Non-familial cherubism.

Singapore Med J. 2007 Sep;48(9):e253-7

Authors: Jain V, Gamanagatti SR, Gadodia A, Kataria P, Bhatti SS

Cherubism is a disease that usually affects the jaws in the paediatric population, mostly below five years of age. Radiologically, it closely resembles fibrous dysplasia and other giant cell lesions of the mandible. Computed tomography (CT) is helpful in defining the true extent of cherubic lesions, which is often not possible on radiographs due to the overlapping facial bones. We describe the radiographical and CT features of cherubism in a 12-year-old boy and highlight the ability of multidetector CT and various post-processing techniques to accurately depict the anatomical extent of the cherubic lesions.

PMID: 17728954 [PubMed - indexed for MEDLINE]

Audiological findings in cleft palate patients attending speech camp.

Indian J Med Res. 2007 Jun;125(6):777-82

Authors: D'Mello J, Kumar S

BACKGROUND & OBJECTIVE: Hearing impairment is one of the associated problems seen particularly in children with cleft palate rather than cleft lip alone. This has received very little attention in the area of cleft care although research shows that hearing impairment affects language development The present study was carried not to find out the type and pattern of audiogram in cases attending a speech camp, average degree of hearing loss and its relation to the side of cleft, and the acoustic immittance findings and its relation to the otological evaluation. The parental awareness about the hearing problem was also assessed. METHODS: The study was conducted on cleft palate patients attending a speech camp. In all, there were 43 patients (19 males and 24 females) in the age range of 3-22 yr. All had undergone audiological assessment, speech and language evaluation, and otological evaluation using standard procedures. RESULTS: Hearing loss was seen in 38 (88.38%) patients. It was the first audiological assessments they ever had. The average pure tone Thresholds revealed a reverse-ski pattern with a wide air-bone gap. The degree of hearing loss ranged from 25 to 68 dB indicating that untreated otitis media resulted in moderate to moderately severe degree of hearing loss. The immittance findings supported the extent of extracranial complications identified on otoscopic examination. There were more patients with unilateral cleft of the left side with greater hearing loss in the ear alongside the cleft. INTERPRETATION & CONCLUSION: Hearing loss is prevalent in more than three-fourths of the patients attending the speech camp. There is a need for early identification and intervention of middle ear effusion for all cleft palate cases.

PMID: 17704556 [PubMed - indexed for MEDLINE]

A dosage-dependent role for Spry2 in growth and patterning during palate development.

Mech Dev. 2007 Sep-Oct;124(9-10):746-61

Authors: Welsh IC, Hagge-Greenberg A, O'Brien TP

The formation of the palate involves the coordinated outgrowth, elevation and midline fusion of bilateral shelves leading to the separation of the oral and nasal cavities. Reciprocal signaling between adjacent fields of epithelial and mesenchymal cells directs palatal shelf growth and morphogenesis. Loss of function mutations in genes encoding FGF ligands and receptors have demonstrated a critical role for FGF signaling in mediating these epithelial-mesenchymal interactions. The Sprouty family of genes encode modulators of FGF signaling. We have established that mice carrying a deletion that removes the FGF signaling antagonist Spry2 have cleft palate. We show that excessive cell proliferation in the Spry2-deficient palate is accompanied by the abnormal progression of shape changes and movements required for medially directed shelf outgrowth and midline contact. Expression of the FGF responsive transcription factors Etv5, Msx1, and Barx1, as well as the morphogen Shh, is restricted to specific regions of the developing palate. We detected elevated and ectopic expression of these transcription factors and disorganized Shh expression in the Spry2-deficient palate. Mice carrying a targeted disruption of Spry2 fail to complement the craniofacial phenotype characterized in Spry2 deletion mice. Furthermore, a Spry2-BAC transgene rescues the palate defect. However, the BAC transgenic mouse lines express reduced levels of Spry2. The resulting hypomorphic phenotype demonstrates that palate development is Spry2 dosage sensitive. Our results demonstrate the importance of proper FGF signaling thresholds in regulation of epithelial-mesenchymal interactions and cellular responses necessary for coordinated morphogenesis of the face and palate.

PMID: 17693063 [PubMed - indexed for MEDLINE]

Abnormal brain structure in children with isolated clefts of the lip or palate.

Arch Pediatr Adolesc Med. 2007 Aug;161(8):753-8

Authors: Nopoulos P, Langbehn DR, Canady J, Magnotta V, Richman L

OBJECTIVE: To evaluate brain structure in a sample of children with isolated clefts of the lip and/or palate (ICLP). DESIGN: Case-control study. SETTING: Tertiary care center. PARTICIPANTS: A large sample of 74 children aged 7 to 17 years with ICLP was compared with a healthy control group, matched by age and sex. MAIN EXPOSURE: Isolated cleft lip and/or palate. OUTCOME MEASURES: General measures of height and head circumference were obtained. Brain structure was evaluated using magnetic resonance imaging, generating both general and regional brain measures (volumes). RESULTS: Height was significantly lower in the ICLP group (F = 4.83, P = .03). After controlling for this smaller body size, children with ICLP had abnormally small brains with both cerebrum (F = 4.47, P = .04) and cerebellum (F = 14.56, P <.001) volumes substantially decreased. Within the cerebrum, the frontal lobe was preferentially decreased (F = 7.22, P = .008) and subcortical nuclei were also substantially smaller (F = 4.18, P = .003). Tissue distribution of cortical gray matter and white matter within the cerebrum were abnormal in boys with ICLP (larger cortical volume, smaller volume of white matter) but proportional to controls in girls with ICLP. CONCLUSIONS: Children with ICLP have abnormal brain structure, potentially due to abnormal brain development. The fact that the pattern of brain abnormalities in children with ICLP is dramatically different from the pattern of brain abnormalities seen in adults with ICLP suggests that brain growth and development trajectory is also abnormal in subjects with ICLP.

PMID: 17679656 [PubMed - indexed for MEDLINE]

Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.

BMC Med Genet. 2007;8:48

Authors: Kumar RA, Everman DB, Morgan CT, Slavotinek A, Schwartz CE, Simpson EM

BACKGROUND: A disruption of sorting nexin 3 (SNX3) on 6q21 was previously reported in a patient with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and t(6;13)(q21;q12) but no SNX3 mutations were identified in another sporadic case of MMEP, suggesting involvement of another gene. In this work, SNX3 was sequenced in three patients not previously studied for this gene. In addition, we test the hypothesis that mutations in the neighbouring gene NR2E1 may underlie MMEP and related phenotypes. METHODS: Mutation screening was performed in five patients: the t(6;13)(q21;q12) MMEP patient, three additional patients with possible MMEP or a related phenotype, and one patient with oligodactyly, ulnar aplasia, and a t(6;7)(q21;q31.2) translocation. We used sequencing to exclude SNX3 coding mutations in three patients not previously studied for this gene. To test the hypothesis that mutations in NR2E1 may contribute to MMEP or related phenotypes, we sequenced the entire coding region, complete 5' and 3' untranslated regions, consensus splice-sites, and evolutionarily conserved regions including core and proximal promoter in all five patients. Two-hundred and fifty control subjects were genotyped for any candidate mutation. RESULTS: We did not detect any synonymous nor nonsynonymous coding mutations of NR2E1 or SNX3. In one patient with possible MMEP, we identified a candidate regulatory mutation that has been reported previously in a patient with microcephaly but was not found in 250 control subjects examined here. CONCLUSION: Our results do not support involvement of coding mutations in NR2E1 or SNX3 in MMEP or related phenotypes; however, we cannot exclude the possibility that regulatory NR2E1 or SNX3 mutations or deletions at this locus may underlie abnormal human cortical development in some patients.

