Clinical Genetics 1975: 7: 144147
Familial primary vesicou reteral refIux K. FRIED,E. YUVAL,A. EIDELMAN, AND S. BEER Departments of Genetics, Urology and Pediatrics, Asaf Harofe Hospital, Tel-Aviv University Medical School, Zerifin, Israel T w o families with all children affected by primary vesicoureteral reflux are reported. Both sets of parents were examined and onIy in one family the mother was also affected by unilateral reflux. This congenital lesion has only recently been recognized as a common disease, but because diagnosis depends on voiding cystography, it is not made until the child or adult becomes symptomatic or presents with end-stage renal disease. As
most cases are sporadic, a multiple factorial mode of inheritance is most probable, but an autosomal dominant or recessive gene cannot be excluded as the cause of the disease in some families. It is recommended that all first degree relatives of the patients should be investigated, in order to detect asymptomatic cases of this condition, which is likely to cause progressive renal damage and may have fatal termination due to renal failure. Received 16 July, accepted for publication 16 September 1974
T h e non-obstructive variety of vesicoureteral reflux is a primary or congenital anomaly wherein the basic defect is an anatomic and physiologic abnormality at the ureterovesical junction (Ambrose 1969, Tanagho et al. 1969, Lynch & Egan 1973). Intrinsically defective “sphincteric” musculature of the intravesical ureter, congenital absence of muscle in the submucosal segment of the intravesical ureter and combined deficiency in the length and absence of the muscle in the submucosal segment of the ureter have all been blamed for a defective antireflux mechanism. This congenital anomaly is often responsible for progressive renal damage and may lead to endstage renal failure (Salvatierra et al. 1973). Most cases are sporadic, but familial cases, often among siblings, have been described (Mulcahy et al. 1970, Amar 1972, Geist & Antolak 1972, Mounger & Scott 1972) to
list only some of the more important or recent reports. T h e purpose of this report is to describe two families with familial primary vesicoureteral reflux and t o discuss the mode of inheritance of this congenital malformation.
Case Reports Family A . T h e parents were both Sephardic
Jews from Bulgaria and were not related. T h e father was born in 1921 a n d the mother in 1935. The mother had suffered from repeated urinary tract infections. Left side vesicoureteral reflux with bilateral para-ureteral diverticula were found o n voiding cystography (Fig. 1). Intravenous pyelography demonstrated pyelonephritic changes in the left kidney (Fig. 2). On examination, the father
FAMILIAL PRIMARY VESICOURETERAL REFLUX
145
eral reflux (Fig. 3). H e underwent surgical correction of the vesicoureteral reflux at the age of 2 years. Family B . The parents were both Ashkenazi Jews and were not related. The father was born in 1945 and the mother in 1947. Both parents had normal voiding cystourethrograms. The mother had suffered from repeated urinary tract infections and the father was known to have habitual dislocation of the right shoulder. Both children are females and were found t o have bilateral vesicoureteral reflux. The first daughter was born in 1967. She was found to have bilateral vesicoureteral reflux (as the cause of urinary tract
Fig. 1. Family A, mother. Voiding cystourethrograrn. Left vesicoureteral reflux with bilateral para-ureteral diverticula are present.
was found not to have reflux. All three children are males and were found to have vesicoureteral reflux. The first son, born in 1965, was found, at the age of 8 years, to have external urethral meatal stenosis and hypoplastic right kidney in addition to right massive vesicoureteral reflux. He underwent meatotomy and at present he is under observation and antibacterial maintenance therapy, awaiting operation. The second son was born in 1969. He was found, at the age of 2 years, to have, in addition to bilateral vesicoureteral reflux, bilateral hydronephrosis with extremely poor function of the left kidney. He underwent bilateral surgical correction of the vesicoureteral reflux. The third and last son was born in 1971. He was found to have bilateral VeSiCOUret-
Fig. 2. Family A, mother (same individual as in Fig. 1). Intravenous pyelogram. Pyelonephritic changes in the left kidney are demonstrated.
146
FRIED, YUVAL, EIDELMAN, AND BEER
Flg. 3. Family A, third son, 2 years old. Voiding cystourethrogram. Bilateral vesicoureteral roflux is demonstrated.
