Facial clefts in the west of Scotland in the period 1980-1984: epidemiology and genetic diagnoses.

Two hundred and eighty six cases of cleft lip, cleft palate, or both were identified in a study attempting complete ascertainment of babies with facial clefts born to women resident in the west of Scotland in a five year period beginning 1 January 1980. The total birth prevalence (TBP) of these defects over this period was 1.53 per 1000. The TBP for cleft lip with or without cleft palate (CL[P] was 0.74 per 1000 and for cleft palate (CP) was 0.79 per 1000; 26% of CL[P] and 39.5% of CP cases had one or more major congenital anomaly associated with their facial cleft and in over half of these cases a specific genetic or syndrome diagnosis could be made. In comparison to previous European reports this study shows a high incidence of associated abnormalities and a remarkably low ratio of CL[P]:CP cases.     

Congenital malformations in births with orofacial clefts among 3.6 million California births, 1983-1997

Few population-based epidemiologic data are available on malformation phenotypes that co-occur with orofacial clefts. We explored the occurrence of structural congenital malformations in offspring with cleft palate (CP) and in offspring with cleft lip with or without CP (CLP), using data from a population-based active surveillance system. Ascertainment was performed among 3548991 liveborn and 23239 stillborn offspring of California women who delivered in nonmilitary hospitals during the period, 1983-1997. Structural congenital malformations were found in 91888 births. Among them, 2343 had CP and 4072 had CLP. Malformations were grouped according to 3- and 4-digit codes of the British Pediatric Association (BPA). Prevalences of each malformation grouping, defined by these codes, were calculated among: (1). all births with CP; (2). all births with CLP; (3). all births without CP or CLP but with another structural malformation; and (4). all births in the population at risk. These various prevalence measures were the basis of estimating relative risks. Observed relative risks indicated that some phenotypes were more likely and some were less likely to co-occur with either CP or CLP, with relative risks ranging from 0.5 to 2.4. For both CP and CLP, estimated relative risks were highest for malformations involving the respiratory system and lowest for spina bifida. The exclusion of all births (n = 10702) with chromosomal anomalies from comparisons did not materially alter observed relative risk estimates. Computations extended to 4-digit level BPA codes revealed elevated risks for a number of more specific diagnoses seen within the larger (3-digit level) groupings defined as eye, ear, respiratory, upper alimentary tract, and other musculoskeletal anomalies. In this large population-based cohort of infants and fetuses with CLP or CP, we observed several noncleft malformation groupings to be more common and others to be less common in their co-occurrence with orofacial clefts relative to their co-occurrence with any other malformation. These observed patterns tended to be similar for CP and for CLP.     

Face-to-Face Interaction Between Infants with Orofacial Clefts and Their Mother

Compared mother-infant face-to-face (en face) interaction among3-month-old infants with cleft lip and palate (CLP), infantswith isolated cleft palate (CP), or nonimpaired infants (NI).The Monadic Phase system (Tronick, Als, & Brazelton, 1980)was used to describe patterns of laboratory en face interactionin 116 mother-infant dyads. Diagnostic group comparisons ofpercentages of monadic phases and infant-mother monadic phasesequences revealed more similarities than differences. However,CP group mothers appeared less involved in en face interactionthan mothers in the CLP group. Low maternal involvement in thecombined cleft groups was predicted by concurrent measures ofinfant characteristics including infant negative reactivity,whereas low maternal involvement in the comparison group waspredicted by maternal characteristics including low psychologicaldistress. There was little evidence to suggest that anomalousfacial appearance is a significant factor influencing the qualityof early mother-infant interaction. Assessing other characteristicsof the infant and the broader social context is also important.     

Epidemiological and genetic study in 207 cases of oral clefts in Alsace, north-eastern France.