PMID: 17655765 [PubMed - indexed for MEDLINE]

Maxillary corticotomy and extraoral orthopedic traction in mature teenage patients: a case report.

J Contemp Dent Pract. 2007;8(5):76-84

Authors: Pelo S, Boniello R, Gasparini G, Longobardi G

AIM: The authors' propose to combine the reverse pull headgear with a Delaire type face mask and a maxillary corticotomy to treat a Class III non-growing patient with maxillary retrusion. The aim of this report is to present two cases in which this treatment strategy was successful. BACKGROUND: Several studies suggest the majority of Class III dento-skeletal malocclusions have components of maxillary retrusion. Early treatment of these patients with maxillary protraction devices have shown promising results. Facemask therapy has some important limits. Most important is the optimal timing of treatment between the ages of six to ten years. Closure of the maxillary suture occurs as a child ages which results in an increase of maxillary resistance to protraction. REPORT: A proposed therapy carried out in orthodontic and surgical phases was used in the treatment of two young patients. They were both beyond the optimal age range for the application of the orthopedic device (a girl 15 years old and a boy 16 years old), however, they had not reached the necessary skeletal maturity for orthognathic surgery. SUMMARY: The described technique has the advantage of being quick and easy to perform with a low surgical risk yielding satisfactory results after 15-20 days of therapy instead of the six to nine months associated with traditional procedures.

PMID: 17618333 [PubMed - indexed for MEDLINE]

Root development of permanent lateral incisor in cleft lip and palate children: a radiographic study.

Indian J Dent Res. 2007 Apr-Jun;18(2):82-6

Authors: Deepti A, Muthu MS, Kumar NS

OBJECTIVE: The objective of this study was to compare the root development of lateral incisor on the cleft side with the root development of its contralateral tooth in cleft lip and palate children. SETTING: Cleft lip and palate wing, Meenakshi Ammal Dental College and Hospital, Chennai, South India. MATERIALS AND METHODS: A sample of 96 orthopantamograms of patients with unilateral orbilateral cleft lip and/or cleft palate was selected, regardless of sex and race. MAIN OUTCOME MEASURE: Orthopantamograms were analyzed for root development of lateral incisor on the cleft and non cleft side. Associated anomalies like hypodontia, supernumerary teeth, malformed lateral incisors and root development of canine, if present, were recorded. FINDINGS AND CONCLUSIONS: Root development of permanent lateral incisor was delayed on the cleft side compared to the non cleft side. There was a statistically significant relationship between levels of root development of lateral incisors on the cleft side within the different study groups(P < 0.05). Incidence of hypodontia increased in proportion to cleft severity. Frequency of missing second premolars, supernumerary teeth and malformed lateral incisors increased in cleft lip and palate patients. Root development of canine showed a slight delay on the cleft side when compared to the canine on the noncleft side.

PMID: 17502714 [PubMed - indexed for MEDLINE]

Effects of activator and high-pull headgear combination therapy: skeletal, dentoalveolar, and soft tissue profile changes.

Eur J Orthod. 2007 Apr;29(2):140-8

Authors: Mar&#x15F;an G

The aim of this study was to evaluate skeletal, dentoalveolar, and soft tissue profile changes with activator and high-pull headgear combination therapy in patients with Class II malocclusions caused by maxillary prognathism and mandibular retrognathism. The subjects, all in the mixed dentition, were selected from a single centre and were divided into two groups: 28 patients were treated with an incisor double capping activator and a high-pull headgear combination appliance (13 girls, 15 boys mean chronological age 11.7 +/- 1.2 years, skeletal age 12.1 +/- 1.4 years) and an untreated group of 28 subjects (14 girls, 14 boys mean chronological mean age 11.9 +/- 1.1 years, skeletal age 12.3 +/- 1.3 years). The skeletal, dentoalveolar, and soft tissue profile changes that occurred were compared on lateral cephalograms taken before treatment (T0) and after 1.1 +/- 0.3 years when the combination appliance was removed (T1). In the control group, the radiographs were obtained at the start (T0) and after an observation period 1.2 +/- 0.4 years (T1). Statistical analysis was undertaken with Wilcoxon's ranked-sum test for intra-group comparisons and differences between groups with t-test and Bonferroni's test at a level of significance of P < 0.05. Activator and high-pull headgear combination treatment in these growing patients resulted in a correction of the skeletal Class II relationship (ANB -3.4 degrees), a restriction of maxillary growth (SNA -2.0 degrees, OLp-A -2.3 mm), an advancement of the mandibular structures (SNB +2.6 degrees, FH-NPg +2.3 degrees, OLp-B +2.7 mm, OLp-Pg +2.2 mm), an increase in lower face height (ANS-Me +3.9 mm), a correction of the overjet (-5.4 mm), an improvement in overbite (-2.2 mm), uprighting of the maxillary incisors (U1-FH -5.3 degrees, OLp-U1 -2.5 mm), protrusion of the mandibular incisors (IMPA +2.0 degrees, OLp-L1 +2.7 mm), and a correction of the dental Class II malocclusion (OLp-L6 +3.5 mm). The soft tissue profile changes were a correction of facial convexity (G'-Sn-Pg' angle 2.3 degrees, Mlf-Li-x-axis angle 9.1 degrees), and an increase in lower antero-posterior (Mlf-y-axis 5.6 mm, Pg'-y-axis 5.3 mm), and lower vertical (Sls-x-axis 3.8 mm, Pg'-x-axis 3.8 mm, Me'-x-axis 5.1 mm) soft tissue dimensions. The mentolabial fold depth (Mlf-E line) also significantly decreased, -0.8 mm in the treated group. The activator and high-pull headgear combination appliance was effective in treating growing patients with maxillary prognathism, mandibular deficiency, and facial convexity by a combination of skeletal and dentoalveolar changes and improvement in the soft tissue facial profile.

PMID: 17488997 [PubMed - indexed for MEDLINE]

Giant cell lesions with a Noonan-like phenotype: a case report.

J Contemp Dent Pract. 2007;8(4):67-73

Authors: Cancino CM, Gai&#xE3;o L, Sant'Ana Filho M, Oliveira FA

AIM: The purpose of this article is to describe a case of multiple giant cell lesions of the mandible that occurred in a 14-year-old girl with phenotypic characteristics associated with Noonan Syndrome (NS). BACKGROUND: NS is a dysmorphic disorder characterized by hypertelorism, short stature, congenital heart defects, short and webbed neck, skeletal anomalies, and bleeding diathesis. REPORT: A 14-year-old girl with a previous diagnosis of NS (sporadic case) presented with multiple radiolucent lesions in the body and ramus of her mandible. SUMMARY: In terms of clinical behavior and the described radiographic characteristics, giant cells lesions with Noonan-like phenotype can be considered a form of cherubism. Therefore, surgical intervention is not necessary, but radiographic follow-up and observation is very important during the control and gradual regression of the lesions.

PMID: 17486189 [PubMed - indexed for MEDLINE]

Congenital fusion of the jaws.

Indian J Pediatr. 2007 Apr;74(4):416-8

Authors: Mortazavi SH, Motamedi MH

Congenital fusion of the jaws is quite rare. It may be unilateral or bilateral and involves only the soft tissues or both the hard and soft tissues. This anomaly may be seen separately or in association with syndromes. Maxillomandibular fusion restricts mouth opening causing problems in feeding, swallowing and respiration. This condition can be easily treated. However, in long-standing cases, growth anomalies from TMJ ankylosis may occur.