infection), which was corrected surgically at 4 years of age. The other daughter was born in 1970. She was found to have bilateral vesicouretera1 reflux as the cause of repeated urinary tract infections. She has not yet been operated on. Both girls are mildly obese at the age of 7 and 4 years, respectively. Discussion
Primary vesicoureteral reflux has only recently been recognized as a common internal malformation. Because the diagnosis cannot be made on clinical grounds alone, and the condition is usually asymptomatic in infancy, there are no estimates of its prevalence in any population. Mounger &
Scott (1972) commented on the relative rarity of this condition among the Black in contrast to the White population in Alabama. The problem of calculating prevalence is further complicated by reports of spontaneous cure of reflux (Geist & Antolak 1972). The situation has some similarity in this regard to an unrelated congenital malformation, ventricular septa1 defect, for which spontaneous cure is well known. From reports of relatively large groups of patients from a single department, such as the report of 320 patients by Amar (1972), it seems that the frequency of this malformation is in the order of about l in 1000. As most cases are sporadic, a multiple factorial mode of inheritance is most probable, but an autosomal dominant or recessive gene cannot be excluded as the cause of the disease in some families. It is recommended that all first degree relatives of the patients, whether symptomatic or not, should be investigated in order to detect unrecognized cases of this condition, which may have fatal termination due to renal failure.
References
Amar, A. D. (1972). Familial vesicoureteral reflux. J . Urol. (Baltimore) 108, 969-971. Arnbrose, S. S. (1969). Reflux pyelonephritis in adults secondary to congenital lesions of the ureteral orifice. J . Urol. (Baltimore) 102, 302-304. Geist, R. W. & S. J. Antolak Jr. (1972). The clinical problems of children with sterile ureteral reflux. J . Urol. (Baltimore) 108, 343-346. Lynch, H. T. & J. D. Egan (1973). The kidney and urogenital tract. Clinical Genetics. 2nd. ed. ed. Sorsby, A. London, Butterworths. pp. 494-516. Mounger, E. J. & E. V. Z. Scott (1972) Surgical correction of vesicoureteral reflux. J . Urol. (Baltimore) 108, 347-350. Mulcahy, J. J., P. P. Kelalis, G. B. Strickler & E. C. Burke (1970). Familial vesicoureteral reflux. J . Urol. (Baltinzore) 104, 762-764.
FAMILIAL PRIMARY VESICOURETERAL REFLUX
Salvatierra, Jr. O., S. L. Kountz & F. 0. Belzer (1973). Primary vesicoureteral reflux and end-stage renal disease. J . Amer. m e d . Ass. 226, 1454-1456. Tanagho, E. A., T. H. Guthrie & R. P. Lyon (1969). The intravesical ureter in primary reflux. J . Urol. (Baltimore) 101, 824-832.
Address: K . Fried M.D., P h D . University Department of Genetics Asuf Harofe Hospital Zerifin Israel
147
Familial primary vesicou reteral refIux K. FRIED,E. YUVAL,A. EIDELMAN, AND S. BEER Departments of Genetics, Urology and Pediatrics, Asaf Harofe Hospital, Tel-Aviv University Medical School, Zerifin, Israel T w o families with all children affected by primary vesicoureteral reflux are reported. Both sets of parents were examined and onIy in one family the mother was also affected by unilateral reflux. This congenital lesion has only recently been recognized as a common disease, but because diagnosis depends on voiding cystography, it is not made until the child or adult becomes symptomatic or presents with end-stage renal disease. As
most cases are sporadic, a multiple factorial mode of inheritance is most probable, but an autosomal dominant or recessive gene cannot be excluded as the cause of the disease in some families. It is recommended that all first degree relatives of the patients should be investigated, in order to detect asymptomatic cases of this condition, which is likely to cause progressive renal damage and may have fatal termination due to renal failure. Received 16 July, accepted for publication 16 September 1974
T h e non-obstructive variety of vesicoureteral reflux is a primary or congenital anomaly wherein the basic defect is an anatomic and physiologic abnormality at the ureterovesical junction (Ambrose 1969, Tanagho et al. 1969, Lynch & Egan 1973). Intrinsically defective “sphincteric” musculature of the intravesical ureter, congenital absence of muscle in the submucosal segment of the intravesical ureter and combined deficiency in the length and absence of the muscle in the submucosal segment of the ureter have all been blamed for a defective antireflux mechanism. This congenital anomaly is often responsible for progressive renal damage and may lead to endstage renal failure (Salvatierra et al. 1973). Most cases are sporadic, but familial cases, often among siblings, have been described (Mulcahy et al. 1970, Amar 1972, Geist & Antolak 1972, Mounger & Scott 1972) to
list only some of the more important or recent reports. T h e purpose of this report is to describe two families with familial primary vesicoureteral reflux and t o discuss the mode of inheritance of this congenital malformation.
