Familial Renal Adysplasia

Familial Renal Adysplasia Belinda Murugasu, MD, Barbara R. Cole, MD, Edith P. Hawkins, MD, Susan H. Blanton, PhD, Susan B. Conley, MD, and Ronald J. Portman, MD • Renal dysplasia and agenesis as isolated findings are usually considered sporadic, non inherited abnormalities. We report three kindreds with familial renal adysplasia. Two or more children were affected in each of the families and at least one member-whether proband, sibling, or parent-had a clinically silent anomaly. Normal kidneys in the parents did not preclude the occurrence of renal adysplasia in more than one child. The empiric risks for offspring and first-degree relatives were 50% and 25%, respectively, suggesting a strong genetic factor such as a major dominant gene with variable expression. Because the disease appears to be genetic in some cases of renal adysplasia, careful screening of the proband's family, subsequent children, and pregnancies is important for the purpose of accurate genetic counseling. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Familial; renal dysplasia; renal agenesis; multicystic dysplastic kidney.

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ENAL DYSPLASIA and agenesis are not uncommonly seen as part of inherited or sporadic syndromes. 1-3 However, as isolated findings, they are usually considered to be sporadic, although there have been reports offamilial cases. 4 - 1O In two centers, we have encountered three kindreds with familial renal adysplasia over a period of 10 years. We describe these families and suggest that screening of the parents and siblings of patients with renal dysplasia or agenesis should be performed for the purpose of accurate genetic counseling. CASE REPORTS We did not include any kindred associated with maternal diabetes or the multiple anomaly syndromes such as sirenomelia, Meckel's syndrome, prune-belly syndrome, and chromosomal aberrations. Potter's syndrome, a malformation sequence, is included, because associated abnormalities are secondary to oligohydramnios due to bilaterally nonfunctioning kidneys. The diagnosis of unilateral multicystic dysplasia was made by sonography demonstrating multiple cysts in the kidney and radionuclide scan showing nonfunction.

Family A (Fig lA) Both A-II-I and A-II-2 were diagnosed by ultrasound at 20 weeks' gestation to have unilaterally abnormal kidneys, but From the Department of Pediatrics and Genetics Centers, University of Texas Health Science Center, Houston, TX; the Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St Louis, MO; and the Department of Pathology, Baylor College of Medicine, Houston, TX. Address reprint requests to Ronald J. Portman, MD, Division ofPediatric Nephrology, Department ofPediatrics, University of Texas Medical School at Houston, 6431 Fannin, Houston, TX 77030. © 1991 by the National Kidney Foundation, Inc. 0272-6386/91/1804-0009$3.00;0 490

normal amounts of amniotic fluid. After term delivery, postnatal ultrasonography and radionuclide scans confirmed the presence of a nonfunctioning multicystic kidney on the right in A-II-l (Figs 2 and 3) and the left in A-II-2. Renal function was within normal limits and there were no associated abnormalities. The parents were white and nonconsanguineous, with normal kidneys by ultrasonographic examination. No other family history of renal disease was noted.

Family B (Fig lB) A 23-year-old white woman (B-I-2) had Stein-Leventhall syndrome and her first two pregnancies were induced by clomiphene. B-II-1 had a normal serum creatinine at the age of 5 years and ultrasonographic screening showed a small but normally configured right kidney, with compensatory hypertrophy of the contralateral kidney. Oligohydramnios during the second pregnancy was detected at 16 weeks, and the mother required medications for uterine contractions in the second trimester, as well as methyldopa for hypertension. At 36 weeks' gestation, a diagnosis of bilateral hydronephrosis was made sonographically. B-II-2 was delivered by cesarean section, but died of respiratory distress 3 hours after birth. Autopsy findings included bilateral pneumothoraces, with pulmonary atelectasis, Potter type 2 bilateral renal multicystic dysplasia, maldeveloped ureters, and a urethral opening in the rectum. Facies and other organs were normal. B-II-3 was conceived without drug treatment, but sonography at 36 weeks showed bilateral hydronephrosis, with a normal bladder. Amniotic fluid was adequate and delivery uneventful. Postnatal investigations showed a right nonfunctioning multicystic kidney and a left ureteropelvic junction obstruction with hydronephrosis. The left-sided obstruction was surgically repaired and the child did well. At 5 years of age, his inulin clearance was 77 mL/min/1.73 m2 body surface area and appears to have remained stable over the subsequent 2 years. Parents then underwent ultrasonography and B-I-2 was found to have a relatively small left kidney, with a peripelvic cyst. Renal scan showed no function in that kidney. B-I-I had a normal renal ultrasound, as did three other members of the extended family (not shown in Fig JB).

