Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology

Halitosis, Oral Health and Quality of Life during Treatment with Invisalign(A (R)) and the Effect of a Low-dose Chlorhexidine Solution

This study examined how halitosis, oral dryness and general oral health were impacted during treatment with the Invisalign(A (R)) system. Furthermore, the effect of a lowdose chlorhexidine solution (CHX) was evaluated. Thirtyone patients with good periodontal health participated in this crossover study and were divided into two groups (group 1: CHX/no CHX, group 2: no CHX/CHX). The following parameters were recorded during the first 8 months of Invisalign(A (R)) treatment: stimulated saliva flow rate, organoleptic index, tongue coating index, measurement of the oral volatile sulfur compound level (ppb), modified gingival and plaque index and bleeding on probing index. Professional oral cleaning was performed at the beginning of each period lasting 3 months. The patients received a questionnaire at the first, third, fourth, sixth and eighth control visits. The very low volatile sulfur compound level was significantly decreased by CHX (0.06%) during the first examination period (p = 0.02), i.e. for the first group of patients only. Neither halitosis, nor oral dryness, nor high plaque or gingival index measurements were observed. Oral health-related quality of life was hardly influenced by wearing aligners and oral hygiene habits were very good. This study provides evidence that Invisalign(A (R)) treatment is characterized by only minimal impairment of overall oral health and the associated quality of life. Consequently, it appears unnecessary to recommend the general adjunctive use of a low-dose chlorhexidine mouthwash during treatment with Invisalign(A (R))

Orthodontics as a Specialist Field in the Center for Rare Diseases Interdisciplinary treatment of patients with cleft lip and palate and Robin Sequence

This article describes the management of patients with cleft lip and palate and Robin Sequence from prenatal diagnosis to the end of growth. Orthodontic treatment management of patients with oro- and craniofacial malformations is complex, time-consuming and needs an interdisciplinary coordination. A network of specialized centers offers the best possible interdisciplinary expertise in rare diseases. The goals and organization of these specialized centers will be explained in the following. A central aim is to be available as a low-threshold contact and to support resident orthodontists in treatment planning, timing and trouble-shooting. A basic knowledge of the most common cranio- and orofacial anomalies and know ledge of early treatment steps such as the early therapy with a palatal plate (with or without extended spur) are important for orthodontic practitioners. This is the only way to ensure safe, effective therapy and stable esthetic and functional rehabilitation. Functional impairments, as well as skeletal and dental anomalies, require anticipatory orthodontic planning in this patient group. Any surgical procedures that may be necessary must be considered in the treatment sequence, and treatment decisions should always be made with the goal of making the treatment as effective as possible

Interdisciplinary Treatment of Patients with Congenital Malformations - Interaction of Dysfunction and Dysgnathia

This article deals with the interaction of dysfunction and dysgnathia using the example of craniofacial and orofacial malformations. First, it lays out how abnormal form impedes a proper function: In patients with cleft lip and palate, the malformation negatively affects pronunciation, hearing, tooth and jaw position, aesthetics, and social behavior. To regain proper function, the form needs correction in terms of surgical reconstruction of the cleft tissues in the first year of life. Secondly, it shows that abnormal function can also impede a proper form: In patients with cleft lip and palate, the tongue penetrates the cleft area, preventing the cleft segments from converging. A palatal plate helps to normalize the function and steers the growth of the cleft segments. In a similar vein, in newborns with Pierre Robin sequence, a therapy with a pre-epiglottic baton plate can prevent life-threatening respiratory disorders. Born with a mandibular retrognathia, these patients profit from the recovered function providing a coordinated physiological upper and lower jaw growth. To summarize, the interaction between form and function becomes manifest in the reinforcement of the dysmorphia through dysfunction, but also in the reciprocal improvement during very early therapy. Applied to patients without congenital malformations, it explains why certain forms of dysgnathia should be treated at a very early stage

Impact of Maternal Smoking on Nonsyndromic Clefts: Sex-Specific Associations With Side and Laterality

