Differential diagnosis of fetal hyperechogenic cystic kidneys unrelated to renal tract anomalies: a multicenter study

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1 Ultrasound Obstet Gynecol 2006; 28: Published online 8 November 2006 in Wiley InterScience ( DOI: /uog.3856 Differential diagnosis of fetal hyperechogenic cystic kidneys unrelated to renal tract anomalies: a multicenter study K. CHAUMOITRE*, M. BRUN, M. CASSART, B. MAUGEY-LAULOM, D. EURIN, F. DIDIER and E. F. AVNI, for the Groupe Radiopédiatrique de Recherche en Imagerie Foetale (GRRIF) Departments of Medical Imaging, *Hôpital Nord, CHU Marseille and Regional Maternity, Nancy, Department of Medical Imaging A, Hôpital Pellegrin, CHU Bordeaux and Department of Pediatric Imaging, Charles Nicolle Hospital, Rouen, France and Department of Medical Imaging, Erasme University Hospital, Brussels, Belgium KEYWORDS: Bardet Biedl syndrome; cyst; fetus; kidney; Meckel Gruber syndrome; polycystic kidney diseases; prenatal diagnosis; ultrasonography ABSTRACT Objectives To identify important factors in the differential diagnosis of renal cysts associated with hyperechogenic kidneys. Methods This was a retrospective multicenter study. We identified 93 fetuses presenting between 1990 and 2002 with hyperechogenic kidneys and which had a diagnosis of nephropathy confirmed later. We analyzed retrospectively the prenatal ultrasound findings of those fetuses which were found sonographically to have renal cysts. Results Of the 93 fetuses presenting with hyperechogenic kidneys and with a later diagnosis of nephropathy, there were 28 with autosomal dominant polycystic kidney disease (ADPKD), 31 with autosomal recessive polycystic kidney disease (ARPKD), 11 with Bardet Biedl syndrome, nine with Meckel Gruber syndrome, six with Ivemark II syndrome, one with Jarcho Levin syndrome, one with Beemer syndrome and one with Meckellike syndrome. One third of the fetuses (30/93) had renal cysts. Cystic characteristics (size, location, number) were not very useful for diagnosis; more useful was diagnosis of an associated malformation. Three (11%) of the fetuses with ADPKD had cysts, as did nine (29%) of those with ARPKD, three (27%) of those with Bardet Biedl syndrome, all (100%) of those with Meckel Gruber syndrome, three (50%) of those with Ivemark II syndrome, and each of the three cases with other syndromes (Jarcho Levin, Beemer and Meckel-like syndromes). None of the cases with trisomy 13 had cysts. There were no associated malformations in the 12 cases with renal cysts and polycystic kidney disease; the other 18 cases with renal cysts were associated with malformations that were often specific, such as polydactyly in Bardet Biedl and Beemer syndromes, occipital defect and Dandy Walker malformation in Meckel Gruber or Meckel Gruber-like syndromes, and thoracic and/or vertebral abnormalities in Jarcho Levin and Beemer syndromes. Conclusion Renal cysts associated with hyperechogenic kidneys are not rare. The clue to diagnosis is the demonstration of an associated malformation. If no malformation is found, the main diagnosis remains polycystic kidney disease, i.e. ARPKD or ADPKD. Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION The prenatal management of hyperechogenic kidneys is challenging. Kidney hyperechogenicity is diagnosed after 17 weeks gestation when the kidneys appear more echogenic than do the liver or spleen 1. Such abnormal echogenicity can result from the presence of multiple microscopic cysts, dysplasia or tubular dilatation. The differential diagnosis must take into account the family history and the presence of associated anomalies. Renal cystic diseases should be suspected in the case of macrocysts but also in the presence of hyperechogenic kidneys 1. In this retrospective study we analyzed renal sonographic data in 93 fetuses that presented with hyperechogenic kidneys and had a diagnosis of nephropathy confirmed later (renal tract anomalies, i.e. obstructive cystic dysplasia or multicystic dysplastic kidney (MKD), excluded) and we described the Correspondence to: Dr K. Chaumoitre, Service d Imagerie Médicale, Hôpital Nord, Chemin des Bourrellys, Cedex 20, Marseille, France ( kathia.chaumoitre@ap-hm.fr) Accepted: 18 May 2006 Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 912 Chaumoitre