American Journal of Kidney Diseases, Vol XVIII, No 4 (October), 1991: pp 490-494

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C-III-4 was screened by ultrasound imaging at 1 year of age and also had an absent left kidney, which was confirmed by excretory urography. She was well and had a serum creatinine level within normal limits. At 32 weeks' gestation, sonography demonstrated oligohydramnios and a single kidney in C-III-5. He died soon after birth from severe respiratory distress and bilateral pneumothoraces. He had a Potter's facies, but no skeletal anomalies. Chromosome analysis showed a normal 46, XY karyotype. At autopsy, bilateral pleural effusions with small atelectatic lungs were found, as well as bilateral renal agenesis, poorly developed renal vessels, a poorly formed bladder with no lumen, and a partially occluded proximal urethra. The parents were white and were not consanguineous and had normal intravenous urograrns. All three pregnancies were uncomplicated. In the rest offamily, C-I-I had kidney stones, C-I-4 died of renal failure of unknown etiology at the age of 74 years, and a distant maternal relative had a nephrectomy in infancy because of a "small kidney."

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These three families comprise all the known families with two or more affected offspring seen in two centers. The affected individuals described can be considered as part of the spectrum of the same disease, namely hereditary renal adysplasia. 5 The empiric risk for additional affected offspring in these families is 50% (1/2), while the risk to first-degree relatives is 25% (2/8). DISCUSSION

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Fig 1. (A-C) Renal malfonnations in families A, B, and C. *Radiological investigations were performed. !I, Right unilateral dysplasia; 11, left unilateral dysplasia; ~, bilateral dysplasia; [J, right unilateral agenesis; II, left unilateral agenesis; ., bilateral agenesis; ClI, right abnormal kidney; [J, left abnormal kidney.

Family C (Fig IC) C-III-3 presented with an Escherichia coli urinary tract infection at the age of 18 months and radiographic investigations showed right renal agenesis, left vesicoureteric reflux, and ureteropelvic junction obstruction with hydronephrosis. Pyeloplasty and reimplantation of the left ureter was performed, but he had renal impairment with a serum creatinine of 177 I'mol/L (1.9 mgJdL). He also had a hemivertebra at T2, with torticollis, and developed seizures at 4 years of age. Both audiometry and computerized tomography of the head were normal. He subsequently progressed to end-stage renal disease at 9 years of age and required dialysis and transplantation.

Because of a postulated common pathogenesis, renal agenesis, small kidneys with solid dysplasia and large kidneys with cystic or solid dysplasia can be viewed as a continuum. 2,IO,1I In its multicystic form, renal dysplasia is the most common, unilateral intra-abdominal mass in the neonate, 1,12 as well as the most common congenital renal anomaly.13 Although it is generally considered a sporadic anomaly;·3 there have been reports of familial renal adysplasia. 5.1Q,14.18 Autosomal dominant with variable penetrance,5,6,9,1Q autosomal recessive,I4-16 and sex-linked inheritance l7 have all been suggested, and multifactorial inheritance5 remains a possibility. Buchta et al 5 first coined the term hereditary renal adysplasia (HRA) when they described two families with absence of and/or hypoplasia/dysplasia of the kidneys. The familial nature of congenital absence and severe dysgenesis of both kidneys has also been described by Roodhooft et al,19 who found that 9% of parents and siblings had asymptomatic renal malformations. In fam-

