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Renal tubular dysgenesis (RTD) - an important cause of the oligohydramnion-sequence
PATHOLOGY RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journaI5lprp
Renal Tubular Dysgenesis (RTD) - An Important Cause of the Oligohydramnion-Sequence Report of 3 Cases and Review of the Literature Jbrg Kriegsmann', Wiltrud Coerdt 2 , Friedrich Kommoss', Rolf Beetz3, Christian Hallermann 2 and Horst Muntefering 2 'Institute of Pathology, 'Department of Pediatric Pathology, and lChildrens Hospital of the Johannes Gutenberg University, Mainz, Germany
Summary Renal tubular dysgenesis (RTD) is a disorder characterized by neonatal renal failure and regular gross renal architecture, although the histological features of immature and shortened proximal tubules lead to neonatal death. The pathogenesis of this condition includes a congenital familial condition, a twin-twin transfusion syndrome, and an angiotensin-converting enzyme inhibitor intake by the mother. The clinical picture shows an association with oligohydramnia, pulmonary hypoplasia, and skull ossification defects. In the present paper, we report the occurrence of RTD in three infants of a con sanguinous couple and compared our data with those of the literature. Our data contirm that late second trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney.
Key words: Renal tubular dysgenesis - Oligohydramnion sequence - Case report
Introduction In 1983, Allanson et al [1J described two stillborn sibs with diffuse renal tubular hypoplasia. In the following years, more than 70 cases have been reported, and many reports on associated conditions and pathogenetic clues have been provided in the literature ever since. Pathol. Res. Praet. 196: 861-865 (2000)
RTD is a rare condition that is found in stillborn infants and neonates surviving only several days. The clinical picture is compatible with that of Potter or oligohydramnion sequence appearing by 20--23 weeks of gestation [2, 7, 15, 17, 19,21,24,25,29,31, 33-35 j. The precise molecular mechanism leading to the phenotype of RTD is not clear. Etiologic factors include an inherited autosomal condition, because RTD is often associated with parental consanguinity {3, 17, 19, 22,23, 29,35], as in this family. RTD has been reported in twins [6, 7, 11,26,29,30, 33], but only in those monozygotic twins showing evidence of the twin-twin transfusion syndrome [11, 26], and particularly in those donor twins with oligohydramnion and growth restrictjon [6j. Others suggest renal hypoperfusion as a pathogenetic mechanism leading to the development of RTD [5, 8, II, 17, 21, 33, 35 J. Data supporting this view include absent renal efferent arterioles [35/, renal vein thrombosis [21, 27/, occurrence in cases with maternal use of ACE inhibitors [5, 33J, and the above mentioned twintwin transfusion syndrome. It has been demonstrated that RTD is associated with other conditions, such as pulmonary hypoplasia or neonatal respiratory failure [4, 5,11,17,21,32-34/ and abnormalities of the skull (mainly ossification defects) in some cases [3, 16, 17,20-22, 31, 33 j. In addition, an association with liver disease has been described [4, 16, 31,35j. We report on a family with three children having renal tubular dysgenesis and review the literature. Addre.'iis for correspondence: J. Kriegsmann, Institut fUr
Pathoiogie, Johannes-Gutenberg-UniversiUit Mainz, Langen-
bcckstraBc 1,55101 Mainz, Germany. 0344-033812000/196/12-86 ' $15.00/0
862 . 1. Kriegsmann et al.
