Objective Assessment of Internal Nasal Dimensions and Speech Resonance in Individuals With Repaired Unilateral Cleft Lip and Palate After Rhinoseptoplasty

The objective of the current study was to analyze the effects of rhinoseptoplasty on internal nasal dimensions and speech resonance of individuals with unilateral cleft lip and palate, estimated by acoustic rhinometry and nasometry, respectively. Twenty-one individuals (aged 15-46 years) with previously repaired unilateral cleft lip and palate were analyzed before (PRE), and 6 to 9 (POST1) and 12 to 18 months (POST2) after surgery. Acoustic rhinometry was used to measure the cross-sectional areas (CSAs) of segments corresponding to the nasal valve (CSA1), anterior portion (CSA2), and posterior portion (CSA3) of the lower turbinate, and the volumes at the nasal valve (V1) and turbinate (V2) regions at cleft and noncleft sides, before and after nasal decongestion with a topical vasoconstrictor. Nasometry was used to evaluate speech nasalance during the reading of a set of sentences containing nasal sounds and other devoid of nasal sounds. At the cleft side, before nasal decongestion, there was a significant increase (P < 0.05) in mean CSA1 and V1 values at POST1 and POST2 compared with PRE. After decongestion, increased values were also observed for CSA2 and V2 at POST2. No significant changes were observed at the noncleft side. Mean nasalance values at PRE, POST1, an POST2 were not different from each other in both oral and nasal sentences. The measurement of CSAs and volumes by acoustic rhinometry revealed that rhinoseptoplasty provided, in most cases analyzed, a significant increase in nasal patency, without concomitant changes in speech resonance, as estimated by nasalance assessment.

A New Yardstick for Rating Dental Arch Relationship in Patients With Complete Bilateral Cleft Lip and Palate

Objective: To develop yardsticks for assessment of dental arch relationship in young individuals with repaired complete bilateral cleft lip and palate appropriate to different stages of dental development. Participants: Eleven cleft team orthodontists from five countries worked on the projects for 4 days. A total of 776 sets of standardized plaster models from 411 patients with operated complete bilateral cleft lip and palate were available for the exercise. Statistics: The interexaminer reliability was calculated using weighted kappa statistics. Results: The interrater weighted kappa scores were between .74 and .92, which is in the ""good"" to ""very good"" categories. Conclusions: Three bilateral cleft lip and palate yardsticks for different developmental stages of the dentition were made: one for the deciduous dentition (6-year-olds` yardstick), one for early mixed dentition (9-year-olds` yardstick), and one for early permanent dentition (12-year-olds` yardstick).

A Longitudinal Three-Center Study of Dental Arch Relationship in Patients With Bilateral Cleft Lip and Palate

Objective: To compare and evaluate longitudinally the dental arch relationships from 4.5 to 13.5 years of age with the Bauru-BCLP Yardstick in a large sample of patients with bilateral cleft lip and palate (BCLP). Design: Retrospective longitudinal intercenter outcome study. Patients: Dental casts of 204 consecutive patients with complete BCLP were evaluated at 6, 9, and 12 years of age. All models were identified only by random identification numbers. Setting: Three cleft palate centers with different treatment protocols. Main Outcome Measures: Dental arch relationships were categorized with the Bauru-BCLP yardstick. Increments for each interval (from 6 to 9 years, 6 to 12 years, and 9 to 12 years) were analyzed by logistic and linear regression models. Results: There were no significant differences in outcome measures between the centers at age 12 or at age 9. At age 6, center B showed significantly better results (p = .027), but this difference diminished as the yardstick score for this group increased over time (linear regression analysis), the difference with the reference category (center C, boys) for the intervals 6 to 12 and 9 to 12 years being 10.4% (p = .041) and 12.9% (p = .009), respectively. Conclusions: Despite different treatment protocols, dental arch relationships in the three centers were comparable in final scores at age 9 and 12 years. Delaying hard palate closure and employing infant orthopedics did not appear to be advantageous in the long run. Premaxillary osteotomy employed in center B appeared to be associated with less favorable development of the dental arch relationship between 9 and 12 years.

Longitudinal Study of Growth of Children With Unilateral Cleft-Lip Palate From Birth to Two Years of Age

Objective: To study the growth of children with complete unilateral cleft lip and palate (UCLP) from birth to 2 years of age and to construct specific UCLP growth curves. Design: Physical growth was a secondary outcome measure of a National Institutes of Health-sponsored longitudinal, prospective clinical trial involving the University of Florida (United States) and the University of Sao Paulo (Brazil). Patients: Six hundred twenty-seven children with UCLP, nonsyndromic, both genders. Methods: Length, weight, and head circumference were prospectively measured for a group of children enrolled in a clinical trial. Median growth curves for the three parameters (length, weight, head circumference) were performed and compared with the median for the National Center for Health Statistics (NCHS) curves. The median values for length, weight, and head circumference at birth and 6, 12, 18, and 24 months of age were plotted against NCHS median values and statistically compared at birth and 24 months. Setting: Hospital de Reabilitacao de Anomalias Craniofaciais, Universidade de Sao Paulo, Bauru, Brazil (HRAC-USP). Results: At birth, children of both genders with UCLP presented with smaller body dimensions in relation to NCHS median values, but the results suggest a catch-up growth for length, weight, and head circumference for girls and for weight (to some degree) and head circumference for boys. Conclusions: Weight was the most compromised parameter for both genders, followed by length and then head circumference. There was no evidence of short stature. This study established growth curves for children with UCLP.

