American Journal of Medical Genetics 38:626-629 (1991)

Epidemiological Aspects of Mendelian Syndromes in a Spanish Population Sample: 11. Autosomal Recessive Malformation Syndromes M. L. Martinez-Frias, E. Bermejo, A. Cereijo, M. Sanchez, M. Lopez, and C. Gonzalo Estudio Colaboratiuo Espaiiol de Malformaciones Congenitas (ECEMCI, Instituto Nacional de la Salud, Hospital Universitario San Carlos. Facultad de Medicina, Uniuersidad Complutense, Madrid, Spain

From April, 1976, to December, 1988,the Spanish Collaborative Study of Congenital Malformations (ECEMC) monitored a total population of 710,815 liveborn infants in 16 of 17 Spanish Regions and identified 14,439 (2.0%) with congenital defects. Among the malformed children, we identified 73 with well recognized autosomal recessive syndromes, for an overall prevalence rate of 10.3 per 100,000 livebirths and a total carrier frequency of 1/49. Considering the Spanish Regions (Comunidades Autonomas), we analyzed the geographical distributions of these syndromes that were homogeneous. We studied the place of birth of the grandparents to determine the distribution of the gene as well as the gene flow. KEY WORDS: prevalence, geographical distribution of congenital defects, birth defects, carrier frequency, Meckel syndrome

genitas; ECEMC), we studied the autosomal recessive malformation syndromes identified, estimating the minimum birth prevalence rate, carrier frequency, and geographical distribution.

MATERIAL AND METHODS b o r n April, 1976, to December, 1988, the ECEMC monitored 710,815 liveborn children in 16 of the 17 Spanish Regions (Comunidades Autonomas) and identified 14,439 (2.03%) cases of children with congenital defects. The ECEMC is a hospital-based, case-control study and surveillance system. Cases and controls are ascertained a t each of the 45 collaborating hospitals by pediatricians, who perform a physical examination on each newborn infant within the first 3 days of life. The ECEMC was described a t the first part of this study and in other publications [Martinez-bias et al., 1984,1990, this issue]. We excluded for the present study those cases in which a n autosomal recessive malformation syndrome was suspected but not confirmed due to a lack of information. We considered the Spanish Regions to study the geographic distribution of the syndromes, using the places where the children were born to estimate the prevalence of the condition in the different Regions and the birth places of the grandparents of each child with a specific syndrome to estimate the gene flow.Since the ECEMC is a surveillance system, and assuming population equilibrium [Emery, 19761, we used the Hardy-Weinberg law to estimate the frequency of the gene and carriers in our population.

INTRODUCTION There are few studies that have analyzed the Mendelian malformation syndromes from a n epidemiologic approach [Camera and Mastroiacovo, 1982; Nelson and Holmes, 1989; Martinez-Frias et al., this issue], and most of them are on the Meckel syndrome [Fried, 1973; McKusick, 1978; Goodman and Motulsky, 1979; Lurie et al., 1984; Salonen and Norio, 1984; Young et al., 19851. RESULTS This is probably because that syndrome is one of the Among 14,439 malformed babies, we identified 73 most frequent among liveborn infants. infants with recognized autosomal recessive malformaUsing the malformed infants registered by the Spantion syndromes, for a minimum prevalence rate of 10.3 ish Collaborative Study of Congenital Malformations per 100,000 liveborn infants (or 1/9,737 live births). We (Estudio Colaborativo Espanol de Malformaciones Conalso found 41 babies (5.77 per 100,000 liveborn children) with multiple congenital defects who had another sib affected with the same pattern of multiple congenital Received for publication January 24, 1990; revision received anomalies (MCA), suggesting autosomal recessive inJ u n e 20, 1990. heritance, although a n undetected chromosome anomAddress reprint request to Maria-Luisa Martinez-Frias, aly cannot be excluded. ECEMC, Facultad de Medicina, Universidad Complutense, 28040 Table I shows the prevalence rate of the different types Madrid, Spain. 0 1991 Wiley-Liss, Inc.

