Familial recurrence-pattern analysis of cleft lip with or without cleft palate.

Cleft lip with or without cleft palate (CL/P) is a common congenital malformation with an incidence in European white populations of about 1/1,000. The familial clustering of CL/P has been extensively characterized, and epidemiological studies have proposed monogenic models (with reduced penetrance), multifactorial/threshold models, and mixed major-gene/multifactorial models to explain its inheritance. The recognition of an association between two RFLPs at the transforming growth factor alpha (TGFA) locus and CL/P supports a major-gene component to the etiology of CL/P. Risch has shown that the recurrence risk ratio lambda R (risk to relatives, vs. population prevalence) is a useful pointer to the mode of inheritance. Here we further develop the use of lambda R to analyze recurrence-risk data for CL/P. Recurrence risks for first-, second-, and third-degree relatives equate well with oligogenic models with as few as four loci. A monogenic/additive model is strongly rejected. The limited available twin data are also consistent with this model. A "major gene" interacting epistatically with an oligogenic background is shown to be a plausible alternative. Power calculations for a linkage study to map the CL/P major-risk locus suggest that a sample of 50 affected sib pairs will be adequate, but linkage to minor-risk loci will require very much larger samples.     

Birth prevalence of cleft lip and palate in British Columbia between 1952 and 1986: stability of rates.

We examined the birth prevalence of cleft lip with or without cleft palate and of isolated cleft palate in British Columbia between 1952 and 1986 using the data of the BC Health Surveillance Registry. The rates fluctuated over the study period, but linear trend analysis showed no increase or decrease for cleft lip with or without cleft palate; however, there was a significant increase for isolated cleft palate, attributed to improved ascertainment around 1963-66. Given the possible effects of newer agents used in both silviculture and agriculture, as well as the general concern over drugs and other environmental agents, such a long-term monitoring program is important. Furthermore, if significant clustering occurs, good background data are essential for comparison. The general public''s perception is that the rates of birth defects are increasing. Our findings should give some reassurance with respect to orofacial clefts.     

A prospective evaluation of the prevalence of submucous cleft palate in patients with isolated cleft lip versus controls.

Although there is an established relationship between cleft lip and overt cleft palate, the relationship between isolated cleft lip and submucous cleft palate has not been investigated. To test the hypothesis that patients with isolated cleft lip have a greater association with submucous cleft palate, a double-armed prospective trial was designed. A study group of 25 consecutive children presenting with an isolated cleft lip, with or without extension through the alveolus but not involving the secondary palate, was compared with a control group of 25 children with no known facial clefts. Eligible patients were examined for the presence of physical criteria associated with classic submucous cleft palate, namely, (1) bifid uvula, (2) absence of the posterior nasal spine, and (3) zona pellucida. Nasoendoscopy was subsequently performed just after induction of general anesthesia, and the findings were correlated with digital palpation of the palatal muscles. Patients who did not satisfy all three physical criteria and in whom nasoendoscopy was distinctly abnormal relative to the control group were classified as having occult submucous cleft palate. Classic submucous cleft palate was found in three study group patients (12 percent), all of whom had flattening or a midline depression of the posterior palate and musculus uvulae on nasoendoscopy and palpable diastasis of the palatal muscles under general anesthesia. An additional six study group patients (24 percent) had similar nasoendoscopic criteria and palpable diastasis of the palatal muscles; they were classified as having occult submucous cleft palate. No submucous cleft palate was identified in the control group. Seventeen patients in the study group had an alveolar cleft with a 53 percent (9 of 17) prevalence of submucous cleft palate. In the present study, classic submucous cleft palate in association with isolated cleft lip was 150 to 600 times the reported prevalence in the general population. All children with an isolated cleft lip should undergo peroral examination and speech/resonance assessment no later than the age of 3 years. Any child with an isolated cleft lip with velopharyngeal inadequacy or before an adenoidectomy should be assessed by flexible nasal endoscopy to avoid missing an occult submucous cleft palate.     

Genetics of susceptibility to 6-aminonicotinamide-induced cleft palate in the mouse: studies in congenic and recombinant inbred strains

In a search for genetic differences in susceptibility to cleft palate, congenic and recombinant inbred strains of mice were treated with 6-aminonicotinamide or control injections. Of six loci tested, only the chromosome segment marked by N-acetyl transferase was found to affect susceptibility to 6-aminonicotinamide-induced cleft palate. This chromosome segment is known to affect glucocorticoid-induced cleft palate and phenytoin-induced cleft lip with or without cleft palate in these strains of mice.     

