Hum Genet (1992) 89: 557-560
9 Springer-Verlag1992
Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p Luis Izquierdo 1, Mary Porteous 2, Pedro G. Paramo 3, and J. Michael Connor 1 1University Department of Medical Genetics, Duncan Guthrie Institute, Yorkhill, Glasgow G3 8SJ, UK 2Department of Human Genetics, Newcastle, UK aDepartment of Urology, Hospital Universitario San Carlos, Madrid, Spain Received September 15, 1991 / Revised January 8, 1992
Summary. Hereditary hydronephrosis (MIM 143400) is an autosomal dominant trait that causes unilateral or bilateral pelvi-ureteric junction (PUJ) obstruction. Linkage analysis was undertaken in 5 families with hereditary PUJ obstruction using the major histocompatibility complex locus as a test marker. The data as a whole supported a hereditary hydronephrosis locus on 6p. Maximal lod scores were 3.090 at a recombination fraction of 0.1 with full penetrance, and 2.486 at a recombination fraction of 0.1 with a penetrance of 90%. However, analysis of two point lod scores using the H O M O G program revealed significant evidence for genetic heterogeneity with one locus on 6p in 4 of the families, and a different locus in one family. After exclusion of this unlinked family, two point analysis gave a maximal lod score of 3.9 at a recombination fraction of 0.05 with full penetrance, and 4.2 at a recombination fraction of 0.0 with 90% penetrance. These data support the assignment of one of the loci for hereditary hydronephrosis to chromosome 6p.
Introduction Prospective studies of patients detected during routine antenatal ultrasound scanning have indicated an overall incidence of clinically significant uropathy of 1 in 500 (Thomas 1990). Pelvi-ureteric junction (PUJ) obstruction accounts for 50% of cases with vesico-ureteric reflux (15%), multicystic dysplasia (15%), posterior urethral valves (10%) and other pathologies (10%) in the remainder. In such prospective studies, the majority of patients with PUJ obstruction remain asymptomatic and relatively few develop symptoms, such as abdominal pain or hematuria, and only 2 0 % - 3 0 % require surgical intervention on the basis of symptoms and/or deteriorating renal function (Arnold and Rickwood 1990; Ransley Correspondence to: L. Izquierdo
et al. 1990). These prospective studies have also found that spontaneous resolution of documented PUJ obstruction is not infrequent. For example, in the study of Arnold and Rickwood (1990), 10% of clinically significant PUJ obstructions were spontaneously resolved during a follow-up period of up to 4 years. A total of 22 families has now been described with hereditary PUJ obstruction showing a pattern consistent with autosomal inheritance, but with variable expression and incomplete penetrance (Paramo et al. 1991). Variable expression is apparent both within and between families for bilaterality, the presence or absence of symptoms, and pathological findings. Sengar et al. (1979) first noted cosegregation of the major histocompatibility complex with hereditary hydronephrosis. Their proband had developed renal failure and, with a view to renal transplantation, family members were histocompatibility antigen ( H L A ) typed; those with shared haplotypes undertook renal studies that revealed that 5 out of the 13 sibs were affected. Formal linkage analysis was not carried out and we thus wish to describe linkage analysis using the major histocompatibility complex in a new family with hereditary hydronephrosis, together with four previously published families.