Recessive Malformation Syndromes in Spain TABLE 11. Frequency of Recessive Gene Carriers in the ECEMC*

TABLE I. Prevalence of Autosomal Recessive Syndromes in the ECEMC Syndrome ~Achondrogenesis I1 Bartsocas-Papas Bowen-Conradi Campomelic dwarfism Carpenter Congenital adrenal hyperplasia Cryptophthalmos Diastrofic dwarfism Ellis-van Creveld Fanconi pancytopenia Fibrochondrogenesis Fryns Hypophosphatasia Hypothyroidism Jeune Kaufman-McKusick Meckel Mucoviscidosis Pena-Shokeir I phenotype (fetal akinesia) Polycystic kidney infantile Rhizomelic chondrodysplasia punctata Saldino-Noonan Shwachman Seckel Smith-Lemli-Opitz Spondylothoracic dysplasia Thrombocytopenia-radial aplasia (TAR) Total recessive syndromes Patterns of MCA" Total

Per Number 100,000 1 1 2 3 1 7 2 1 6 2 1 1 2 1 1 1 9 1

0.14 0.14 0.28 0.42 0.14 0.98 0.28 0.14 0.84 0.28 0.14 0.14 0.28 0.14 0.14 0.14 1.27 0.14

6 10 2 1 1

0.84 1.41 0.28 0.14 0.14 0.14 0.42 0.42 0.42 10.27 5.77 16.04

1

3 3 3 73 41 114

a MCA, Multiple congenital anomalies that could be considered recessive malformation syndromes.

of autosomal recessive malformation syndromes identified in our program. The 5 most frequent were polycystic kidney infantile (1.41 per 100,000 live births), Meckelsyndrome (1.271, congenital adrenal hyperplasia (0.981, Ellis-van Creveld syndrome (0.841, and Pena-Shokeir I phenotype (fetal akinesia) (0.84). In Table I, we also indicate the birth prevalence rate for conditions with a family history that could suggest autosomal recessive inheritance. Seven of 41 cases (17.1%)also had parental consanguinity. Although the existence of 2 sibs with the same pattern of MCA could actually represent a n undetected chromosome problem, we can also consider i t as a possible autosomal recessive condition. Then, the total prevalence for autosomal recessive conditions is 16.04 per 100,000 liveborn infants. Assuming t h a t HardyWeinberg equilibrium applies in our population [Emery, 19761, the gene frequency (9) for autosomal recessive malformation syndromes in our study is 0.010, and the frequency of heterozygote carriers is 0.02 or 1/49. If we include a s recessive syndromes those cases with a pattern of MCA and a family history suggesting autosomal recessive inheritance, the total frequency of carriers would become 0.025 or 1/40 (Table 11). We studied the geographic distribution of the syndromes by 16 of 17 Spanish Regions represented in our

627

. .

~~~~

Recessive syndromes

Recessive MCA

Total

119,737 1149.3

1117,337 1165.8

116,235 1139.5

~~~

Prevalence ( = p2)

Carriers (2pq) ' p + q = l

program. Table I11 shows the prevalence figures and exact 95% confidence intervals (Poisson distribution) of autosomal recessive syndromes by Regions. We selected those conditions with 7 or more cases to analyze their distribution among the Regions. Three syndromes reach this level: Meckel(9 cases), polycystic kidneys (10 cases), and congenital adrenal hyperplasia (7 cases). The carrier frequencies of these 3 conditions are 1/140, 11133, and 1/159, respectively. Table IV indicates the prevalence figures and exact 95% confidence intervals for Poisson distribution of these 3 conditions by Spanish Regions. The differences between regions are not statistically significant. Since these frequencies refer to the Region where the births occurred, we looked a t the Region where the 4 grandparents of each child with those syndromes were born. Only for Meckel syndrome the origin of the families differs from the place of children's birth. As is shown in Figure 1,in each one of the 9 cases of Meckel syndrome, 4 grandparents were born in the same village. Such villages belong to only 2 Spanish Regions, Andalucia and Castilla-La Mancha, instead of the 4 in which the 9 children were born (Andalucia, Castilla-La Mancha, Madrid, and Murcia). Initially, we had 2 cases born in the Region of Madrid and 2 in that of Murcia. One of the 2 cases born in Madrid came from Andalucia and the other from Castilla-La Mancha, because their families emigrated to Madrid (gene flow by migration). The situTABLE 111. Distribution of Prevalences of Autosomal Recessive Syndromes by Spanish Regions

