Etiological subgroups in non-syndromic isolated cleft palate. A genetic-epidemiological study of 52 Danish birth cohorts.

Isolated cleft palate (CP) is considered to be a heterogeneous trait with an important genetic contribution to the etiology. Multifactorial-threshold models of non-syndromic CP inheritance assume a female predominance. The present study of 52 Danish birth cohorts, using several ascertainment sources, identified 2301 CP cases. It was found that, although females tended to be more severely affected than males, the overall sex ratio was close to one. For the latter half of the study period (1962-87), which probably had the best ascertainment, the sex ratio for non-syndromic CP was 0.95 (95% C.I. 0.85-1.07). Marked difference in sex ratios for non-syndromic overt CP including the hard palate (CPH) and non-syndromic overt CP of the soft palate only (CPS) (0.69 vs 1.00, p < 1.00, p < 0.05) suggested that these two conditions may be etiologically distinct, a hypothesis which is embryologically plausible. In agreement with this hypothesis, Danish family data from surgically treated CP cases showed a strong tendency to segregate only one of the CP subtypes within families. Future studies are recommended to test the existence of a possible etiological difference between CPH and CPS.

Cleft lip (+/- cleft palate) in Danish twins, 1970-1990.

A classical twin study is one of the best methods to address the open question of the role of genes and environment in the cause of cleft lip with or without cleft palate [CL(P)]. In addition, when twin concordance rates are combined with information about the risk for CL(P) to more remote relatives, they can help to establish the most likely mode of inheritance for CL(P). The present study was based on three nation wide ascertainment sources of CL(P) in twins in Denmark during the period 1970-1990. The Danish surgical files were found suitable for ascertaining twins with non-syndromic CL(P) and a total of 39 pairs was identified through these files. In more than 70% of the cases, the zygosity assignment was based on unlike-sex or an extensive panel of blood, serum, and enzyme types. More mono- and dizygotic twin (CL(P) cases than expected were found, although the difference was not significant. The proband concordance rate for CL(P) was 60% in monozygotic twins and 10% in dizygotic twins; six cases were of unknown zygosity. This finding indicates that genetic factors play a major role in the cause of CL(P) but environmental and/or stochastic factors are probably acting too. When the familial recurrence patterns analyzed by Mitchell and Risch [1992: Am J Hum Genet 51:323-332] are interpreted in light of these new estimates of monozygotic concordance, they provide further evidence for the finding that no single locus can account for more than a six-fold increase in risk to first-degree relatives.

Isolated cleft palate in Danish multiple births, 1970-1990.

The etiology of most cases of isolated cleft palate (CP) is unknown. The relative importance of genes and environment can be studied using the classical twin method but only few and potentially highly selected CP twin data are available. The present CP twin study was based on four Danish nationwide ascertainment sources of CP multiple births in the period 1970-1990. The ascertainment sources covered the time period from 15 completed weeks of pregnancy to adolescence for the older cohorts. A total of 18 CP cases in multiple births were identified; two monozygotic twin pairs of which one was concordant and eight were dizygotic, discordant twin pairs. Three cases were from two triplet sets, and four discordant twin pairs were of unknown zygosity. The twin concordance rates suggest that genetic factors play a major role in the etiology of CP, but environmental and/or stochastic factors are probably acting as well.

Selection bias in genetic-epidemiological studies of cleft lip and palate.

The possible impact of selection bias in genetic and epidemiological studies of cleft lip and palate was studied, using three nationwide ascertainment sources and an autopsy study in a 10% sample of the Danish population. A total of 670 cases were identified. Two national record systems, when used together, were found suitable for ascertaining facial cleft in live births. More than 95% ascertainment was obtained by means of surgical files for cleft lip (with or without cleft palate) without associated malformations/syndromes. However, surgical files could be a poor source for studying isolated cleft palate (CP) (only a 60% and biased ascertainment), and they cannot be used to study the prevalence of associated malformations or syndromes in facial cleft cases. The male:female ratio was 0.88 in surgically treated cases of CP and was 1.5 in nonoperated CP cases, making the overall sex ratio for CP 1.1 (95% confidence limits 0.86-1.4) The sex ratio for CP without associated malformation was 1.1 (95% confidence limits 0.84-1.6). One of the major test criteria in CP multifactorial threshold models (higher CP liability among male CP relatives) must be reconsidered, if other investigations confirm that a CP sex-ratio reversal to male predominance occurs when high ascertainment is achieved.

[Study of the Danish Malformation Registry for the incidence of cleft lip and palate during 1983-1987]. / Evaluering af det danske misdannelsesregisters registrering af laebe-ganespalter i perioden 1983-1987.