Families and methods Linkage analysis was undertaken in 5 families with hereditary PUJ obstruction (Figs. 1, 2). Family 1 is a three-generation family in which unilateral hydronephrosis confirmed by intravenous pyelography (IVP), ultrasonography (USG) and 99Tc DTPA, was present in the grandfather, the father and two sons (Paramo et al. 1991). Families 2 and 3 were reported by Buscemi et al. (1985). Family 2 is a two-generation family with two sibs affected with PUJ obstruction. The family history is remarkable in that the mother's younger brother had a chronic fight renal disorder suggestive of obstruction, and her mother had a congenital abdominal mass on the right side and chronic urinary tract infection. The mother of the two affected children gave normal renal abdominal ultrasound
558 Family 4
Family 1 Family 2
nhnh*OOd a/c a/c a/c a/d aid a/d b/c b/d b/d b/d b/d b/d bid
m m a/c
a/e
a/f
c/e
HLA haplotypes a: AW30,BW22 b: A10,BW16 c: A3.B12 d: A1,B8
b/c
HLA haplotypes a: A2,B5,CW2 b: A31,B40,CW2 c: A2,B27,CW2 d: A3,B7,-
HLA haplotypes a: A28,B15(W62),CW7 b: A30,B13,CWc: A2,B17,CWd: A1,B8,CW-
Family 5 Family 3
[]
O
a/b
[]
~ c / d ( ~ _ ~ l [
e/f
dmc 0 m0od
4/1 3/2 3/1 3/1 4/2 NT X/2 NT 5/2
c/a
a: c: d: f:
d/a
die
c/e
HLA haplotypes A2,B16,CW-,DR2 A 1,BW17(W58),CW-,DR6Y A2,B8,CW-,DR3 AW32,BW2I(W50),CW-,DR7
Fig. 1. Three families with hereditary hydronephrosis caused by PUJ obstruction. H L A haplotypes are indicated for each individual except for haplotypes b and e in family 3; these were not given in Busceni et al. (1985)
results. A woman who had affected children in two different marriages comes from family 3. Family 4 is a two-generation family, reported by Sengar et al. (1979), with 5 out of 13 sibs affected. Renal function in both parents and non-affected sibs was normal, and IVP studies did not show urinary tract anomalies. Family 5 is a three-generation family in which the proband had unilateral renal agenesis, hereditary hydronephrosis caused by PUJ obstruction, and familial benign hypercalcemia. Subsequent family screening with ultrasound revealed a sister and brother with unilateral PUJ obstruction and 3 sibs who had familial benign hypercalcemia. The other sibs and mother gave normal ultrasound results. However, a maternal aunt was noted as having had a PUJ obstruction resolved by surgery, but this branch of the family was not further investigated. Two point linkage analysis for the major histocompatibility complex and the hereditary hydronephrosis trait was carried out with the linkage program LIPED using a disease allele frequency of 0.001 and with penetrances of 100% and 90%. Analysis of heterogeneity was undertaken using H O M O G .
Results The lod-scores for different recombination fractions between hereditary PUJ obstruction and the major histocompatibility complex are given in the Tables 1, 2. With 100% penetrance, the maximal lod score was 3.09 at a recombination fraction of 0.1. With 90% penetrance, the maximal lod score was 2.4 at a recombination fraction of 0.1.
5/2
NT 7/1 8/2
9/2 9/2
Fig. 2. Two families with hereditary hydronephrosis caused PUJ obstruction. H L A haplotypes are indicated for each individual in family 4 but, in family 5, haplotypes with the exception of haplotype 1 (A2, B7, DR2) and 2 (A3, B17, DRT) are given as in Mackintosh et al. (1989)
Analysis using H O M O G revealed statistically significant evidence of genetic heterogeneity (P = 0.0307 with 100% penetrance, and P = 0.0219 with 90%), with an indication of a second locus unlinked to the major histocompatibility complex in family 5. After exclusion of this family, the maximal lod score was 3.9 at a recombination fraction of 0.05 with full penetrance (Table 3), and 4.2 at a zero combination fraction with 90% penetrance (Table
