Cliiiiurl Gerietics 1975: 8: 37-47
Congenital urinary tract malformations: epidemiologic and genetic aspects* E. Hoisl, J . FEINGOLD~, H. B E N M A I ZAND ~ M. L. B R I A R D ~
Unite de Recherches sur les Maladies du Mttabolisme chez l’Enfant1, and
Unite de Recherches de GenCtique Medicalez, I.N.S.E.R.M. HApital des Enfants Malades, Paris, France 436 index patients with major congenital urinary tract malformations, 385 with upper and 51 with lower urinary tract anomalies, were studied. A significant male sex predominance
was noted in each group. No apparent correlation was found between parental age, birth order, birth weight and incidence of these malformations. The association with abnormalities outside the urinary tract was more frequent in the upper urinary tract group. In this group, the mean consanguinity index was 283. 10-5 and, among those patients where a family study was made, 16.6 % had positive family histories. The incidence of urinary tract malformations was 4.0 % for the first degree relatives, and 1.1 % for second degree relatives (grandparents only). In this group, the concordance rate was 50 % in four monozygo:ic, and 0 5% (nil) in three dizygotic, twin pairs. The findings, in agreement with studies of other congenital malformations, suggest at least i n part, a multifactorial etiology, particularly in the case of upper urinary tract malformations, depending upon genetic predisposition and environmental factors. Received 8 J u l y , revised 13 December 1974, accepted f o r publication 21 January 1975
Congenital abnormalities of the kidneys and excretory ducts are today among the least understood malformations, both as to frequency and etiology. This is due largely to difficulties in systematic screening during early childhood, related to the rarity of clinical manifestations during the neonatal stage. Nevertheless, it is well established that reno-urinary malformations are relatively common, and account for one third to one quarter of all congenital anomalies. Un-
fortunately, data reported as to frequency in the general population a r e ambivalent, varying from one paper to another, depending on the material studied: detection at birth, morbidity, neonatal autopsies, autopsies at all ages (Rubenstein et al. 1961, Neimann et al. 1965, Kissane 1966, Egli & Stalder 1973, Briard et al. 1975). Moreover, external and internal genital anomalies are frequently confused with studies done on urinary malformations. Excluding polycystic kidneys, it would seem legitimate to
Presented in part at the 4th International Conference on Birth Defects. Vienna, Austria, September 1973. This work was supported by grants from the “Institut National de la Sante et de la Recherche Medicale” (A.T.P. 5). :
38
BOIS, FEINGOLD, BENMAIZ, AND BRIARD
estimate the frequency of major congenital urinary tract malformations ( i t . with clinical signs, necessitating therapeutic intervention) at no more than 4 to 7/1000 (Grampa & Degna Tommasini 1959, Neimann et al. 1965, Klingberg et al. 1971). Such congenital anomalies are generally considered to be embryopathies (Stockhausen 1966, Royer et al. 1970). Knowledge is at present limited as to the familial or genetic aspects of anatomical variations of the urinary tract. A hereditary component has been reported in laboratory animals (Bagg 1929, Fujikura 1970). In man, a familial occurrence has been established in a certain number of urinary tract abnormalities (Girsch & Karpinski 1956, Jewel1 & Buckert 1962, Bercu et al. 1970, Simpson & German 1970, Cook 1972, Buchta et al. 1973, Hack et al. 1974), especially in vesico-renal reflux (Tobenkin 1964, Mulcahy et al. 1970, Amar 1972, Miller & Casperi 1972). A positive family history of vesico-renal reflux has been estimated in about 10 % of cases observed, but the intra-familial distribution of cases and the small numbers in the series studied do not permit any precise understanding of the basic genetic mechanism. Recently, Schmidt et al. (1972) and Burger (1971) emphasized the very low incidence of the vesico-renal reflux and other urinary tract malformations among the black population in varying environments. They believe that there can only be a genetic basis for this phenomenon. In addition, urinary tract malformations have been reported in cases with aberration of the sex-chromosomes, as well as of the autosomes (Lejeune et al. 1965, Egli & Stalder 1973). The main purpose of this paper is to study: 1) the possible cffect of certain epidemiologic factors on the incidence of such abnormalities; and 2) the existence of familial aggregation; thereby allowing a connection to be made between their etiology
and the polygenic inheritance, which is at the base of numerous congenital malformations.