et al. prenatal ultrasound patterns in the 30 that had associated cysts diagnosed by sonography. We have reported previously on the cases of ADPKD (Brun et al. 2 ) and Bardet Biedl syndrome (Cassart et al. 3 ) in our sample. METHODS This was a retrospective multicenter study, conducted in four prenatal centers (in Bordeaux, Nancy, Rouen and Brussels) for the Groupe Radiopédiatrique de Recherche en Imagerie Foetale (GRRIF). Ninety-three patients between 1990 and 2002 attending for routine ultrasound examination presented with fetal hyperechogenic kidneys. All these cases had the diagnosis confirmed subsequently (by clinical and biological follow-up, genetic testing, and fetopathological examination in cases of termination or perinatal death). We analyzed retrospectively prenatal clinical and sonographic data of those that had renal cysts at least 2 mm in diameter. All sonographic examinations were performed on an SSD-5500 (Aloka, Wallingford, CT, USA) or a Power Vision 8000 (Toshiba, Yashimoto, Japan) ultrasound machine by experienced radiologists using MHz probes. The following features were analyzed: renal size (according to the data of Cohen et al. 4 ), echogenic pattern, corticomedullary differentiation (CMD) (absent/present and, if present, normal/increased/reversed), presence of renal cysts (number, size and location), size of the collecting system and any other abnormal sonographic feature. Fetal gender, gestational age at diagnosis and amniotic fluid volume were assessed. All ultrasound images were reviewed by two observers. The whole procedure was in accordance with the recommendations of the institutional ethics board of each center. RESULTS The 93 fetuses with hyperechogenic kidneys included 28 cases of autosomal dominant polycystic kidney disease (ADPKD), 31 cases of autosomal recessive polycystic kidney disease (ARPKD), 11 cases of Bardet Biedl syndrome, nine cases of Meckel Gruber syndrome, six cases of Ivemark II syndrome, five cases of trisomy 13, one case of Jarcho Levin syndrome, one case of Beemer syndrome and one case of Meckel-like syndrome. Approximately one third of these fetuses (30/93) had renal cysts diagnosed by prenatal ultrasound examination: cysts were presents in 11% (3/28) of those with ADPKD, 29% (9/31) of those with ARPKD, 27% (3/11) of those with Bardet Biedl syndrome, 100% (9/9) of whose with Meckel Gruber syndrome, 50% (3/6) of those with Ivemark II syndrome and in the three cases with other syndromes (Jarcho Levin, Beemer and Meckel-like syndromes). None of the five cases of trisomy 13 had renal cysts. There were no associated malformations in the 12 cases of polycystic kidney disease (PKD, i.e. ARPKD and ADPKD) with renal cysts. All the other cases with renal cysts were associated with malformations that were often specific, such as polydactyly in Bardet Biedl and Beemer syndrome, occipital defect and Dandy Walker malformation in Meckel Gruber or Meckel Gruber-like syndromes, and thoracic and/or vertebral abnormalities in Jarcho Levin and Beemer syndromes. Polycystic kidney disease (PKD): Table 1 Among the 28 cases of ADPKD, small bilateral cortical renal cysts were present in only three (11%) cases (Figure 1). There was a family history (maternal) in all Table 1 Characteristics of fetuses with hyperechogenic kidneys and cysts diagnosed with polycystic kidney disease (PKD) (n = 12) PKD Gender GA (weeks) Family history of PKD Kidney size* CMD AF Cyst size (mm) n Location Unilat/ Bilat Postnatal follow-up ADPKD M 22 Yes + 2 Dim Norm < 5 Few Cortex Bilat No CRF at 4 years (n = 3) M 22 Yes + 1 Dim Norm < 5 Few Cortex Bilat No CRF at 4 years F 30 Yes + 5 Abst Norm < 7 Few Cortex, paracalyceal Bilat CRF and hypertension at 3 years ARPKD M 22 No + 3 Rev Dim < 5 Num Diffuse Bilat TOP 29 weeks (n = 9) M 19 Yes Inc Norm < 5 Num Cortex Bilat TOP 22 weeks F 13 Yes + 11 Rev Dim < 5 Num Cortex Unilat Death day 1 F 32 Yes Abst Norm > 5 Num Cortex Unilat CRF at 3 years, transplant M 22 Yes + 2 Rev Dim < 5 One Medulla Unilat TOP 24 weeks M 23 Yes + 15 Rev Dim > 5 One Medulla Unilat Death day 5 F 32 No + 4 Abst Dim < 5 Num Medulla Bilat TOP 33 weeks M 30 Yes + 4 Abst Dim > 5 One Medulla Unilat CRF at 7 years M 27 No + 3 Abst Abst < 5 Num Cortex Bilat CRF, death at 7 months None of these cases had associated malformations. *Renal length expressed as SD of the mean 4. Abst, absent; ADPKD, autosomal dominant polycystic kidney disease; AF, amniotic fluid; ARPKD, autosomal recessive polycystic kidney disease; Bilat, bilateral; CMD, corticomedullary differentiation; CRF, chronic renal failure; Dim, diminished; F, female; GA, gestational age at diagnosis; Inc, increased; M, male; Norm, normal; Num, numerous; Rev, reversed; TOP, termination of pregnancy; Unilat, unilateral.