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Fig 2. Renal sonogram of patient A-I-1 showing multiple cysts in the right dysplastic kidney.

ily B, diagnosis of clinically significant anomalies in two children resulted in family screening and the discovery of two other members with mild but definite renal tract abnormalities. Bankier et al20 also studied the pedigrees of perinatally lethal renal dysplasia and found 3.6% of siblings similarly affected. This was in agreement with the study of Carter et al,18 where the empiric recurrence risk was 3.5%. The probands in these studies had lethal disease, but the two children in our family A had asymptomatic multicystic kidneys, emphasizing that recurrence can oc-

Fig 3. Technetium 99mlabeled DTPA scan of patient A-I-1 showing no perfusion of the right dysplastic kidney and a nonnally functioning left kidney.

cur even when the anomaly is silent and not lethal. Renal ultrasound anomalies in parents were not significant in Bankier's study,20 in contrast to Roodhooft's data. 19 In our families A and C, radiographically normal urinary tracts were present in the parents, although more than one child was affected, similar to some of the families with HRA described by McPherson et a1. 6 Their literature review of familial renal agenesis (with and without nonurogenital anomalies) concluded that 20% to 36% of HRA were dominantly in-

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herited and that the empiric recurrence risk was 15% to 20% for severe bilateral disease in such families. 6 Our study of three families is too small to determine the mode(s) of inheritance or to estimate accurate recurrence risks. However, the proportion of additional affected members is high, suggesting a strong genetic factor such as a major dominant gene with variable expression. This model is consistent with the one proposed by McPherson et al6 that estimated penetrance to be between 50% and 90%. That no more than three multiplex families were observed over an extended period (10 years), suggests that only a small proportion of families have a strong genetic component. A family study of multicystic and aplastic types of renal dysplasia by Al Saadi et al 3 concluded that cases can be sporadic with an insignificant recurrence risk. However, the three families in our report were diagnosed only because of a high index of suspicion and more such families that have not been screened may exist. Additionally, since we ascertained only those families with at least two clearly affected individuals, we cannot combine our data with that of Al Saadi et al to estimate what proportion of families may be segregating for a common gene. In a dominant disorder, one expects the proportion of affected siblings and the proportion of affected first-degree relatives to be the same.

However, there is significant mortality and morbidity associated with this disorder, so that severely affected individuals may be seen in sibships, but will rarely reproduce. Reports of familial bilateral renal agenesis are more common than bilateral dysplasia6 and some believe that the recurrence risk of dysplasia is much lower than agenesis. 20 In families with bilateral disease, unilateral agenesis was the most common associated asymptomatic anomaly. 19 It is interesting that two of our three families were affected by dysplasia, rather than agenesis. Renal dysplasia is a significant cause of endstage renal disease,21,22 especially if bilateral or if there is an anomaly of the contralateral urinary tract. 23 ,24 Although function in multicystic kidneys is occasionally seen,4,25 there is reduced tissue reserve in all forms of dysgenesis. Early detection with control of hypertension and perhaps nutritional therapy may retard progression of damage. In conclusion, this report emphasizes that for the purpose of accurate genetic counseling, careful screening of families with an affected proband is important, as malformations may be clinically silent. Moreover, families with an affected proband should be informed that, in some cases, the disease appears to be genetic with a significant risk of recurrence and that antenatal screening is advisable regardless ofthe findings in the parents.