Objective: To compare the incidence of right-sided versus left-sided, and unilateral versus bilateral, nonsyndromic clefting in the affected offspring of smoking and nonsmoking mothers. Design: Self-report data on periconceptual and first trimester smoking behavior were collected from 842 mothers of children with nonsyndromic orofacial clefting. Differences in the incidence of left- versus right-sided clefts, and of unilateral versus bilateral clefts, were analyzed between the children of smoking and nonsmoking mothers. Setting: Interviews and clinical examinations took place at 8 specialist centers in Germany. Patients and Participants: Children with nonsyndromic clefts were recruited during the course of surgical or orthodontic treatment, or within the context of the annual control consultation. Patients with cleft palate only or missing data were excluded. The final cohort comprised 842 patients (540 males and 302 females) with unilateral or bilateral clefts. The respective mothers were interviewed. Main Outcome Measure: Side and laterality of nonsyndromic clefts were the main outcome measures. Results: Children of smoking mothers more often had right-sided clefts than children of nonsmoking mothers (42% right-sided clefts in children of smoking mothers vs 31% of nonsmoking mothers). Children of smoking mothers more often had bilateral clefts than children of nonsmoking mothers (35% bilateral clefts in children of smoking mothers vs 29% of nonsmoking mothers). Sex-specific analyses confirmed substantially and statistically significant associations only for girls. Conclusions: The results suggest that maternal smoking is a sex-specific, exogenous determinant of laterality and side in nonsyndromic clefts

Prenatal indices for mandibular retrognathia/micrognathia

Micro- and retrognathia of mandibular origin may lead to life-threatening respiratory problems in connection with glossoptosis immediately after birth. Prenatal screening for this malformation is therefore increasingly important. Today this is accomplished by predominantly subjective standards. Objective criteria have been proposed but have not become established. We therefore made an effort to develop indices that would identify major skeletal discrepancies or micrognathia in as straightforward a fashion as possible during routine prenatal sonography. Series of fetal jaw sonograms (Toshiba Aplio MXA (R)) were obtained in 313 women with normal pregnancies from weeks 19-29 of gestation. Upper- and lower-jaw landmarks were interactively located on screen and evaluated for reproducibility. Linear parameters representative of maxillary and mandibular length (SpA'aEuroSpP' and Rami-SymMe) were measured and related to femur length and gestational age. Based on these data, indices for maxillary, and mandibular length were derived and analyzed. High correlations were identified for mandibular length both with gestational age (R = 0.845; R-2 = 0.713) and with femur length (correlation coefficients (R) = 0.839; coefficients of determination (R-2) = 0.704). For maxillary length, the respective correlation coefficients were 0.691 (R-2 = 0.477) and 0.656 (R-2 = 0.430). Estimates of mandibular and maxillary length based on gestational age and femur length were obtained by regression analysis. The mean bimaxillary length ratio was 0.628 +/- 0.043. Maxillary and mandibular growth can be objectively evaluated via indices. It is conceivable to develop this approach into a sensitive and reliable method of prenatal jaw screening for major skeletal anomalies and congenital malformations

Prenatal Diagnosis of Robin Sequence: Sensitivity, Specificity, and Clinical Relevance of an Index for Micrognathia

Objective: Micrognathia in connection with glossoptosis (called Robin sequence) may lead to life-threatening respiratory problems immediately after birth. An objective detection during prenatal routine ultrasound sonography is possible using an index that relates fetal lower jaw length to femur length or gestational age. The aim of this study was to test the method's sensitivity and specificity and to discuss its predictive power concerning neonatal respiratory insufficiency. Design: Patients with subjectively identified suspicious signs in the sagittal profile view were included in the study: Two-dimensional serial ultrasound scans of their fetal mandible were used to measure the lower jaw lengths and compare them to predicted values according to an index, derived from 313 healthy fetuses. Follow-up data provided additional information on the clinical appearance of the newborns. Results: The index showed a high sensitivity: 15 of the 16 cases with a micrognathia were correctly diagnosed (sensitivity of 93.75%). Follow-up data showed that newborns with similar index values differed in terms of their upper airway obstruction and treatment need. Conclusion: Fetal mandibular micrognathia can be objectively evaluated with the help of the index. The method allows an early detection of micrognathia, which helps to take the necessary steps for proper treatment of potential life-threatening respiratory impairment. Observations ranging outside the prediction interval could prompt the ultrasonographer to check for other associated malformations