3 Hyperechogenic cystic kidneys 913 Figure 1 Ultrasound image of a 22-week fetus with autosomal dominant polycystic kidney disease showing hyperechogenic kidney with a rim of cortical cysts. The kidney is enlarged (+ 2 SD) and there is no corticomedullary differentiation. three.thekidneysizerangedfrom+ 1SDto+ 5 SD, the renal cortex was hyperechogenic, and the medulla was hyperechogenic and associated with diminished or absent CMD. Amniotic fluid volume was normal in all three cases. There were no associated malformations. After birth, follow-up revealed two to be normal at 4 years of age and one child had elevated blood pressure and moderate renal failure at 3 years of age. Among the 31 cases of ARPKD, prenatal renal cysts were present in nine (29%) cases (Figure 2). There was a family history (recurrence or consanguinity) in six (67%) cases. Size, number and location of the cysts were variable. Kidneys were markedly enlarged (mean + 5 SD) and amniotic fluid volume was diminished or absent in 78% of the cases. There were no associated malformations. Outcome was poor, with four terminations of pregnancy (TOP), two neonatal deaths, one death at 7 months and only two survivors (3 and 7 years of follow-up), both of which suffered severe renal failure. Syndromes: (Table 2) Among the 11 cases of Bardet Biedl syndrome, cystic lesions were present in three fetuses (27%). There was a solitary medullar lesion in one fetus, multiple medullar lesions in the second and a medullar cyst associated with multiple small cortical cystic lesions in the third. There was a family history in one case (brother). There were associated malformations in each of these cases, including polydactyly in all three. The kidney size ranged from + 1SDto+ 4 SD. There was an absence of CMD in all cases. The sonographic appearance of the kidneys changed over time; two of the three fetuses which presented with renal cystic lesions in utero showed complete regression of the cysts after birth; in the third, the cystic lesions increased in number and size for more than 2 years. Renal cystic lesions were present in all nine of our cases of Meckel Gruber syndrome. Cysts were tiny, their Figure 2 Ultrasound image of a 22-week fetus with autosomal recessive polycystic kidney disease showing hyperechogenic kidney with a medullar cyst (arrow). The kidney is moderately enlarged (+ 2 SD) and there is no corticomedullary differentiation. diffuse location involved the whole renal parenchyma, and there was no CMD (Figure 3). There were associated malformations in all cases, including occipital defect with or without encephalocele in seven cases and vermian agenesis or Dandy Walker malformation in five. There was a family history in one third of the cases. The kidney size was markedly enlarged (mean + 5 SD) and there was an absence of CMD in all cases. Amniotic fluid volume was decreased in 78% of the cases. All nine cases were terminated and the diagnosis was confirmed by fetopathological examination. One fetus in our series was diagnosed with Meckel Gruber-like syndrome, with hyperechogenic and cystic kidneys associated with vermian agenesis and femoral incurvation. A TOP was performed. Renal cystic lesions were present in three of our six cases of Ivemark II syndrome. In two of these cases, early diagnosis was easy because of a family history of Ivemark syndrome; no associated anomalies were diagnosed on sonography even though the fetopathological examinations showed liver and pancreatic dysplasia in both cases. In the third case, renal cysts were associated with severe oligohydramnios and a Potter sequence. In this case too, the final diagnosis of Ivemark II was made by fetopathological examination (pancreatic dysplasia). None of the three cases had splenic anomalies. Ultrasound examination of these three cases was difficult because of severe oligohydramnios.