Holoprosencephaly, Ectrodactyly, and Bilateral Cleft of Lip and Palate: Exclusion of SHH, TGIF, SIX3, GLI2, TP73L, and DHCR7 as Candidate Genes

We describe a Brazilian boy with semilobar holoprosencephaly, ectrodactyly, bilateral cleft of lip and palate, and severe mental retardation. The karyotype was normal and the screening for mutations in the genes SHH, TGIF, SIX3, GLI2 TP73L, and DHCR7 did not show any change. This rare condition was described previously in seven male patients. Clinical and genetic aspects are discussed. (C) 2009 Wiley-Liss, Inc.

Tooth Abnormalities of Number and Position in the Permanent Dentition of Patients With Complete Bilateral Cleft Lip and Palate

Objective: To radiographically evaluate the prevalence of tooth abnormalities of number and position in the permanent dentition of individuals with complete bilateral cleft lip and palate. Design: Cross-sectional retrospective. Setting: Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, Bauru, Brazil. Patients: Two hundred five individuals with complete bilateral cleft lip and palate. Interventions: Analysis of patient records and panoramic radiographs. Main outcome measures: Evaluation of hypodontia and supernumerary teeth and analysis of the position of the permanent maxillary lateral incisor in relation to the alveolar cleft. Results: Hypodontia was observed in 144 patients (70.2%), and the highest prevalence was observed for the maxillary lateral incisor. When both lateral incisors were present (43%), they were primarily located on the distal side of the cleft (25%). Supernumerary teeth were observed in 11.7% of individuals. Conclusion: Patients with cleft lip and palate presented high prevalence of hypodontia and supernumerary teeth. The prevailing characteristics of their location may suggest the presence of a similar genetic component for the occurrence of hypodontia and cleft.

Enamel Defects in Maxillary Central Incisors of Infants With Unilateral Cleft Lip

Objective: To evaluate the presence of enamel alterations in deciduous maxillary central incisors of infants with unilateral cleft lip and alveolar ridge, with or without cleft palate, and to compare the occurrence and location of these alterations between the central incisor adjacent to the cleft and the contralateral incisor. Design: Intraoral clinical examination was performed after tooth cleaning and drying by a single examiner with the aid of a dental mirror, dental probe, and artificial light, with the child positioned on a dental chair. The defects were recorded in a standardized manner according to the criteria of the Modified Developmental Defects of Enamel Index. Setting: Hospital for Rehabilitation of Craniofacial Anomalies (HRAC) at Bauru, Sao Paulo, Brazil. Patients: One hundred one infants were evaluated. All were white, of both genders, aged 12 to 36 months and had at least two thirds of the crowns of maxillary incisors erupted. Results: Demarcated opacity was the most common defect at both cleft and noncleft sides, followed by diffuse opacity. The occurrence of hypoplasia at the cleft side was 11.8%. Most defects affected less than one third of the crown. Conclusion: The occurrence of enamel defects in deciduous maxillary central incisors of patients with unilateral cleft lip was 42.6%, mainly affecting the cleft side as to both number and severity.

Dental anomalies of number in the permanent dentition of patients with bilateral cleft lip: Radiographic study

Objective: To radiographically evaluate the prevalence of dental anomalies in patients with complete and incomplete bilateral cleft lip, comparing the prevalence of anomalies between genders and cleft types. Setting: Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo (HRAC/USP), Bauru, Sao Paulo, Brazil. Participants: 150 randomly selected panoramic radiographs of individuals with complete or incomplete bilateral cleft lip; patient age 12 to 25 years (mean age 13.8 years). Results: Data were statistically analyzed to compare the possible association between presence of hypodontia and supernumerary teeth, according to gender and cleft type. Among the 150 patients evaluated, 80 (53.3%) were male and 70 (46.6%) were female. Since no statistically significant difference was found in hypodontia between genders, data were grouped for analysis, revealing prevalence of 31.6% for complete clefts and 26.8% for incomplete clefts. Concerning supernumerary teeth, the prevalence for the male patients was 28.2% for complete cleft lip and 29.2% for incomplete cleft lip. For female patients, the prevalence was significantly (p = .006) lower for complete cleft lip (17.5%) than for incomplete cleft lip (46.6%). Conclusions: The present results suggest that the prevalence of hypodontia was higher in patients with complete cleft lip, and the prevalence of supernumerary teeth was higher in patients with incomplete cleft lip, in agreement with previous studies.