PMID: 17476091 [PubMed - indexed for MEDLINE]

Cherubism in siblings: A case report.

J Indian Soc Pedod Prev Dent. 2007 Mar;25(1):27-9

Authors: Sarda D, Kothari P, Kulkarni B, Pawar P

Cherubism is a benign disease of bones affecting the jaws and giving a characteristic cherubic appearance to the patient. On radiography, the lesions exhibit bilateral multilocular radiolucent areas. Histopathology shows numerous multinucleated giant cells in the background of proliferating fibrous connective tissue. Cherubism can be a solitary case. The present report describe cherubism in two siblings and briefly review the literature on this subject.

PMID: 17456964 [PubMed - indexed for MEDLINE]

Proximal femoral focal deficiency as a manifestation of Antley-Bixler syndrome: a case report.

J Orthop Surg (Hong Kong). 2007 Apr;15(1):84-6

Authors: Sulaiman AR, Nawaz H, Munajat I, Sallehudin AY

We report a case of the Antley-Bixler syndrome in an 11-year-old girl. She presented with bilateral proximal femoral focal deficiency, right clubfoot, left radiohumeral synostosis, bilateral ear hypoplasia, cleft palate, tongue tie, missing teeth, congenital heart disease, a pelvic kidney with hydronephrosis, and mental retardation. Proximal femoral focal deficiency has never been reported before as a manifestation of Antley-Bixler syndrome. Her mother was exposed to radiation during an intravenous urogram done in the first trimester of pregnancy. Exposure to radiation has not been implicated as a cause of Antley-Bixler syndrome.

PMID: 17429125 [PubMed - indexed for MEDLINE]

Multiple functions of Snail family genes during palate development in mice.

Development. 2007 May;134(9):1789-97

Authors: Murray SA, Oram KF, Gridley T

Palate development requires precise regulation of gene expression changes, morphogenetic movements and alterations in cell physiology. Defects in any of these processes can result in cleft palate, a common human birth defect. The Snail gene family encodes transcriptional repressors that play essential roles in the growth and patterning of vertebrate embryos. Here we report the functions of Snail (Snai1) and Slug (Snai2) genes during palate development in mice. Snai2(-/-) mice exhibit cleft palate, which is completely penetrant on a Snai1 heterozygous genetic background. Cleft palate in Snai1(+/-) Snai2(-/-) embryos is due to a failure of the elevated palatal shelves to fuse. Furthermore, while tissue-specific deletion of the Snai1 gene in neural crest cells does not cause any obvious defects, neural-crest-specific Snai1 deletion on a Snai2(-/-) genetic background results in multiple craniofacial defects, including a cleft palate phenotype distinct from that observed in Snai1(+/-) Snai2(-/-) embryos. In embryos with neural-crest-specific Snai1 deletion on a Snai2(-/-) background, palatal clefting results from a failure of Meckel's cartilage to extend the mandible and thereby allow the palatal shelves to elevate, defects similar to those seen in the Pierre Robin Sequence in humans.

PMID: 17376812 [PubMed - indexed for MEDLINE]

Impaired FGF signaling contributes to cleft lip and palate.

Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4512-7

Authors: Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM, Russo ET, Vieira AR, Dod&#xE9; C, Mohammadi M, Marazita ML, Murray JC

Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect resulting from a combination of genetic and environmental factors. Several members of the FGF and FGFR families are expressed during craniofacial development and can rarely harbor mutations that result in human clefting syndromes. We hypothesized that disruptions in this pathway might also contribute to NS CLP. We sequenced the coding regions and performed association testing on 12 genes (FGFR1, FGFR2, FGFR3, FGF2, FGF3, FGF4, FGF7, FGF8, FGF9, FGF10, FGF18, and NUDT6) and used protein structure analyses to predict the function of amino acid variants. Seven likely disease-causing mutations were identified, including: one nonsense mutation (R609X) in FGFR1, a de novo missense mutation (D73H) in FGF8, and other missense variants in FGFR1, FGFR2, and FGFR3. Structural analysis of FGFR1, FGFR2, and FGF8 variants suggests that these mutations would impair the function of the proteins, albeit through different mechanisms. Genotyping of SNPs in the genes found associations between NS CLP and SNPs in FGF3, FGF7, FGF10, FGF18, and FGFR1. The data suggest that the FGF signaling pathway may contribute to as much as 3-5% of NS CLP and will be a consideration in the clinical management of CLP.

PMID: 17360555 [PubMed - indexed for MEDLINE]

Prosthetic rehabilitation of a completely edentulous patient with palatal insufficiency.

Indian J Dent Res. 2007 Jan-Mar;18(1):35-7

Authors: Bhat AM

This article presents a case report of a completely edentulous patient with palatal insufficiency successfully rehabilitated with closed hollow bulb obturator prosthesis and also describes a simple technique for fabricating a two-piece hollow bulb obturator that allows for control of the bulb's wall thickness and weight of the prosthesis.

PMID: 17347544 [PubMed - indexed for MEDLINE]

MSX1 polymorphism associated with risk of oral cleft in Korea: evidence from case-parent trio and case-control studies.

Yonsei Med J. 2007 Feb 28;48(1):101-8

Authors: Park J, Park BY, Kim HS, Lee JE, Suh I, Nam CM, Kang DR, Kim S, Yun JE, Go EN, Jee SH, Beaty TH

Orofacial clefts, including cleft lip with or without palate (CL/P) and cleft palate (CP), are one of the most common congenital malformations in Asian populations, where the rate of incidence is higher than in European or other racial groups. A number of candidate genes have been identified for orofacial clefts, although no single candidate has been consistently identified in all studies. We performed case-parent trio and case- control studies on 6 single nucleotide polymorphisms (SNPs) in the MSX1 gene using a sample of 52 CL/P and CP probands from Korea. In the case-control study, the allele frequencies of 6 MSX1 SNPs were compared between 52 oral cleft cases and 96 unmatched controls. For the case-parent trio study, single-marker and haplotype-based tests of transmission disequilibrium using allelic and genotypic tests revealed significant evidence of linkage in the presence of disequilibrium for 1170 G/A of exon 2. With the GG genotype as a reference group among GG, GA, and AA genotypes at 1170G/A, the disease risk decreased with the presence of the A allele (AA genotype: OR=0.26, 95% CI=0.10-0.99). These results are consistent with evidence from other studies in the US and Chile and confirm the importance of the MSX1 genotype in determining the risk of CL/P and CP in Koreans.

PMID: 17326252 [PubMed - indexed for MEDLINE]

EEC syndrome.

Indian J Ophthalmol. 2007 Mar-Apr;55(2):162-3

Authors: Kumar HN, Kugar TS, Rao RJ, Kodkany S

PMID: 17322619 [PubMed - indexed for MEDLINE]

The Walker-Warburg syndrome with cleft lip and palate.

Singapore Med J. 2007 Feb;48(2):e66-7

Authors: Pratap A, Agrawal A, Tiwari A, Lakshmi R, Rajbanshi S

The Walker-Warburg syndrome is a rare and lethal autosomal recessive disorder. We report a newborn male infant with the Walker-Warburg syndrome. He had typical clinical features, including lissencephaly, congenital muscular dystrophy and an ocular abnormality associated with cleft lip and palate without hydrocephalus.