Case Reports Family A . T h e parents were both Sephardic
Jews from Bulgaria and were not related. T h e father was born in 1921 a n d the mother in 1935. The mother had suffered from repeated urinary tract infections. Left side vesicoureteral reflux with bilateral para-ureteral diverticula were found o n voiding cystography (Fig. 1). Intravenous pyelography demonstrated pyelonephritic changes in the left kidney (Fig. 2). On examination, the father
FAMILIAL PRIMARY VESICOURETERAL REFLUX
145
eral reflux (Fig. 3). H e underwent surgical correction of the vesicoureteral reflux at the age of 2 years. Family B . The parents were both Ashkenazi Jews and were not related. The father was born in 1945 and the mother in 1947. Both parents had normal voiding cystourethrograms. The mother had suffered from repeated urinary tract infections and the father was known to have habitual dislocation of the right shoulder. Both children are females and were found t o have bilateral vesicoureteral reflux. The first daughter was born in 1967. She was found to have bilateral vesicoureteral reflux (as the cause of urinary tract
Fig. 1. Family A, mother. Voiding cystourethrograrn. Left vesicoureteral reflux with bilateral para-ureteral diverticula are present.
was found not to have reflux. All three children are males and were found to have vesicoureteral reflux. The first son, born in 1965, was found, at the age of 8 years, to have external urethral meatal stenosis and hypoplastic right kidney in addition to right massive vesicoureteral reflux. He underwent meatotomy and at present he is under observation and antibacterial maintenance therapy, awaiting operation. The second son was born in 1969. He was found, at the age of 2 years, to have, in addition to bilateral vesicoureteral reflux, bilateral hydronephrosis with extremely poor function of the left kidney. He underwent bilateral surgical correction of the vesicoureteral reflux. The third and last son was born in 1971. He was found to have bilateral VeSiCOUret-
Fig. 2. Family A, mother (same individual as in Fig. 1). Intravenous pyelogram. Pyelonephritic changes in the left kidney are demonstrated.
146
FRIED, YUVAL, EIDELMAN, AND BEER
Flg. 3. Family A, third son, 2 years old. Voiding cystourethrogram. Bilateral vesicoureteral roflux is demonstrated.
infection), which was corrected surgically at 4 years of age. The other daughter was born in 1970. She was found to have bilateral vesicouretera1 reflux as the cause of repeated urinary tract infections. She has not yet been operated on. Both girls are mildly obese at the age of 7 and 4 years, respectively. Discussion
Primary vesicoureteral reflux has only recently been recognized as a common internal malformation. Because the diagnosis cannot be made on clinical grounds alone, and the condition is usually asymptomatic in infancy, there are no estimates of its prevalence in any population. Mounger &
Scott (1972) commented on the relative rarity of this condition among the Black in contrast to the White population in Alabama. The problem of calculating prevalence is further complicated by reports of spontaneous cure of reflux (Geist & Antolak 1972). The situation has some similarity in this regard to an unrelated congenital malformation, ventricular septa1 defect, for which spontaneous cure is well known. From reports of relatively large groups of patients from a single department, such as the report of 320 patients by Amar (1972), it seems that the frequency of this malformation is in the order of about l in 1000. As most cases are sporadic, a multiple factorial mode of inheritance is most probable, but an autosomal dominant or recessive gene cannot be excluded as the cause of the disease in some families. It is recommended that all first degree relatives of the patients, whether symptomatic or not, should be investigated in order to detect unrecognized cases of this condition, which may have fatal termination due to renal failure.
References
Amar, A. D. (1972). Familial vesicoureteral reflux. J . Urol. (Baltimore) 108, 969-971. Arnbrose, S. S. (1969). Reflux pyelonephritis in adults secondary to congenital lesions of the ureteral orifice. J . Urol. (Baltimore) 102, 302-304. Geist, R. W. & S. J. Antolak Jr. (1972). The clinical problems of children with sterile ureteral reflux. J . Urol. (Baltimore) 108, 343-346. Lynch, H. T. & J. D. Egan (1973). The kidney and urogenital tract. Clinical Genetics. 2nd. ed. ed. Sorsby, A. London, Butterworths. pp. 494-516. Mounger, E. J. & E. V. Z. Scott (1972) Surgical correction of vesicoureteral reflux. J . Urol. (Baltimore) 108, 347-350. Mulcahy, J. J., P. P. Kelalis, G. B. Strickler & E. C. Burke (1970). Familial vesicoureteral reflux. J . Urol. (Baltinzore) 104, 762-764.
FAMILIAL PRIMARY VESICOURETERAL REFLUX
Salvatierra, Jr. O., S. L. Kountz & F. 0. Belzer (1973). Primary vesicoureteral reflux and end-stage renal disease. J . Amer. m e d . Ass. 226, 1454-1456. Tanagho, E. A., T. H. Guthrie & R. P. Lyon (1969). The intravesical ureter in primary reflux. J . Urol. (Baltimore) 101, 824-832.
Address: K . Fried M.D., P h D . University Department of Genetics Asuf Harofe Hospital Zerifin Israel
147