4 914 Chaumoitre et al. Table 2 Characteristics of fetuses with hyperechogenic kidneys and cysts diagnosed with a syndrome (n = 18) Syndrome GA (weeks) Family history Kidney size* AF Malformation Cyst size (mm) n Location Unilat/Bilat Postnatal follow-up Bardet Biedl (n = 3) 25 No + 1 Norm Hexadactyly < 5 One Medulla Unilat Good outcome 36 No + 4 Dim Polydactyly, Hirschprung < 5 Few Medulla Bilat CRF at 1 year 24 Yes + 1 Inc Hexadactyly, minor ventriculomegaly, micropenis < 7 Few Cortex, Medulla Bilat Unilat Obesity and mental retardation at 4 years Meckel Gruber (n = 9) 25 No + 5 Dim Occ defect, vermian agenesis < 5 Num Diffuse Bilat TOP 27 weeks 6 11 Num Diffuse Bilat TOP 21 weeks 21 Yes + 5 Dim Occ defect, vermian agenesis, club feet 18 No + 5 Dim Occ encephalocele > 5 Num Diffuse Bilat TOP 23 No + 5 Dim Ventriculomegaly, vermian agenesis 3 6 Num Diffuse Bilat TOP 29 weeks 17 Yes + 3 Norm Occ encephalocele, microcephaly NA Num Diffuse Bilat TOP 22 No > 5 Dim Occ defect, DW, ventriculomegaly 2 10 Num Diffuse Bilat TOP 22 weeks 24 No Dim Occ encephalocele, polydactyly NA Num Diffuse Bilat TOP 13 Yes + 3 Norm Occ encephalocele, polydactyly < 5 Num Diffuse Bilat TOP 15 weeks 18 No + 3 Dim DW, ventriculomegaly < 5 Num Diffuse Bilat TOP 18 weeks Meckel Gruber like (n = 1) 22 Cons N Dim Vermian agenesis, femoral incurvation < 5 Few Cortex Bilat TOP Ivemark II (n = 3) 20 Yes Dim US: none < 5 Few Cortex Bilat TOP FP: liver and pancreatic dysplasia 26 No + 2 Dim US: Potter aspect < 5 Num Diffuse Bilat TOP FP: pancreatic dysplasia 21 Yes + 8 Dim US: none < 5 Num Diffuse Bilat TOP FP: liver and pancreatic dysplasia Jarcho Levin (n = 1) 22 No Dim Thoracic and vertebral 6 Num NA Bilat TOP Beemer (n = 1) 22 Cons 2 Dim Platyspondyly, narrow thorax, micromelia < 5 Num Cortex Bilat TOP In all of these cases, there was an absence of corticomedullary differentiation. *Renal length expressed as SD of the mean 4. Abst, absent; AF, amniotic fluid; Bilat, bilateral; Cons, consanguinity; CRF, chronic renal failure; Dim, diminished; DW, Dandy Walker malformation; FP, fetopathological examination; GA, gestational age at diagnosis; Inc, increased; NA, not available; Norm, normal; Num, numerous; Occ, occipital; TOP, termination of pregnancy; Unilat, unilateral; US, ultrasound.

