Journal of Perinatology (2008) 28, 736–742 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp ORIGINAL ARTICLE Post-mortem examination of prenatally diagnosed fatal renal malformation

N Kumari1, M Pradhan2, VH Shankar2, N Krishnani1 and SR Phadke2 1Department of Pathology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, UP, India and 2Department of Medical Genetics, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, UP, India

Introduction Objective: Renal malformations can be associated with genetic syndromes Congenital renal malformations are a common cause of perinatal and chromosomal disorders. Fetal autopsy including histopathological death.1 One such mishap creates anxiety in the couple for the fear examination of kidney is important to arrive at definite diagnosis. The of similar recurrence in future pregnancies. The recurrence risk of objective was to assess importance of fetal autopsy and histopathology. these disorders varies from negligibly low to 25 to 50% depending Study Design: Retrospective analysis of cases with fetal renal on the genetic component in the etiology of the disorder. Every malformations was done. All fetuses terminated were examined with effort should be made to identify the etiology of perinatal death so whole body radiograph, external and internal examination and that appropriate genetic counseling can be given. Targeted histopathological examination. anomaly scan can detect fetal renal malformations and associated Result: A total of 21 cases with renal malformations were studied. Of all oligohydramnios, which will predict the prognosis. However, fetal 3 were of bilateral renal agenesis, 4 showed autosomal recessive polycystic autopsy including histopathological examination is important for kidney disease and 13 showed features of multicystic kidney. Three of identifying definite etiology. Moreover, renal anomalies can also be these had hyperplasic-enlarged bladder and autopsy confirmed urorectal a part of congenital syndromes involving multiple organs, and septum malformations in two cases and posterior urethral valve in one identification of these abnormalities may significantly change the case. One case had associated malformations like encephalocele that recurrence risk in future pregnancies. The objective of the present suggested diagnosis of Meckel–Gruber syndrome and another had study was to review our cases with fetal renal malformations, to associated lateral body wall defect. In five cases kidney was hypoplastic assess the importance of fetal autopsy and histopathology. suggestive of Potter type IIa.

Conclusion: Ultrasound is an effective diagnostic modality; however Methods fetal autopsy after termination of pregnancy is important to arrive at a definitive diagnosis. It’s important to distinguish between autosomal The study was carried out as a retrospective analysis of cases with recessive polycystic kidney disease (ARPKD) and cystic dysplastic kidney as fetal renal malformations in a tertiary referral center in 5-year recurrence risk is 3% in case of cystic renal dysplasia in contrast to 25% in period (2001 to 2005). The fetuses were of different gestational case of ARPKD. Gross examination may point toward syndromic diagnosis ages. All fetuses terminated were examined according to the like Meckel–Gruber syndrome; hence mode of prenatal diagnosis may routinely followed protocol. This included a photograph, whole vary in subsequent pregnancies. body radiograph, external and internal examination including Journal of Perinatology (2008) 28, 736–742; doi:10.1038/jp.2008.93; histopathological examination of the relevant tissues. published online 3 July 2008 A chromosomal analysis was carried out whenever fresh tissue was available. All post-mortem examinations were carried out with Keywords: multicystic dysplastic kidney; autosomal recessive polycystic written consent of the father or relatives who brought the fetus. kidney; urorectal septal malformation

