle (PFM) contraction task. PFM function was assessed by dynamometry, and vulvovaginal tissue elasticity was measured using the Vaginal Atrophy Index.Results: PFMT significantly improved blood flow parameters in both arteries (p < 0.05) and significantly increased the speed of PFM relaxation after a contraction (p = 0.003). After the intervention, a marginally significant decrease in PFM tone was observed, as well as an increase in PFM strength (p = 0.060 and p = 0.051, respectively). Finally, improvements in skin elasticity and introitus width were observed as measured by the Vaginal Atrophy Index (p < 0.007).Conclusion: Our findings suggest that PFMT improves blood flow in vulvovaginal tissues, PFM relaxation capacity, and vulvovaginal tissue elasticity in postmenopausal women with GSM and UI.

Hereditary axonal neuropathy related to MME gene mutation in a family with fetomaternal alloimmune glomerulonephritis.

We report a consanguineous family with a homozygous and heterozygous membrane metallo-endopeptidase (MME) mutation (c.467delC) and two clinical conditions: fetomaternal alloimmune membranous glomerulopathy (FMG) and hereditary motor and sensory axonal neuropathy. The penetrance of both phenotypes was variable. Some individuals experienced unusually fast neurological degradation. Pain and vasomotor signs were frequent complaints, possibly due to a loss of the neutral endopeptidase (NEP, the MME gene product) function and its subsequent inability to degrade substance P and vasomotor peptides. Electrophysiological and nerve biopsy findings were consistent with predominantly axonal neuropathy. This specific clinical phenotype was attributed to a c.467delC MME gene mutation. Diagnosis of such a mutation is important but can be challenging, due to allele dropout. Heterozygous subjects who had already reached the expected age of disease onset had peripheral neuropathy, but also suffered from additional diseases. Neurologists should advise women of childbearing age with MME mutations to seek pre-pregnancy genetic advice and nephrologists should search for neuropathy in patients with FMG.

[An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction]. / Traduction française de la terminologie commune de l'International Urogynecological Association (IUGA) et de l'International Continence Society (ICS) relative à la prise en charge conservatrice et non pharmacologique des troubles pelvi-périnéaux de la femme.

INTRODUCTION: There has been an increasing need for the terminology for the conservative management of female pelvic floor dysfunction to be collated in a clinically-based consensus report. METHODS: This report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology and nursing were invited to comment on the paper. RESULTS: A terminology report for the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically-based with the most common symptoms, signs, assessments, diagnoses and treatments defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Keeping the pelvic floor healthy.

Female pelvic floor muscles form a diaphragm that spans the entire pelvic cavity. They consist of the fibers of the coccygeus and the levator ani muscles, the latter of which is composed of five parts. Together with their fascia, the pelvic floor muscles provide support for the urethra, the vagina, and the rectum and constrict the urethral, vaginal, and anal orifices. Alterations in the composition of the pelvic floor muscles at menopause appear to affect their properties and, thereby, their ability to function adequately. This can lead to an increased prevalence in urinary incontinence and other lower urinary tract dysfunction, pelvic organ prolapse, and genitourinary syndrome of menopause. This article aims to define the pelvic floor muscles and functions and to summarize the direct and indirect changes to women's pelvic floor muscles during and after menopause and through aging. A particular focus is also given to the evidence-based literature on how to keep pelvic floor muscles healthy during menopause and in postmenopause using conservative management therapy.

Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women: an abridged Cochrane systematic review.