Care Report We report on a consanguinous couple with congenital renal dysplasia in three children who died within several days after birth of renal failure and cardiopulmonary complications. The couple has two healthy children. Two former pregnancies led to miscarriages. 1. The woman presented in her third pregnancy with oligohydramnion. Her first child is healthy, and one miscarriage was reported. In the second pregnancy, a female child was delivered at 33 weeks of gestation. The child had been anuric since delivery, and a severe lung hypoplasia was diagnosed. Oysmorphic features of the child included a small bell-shaped thorax and plump hands. An additional finding was low muscular tonus. An ultrasound examination showed kidneys of normal size with slightly increased echogenicity. Severe hypotension persisted despite the application of high katecholamine doses until death at 7 days. The parents refused autopsy but allowed kidney hiopsy, which histologically revealed glomerular crowding and tubules lined by small , darkly stained
cclls that cannot be differentiated histologically into proximal and distal convoluted tubules. In addition, moderate interstitial fibrosis was found. Chromosomal analysis revealed a regular female 46,XX karyotype. 2, This pregnancy, complicated by oligohydramnion, was terminated by cesarean section at 32 weeks of gestation because of pathological CTG and asphyxia. The female newborn died on the same day. A clinical diagnosis of Potter-sequence was made. Postmortal ultrasonography revealed hypoplastic kidneys. On autopsy, oligohydramnion sequence was confirmed, Ioint contractures were noted. The skull showed poor ossification, The lung was severely hypoplastic. On macroscopical examination, the urogenital tract did not show any abnormalities. Histological investigation of the kidney displayed the same picture as in case I using H&E staining (Fig. 1). These findings were supported by immunohistochemistry with antibodies against epithelial membrane antigen (EMA). Nearly all the tubules were positive when using this technique (Fig. 2).
Fig. I. Kidney biopsy with the typical histological picture of renal tubular dysgenesis with crowding of glomeruli and immature tubular structures (xl 50).
Fig. 2. Patient 2: Kidney with crowding of the glomeruli. Nearly all tubules stained positively for EMA, suggesting immaturity of these structures (x lSO).
Tubular Dysgenesis - Case Report and Review of the Literature . 863
Fig. 3. Patient 3 with typical Potter facies.
Fig. 4. X-ray of case 3 with skull ossification defects. Most remarkable is the slight calcification of the bone framework.
In addition, periodic acid-Schiff (PAS) stains for proximal tubule brush borders were negative, as confirmed by electron microscopy, since we failed to detect brush borders, even if this technique was complicated due to autolysis. Chromosomal analysis revealed a regular female 46,XX karyotype. 3. The seventh pregnancy was also complicated by oligohydramnion and resulted in the delivery of a male newborn at 30 weeks of gestation by cesarian section because of pathological CTG and asphyxia. The child showed Potter facies (Fig. 3). Skull ossification defects (Fig. 4) included microcephaly, widely separated sutures, and very large fontanelles. Furthermore, joint abnonna/ities with ulnar deviation of the hands were detected. The child had been anuric from birth. the creatinine increased, from initial 1.9 mgldl to 5.5 mg/dl. Ultrasound imaging showed markedly enlarged kidneys. Intensive care was required because of respiratory failure, but the situation was complicated by a pneumothorax. Severe hypotension could not be prevented despite
the application of very high doses of catecholamins. In addition, intracranial bleeding occurred. The patient died at 14 days. Neither kidney biopsy nor autopsy was performed, since the parents had refused permission.
Discussion In RTO, the affected kidneys may be small {4, IIJ but usually are enlarged {5, 21, 33-35, and the present case 3J or of nonnal size {l, 2, 4, 5, 17,23,29,31,33, 34, and the present cases 1 and 3 j. The typical histological pattern of renal tubular dysgenesis could be demonstrated in cases I and 2 (Figs. 1; 2), while the parents refused kidney biopsy in the third case. Histologically, the glomeruli appeared to be crowded. There was an increased number of layers (or generations) of glomeruli {21 f. The most striking abnormality was the "primitive" aspect of all the tubular structures {2f. This disorder is mainly characterized by the absence of recognizable renal proximal tubules. The tubu-
864 . 1. Kriegsmann et al.