Materials and Methods The present study is based on a series of 436 children (“index patients”, 264 males and 172 females), hospitalized at the Clinique des Maladies du Rein (HBpital des Enfants Malades, Paris) for congenital urinary tract abnormalities with clinical findings necessitating therapeutic intervention. All were investigated by cystography and/or excretory pyelography. Excluding the cases of hereditary polycystic kidneys, a variety of primary anatomic abnormalities were found. After comparative studies on each type of malformation, and taking into consideration embryologic data, the total sample was divided into two main groups (Table 1): 1) the upper urinary tract group A (385 patients), and 2)
Table 1
Distribution of 436 patients found to have various primary urinary tract malformations Group A: Upper urlnary tract Abnormalities of the renal parenchyma (hypoplasia, dysplasia, oligonephronic hypoplasia) Calyceal anomalies Solitary kidney Renal ectopia Abnormalities of uretero-pelvic junction Ureteral and pelvic duplication Idiopathic mega-ureter Vesico-renal reflux Total
67 7 30 21 61 58 66 75 385
Group 6 : Lower urinary tract Bladder exstrophy Urethral obstruction Bladder diverticulum Urethral valves Other abnormalities
8 5 2 19 17
Total
51
CONGENITAL URINARY TRACT MALFORMATIONS
a small group, B, for the lower urinary tract (51 patients). The latter group of patients presented with only a single urinary anomaly. Of the patients in Group A, 10.4 % presented with two or more urinary tract malformations. Only those lesions considered as primary, or those responsible for the patient seeking medical care were considered. Thus although selection may seem arbitrary, the bias, if any, was minor, since the subgroups of the upper urinary tract group did not differ appreciably. Data were obtained by medical and surgical records, and by interviewing the families, or from questionnaires sent to them by mail. All the index patients were French Caucasians, born in Paris (49), in provincial towns (250), or in rural areas (137). This corresponds approximately to the general distribution of the French population. The study of consanguinity, occurrence of
39
twins, and familial occurrence was made exclusively on patients with only urinary tract malformations. Those with associated abnormalities outside the urinary tract were excluded. With regard to familial occurrence, only relatives for whom it was possible to obtain documentary confirmation of major malformations were considered. Abnormalities discovered by chance, not having presented with clinical signs or symptoms, were not considered. Complete family histories were obtained for the first degree relatives (parents, siblings) in 181 cases (upper urinary tract) and in 18 cases (lower urinary tract): information exclusively concerning the siblings was obtained in 24 cases and in 6 cases, respectively. A certain number of well-documented cases were ascertained for second and third degree relatives, but the exact total number of these relatives is not known. Thus, the
Table 2 Epidemiologic study. Comparison of upper and lower urinary tract malformations Upper urinary tract malformations (Group A)
Lower urinary tract malformations (Group B)
No.
No.
385 284 286 350
0.57*; 30.91 f 6.46 27.70 ? 6.24 2.38 f 1.71
Male birth weight (9)
186
3210 k 630
Female birth weight (9)
137
Index Mean Mean Mean
of masculinity paternal age (years) maternal age (years) birth order
Single, outside the urinary tract, associated malformations Multiple, outside the urinary tract, associated malformations
\
51 45 45 49
0.80 31.33 f 6.93 26.76 f 6.55 2.47 f 1.86
37
3490 k 770'
3186 f 604
9
3150 f 510
385
14 ' / a
51
9.8 Vn
385
13 %
51
9.8 010
;
Controls
.
No.
20,163(1) (2) (2) 21,347 (3) 11,657 (3) 9,690 (3)
0.52 31.05 f 6.64 27.64 f 5.53 2.35 k 1.68 3344 f 517 3220 f 486
(1) Briard et al. 1975.
(2) French Vital Statistics INSEE. (3) Feingold et al. 1970.
...
Statistical differences between: Groups A and B ('P trols P.( 2 0.05, M I P 0.01, P 5 0.001).