PMID: 17304384 [PubMed - indexed for MEDLINE]

Gene expression analysis reveals that formation of the mouse anterior secondary palate involves recruitment of cells from the posterior side.

Int J Dev Biol. 2007;51(2):167-72

Authors: Li Q, Ding J

Cleft palate is a common birth defect caused by disruptions in secondary palate development. Anterior-posterior (A-P) regional specification plays a critical role in palate development and fusion. Previous studies have shown that at the molecular level, the anterior palate can be defined by the expression of Shox-2 and the posterior palate by Meox-2 expression in certain mouse strains. Here, we have extended previous studies by performing a more detailed analysis of these genes during mouse palate development. We found that the expression patterns of Shox-2 and Meox-2 are dynamic during palate development. At embryonic day 12.5 (E12.5), Shox-2 expression is localized to the anterior end and its expression domain covers less than 25% of the length of the palate shelf. The Shox-2 expression domain then gradually expands towards the posterior end and ultimately occupies more than 60% of the palate shelf by E14.5. The expansion of the Shox-2 domain may involve induction of Shox2 expression in additional cells. Reciprocally, the Meox-2 expression domain at E12.5 covers a large portion of the palate shelf, a region more than 70% of the entire palate, but then regresses to the posterior 25% by E14.5. This regression is likely caused by the repression of Meox-2 expression in certain Meox2 expressing cells, rather than the cessation of cell proliferation. Therefore, certain Meox-2 positive "primitive posterior cells" are differentiated/converted into Shox-2 positive "definitive anterior cells" during A-P regional specification.

PMID: 17294368 [PubMed - indexed for MEDLINE]

Bone grafting with platelet-rich plasma in alveolar cleft. Case report.

Minerva Stomatol. 2007 Jan-Feb;56(1-2):63-71

Authors: Rullo R, Festa VM, Guida L, Laino G

Bone grafting of the alveolus has become an essential part of the contemporary surgical management of oral clefts. The benefits of this procedure are the stabilization of the maxillary arch, elimination of oronasal fistulae, the reconstruction of the soft tissue nasal base support, creation of bony support for subsequent tooth eruption or, when they are not present or not preserved, for implants application. The authors show a case of bone grafting with the aid of platelet-rich plasma (PRP). Because of the difficulties due to the oral cleft and to its surgical reparation (big size of bone defect, hard scars and sclerotic soft tissue) the authors decided to add PRP to a bone graft taken from the chin. PRP contains a high concentration of growth factors and is able to stimulate both wound and bone regeneration. Infact, the authors have observed very good results both in bone integration and in soft tissue reparation.

PMID: 17287708 [PubMed - indexed for MEDLINE]

Few associations of candidate genes with nonsyndromic orofacial clefts in the population of Lithuania.

J Appl Genet. 2007;48(1):89-91

Authors: Mork&#x16B;niené A, Steponaviciūt D, Utkus A, Kucinskas V

Nonsyndromic orofacial clefting (NS-OFC) is a common complex multifactorial trait with a considerable genetic component and a number of candidate genes suggested by various approaches. Twenty biallelic and microsatellite DNA markers in the strong candidate loci TGFA, TGFB3, GABRB3, RARA, and BCL3 were analysed for allelic association with the NS-OFC phenotype in 112 nuclear families (proband + both parents) from Lithuania by using the transmission disequilibrium test (TDT). Associations were found between the TGFA gene marker rs2166975 and nonsyndromic cleft palate only (CPO) phenotype (p = 0.045, df 1) as well as between the D2S292 marker and the cleft lip with or without cleft palate (CL/CP) phenotype in allele-wise TDT (P = 0.005, df 9) and genotype-wise TDT (P = 0.021, df 24). A weak association (P = 0.085, df 3) of the BCL3 marker (BCL3 gene) with the risk of CPO was also found. Thus our initial results support the contribution of allelic variation in the TGFA locus to the aetiology of CL/CP in the population of Lithuania but they do not point to TGFA as a major causal gene. Different roles of the TGFA and BCL3 genes in the susceptibility to NS-OFC phenotypes are suggested.

PMID: 17272867 [PubMed - indexed for MEDLINE]

Folic acid supplements and risk of facial clefts: national population based case-control study.

BMJ. 2007 Mar 3;334(7591):464

Authors: Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, Vindenes H, Vollset SE, Drevon CA

OBJECTIVE: To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. DESIGN: National population based case-control study. SETTING: Infants born 1996-2001 in Norway. PARTICIPANTS: 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. MAIN OUTCOME MEASURES: Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. RESULTS: Folic acid supplementation during early pregnancy (> or =400 microg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). CONCLUSIONS: Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

PMID: 17259187 [PubMed - indexed for MEDLINE]

Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype.

Mol Med. 2006 Sep-Oct;12(9-10):237-45

Authors: Baroni T, Bellucci C, Lilli C, Pezzetti F, Carinci F, Becchetti E, Carinci P, Stabellini G, Calvitti M, Lumare E, Bodo M

During embryogenesis, a complex interplay between extracellular matrix (ECM) molecules, regulatory molecules, and growth factors mediates morphogenetic processes involved in palatogenesis. Transforming growth factor-beta (TGF-beta), retinoic acid (RA), and gamma-aminobutyric acid (GABA)ergic signaling systems are also potentially involved. Using [3H]glucosamine and [35S]methionine incorporation, anion exchange chromatography, semiquantitative radioactive RT-PCR, and a TGF-beta binding assay, we aimed to verify the presence of phenotypic differences between primary cultures of secondary palate (SP) fibroblasts from 2-year-old subjects with familial nonsyndromic cleft lip and/or palate (CLP-SP fibroblasts) and age-matched normal SP (N-SP) fibroblasts. The effects of RA--which, at pharmacologic doses, induces cleft palate in newborns of many species--were also studied. We found an altered ECM production in CLP-SP fibroblasts that synthesized and secreted more glycosaminoglycans (GAGs) and fibronectin (FN) compared with N-SP cells. In CLP-SP cells, TGF-beta3 mRNA expression and TGF-beta receptor number were higher and RA receptor-alpha (RARA) gene expression was increased. Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts. In N-SP and CLP-SP fibroblasts, RA decreased GAG and FN secretion and increased TGF-beta3 mRNA expression but reduced the number of TGF-beta receptors. TGF-beta receptor type I mRNA expression was decreased, TGF-beta receptor type II was increased, and TGF-beta receptor type III was not affected. RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells. These results show that CLP-SP fibroblasts compared with N-SP fibroblasts exhibit an abnormal phenotype in vitro and respond differently to RA treatment, and suggest that altered crosstalk between RA, GABAergic, and TGF-beta signaling systems could be involved in human cleft palate fibroblast phenotype.

PMID: 17225872 [PubMed - indexed for MEDLINE]

[Value of 3D-4D sonography in fetal and gynecological ultrasound examination: principles and indications]

J Radiol. 2006 Dec;87(12 Pt 2):1969-92

Authors: Levaillant J

Three-dimensional ultrasound has become an essential tool for visualization of fetal structures in the past few years. The recent improvements in transducers and signal processing provide new information, particularly in obstetrics and gynecology sonography. The present paper will present the most recent advances in volume acquisition and presentation modes followed by results of fetal organ visualization in normal and abnormal cases as well as applications in gynecology.

PMID: 17211311 [PubMed - indexed for MEDLINE]

Amniotic fluid induces rapid epithelialization in the experimentally ruptured fetal mouse palate--implications for fetal wound healing.