lar cells do not show an abundance of eosinophilic cytoplasm and brush borders, which are characteristically present in normal convoluted tubules 121}. PAS stain failed to reveal any proximal tubular brush borders, which would normally be well stained even in premature babies {2}, as may be confirmed by immunohistological investigation. Since RTD is a disorder of altered tubular development with a loss of morphologically distinguishable proximal tubules {26}, proximal tubular structures could not be detected by immunohistochemistry. Epithelial membrane antigen and peanut lectin reactivity can be shown on the apical surface of all the tubules, in contrast to what is seen in the normal cases of comparable age, where the proximal tubules show no reactivity {2]. Markers for proximal tubular ditferentiation not present in RTD include reactivity with Lotus teragonobus (LTA) {l2, 14, 18, 26}, CDI5 {1O, 281, alpha I-antitrypsin {J3 , 23}, lysozyme {IO, 24}, and fumarylacetoacetone hydrolase (FAH) {26I. Electron microscopy confirmed the absence of microvillous stmctures on cortical tubular cells, although some tubules contained rudimcntary proximal tubular brush borders {21,31l. The histological , immunohistological , and electron microscopical data confirm the view that RTD represents a disorder with a fundamental derangement of nephrogenesis 12l. The precise etiology and pathogenetic mechanisms leading to renal tubular dysgenesi s are not clear. According to the literature, two main mechanisms, autosomal recessive inheritance and ischemia, playa major role in the pathogenesis of this disease. The first factor, as supported by our data, is autosomal recessive inheritance, as RTD is often associated with parental consanguinity {3, 17, 19,22,23,29, 35]. The affected pregnancies often result in early loss, stillbirth, or in children with oligohydramnions, intrauterine growth retardation, skull ossification defects, and early onset of renal failure {I 71. As a second factor, longstanding renal hypoperfusion in RTD has been shown to be associated with absent renal efferent arteriols {35I or renal vein thrombosis {21, 27 l. Furthermore, RTD has been described in twins and was found among those monozygotic twins showing evidence of twin-twin transfusion syndrome {ll, 261, particularly in those donor twins with oligohydramnion and growth restriction {6J. Twin-twin transfusion syndrome is characterized by placental shunting of blood from a growth-restricted donor to a large plethoric recipient [26, 36/. The hypothesis of longstanding hypoperfusion is supported by cases in which maternal application of ACE inhibitor causes RTD and leads to fetal ACE inhibitor syndrome [5, 33/. Bernstein and Barajas 181 showed a large amount of renin in renal tissue with RTD, far exceeding that of normal kidneys. They speculated that
the increased accumulation of renin may reflect local vasoconstriction, which could be responsible for reduced glomerular perfusion. Other data supporting the view that alt~tions in the renin angiotensin system contribute to inis disease complex include the findings of Kumar et al. [17]. These authors found increased renin levels in some children. Since the angiotensin renin system plays a role in nephronogenesis in animal models {9I, and angiotension II induces some immediate early genes in proximal tubular cells {37/, Kumar et al. {I 7} hypothesized that a lack of Angiotensin II may contribute to the embryopathy seen in inherited RTD and fetal ACE inhibitor syndrome. Some cases, including two of ours, are characterized by an association of RTD with skull ossification defects {3, 5, 16, 17,20-22, 31]. RTD may occur in various clinical settings or is associated with certain clinical features outside the kidney. The association of RTD with skull ossification defects was first described in angiotensin-converting enzyme inhibitor fetopathy {51 ; however, in the meantime, alterations of the skull are also reported in RTD not caused by this medication {17}. Numerous reports emphasized the role of pulmonary hypoplasia or neonatal respiratory failure {4, 5,11,17, 21,23,29,33,34}. Renal tubular dysgenesis may be associated with liver disease (4, 16, 31 , 351, including liver fibrosis (35) or neonatal hemochromatosis [4, 16J. Patients with RTD showed severe oliguria or anuria resistant to treatment (5, 6,8, 21,23,27,31 , 33 l. One of the most remarkable clinical features in some infants, including those presented in this paper, was profound refractory hypotension [17]. In summary our data emphasize that the latesecond trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney. An early and precise diagnosis allows us to provide parents and physicians with thorough information regarding management decisions. Finally, genetic counseling is recommended in the case of consanguinity.