4). Discussion These data provide evidence for linkage of hereditary hydronephrosis caused by PUJ obstruction to the major histocompatibility complex on chromosome 6p. The analysis is complicated by the variable expression of this trait and by reduced penetrance that, at least in part, reflects spontaneous resolution in older individuals. The spectrum of hereditary hydronephrosis may be wider than PUJ obstruction alone, and may include paraureteric diverticula, bifid ureters and vesico-ureteric reflux on the basis of an increased incidence of these findings both in patients and in their first degree relatives (Atwell 1985). Dwoskin (1979) reviewed 37 siblings of 20 probands with PUJ obstruction and found that 14 had some type of uropathy, including 3 with PUJ obstruction. Atwell (1985) studied first degree relatives of 19 probands with PUJ obstruction and found PUJ obstruction in 9, duplex ureter in 3, and vesico-ureteric reflux in one. Atwell and Allen (1980) studied first degree relatives of 22 patients with paraureteric diverticula and found 5 duplications of the pelvicaliceal sys-
559 Table 1. Linkage analysis in 5 families with hereditary hydronephrosis caused by PUJ obstruction at 100% penetrance
0.000 Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Mackintosh et al. (1989)
Family 1 Family 2 Family 3 Family 4 Family 5
Total
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.903 0.301 0.903 0.000 -99.99
0.902 0.300 0.902 0.607 -2.831
0.836 0.258 0.836 2.044 - 1.712
0.766 0.215 0.766 2.063 -0.720
0.612 0.134 0.517 1.750 -0.271
0.438 0.064 0.298 1.231 -0.061
0.238 0.017 0.094 0.557 0.000
0.000 0.000 0.000 0.000 0.000
- 97.88
- 0.120
2.262
3.090
2.742
1.970
0.906
0.000
Table 2. Linkage analysis in 5 families with hereditary hydronephrosis caused by PUJ obstruction at 90% penetrance 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Mackintosh et al. (1989)
Family i Family 2 Family 3 Family 4 Family 5
Total
0.000
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.862 0.301 0.802 2.281 -4.180
0.860 0.300 0.819 2.280 -3.682
0.797 0.258 0.736 2.191 -1.729
0.729 0.215 0.647 2.044 -1.148
0.582 0.134 0.457 1.641 -0.523
0.415 0.064 0.257 1.118 -0.204
0.224 0.017 0.079 0.481 -0.047
0.000 0.000 0.000 0.000 0.000
0.066
0.577
2.253
2.486
2.291
1.650
0.759
0.000
Table 3. Linkage analysis in 4 families with hereditary hydronephrosis caused by PUJ obstruction at 100% penetrance after exclusion of family 5 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979)
Family i Family 2 Family 3 Family 4
Total
0.000
0.010
0.050
0.100
0.200
0,300
0.400
0.500
0.903 0.301 0.903 0.000
0.902 0.300 0.902 0.607
0.836 0.258 0.836 2.044
0.766 0.215 0.766 2.063
0.612 0.134 0.517 1.750
0.438 0.064 0.298 1.231
0.238 0.017 0.094 0.557
0.000 0.000 0.000 0.000
2.107
2.711
3.974
3.810
3.013
2.031
0.906
0.000
Table 4. Linkage analysis in 4 families with hereditary hydronephrosis caused by PUJ obstruction at 90% penetrance after exclusion of family 5 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Total
Family 1 Family 2 Family 3 Family 4
0.000
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.862 0.301 0.802 2.281
0.860 0.300 0.819 2.280
0.797 0.258 0.736 2.191
0.729 0.215 0.647 2.044
0.582 0.134 0.457 1.641
0.415 0.064 0.257 1.118
0.224 0.017 0.079 0.486
0.000 0.000 0.000 0.000
4.246
4.259
3.982
3.635
2.814
1.854
0.712
0.000
t e m , 3 with v e s i c o - u r e t e r i c reflux, 1 with P U J o b s t r u c tion, and 1 paraureteric diverticulum. The frequency of d u p l e x u r e t e r is also i n c r e a s e d f r o m t h e g e n e r a l p o p u l a tion f r e q u e n c y o f 0.7% to 3 . 3 % in p a t i e n t s with P U J o b s t r u c t i o n ( A t w e l l 1985; T h o m a s et al. 1982); vesicou r e t e r i c reflux coexists in 10% o f p a t i e n t s with P U J o b s t r u c t i o n ( M a i z e l s et al. 1984; T h o m a s et al. 1982; L e b o w i t z a n d B l i c h m a n 1983). S e n g a r et al. (1979) p e r f o r m e d H L A t y p i n g in 4 twog e n e r a t i o n families with 2 o r m o r e m e m b e r s a f f e c t e d