The Danish Register of Congenital Malformations at the National Board of Health is used for surveillance and research. More than 10% of all patients registered have oral cleft diagnoses. This report evaluates the completeness of the Register of Congenital Malformations as regards registration of oral cleft patients born in Denmark in the period 1983-1987. The register is limited to congenital anomalies diagnosed in hospitals in the child's first year of life. The investigation shows, that the register is suitable for surveillance of clefts, because the completeness of registration was constant during the five-year period 1983-1987. The completeness was more than 90% of all known cases, and probably higher for severe clefts and cases with associated anomalies. Identical diagnosis was found in 93% of all patients registered in The Register of Congenital Malformations with at least one other source of ascertainment. In addition, the investigation disclosed misclassification of a small oral-cleft-subgroup and the need for an additional diagnosis in the coding. The register can only be used for surveillance and research in congenital anomalies, which are usually diagnosed in the child's first year of life.

Antisperm antibodies and fertility after vasovasostomy: a follow-up study of 216 men.

A group of 216 vasovasostomized men were tested with the mixed antiglobulin reaction for immunoglobulin (Ig)G, IgA, and secretory IgA antisperm antibodies bound to the sperm membrane. Free antisperm antibodies in serum and seminal plasma were detected with the gelatin agglutination test and the tray agglutination test. The results were related to the conception rates. In a subgroup with a pure IgG response, the conception rate reached 85.7%, whereas only 42.9% of the men who also had IgA on the sperm induced pregnancy. When 100% of the spermatozoa were covered with IgA, the conception rate was reduced to 21.7%. The combination of IgA on all sperm and a strong immune response (titer in serum greater than or equal to 256) was associated with a conception rate of zero.

Cleft lip and palate in Denmark, 1976-1981: epidemiology, variability, and early somatic development.

The present investigation describes the incidence and variability of the primary cleft condition in all Danish infants born with cleft lip, cleft palate, or both, from 1976 to 1981 and analyzes general somatic growth from birth to age 22 months. Because of excellent sampling conditions in Denmark, the study material is nearly complete. Six hundred and seventy-eight infants with facial clefts were born during the period, corresponding to 1.89 per 1,000 of all newborns. Six hundred and two patients were examined--most of them twice: at 2 months and at 22 months. Material uptake included plaster casts of the upper jaw, cephalometric films in three projections, anthropometric registrations, and information from hospital charts. A detailed grading of the clefts according to severity was carried out. Sex distribution was 61% males and 39% females, of whom 34% had isolated cleft lip, 39% combined cleft lip and palate, and 27% an isolated cleft palate. Left-sided clefts were most frequent. In the combined cleft lip and palate group, 90% exhibited subtotal or total clefts, whereas the clefts were less severe in the isolated cleft lip and isolated cleft palate patients. Birth weight and length showed values close to the average for Danish newborns, but a lag was seen in infants in whom severe palatal cleft was included. The extended method of classification was suggested to select subgroups for special care.

Malocclusion in complete unilateral and bilateral cleft lip and palate. The results of a change in the surgical procedure.

In 1972 the surgical interference with the cleft in the hard palate was changed to a one-layer closure by a vomer flap. The purpose of the present investigation was to examine the effect of this change in the surgical management on the width of the maxillary dental arch and the frequency of malocclusion. Two groups of CLP children were examined: group 1 consisted of 58 children operated on before and in 1972. Group 2 consisted of 72 children operated on after 1972. All of the children had been operated on by the same surgeon. The remainder of the surgical procedures was the same in the two groups. No significant differences were observed, either in the maxillary dental arch width or in the frequency of malocclusion. A minor decrease in the frequency of mandibular overjet and crossbite was seen in the vomer group. Less need for closure of fistulas in the anterior part of the hard palate was seen in group 2.

Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data.

The genetic basis of cleft lip with or without cleft palate [CL(P)] remains unresolved. The controversy on the role of a major gene is confounded with possible population differences. This study examines the issue of population differences by comparing two contrasting populations: Caucasians and Japanese. Japanese are known to have higher population incidence of CL(P) and yet lower recurrence risks among relatives. The study subjects consist of 2,998 nuclear families of the Danish population and 627 families of the Japanese population. The uniformly coded data were subjected to complex segregation analysis based on the mixed model. The analysis has revealed that the Danish data can be best explained by a combination of major gene action and multifactorial inheritance. The best-fitting model is characterized by recessive gene with displacement effect (t) of 2.7 in the standardized unit and gene frequency of .035. The heritability is estimated as .97. The transmission probability of Aa----a for the major gene is consistent with 1/2. On the contrary, the Japanese data can be best accounted for only by multifactorial inheritance with the heritability estimate of .77. No major heterogeneity could be detected between subsets of the data within the populations as grouped by types of ascertainment or mating. It is thus concluded that the observed inconsistency between the two populations is explained by a significant role of major gene in the Caucasian population, but not in the Japanese population.