Results Of the 21 cases with renal malformations, 3 were identified as Correspondence: Dr M Pradhan, Department of Medical Genetics, Sanjay Gandhi Post- bilateral renal agenesis. Axial and sagittal sonogram of the fetal Graduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, UP, India. abdomen showed nonvisualization of kidneys on both sides, E-mail: [email protected] Received 31 August 2007; revised 11 March 2008; accepted 26 March 2008; published online nonvisualization of urinary bladder and severe oligohydramnios. 3 July 2008 Ultrasonogram in four cases showed enlarged hyperechogenic Prenatally diagnosed renal malformation N Kumari et al 737 kidneys with loss of corticomedullary differentiation and severe encephalocele that suggest the diagnosis of Meckel–Gruber oligohydramnios suggestive of autosomal recessive polycystic syndrome (Figures 3a and b). Another case (case no. 21) had kidney disease (ARPKD; Figure 1). One couple had history of associated lateral body wall defect. In five cases kidney was similar condition in previous pregnancy. The diagnosis of ARPKD hypoplastic suggestive of Potter type IIa associated with severe was confirmed on histopathological examination. One fetus had oligohydramnios. The couple decided for termination of pregnancy hydronephrosis with normal amount of amniotic fluid, delivered at as their previous child had similar problem with vesicoureteric term and died on the 5th postnatal day due to septicemia. Fetal reflux in the normal kidney. No cytogenetic abnormality was autopsy confirmed the hydronephrosis. Examination of the parents detected in any of the fetuses. All 21 cases with ultrasonographic revealed hydronephrosis in the mother. and fetal autopsy finding are given in Table 1. The sonological features of multicystic kidney were present in 13 cases. Of these, two cases had hyperplastic-enlarged bladder, suggestive of lower urinary tract obstruction. Fetal autopsy Discussion confirmed the diagnosis as urorectal septum malformations Urinary tract abnormalities have a profound effect on pregnancy (URSMs) in one case and posterior urethral valve in another case outcome, especially when associated with oligohydramnios. Severe (Figure 2). One case had associated malformations like oligohydramnios cause fatal pulmonary hypoplasia and poor fetal

Figure 1 Ultrasonography of autosomal recessive polycystic kidneys showing Figure 2 Distended urinary bladder and bilateral ureters in case of posterior hazy appearance. urethral value.

Figure 3 (a) Case of Meckel Gruber syndrome showing ambiguous genitalia and polydactyly of hands and feet. (b) X-ray findings showing anencephaly in case of Meckel Gruber syndrome.

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Table 1 Ultrasonography findings with fetal autopsy correlation in cases with fetal renal malformations

Case USG findings Fetal autopsy findings Histopathology findings Final no. diagnosis

1 Severe oligohydramnios Grossly enlarged kidney, maintained reniform KidneyFelongated cysts radiating from cortex to ARPKD Large echogenic kidneys shape, tiny cysts visible on external surface medulla lined by cuboidal to flattened lining Nonvisualization of bladder epithelium. Few normal glomeruli seen within septa. LiverFexpanded portal tracts with increased dilated bile ducts 2 Bilateral enlarged kidney with Bilateral enlarged kidneys/spongy appearance KidneyFelongated cysts radiating from cortex to ARPKD cystic spaces, severe Ureter and bladder normal medulla lined by cuboidal to flattened lining oligohydramnios, epithelium. Few normal glomeruli were seen in septa nonvisualization of UB 3 Enlarged kidneys with severe Potter facies Same as above ARPKD oligohydramnios Large kidneys with spongy appearance 4 Enlarged kidneys Both kidneys are enlarged, cut section had Same as above ARPKD Severe oligohydraminos spongy appearance Bladder seen 5 Oligohydramnios Enlarged misshapen kidneys, loss of reniform KidneyFcysts located in the cortex, communicating MCDK Enlarged multicystic kidney shape and dilated ureter in places, small immature tubules lined by cuboidal URSM Distended UB Large cystic mass (bladder) epithelium and surrounded by a collar of cellular Anal opening absent mesenchyme. No heterologous tissue identified. URSMFfibromuscular tissue lined by immature urothelium and focal calcification 6 Enlarged multicystic kidney Abnormal genitalia Cortical renal cysts communicating in places, small MCDK Severe oligohydramnios Bilateral small kidney immature tubules lined by cuboidal epithelium and URSM Nonvisualization UB? URSM Urethral agenesis surrounded by a collar of cellular mesenchyme. No heterologous tissue identified. Intranuclear CMV inclusions identified in some tubular epithelial cells, testicular tissue present. 7 Severe oligohydramnios Dilated thin UB Cortical renal cysts communicating in places, small MCDK Dilated bladder Hydroureter immature tubules lined by cuboidal epithelium and PUV Dilated pelvicalyceal system Multicystic dysplastic kidney surrounded by a collar of mesenchyme. No heterologous tissue identified 8 Enlarged kidney Encephalocele Dysplastic features same as above MCDK Encephalocele Enlarged kidney Meckel– Severe oligohydramnios Gruber syndrome 9 Dysplastic kidney Massively thickened bladder, minimal dilatation Unilateral small sized kidney with dysplastic features MCDK Dilated ureter of ureter, PUJ obstruction as above, contralateral PUJ obstruction and dilated (hypoplastic PUJ obstruction pelvis kidneys) Oligohydramnios 10 Severe oligohydramnios; left Left cystic kidney, right small kidney Dysplastic features same as above MCDK cystic kidney, nonvisualization of Bilateral low set ears (hypoplastic UB kidneys) 11 Oligohydramnios Multicystic kidney (right) Unilateral small sized kidney with dysplastic features MCDK Left kidney not visualized Renal agenesis (left) as above (hypoplastic Right kidney enlarged kidneys) 12 Multicystic dysplastic kidney, Very small kidneys Unilateral small-sized kidney with dysplastic features MCDK severe oligohydramnios same as above (hypoplastic) 13 Bilateral small kidneys with Bilateral small kidneys with a left-sided unilocular Unilateral hypoplastic cystic dysplastic kidney, MCDK unilateral unilocular renal cyst renal cyst, contralateral PUJ obstruction and contralateral PUJ obstruction and dilated pelvis (hypoplastic dilated pelvis kidneys)