Pelvic floor muscle training (PFMT) is a first-line therapy for women with stress, urgency or mixed urinary incontinence (UI). Supervision and content of PFMT programmes is highly variable. The most effective approach to training is not known. The aim of the review was to compare the effects of different approaches to PFMT for women with UI. This was a systematic review with meta-analysis of randomized or quasi-randomized trials in women with stress, urgency or mixed UI that compared one approach to PFMT with another. The Cochrane Incontinence Group Specialised Trials Register (17 May 2011) was searched. Two reviewers independently assessed trials for eligibility and risk of bias, and extracted data. Data were analyzed as described in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.2.2). From 574 records we included 21 trials (1490 women randomized) that addressed 11 comparisons. Comparisons made included: differences in training supervision (amount, individual versus group), in approach (one versus another, the effect of an additional component) and the exercise training (type of contraction, frequency of training). There were few trials or data in any comparison. In women with stress UI, 10% who received more health professional contact (weekly or twice-weekly group supervision plus individual appointments) did not report improvement compared to 43% who had individual appointments only (risk ratio for no improvement 0.29, 95% confidence interval 0.15 to 0.55, four trials). While women receiving more contact were more likely to report improvement, the confidence interval was wide, and more than half of "controls" reported improvement. This finding, of subjective improvement in both active treatment groups, with more improvement reported by those receiving more health professional contact, was consistent throughout the review. Considerable caution is needed in interpreting the results of the review. Existing evidence is insufficient to make any strong recommendations about the best approach to PFMT. A consistent pattern of more self-reported improvement with more health professional contact was observed; the few data consistently showed that women receiving regular (e.g. weekly) supervision were more likely to report improvement than women doing PFMT with little or no supervision. The clinical rehabilitation impact is to offer women reasonably frequent health professional contact during supervised PFMT.

Chorea associated with anti-phospholipid antibodies: case report.

A seventeen year-old boy developed left sided chorea in a few days, subsequently involving the four limbs. Although he presented a marfanoid phenotype, genetic analysis of the Fibrillin 1 was normal. The genes for familial chorea and Huntington's disease were also negative. Biological tests showed normal serum homocystein, but revealed very high levels of anti-beta2-GP1 IgG, anticardiolipin and lupus anticoagulant, which remained at similar values for a period of over three months. Electroencephalogram and cerebral magnetic resonance imaging (MRI) showed no abnormalities. Brain PET-scan disclosed bilateral striatal hypermetabolism. The patient was treated with methylprednisolone and low dose of acetylsalicylic acid. He improved markedly after six weeks of treatment, and choreic movements disappeared completely after two months. A control PET-scan performed at this time showed reversion of striated hypermetabolism to a normal pattern. The pathogenic aspects of this relatively rare case of chorea are discussed.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction.

BACKGROUND: Microdeletions at 17q21.31 have recently been shown to cause a novel syndrome. Here we identify the reciprocal 17q21.31 duplication syndrome in 4 patients. METHOD: Patients with the 17q21.31 duplication were identified by screening a large cohort of patients (n = 13,070) with mental retardation and congenital malformation by comparative genomic hybridisation microarray. Parental origin was investigated in 3 patients by quantitative polymerase chain reaction and microsatellite genotyping. RESULTS: In three cases it was possible to show that duplication arose de novo. Intellectual skills range from normal to mild mental retardation. Patients are characterised by poor social interaction, with relationship difficulties, reminiscent of autistic spectrum disorders. Other features are rather variable with no striking common phenotypic features. Parental origin was investigated for 3 patients. In all cases duplication was of maternal origin either through interchromosomal (2 cases) or interchromatid (1 case) rearrangement. The 3 mothers are all carriers of the inverted H2 haplotype, emphasising the role of local genomic architecture alteration as a predisposing factor for this duplication. CONCLUSION: Autistic features observed in our patients suggest that genes in the duplicated interval should be considered as candidates for disorders in the autistic spectrum. Other phenotypic observations are rather variable or aspecific. This adds 17q21.31 duplications to a growing group of recently identified genomic disorders with variable penetrance and expressivity.

99mTc-HMPAO labelled white blood cell scintigraphy in patients with osteoarticular infection: the value of late images for diagnostic accuracy and interobserver reproducibility.

The objectives of this study were to evaluate the diagnostic value of 99mTc-HMPAO labelled white blood cell scintigraphy (WBCS) in patients with suspected osteomyelitis using late images and to study interobserver reproducibility. This study prospectively included 120 patients, and after a follow-up of one year, only 70 patients (n = 49 with implants, n = 21 without implants) were selected. The final diagnosis of infection was based either on microbiological data (n = 54) or follow-up (n = 16). We performed WBCS with 4 h and 24 h scans. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 77%, 72%, 83%, 64%, and 75% at 4 h, and 74%, 87%, 91%, 59%, and 79% at 24 h, respectively. The interobserver reproducibility shows a 63% prevalence of agreement between results (kappa = 0.5) at 4 h and 80% (kappa = 0.74) at 24 h, respectively. WBCS with 24-h images improves specificity and interobserver reproducibility in patients with suspected osteoarticular sepsis.