with v e s i c o u r e t e r i c reflux a n d n o t i c e d c o s e g r e g a t i o n of the trait in 16 p h a s e u n k n o w n m e i o s e s with H L A ; h o w e v e r , no f o r m a l l i n k a g e analysis was p e r f o r m e d . M a c k i n t o s h et al. (1989) c a r r i e d o u t l i n k a g e analysis in 2 families with v e s i c o u r e t e r i c reflux a n d f o u n d a m a x i m a l l o d s c o r e o f 3.326 at 0 = 0.05. T h e s e studies s u p p o r t l o c a l i z a t i o n o f h e r e d i t y v e s i c o u r e t e r i c reflux to 6p a n d , in c o n j u n c t i o n with t h e f a m i l y studies d e s c r i b e d a b o v e , support the idea of a disease spectrum including PUJ o b s t r u c t i o n a n d v e s i c o - u r e t e r i c reflux c a u s e d b y m u t a -
560 tion in a single locus or closely linked loci on 6p. Analysis of further families needs to take into account the natural history of this condition, the range of expression and the n e e d to use appropriate m e a n s of investigation. For example, screening of family m e m b e r s with abdominal ultrasound alone would not detect vesicoureteric reflux, ureteric diverticula or double ureter. The family described by Mackintosh et al. (1989) also showed autosomal d o m i n a n t hypercalcemia but was otherwise indistinguishable from the hereditary hydronephrosis families showing linkage to the m a j o r histocompatibility complex. F u r t h e r genetic h e t e r o g e n e i t y is also likely in hereditary hydronephrosis, as autosomal d o m i n a n t families have also b e e n described in which the whole urinary tract is dilated in family m e m b e r s (MacKay 1945; M c C o r m a c k 1982; Wladimiroff et al. 1985).
References Arnold AJ, Rickwood AMK (1990) Natural history of pelviureteric obstruction detected by prenatal sonography. Br J Urol 65 : 91 Atwell JD (1985) Familial pelviureteric junction hydronephrosis and its association with a duplex pelvicaliceal system and vesicoureteric reflux. A family study. Br J Urol 57 : 365 Atwell JD, Allen NH (1980) The interrelationship between paraureteric diverticula, vesicoureteral reflux and duplication of the pelvicaliceal collecting system: a family study. Br J Urol 52 : 269-273 Buscemi M, Shanske A, Mallet E, Ozoktay S, Hanna MK (1985) Dominantly inherited ureteropelvic junction obstruction. Urology 26 : 568
Dwoskin JY (1979) Ureteropelvic junction obstruction and sibling uropathology. Urology 13 : 153 Lebowitz RL, Blickman JG (1983) The coexistence of ureteropelvic junction obstruction and reflux. Am J Roent 140:231-238 MacCormak M (1982) Prenatal detection of the autosomal dominant type of congenital hydronephrosis by ultrasonography. Prenat Diagn 2 : 157-161 Mackintosh M, Almarhoos G, Heath DA (1989) HLA linkage with familial vesicoureteral reflux and familial pelvi-ureteric junction obstruction. Tissue Antigens 34:185-189 MacKay M (1945) Congenital bilateral megaloureters with hydronephrosis. A remarkable family history. Proc R Soc Med 38: 567-568 Maizels M, Smith CK, Firlit CF (1984) The management of children with vesico-ureteral reflux and ureteropelvic junction obstruction. J Urol 131:722-727 Paramo P, Izquierdo L, Paramo PS, LLorente L, Uson AC (1991) Hereditary hydronephrosis: a three generation family. Eur J Urol (in press) Ransley PG, Dhillon HK, Godon I, Duffy PG, Dillon MJ, Barrat TM (1990) The postnatal management of hydronephrosis diagnosed by prenatal ultrasound. J Urol 144 : 584 Sengar DPS, Rashid A, Wolfish (1979) Familial urinary tract anomalies. J Urol 121 : 194 Thomas DFM (1990) Fetal uropathy. Br J Urol 66:225 Thomas DFM, Agarwal M, Laidin AZ, Eckstein HB (1982) Pelviureteric obstruction in infancy and childhood. A review of 117 patients. Br J UroI 54 : 204-208 Wladimiroff JW, Beemer FA, Scholtmeyer R J, Stewart PA, Spritzer R, Wolf ED (1985) Failure to detect fetal obstrtictive uropathy by second trimester ultrasound. Prenat Diagn 5:4146
