Prune Belly Syndrome and Fetal Ascites IAN W MONIE AND BARBARA J. MONIE Department of Anatomy, Unwersity o f California, San Francisco, California 94143
ABSTRACT A case of prune belly syndrome (PBS) in a 22 week male fetus is described. All t h e features characteristic of t h e syndrome were present: absence of abdominal muscle; dilatation of t h e bladder, ureters, and renal pelves; and undescended testes. In addition, there was marked ascites. The rectus abdominis muscles were entirely absent whereas other abdominal muscles were only absent centrally. Between regions of normal and absent musculature muscle fibers were sparse, enlarged, frequently disrupted, and mostly in t h e myotubule stage. The prostate was thin-walled and its urethra greatly expanded. The testes lay close to t h e corresponding ureters and each ductus deferens was only partially present. I t is considered t h a t prostatic dysgenesis and fetal ascites a r e key factors in t h e causation of PBS. Prune belly syndrome (PBS) is charac- fetus. Some comments are offered on t h e possiterized by absence of abdominal wall muscula- ble genesis of prune belly and of t h e other abture, marked dilatation of the bladder and normalities comprising t h e syndrome. ureters, and incompletely descended testes; MATERIALS AND METHODS occasionally, i t is accompanied by clubfoot, spina bifida, or abnormalities of the carThe intact male fetus along with its cord diovascular or urogenital systems. Details of and placenta was aborted by a 16 year-old the various pathological and clinical features mother after a gestation period estimated at of PBS have been amply described elsewhere 22 weeks and when received by us had been (Housden, '34; N u n n a n d Stephens, '61; preserved in formalin for about 9 years. The Warkany, '71; Welch and Kearney, '74). A history was brief and unremarkable. For commodified and usually less severe form of t h e parison, a normal-appearing male fetus of syndrome has been reported in a few females similar length and time of preservation was (Rabonowitz and Schillinger, '77; Wigger and selected as a "control." Blanc, '77). Both fetuses were dissected and selected The genesis of PBS has been much disput- organs removed and weighed. Portions of t h e ed with disagreement centering mainly on abdominal wall, several muscles, and some whether t h e absence of abdominal muscula- other organs were excised, embedded i n parture is a primary defect (Osler, '01; Afifi e t affin, and cut at 7 to 10 Fm. Sections were al., '72) or a secondary defect due to pressure stained with hematoxylin and eosin, Malloryfrom t h e distended bladder and ureters alone Azan, or Verhoeff-van Gieson, as considered (Sturnme, '03; Eagle and Barrett, '50), or in appropriate. In addition, small portions of t h e combination with ascites (Guthrie, 1896; abdominal wall were removed, teased in glyHousden, '34).The suggestion t h a t a deficien- cerin, and examined in t h e unstained s t a t e to cy of autonomic ganglion cells innervating t h e determine t h e location of muscle. bladder and ureters might be involved has not RESULTS found much support. While genetic factors may play a role in PBS, no clear-cut evidence The fetus was normal in appearance except of inheritance has yet been demonstrated for marked distension of t h e abdomen. It mea(Warkany, '711, In a few cases, chromosomal sured 165 mm crown-rump, weighed 450 gm, abnormalities have been observed (Harley et and had a greatest abdominal girth of 235 mm al., '72). (fig. 1). The control fetus measured 162 mm The following account concerns PBS accomReceived Apr. 21. '78. Accepted Aug. 1 1 , '78. panied by marked ascites in a 22 week-old TERATOLOGY(1979)19: 111-118.
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n
Fig. 1 Male fetus with PBS showing marked distension of the abdomen. X - area where thinned bladder wall is in intimate contact with amnion.
crown-rump weighed 348 gm, and had a greatest abdominal girth of 125 mm. The remarks which follow refer to the abnormal fetus unless otherwise indicated. The skin of the abdominal wall was tense and smooth, except for some fine creases, with subcutaneous hemorrhages in the circum- and infra-umbilical regions. The cord contained two arteries and one vein and flared slightly a t its attachment to the body wall. The abdominal cavity contained 46 ml of fluid and was dominated by the greatly distended bladder, ureters, and kidneys (fig. 21, all of which, when drained, yielded 44 ml of urine. Both fluids were similar in appearance
and on standing each presented a clear colorless supernatant and an equal amount of precipitated debris. No sophisticated chemical tests were attempted in view of the long period of preservation. After removal of fluid the fetus weighed 360 gm which was close to that of the control. The latter contained no measurable fluid in either the peritoneal cavity or the ureters, and had only 0.6 ml of urine in the bladder. The abdominal wall, lax and folded after the removal of fluid, was extremely thin and when examined under a dissecting microscope showed complete absence of the rectus abdominis muscles. The other abdominal muscles were absent centrally but detectable laterally. Intercostal nerves were traceable in the abdominal wall and visible in areas with and without muscle fibers. Microscopic examination of teased preparations and of sections of the abdominal wall confirmed the gross findings. Absent muscle was replaced by fibrous tissue and extravasated blood. Where muscle was sparse, individual fibers varied greatly in diameter, many being quite large with centrally-placed nuclei characteristic of myotubules (fig. 5 ) . In the same regions, disrupted muscle fibers were common (figs. 7, 8),while farther laterally, although sparse, they were normal in appearance and similar to those in the psoas and sartorius muscles. Sections of corresponding muscles in t h e control showed n o abnormalities nor were myotubules seen (figs. 6,9). The greatly enlarged bladder extended to the umbilicus where it came into contact with the amnion (fig. 1 ) ; inferiorly its ventral wall lay in close contact with the thin abdominal wall but was easily separated from it. The urachus could not be identified. The umbilical arteries pursued normal courses (fig. 2). The bladder wall was thinnest (1 mm) ventrally, and thickest (4 mm) infero-dorsally with a lining smooth and free from trabeculations. Inferiorly, it communicated with a smaller chamber formed by the greatly expanded prostatic urethra and this, in turn, opened into the membranous urethra which was of normal caliber (figs. 3, 4). Sections of the bladder revealed a sparsity of muscle except in the trigonal region where bundles of muscle fibers were interwoven with masses of connective tissue. Nerves and ganglion cells were clearly visible near the terminations of the ureters, in the bladder wall, and inferiorly on the outer aspect of the prostate.