National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001

BACKGROUND: In the United States, birth defects affect approximately 3% of all births, are a leading cause of infant mortality, and contribute substantially to childhood morbidity. METHODS: Population-based data from the National Birth Defects Prevention Network were combined to estimate the prevalence of 21 selected defects for 1999-2001, stratified by surveillance system type. National prevalence was estimated for each defect by pooling data from 11 states with active case-finding, and adjusting for the racial/ethnic distribution of US live births. We also assessed racial/ethnic variation of the selected birth defects. RESULTS: National birth defect prevalence estimates ranged from 0.82 per 10,000 live births for truncus arteriosus to 13.65 per 10,000 live births for Down syndrome. Compared with infants of non-Hispanic (NH) white mothers, infants of NH black mothers had a significantly higher birth prevalence of tetralogy of Fallot, lower limb reduction defects, and trisomy 18, and a significantly lower birth prevalence of cleft palate, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, gastroschisis, and Down syndrome. Infants of Hispanic mothers, compared with infants of NH white mothers, had a significantly higher birth prevalence of anencephalus, spina bifida, encephalocele, gastroschisis, and Down syndrome, and a significantly lower birth prevalence of tetralogy of Fallot, hypoplastic left heart syndrome, cleft palate without cleft lip, and esophageal atresia/tracheoesophageal fistula. CONCLUSIONS: This study can be used to evaluate individual state surveillance data, and to help plan for public health care and educational needs. It also provides valuable data on racial/ethnic patterns of selected major birth defects.     

Recurrent cleft lip and palate in siblings of a patient with malabsorption syndrome, probably caused by hypovitaminosis a associated with folic acid and vitamin B(2) deficiencies

We present a woman with metabolic disorders secondary to malabsorption and renal disease who gave birth to a stillborn male fetus with left unilateral cleft lip and palate and a live born infant with left unilateral cleft lip and palate. We discuss potential cofactors that could be implicated in the abnormal embryonic process.     

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.     

Cleft palate: more genetic lessons from mice

Cleft palate occurred in high frequency (14%) in the F2 generation of the cross between two stocks of mice, LGG and SELH, neither of which produces more than 2% cleft palate. The cleft palate trait results from a new combination of alleles that is not present in either parental stock. The lack of cleft palate in the F2 generation after outcrosses of both parental stocks to other strains shows that this new combination of alleles has specific contributions from both parental strains, and also that there must be at least two loci involved. A deficiency of Mod-1 homozygotes in the SELH/LGG F2 adults suggests that one of the loci involved may be linked to Mod-1 and that the number of loci involved is few. Significantly more F2 males (19%) than females (9%) were affected with cleft palate. The data can be explained by a two-locus epistatic model with a dominant mutation (P) at one locus that causes cleft palate when not suppressed by or compensated for by a dominant allele (S) at a second locus. The parental stocks would be PPSS and ppss. In the F2 generation, the new combinations PPss and Ppss would express cleft palate, a total expected of 19%. Similar new combinations of alleles at two loci may explain some instances of high occurrence of cleft palate or other developmental threshold traits in previously unaffected human families.     

Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives

Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology.Design Population based cohort study.Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period.Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft.Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts.Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The “crossover” risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence.Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation.     

Increased head circumference and facial cleft as presenting signs of the nevoid basal-cell carcinoma syndrome.

We report a child with nevoid basal-cell carcinoma syndrome (NBCCS) who showed an enlarged head circumference and cleft lip/cleft palate as sole signs of this syndrome at birth. Careful follow up and re-evaluation of this patient enabled us to diagnose the syndrome. Moreover, inspection of her father and sister indicated that they were also affected. An updated review of reported cases indicates that facial cleft occurs in approximately 5% of NBCCS patients. Various aspects of the disease and general measures for its monitoring and treatment are briefly discussed.     

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.     

Mitochondrial DNA origins of the Latvian clefting population

Latvia has one of the highest prevalence of isolated cleft lip with or without cleft palate (CL/P) in Europe. To clarify the genetic origins of the Latvian cleft population and establish a method for genetic mapping, mitochondrial DNA variation was studied in a population affected with clefting. One-hundred and seven subjects and 351 samples from unrelated healthy volunteers representing four anthropologically, archaeologically and ethno-linguistically different regions of Latvia were selected. The case group showed a higher frequency of haplogroups U4 (p=0.02) and U5 (p=0.0003) than in non-U haplogroups. We hypothesize that U4 and U5 mtDNA haplotype carriers may also carry susceptibility genes for clefts. Future studies will take into consideration these definitions based on mtDNA haplotypes when analyzing genetic variations and their possible contribution to CL/P susceptibility.     

van der Woude syndrome in two families in China

We report on two unrelated families from the Beijing area in which the autosomal dominant gene for van der Woude syndrome (VWS) is segregating. The clinical features include paramedian lower lip pits (fistula labii inferioris congenita), cleft palate, and cleft lip with or without cleft palate. All three of the clinical features may occur together in an affected individual, or any two together, or any one as a single feature of an individual who carries the gene. The probands in each of our families also have ankyloglossia. This is the first report of VWS from China.     