The epidemiology of oral clefts was studied in the geographical area covered by our registry of congenital malformations. For each of the 207 new cases studied during the period 1979 to 1987, more than 50 factors were compared in probands and controls. The incidence of oral clefts was 1.75 per 1000, with cleft lip/palate (CL(P] 0.98 and cleft palate only (CP) 0.77 per 1000. A total of 8.2% of cleft cases were stillbirths and 5.3% were induced abortions. The more common types of associated malformations in the 76 affected cases (36.7%) with at least one anomaly other than oral cleft were neural tube defects and skeletal malformations. At birth, infants with oral clefts and other malformations were smaller, weighed less, and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with oral clefts were more often complicated by threatened abortion, polyhydramnios, and arterial hypertension. There was a significant association between clefting and consanguinity; heritability of CL(P) was 81% and first degree relatives of probands had more than three times the prevalence of noncleft malformations as controls. These results are of relevance to genetic counselling.     

Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non-syndromic, which refers to etiology.     

Fetal mortality in oral cleft families (IX): factors relating to the occurrence of sporadic clefts

Pedigree data on 854 probands with cleft lip and/or cleft palate from the State of Indiana are presented. These include 123 probands with cleft lip alone (CL), 453 with cleft lip and palate (CLP), and 278 with isolated cleft palate (CP). Probands and families were interviewed at the Indiana University Medical Center during the years 1962–1980. Among features of special interest are an excess of bilateral CLP (46% of all CLP cases) and a significantly greater number of older mothers and fathers (over 34 years old) than in the general population. An apparent increase in the proportion of sporadic cases with time may be due to bias in ascertainment.
It is suggested that the increased proportions of more severe clefts and older parents are among several factors which contribute to the incidence of fetal mortality in a cleft population. The association of fetal mortality with liability to clefting introduces a more precise way to define a sporadic cleft. That is, a truly sporadic cleft is one conceived as a single occurrence event and has survived to become a liveborn cleft child whereas other apparently sporadic cleft individuals represent the surviving cleft in a sibship in which fetal mortality has eliminated all other cleft offspring already conceived.
This observation has applications to the collection and interpretation of genetic pedigree data for clefts as well as many other genetic conditions.     

Taking it to the max: the genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology

The rapid proliferative expansion and complex morphogenetic events that coordinate the development of the face underpin the sensitivity of this structure to genetic and environmental insult and provide an explanation for the high incidence of midfacial malformation. Most notable of these malformations is cleft lip with or without cleft palate (CLP) that, with an incidence of between one in 600 and one in 1000 live births, is the fourth most common congenital disorder in humans. Despite the obvious global impact of the disorder and some recent progress in identifying causative genes for some prominent syndromal forms, our knowledge of the key genetic factors contributing to the more common isolated cases of CLP is still remarkably patchy. The current understanding of the molecular and cellular processes that orchestrate morphogenesis of the midface, with emphasis on events leading to fusion of the lip and primary palate, is detailed in this review. The roles of crucial factors identified from relevant animal model systems, including BMP4 and SHH, and the likely events perturbed by key genes pinpointed in human studies [such as PVRL1, IRF6p63, MID1, MSX1, and PTCH1] are discussed in this light. New candidates for human CLP genes are also proposed.     

Facial clefting in an Arab town in Israel

To study the prevalence of cleft palate and cleft lip with or without cleft palate in an Israeli Arab town, questionnaires were sent to the parents of 1375 pupils in grades 1 and 2 in all seven primary schools in the town of Taibe, and 1281 responded. The information requested included data about siblings and members of the parental generation to give a total of 16 174, and the presence of consanguinity and history of exposure to medication, radiation, smoking or alcohol during pregnancy. There were four affected individuals among the index cases, of whom two had cleft palate only and two cleft lip with cleft palate, giving prevalence rates for each of these of 1.56/1000. Adding to these the number of affected siblings gave a total of 10 affected individuals; two with cleft palate only (0.39/1000) and eight with cleft lip with or without cleft palate (1.56/1000). Among the parental generation, of 16 reported affected individuals, two had cleft palate only (0.18/1000) and 14 cleft lip with or without cleft palate (1.26/1000). The overall prevalence rate for all 26 affected individuals was 1.6/1000; four of these had cleft palate only (0.24/1000) and 22 had cleft lip with or without cleft palate (1.36/1000). There were no cases whose mothers had been exposed to medication, radiation, smoking or alcohol during pregnancy. The effect of consanguinity was not significant (P < 0.92). This study shows that the prevalence of facial clefting in an Israeli Arab community is consistent with that in the general population worldwide.     