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Table 1 Continued

Case USG findings Fetal autopsy findings Histopathology findings Final no. diagnosis

14 Multicystic kidneys Both kidneys enlarged with superficial cystic Enlarged kidneys with dysplastic features same as MCDK Severe oligohydramnios spaces, hypoplastic ureter and UB above 15 Unilateral multicystic kidney Right kidneyFmultiple cysts and enlarged Enlarged kidneys with dysplastic features same as MCDK above 16 Gross hydronephrosis Cystic kidney Renal dysplasia with dysplastic features same as above MCDK 17 Bilateral dilated PCS Bilateral dilated PCS Bilateral HDN Hereditary Normal amniotic fluid HDN 18 Severe oligohydramnios, Bilateral renal agenesis, absent ureter, severe No kidney tissue identified Bilateral nonvisualization of UB? Absent hypoplastic bladder Renal kidney Agenesis 19 Severe oligohydramnios Potter facies, absent kidney on both sides, flat No kidney tissue identified Bilateral Nonvisualization of kidney adrenals, absent ureter and bladder Renal Agenesis 20 Oligohydramnios Bilateral renal agenesis No kidney tissue identified Bilateral Nonvisualization of kidney Renal agenesis 21 Multicystic kidneys Left lateral body wall defect, both kidneys, Bilateral enlarged kidneys with dysplastic features MCDK adrenals, and gut protruding out of the defect with bilateral enlarged cystic kidneys