Congenital urinary tract malformations: epidemiologic and genetic aspects* E. Hoisl, J . FEINGOLD~, H. B E N M A I ZAND ~ M. L. B R I A R D ~
Unite de Recherches sur les Maladies du Mttabolisme chez l’Enfant1, and
Unite de Recherches de GenCtique Medicalez, I.N.S.E.R.M. HApital des Enfants Malades, Paris, France 436 index patients with major congenital urinary tract malformations, 385 with upper and 51 with lower urinary tract anomalies, were studied. A significant male sex predominance
was noted in each group. No apparent correlation was found between parental age, birth order, birth weight and incidence of these malformations. The association with abnormalities outside the urinary tract was more frequent in the upper urinary tract group. In this group, the mean consanguinity index was 283. 10-5 and, among those patients where a family study was made, 16.6 % had positive family histories. The incidence of urinary tract malformations was 4.0 % for the first degree relatives, and 1.1 % for second degree relatives (grandparents only). In this group, the concordance rate was 50 % in four monozygo:ic, and 0 5% (nil) in three dizygotic, twin pairs. The findings, in agreement with studies of other congenital malformations, suggest at least i n part, a multifactorial etiology, particularly in the case of upper urinary tract malformations, depending upon genetic predisposition and environmental factors. Received 8 J u l y , revised 13 December 1974, accepted f o r publication 21 January 1975
Congenital abnormalities of the kidneys and excretory ducts are today among the least understood malformations, both as to frequency and etiology. This is due largely to difficulties in systematic screening during early childhood, related to the rarity of clinical manifestations during the neonatal stage. Nevertheless, it is well established that reno-urinary malformations are relatively common, and account for one third to one quarter of all congenital anomalies. Un-
fortunately, data reported as to frequency in the general population a r e ambivalent, varying from one paper to another, depending on the material studied: detection at birth, morbidity, neonatal autopsies, autopsies at all ages (Rubenstein et al. 1961, Neimann et al. 1965, Kissane 1966, Egli & Stalder 1973, Briard et al. 1975). Moreover, external and internal genital anomalies are frequently confused with studies done on urinary malformations. Excluding polycystic kidneys, it would seem legitimate to
Presented in part at the 4th International Conference on Birth Defects. Vienna, Austria, September 1973. This work was supported by grants from the “Institut National de la Sante et de la Recherche Medicale” (A.T.P. 5). :
38
BOIS, FEINGOLD, BENMAIZ, AND BRIARD
estimate the frequency of major congenital urinary tract malformations ( i t . with clinical signs, necessitating therapeutic intervention) at no more than 4 to 7/1000 (Grampa & Degna Tommasini 1959, Neimann et al. 1965, Klingberg et al. 1971). Such congenital anomalies are generally considered to be embryopathies (Stockhausen 1966, Royer et al. 1970). Knowledge is at present limited as to the familial or genetic aspects of anatomical variations of the urinary tract. A hereditary component has been reported in laboratory animals (Bagg 1929, Fujikura 1970). In man, a familial occurrence has been established in a certain number of urinary tract abnormalities (Girsch & Karpinski 1956, Jewel1 & Buckert 1962, Bercu et al. 1970, Simpson & German 1970, Cook 1972, Buchta et al. 1973, Hack et al. 1974), especially in vesico-renal reflux (Tobenkin 1964, Mulcahy et al. 1970, Amar 1972, Miller & Casperi 1972). A positive family history of vesico-renal reflux has been estimated in about 10 % of cases observed, but the intra-familial distribution of cases and the small numbers in the series studied do not permit any precise understanding of the basic genetic mechanism. Recently, Schmidt et al. (1972) and Burger (1971) emphasized the very low incidence of the vesico-renal reflux and other urinary tract malformations among the black population in varying environments. They believe that there can only be a genetic basis for this phenomenon. In addition, urinary tract malformations have been reported in cases with aberration of the sex-chromosomes, as well as of the autosomes (Lejeune et al. 1965, Egli & Stalder 1973). The main purpose of this paper is to study: 1) the possible cffect of certain epidemiologic factors on the incidence of such abnormalities; and 2) the existence of familial aggregation; thereby allowing a connection to be made between their etiology
and the polygenic inheritance, which is at the base of numerous congenital malformations.