Associated anomalies in multi-malformed infants with cleft lip and palate: An epidemiologic study of nearly 6 million births in 23 EUROCAT registries

We studied 5,449 cases of cleft lip (CL) with or without cleft palate (CL/P) identified between 1980 and 2000 from the EUROCAT network of 23 registers (nearly 6 million births) in 14 European countries. We investigated specific types of defects associated with clefts. Among CL/P cases (prevalence = 9.1 per 10,000), 1,996 (36.6%) affected only the lip (CL) and 3,453 (63.4%) involved CL and palate (CLP). A total of 3,860 CL/P cases (70.8%) occurred as isolated anomalies and 1,589 (29.2%) were associated with other defects such as multiple congenital anomalies of unknown origin (970), chromosomal (455) and recognized syndromes (164). Associated malformations were more frequent in infants who had CLP (34.0%) than in infants with CL only (20.8%). Among multi-malformed infants, 2 unrelated anomalies were found in 351 cases, 3 in 242 cases, and 4 or more in 377 cases. Among 5,449 CL/P cases, 4,719 were live births (LB) (86.6%), 203 stillbirths (SB) (3.7%), while 508 (9.3%) were terminations of pregnancy (ToP). CL/P occurred significantly more frequently in males (M/F = 1.70), especially among total isolated cases (M/F = 1.87) and CLP isolated cases (M/F = 1.92). The study confirmed that musculoskeletal, cardiovascular, and central nervous system defects are frequently associated with CL/P. An association with reduction anomalies of the brain was found. This association suggests that clinicians should seek to identify structural brain anomalies in these patients with CL/P as the potential functional consequences may be important for rehabilitation and clinical management.     

Cognitive and psychomotor development of infants with orofacial clefts

OBJECTIVE: To compare at ages 3, 12, and 24 months the cognitive and psychomotor development of 29 infants with cleft lip and palate (CLP), 28 infants with cleft palate only (CPO), and a demographically matched comparison (COMP) group of 69 infants; to examine predictors of cognitive status at age 24 months in the cleft group. METHODS: Infants were administered the Bayley Scales of Infant Development (BSID), mother-infant interactions were observed, and medical records were reviewed. RESULTS: CLP and CPO groups scored lower than the COMP group on the BSID, but did not differ from one another. Cleft group infants scored lower than COMP group infants on BSID items assessing nonverbal and expressive language skills. Quality of maternal interaction predicted the 2-year Mental Development Index (MDI) scores of infants with clefts. CONCLUSIONS: Infants with clefts show relative deficits in cognitive and psychomotor development. Cognitive deficits are apparent in nonverbal as well as verbal areas of performance.     

Complete cleft lip and palate without bone grafting and its effect on craniofacial morphology in three planes

The aim of the study was to analyze the morphology of the viscerocranium in patients with unilatertal or bilateral cleft lip and palate (CLP) who had undergone no surgical intervention of the alveolous meaning that no bone grafting was conducted. In this cross-sectional study 47 patients with complete unilateral (UCLP) or bilateral clefts (BCLP) were examined, and compared to a group of 42 patients without facial clefts. Each group was subdivided into two age groups (ca. 8 and ca. 15 years) approximately before and after the pubertal growth maximum. All patients with CLP received a complete palate closure by means of velopharyngoplasty at age of three, without any alveolar ridge osteoplasty. The craniofacial morphology of all patients was analysed in three planes (sagittal, coronal, horizontal) with help of model analysis and cephalometric analysis. The craniofacial morphology of all groups of CLP patient differed from that of the control groups. On average, more markedly impaired growth was observed in the older age group. Moderate retrognathic maxilla and slight mandible, a coronal skeletal excess, and a remarkable retrusion of the upper and lower anterior teeth were characteristic. Horizontal restriction of width could only be identified in the region of maxillary canines. CLP patients who had no bone grafting showed that the craniofacial developmental impairment was reasonably slight compared to patients without CLP, although it became more pronounced in the older age groups.     

