Cleft lip with and without cleft palate in blacks: an analysis of 81 patients

The clinical records of 81 black patients with cleft lip with or without cleft palate were reviewed. Four had midline clefts. Of the remaining 77, 45 were unilateral (left 28, right 17), with 11 of these involving only the primary palate. Bilateral clefts were seen in 32, with only 2 involving just the primary palate. Males and females were approximately equal in number. Two were associated with EEC syndrome. Other congenital anomalies were seen in 9 patients. The family history was positive for clefts in 5 of 65 patients (7.7 percent). A review of 255 white patients with cleft lip with or without cleft palate revealed a positive family history in 94 (37 percent). The difference was statistically significant.     

Unilateral clefts: a new defect of the rat secondary palate

As shown in a previous study [Schüpbach et al, 1984], different types of total and partial clefts of the secondary palate can be produced through amniocentesis performed in Sprague-Dawley rats at day 16.2 of gestation. Among these were a small number of unilateral clefts that were examined in the scanning electron microscope and in Epon sections. The 410 treated amnions yielded a total of 395 viable fetuses. Total clefts occurred in 48.9% of viable fetuses examined at day 17.8 and in 21.8% of those examined at days 19.3. Partial clefts were observed in 14.1% and 18.5% of viable fetuses examined at days 17.8 and 19.3, respectively. Unilateral clefts were observed in 3.8-10.2% of the partial clefts and in 0.5-1.8% of all viable fetuses. The eight animals with unilateral clefting included fetuses with a total unilateral cleft in the anterior hard palate. Morphological observations suggested that under conditions of delayed palatal closure total unilateral clefts may be the result of initial elevation of one, and delayed elevation of the other, shelf and partial unilateral clefts probably represent the result of an incomplete retrograde closure.     

Facial clefts in Saudi Arabia: an epidemiologic analysis in 179 patients

One hundred and seventy-nine consecutive cases of facial clefts that were treated at the King Khalid University Hospital, in Riyadh, Saudi Arabia, were analyzed for an epidemiologic study. Isolated cleft lip was present in 38 percent, cleft of lip and palate in 37.4 percent, and cleft of the posterior palate in only 22.4 percent. There was a male preponderance in all types. In cases of cleft lip with or without cleft palate, the more commonly affected side was the left, followed by bilateral cases. Associated malformations were present in 13.4 percent. A positive family history was found in 26.8 percent of cases. A significant number of patients (7.8 percent) were first seen at more than 10 years of age. The incidence of facial clefts at this hospital was 0.3 per 1000 live births, computed over a period of 6 years. This incidence is significantly lower than that reported from European and Far Eastern countries.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population

Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population.     

Epidemiological and genetic study of 200 cases of oral cleft in the Emilia Romagna region of northern Italy

Epidemiological and genetic variables in clefts were analyzed during the years 1978-1986 in a case-control study of congenital malformations in the Emilia Romagna region of northern Italy. Among 150,168 newborns, 200 cases of cleft were detected, yielding a prevalence of 1.33 per 1,000. These clefts consisted of 112 (0.075%) cases of cleft lip with or without cleft palate (CL +/- P) and 88 cases (0.058%) of cleft palate (CP). Coexisting abnormalities were found in 32% of cases. The heritability coefficient of CL +/- P was 0.84. No cluster in time or space could be demonstrated. Epilepsy was the only maternal risk factor found to be correlated with clefts. A predominance of males was found among CL +/- P cases.     

Maternal fever during early pregnancy and the risk of oral clefts

An increased risk of birth defects after hyperthermic exposures has been confirmed in animal studies, but population studies have yielded inconsistent results. Oral clefts are a common birth defect and have been associated with these exposures in some of these studies. In this study, data from the National Birth Defects Prevention Study was used to evaluate the association of maternal report of febrile illness in early pregnancy and the risk of oral clefts. All oral cleft cases born between 1997 and 2004 were compared with nonmalformed controls born in the same geographical region during the same time period. Mothers reporting febrile illness during pregnancy were stratified by fever grade and antipyretic use. Logistic regression models were used to generate crude and adjusted odds ratios for exposure to fever and association with each oral cleft phenotype. The dataset included 5821 controls, 1567 cases of cleft lip with or without cleft palate (CL+/?P) and 835 cases of cleft palate only. A modestly increased risk was observed for isolated CL+/?P (odds ratio, 1.28; 95% confidence interval, 1.01–1.63). Stratification by fever grade (body temperature <101.5° or ≥101.5°F) did not yield significant differences in risk. Risk estimates were higher among women who reported a fever, but did not take antipyretics to control their fever, particularly for nonisolated compared with isolated oral clefts. This finding suggests that adequate control of fever may diminish the deleterious effects of fever in cases of oral cleft. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

The location of the ligand-binding site of carbohydrate-binding modules that have evolved from a common sequence is not conserved.