5 Hyperechogenic cystic kidneys 915 Figure 3 Ultrasound examination of a 24-week fetus presenting with large cystic kidneys (a, calipers) associated with polydactyly (b, ellipse) and encephalocele (c, arrow) with ventriculomegaly (c, star). The kidney is markedly enlarged (+ 4.5 SD) and there is no corticomedullary differentiation. Sonographic diagnosis of Meckel Gruber syndrome was confirmed after termination of the pregnancy. Our only case of Jarcho Levin syndrome was diagnosed at 22 weeks and presented numerous renal cysts with an absence of CMD and severe oligohydramnios. The associated malformations (spondylocostal and costovertebral dysplasia) allowed sonographic diagnosis, and a TOP was performed. One case in our series was diagnosed with Beemer syndrome (short-rib polydactyly syndrome). Ultrasound examination performed at 22 weeks of gestation showed small hyperechogenic kidneys with numerous cortical cysts and oligohydramnios. The thorax was narrow and there was platyspondyly associated with micromelia and incurvated long bones. A TOP with fetopathological examination confirmed the diagnosis of Beemer syndrome and identified polydactyly of the feet that had not been noticed on ultrasound examination. The parents were first cousins. DISCUSSION Large hyperechogenic kidneys are seen occasionally at the time of a routine ultrasound examination. They represent a difficult diagnosis especially when the amniotic fluid volume is normal. The presence of renal cysts in association with hyperechogenic kidneys is not uncommon and management of these cases has not been described in the literature. Before searching for a nephropathy, diagnoses of renal tract anomalies (obstructive cystic dysplasia or MKD) must be excluded. MKD is usually unilateral, with a normal contralateral kidney, and the typical sonographic findings include a mass with multiple cysts of varying sizes without connections between them and without normal parenchyma. The main differential diagnosis is ureteropelvic junction (UPJ) obstruction 5. Obstructive cystic dysplasia can occur with UPJ obstruction or with other urinary tract obstructions, such as posterior urethral valves in male fetuses. Simple renal cyst can also be a differential diagnosis, especially in early pregnancy. Blazer et al. 6 described 28 fetuses with simple renal cyst (1/1100 pregnancies). In the absence of associated anatomical or chromosomal abnormalities, the majority of cysts will resolve during pregnancy without sequelae (89% in their series). They concluded that this transient evolution may represent a distinct entity within the spectrum of cystic kidney diseases 6. In the case of renal cysts associated with hyperechogenic kidneys, genetic survey and ultrasound examination of the parents and grandparents is useful. A detailed ultrasound examination is mandatory, with careful attention being paid to hands and feet, thorax and spine, and posterior fossa. Fetal kidneys must be measured and compared with reference tables 4, and CMD, renal echogenicity, cyst characteristics (size, location, number) and amniotic fluid volume must be analyzed. Karyotyping should be discussed, particularly if other malformations are detected 7. Our retrospective study was based on ultrasound examinations and none of the cases underwent magnetic resonance imaging (MRI). Over the last 10 years, fast single-shot MRI has become recognized as a powerful tool with which to explore fetal brain abnormalities. Its contribution to the analysis of urinary tract abnormalities is far less well-developed, although this method has been proved useful in small series 8 10.Withregardto nephropathy, the potential contribution of MRI is not currently well-defined and ultrasound examination is still the major imaging tool, despite its usefulness in cases with inconclusive sonographic findings (maternal obesity and/or oligohydramnios). T2-weighted images with high resolution have allowed visualization of cysts in cases of ARPKD 9,11. The fetal MRI appearance of ARPKD has been described with increased renal signal intensity on T2-weighted images 12 and low renal signal intensity on T1-weighted images 13 as a result of high water content in the renal parenchyma, consistent with tiny renal cysts. RARE-MR urography (thick-slab heavily T2-weighted sequence) can be used to show directly the microcystic dilatation of collecting ducts, as described by Kern et al. 14 in children. The use of this sequence in the fetus has been described recently 15,16. MRI is not hampered by a lack of amniotic fluid and, in addition to renal analysis, it can be used to look for pulmonary hypoplasia or associated brain malformations.