ICD‐10 impact on ascertainment and accuracy of oral cleft cases as recorded by the Brazilian national live birth information system

We compared Brazilian oral cleft (OC) frequencies between the population‐based Brazilian System of Live Birth (SINASC) and the hospital‐based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD‐10) for congenital defects coding, ECLAMC uses ICD‐8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7–1.8), cleft lip (CL) 1.6 (1.5–1.7), and cleft palate (CP) 2.0 (1.9–2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0–12.1), CL 5.5 (4.5–6.7), and CP 4.4. (4.5–6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital‐based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD‐10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD‐10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD‐10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD‐10 coding system, and must be adjusted, given its relevance worldwide.

     

Complete trisomy 9 in two liveborn infants.

Two unrelated newborn infants with multiple malformations were found to have complete trisomy 9 in all cells examined. In both, the phenotype was similar, consisting of characteristic facial appearance (microphthalmia, bulbous nose, micrognathia, cleft palate, low set ears), skeletal abnormalities (dislocated joints, flexion contractures of the fingers), cardiovascular malformations (persistent left superior vena cava, ventricular septal defect), hypoplastic genitalia, renal anomalies, and central nervous system malformations. Both died during the first few hours of life. Comparison of these two infants with the previously reported cases reveals a consistent pattern of malformations and very short survival associated with trisomy 9. These cases illustrate the importance of doing chromosome studies on infants with congenital malformations dying in the newborn period and the usefulness of such studies in counselling parents regarding the risk of recurrence.     

Brief Report: Cleft Lip and Palate: Longitudinal Behavior and Relationships of Cleft Conditions to Behavior and Achievement

Analyzed longitudinal behavior ratings (ANOVAs) for 44 children(ages4–12)with cleft lip and palate and cleft palate only (CLP) and examinedthe relationship of speech, hearing, and facial disfigurementat age 9 in predicting behavioral characteristics and schoolachievement (multiple regression). Results indicate increasinglevels of social inhibition over age for girls with CLP, butless so for boys. There were also increasing levels of conductproblems for older girls with CLP with variable age fluctuationfor boys. Attempts to relate speech, hearing, or facial disfigurementto prediction of behavior or achievement at age 9 were not revealingand further analysis with larger samples is indicated.     

Classification and birth prevalence of orofacial clefts

To determine the proportion and birth prevalence of “typical” orofacial clefts (cleft lip (CL), cleft palate (CP), cleft lip and palate (CLP)) and “atypical” clefts (median, transversal, or oblique facial clefts) and the conditions in which they occur, we analyzed a population-based sample of 4,433 cases ascertained from 2,509,881 California births. We classified cases into: isolated cleft anomalies, sequences of the primary defect, chromosomal aberrations, monogenic syndromes, results of known teratogens, associations, multiple congenital anomaly (MCA) of unknown etiology, or conjoined twins. The birth prevalence of isolated CL±P was 0.77 per 1,000 births (CL 0.29/1,000, CLP 0.48/1,000) and of isolated CP, 0.31 per 1,000 births. Non-Hispanic Whites had the greatest prevalence of isolated clefts, Asians slightly lower prevalences, and Blacks the lowest. Asians had the lowest prevalence of Robin sequence and non-Hispanic Whites the highest, twice that of Hispanics. Hispanics, followed by Asians, had the highest prevalence of CL±P with MCA; non-Hispanic Whites had the lowest. Asians had the lowest prevalence of CP; in Whites and Hispanics it was almost twice as high. Blacks had the highest CL:CLP ratio, followed by non-Hispanic Whites and Asians; Hispanics had the lowest. Isolated anomalies constituted 61.67% of clefts. In the total sample there were 3.9% sequences, 8.79% chromosomal aberrations, 6.02% monogenic syndromes, 0.2% known teratogens, 0.79% associations, 18.55% MCA of unknown etiology, and 0.1% in conjoined twins. This study supports evaluation of each child on a “case” level, and provides a framework for genetic counseling and other studies focused on causes and prevention of these serious anomalies. Am. J. Med. Genet. 75:126–137, 1998. © 1998 Wiley-Liss, Inc.     

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

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.     

Clustering of malformations in the families of South American oral cleft neonates.