9 Springer-Verlag1992
Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p Luis Izquierdo 1, Mary Porteous 2, Pedro G. Paramo 3, and J. Michael Connor 1 1University Department of Medical Genetics, Duncan Guthrie Institute, Yorkhill, Glasgow G3 8SJ, UK 2Department of Human Genetics, Newcastle, UK aDepartment of Urology, Hospital Universitario San Carlos, Madrid, Spain Received September 15, 1991 / Revised January 8, 1992
Summary. Hereditary hydronephrosis (MIM 143400) is an autosomal dominant trait that causes unilateral or bilateral pelvi-ureteric junction (PUJ) obstruction. Linkage analysis was undertaken in 5 families with hereditary PUJ obstruction using the major histocompatibility complex locus as a test marker. The data as a whole supported a hereditary hydronephrosis locus on 6p. Maximal lod scores were 3.090 at a recombination fraction of 0.1 with full penetrance, and 2.486 at a recombination fraction of 0.1 with a penetrance of 90%. However, analysis of two point lod scores using the H O M O G program revealed significant evidence for genetic heterogeneity with one locus on 6p in 4 of the families, and a different locus in one family. After exclusion of this unlinked family, two point analysis gave a maximal lod score of 3.9 at a recombination fraction of 0.05 with full penetrance, and 4.2 at a recombination fraction of 0.0 with 90% penetrance. These data support the assignment of one of the loci for hereditary hydronephrosis to chromosome 6p.
Introduction Prospective studies of patients detected during routine antenatal ultrasound scanning have indicated an overall incidence of clinically significant uropathy of 1 in 500 (Thomas 1990). Pelvi-ureteric junction (PUJ) obstruction accounts for 50% of cases with vesico-ureteric reflux (15%), multicystic dysplasia (15%), posterior urethral valves (10%) and other pathologies (10%) in the remainder. In such prospective studies, the majority of patients with PUJ obstruction remain asymptomatic and relatively few develop symptoms, such as abdominal pain or hematuria, and only 2 0 % - 3 0 % require surgical intervention on the basis of symptoms and/or deteriorating renal function (Arnold and Rickwood 1990; Ransley Correspondence to: L. Izquierdo
et al. 1990). These prospective studies have also found that spontaneous resolution of documented PUJ obstruction is not infrequent. For example, in the study of Arnold and Rickwood (1990), 10% of clinically significant PUJ obstructions were spontaneously resolved during a follow-up period of up to 4 years. A total of 22 families has now been described with hereditary PUJ obstruction showing a pattern consistent with autosomal inheritance, but with variable expression and incomplete penetrance (Paramo et al. 1991). Variable expression is apparent both within and between families for bilaterality, the presence or absence of symptoms, and pathological findings. Sengar et al. (1979) first noted cosegregation of the major histocompatibility complex with hereditary hydronephrosis. Their proband had developed renal failure and, with a view to renal transplantation, family members were histocompatibility antigen ( H L A ) typed; those with shared haplotypes undertook renal studies that revealed that 5 out of the 13 sibs were affected. Formal linkage analysis was not carried out and we thus wish to describe linkage analysis using the major histocompatibility complex in a new family with hereditary hydronephrosis, together with four previously published families.
