American Journal of Medical Genetics 38:622-625 (1991)

Epidemiological Aspects of Mendelian Syndromes in a Spanish Population Sample: I. Autosomal Dominant Malformation Syndromes M. L. Martinez-Frias, A. Cereijo, E. Bermejo, M. Lopez, M. Sanchez, and C. Gonzalo Estudio Colaborativo Espariol de Malformaciones Congknitas (ECEMC), Instituto Nacional de la Salud, Hospital Universitario S a n Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain

Using a sample of 710,815 liveborn infants throughout Spain, monitored from April, 1976, to December, 1988, by the Spanish Collaborative Study of Congenital Malformations (ECEMC),we estimated the prevalence of each recognized autosomal dominant malformation syndrome for a total prevalence figure of 12.1 per 100,000 live births, including all detected autosomal dominant malformation syndromes. We estimated that the mutation rate for those syndromes was 48.5 per 1,000,000 gametes. The geographical distribution of these syndromes was homogeneous in the Spanish Regions.

genital Malformations (Estudio Colaborativo Espafiol de Malformaciones Congenitas; ECEMC), we estimated birth prevalance rate, mutation rate, and geographical distribution for autosomal dominant malformation syndromes in a Spanish population sample.

MATERIAL AND METHODS From April, 1976, to December, 1988, the ECEMC monitored 710,815 liveborn infants in 16 of the 17 Spanish Regions (Comunidades Autonomas) and identified 14,439 (2.03%) children with congenital defects. The ECEMC is a hospital-based, case-control study and surveillance system. Cases and control infants are ascertained a t each collaborating hospital by pediatricians who perform a physical examination on each newborn infant within the first 3 days of life. KEY WORDS: prevalence, geographical disCases are all newborn infants with major or minor tribution of congenital decongenital defects observed during this period. Photofects, mutation rate graphs, radiographs, and autopsy reports are included when available. For each malformed baby, the next nonmalformed infant of the same sex born at the same INTRODUCTION hospital is selected as a control subject. Mothers of cases Most Mendelian multiple congenital anomalies and control infants are interviewed to collect pregnancy (MCA) syndromes are studied on the basis of case re- and family histories as well as demographic data. Deports and review of the literature, but there are very few scriptions of the ECEMC have been published elsewhere studies that approach the problem from a n epide- [Martinez-Frias et al., 1984, 1987, 1988a, b]. All regismiologic perspective [Slatis, 1955; Stevenson, 1957; tered cases are reviewed by a group of congenital defects Gardner, 1977; Tunte and Lenz, 1967; Carothers et al., specialists in a n attempt to define the precise diagnosis. 1986; Martinez-Frias et al., 198813; Nelson and Holmes, In that we used data from a congenital defects registry, 19891.One of the reasons could be that, for years, most of our study is in regard to multiple congenital anomalies the registries did not have a careful clinical analysis to (MCA) syndromes. We considered a s autosomal domiidentify patterns of association and well established nant malformation syndromes those conditions with a syndromes. Recently, this situation has changed and definite diagnosis. Cases in which a n autosomal domiepidemiologic studies are done on specific patterns of nant syndrome was suspected but not confirmed were congenital defects [Khoury et al., 1987; Martinez-Frias excluded. et al., 1988a, b, 19901. We estimated the mutation rate of dominant MCA Using data of the Spanish Collaborative Study of Con- syndromes. A dominant mutation was defined as a patient with one of the autosomal dominant malformation syndromes with unremarkable family history. This definition is consistent with that used in previous studies Received for publication J a n u a r y 24, 1990; revision received [Stevenson, 1957; Gardner, 1977; Martinez-Frias et al., J u n e 20, 1990. 1988a,b; Nelson and Holmes, 19891. For conditions with Address reprint requests to Maria-Luisa Martinez-fiias, fitness >0, it was assumed that there was no question ECEMC, Facultad de Medicina, Universidad Complutense, 28040 about paternity. We considered the Spanish Regions to Madrid, Spain. 0 1991 Wiley-Liss, Inc.

Mendelian Syndromes in Spain

TABLE I. Prevalence of Autosomal Dominant Syndromes in the ECEMC

study the geographic distribution of the identified autosoma1 dominant malformation syndromes.