Human Stem Cell Cultures from Cleft Lip/Palate Patients Show Enrichment of Transcripts Involved in Extracellular Matrix Modeling By Comparison to Controls

Nonsyndromic cleft lip and palate (NSCL/P) is a complex disease resulting from failure of fusion of facial primordia, a complex developmental process that includes the epithelial-mesenchymal transition (EMT). Detection of differential gene transcription between NSCL/P patients and control individuals offers an interesting alternative for investigating pathways involved in disease manifestation. Here we compared the transcriptome of 6 dental pulp stem cell (DPSC) cultures from NSCL/P patients and 6 controls. Eighty-seven differentially expressed genes (DEGs) were identified. The most significant putative gene network comprised 13 out of 87 DEGs of which 8 encode extracellular proteins: ACAN, COL4A1, COL4A2, GDF15, IGF2, MMP1, MMP3 and PDGFa. Through clustering analyses we also observed that MMP3, ACAN, COL4A1 and COL4A2 exhibit co-regulated expression. Interestingly, it is known that MMP3 cleavages a wide range of extracellular proteins, including the collagens IV, V, IX, X, proteoglycans, fibronectin and laminin. It is also capable of activating other MMPs. Moreover, MMP3 had previously been associated with NSCL/P. The same general pattern was observed in a further sample, confirming involvement of synchronized gene expression patterns which differed between NSCL/P patients and controls. These results show the robustness of our methodology for the detection of differentially expressed genes using the RankProd method. In conclusion, DPSCs from NSCL/P patients exhibit gene expression signatures involving genes associated with mechanisms of extracellular matrix modeling and palate EMT processes which differ from those observed in controls. This comparative approach should lead to a more rapid identification of gene networks predisposing to this complex malformation syndrome than conventional gene mapping technologies.

Holoprosencephaly and Holoprosencephaly-Like Phenotypes: Review of Facial and Molecular Findings in Patients From a Craniofacial Hospital in Brazil

Here we report on the clinical and genetic data for a large sample of Brazilian patients studied at the Hospital de Reabilitacao de Anomalas Craniofaciais-Universidade de Sao Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype. The sample included patients without detected mutations in some HPE determinant genes such as SHH, GLI2, SIX3, TGIF, and PTCH, as well as the photographic documentation of the previously reported patients in our Center. The HPE-L phenotype has been also called of HPE ``minor forms"" or ""microforms,"" The variable phenotype, the challenge of genetic counseling, and the similarities to patients with isolated cleft lip/palate are discussed. (c) 2010 Wiley-Liss, Inc.

Frontonasal Dysplasia, Severe Neuropsychological Delay, and Midline Central Nervous System Anomalies: Report of 10 Brazilian Male Patients

Here we report on 10 male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and severe central nervous system involvement. Imaging studies disclosed absence of the corpus callosum, midline cysts, and an abnormally modeled cerebellum. Neuronal heterotopias were present in five patients and parieto-occipital encephalocele in three patients. We suggest that this pattern found exclusively in males, most likely represents a newly recognized syndrome distilled from the group of disorders subsumed under frontonasal dysplasia. (C) 2009 Wiley-Liss, Inc.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.

Chronic Suppurative Otitis Media in Cleft Palate: Microorganism Etiology and Susceptibilities

Objective: To investigate the microbial etiology of suppurative chronic otitis media (SCOM) in patients with complete cleft lip and palate and isolated cleft palate and to determine the sensitivity of isolated microorganisms to antibiotics by drug diffusion from impregnated discs in agar and the minimum inhibitory concentration of each drug to these microorganisms by drug dilution in agar. Design/Patients: Effusion samples of SCOM obtained from 40 patients with cleft lip and palate registered at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, at Bauru, Brazil, were bacteriologically analyzed by cultures. The isolated bacteria were submitted to an in vitro susceptibility test to clinically used drugs. Results: Positive cultures were obtained in 100% of studied cases. Among the 57 strains observed, the most frequent were Pseudomonas aeruginosa (35%), Staphylococcus aureus (15.5%), Enterococcus faecalis (14%), and Proteus mirabilis (12%). The frequency of Gram-negative bacilli (enterobacteriaceae and nonfermentative bacilli) was 67%. Pseudomonas aeruginosa presented the highest sensitivity to ciprofloxacin, and enterobacteriaceae exhibited the highest sensitivity to gentamicin. The strains of S. aureus and E. faecalis presented the highest sensitivity to imipenem and sulfamethoxazole/trimethoprim, respectively. Conclusion: Patients with cleft lip and palate presenting with SCOM exhibited 100% positive cultures, with the highest frequency of Pseudomonas and enterobacteriaceae. With regard to the action of antibiotics, imipenem was effective against the four species of isolated microorganisms, followed by ciprofloxacin, which was effective against 75% of isolated species.

Prospective Clinical Trial Comparing Outcome Measures Between Furlow and von Langenbeck Palatoplasties for UCLP

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 x 2 x 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.

Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton

Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To Study this, pregnant once were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved Lip to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocyres, in addition to a slight delay in endochondral and intramembranous ossification. This Suggests that LIP to E 16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly (similar to 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast. D2 mRNA expression increased significantly by E18.5 and markedly (similar to 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time Suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development. (c) 2008 Elsevier Inc. All rights reserved.