Pelvic floor muscle training versus no treatment for urinary incontinence in women. A Cochrane systematic review.

BACKGROUND: Pelvic floor muscle training is the most commonly used physical therapy treatment for stress urinary incontinence. It is sometimes recommended for mixed and less commonly for urge urinary incontinence. OBJECTIVES: The aim of this paper was to determine the effects of pelvic floor muscle training for women with urinary incontinence in comparison to no treatment, placebo or sham treatments, or other inactive control treatments. METHOD: The Cochrane Incontinence Group Specialized Trials Register was searched up until December 1, 2004. The review included randomized or quasi-randomized trials in women with stress, urge or mixed urinary incontinence. One arm of the trial comprised pelvic floor muscle training, the other comprised either no treatment, placebo, sham, or other inactive control treatment. The trials were independently assessed for eligibility and methodological quality. Data were extracted then cross-checked by the two authors. Disagreements were resolved by discussion. The data were processed as described in the Cochrane Handbook. The trials were sub-grouped by diagnosis. Formal meta-analysis was not undertaken because of study heterogeneity. RESULTS: Thirteen trials involving 714 women met the inclusion criteria; however, only six trials (403 women) contributed to data analysis. CONCLUSION: Overall, the review provides support for the widespread recommendation that pelvic floor muscle training be included in first-line conservative management programs for women with stress, urge or mixed urinary incontinence.

Changes in levator ani anatomical configuration following physiotherapy in women with stress urinary incontinence.

PURPOSE: We quantified the effect of pelvic floor muscle training on the anatomical configuration of the levator ani using magnetic resonance imaging. MATERIALS AND METHODS: Five female participants with stress urinary incontinence underwent magnetic resonance imaging before and after participating in a pelvic floor muscle physiotherapy program. Axial T1-weighted images of the levator ani were taken with the participant in a supine position. Source images were then manually segmented and surface modeling was applied to build a 3-dimensional model of the levator ani. Models were then measured to determine the levator ani surface area as well as the encircled volume at rest and during voluntary contraction. The percentage of levator ani retraction and symphysis pubis movement during voluntary contraction before and after physiotherapy were also measured. RESULTS: After physiotherapy the levator ani surface area at rest was significantly smaller than before physiotherapy, decreasing from 677.11 +/- 45.00 to 620.48 +/- 36.14 mm(2) (p = 0.04). The relative reduction in volume encircled by the levator ani during contraction increased significantly from -11.66 +/- 7.42 to -26.02 +/- 13.52 mm(3) (p = 0.04). Levator ani surface retraction during a voluntary contraction increased significantly from 65.61% +/- 17.07% to 81.70% +/- 16.30% (p = 0.02). Symphysis pubis movement during pelvic floor muscle contraction decreased from 1.45 +/- 1.32 to 0.44 +/- 0.61 mm (p = 0.05). CONCLUSIONS: Findings from this preliminary study indicate that pelvic floor muscle training results in anatomical changes in the levator ani and reduction of pubic movement. These results provide insight into the possible anatomical mechanisms through which physiotherapy enables the pelvic floor muscle to minimize urine leakage.

Fluorescence in situ hybridization analysis of 110 hematopoietic disorders with chromosome 5 abnormalities: do de novo and therapy-related myelodysplastic syndrome-acute myeloid leukemia actually differ?