Genetic approaches to identify disease genes for birth defects with cleft lip/palate as a model

BACKGROUND: Understanding the etiology of birth defects is an important step toward developing improved treatment and preventive strategies. Most birth defects have an underlying genetic basis, ranging from single genes playing dominant or recessive roles in Mendelian disorders to a mixture of contributions from multiple genes and environmental triggers in complex traits. The purpose of this article is to provide an overview of genetic approaches to identifying disease genes for genetically complex birth defects. METHODS: A review of the literature describing successes and limitations for identifying disease genes for complex traits was conducted. RESULTS: Cleft lip and cleft palate are common congenital anomalies with significant medical, psychological, social, and economic ramifications. The Online Mendelian Inheritance in Man catalog (OMIM; http://www3.ncbi.nlm.nih.gov/Omim) lists more than 400 single-gene causes of clefts of the lip and/or palate. Genetic causes of clefting also include chromosomal rearrangements, genetic susceptibility to teratogenic exposures, and complex genetic contributions of multiple genes. CONCLUSIONS: Genetic causes of birth defects can be identified using an increasingly powerful combination of careful sample collection, molecular analytic methods, and statistical evaluations. We will describe a range of approaches to search for genetic factors of birth defects and use our own work with cleft lip and palate as a model.     

唇瘘、腭裂及唇裂综合征两个家系的遗传分析

我们在此报道北京地区没有亲缘关系的两个家庭中属于van der woude综合征的常染色体显性遗传病,其临床症状包括下唇近中线处唇瘘(下唇有先天性向下的瘘管)、腭裂、唇裂(具有或不具有腭裂)。这三个临床症状可以同时发生在一个受累个体身上,或任何两个症状出现在一个个体身上。这种人携带了这种致病基因。在我们所报道的家庭中,先证者每人还具有舌系带过短的体征。     

Effect of low and chronic radiation exposure: a case-control study of mental retardation and cleft lip/palate in the monazite-bearing coastal areas of southern Kerala

A population-based 1:3 age-matched case-control study was conducted during 2006-2009 to assess the role of high-level natural radiation (>1 mSv/year) on congenital mental retardation and cleft lip/palate in the southwest coastal area of Kerala. Dosimetry was carried out in the house where parents resided during conception and the subsequent two trimesters of pregnancy of the study subject. Conditional logistic regression did not suggest any statistically significant association of either mental retardation (n = 445) or cleft lip/palate (n = 116) with high-level natural radiation. The odds of mental retardation and cleft lip/palate among those exposed to high-level natural radiation relative to normal levels of natural background radiation (≤1 mSv/year) were 1.26 (95% CI: 0.91-1.73) and 0.56 (95% CI: 0.31-1.02), respectively, after controlling for gender and maternal age at birth of the study subject. The data did not suggest any dose-related trend in the risk of either mental retardation (P = 0.113) or cleft lip/palate (P = 0.908). Notwithstanding the use of a single dose estimate to reconstruct past radiation exposure and the complex etiology of congenital malformations, it may reasonably be concluded that the prevailing high-level natural radiation in the study area does not appear to increase the risk of either mental retardation or cleft lip/palate among offspring of parents staying in the area.     

General body growth in children with cleft palate and related disorders: age differences

Clefts of the lip and palate, separately or in combination, are among the most frequent congenital defects seen today. Their etiology is heterogeneous and may include hormonal factors, which suggest the possibility of growth effects. Whether affected children are smaller than others has not been determined. We recently showed that growth status is associated with type of cleft. We hypothesized genetic alterations in metabolic pathways that alter prenatal growth, producing clefts; some of these alterations also alter postnatal growth. Since the levels of growth-regulating hormones change during ontogeny, we expected age differences in the degree of growth deficit seen. To test this hypothesis, we examine here the cross-sectional means and distributions of standard deviation (z) scores for height and body mass indices (BMIs) for 144 children with the diagnoses unilateral cleft lip and palate (uCLP) and isolated cleft palate (iCP). We find that alteration in growth status is associated with age group as well as sex and diagnosis.     

Genetics of nonsyndromic cleft lip with or without cleft palate: is there a Mendelian sub-entity?

The mode of inheritance of nonsyndromic cleft lip with or without cleft palate (NSCLP) is still a matter of dispute. We performed segregation analysis on three data sets of families ascertained through an affected child with NSCLP. The first two data sets were selected in France and were pooled for a global analysis. No major gene effect could be evidenced in spite of a very large number of families (666 pedigrees including 719 nuclear families). The third data set was British and consisted of three-generation families including the offspring of probands. A major gene effect, as well as a strong residual multifactorial component, were highly significant and we could show that this evidence almost entirely came from the information on probands' offspring. We conclude that a mixture of monogenic and of multifactorial cases is probably the best explanation for the observations made in this study. Analyses performed in pedigrees with multiple cases closely related might allow reducing heterogeneity and help identifying those Mendelian sub-entities.