Facial clefts in sibs and children of epileptic patients.

The prevalence of facial clefts in sibs and children of 2,072 epileptics ascertained in a defined region was determined by record linkage with a national cleft register, which also provided expected figures. Observed/expected ratios were increased only for cleft lip with or without cleft palate if the mother had manifested epilepsy: it was 4.7 when anticonvulsants were given before and during pregnancy, 2.7 in cases with no treatment, and zero in children born prior to maternal epilepsy. Children of epileptic men and sibs of epileptics showed no increase. The prevalence of isolated cleft palate was not above expectation in any group.

Surgical and speech results following palatopharyngoplasty operations in Denmark 1959-1977.

This study analysed surgical results from 600 palatopharyngoplasties (PPP), performed from 1959-77 by Dr. Poul Fogh-Andersen, Copenhagen, and the speech results in 140 of these cases. There were 205 cases of cleft lip and palate (CLP), 133 of cleft palate (CP), 104 of submucous cleft palate (SMCP), 138 of velopharyngeal insufficiency (VPI), and 20 cases of velar paresis. At surgery 62% were younger than ten years, and 5% were older than 30 years. Speech results were evaluated from pre- and postoperative tape recordings. Normal nasal resonance was obtained in 74%, improvement to mild symptoms in 24%. Submucous cleft palate cases had the highest rate of normalization, VPI cases the lowest. The cases with severest hypernasality had the lowest normalization rate. Age and operative procedure were of minor importance in relation to speech results, but surgical complications were fewer in subjects younger than ten years. Postoperative speech therapy was given to 38%, predominantly to subjects with compensatory voice and articulation problems.

Electric oral burns in Danish children with special reference to prevention.

68 children, most of them 1-3 years old, with electric burns of the mouth from slight cases to severe burns with extensive necroses were treated over a 30-year period. Principles of primary conservative treatment and secondary reconstructive surgery are mentioned. A Stein- Abbe flap procedure, single or double, has been the method-of-choice in severe defect of the lower lip. In the majority of the cases the accident was caused by a defective bakelite plug from the detachable cord of a popular electric vacuum cleaner of Danish origin. In 1968 a plea was made for a change of this kind of plug to a better type made of an unbreakable plastic material. As a prophylactic measure this intervention seems to have been very useful in so far as the number of these senseless accidents has decreased dramatically in Denmark during the last 15 years.

Comparison of craniofacial morphology in infants with incomplete cleft lip and infants with isolated cleft palate.

The craniofacial morphology was compared in 30 infants with incomplete left-sided cleft lip and 30 infants with isolated cleft palate. Cephalometric radiographs were obtained prior to any surgical management at 2-3 months of age in the lateral, anteroposterior and axial projections. Compared to the cleft lip group, the infants with isolated cleft palate showed the following characteristics: short anterior cranial base, short maxilla, reduced posterior maxillary height, reduced dimensions of the mandible--especially mandibular length--, narrow naso- and oropharyngeal airway. The cleft lip group had larger interorbital width and symmetry deviations in the anterior art of the maxilla. It was concluded that already at two months of age and prior to any surgical interference significant differences in craniofacial morphology distinguished the group with clefts of the secondary palate from the group with clefts of the primary palate.

Immunoglobulin classes, secretory component, and sperm agglutinins in semen after vasovasostomy.

The immunoglobulin classes of the sperm-agglutinating antibodies in the seminal fluid and serum from four vasovasostomized men, as well as in operatively obtained testis-epididymis fluid from two of them, were investigated by specific solid-phase absorption of IgG, IgM, and IgA. In two patients the major part of the seminal agglutinins was IgA, and in one IgG, indicating that both local production and diffusion of sperm agglutinins from serum to the testis-epididymis compartment may take place. The total levels of immunoglobulins in seminal fluid generally increased after the operation, and IgM was present in two postvasovasostomy samples. This suggests a pathotopic potentiation effect of the vasectomy on the epithelial lining of the testis-epididymis compartment. Comparison of the results of solid-phase absorption with anti-IgA and anti-secretory component (SC) pointed to the presence of "free" SC in postvasovasostomy seminal fluid.

Cleft palate: a genetic and epidemiologic investigation.