Spanish Regions

Total liveborn infants

Recessive Per N 100,000

Exact 95% confidence interval

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

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

6 0 2 0 0 7 12 4 2 5 1 8 7 6 12 1 73

2.2-13.3 0-483.0 2.7-81.5 0-96.5 0-39.5 3.0-15.3 5.5-18.7 1.5-13.8 1.3-39.8 2.2-15.9 0.1-32.7 8.7-39.7 13.2-67.6 6.4-38.2 7.8-26.2 0.1-22.1 8.0-12.9

6.1 0 22.6 0 0 7.4 10.7 5.4 11.0 6.8 5.9 20.2 32.8 17.6 15.5 4.0 10.3

628

Martinez-Friaset al. TABLE IV. Prevalence per 100,000 and Exact 95% Confidence Intervals (CI) for Most Frequent Autosomal Recessive Syndromes bv SrJanish Reaions

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

Adrenogenital syndrome Preval. CI 0 0 0 0 0 2.1 0 0 0 1.4 0 0 0 2.9 3.8 0

1.0

0-3.75 0-481.6 0-41.6 0-93.7 0-39.4 0.3-7.7 0-3.3 0-5 0-20.3 .03-7.6 0-21.6 0-9.3 0-17.3 0.1-16.3 0.8-11 0-14.7 0.4-2.0

Meckel syndrome Preval. CI 1.0 .03-5.7 0 0 0 0 0 3.6 0 0 0 0 5.1 9.4 0 0 0

1.3

0-481.6 0-41.6 0-93.7 0-39.4 0-3.9 1-9.1 0-5 0-20.3 0-5.0 0-21.6 0.6-18.2 1.1-33.9 0-10.8 0-4.6 0-14.7 0.6-2.4

Polycystic kidney infantile Preval. CI 0 0 0 0 0 2.1 0 0 0 1.4 0 7.6 9.4 2.9 1.3 0 1.4

0-3.75 0-481.6 0-41.6 0-93.7 0-39.4 0.3-7.7 0-3.3 0-5 0-20.3 .03-7.6 0-21.6 1.6-22.1 0-17.3 0.1-16.3 .03-7 0-14.7 0.7-2.6

Canarias Andalucla

Fig. 1. Distribution of cases of Meckel syndrome by the infants’ grandparents place of birth. Solid circles, cases of Meckel syndrome by grandparents place of birth. Open circles, infants place of birth although their families are living in the region of origin of grandparents. Solid arrows, cases born in Madrid. Families emigrated to Madrid from other Regions. Dashed arrows, cases born in a region other than the one where their families are living (same where grandparents were born).

1

Recessive Malformation Syndromes in Spain

ation was different for the 2 cases born in Murcia, because their families still live one in Castilla-La Mancha and the other one in Andalucia. Both children were born in Murcia because the maternity hospitals of that Region were the nearest to the villages where the families of these 2 cases lived; consequently, the frequency of the gene belongs to these 2 Regions: Andalucia and CastillaLa Mancha instead of the region where the children were born (false gene flow, because it does not change the genic background).

DISCUSSION To our knowledge this is the first study with a large sample size on the rate of autosomal recessive malformation syndromes. However, in that we considered only livebirths and, in several cases, we have no autopsy reports and chromosomal analysis, we have to assume some degree of underascertainment and heterogeneity. The interpretation of the findings should be considered in the light of the limitation of our data. We have not found prevalence figures in other populations for all the conditions included in this study, probably because most of them are, in fact, very infrequent and can be practically limited to the Meckel syndrome [Fried, 1973; Seller, 1978; Moerman et al., 1982; Salonen and Norio, 1984; Lurie et al., 1984; Young et al., 1985; Nelson and Holmes, 19891 and to those recessive conditions studied in the Amish population [McKusick, 1978; Goodman and Motulsky, 19791. Our frequency for Meckel syndrome is within the range observed for other populations. The lowest reported rate for that syndrome is 1 in 140,000 births in a British population [Seller, 19781 and the highest is 1in 1,304 births for a group of Gujaratis living in England [Young et al., 19851. The prevalence of a n autosomal recessive condition should be considered related to the degree of consanguinity or endogamy in the studied population [Steinberg et al., 1967; Schurig e t al., 19801. These are important factors to take into account when a high prevalence of recessive conditions is observed in isolated populations. Parental families of our 9 cases with Meckel syndrome come from small villages of 2 neighboring Spanish Regions, Castilla-La Mancha and Andalucia, both with a high tradition of endogamy. The present rate of consanguineous marriages in our control populations is 1.9%,being 3.5% in Castilla-La Mancha and 1.8% in Andalucia. Therefore, the high frequency of Meckel syndrome in these 2 Regions should be secondary to a higher level of inbreeding in previous generations. In endogamic populations, such a s these, although inbreeding may have been decreasing, the frequency of carriers may still remain high enough to increase the risk for autosomal recessive disorders, and this seems to be the situation of Meckel syndrome in Andalucia and Castilla-La Mancha. We did not try to identify the founder affected, only to detect if the observed frequency in each Spanish Region was biased, as occurred in Murcia. Furthermore, studying the Region of origin of the families is important to determine the real gene flow and the changes by migrations in the genetic background of a