Abbreviations: ARPKD, autosomal recessive polycystic kidney disease; CMV, cytomegalic virus; HDN, hydronephrosis; MCDK, multicystic dysplastic kidney; PUV, posterior urethral valve; PUJ, pelviureteric junction obstruction; PCS, pelvicalyceal system; UB, urinary bladder; URSM, urorectal septal malformation; USG, ultrasonography. survival. Ultrasound is a very effective diagnostic modality for pregnancy. The increased prevalence of a range of renal anomalies identifying fetal urinary tract anomalies.2 The information within affected families raises the possibility that isolated renal provided by the antenatal sonography regarding fetal genitourinary malformation results from unidentified gene–environmental anomalies assists the clinician to decide regarding further interactions.4,6,7 We diagnosed three cases with bilateral renal antenatal management. The immediate decision regarding agenesis on antenatal ultrasonography and confirmed in fetal prognosis (life and function) of the fetus is taken considering autopsy examination. severity of oligohydramnios and visualization of urinary bladder. Renal cystic diseases may be difficult to define on an ultrasound Severe oligohydramnios and nonvisualization of urinary bladder is scan as oligohydramnios is usually associated. Renal dysplasia is associated with poor renal function.3,4 In our case series all cases diagnosed on the basis of histology. The differentiation between except one had severe oligohydramnios. One case with bilateral autosomal recessive polycystic renal disease and cystic renal hydronephrosis with normal amniotic fluid survived till term and dysplasia is based on histopathology. The antenatal diagnosis of delivered a term baby. Long-term follow-up of fetuses with cystic renal disease is inferred from the characteristic presentation oligohydramnios due to renal causes is reviewed in a recent of multiloculated abdominal mass consisting of multiple literature.5 Definitive etiological diagnosis may be difficult by thin-walled cysts, which do not appear to connect. In contrast, the ultrasound examination due to associated oligohydramnios. Fetal typical in utero presentation of autosomal recessive polycystic autopsy after termination of pregnancy is important to arrive at a kidney disease (ARPKD) is enlarged hyperechogenic kidney with definitive diagnosis. loss of corticomedullary differentiation, presumably due to the During 5th week of gestation, the ureteric bud arises, one on numerous small cysts that are undetectable by ultrasound.8 each side. If the ureteric bud does not form, renal agenesis occurs. Definitive diagnosis is important as recurrence risk is 3% Diagnosis of bilateral renal agenesis can be done reasonably well in case of cystic renal dysplasia in contrast to 25% in case of antenatally. The diagnosis is considered when the triadFsevere ARPKD. In view of high recurrence risk and poor prognosis of oligohydramnios, persistent nonvisualization of bladder, severe ARPKD, there is a strong demand for prenatal diagnosis. nonvisualization of kidneyFis observed. Accurate prediction of ARPKD is caused primarily, if not exclusively by mutations in bilateral renal agenesis is critical for prenatal counseling of parents PKHD1 gene.9 Although linkage analysis-based prenatal diagnosis as this is a uniformly fatal condition. Bilateral renal agenesis is a is feasible in most cases, it is associated with misdiagnosis in sporadic condition with negligible low recurrence risk in future families without pathologically proven diagnosis. Moreover, it is