Families and methods Linkage analysis was undertaken in 5 families with hereditary PUJ obstruction (Figs. 1, 2). Family 1 is a three-generation family in which unilateral hydronephrosis confirmed by intravenous pyelography (IVP), ultrasonography (USG) and 99Tc DTPA, was present in the grandfather, the father and two sons (Paramo et al. 1991). Families 2 and 3 were reported by Buscemi et al. (1985). Family 2 is a two-generation family with two sibs affected with PUJ obstruction. The family history is remarkable in that the mother's younger brother had a chronic fight renal disorder suggestive of obstruction, and her mother had a congenital abdominal mass on the right side and chronic urinary tract infection. The mother of the two affected children gave normal renal abdominal ultrasound
558 Family 4
Family 1 Family 2
nhnh*OOd a/c a/c a/c a/d aid a/d b/c b/d b/d b/d b/d b/d bid
m m a/c
a/e
a/f
c/e
HLA haplotypes a: AW30,BW22 b: A10,BW16 c: A3.B12 d: A1,B8
b/c
HLA haplotypes a: A2,B5,CW2 b: A31,B40,CW2 c: A2,B27,CW2 d: A3,B7,-
HLA haplotypes a: A28,B15(W62),CW7 b: A30,B13,CWc: A2,B17,CWd: A1,B8,CW-
Family 5 Family 3
[]
O
a/b
[]
~ c / d ( ~ _ ~ l [
e/f
dmc 0 m0od
4/1 3/2 3/1 3/1 4/2 NT X/2 NT 5/2
c/a
a: c: d: f:
d/a
die
c/e
HLA haplotypes A2,B16,CW-,DR2 A 1,BW17(W58),CW-,DR6Y A2,B8,CW-,DR3 AW32,BW2I(W50),CW-,DR7
Fig. 1. Three families with hereditary hydronephrosis caused by PUJ obstruction. H L A haplotypes are indicated for each individual except for haplotypes b and e in family 3; these were not given in Busceni et al. (1985)
results. A woman who had affected children in two different marriages comes from family 3. Family 4 is a two-generation family, reported by Sengar et al. (1979), with 5 out of 13 sibs affected. Renal function in both parents and non-affected sibs was normal, and IVP studies did not show urinary tract anomalies. Family 5 is a three-generation family in which the proband had unilateral renal agenesis, hereditary hydronephrosis caused by PUJ obstruction, and familial benign hypercalcemia. Subsequent family screening with ultrasound revealed a sister and brother with unilateral PUJ obstruction and 3 sibs who had familial benign hypercalcemia. The other sibs and mother gave normal ultrasound results. However, a maternal aunt was noted as having had a PUJ obstruction resolved by surgery, but this branch of the family was not further investigated. Two point linkage analysis for the major histocompatibility complex and the hereditary hydronephrosis trait was carried out with the linkage program LIPED using a disease allele frequency of 0.001 and with penetrances of 100% and 90%. Analysis of heterogeneity was undertaken using H O M O G .
Results The lod-scores for different recombination fractions between hereditary PUJ obstruction and the major histocompatibility complex are given in the Tables 1, 2. With 100% penetrance, the maximal lod score was 3.09 at a recombination fraction of 0.1. With 90% penetrance, the maximal lod score was 2.4 at a recombination fraction of 0.1.
5/2
NT 7/1 8/2
9/2 9/2
Fig. 2. Two families with hereditary hydronephrosis caused PUJ obstruction. H L A haplotypes are indicated for each individual in family 4 but, in family 5, haplotypes with the exception of haplotype 1 (A2, B7, DR2) and 2 (A3, B17, DRT) are given as in Mackintosh et al. (1989)
Analysis using H O M O G revealed statistically significant evidence of genetic heterogeneity (P = 0.0307 with 100% penetrance, and P = 0.0219 with 90%), with an indication of a second locus unlinked to the major histocompatibility complex in family 5. After exclusion of this family, the maximal lod score was 3.9 at a recombination fraction of 0.05 with full penetrance (Table 3), and 4.2 at a zero combination fraction with 90% penetrance (Table