Literature 1. Allanson IE, Pantzar JT, Macleod PM (1983) Possible new
autosomal
recessive
syndrome
with
unusual
histopathological changes. Am J Med Genet 16: 57-60 2. Allanson JE, Hunter AGW, Mettler GS, Jimenez C ( 1992) Renal tubular dysgenesis: A not uncommon autosomal recessive syndrome: A review_ Am J Med Genet 43: 811 - 814 3. Ariel [, Wells TR, Landing BH, Sagi M, Bar-Oz B, Ron N, Rosenmann E ([995) Familial renal tubular dysgene-
Tubular Dysgenesis - Case Report and Re view of the Literature . 865
sis: a disorder not isolated to proximal convoluted tubul es. Pediatr Pathol Lab Med 15: 915- 922 4. Bale PM. Kann AE. Dorney SFA ( 1994) Renal proximal
tubular dysgenesis associated with severe neonatal hemosiderotic liver di sease. Pediatr Pathol 14: 479-489
5. Barr M, Cohen MM (1991) ACE inhibitor fetopathy and hypocalvaria: The kidney- skull connection. Teratology 44:485-495 6. Barr M, Sedman AB, Heidelberger KP (1998) Renal tubular dysgenesis in twins. Pediatr Nephrol/2: 408-413 7. Bernstein J (1988) Renal tubular dysgenesis. Ped.iatr Pathol 8: 453-456 8. Bernstein J, Barajas L (1994) Renal tubular dysgcnesis:
evidence of abnormality in the renin-angiotensin system.
J Am Soc Nephrol 5: 224-227 9. Correa-ROller R, Perez-Castillo A. Chmielewski D. Rosenberg ME (1992) Relationshi p between renin. angiotensinogen and histone H2b messenger ribonucleic acid in the maturing rat kidney. Nephron 62: 322- 327 10. Endo H, Oka T (1997) Renal tubular abnormalities in hydrops fetalis: a histological and immunohistochemical sllldy. Early Hum Dev 48: 11-21 II. Genest DR, Lage JM (1991) Absence of normal-appearing proximal tubules in the fetal and neonatal kidn ey: prevalence and significance. Hum Pathol 22: 147- 153 12. Faraggiana T, Ma1chiodi F, Artie P, Churg J (1982) Lectin-peroxidase conjugate reactivity in normal human kidney. J Histochem Cytochem 30: 451-458 13. Flemming 5, Gibson AAM (1986) Proteinase inhibitors in the kidney and its tumors. Histopathology 10: 1303-1313 14. Henningar RA, Schulte BA, Spicer SS ( 1985) Heterogeneous di stribution of glycoconjugates in human kidney tubules. Anat Rec 211: 37fr-390 15. Hill LM , Hill LA (1997) Renal tubular dysgenesis: a cause of second trimester oligohydramnions. J Vltrasound Med 16: 627-{)30 16. Johal JS , Thorp JW, Oyer CE (1998) Neonatal hemochromatosis, renal tubular dysgenesis, and hypocal varia in a neonate. Pediatr Dev Patholl: 433-437 17. Kumar D, Moss G, Primhak R. Coombs R (1997) Congenital renal tubular dysplasia and sk ull ossification defects similar to teratogenic effects of angiotensin convelting enzyme (ACE) inhibitors. J Med Genet 34: 541-545 18. Landing BH , Ang SM. Herta N, Larson EF, Turner M (1994) Labeled lectin studies of renal tubul ar dysgenesis and renal tubular atrophy of postnatal renal ischemia and end-stage kidney disease. Pediatric Pathol14: 87-99 19. MacMahon P , Blackie RAS. House MJ et al (1990) A further famil y with congenital renal proximal tubular dysgenesis. J Med Genet 27: 3935-398 20. McFadden DE, Pantzar JT, Van Allen MI, Langlois 5 ( 1997) Renal tubular dysgenesis with calvarial hypoplasia: report of two additional cases and review. J Med Gen 34: 84fr-848 21. Metzman RA. Husson MA, Dellers EA (1993) Renal tubular dysgenesis: A description of early renal maldevelopment in siblings. Pediatr Pathol 13: 239- 248
22. Milunsky JM, Genest DR, Milunsky A (1997) Renal tubular dysgenesis wi th microcephaly. Pedialr Nephrol
II: 494-496