Int J Dev Biol. 2007;51(1):67-77

Authors: Takigawa T, Shiota K

Cleft of the secondary palate is one of the most common congenital birth defects in humans. The primary cause of cleft palate formation is a failure of fusion of bilateral palatal shelves, but rupture of the once fused palate has also been suggested to take place in utero. The possibility of post-fusion rupture of the palate in humans has hardly been accepted, mainly because in all the cleft palate cases, the cleft palatal edge is always covered with intact epithelium. To verify whether the intrauterine environment of the fetus plays roles in wound healing when the once fused palate is torn apart, we artificially tore apart fetal mouse palates after fusion and cultivated them in culture medium with or without mouse or human amniotic fluid. We thereby found that the wounded palatal edge became completely covered with flattened epithelium after 36 hours in culture with amniotic fluid, but not in culture without amniotic fluid. Using histological and scanning electron microscopic analyses of the healing process, it was revealed that the epithelium covering the wound was almost exclusively derived from the adjacent nasal epithelium, but not from the oral epithelium. Such actions of amniotic fluid on the fetal wound were never simulated by exogenous epidermal growth factor (EGF), albumin, or both. In addition, the rapid epithelialization induced by amniotic fluid was not prevented by either PD168393 (an inhibitor of the EGF receptor-specific tyrosine kinase) or SB431542 (a specific inhibitor of TGFbeta receptor type I/ALK5). The present study provides new insights into the unique biological actions of amniotic fluid in the repair of injured fetal palate.

PMID: 17183466 [PubMed - indexed for MEDLINE]

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Am J Hum Genet. 2007 Jan;80(1):76-90

Authors: Shi M, Christensen K, Weinberg CR, Romitti P, Bathum L, Lozada A, Morris RW, Lovett M, Murray JC

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.

PMID: 17160896 [PubMed - indexed for MEDLINE]

A novel mutation in the SH3BP2 gene causes cherubism: case report.

BMC Med Genet. 2006;7:84

Authors: Li CY, Yu SF

BACKGROUND: Cherubism is a rare hereditary multi-cystic disease of the jaws, characterized by its typical appearance in early childhood, and stabilization and remission after puberty. It is genetically transmitted in an autosomal dominant fashion and the gene coding for SH3-binding protein 2 (SH3BP2) may be involved. CASE PRESENTATION: We investigated a family consisting of 21 members with 3 female affected individuals with cherubism from Northern China. Of these 21 family members, 17 were recruited for the genetic analysis. We conducted the direct sequence analysis of the SH3BP2 gene among these 17 family members. A disease-causing mutation was identified in exon 9 of the gene. It was an A1517G base change, which leads to a D419G amino acid substitution. CONCLUSION: To our knowledge, the A1517G mutation has not been reported previously in cherubism. This finding is novel.

PMID: 17147794 [PubMed - indexed for MEDLINE]

Comparison of the headgear activator and Herbst appliance--effects and post-treatment changes.

Eur J Orthod. 2006 Dec;28(6):594-604

Authors: Phan KL, Bendeus M, H&#xE4;gg U, Hansen K, Rabie AB

The aim of this study was to evaluate the effects of the headgear activator (HGA) and Herbst appliance during active treatment and retention and at follow-up in children with a skeletal Class II malocclusion. The two groups comprised 16 consecutive male patients (mean age 11.6 +/- 1.42 years) treated with a HGA and 16 male patients (mean age 12.6 +/- 1.13 years) treated with a Herbst appliance and Andresen activator (HAA) sampled from a larger pool using similar selection criteria. Growth data were obtained for the two groups. Lateral cephalograms taken at the start, after 6 months of treatment, after 12 months of active treatment or 6 months of retention, and at the 24-month follow-up were analysed. The total changes over the whole observation period (T0-T3) did not differ significantly between the groups; there was, however, a statistically significant increase in jaw prognathism (P < 0.05) and improvement of the molar relationship (P < 0.05) in the HAA group as compared with the HGA group. During the initial treatment phase (T0-T1), the overall treatment effects were statistically more pronounced in the HAA group than in the HGA group. Despite significant differences in treatment effects and changes between the two devices, there were no significant overall changes at follow-up except for the prognathism, i.e. maxillary prognathism decreased with treatment with the HGA while mandibulars prognathism continued to increase with HAA treatment.

PMID: 17142260 [PubMed - indexed for MEDLINE]

A novel missense mutation in Van der Woude syndrome: usefulness of fingernail DNA for genetic analysis.

J Dent Res. 2006 Dec;85(12):1143-6

Authors: Matsuzawa N, Shimozato K, Natsume N, Niikawa N, Yoshiura K

Van der Woude syndrome (VWS) is an autosomal-dominant oral facial disorder. To find a gene mutation in a Japanese family using fingernail DNA samples, we performed this study. We hypothesized that a gene mutation in IRF6 might be involved in VWS, and that fingernail DNA samples may be valuable for detecting such mutations. Linkage and haplotype analyses of the family mapped the disease locus to the 1q32-q41 region. Mutation analysis with an improved extraction method for fingernail DNA detected a novel missense mutation (1046A>T, E349V) in exon 7 of IRF6 in all the affected members of the family. Since the E349V change may disturb the hydrophobic core and affect regulatory activity of IRF6, it is most likely that the mutation is causative for VWS in this family. Fingernail DNA is thus useful for linkage and mutation analyses, since the fingernail can be easily obtained non-invasively, sent through the mail, and stored for a long period. We emphasize here the usefulness of fingernail DNA for the genetic analysis of a disease.

PMID: 17122170 [PubMed - indexed for MEDLINE]

Bilateral TMJ disk displacement induces mandibular retrognathia.

J Dent Res. 2006 Dec;85(12):1118-23

Authors: Bryndahl F, Eriksson L, Legrell PE, Isberg A

Unilateral non-reducing TMJ disk displacement has been shown to retard mandibular growth on the ipsilateral side, with facial asymmetry a sequela. We hypothesized that bilateral affliction would impair mandibular growth bilaterally, generating mandibular retrognathia. Non-reducing TMJ disk displacement was surgically created in 10 growing New Zealand White rabbits. Ten additional rabbits served as a sham-operated control group. Facial growth was followed in serial cephalograms, with tantalum implants, during a period corresponding to childhood and adolescence in man. The results verified that bilateral non-reducing TMJ disk displacement retarded mandibular growth bilaterally, the extent corresponding to mandibular retrognathia in man. Maxillary growth was also retarded, but to a lesser degree. Growth impairment fluctuated over time, the most striking retardation occurring during periods of general growth acceleration. This should be taken into consideration when orthodontic treatment, aimed at stimulating mandibular growth, is initiated in adolescent individuals with non-reducing TMJ disk displacement.

PMID: 17122165 [PubMed - indexed for MEDLINE]

Tissue inhibitors of metalloproteinases (TIMPs): their biological functions and involvement in oral disease.

J Dent Res. 2006 Dec;85(12):1074-84

Authors: Verstappen J, Von den Hoff JW

Several families of enzymes are responsible for the degradation of extracellular matrix (ECM) proteins during the remodeling of tissues. An important family of such enzymes is that of the matrix metalloproteinases (MMPs). To control MMP-mediated ECM breakdown, tissue inhibitors of metalloproteinases (TIMPs) are able to inhibit MMP activity. A disturbed balance of MMPs and TIMPs is found in various pathologic conditions, such as cancer, rheumatoid arthritis, and periodontitis. The role of MMPs in pathology has been extensively described in the literature. The main focus of this review lies in the biological functions of TIMPs and their occurrence in disease, especially in the head and neck area. Their biological functions and their role in diseases like oral cancers and periodontitis, and in the development of cleft palate, will be discussed. Finally, the diagnostic and therapeutical opportunities of TIMPs will be evaluated.