The relatives of 741 newborn children with non-syndromic cleft lip with or without cleft palate (CL +/- P), of 115 with isolated cleft palate (CP), and of equal numbers of appropriate controls were screened for the presence of the same or different malformations. The main findings were as follows. (1) The frequency of familial cases of CL +/- P (17.3%) was much higher than the prevalence of this malformation among the relatives of controls (0.5%). (2) The sibs of CL +/- P subjects showed a higher prevalence of this condition than their parents (2.9% v 1.6%). (3) The degree of genetic determination of this condition should be high (70 to 74%), and the data in general favour a multifactorial model of inheritance, with different thresholds between sexes. However, the action of dominant genes cannot be excluded since selection or dominant genes or both could be postulated to explain the parent/sib difference. (4) The frequency of other malformations was also significantly raised in the families of CL +/- P probands, as compared to controls (12.1% v 6.2%). (5) The prevalence of these other malformations was higher among sibs (1.6%) than parents (0.7%) of CL +/- P babies. (6) A general susceptibility to malformations and different exposure to selective agents may explain these latter findings. (7) None of the comparisons involving CP children yielded significant results.     

Phenotypic overlap of the BBB and G syndromes.

Three males with similar malformations including hypertelorism, telecanthus, cleft lip and palate, and hypospadias, have been evaluated. One also had a laryngotracheoesophageal cleft and therefore was considered to have the G syndrome. The other two had no stridor, aspiration, or difficulty swallowing, and were considered to have the BBB syndrome. Both disorders are associated with multiple malformations and can be most readily distinguished by the presence of laryngoesophageal abnormalities in the G syndrome and differences in facial features evident later in childhood. The BBB syndrome appears to be inherited as an X-linked disorder with the affected female showing only telecanthus and hypertelorism. The G syndrome exhibits autosomal dominant inheritance with males more severely affected, although a few few females have had serious malformations in addition to telecanthus and hypertelorism. In the family with the G syndrome evaluated for this report, the mother of the affected infant had telecanthus, hypertelorism, and anosmia, the latter a feature not previously noted in this disorder.     

Phenotypic overlap of the BBB and G syndromes

Three males with similar malformations including hypertelorism, telecanthus, cleft lip and palate, and hypospadias, have been evaluated. One also had a laryngotracheoesophageal cleft and therefore was considered to have the G syndrome. The other two had no stridor, aspiration, or difficulty swallowing, and were considered to have the BBB syndrome. Both disorders are associated with multiple malformations and can be most readily distinguished by the presence of laryngoesophageal abnormalities in the G syndrome and differences in facial features evident later in childhood. The BBB syndrome appears to be inherited as an X-linked disorder with the affected female showing only telecanthus and hypertelorism. The G syndrome exhibits autosomal dominant inheritance with males more severely affected, although a few few females have had serious malformations in addition to telecanthus and hypertelorism. In the family with the G syndrome evaluated for this report, the mother of the affected infant had telecanthus, hypertelorism, and anosmia, the latter a feature not previously noted in this disorder.     

Misclassification risk of patients with bilateral cleft lip and palate and manifestations of median facial dysplasia: A new variant of del(22q11.2) syndrome?

The generic term median facial dysplasia (MFD) describes a subgroup of patients with cleft lip and palate exhibiting characteristic craniofacial defects: (1) short prolabium, (2) absence of frenulum labii, (3) hypoplasia of premaxilla, (4) absent upper central and lateral incisors of the cleft side, and (5) deficient septal cartilage and nasal spine. Gross brain malformations are usually absent in MFD. The same craniofacial malformations are also described in patients with holoprosencephaly sequence (HPE-S). We report on two male patients with bilateral cleft lip and palate showing the facial findings of MFD or HPE-S. Additional congenital malformations were anal atresia in one patient and severe cardiac defect in the other. In both, HPE was excluded by brain imaging, although uncommon brain anomalies were detected consisting of multiple white-matter lesions in the one patient and unusual enlargement and tortuosity of intracerebral blood vessels in both patients. In addition to facial anomalies, the patients also had psychiatric problems typically seen in velo-cardio-facial syndrome (VCFS). Fluorescence in situ hybridization (FISH) analysis confirmed a 22q11.2 microdeletion in both.