23. Moldavsky M, Shahin A, Turani H (1994) Renal tubular dysgenesis present in a newborn with meconium ileus. Pediatr Pathol 14: 245- 251 24. Moldavsky M (2000) Lysozyme immunostai ning in renal lUbulardysgenesis. Pediatr Dev Pathol 3: 200-201 25. Newbould MJ. Lendon M, Barson AJ (1994) Oligohy-
dramnions sequence: the speclrum of renal malformations. Br J Obstet GynaecollOI: 598-604
26. Oberg KC. Pestaner JP, Bielamowicz L, Hawkins EP (1999) Renal tubular dysgenesis in twin twin transfu sion syndrome. Pediatr Dev Pathol 2: 25-32 27. Ortmann M, Querfeld V. Stollorz M, SchrOder R (1995) Renal tubular dysgenesis with fet al renal vein thrombosis. Pathologe 16: 143- 147 28. Platt JL, LeBien TW. Michael AF (1983) Stages of renal
ontogensis identified by monoclonal antibodies reactive
with Iymphohemopoietie differentiation antigens. J Exp Med 157: 155- 172 29. Querfeld V_ Ortmann M. Vi erzigA. Roth B (1996 ) Renal tubular dysgenesis. A report of two cases. J P erinatol 16: 498-500 30. Restaino I, Kaplan BS, Kaplan P, Rosenberg HK, Witzlcben C, Roberts N (1991) Renal dysgenesis in a
monozygotic twin: association with in utero exposure to
indomethacin. Am J Med Genet 39: 252- 257 3 1. Russo R, D'Anniento M, Veccione R (1991) Renal tubular dy sgenesis and very large cranial fontanels in a family with acrocephalosyndactyly s.c. type. Am J Med Genet 39: 482-485 32. Scarcella A, Pecoraco C. Dagnello R, Sole AN (1994) Renal tubular dysgenesis without pulmonary hypoplasia. Pediatr Nephrol 8: 21 fr-2 17 33. Schwartz BR, Lage J M, Pober BR, Driscoll SG (1986) Isolated congenital renal tubular immaturity in si blings. Hum Pathol1 7: 1259-1263 34. Swinford AE, Bernstein J, Toriello HV, Higgins JV (1989) Renal tubular dysgenesis: delayed onset of oligohydramnions. Am J Med Genet 32: 127- 132 35. Voland JR, Hawkins EP, Wells TR, Saunders B, Jones M, Bernischke K (1985) Congenital hypernephronic nephro-
megaly with tubular dysgenesis: A distinctive inherited renal anomaly. Pediatr Pathol4: 231 - 245
36. Weiner CP, Ludomirski A (1994) Diagnosis, pathophysi-
ology and treatment of chronic twin-to-twin transfusion syndrome. Fetal Diagn Ther 9: 283- 290
37. Wolf G, Neilson EG (1990) Angiotensin II induces cellular growth in cultured murine pro xi mal tubular cells. AM J Physiol259: F768-777
Received: April 7, 2000 Accepted in revised version: August 10, 2000
Renal Tubular Dysgenesis (RTD) - An Important Cause of the Oligohydramnion-Sequence Report of 3 Cases and Review of the Literature Jbrg Kriegsmann', Wiltrud Coerdt 2 , Friedrich Kommoss', Rolf Beetz3, Christian Hallermann 2 and Horst Muntefering 2 'Institute of Pathology, 'Department of Pediatric Pathology, and lChildrens Hospital of the Johannes Gutenberg University, Mainz, Germany
Summary Renal tubular dysgenesis (RTD) is a disorder characterized by neonatal renal failure and regular gross renal architecture, although the histological features of immature and shortened proximal tubules lead to neonatal death. The pathogenesis of this condition includes a congenital familial condition, a twin-twin transfusion syndrome, and an angiotensin-converting enzyme inhibitor intake by the mother. The clinical picture shows an association with oligohydramnia, pulmonary hypoplasia, and skull ossification defects. In the present paper, we report the occurrence of RTD in three infants of a con sanguinous couple and compared our data with those of the literature. Our data contirm that late second trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney.