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Figure 5 Microscopic examination of kidney from case of multicystic dysplastic Figure 4 Microscopic examination of kidney from case of autosomal recessive kidney showing primitive tubules surrounded by a collar of immature polycystic kidney showing radiating cysts from cortex to medulla and normal mesenchymal tissue. H&E X40. Glomerular structures within the cyst wall. H&E X40. including cartilage, cysts and abnormal tubule forms when the not possible in families where DNA of the affected child is not distal ureteric bud is atretic. Dysplastic kidneys may even disappear available. PKHD1 mutation analysis has proven to be an completely, both before and after birth, suggesting that many efficient and effective alternative method for definite prenatal patients diagnosed with renal agenesis may have originally had diagnosis.10,11 dysplasia.12 In our series, case 11 had dysplastic small kidney on We had 16 cases of cystic kidney. Of these four cases were right side with renal agenesis in left side, explaining this confirmed to have ARPKD by histopathological examination. Gross phenomenon. examinations in cases of autosomal recessive kidneys showed Cystic renal dysplasia with obstruction is another form of renal enlarged kidneys with maintained reniform shape and numerous dysplasia. The kidney initially develops normally but later subjected tiny cysts visible on the external surface. Microscopy of these to increased backpressure due to severe urinary tract obstruction in specimens revealed radiating cysts from cortex to medulla lined by early pregnancy. Most often this process is bilateral and should be cuboidal to flattened epithelium and presence of few normal suspected by a distended hypertrophied bladder in antenatal glomerular structures within the septa of cyst (Figure 4). ultrasound. The lower urinary tract should be carefully assessed in Examination of liver in one case showed expanded portal tracts all cases of presumed renal dysplasia during fetal autopsy. URSMs and increased number of bile ducts at the periphery, some of which is a sporadic malformation with a negligible or no known risk of were cystically dilated. In cases of multicystic dysplastic kidneys, the recurrence in future pregnancy.13,14 Features like abnormal kidneys were either small or enlarged and showed loss of normal genitalia (case 6) and absent anal opening (case 5) helped us to reniform shape of the organ. Cysts were not visible grossly on outer diagnose this condition. Another common condition that can surface. Microscopic examination showed variable-sized cystic present in a male child is posterior urethral valve. spaces, some of which were communicating with each other, Detection of dysplastic kidney should warrant a detailed located mainly in the peripheral cortical zone and lined by examination of the fetus for other structural anomalies including cuboidal epithelium. Immature glomeruli were observed within the heart, spine, extremities, face and umbilical cord, because up to septa of cysts. In other areas small tubules surrounded by a collar 35% of cases may have extra renal anomalies especially with of cellular mesenchymal tissue were seen (Figure 5). One case of bilateral dysplastic kidney.15 This is important for assessing the multicystic dysplastic kidney showed presence of heterologous tissue prognosis of the fetus as well as for definitive diagnosis that will in the form of cartilage. In one case it was a surprise to find have implications during genetic counseling. In case 8 association classical cytomegalic viral inclusions displaying enlarged nuclei of cystic dysplasia with encephalocele helped us to diagnose the with eosinophilic round intranuclear inclusions surrounded by a condition as Meckel–Gruber syndrome which is autosomal clear zone. recessive in inheritance with 25% recurrence risk in future Dysplastic kidneys can be of any size, ranging between massive offsprings. Meticulous autopsy is necessary to establish the kidneys with multiple large cysts to small hypoplastic kidneys. diagnosis of Meckel–Gruber syndrome16,17 (Figure 3a). In Instead of a normal kidney, a mass of disorganized tissue contrast, another case with multicystic dysplastic kidney had lateral