An examination of kindred histories of 561 Danish probands who have non-syndromic CP has indicated that neither a multifactorial-threshold model nor a single major locus model is completely compatible with the data. This suggests etiologic heterogeneity for CP, which was tested with kindred data. As recommended by Smith (1976), at attempt to define partially this heterogeneity within the CP phenotype was undertaken by grouping and comparing the kindred data. It is both reasonable and heuristic to propose that CP,, as defined in this investigation, is composed of three groups: (1) Syndromic CP; (2) Familial CP, which appears to have an autosomal dominant component to its etiology, and (3) Non-familial CP which, by demonstrating an increasing frequency of CP and a maternal age effect, appears to be related to environmental factors which may cause CP or other malformations.

Facial clefts among epileptic patients.

Anticonvulsants have been suspected of teratogenicity, with facial clefts being the malformation most frequently associated with maternal anticonvulsant therapy. Paternal epilepsy has also been suggested as a factor in the genesis of birth defects, including facial clefts. An association between epilepsy per se and facial clefts would be reflected in a higher facial cleft prevalence among epileptics, and consequently result in an increase of such malformations among their children. The prevalence of facial clefts was determined in an unselected group of 3,203 epileptic probands: their personal data were cross-matched with a complete file of Danish facial cleft patients born between 1934 and 1977. Eleven epileptic probands had a facial cleft, which is twice the expected number. The increased prevalence of cleft defects among epileptics could partly explain why more of their children have facial clefts.

Association between failure to impregnate after vasovasostomy and sperm agglutinins in semen.

Sperm agglutinins emerging from the reopened part of the vas deferens were found in the seminal fluid of 10 out of 29 men after vasovasostomy. There was a strong association between the presence of these antibodies and the failure to impregnate over a period of 14 to 33 months. Of 20 couples, 11 pregnancies resulted among the 13 women whose men had no sperm agglutinins in the seminal fluid, but only 1 among the 7 whose men had such antibodies, 2p = 0.0044. The presence of sperm agglutinins in the seminal fluid was always associated with their presence in the serum, usually in a higher titre. Preoperative serum levels thus are highly predictive of ability to impregnate after reversal of vasectomy.

PIP: 29 men underwent vasovasostomy from 8 months to 8 years after vasectomy. Ejaculates and sera of these men were collected 3, 6, 9, and 12 months after reanastomosis surgery. Sperm agglutinins in serum and in seminal plasma were then measured by the tray agglutination test and titers greater than 4 were considered positive reactions. Follow-up questionnaires to determine the actual period over which attempts to inpregnate had been made were also sent to these 29 men and their partners. 10 of the 29 men were found to have sperm agglutinins, emerging from the reopened part of the vas deferens, in seminal fluid. There was a strong association between the presence of these antibodies and failure to impregnate over a period of 14-33 months. Of 20 couples involved, 11 pregnancies resulted among the 13 women whose men had no sperm agglutinins in seminal fluid, but only 1 pregnancy had occurred among the 7 whose men had such antibodies (2P=.0044). The presence of sperm agglutinins in seminal fluid was invariably associated with their presence in serum, and usually in a higher titer. Preoperative serum levels thus should have predictive value of ability to impregnate after vasectomy reversal.

Cleft lip+/-cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968.

In recent years there has been some controversy over the analytical designs and the meaning of varying results with regard to studies of facial clefting and other common congenital malformations. Regardless, it is still unclear as to the nature of the genetic and environmental components of the etiology as well as the nature of the relevant pathogenetic mechanisms. Despite claims to the contrary, the predictions of a particular multifactorial/threshold inheritance (MF/T) model delineated by Carter [1977d] and others are not well supported by studies worldwide. The present study population consists of 1,895 persons born in Denmark with cleft lip with or without cleft palate (CL +/- P) between 1941 and 1968. A test of the MF/T predictions revealed the following: 1) the incidence of CL +/- P in siblings was 40 X greater than that in the general population 2) the risk to siblings of CL +/- P females was not significantly different from the risk to siblings of CL +/- P males; 3) recurrence risk for siblings of CL +/- P probands was dependent upon the proband's cleft type; 4) only 0.4% of the variation in risk to the siblings born after the proband could be accounted for by the number of previously affected siblings; 5) the consanguinity rate was 6 times less than the general population rate; 6) heritability estimates from siblings and parents by sex suggest, either the presence of significant dominance effects, or a common sibling environment component in the etiology of the disorder. Further, testing with a multiple-sex threshold method, designed and provided us by [Kidd and Spence, 1976] revealed that neither the MF/T nor single-major locus with random environmental variation provided a good fit. In light of recent experimental mouse and human data, an alternative model of monogenic-dependent susceptibility to a variety of teratogens is discussed.