Key words: Renal tubular dysgenesis - Oligohydramnion sequence - Case report
Introduction In 1983, Allanson et al [1J described two stillborn sibs with diffuse renal tubular hypoplasia. In the following years, more than 70 cases have been reported, and many reports on associated conditions and pathogenetic clues have been provided in the literature ever since. Pathol. Res. Praet. 196: 861-865 (2000)
RTD is a rare condition that is found in stillborn infants and neonates surviving only several days. The clinical picture is compatible with that of Potter or oligohydramnion sequence appearing by 20--23 weeks of gestation [2, 7, 15, 17, 19,21,24,25,29,31, 33-35 j. The precise molecular mechanism leading to the phenotype of RTD is not clear. Etiologic factors include an inherited autosomal condition, because RTD is often associated with parental consanguinity {3, 17, 19, 22,23, 29,35], as in this family. RTD has been reported in twins [6, 7, 11,26,29,30, 33], but only in those monozygotic twins showing evidence of the twin-twin transfusion syndrome [11, 26], and particularly in those donor twins with oligohydramnion and growth restrictjon [6j. Others suggest renal hypoperfusion as a pathogenetic mechanism leading to the development of RTD [5, 8, II, 17, 21, 33, 35 J. Data supporting this view include absent renal efferent arterioles [35/, renal vein thrombosis [21, 27/, occurrence in cases with maternal use of ACE inhibitors [5, 33J, and the above mentioned twintwin transfusion syndrome. It has been demonstrated that RTD is associated with other conditions, such as pulmonary hypoplasia or neonatal respiratory failure [4, 5,11,17,21,32-34/ and abnormalities of the skull (mainly ossification defects) in some cases [3, 16, 17,20-22, 31, 33 j. In addition, an association with liver disease has been described [4, 16, 31,35j. We report on a family with three children having renal tubular dysgenesis and review the literature. Addre.'iis for correspondence: J. Kriegsmann, Institut fUr
Pathoiogie, Johannes-Gutenberg-UniversiUit Mainz, Langen-
bcckstraBc 1,55101 Mainz, Germany. 0344-033812000/196/12-86 ' $15.00/0
862 . 1. Kriegsmann et al.
Care Report We report on a consanguinous couple with congenital renal dysplasia in three children who died within several days after birth of renal failure and cardiopulmonary complications. The couple has two healthy children. Two former pregnancies led to miscarriages. 1. The woman presented in her third pregnancy with oligohydramnion. Her first child is healthy, and one miscarriage was reported. In the second pregnancy, a female child was delivered at 33 weeks of gestation. The child had been anuric since delivery, and a severe lung hypoplasia was diagnosed. Oysmorphic features of the child included a small bell-shaped thorax and plump hands. An additional finding was low muscular tonus. An ultrasound examination showed kidneys of normal size with slightly increased echogenicity. Severe hypotension persisted despite the application of high katecholamine doses until death at 7 days. The parents refused autopsy but allowed kidney hiopsy, which histologically revealed glomerular crowding and tubules lined by small , darkly stained
cclls that cannot be differentiated histologically into proximal and distal convoluted tubules. In addition, moderate interstitial fibrosis was found. Chromosomal analysis revealed a regular female 46,XX karyotype. 2, This pregnancy, complicated by oligohydramnion, was terminated by cesarean section at 32 weeks of gestation because of pathological CTG and asphyxia. The female newborn died on the same day. A clinical diagnosis of Potter-sequence was made. Postmortal ultrasonography revealed hypoplastic kidneys. On autopsy, oligohydramnion sequence was confirmed, Ioint contractures were noted. The skull showed poor ossification, The lung was severely hypoplastic. On macroscopical examination, the urogenital tract did not show any abnormalities. Histological investigation of the kidney displayed the same picture as in case I using H&E staining (Fig. 1). These findings were supported by immunohistochemistry with antibodies against epithelial membrane antigen (EMA). Nearly all the tubules were positive when using this technique (Fig. 2).
Fig. I. Kidney biopsy with the typical histological picture of renal tubular dysgenesis with crowding of glomeruli and immature tubular structures (xl 50).