Polysaccharide-degrading enzymes are generally modular proteins that contain non-catalytic carbohydrate-binding modules (CBMs), which potentiate the activity of the catalytic module. CBMs have been grouped into sequence-based families, and three-dimensional structural data are available for half of these families. Clostridium thermocellum xylanase 11A is a modular enzyme that contains a CBM from family 6 (CBM6), for which no structural data are available. We have determined the crystal structure of this module to a resolution of 2.1 A. The protein is a beta-sandwich that contains two potential ligand-binding clefts designated cleft A and B. The CBM interacts primarily with xylan, and NMR spectroscopy coupled with site-directed mutagenesis identified cleft A, containing Trp-92, Tyr-34, and Asn-120, as the ligand-binding site. The overall fold of CBM6 is similar to proteins in CBM families 4 and 22, although surprisingly the ligand-binding site in CBM4 and CBM22 is equivalent to cleft B in CBM6. These structural data define a superfamily of CBMs, comprising CBM4, CBM6, and CBM22, and demonstrate that, although CBMs have evolved from a relatively small number of ancestors, the structural elements involved in ligand recognition have been assembled at different locations on the ancestral scaffold.     

Rare facial clefts: treatment during charity missions in developing countries

During 10 charity missions in developing countries, 14 patients of a total of 374 children with cleft lip and palate deformities were treated for rare facial clefts. There were three midline clefts (Tessier no. 0 cleft, n = 1; Tessier no. 14 cleft, n = 2), four oblique facial clefts (Tessier no. 3 cleft, n = 2; Tessier no. 5 cleft, n = 2), and seven lateral facial clefts (Tessier no. 7 cleft). Surgical treatment focused on cleft repair by soft-tissue reconstruction apart from two Tessier no. 14 clefts, in which the bony gap was also closed using bone grafts from the iliac crest. The postoperative course was uneventful except for one local wound infection that was treated successfully using oral antibiotics. This article summarizes the authors' experience with the surgical management of these malformations and considers the limitations under conditions of charity missions in developing countries. Furthermore, some rare forms of cleft formation are added to the existing literature.     

Dominant inheritance of cleft of the soft palate

Summary A family is described with apparent dominantly inantly inherited complete cleft of the soft palate. The complexity of the genetics of oral clefts is emphasized.The inheritance of oral clefts is complex. Different modes of inheritance have been reported for clefts both simple and in syndromes (Gorlin et al., 1971), but the majority of cases of nonsyndromal clefts appears to have a low, yet significant, genetic component (Fraser et al., 1974). This report describes a family with cleft of the soft palate which appears to follow a dominant pattern of inheritance. To our knowledge this in the first reported instance of dominantly inherited cleft palate.     

Application of high resolution SNP arrays in patients with congenital oral clefts in south China