PMID: 17122157 [PubMed - indexed for MEDLINE]

Type of oral cleft and mothers' perceptions of care, health status, and outcomes for preadolescent children.

Cleft Palate Craniofac J. 2006 Nov;43(6):715-21

Authors: Damiano PC, Tyler MC, Romitti PA, Momany ET, Canady JW, Karnell MP, Murray JC

OBJECTIVE: To evaluate the outcomes of care for children by type of oral cleft. DESIGN: Data were collected through structured telephone interviews during 2003 in Iowa with mothers of 2- to 12-year-old children with oral clefts. Interviews with mothers of children with clubfoot and statewide data on Iowa children were used for comparison. PARTICIPANTS: Participants included mothers of children in Iowa born between 1990 and 2000 with nonsyndromic oral clefts. Children were identified by the statewide Iowa Registry for Congenital and Inherited Disorders. MAIN OUTCOME MEASURES: Rating of cleft care, severity of condition, health status, esthetic outcome, speech, and school performance were evaluated by type of oral cleft. RESULTS: Children with cleft lip and palate were most likely to have their clefts rated as very severe. Children with palatal involvement were reported to have a lower health status and were almost twice as likely to be identified as having a special health care need compared with either children with cleft lip or children statewide. Children with cleft lip had more esthetic concerns; children with palatal involvement had the most speech concerns. CONCLUSIONS: Although mothers generally believed their children had received high-quality care, ratings of the children's current health status and outcomes of care varied significantly by type of cleft (cleft lip, cleft palate, and cleft lip and palate). Differences observed in this population-based study support the proposition that cleft type should be considered when examining outcomes of care for children with oral clefts.

PMID: 17105335 [PubMed - indexed for MEDLINE]

Survey of the patients with cleft lip and palate in China who were funded for surgery by the Smile Train Program from 2000 to 2002.

Chin Med J (Engl). 2006 Oct 20;119(20):1695-700

Authors: Zhou QJ, Shi B, Shi ZD, Zheng Q, Wang Y

BACKGROUND: Cleft lip (CL) and cleft palate (CP) are two of the most frequent congenital malformations. Many epidemiologic studies on this deformity have been conducted worldwide, often producing inconsistent results. This study assessed epidemiology and some genetic aspects of cleft lip and palate in a Chinese sample from the Smile Train Program and to compare with other methodologically sound surveys. METHODS: The general information, family history, classification of cleft and associated malformations of 8000 CL and CP surgery patients were analyzed. RESULTS: Of the 8000 cases, 7812 had complete data. The distribution of cleft types is 17.04% with CP, 23.39% with CL and 59.58% with cleft lip and palate (CLP). Unilateral clefts were more common than bilateral, with unilateral to bilateral ratios being 10.4:1 for CL, and 3.42:1 for CLP. The overall male:female ratio was 2.01:1. Left sided defects were more common than right sided regardless of sex, 1.90:1 for CL and 1.96:1 for CLP. CLP and CL were more common in males than in females with sex ratios (SR) of 2.88:1 and 1.85:1 respectively, whereas CP was more common in females with SR of 0.76:1. Associated malformations (2.89%), involved 29 CP cases, 41 CL and 156 CLP. The frequency of associated malformations in CLP (3.35%) was higher than CL (2.24%) and CP (2.22%) (P < 0.05). Patients with CP or CLP were born less often in the winter than in the summer (P < 0.05). A history of family members having clefts occurred in 6.84% of patients. The proportion of CLP cases (7.56%) was significantly higher than that of CL cases (5.64%) (P < 0.05). CONCLUSIONS: The different types of clefts appeared in the highest proportion in CLP and lowest proportion in CP. Males are more common with CL and CLP and less common with CP. These characteristics are the same as those of other Chinese surveys but different from some European reports.

PMID: 17097016 [PubMed - indexed for MEDLINE]

PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations.

Am J Med Genet A. 2006 Dec 1;140(23):2562-70

Authors: Avila JR, Jezewski PA, Vieira AR, Orioli IM, Castilla EE, Christensen K, Daack-Hirsch S, Romitti PA, Murray JC

Poliovirus Receptor Like-1 (PVRL1) is a member of the immunoglobulin super family that acts in the initiation and maintenance of epithelial adherens junctions and is mutated in the cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1, OMIM #225000). In addition, a common non-sense mutation in PVRL1 was discovered more often among non-syndromic sporadic clefting cases in Northern Venezuela in a previous case-control study. The present work sought to ascertain the role of PVRL1 in the sporadic forms of orofacial clefting in multiple populations. Multiple rare and common variants from all three splice isoforms were initially ascertained by sequencing 92 Iowan and 86 Filipino cases and CEPH controls. Using a family-based analysis to examine these variants, the common glycine allele of the G361V coding variant was significantly overtransmitted among all orofacial clefting phenotypes (P = 0.005). This represented G361V genotyping from over 800 Iowan, Danish, and Filipino families. Among four rare amino acid changes found within the V1 and C1 domains, S112T and T131A were found adjacent to critical amino acid positions within the V1 variable domain, regions previously shown to mediate cell-to-cell and cell-to-virus adhesion. The T131A variant was not found in over 1,300 non-affected control samples although the alanine is found in other species. The serine of the S112T variant position is conserved across all known PVRL1 sequences. Together these data suggest that both rare and common mutations within PVRL1 make a minor contribution to disrupting the initiation and regulation of cell-to-cell adhesion and downstream morphogenesis of the embryonic face.

PMID: 17089422 [PubMed - indexed for MEDLINE]

Prosthetic assessment in cleft lip and palate patients: a case report with oronasal communication.

Med Oral Patol Oral Cir Bucal. 2006 Nov-Dec;11(6):E493-6

Authors: Sala Mart&#xED; S, Merino Tessore MD, Escuin Henar T

The cleft lip and palate patient is mainly characterized by the presence of an oronasal communication, malformation or agenesis of the teeth close to the cleft, and deficient sagittal and transverse growth of the maxilla. These patients require various treatments involving a multidisciplinary team, which may include a maxillofacial surgeon, an orthodontist, a speech therapist, a paediatrician, a general dentist, a prosthodontist, an ENT specialist, a psychologist and all those professionals who can help provide functional, aesthetic and psychological improvement. This report describes a case of prosthetic rehabilitation in a patient with cleft lip and palate and an oronasal fistula (communication) following surgery. Different prosthetic treatments are described, with emphasis being placed on the approach chosen after to discuss the various limitations which arose.

PMID: 17072253 [PubMed - indexed for MEDLINE]

The effect of tongue appliance on the nasomaxillary complex in growing cleft lip and palate patients.