4). Discussion These data provide evidence for linkage of hereditary hydronephrosis caused by PUJ obstruction to the major histocompatibility complex on chromosome 6p. The analysis is complicated by the variable expression of this trait and by reduced penetrance that, at least in part, reflects spontaneous resolution in older individuals. The spectrum of hereditary hydronephrosis may be wider than PUJ obstruction alone, and may include paraureteric diverticula, bifid ureters and vesico-ureteric reflux on the basis of an increased incidence of these findings both in patients and in their first degree relatives (Atwell 1985). Dwoskin (1979) reviewed 37 siblings of 20 probands with PUJ obstruction and found that 14 had some type of uropathy, including 3 with PUJ obstruction. Atwell (1985) studied first degree relatives of 19 probands with PUJ obstruction and found PUJ obstruction in 9, duplex ureter in 3, and vesico-ureteric reflux in one. Atwell and Allen (1980) studied first degree relatives of 22 patients with paraureteric diverticula and found 5 duplications of the pelvicaliceal sys-
559 Table 1. Linkage analysis in 5 families with hereditary hydronephrosis caused by PUJ obstruction at 100% penetrance
0.000 Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Mackintosh et al. (1989)
Family 1 Family 2 Family 3 Family 4 Family 5
Total
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.903 0.301 0.903 0.000 -99.99
0.902 0.300 0.902 0.607 -2.831
0.836 0.258 0.836 2.044 - 1.712
0.766 0.215 0.766 2.063 -0.720
0.612 0.134 0.517 1.750 -0.271
0.438 0.064 0.298 1.231 -0.061
0.238 0.017 0.094 0.557 0.000
0.000 0.000 0.000 0.000 0.000
- 97.88
- 0.120
2.262
3.090
2.742
1.970
0.906
0.000
Table 2. Linkage analysis in 5 families with hereditary hydronephrosis caused by PUJ obstruction at 90% penetrance 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Mackintosh et al. (1989)
Family i Family 2 Family 3 Family 4 Family 5
Total
0.000
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.862 0.301 0.802 2.281 -4.180
0.860 0.300 0.819 2.280 -3.682
0.797 0.258 0.736 2.191 -1.729
0.729 0.215 0.647 2.044 -1.148
0.582 0.134 0.457 1.641 -0.523
0.415 0.064 0.257 1.118 -0.204
0.224 0.017 0.079 0.481 -0.047
0.000 0.000 0.000 0.000 0.000
0.066
0.577
2.253
2.486
2.291
1.650
0.759
0.000
Table 3. Linkage analysis in 4 families with hereditary hydronephrosis caused by PUJ obstruction at 100% penetrance after exclusion of family 5 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979)
Family i Family 2 Family 3 Family 4
Total
0.000
0.010
0.050
0.100
0.200
0,300
0.400
0.500
0.903 0.301 0.903 0.000
0.902 0.300 0.902 0.607
0.836 0.258 0.836 2.044
0.766 0.215 0.766 2.063
0.612 0.134 0.517 1.750
0.438 0.064 0.298 1.231
0.238 0.017 0.094 0.557
0.000 0.000 0.000 0.000
2.107
2.711
3.974
3.810
3.013
2.031
0.906
0.000
Table 4. Linkage analysis in 4 families with hereditary hydronephrosis caused by PUJ obstruction at 90% penetrance after exclusion of family 5 0
Paramo et al. (1991) Buscemi et al. (1985) Buscemi et al. (1985) Sengar et al. (1979) Total
Family 1 Family 2 Family 3 Family 4
0.000
0.010
0.050
0.100
0.200
0.300
0.400
0.500
0.862 0.301 0.802 2.281
0.860 0.300 0.819 2.280
0.797 0.258 0.736 2.191
0.729 0.215 0.647 2.044
0.582 0.134 0.457 1.641
0.415 0.064 0.257 1.118
0.224 0.017 0.079 0.486
0.000 0.000 0.000 0.000
4.246
4.259
3.982
3.635
2.814
1.854
0.712
0.000
t e m , 3 with v e s i c o - u r e t e r i c reflux, 1 with P U J o b s t r u c tion, and 1 paraureteric diverticulum. The frequency of d u p l e x u r e t e r is also i n c r e a s e d f r o m t h e g e n e r a l p o p u l a tion f r e q u e n c y o f 0.7% to 3 . 3 % in p a t i e n t s with P U J o b s t r u c t i o n ( A t w e l l 1985; T h o m a s et al. 1982); vesicou r e t e r i c reflux coexists in 10% o f p a t i e n t s with P U J o b s t r u c t i o n ( M a i z e l s et al. 1984; T h o m a s et al. 1982; L e b o w i t z a n d B l i c h m a n 1983). S e n g a r et al. (1979) p e r f o r m e d H L A t y p i n g in 4 twog e n e r a t i o n families with 2 o r m o r e m e m b e r s a f f e c t e d