Chromosome microarray analysis (CMA) has proven to be a powerful tool in postnatal patients with intellectual disabilities. However, the diagnostic capability of CMA in patients with congenital oral clefts remain mysterious. Here, we present our clinical experience in implementing whole-genome high-resolution SNP arrays to investigate 33 patients with syndromic and nonsyndromic oral clefts in whom standard karyotyping analyses showed normal karyotypes. We aim to identify the genomic aetiology and candidate genes in patients with congenital oral clefts. CMA revealed copy number variants (CNVs) in every patient, which ranged from 2 to 9 per sample. The size of detected CNVs varied from 100 to 3.2 Mb. In 33 patients, we identified six clinically significant CNVs. The incidence of clinically significant CNVs was 18.2% (6/33). Three of these six CNVs were detected in patients with nonsyndromic clefts, including one who presented with isolated cleft lip with cleft palate (CLP) and two with cleft palate only (CPO). The remaining three CNVs were detected in patients with syndromic clefts. However, no CNV was detected in patients with cleft lip only (CLO). The six clinically significant CNVs were as follows: 8p23.1 microduplication (198 kb); 10q22.2-q22.3 microdeletion (1766 kb); 18q12.3 microduplication (638 kb); 20p12.1 microdeletion (184 kb); 6q26 microdeletion (389 kb); and 22q11.21-q11.23 microdeletion (3163 kb). In addition, two novel candidate genes for oral clefts, KAT6B and MACROD2, were putatively identified. We also found a CNV of unknown clinical significance with a detection rate of 3.0% (1/33). Our results further support the notion that CNVs significantly contributed to the genetic aetiology of oral clefts and emphasize the efficacy of whole-genome high-resolution SNP arrays to detect novel candidate genes in patients with syndromic and nonsyndromic clefts.     

Identification of a mechanochemical checkpoint and negative feedback loop regulating branching morphogenesis

Cleft formation is the initial step in submandibular salivary gland (SMG) branching morphogenesis, and may result from localized actomyosin-mediated cellular contraction. Since ROCK regulates cytoskeletal contraction, we investigated the effects of ROCK inhibition on mouse SMG ex vivo organ cultures. Pharmacological inhibitors of ROCK, isoform-specific ROCK I but not ROCK II siRNAs, as well as inhibitors of myosin II activity stalled clefts at initiation. This finding implies the existence of a mechanochemical checkpoint regulating the transition of initiated clefts into progression-competent clefts. Downstream of the checkpoint, clefts are rendered competent through localized assembly of fibronectin promoted by ROCK I/myosin II. Cleft progression is primarily mediated by ROCK I/myosin II-stimulated cell proliferation with a contribution from cellular contraction. Furthermore, we demonstrate that FN assembly itself promotes epithelial proliferation and cleft progression in a ROCK-dependent manner. ROCK also stimulates a proliferation-independent negative feedback loop to prevent further cleft initiations. These results reveal that cleft initiation and progression are two physically and biochemically distinct processes.     

Recognition of cello-oligosaccharides by a family 17 carbohydrate-binding module: an X-ray crystallographic, thermodynamic and mutagenic study.

The crystal structure of the Clostridium cellulovorans carbohydrate-binding module (CBM) belonging to family 17 has been solved to 1.7 A resolution by multiple anomalous dispersion methods. CBM17 binds to non-crystalline cellulose and soluble beta-1,4-glucans, with a minimal binding requirement of cellotriose and optimal affinity for cellohexaose. The crystal structure of CBM17 complexed with cellotetraose solved at 2.0 A resolution revealed that binding occurs in a cleft on the surface of the molecule involving two tryptophan residues and several charged amino acids. Thermodynamic binding studies and alanine scanning mutagenesis in combination with the cellotetraose complex structure allowed the mapping of the CBM17 binding cleft. In contrast to the binding groove characteristic of family 4 CBMs, family 17 CBMs appear to have a very shallow binding cleft that may be more accessible to cellulose chains in non-crystalline cellulose than the deeper binding clefts of family 4 CBMs. The structural differences in these two modules may reflect non-overlapping binding niches on cellulose surfaces.     

Medical sequencing of candidate genes for nonsyndromic cleft lip and palate

Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Étude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.     

Tissue expansion in the reconstruction of Tessier craniofacial clefts: a series of 17 patients

Tessier craniofacial clefts are among the most surgically challenging examples of craniofacial dysmorphology. These clefts are characterized by hypoplasia of soft-tissue and skeletal elements throughout the three-dimensional extent of the cleft. Whereas bone grafting and craniofacial osteotomies have been successful toward correcting the underlying skeletal abnormalities, the ultimate success of these reconstructions has been limited by the deficiency of skin and soft tissue. This deficiency demands reconstruction ideally with tissue of like texture, consistency, and, especially in the face, color. Craniofacial tissue expansion was used toward reconstructing these facial clefts with like-quality tissue, allowing for tension-free reconstruction after osteotomy and bone grafting. Seventeen patients with Tessier craniofacial clefts underwent preoperative craniofacial soft-tissue expansion in the surgical management of their clefts. Tissue expansion was used in the primary correction of facial clefts in eight patients, with nine patients undergoing expansion before secondary surgery. In this series, tissue expansion has evolved as an important element in overcoming the skin and soft-tissue deficiency associated with these clefts, allowing for tension-free closure and improved aesthetic results in these surgically challenging patients.     