Materials and Methods The present study is based on a series of 436 children (“index patients”, 264 males and 172 females), hospitalized at the Clinique des Maladies du Rein (HBpital des Enfants Malades, Paris) for congenital urinary tract abnormalities with clinical findings necessitating therapeutic intervention. All were investigated by cystography and/or excretory pyelography. Excluding the cases of hereditary polycystic kidneys, a variety of primary anatomic abnormalities were found. After comparative studies on each type of malformation, and taking into consideration embryologic data, the total sample was divided into two main groups (Table 1): 1) the upper urinary tract group A (385 patients), and 2)
Table 1
Distribution of 436 patients found to have various primary urinary tract malformations Group A: Upper urlnary tract Abnormalities of the renal parenchyma (hypoplasia, dysplasia, oligonephronic hypoplasia) Calyceal anomalies Solitary kidney Renal ectopia Abnormalities of uretero-pelvic junction Ureteral and pelvic duplication Idiopathic mega-ureter Vesico-renal reflux Total
67 7 30 21 61 58 66 75 385
Group 6 : Lower urinary tract Bladder exstrophy Urethral obstruction Bladder diverticulum Urethral valves Other abnormalities
8 5 2 19 17
Total
51
CONGENITAL URINARY TRACT MALFORMATIONS
a small group, B, for the lower urinary tract (51 patients). The latter group of patients presented with only a single urinary anomaly. Of the patients in Group A, 10.4 % presented with two or more urinary tract malformations. Only those lesions considered as primary, or those responsible for the patient seeking medical care were considered. Thus although selection may seem arbitrary, the bias, if any, was minor, since the subgroups of the upper urinary tract group did not differ appreciably. Data were obtained by medical and surgical records, and by interviewing the families, or from questionnaires sent to them by mail. All the index patients were French Caucasians, born in Paris (49), in provincial towns (250), or in rural areas (137). This corresponds approximately to the general distribution of the French population. The study of consanguinity, occurrence of
39
twins, and familial occurrence was made exclusively on patients with only urinary tract malformations. Those with associated abnormalities outside the urinary tract were excluded. With regard to familial occurrence, only relatives for whom it was possible to obtain documentary confirmation of major malformations were considered. Abnormalities discovered by chance, not having presented with clinical signs or symptoms, were not considered. Complete family histories were obtained for the first degree relatives (parents, siblings) in 181 cases (upper urinary tract) and in 18 cases (lower urinary tract): information exclusively concerning the siblings was obtained in 24 cases and in 6 cases, respectively. A certain number of well-documented cases were ascertained for second and third degree relatives, but the exact total number of these relatives is not known. Thus, the
Table 2 Epidemiologic study. Comparison of upper and lower urinary tract malformations Upper urinary tract malformations (Group A)
Lower urinary tract malformations (Group B)
No.
No.
385 284 286 350
0.57*; 30.91 f 6.46 27.70 ? 6.24 2.38 f 1.71
Male birth weight (9)
186
3210 k 630
Female birth weight (9)
137
Index Mean Mean Mean
of masculinity paternal age (years) maternal age (years) birth order
Single, outside the urinary tract, associated malformations Multiple, outside the urinary tract, associated malformations
\
51 45 45 49
0.80 31.33 f 6.93 26.76 f 6.55 2.47 f 1.86
37
3490 k 770'
3186 f 604
9
3150 f 510
385
14 ' / a
51
9.8 Vn
385
13 %
51
9.8 010
;
Controls
.
No.
20,163(1) (2) (2) 21,347 (3) 11,657 (3) 9,690 (3)
0.52 31.05 f 6.64 27.64 f 5.53 2.35 k 1.68 3344 f 517 3220 f 486
(1) Briard et al. 1975.
(2) French Vital Statistics INSEE. (3) Feingold et al. 1970.
...
Statistical differences between: Groups A and B ('P trols P.( 2 0.05, M I P 0.01, P 5 0.001).