629

specific area. This is important for prevention because for many of these conditions it would be possible to direct a prenatal diagnosis and genetic counseling to the population a t risk. This will increase the efficacy of our effort.

ACKNOWLEDGMENTS We thank all the physicians who constitute the collaborating group of the ECEMC and collected the information. We gratefully acknowledge the cooperation of Dr. J.L. Frias (Nebraska) 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 Direccion General de Planificacion Sanitaria, Ministerio de Sanidad y Consumo, Spain. REFERENCES Camera G, Mastroiacovo P (1982):Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. In Papadatos CJ, Bartsocas CS (eds):“Skeletal Dysplasias.” New York: Alan R. Liss Inc., pp 441-449. Emery AEH (1976): “Methodology in Medical Genetics. An Introduction to Statistical Methods.” London: Churchill Livingstone. Fried K (1973):Relatively high prevalence of Meckel syndrome among the Jews. Israel J Med Sci 9:1399. Goodman R, Motulsky A (1979):“Genetic Diseases Among Ashkenazi Jews.” New York: Raven Press. Lurie IW, Prytkou AN, Meldere LV (1984):Meckel syndrome in different populations. Am J Med Genet 18:661-669. Martinez-Frias ML, Salvador J , Prieto L, Zaplana J (1984): Epidemiological study of gastroschisis and omphalocele in Spain. TeratolO ~ Y 29:377-382. Martinez-Frias ML, Salvador J (1987):“Manual Operacional.”Madrid: (Ed.) ECEMC. Martinez-Frias ML, Frias JL, Salvador J (1990):ClinicaUepidemiological analysis of malformations. Am J Med Genet 35121-125. Martinez-Frias ML, Cereijo A, Bermejo E, L6pez MV, Sanchez M, Gonzalo C: Epidemiological aspects of mendelian syndromes in a Spanish population sample: I. Autosomal dominant malformation syndromes. Am J Med Genet (this issue). McKusick VA (1978): “Medical Genetic Studies of the Amish.” Baltimore: The Johns Hopkins University Press. McKusick VA (1988):“Mendelian Inheritance in Man. Catalog of Autosoma1 Dominant, Autosomal Recessive, and X-Linked Phenotypes.” Baltimore: The Johns Hopkins University Press. Moerman P, Verbeken E, Fryns JP, Goddeeris P, Lauweryns JM (1982): The Meckel syndrome. Pathological and cytogeneticobservations in eight cases. Hum Genet 62240-245. Nelson K, Holmes LB (1989): Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 320:19-23. Salonen R, Norio R (1984):The Meckel syndrome in Finland: Epidemiologic and genetic aspects. Am J Med Genet 18:691-698. Schurig V, Bowen P, Harley F, Schiff D (1980):The Meckel syndrome in the Hutterites. Am J Med Genet 5:373-381. Seller MJ (1978): Meckel syndrome and the prenatal diagnosis of neural tube defects. J Med Genet 15:462-465. Steinberg AG, Bleibtreu HK, Kurczynski TW, Martin AO, Kurczynski EM (1967):Genetic studies on a n inbread human isolate. In Crowe J E , Nee1J V (eds):“Proceedings ofthe 3rd International Congress of Human Genetics.”Baltimore: The Johns Hopkins University Press, pp 267-289. Young ID, Rickett AB, Clarke M (1985): High incidence of Meckel’s syndrome in Gujarati Indians. J Med Genet 22:301-304.

Epidemiological aspects of Mendelian syndromes in a Spanish population sample: II. Autosomal recessive malformation syndromes.

From April, 1976, to December, 1988, the Spanish Collaborative Study of Congenital Malformations (ECEMC) monitored a total population of 710,815 liveb...
393KB Sizes 0 Downloads 0 Views