Fig. 2. Patient 2: Kidney with crowding of the glomeruli. Nearly all tubules stained positively for EMA, suggesting immaturity of these structures (x lSO).
Tubular Dysgenesis - Case Report and Review of the Literature . 863
Fig. 3. Patient 3 with typical Potter facies.
Fig. 4. X-ray of case 3 with skull ossification defects. Most remarkable is the slight calcification of the bone framework.
In addition, periodic acid-Schiff (PAS) stains for proximal tubule brush borders were negative, as confirmed by electron microscopy, since we failed to detect brush borders, even if this technique was complicated due to autolysis. Chromosomal analysis revealed a regular female 46,XX karyotype. 3. The seventh pregnancy was also complicated by oligohydramnion and resulted in the delivery of a male newborn at 30 weeks of gestation by cesarian section because of pathological CTG and asphyxia. The child showed Potter facies (Fig. 3). Skull ossification defects (Fig. 4) included microcephaly, widely separated sutures, and very large fontanelles. Furthermore, joint abnonna/ities with ulnar deviation of the hands were detected. The child had been anuric from birth. the creatinine increased, from initial 1.9 mgldl to 5.5 mg/dl. Ultrasound imaging showed markedly enlarged kidneys. Intensive care was required because of respiratory failure, but the situation was complicated by a pneumothorax. Severe hypotension could not be prevented despite
the application of very high doses of catecholamins. In addition, intracranial bleeding occurred. The patient died at 14 days. Neither kidney biopsy nor autopsy was performed, since the parents had refused permission.
Discussion In RTO, the affected kidneys may be small {4, IIJ but usually are enlarged {5, 21, 33-35, and the present case 3J or of nonnal size {l, 2, 4, 5, 17,23,29,31,33, 34, and the present cases 1 and 3 j. The typical histological pattern of renal tubular dysgenesis could be demonstrated in cases I and 2 (Figs. 1; 2), while the parents refused kidney biopsy in the third case. Histologically, the glomeruli appeared to be crowded. There was an increased number of layers (or generations) of glomeruli {21 f. The most striking abnormality was the "primitive" aspect of all the tubular structures {2f. This disorder is mainly characterized by the absence of recognizable renal proximal tubules. The tubu-
864 . 1. Kriegsmann et al.
lar cells do not show an abundance of eosinophilic cytoplasm and brush borders, which are characteristically present in normal convoluted tubules 121}. PAS stain failed to reveal any proximal tubular brush borders, which would normally be well stained even in premature babies {2}, as may be confirmed by immunohistological investigation. Since RTD is a disorder of altered tubular development with a loss of morphologically distinguishable proximal tubules {26}, proximal tubular structures could not be detected by immunohistochemistry. Epithelial membrane antigen and peanut lectin reactivity can be shown on the apical surface of all the tubules, in contrast to what is seen in the normal cases of comparable age, where the proximal tubules show no reactivity {2]. Markers for proximal tubular ditferentiation not present in RTD include reactivity with Lotus teragonobus (LTA) {l2, 14, 18, 26}, CDI5 {1O, 281, alpha I-antitrypsin {J3 , 23}, lysozyme {IO, 24}, and fumarylacetoacetone hydrolase (FAH) {26I. Electron microscopy confirmed the absence of microvillous stmctures on cortical tubular cells, although some tubules contained rudimcntary proximal tubular brush borders {21,31l. The histological , immunohistological , and electron microscopical data confirm the view that RTD represents a disorder with a fundamental derangement of nephrogenesis 12l. The precise etiology and pathogenetic mechanisms leading to renal tubular dysgenesi s are not clear. According to the literature, two main mechanisms, autosomal recessive inheritance and ischemia, playa major role in the pathogenesis of this disease. The first factor, as supported by our data, is autosomal recessive inheritance, as RTD is often associated with parental consanguinity {3, 17, 19,22,23,29, 35]. The affected pregnancies often result in early loss, stillbirth, or in children with