Midline cervical cleft

Midline cervical cleft is a rare congenital anomaly of the ventral neck. A series of 12 cases of midline cervical clefts over a 30-year period is reported. This anomaly is part of a spectrum of midline branchiogenic syndromes resulting from abnormal migration of cells derived from the branchial arches. The preferred operative correction requires complete excision of the cleft with its underlying fibrous cord and closure with multiple Z-plasties.     

Protein clefts in molecular recognition and function.

One of the primary factors determining how proteins interact with other molecules is the size of clefts in the protein's surface. In enzymes, for example, the active site is often characterized by a particularly large and deep cleft, while interactions between the molecules of a protein dimer tend to involve approximately planar surfaces. Here we present an analysis of how cleft volumes in proteins relate to their molecular interactions and functions. Three separate datasets are used, representing enzyme-ligand binding, protein-protein dimerization and antibody-antigen complexes. We find that, in single-chain enzymes, the ligand is bound in the largest cleft in over 83% of the proteins. Usually the largest cleft is considerably larger than the others, suggesting that size is a functional requirement. Thus, in many cases, the likely active sites of an enzyme can be identified using purely geometrical criteria alone. In other cases, where there is no predominantly large cleft, chemical interactions are required for pinpointing the correct location. In antibody-antigen interactions the antibody usually presents a large cleft for antigen binding. In contrast, protein-protein interactions in homodimers are characterized by approximately planar interfaces with several clefts involved. However, the largest cleft in each subunit still tends to be involved.     

Maternal multivitamin use and orofacial clefts in offspring

BACKGROUND: Cleft lip with or without cleft palate (CLP) and cleft palate alone (CP) affect approximately 1 in 1000 infants and 1 in 2,500 infants, respectively. Studies of the relation between orofacial clefts and multivitamins or folic acid have been inconsistent. METHODS: We used data from a population-based case-control study involving 309 nonsyndromic cleft-affected births (222 with CLP, 87 with CP) and 3,029 control births from 1968 to 1980 to evaluate the relation between regular multivitamin use and the birth prevalence of orofacial clefts. RESULTS: We found a 48% risk reduction for CLP (odds ratio = 0.52, 95% confidence interval = 0.34-0.80) among mothers who used multivitamins during the periconceptional period or who started multivitamin use during the first postconceptional month, after controlling for several covariates. The risk reduction for CP was less than those for CLP (odds ratio = 0.81, 95% confidence interval = 0.44-1.52); however, a small number of CP cases limited interpretation. No risk reductions for CLP or CP were found for women who began multivitamin use in the second or third month after conception. CONCLUSIONS: The magnitude of the risk reduction in our study is comparable to those of other recent studies; our study does not support the contention that only large dosages of folic acid are needed to prevent orofacial clefts. More studies are needed to test the effects of multivitamins and varying dosages of folic acid on the recurrence and/or occurrence of orofacial clefts to provide information needed to determine possible prevention strategies. Published 2001 Wiley-Liss, Inc.     

Birth order and oral clefts: a meta analysis

BACKGROUND: There is evidence that late birth order is associated with some complex disorders. For orofacial clefts there is no consensus as to whether increased birth order is associated or not. A meta-analysis of published data on cleft lip or cleft palate (CL/P and CP) was carried out to ascertain whether there is an increased risk for children of high birth order to have an oral cleft. METHODS: All data available with information regarding the frequency of live births and CL/P and CP cases by birth order (1, 2, 3, and 4 or more) were included in the analysis, and the birth order category "1" was considered to be with no risk (OR = 1.0). RESULTS: Children with higher birth order are more likely to have CL/P and CP with odds ratios increasing with birth order to a peak of 3.0 in children birth order "4 or more." Results are not different when isolated and syndromic cases are combined. CONCLUSIONS: CL/P and CP occurrence is correlated with increasing birth order. Further studies, taking into consideration sample size and factors such as income status, race, paternal age, vitamin intake, and social habits, should be done to determine conclusively the association between birth order and oral clefts.