Since Dr. Fogh-Andersen's legendary 1942 thesis, the Danish facial cleft population has been one of the most extensively studied in terms of epidemiology and genetic-epidemiology. The etiology of cleft lip and/or palate (CLP) is still largely an enigma, and different results concerning environmental and genetic risk factors are obtained in different countries and regions. This may be due to etiological heterogeneity between settings. Therefore, an in-depth studied area with an ethnically homogeneous population, such as Denmark, has provided one of the best opportunities for progress in CLP etiological research. The present review summarizes epidemiological and genetic-epidemiological studies conducted in the 20th century Danish facial cleft population. Furthermore, analyses of sex differences, time trends and seasonality for more than 7000 CLP cases born in Denmark in the period 1936 to 1987 are presented. The review also points toward the excellent opportunities for continued etiological CLP research in Denmark in the 21st century using already established resources and an on-going prospective cohort study of 100,000 pregnant women.
Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP.
This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes.
A retrospective chart review of antenatal and post-natal medical charts was completed for a ten-year period between January 2000 and December 2009. At least 2 years of available post-natal clinical information was required for inclusion in the study.
A total of 97 cases of antenatally isolated CLP were ascertained. Fifteen pregnancies were terminated. Follow-up data were available for 81 liveborns, though 4 were lost to follow-up prior to 2 years of age. Twelve of the 77 children meeting study criteria were identified to have other major malformations and/or developmental disability either later in the pregnancy or post-natally. Findings included familial clefting syndromes, trisomy 21, autism spectrum disorders, brain malformations, fetal alcohol syndrome and Kabuki syndrome, among other findings. Another 11 children had additional anomalies of minor impact. Examples of findings include a perimembranous ventricular septal defect, mild unilateral optic nerve hypoplasia, mild pulmonary artery stenosis with a small atrial septal defect, and transient delays in fine and gross motor skills. No children with clefting of the lip only had major additional diagnoses.
The existence of a major gene (or genes) that contributes significantly to the familial clustering of cleft lip with or without cleft palate (CL(P)) has been suggested by genetic epidemiology studies and supported by patient-control genotype association studies with a candidate gene. Here we present an analysis of the familial recurrence risk data for isolated cleft palate (CP) and show that an oligogenic model with six genes of equal effect fits the data best. The discrimination between alternative models is, however, poor and a major locus that explains half of the familial recurrence is plausible. The prospects for identification of susceptibility loci for CP are discussed.
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.
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.
Extensive review of the literature since 1884 on cleft-twin sets yielded 364 cleft-twin sets. Of these, 118 were monozygotic (MZ) and 246 dizygotic (DZ) sets. In addition, Danish material on cleft twins, like our Finnish material, reflects the total number of clefts and cleft twins on a well-defined population during a well-defined time interval. Both sets of material also contain slightly over 100 pairs of twins. The Danish material and the literature review were compared to the Finnish material. The hospital records of all Finnish patients with operated clefts who were born between 1948 and 1987 were reviewed. Information was gathered regarding each patient, his parents, the pregnancy, and his twin or triplet siblings and other siblings. This search produced 105 sets of twins and three sets of triplets with clefts, 15 sets of twins being concordant regarding clefting. This resulted in a total of 120 cleft siblings, and the corrected cleft incidence of 1.72 promille, close to the overall cleft incidence rate in Finland between 1948 and 1975. Twinning was found to be associated neither with an increased nor with a decreased risk of clefting, and clefting could not be seen to increase twinning. Zygosity could be verified in 88 sets of twins; the total number of MZ sets was 17, and of DZ was 71, a 19% MZ rate. Although a higher incidence of clefting in MZ-twin sets has been proposed, no such higher or lower incidence could be found in our material. Recognized syndromes were found in 15 sets (14%), slightly higher than found in a large Finnish study on cleft probands (8.4%). Of these, three sets were monozygotic (MZ), all of them cleft palate (CP) and male sets, whereas eight sets were dizygotic (DZ). All 15 sets were CP only, with no one set with cleft lip and palate [CL(P)]. In our total Finnish-twin material of 105 sets, we found the CL(P)/CP ratio to be 39/66 (37%/63%). In all of the 120 affected siblings, the ratio was 35%/65%. The very high rate of 63% of CP twins is about two to three times higher than that reported in the literature of 364 sets where the CP ratio is 23%; compared to the Danish material with a CP ratio of 17%, it is almost four-fold. The overall CP rate in all clefts (not restricted to twins) in Finland compared to the rate in our neighboring Scandinavian countries was very much in line with this very big difference seen in the CP rate in our twin material. The CL(P) incidence in our Finnish material is 0.61 promille and the CP incidence 1.11 promille. For MZCL(P), the incidence was 0.38 promille; for MZCP, 0.91 promille; for DZCL(P), 0.52 promille, and for DZCP, 0.99 promille. Compared to the Danish figures both the MZCP and DZCP incidence figures are nearly four-fold, with the MZCL(P) somewhat lower, and DZCL(P) less than half that number. The sex distribution of all cleft patients in our material was 44% male/56% female. Both in the Danish material and in the literature, it was the reverse. This difference is probably due mostly to the higher ratio of CP in the Finnish material. The CP group has a higher proportion of females in all these materials. The concordance (C) of the whole Finnish-twin material is 14%, compared to 16.5% reported in the literature and 8% for the Danish twins. The concordance for CL(P) in our material is many times lower (2.6%) than in the literature (17.1%) and in the Danish material (8%). In the Finnish twins, the C for CP is higher (17%) than that for the Danish (6%) and for the literature cleft-twin populations (14.3%). This is also true for the MZ and DZ subgroups. The heritability index (H) in CL(P) is lower for the Finns (17%) than for the Danish (45%) and for the literature materials (43%), and higher for CP (Finns 49%, Danish 33%, literature 36%). All of these data strongly suggest the quite different genetic behavior of both CL(P) and CP in Finland, with a much lower genetic component in the CL(P) and a higher in the CP.
Comment In: Cleft Palate Craniofac J. 1996 Nov;33(6):5308939382
A total of 251 children with isolated cleft palate were examined. Orthopantomograms, taken at the age of 6-12 years, were used in the detection of hypodontia of the permanent teeth, excluding the third molars. The findings were: 1. Familial history of clefting has no pronounced effect on the prevalence of hypodontia; 2. The prevalence of hypodontia was significantly higher in children with conical elevation of the lower lip than in those without it (40% to 25%), and increased with increasing extension of the cleft; 3. Cleft palate was associated with conical elevation and/or hypodontia in 56% of the subjects. The same etiological factor or factors seems to be responsible for the formation of the cleft, for conical elevation, and for hypodontia.