RESULTS Among 14,439 malformed babies, we identified 86 infants with autosomal dominant malformation syndromes for a prevalence rate of 12.1 per 100,000 liveborn infants or 1/8,265 live births. Table I shows the prevalence figures for the different types of autosomal dominant syndromes identified in our program. The 5 most frequent ones were: achondroplasia (2.53 per 100,000 live births), thanatophoric dwarfism (1.69), Crouzon syndrome (1.55), Apert syndrome (1.271, and TreacherCollins syndrome (1.27).Among the 86 cases with dominant syndromes, 17 (19.8%) were familial and 69 (80.2%)sporadic (new mutation). This implies a total mutation rate of 48.5 per 1,000,000 gametes. Table I1 shows the geographic distribution of familial and sporadic cases by the 16 Spanish Regions represented in our program and the exact 95% confidence intervals (Poisson distribution) for the total cases. The observed differences are not statistically significant. We also looked a t the distribution among the Spanish Regions (Table 111) of the 5 most frequent syndromes (Treacher Collins, thanatophoric dwarfism, achondroplasia, Apert, and Crouzon). DISCUSSION In that we considered only liveborn infants and, in several cases, we have no autopsy reports or chromosomal analysis, we have to assume some degree of underascertainment. This is more important in some conditions, such as Stickler or Noonan syndromes, that are difficult to detect during the first 3 days of life. Some of the cases of Stickler syndrome were recognized because the father or the mother was affected; then, we have a lack of detection for the sporadic cases (or new mutations). On the other hand, in syndromes such as blepharophimosis, sometimes it is difficult to know if the parents are less severely affected. Even though we

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Number Per of cases 100.000

Svndrome Achondroplasia Adams-Oliver Aniridia type I Apert Beals Blepharophimosis Cleido-cranial dysostosis Congenital myotonic dystrophy Conradi-Hunermann Crouzon EEC" Freeman-Sheldon Hay-Wells Noonan Opitz-F'rias Pfeiffer Robinow Spondylo-epiphyseal dysplasia Stickler Thanatophoric dwarfism Treacher-Collins Waardenburg Total a

18 1 1 9 1 1 3 2 1 11 1 1 2 1 1 2 1 3 2 12 9 2 86

2.53 0.14 0.14 1.27 0.14 0.14 0.42 0.28 0.14 1.55 0.14 0.14 0.28 0.14 0.14 0.28 0.14 0.42 0.28 1.69 1.27 0.42 12.10

EEC, ectrodactyly-ectodermal dysplasia-clefting syndrome.

think that it is important to determine the frequency of the detected cases, our figures of prevalence and mutation rate, as we stated in our previous paper [MartinezF'rias et al., 1988a1, should be considered as tentative (or the minimal estimation) for our population. Although we cannot exclude that, for some cases, the information from the family was not complete, and such cases may have been classified as a dominant mutation, and for other cases we had a lack of detection of sporadic ones, the mutation rate we found is within the expected human mutation rate [Vogel and Rathenberg, 19751, with slight differences from those reported by other

TABLE 11. Prevalences of Autosomal Dominant Syndromes by Spanish Regions

Spanish Regions Andalucia Aragon Asturias Baleares Canarias Castilla-Leon Castilla-La Mancha Cataluna Extremadura Galicia La Rioja Madrid Murcia Navarra Pais Vasco Valencia Total

Familial

Sporadic

0 0 0 1 0 4 4 1 0 2 0 2 1 0 2 0 17

11 0 2 0 0 8 9 7 1 8 0 5 3 6 9 0 69

N

Total cases Per 100,000

~

11 0 2 1 0 12 13 8 1 10 0 7 4 6 11 0 86

11.2 -

22.6 25.4 -

12.7 11.6 10.7 5.5 13.6 -

17.7 18.8 17.6 13.8 12.1

95% CI

Total births

5.6-20 0-481.6 2.7-81.5 0.6-141.5 0-39.4 6.6-22.3 6.2-19.8 4.6-2 1.2 0.1-30.7 6.5-25.1 0-21.6 7.1-36.4 5.1-48.1 6.5-38.2 6.9-24.6 0-14.7 9.7-15.0

98,293 766 8,859 3,936 9,367 94,129 112,318 74,423 18,143 73,419 17,056 39,605 21,316 34,155 79,872 25,158 710,815

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Martinez-F’riaset al. TABLE 111. Distribution of Five Autosomal Dominant Syndromes bv SDanish Regions Syndrome ~

Spanish Regions Andalucia Arag6n Asturias Baleares Canarias Castilla-Leon Castilla-La Mancha Cataluiia Extremadura Galicia La Rioja Madrid Murcia Navarra Pais Vasco Valencia Total