J Indian Soc Pedod Prev Dent. 2006 Sep;24(3):136-9

Authors: Jamilian A, Showkatbakhsh R, Boushehry MB

Midfacial deficiency is a common feature of cleft lip and palate patients due to scar tissue of the lip and palate closure procedure. The aim of this study was to evaluate the effectiveness of the physiological force of the tongue to move the maxilla in forward position. This research has been done experimentally by, before and after treatment following up in private practice. Ten patients (6 female, 4 male) with complete bilateral cleft lip and palate were selected. All of them had Cl III malocclusion with maxillary deficiency due to scar tissue of lip and palate surgery. Their age ranged from 7.6 to 9.8 years. All the patients were delivered tongue appliance to transfer the force of the tongue to maxillary complex. The mean observation time was 13+/-2 months to achieve positive overjet. Pre- and post-lateral cephalograms were compared to evaluate the skeletal changes with paired t-test. The results showed that after the application of tongue appliance, normal sagittal maxillomandibular relationship was achieved. SN-ANS angle was increased 1.9+/-1.8 - P < 0.03. This study showed that the tongue appliance could transfer considerable force during rest and swallowing period to the maxilla. This method might be considered to improve the deficient maxilla by means of growth modification and redirect concept.

PMID: 17065780 [PubMed - indexed for MEDLINE]

Cleidocranial dysplasia: importance of radiographic images in diagnosis of the condition.

J Oral Sci. 2006 Sep;48(3):161-6

Authors: Tanaka JL, Ono E, Filho EM, Castilho JC, Moraes LC, Moraes ME

Cleidocranial dysplasia (CCD) is a rare syndrome usually caused by an autosomal dominant gene, although 40% of cases of CCD appear spontaneously with no apparent genetic cause. This condition is characterized by several cranial malformations and underdevelopment, absence of the clavicles, and multiple supernumerary and impacted permanent teeth. The diagnosis of this condition is usually based on the presence of the main features (supernumerary teeth, partial or total absence of one or both the clavicles, and bony malformations) and on clinical and familial evidence. The bony and dental features of CCD may be visualized on radiographic images of the face and skull. Here, we present a familial case of CCD and discuss the importance of dental radiographs in diagnosis of the condition.

PMID: 17023750 [PubMed - indexed for MEDLINE]

Treatment of mandibular prognathism.

J Formos Med Assoc. 2006 Oct;105(10):781-90

Authors: Chang HP, Tseng YC, Chang HF

Mandibular prognathism (MP) or skeletal Class III malocclusion with a prognathic mandible is one of the most severe maxillofacial deformities. Facial growth modification can be an effective method of resolving skeletal Class III jaw discrepancies in growing children with dentofacial orthopedic appliances including the chincup, face mask, maxillary protraction combined with chincup traction and the Fr&#xE4;nkel functional regulator III appliance. Orthognathic surgery in conjunction with orthodontic treatment is required for the correction of adult MP. The two most commonly applied surgical procedures to correct MP are sagittal split ramus osteotomy (SSRO) and intraoral vertical ramus osteotomy. Both procedures are suitable for patients in whom a desirable occlusal relationship can be obtained with a setback of the mandible, and each has its own advantages and disadvantages. In bilateral SSRO, the intentional ostectomy of the posterior part of the distal segment can offer long-term positioned stability. This may be attributable to reduction of tension in the pterygomasseteric sling that applies force in the posterior mandible. While various environmental factors have been found to contribute to the development of MP, heredity plays a substantial role. The relative contributions of genetic and environmental components in the etiology of MP are unclear. The recent identification of the genetic susceptibilities to MP constitutes the first step toward understanding the molecular pathogenesis of MP. Further studies in molecular biology are needed to identify the gene-environment interactions associated with the phenotypic diversity of MP and the heterogenic developmental mechanisms thought to be responsible for them.

PMID: 17000450 [PubMed - indexed for MEDLINE]

Novel IRF6 mutations in Chinese patients with Van der Woude syndrome.

J Dent Res. 2006 Oct;85(10):937-40

Authors: Du X, Tang W, Tian W, Li S, Li X, Liu L, Zheng X, Chen X, Lin Y, Tang Y

Van der Woude syndrome (VWS) (OMIM 119300) is a dominantly inherited, developmental disorder that is characterized by pits and/or sinuses of the lower lip and a cleft lip and/or cleft palate. Mutations in the interferon regulatory factor 6 gene (IRF6) have been recently identified in patients with VWS, with more than 60 mutations reported. However, the VWS phenotype, IRF6 mutation genotypes, and their interrelationships in Chinese VWS patients have not been studied. Here, we report 11 Chinese families with variable clinical phenotypes of VWS and identified mutations in all patients. Of the 11 mutations, 8 appeared to be novel: CC5.6GT, T342A, 566delA, C748T, C756A, C989A, C1209G, and 1316delT. Seven mutations caused a change or loss of the IRF6 domain. The marked phenotypic variation may be caused by the action of certain modifier genes on IRF6 function.

PMID: 16998136 [PubMed - indexed for MEDLINE]

SUMO1 haploinsufficiency leads to cleft lip and palate.

Science. 2006 Sep 22;313(5794):1751

Authors: Alkuraya FS, Saadi I, Lund JJ, Turbe-Doan A, Morton CC, Maas RL

The posttranslational modification sumoylation can have multiple effects on its substrate proteins. We studied a patient with isolated cleft lip and palate and a balanced chromosomal translocation that disrupts the SUMO1 (small ubiquitin-related modifier) gene, resulting in haploinsufficiency. In mouse, we found that Sumo1 is expressed in the developing lip and palate and that a Sumo1 hypomorphic allele manifests an incompletely penetrant orofacial clefting phenotype. Products of several genes implicated in clefting are sumoylated, and the Sumo1 hypomorphic allele interacts genetically with a loss-of-function allele for one of these loci. Thus, sumoylation defines a network of genes important for palatogenesis.

PMID: 16990542 [PubMed - indexed for MEDLINE]

Identification and characterization of a novel gene, Mcpr1, and its possible function in the proliferation of embryonic palatal mesenchymal cells.

J Biol Chem. 2006 Nov 10;281(45):33997-4008

Authors: Xuan DY, Li X, Deng ZH, Zhang HL, Feng PX, Duan XY, Jin Y

We cloned a novel mouse cDNA, Mcpr1 (mouse cleft palate-related gene 1), between retinoic acid (RA)-treated murine embryonic palatal and control shelves by improved subtractive hybridization. Its transcript was identified by Northern blotting. The open reading frame encodes 132 amino acids and shows almost no identity to other genetic products. Mcpr1 expression could be detected extensively in adult mouse tissues and during murine embryonic development. It was identified to be significantly stimulated by RA in murine palatal shelves at embryonic day 12 and in palatal mesenchymal cells in vitro. We demonstrate that MCPR1 protein was localized primarily in the cytoplasm and could be synthesized and secreted by transfected COS-7 cells. Both the secretory and recombinant proteins of Mcpr1 inhibited proliferation of murine embryonic palatal mesenchymal cells and impeded the progression from the G1 to S phase in the cell cycle. The cells were prone to apoptosis after exposure to glutathione S-transferase-MCPR1. Furthermore, knockdown of MCPR1 protein levels by antisense oligodeoxynucleotides promoted progression of cells from the G1 to S phase and completely abolished the RA-induced block of the cell cycle from the G1 to S phase. These findings suggest that Mcpr1 might function as one of the RA-up-regulated genes involved in inhibiting cell proliferation during palatogenesis and RA-induced cleft palate by regulating proliferation and apoptosis of embryonic palatal mesenchymal cells and might even play a role in the development of many other organs.

PMID: 16963447 [PubMed - indexed for MEDLINE]

Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development.

Am J Hum Genet. 2006 Oct;79(4):668-78

Authors: Britanova O, Depew MJ, Schwark M, Thomas BL, Miletich I, Sharpe P, Tarabykin V

The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.

PMID: 16960803 [PubMed - indexed for MEDLINE]

Cholesterol precursors and facial clefting.