with v e s i c o u r e t e r i c reflux a n d n o t i c e d c o s e g r e g a t i o n of the trait in 16 p h a s e u n k n o w n m e i o s e s with H L A ; h o w e v e r , no f o r m a l l i n k a g e analysis was p e r f o r m e d . M a c k i n t o s h et al. (1989) c a r r i e d o u t l i n k a g e analysis in 2 families with v e s i c o u r e t e r i c reflux a n d f o u n d a m a x i m a l l o d s c o r e o f 3.326 at 0 = 0.05. T h e s e studies s u p p o r t l o c a l i z a t i o n o f h e r e d i t y v e s i c o u r e t e r i c reflux to 6p a n d , in c o n j u n c t i o n with t h e f a m i l y studies d e s c r i b e d a b o v e , support the idea of a disease spectrum including PUJ o b s t r u c t i o n a n d v e s i c o - u r e t e r i c reflux c a u s e d b y m u t a -
560 tion in a single locus or closely linked loci on 6p. Analysis of further families needs to take into account the natural history of this condition, the range of expression and the n e e d to use appropriate m e a n s of investigation. For example, screening of family m e m b e r s with abdominal ultrasound alone would not detect vesicoureteric reflux, ureteric diverticula or double ureter. The family described by Mackintosh et al. (1989) also showed autosomal d o m i n a n t hypercalcemia but was otherwise indistinguishable from the hereditary hydronephrosis families showing linkage to the m a j o r histocompatibility complex. F u r t h e r genetic h e t e r o g e n e i t y is also likely in hereditary hydronephrosis, as autosomal d o m i n a n t families have also b e e n described in which the whole urinary tract is dilated in family m e m b e r s (MacKay 1945; M c C o r m a c k 1982; Wladimiroff et al. 1985).
References Arnold AJ, Rickwood AMK (1990) Natural history of pelviureteric obstruction detected by prenatal sonography. Br J Urol 65 : 91 Atwell JD (1985) Familial pelviureteric junction hydronephrosis and its association with a duplex pelvicaliceal system and vesicoureteric reflux. A family study. Br J Urol 57 : 365 Atwell JD, Allen NH (1980) The interrelationship between paraureteric diverticula, vesicoureteral reflux and duplication of the pelvicaliceal collecting system: a family study. Br J Urol 52 : 269-273 Buscemi M, Shanske A, Mallet E, Ozoktay S, Hanna MK (1985) Dominantly inherited ureteropelvic junction obstruction. Urology 26 : 568
Dwoskin JY (1979) Ureteropelvic junction obstruction and sibling uropathology. Urology 13 : 153 Lebowitz RL, Blickman JG (1983) The coexistence of ureteropelvic junction obstruction and reflux. Am J Roent 140:231-238 MacCormak M (1982) Prenatal detection of the autosomal dominant type of congenital hydronephrosis by ultrasonography. Prenat Diagn 2 : 157-161 Mackintosh M, Almarhoos G, Heath DA (1989) HLA linkage with familial vesicoureteral reflux and familial pelvi-ureteric junction obstruction. Tissue Antigens 34:185-189 MacKay M (1945) Congenital bilateral megaloureters with hydronephrosis. A remarkable family history. Proc R Soc Med 38: 567-568 Maizels M, Smith CK, Firlit CF (1984) The management of children with vesico-ureteral reflux and ureteropelvic junction obstruction. J Urol 131:722-727 Paramo P, Izquierdo L, Paramo PS, LLorente L, Uson AC (1991) Hereditary hydronephrosis: a three generation family. Eur J Urol (in press) Ransley PG, Dhillon HK, Godon I, Duffy PG, Dillon MJ, Barrat TM (1990) The postnatal management of hydronephrosis diagnosed by prenatal ultrasound. J Urol 144 : 584 Sengar DPS, Rashid A, Wolfish (1979) Familial urinary tract anomalies. J Urol 121 : 194 Thomas DFM (1990) Fetal uropathy. Br J Urol 66:225 Thomas DFM, Agarwal M, Laidin AZ, Eckstein HB (1982) Pelviureteric obstruction in infancy and childhood. A review of 117 patients. Br J UroI 54 : 204-208 Wladimiroff JW, Beemer FA, Scholtmeyer R J, Stewart PA, Spritzer R, Wolf ED (1985) Failure to detect fetal obstrtictive uropathy by second trimester ultrasound. Prenat Diagn 5:4146