A retrospective cytogenetic study of acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) was conducted by the Groupe Francophone de Cytogénétique Hématologique (GFCH) to evaluate the structural abnormalities of chromosome 5 associated with other chromosomal abnormalities, in particular of chromosome 7, in these pathologies. In all, 110 cases of AML/MDS were recruited based on the presence of chromosome 5 abnormalities under conventional cytogenetics and supplemented by a systematic fluorescence in situ hybridization study of chromosomes 5 and 7. The abnormalities of the long arm of chromosome 5 (5q) were deletions of various sizes and sometimes cryptic. The 5q abnormalities were associated with translocations in 54% of cases and were simple deletions in 46%. In 68% of cases, 5q deletions were associated with chromosome 7 abnormalities, and 90% of these presented a complex karyotype. Of the 110 patients, 28 had a hematopoietic disorder secondary to chemotherapy, radiotherapy, or both. Among 82 patients with de novo AML/MDS, 63 were older than 60 years. Chromosomal abnormalities often associated hypodiploidy and chromosome 5 and 7 abnormalities in complex karyotypes, features resembling those of secondary hemopathies. Systematic investigation of the exposure to mutagens and oncogenes is thus essential to specify the factors potentially involved in MDS/AML with 5q abnormalities.

Reliability of speed of contraction and endurance dynamometric measurements of the pelvic floor musculature in stress incontinent parous women.

AIMS: To evaluate the test-retest reliability of dynamometric measurements of the pelvic floor muscles (PFM) during speed and endurance tests. METHODS: Nineteen parous women suffering from stress urinary incontinence (SUI) participated in the study. Two PFM evaluation sessions were conducted using the dynamometric speculum. For the speed test, the women were instructed to contract maximally and relax as quickly as possible during a 15-s test period. The speed of contraction was quantified by the rate of force development of the first contraction and the number of contractions performed. The maximal strength value attained during the speed test was also extracted from the curves. For the endurance test, the subjects were asked to maintain a maximal contraction for 90 s. The normalized area under the force curve was utilized as the endurance parameter. The reliability of the data was evaluated using the generalizability theory. Two reliability estimates were calculated, the dependability indices (Phi) and the standard error of measurement (SEM), for one measurement session involving one trial. RESULTS: The indices of dependability obtained indicate that the reliability of the speed of contraction and endurance parameters are good (Phi=0.79-0.92). The corresponding SEMs were 1.39 N/s, 1 contraction, 1.00 N, and 298%*s for the rate of force development, number of contractions, maximal strength and normalized area, respectively. CONCLUSION: This study indicates that the speed of contraction and endurance parameters possess good test-retest reliability. The inclusion of these parameters in the PFM assessment is therefore highly recommended for assessing changes in PFM in incontinent women.

Role of anti-tumour necrosis factor-alpha therapeutic agents in the emergence of infections.

There is increasing interest concerning the possible impact of anti-tumour necrosis factor (TNF)-alpha therapeutic agents on the emergence of infections. However, these agents do not seem to increase the incidence of adverse infectious events significantly. Published observations concern mostly infections of the urinary and upper respiratory tracts that develop in the setting of co-morbidities, such as anterior or concomitant immunosuppressive treatment. Infliximab appears to increase the risk of tuberculosis, but this effect has not been observed with other anti-TNF-alpha agents. To better characterise the adverse infectious effects associated with these agents, physicians should be encouraged to notify the microbiological data relating to all cases.

A gene for an autosomal recessive lower motor neuron disease with childhood onset maps to 1p36.

OBJECTIVE: To describe the clinical features of a novel variant of autosomal recessive lower motor neuron disease (LMND) with childhood onset and to map the disease-causing gene. METHODS: The authors performed a clinical study in a large consanguineous African family. After linkage exclusion to SMN1 and SOD1 loci, they performed a genome-wide linkage analysis to map the underlying genetic defect. RESULTS: This novel variant of LMND with childhood onset and autosomal recessive mode of inheritance is characterized by a progressive symmetric and generalized involvement of the musculature. Four of the five affected patients had muscle weakness since age 3, strongly worsening during childhood and leading to generalized tetraplegia in adulthood. Genetic analyses using homozygosity mapping strategy assigned this progressive generalized LMND locus to an interval of 3.9 cM (or 1.5 megabases) on chromosome 1p36, between loci D1S508 and D1S2633 (Z(max) = 3.79 at theta = 0.00 at locus D1S253). This region encloses 27 candidate genes. CONCLUSION: Genetic mapping of a novel rare phenotype of lower motor neuron disease opens the way toward the identification of a new gene involved in motor neuron degeneration, located in the 1p36 chromosomal region.

Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women.

BACKGROUND: Pelvic floor muscle training is the most commonly used physical therapy treatment for women with stress urinary incontinence. It is sometimes recommended for mixed and less commonly urge urinary incontinence. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with urinary incontinence in comparison to no treatment, placebo or sham treatments, or other inactive control treatments. SEARCH STRATEGY: The Cochrane Incontinence Group Specialised Trials Register was searched. The date of the most recent search was 1 December 2004. SELECTION CRITERIA: Randomised or quasi-randomised trials in women with stress, urge or mixed urinary incontinence (based on symptoms, signs, or urodynamics). One arm of the trial included pelvic floor muscle training (PFMT). Another arm was a no treatment, placebo, sham, or other inactive control treatment arm. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for eligibility and methodological quality. Data were extracted then cross-checked. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook (Higgins 2005). Trials were subgrouped by diagnosis. Formal meta-analysis was not undertaken because of study heterogeneity. MAIN RESULTS: Thirteen trials involving 714 women (375 PFMT, 339 controls) met the inclusion criteria, but only six trials (403 women) contributed data to the analysis. Most studies were at moderate to high risk of bias, based on the trial reports. There was considerable variation in interventions used, study populations, and outcome measures. Women who did PFMT were more likely to report they were cured or improved than women who did not. PFMT women also experienced about one fewer incontinence episodes per day. There were too few data to draw conclusions about effects on other outcomes such as condition specific quality of life. Of the few adverse effects reported, none were serious. The trials in stress urinary incontinent women which suggested greater benefit recruited a younger population and recommended a longer training period than the one trial in women with detrusor overactivity (urge) incontinence. AUTHORS' CONCLUSIONS: Overall, the review provides some support for the widespread recommendation that PFMT be included in first-line conservative management programmes for women with stress, urge, or mixed, urinary incontinence. Statistical heterogeneity reflecting variation in incontinence type, training, and outcome measurement made interpretation difficult. The treatment effect might be greater in younger women (in their 40's and 50's) with stress urinary incontinence alone, who participate in a supervised PFMT programme for at least three months, but these and other uncertainties require testing in further trials.

Orofacial clefting: update on the role of genetics.

INTRODUCTION: Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects in the world. Prevalence varies between populations, with an average of 1/700. CL/P has a major clinical impact, requiring surgical, dental, orthodontic, speech, hearing and psychological management throughout childhood. The aetiology of CL/P is mostly unknown, and it is thought that both genetic and environmental factors play a role. Several causative genes for inherited syndromic forms of CL/P have been identified, and some recent studies have shown that these genes also contribute to the occurrence of isolated forms. Van der Woude syndrome (VWS) is one of the best models for non-syndromic CLP. It is an autosomal dominant disorder characterised by the presence of pits on the lower lip in addition to CL/P. Pits are the only feature distinguishing VWS from isolated clefts. Interestingly, in numerous VWS patients, the lip pits are very small and not readily diagnosed, thus mimicking isolated CL/P. Mutations in the IRF6 gene were shown to be the major genetic cause of VWS.' RESULTS: We performed direct sequence analysis of IRF6 on samples from a large European cohort and identified mutations in 27 (80%) families. This shows that IRF6 is the major causative gene of VWS in Europe also. Moreover, it is the gene to study when a seemingly isolated CL/P patient has minor signs, such as lip pits, since the identification of a mutation in IRF6 is associated with an increase in the risk of having a child with CL/P from 4-6%, the risk of transmission of an isolated cleft, to 50%, the risk of transmission of a dominant Mendelian disorder like VWS. Moreover, we studied the association of isolated CL/P with the IRF6 locus using two variants in a set of 195 patients from Belgium. As in an American study, a clear association was observed. This suggests that IRF6 also contributes to the occurrence of sporadic, isolated CL/P, even if no mutation in the gene can be identified in such patients. CONCLUSION: In conclusion, genes that are mutated in familial syndromic forms of CL/P may be predisposing genetic factors to sporadic isolated CL/P. Due to technological advances and the availability of the human genome sequence, we have now the opportunity to try and unravel the genetic factors behind the various forms of CL/P.