Treacher Collins 3 0 0 0 0 2 1 2 0 0 0 0 0 0 0 0 8

Thanatophoric dwarfism 2 0 1 0 0 0 2 2 0 1 0 1 1 1 1 0 12

authors using different methods of ascertainment [Slatis, 1955; Stevenson, 1957; Blank, 1960; Nelson and Holmes, 19891. Families among whom a parent had a germinal mutation with a single affected child may also have been classified as a dominant mutation, but this type of event is thought to be rare. We have not found prevalence figures for other populations for all the autosomal conditions included in this study, probably because most of them are, in fact, rare and it would be necessary to study large populations with a careful clinical analysis to determine the frequencies. Our prevalence rates for some of the autosoma1 dominant conditions are within the range observed by other authors for different populations [Slatis, 1955; Stevenson, 1957; Gardner, 1977; McKusick, 1988; Nelson and Holmes, 19891. For some of these conditions, we have observed little variation in the prevalence figures with respect to those observed in our previous paper [Martinez-Frias et al., 1988al. These differences could be due to the fact that, in December, 1985, therapeutic abortion was accepted by law in Spain, and conditions that can be detected early in pregnancy could lead to abortion. Since the distribution of all these conditions follows a Poisson model, this could also be responsible for the variation of conditions with very low frequency. If factors related to mutation were different between Regions, we would expect differences in the geographic distribution of autosomal dominant conditions. This could even give us clues to potential mutagenic factors. The differences between the Regions of sporadic or familial cases (Table 11)and by specific types (Table 111)were not statistically significant. This encourages us to think that the mutation rate is not different throughout these Regions. If we establish a surveillance of the frequencies among the different Spanish Regions then we could detect future geographical variation as a first indication of changes in the mutagenic agents. On the other hand, this type of study will allow us to identify populations a t risk and also potential families for molecular genetic studies.

Achondroplasia 3 0 0 0 0 2 4 2 1 1 0 1 1 2 1 0 18

Apert 1 0 0 0 0 1 1 1 0 0 0 0 1 1 3 0 9

Crouzon 1 0 0 0 0 2 1 0 0 5 0 1 0 1 0 0 11

ACKNOWLEDGMENT We are especially grateful to all physicians that constitute the collaborating Group of the ECEMC and collected the information; to Dr. J. L. Frias (Nebraska) for invaluable contributions in clinical analysis, and Drs. J. C. Carey (Utah) and J. F. Cordero (Atlanta) for their comments on the manuscript. This work was supported in part by a grant from the USA-Spain Joint Committee for Scientific and Technological Cooperation and by a grant from the Direccih General de Planificacion Sanitaria, Ministerio de Sanidad y Consumo, Spain. REFERENCES Blank C (1960): Apert’s syndrome (a type of acrocephalosyndactyly): Observation on a British series of 35 cases. Ann Hum Genet 24: 151-164. Carothers AD, McAllison SJ,Paterson CR (1986): Risk of dominant mutation in older fathers. Evidence from osteogenesis imperfecta. J Med Genet 23227-230. Emery AEH (1976): “Methodology in Medical Genetics. An Introduction to Statistical Methods.” London: Churchill Livingstone. Gardner RJM (1977): A new estimate of the achondroplasia mutation rate. Clin Genet 11:31-38. Martinez-Frias ML, Frias JL, Salvador J (1990):Clinical/epidemiological analysis of malformations. Am J Med Genet 35:?21-125. Martinez-Frias ML, Herranz I, Salvador J, Prieto L, Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero J F (1988a): Prevalence of dominant mutations in Spain: Effect of changes in maternal age distribution. Am J Med Genet 31:845-852. Martinez-Frias ML, Ramos-Arroyo MA, Salvador J (1988b): Thanatophoric dysplasia: An autosomal dominant condition? Am J Med Genet 31:815-820. Martinez-Frias ML, Salvador J (1987):“Manual Operacional.”Madrid: (Ed.) ECEMC. Martinez-Frias ML, Salvador J , Prieto L, Zaplana J (1984): Epidemiological study of gastroschisis and omphalocele in Spain. Teratology 29:377-382. McKusick VA (1988): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes.” Baltimore: The Johns Hopkins University Press. Nelson K, Holmes LB (1989): Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 320:19-23.

Mendelian Syndromes in Spain Slatis HM (1955): Comments on the rate of mutation to chondrodystrophy in man. Am J Hum Genet 7:76. Stevenson AC (1957): Achondroplasia: An account of the condition in Northern Ireland. Am J Hum Genet 9:81-91. Tunte W, Lenz W (1967): Zur Haufigkeit und Mutationsrate des ApertSyndroms. Humangenetik 4:104-111.

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Vogel F, Rathenberg R (1975): Spontaneous mutation in man. In Harris H, Hirschhorn K (eds):“Advances in Human Genetics.” New York: Pp 223-318.

Epidemiological aspects of Mendelian syndromes in a Spanish population sample: I. Autosomal dominant malformation syndromes.

Using a sample of 710,815 liveborn infants throughout Spain, monitored from April, 1976, to December, 1988, by the Spanish Collaborative Study of Cong...
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