REFERENCES 1. Kissane JM: Renal cysts in pediatric patients. Pediatr NephroI4:69-77, 1990 2. Taxy JB: Renal dysplasia: A review. Pathol Annu 20: 139-159, 1985 3. Al Saadi AA, Yoshimoto M, Bree R, et al: A family study of renal dysplasia. Am J Med Genet 19:669-677, 1984 4. Cole BR, Kaufman RL, McAlister WH, et al: Bilateral renal dysplasia in three siblings: Report of a survivor. Clin Nephrol 5:83-87, 1976 5. Buchta RM, Viseskul C, Gilbert EF, et al: Familial bilateral renal agenesis and hereditary renal adysplasia. Z Kinderheilkunde 115:111-129, 1973 6. McPherson E, Carey J, Kramer A, et al: Dominantly inherited renal adysplasia. Am J Med Genet 26:863-872, 1987 7. Cain DR, Griggs D, Lackey DA, et al: Familial renal agenesis and total dysplasia. Am J Dis Child 128:377-380, 1974 8. Monn E, Nordshus T: Hereditary renal adysplasia. Acta Paediatr Scand 73:278-280, 1984 9. Squiers EC, Morden RS, Bernstein J: Renal multicystic dysplasia: An occasional manifestation of the hereditary renal adysplasia syndrome. Am J Med Genet Suppl 3:279-284, 1987 10. Curry CJR, Jensen K, Holland J, et al: The Potter se-

quence: A clinical analysis of 80 cases. Am J Med Genet 19: 679-702, 1984 11. Risdon RA, Young LW, Chrispin AR: Renal hypoplasia and dysplasia: A radiological and pathological correlation. Pediatr RadioI3:213-225, 1975 12. Kissane JM: The morphology of renal cystic disease, in Gardner KD Jr (ed): Cystic Diseases of the Kidney. New York, NY, Wiley, 1976, pp 31-63 13. Potter EL: Type II cystic kidney: Early ampullary inhibition, in Normal and Abnormal Development of the Kidney. Chicago, IL, Year Book, 1972, pp 154-181 14. Cain DR, Griggs D, Lackey DA, et al: Familial renal agenesis and total dysplasia. Am J Dis Child 128:377-180, 1974 15. Hack M, Jaffe J, B1ankstein J, et al: Familial aggregation in bilateral renal agenesis. Clin Genet 5:173-177,1974 16. Schinzel A, Hornberger C, Sigrist T: Bilateral renal agenesis in 2 male sibs born to consanguineous parents. J MedGenet 15:314-316, 1978 17. Pashayan HM, Dowd T, Nigro AV: Bilateral absence of the kidneys and ureters: Three cases reported in one family. J Med Genet 14:205-209, 1977

494 18. Carter CO, Evans K, Pescia G: Afamily study of renal agenesis. J Med Genet 16: 176-188, 1979 19. Roodhooft AM, Birnholz JC, Holmes LB: Familial nature of congenital absence and severe dysgenesis of both kidneys. N Eng! J Med 310:1341-1345, 1984 20. Bankier A, DeCampo M, Newell R, et al: A pedigree study of perinatally lethal renal disease. J Med Genet 22: 104111 , 1985 21. Krieger IN, Stubenbord WT, Vaughn ED Jr: Transplantation in children with end stage renal disease of urologic origin. J Urol 124:508-512, 1980 22. Warshaw BL, Edelbrock HH, Ettenger RB, et al. Pro-

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gression to end-stage renal disease in children with obstructive uropathy. J Pediatr 100:183-187, 1982 23. Avni EF, Thoua Y, Laimand B, et aI: Multicystic dysplastic kidney: Evolving concepts, In utero diagnosis and postnatal follow-up by ultrasound. Ann Radiol (Paris) 29:663668, 1986 24. Kleiner B, Filly RA, Mack L, et aI: Multicystic dysplastic kidney: Observations of contralateral disease in the fetal population. Radiology 161 :27-29, 1986 25. Sanders RC, Nussbaum AR, Solez K: Renal dysplasia: Sonographic findings. Radiology 167:623-626, 1988