J Clin Invest. 2006 Sep;116(9):2322-5

Authors: Porter FD

Inborn errors of cholesterol synthesis cause human malformation syndromes, including Smith-Lemli-Opitz syndrome, lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata type 2, and congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Because adequate cholesterol is not transported across the placenta, low cholesterol and elevated sterol precursor levels are present during embryogenesis. It has been debated whether the malformations result from low cholesterol or the buildup of sterol precursors. In this issue of the JCI, Engelking et al. provide evidence that sterol precursor accumulation plays a pivotal role in the genesis of facial malformations (see the related article beginning on page 2356).

PMID: 16955133 [PubMed - indexed for MEDLINE]

Hydrocephalus with cleft lip and palate: an overlap between midline malformation syndromes.

Indian J Pediatr. 2006 Aug;73(8):731-3

Authors: Cakir M, Mungan I, Makuloglu M, Okten A

We present a male infant with hydrocephalus, cleft lip/palate, micrognathia, club foot, laryngeal stenosis and ostium secundum type atrial septal defect. The karyotype was 46 XY. The combination of malformations observed overlaps with the characteristic findings of hydrolethalus syndrome, Meckel syndrome, Smith-Lemli-Opitz syndrome and pseudotrisomy 13. We discussed the differential diagnosis of the case.

PMID: 16936370 [PubMed - indexed for MEDLINE]

Multidisciplinary treatment of mandibular prognathism with multiple congenitally missing teeth.

Bull Tokyo Dent Coll. 2006 Feb;47(1):25-31

Authors: Nishimura R, Nojima K, Nishii Y, Hanai J, Arataki T, Uchiyama T, Yamaguchi H

Surgical orthodontic treatment and dental implant therapy were performed on a man (aged 18 years 8 months) with mandibular prognathism and seven congenitally missing teeth: upper canines, first and second premolars and lower right second premolar. After 17 months of preoperative orthodontic treatment at age 20 years 1 month, sagittal split ramus osteotomy was performed using the remaining upper deciduous teeth as an anchor for intermaxillary fixation. In postoperative orthodontic treatment, the remaining deciduous teeth were extracted, and fixture installation was performed. The entire therapy required 4 years to complete (age 22 years 8 months). After completion of orthodontic treatment, superstructures were put in place. This patient had many dental problems, so multidisciplinary care was performed in conjunction with other departments to improve oral function and facial esthetics.

PMID: 16924156 [PubMed - indexed for MEDLINE]

Combination of congenital cleft lip and palate with con-genital diaphragmatic hernia: a severe disease course.

Chin Med J (Engl). 2006 Aug 5;119(15):1318-20

Authors: Li Y, Xiong WL, Shi B

PMID: 16919195 [PubMed - indexed for MEDLINE]

Genomewide scan for nonsyndromic cleft lip and palate in multigenerational Indian families reveals significant evidence of linkage at 13q33.1-34.

Am J Hum Genet. 2006 Sep;79(3):580-5

Authors: Radhakrishna U, Ratnamala U, Gaines M, Beiraghi S, Hutchings D, Golla J, Husain SA, Gambhir PS, Sheth JJ, Sheth FJ, Chetan GK, Naveed M, Solanki JV, Patel UC, Master DC, Memon R, Antonarakis GS, Antonarakis SE, Nath SK

Nonsyndromic cleft lip with or without cleft palate (CL-P) is a common congenital anomaly with incidence ranging from 1 in 300 to 1 in 2,500 live births. We analyzed two Indian pedigrees (UR017 and UR019) with isolated, nonsyndromic CL-P, in which the anomaly segregates as an autosomal dominant trait. The phenotype was variable, ranging from unilateral to bilateral CL-P. A genomewide linkage scan that used approximately 10,000 SNPs was performed. Nonparametric linkage (NPL) analysis identified 11 genomic regions (NPL>3.5; P<.005) that could potentially harbor CL-P susceptibility variations. Among those, the most significant evidence was for chromosome 13q33.1-34 at marker rs1830756 (NPL=5.57; P=.00024). This was also supported by parametric linkage; MOD score (LOD scores maximized over genetic model parameters) analysis favored an autosomal dominant model. The maximum LOD score was 4.45, and heterogeneity LOD was 4.45 (alpha =100%). Haplotype analysis with informative crossovers enabled the mapping of the CL-P locus to a region of approximately 20.17 cM (7.42 Mb) between SNPs rs951095 and rs726455. Thus, we have identified a novel genomic region on 13q33.1-34 that harbors a high-risk variant for CL-P in these Indian families.

PMID: 16909398 [PubMed - indexed for MEDLINE]

Orthodontic management of achondroplasia.

S Afr Med J. 2006 Jul;96(7):574-5

Authors: Bellardie HH

PMID: 16909171 [PubMed - indexed for MEDLINE]

Cardiovascular and craniofacial defects in Crk-null mice.

Mol Cell Biol. 2006 Aug;26(16):6272-82

Authors: Park TJ, Boyd K, Curran T

The Crk adaptor protein, which is encoded by two splice variants termed CrkI and CrkII, contains both SH2 and SH3 domains but no catalytic region. It is thought to function in signal transduction processes involved in growth regulation, cell transformation, cell migration, and cell adhesion. Although the function of Crk has been studied in considerable detail in cell culture, its biological role in vivo is still unclear, and no Crk-knockout mouse model has been available. Therefore, we generated a complete null allele of Crk in mice by using the Cre-loxP recombination approach. The majority of Crk-null mice die at late stages of embryonic development, and the remainder succumb shortly after birth. Embryos lacking both CrkI and CrkII exhibited edema, hemorrhage, and cardiac defects. Immunohistochemical examination suggested that defects in vascular smooth muscle caused dilation and rupturing of blood vessels. Problems in nasal development and cleft palate were also observed. These data indicate that Crk is involved in cardiac and craniofacial development and that it plays an essential role in maintaining vascular integrity during embryonic development.

PMID: 16880535 [PubMed - indexed for MEDLINE]

Health professionals' assessment of health-related quality of life values for oral clefting by age using a visual analogue scale method.

Cleft Palate Craniofac J. 2006 Jul;43(4):383-91

Authors: Wehby GL, Ohsfeldt RL, Murray JC

OBJECTIVE: To elicit health-related quality of life (HRQL) values associated with oral clefting by age using a visual analogue scale, and to explore the appropriateness of using health professionals as evaluators. METHODS: A representative group of health professionals working on craniofacial and/or cleft palate teams in the United States was sampled. Values (between 0 and 1) representing the HRQL associated with isolated and nonisolated oral clefting for infants, children, adolescents, and adults were obtained. The relationships between selected evaluator characteristics and values were also assessed. RESULTS: Of 330 professionals surveyed, 133 (40%) completed and returned reliable evaluations. Overall, HRQL values were clustered toward the right tail of the scale, indicating modest decreases in HRQL. Most evaluators reported feeling confident in completing the evaluations. HRQL values seemed to vary by team type (cleft palate only versus cleft palate/craniofacial care) and geographic location, but no major differences were found overall for any selected evaluator characteristics. CONCLUSIONS: This study provides HRQL values for oral clefting based on preferences of health professionals that may be useful in evaluating the effectiveness and cost-effectiveness of prevention and treatment strategies, including those carried out in clinical trial studies. The clustered pattern of HRQL values suggests either a consensus among evaluators of a limited burden of oral clefting or an overall lack of understanding of the evaluation task.

PMID: 16854194 [PubMed - indexed for MEDLINE]