6 916 Chaumoitre et al. Table 3 Characteristics of hereditary cystic renal pathologies in our series Transmission Frequency Main findings Fetal renal cysts Autosomal dominant ADPKD 1/ Moderately enlarged hyperechogenic kidneys, increased CMD, normal amniotic fluid volume, uncommon associated malformations 2 Autosomal recessive ARPKD 1/ Enlarged hyperechogenic kidneys, absence of CMD, oligohydramnios 7, uncommon associated malformations Meckel Gruber Rare 22, 25% Medullary cystic dysplasia, severe oligohydramnios, CNS recurrence risk anomaly (occipital defect), polydactyly Bardet Biedl 1/ Enlarged hyperechogenic kidneys (30 100%), absence of CMD, digital anomalies (70%) 3,23,24,25, delayed onset of the classic symptoms 3 Ivemark II Rare 26,27 Asplenia-polysplenia, cystic liver, kidney and pancreas, often diagnosed only by FP examination, prognosis poor 28 Jarcho Levin Beemer Chromosomal aberration Trisomy 13 Rare, high prevalence in Puerto Rico Spondylothoracic dysplasia, generally lethal 29 Rare 2,18,19,20, 11% in our series 31% in our series 100% in our series 27% in our series 50% in our series Uncommon Narrow ribs, micromelia, multiple anomalies of major organs, Uncommon 30 with or without polydactyly 30,31,32 33% 1 (none in our five cases) ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; CMD, corticomedullary differentiation; CNS, central nervous system; FP, fetopathological. Hyperechogenic kidneys and renal cysts (32%) Exclusion of: simple renal cyst, multicystic dysplastic kidney, obstructive cystic dysplasia Family history, ultrasound examination of parents, genetic counseling, karyotyping PKD No Associated malformations Yes syndromes ARPKD polydactyly: (11% cortical cysts, Bardet Biedl AF normal, Beemer kidney size: +1 to +5 SD, family history +++) occipital defect, Dandy Walker malformation: MG or MG-like ADPKD (29% cysts (cortex or medulla), CMD variable, AF diminished in 78%, kidney size: +1.5 to +15 SD (mean +5 SD)) thoracic and/or spine malformation: Jarcho Levin Beemer Figure 4 Management flow chart based on our series, for cases of hyperechogenic kidney with renal cysts. ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; AF, amniotic fluid; CMD, corticomedullary differentiation; MG, Meckel Gruber syndrome. The most frequent genetically transmitted cystic renal diseases are ARPKD and ADPKD 1. Cystic kidneys are part of many hereditary diseases that may present many associated anomalies 1. The hereditary cystic renal pathologies in our series with their main findings are summarized in Table 3. Apart from the pathologies of our sample, renal cysts could be present in other autosomal dominant pathologies (tuberous sclerosis, Beckwith Wiedemann syndrome), autosomal recessive diseases (Jeune, Fryns and Zellwegger syndromes, glutaric aciduria II), chromosomal aberrations (T18, T21), orofacial X-linked syndrome and VACTERL syndrome 1. In our series, the characteristics of the cysts (size, location, number) were not very useful for diagnosis. In 56% of the cases, cysts were small (< 5 mm) and in the majority of the cases they were bilateral (73%), especially in cases of syndromes (89%). Cortical cysts were common in ADPKD (3/3) and occurred in four

7 Hyperechogenic cystic kidneys 917 of nine cases in ARPKD. The number of cysts varied according to the gestational age at diagnosis. It was the presence of an associated malformation that proved most useful in improving diagnostic accuracy. However, sonography is not 100% sensitive, especially in cases of severe oligohydramnios. In these cases amnioinfusion or fetal MRI could be used. In conclusion, renal cysts associated with hyperechogenic kidneys are not uncommon. In our series, location, size and number of cysts were not specific and ultrasound examination was particularly useful in looking for associated malformations (Figure 4). Familial history and genetic survey were also essential. Often, the clue to diagnosis will be the demonstration of an associated malformation. If no malformation is found, the main diagnosis remains PKD, i.e. ARPKD or ADPKD. REFERENCES 1. Avni FE, Garel L, Hall M, Rypens F. 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