oligohydramnions, intrauterine growth retardation, skull ossification defects, and early onset of renal failure {I 71. As a second factor, longstanding renal hypoperfusion in RTD has been shown to be associated with absent renal efferent arteriols {35I or renal vein thrombosis {21, 27 l. Furthermore, RTD has been described in twins and was found among those monozygotic twins showing evidence of twin-twin transfusion syndrome {ll, 261, particularly in those donor twins with oligohydramnion and growth restriction {6J. Twin-twin transfusion syndrome is characterized by placental shunting of blood from a growth-restricted donor to a large plethoric recipient [26, 36/. The hypothesis of longstanding hypoperfusion is supported by cases in which maternal application of ACE inhibitor causes RTD and leads to fetal ACE inhibitor syndrome [5, 33/. Bernstein and Barajas 181 showed a large amount of renin in renal tissue with RTD, far exceeding that of normal kidneys. They speculated that
the increased accumulation of renin may reflect local vasoconstriction, which could be responsible for reduced glomerular perfusion. Other data supporting the view that alt~tions in the renin angiotensin system contribute to inis disease complex include the findings of Kumar et al. [17]. These authors found increased renin levels in some children. Since the angiotensin renin system plays a role in nephronogenesis in animal models {9I, and angiotension II induces some immediate early genes in proximal tubular cells {37/, Kumar et al. {I 7} hypothesized that a lack of Angiotensin II may contribute to the embryopathy seen in inherited RTD and fetal ACE inhibitor syndrome. Some cases, including two of ours, are characterized by an association of RTD with skull ossification defects {3, 5, 16, 17,20-22, 31]. RTD may occur in various clinical settings or is associated with certain clinical features outside the kidney. The association of RTD with skull ossification defects was first described in angiotensin-converting enzyme inhibitor fetopathy {51 ; however, in the meantime, alterations of the skull are also reported in RTD not caused by this medication {17}. Numerous reports emphasized the role of pulmonary hypoplasia or neonatal respiratory failure {4, 5,11,17, 21,23,29,33,34}. Renal tubular dysgenesis may be associated with liver disease (4, 16, 31 , 351, including liver fibrosis (35) or neonatal hemochromatosis [4, 16J. Patients with RTD showed severe oliguria or anuria resistant to treatment (5, 6,8, 21,23,27,31 , 33 l. One of the most remarkable clinical features in some infants, including those presented in this paper, was profound refractory hypotension [17]. In summary our data emphasize that the latesecond trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney. An early and precise diagnosis allows us to provide parents and physicians with thorough information regarding management decisions. Finally, genetic counseling is recommended in the case of consanguinity.
Literature 1. Allanson IE, Pantzar JT, Macleod PM (1983) Possible new
autosomal
recessive
syndrome
with
unusual
histopathological changes. Am J Med Genet 16: 57-60 2. Allanson JE, Hunter AGW, Mettler GS, Jimenez C ( 1992) Renal tubular dysgenesis: A not uncommon autosomal recessive syndrome: A review_ Am J Med Genet 43: 811 - 814 3. Ariel [, Wells TR, Landing BH, Sagi M, Bar-Oz B, Ron N, Rosenmann E ([995) Familial renal tubular dysgene-
Tubular Dysgenesis - Case Report and Re view of the Literature . 865
sis: a disorder not isolated to proximal convoluted tubul es. Pediatr Pathol Lab Med 15: 915- 922 4. Bale PM. Kann AE. Dorney SFA ( 1994) Renal proximal
tubular dysgenesis associated with severe neonatal hemosiderotic liver di sease. Pediatr Pathol 14: 479-489
5. Barr M, Cohen MM (1991) ACE inhibitor fetopathy and hypocalvaria: The kidney- skull connection. Teratology 44:485-495 6. Barr M, Sedman AB, Heidelberger KP (1998) Renal tubular dysgenesis in twins. Pediatr Nephrol/2: 408-413 7. Bernstein J (1988) Renal tubular dysgenesis. Ped.iatr Pathol 8: 453-456 8. Bernstein J, Barajas L (1994) Renal tubular dysgcnesis:
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Received: April 7, 2000 Accepted in revised version: August 10, 2000