Journal of Perinatology Prenatally diagnosed renal malformation N Kumari et al 741 body wall defect, which is a sporadic malformation with low Conclusion 18,19 recurrence risk in future pregnancy. Ultrasound is a very effective diagnostic modality for identifying The prognosis of isolated dysplastic kidney is critically fetal urinary tract anomalies; however, fetal autopsy after dependent on whether there is bilateral or unilateral disease. termination of pregnancy is important to arrive at a definitive Fetuses with unilateral dysplastic kidney have a much better diagnosis. Renal cystic diseases may be difficult to define on an prognosis, especially in the presence of a ‘normal’ contralateral ultrasound scan as oligohydramnios is usually associated. It’s organ. Numerous studies have shown that the risk for associated important to distinguish between ARPKD and cystic dysplastic abnormalities is between 30 and 50%, with the commonest being kidney as recurrence risk is 3% in case of cystic renal dysplasia 20 contralateral malformations such as vesicoureteric reflux. The in contrast to 25% in case of ARPKD. The distinction between risk of hypertension in unilateral multicystic kidney is low; however both entities is definite on histological examination. In view they should be followed up throughout the childhood for early of high recurrence risk and poor prognosis of severe ARPKD, 8 developments of hypertension or any other complications. In one here is a strong demand for prenatal diagnosis. We did not study of unilateral renal agenesis, 4% had died from renal failure identify any cytogenetic abnormalities in all our fetuses. Gross 21 and 13% had decreased renal function. During genetic examination of fetal organs may point toward one syndromic counseling in cases of unilateral malformations, these points diagnosis, for example, Meckel–Gruber syndrome and hence, should be stressed. Illustrated case 15 had isolated right-sided mode of prenatal diagnosis in subsequent pregnancies multicystic dysplastic kidnney (MCDK). However, the couple may vary. decided on termination because of their previous experience with similar condition in the previous child. Their first child had MCDK of one side that later became hypoplastic and also had renal References agenesis. Kidney on the normal side was having vesicoureteric 1 Wiesel A, Queisser-Luft A, Clementi M, Bianca S, Stoll C, EUROSCAN Study Group. reflux and recurrent urinary tract infection (UTI). The child is on Prenatal detection of congenital renal malformations by fetal ultrasonographic prophylaxis therapy with antibiotics. examination: an analysis of 709 030 births in 12 European countries. Eur J Med Genet It is also worth considering ultrasound screening of parents in 2005; 48(2): 131–144. case of fetal renal abnormalities as numerous kindred have been 2 Zhou Q, Ji ZZ, Cardoza J. Value of ultrasound in the diagnosis of congenital renal described with autosomal-dominant inheritance of aplasia, malformations. Di Yi Jun Yi Da Xue Xue Bao 2005; 25(9): 1086–1089. 3 Vanderheyden T, Kumar S, Fisk NM. Fetal renal impairment. Semin Neonatol 2003; dysplasia and other urinary tract abnormalities. In our series, in 8(4): 279–289. case 17, the couple had two fetuses affected with hydronephrosis 4 Wilcox DT, Chitty LS. Non-visualization of fetal bladder: aetiology and management. and ultrasound of the wife showed that she had a hydronephrotic Prenat Diagn 2001; 21: 977–983. kidney. Cases with hereditary hydronephrosis is described previously 5 Klaassen I, Neuhaus TJ, Mueller-Wiefel DE, Kemper MJ. Antenatal oligohydramnios and most of them supporting an autosomal-dominant inheritance. of renal origin: long-term outcome. Nephrol Dial Transplant 2007; 22(2): Underlying etiology is not known in most cases of hereditary 432–439. 6 Schwaderer AL, Bates CM, McHugh KM, McBride KL. Renal anomalies in family hydronephrosis. Familial studies and linkage studies suggested members of infants with bilateral renal agenesis/adysplasia. Pediatr Nephrol 2007; 22 genetic heterogeneity in hereditary hydronephrosis. 22(1): 52–56. Epub 2006 Sep 15. There was no discordance between antemortem diagnosis and 7 Wellesley D, Howe DT. Fetal renal anomalies and genetic syndromes. Prenat Diagn post-mortem findings, however autopsy revealed additional minor 2001; 21: 992–1003. findings in few cases like absence of anal opening in case no. 5 8 Winyard P, Chitty L. Dysplastic and polycystic kidneys: diagnosis, associations and management. Prenat Diagn 2001; 21(11): 924–935. Review. and visualization of urinary bladder in case no. 2 which was 9 Menezes LF, Onuchic LF. Molecular and cellular pathogenesis of autosomal masked by enlarged kidneys on sonography. Similarly polydactyly recessive polycystic kidney disease. Braz J Med Biol Res 2006; 39(12): 1537–1548 and ambiguous genitalia were additional minor findings found on (Review). autopsy in case no. 8, which was diagnosed as Meckel–Gruber 10 Zerres K, Senderek J, Rudnik-Scho¨neborn S, Eggermann T, Kunze J, Mononen T et al. syndrome. In case no. 6 and case no. 21, autopsy revealed New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by additional major findings to make a diagnosis of URSM in case no. mutation analysis of the PKHD1 gene. Clin Genet 2004; 66(1): 53–57. 11 Bergmann C, Senderek J, Schneider F, Dornia C, Ku¨pper F, Eggermann T et al. PKHD1 6 and lateral body wall defect in case no. 21 apart from the mutations in families requesting prenatal diagnosis for autosomal recessive polycystic diagnosis of multicystic dysplastic kidney. kidney disease (ARPKD). Hum Mutat 2004; 23(5): 487–495. Chromosome analysis should be discussed with parents 12 Rottenberg GT, Gordon I, De Bruyn R. The natural history of the multicystic dysplastic particularly when structural abnormalities were detected. kidney in children. Br J Radiol 1997; 70(832): 347–350. Chromosomal abnormalities are detected in 10% cases with cystic 13 He R, Harrison K, Malloy C, Mc Clatchey KD. Pathologic quiz case; multiple congenital birth defects in a full-term infant. Arch Pathol Lab Med 2004; 128: dysplasia, but in all these cases extra renal anomalies are usually e73–e75. associated. We have done chromosomal analysis in all of our cases 14 Patil SJ, Phadke SR. Urorectal septum malformation sequence: Ultrasound correlation and not identified any cytogenetic abnormalities. with fetal examination. Indian J Pediatr 2006; 73(4): 287–293.

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