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Fig. 2 Diagram showing distended bladder and ureters, along with some related structures. The bladder has been tilted forwards and opened to display the expanded prostatic urethra and its connection with the membranous urethra. The umbilical arteries course along the bladder wall. Fig. 3 Diagram depicting bladder and lower urinary tract. The proximal penile urethra is moderately dilated. The relationship of the left ductus deferens to the ureter and bladder is indicated. Fig. 4 Diagram showing the dorsal wall of the greatly expanded prostatic urethra. The fine midline crest is visible. Key: A, aorta; B, bladder; C, sigmoid colon; D, left ductus deferens; E, ejaculatory duct openings; LK, left kidney; LU, left ureter; M, membranous urethra; P, prostatic urethra: R, rectum: RK, right kidney; T, testis; V, inferior vena cava.
The prostatic urethra had very thin walls, and a smooth lining except dorsally where numerous delicate folds extended at right angles from a fine midline crest (fig. 4). The prostatic utricle was not visible but two small depressions indicated the openings of the ejaculatory ducts. The proximal portion of each ductus (vas) deferens was absent and there was no trace of either seminal vesicle. Microscopic examination of the prostatic wall revealed few muscle fibers or gland elements. In contrast, serial sections of the membranous and penile portions of the urethra showed these to be of normal composition and patent throughout with some moderate expansion of the latter channel proximally. The ureters were greatly distended and saccular (figs. 2, 3) but narrowed towards the bladder wall; only their most caudal portions contained muscle fibers. Both kidneys were m a r k e d l y hydronephrotic and larger and heavier than those of the control. In each, the pelvis and calyces were greatly expanded, and the medulla reduced in width. Their cortices, on the other
hand, contained well-formed glomeruli slightly fewer in number but comparable in size to those of the control. Collecting tubules, however, were sparse and mostly dilated while a thick layer of fibrous tissue separated the calyces from the adjoining renal substance; the latter was devoid of cysts or cartilage. Experitoneally, the perinephric tissue had a gelatinous appearance quite unlike that of the control. Each testis and epididymis lay dorsal to the bladder and in contact with the corresponding ureter (fig. 2). The left ductus deferens was traceable caudally for a short distance before terminating blindly but the right ductus did not extend beyond the tail of the epididymis (fig. 3). Neither the gubernacula nor the inguinal folds could be identified in microscopic sections. In the control, each testis lay close to the internal inguinal ring. The combined weights of the testes and epididymides were slightly greater than those of the control. Leydig (interstitial) cells were numerous in the testes of both fetuses. The large and small intestines were smaller
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in diameter than those of t h e control but showed no abnormality which could be a t tributed with certainty to malrotation. Ganglion cells were present in t h e walls of the sigmoid colons of both fetuses. The remaining thoracic and abdominal viscera weighed less and were smaller t h a n those of the control but did not differ in appearance either grossly or microscopically. Sections of the spinal cord were similar in both fetuses. Diagnosis: Prune belly syndrome accompanied by ascites. DISCUSSION
The most striking aspect of this case is the combination of PBS and marked ascites which is not a feature of full term infants with this syndrome. The latter finding confirms t h e suggestion of Guthrie (1896), some eighty years ago, t h a t fetal ascites was t h e most likel y cause of stretching of t h e abdominal wall and of damage to t h e muscle within it. This, however, seems to be t h e first time t h a t t h e predicted combination has been observed and reported. Absence of a midline defect suggests t h a t abnormality of the anterior abdominal wall occurred after t h e tenth week when it is fully formed and t h e midgut loop derivatives have returned to the peritoneal cavity. Considering all of t h e findings, it is felt t h a t PBS in this instance resulted from a series of developmental disturbances which took place in the following order: prostatic dysgenesis; dilatation of t h e bladder, ureters and renal pelves; transient ascites; and severe stretching of the anterior abdominal wall. The case for such a hypothesis is now presented. Prostatic dysgenesis This is believed to be t h e key developmental disturbance which leads to PBS and explains why i t is confined almost entirely to males. The prostate forms mainly d u r i n g t h e fourth month when t h e wall of t h e urogenital sinus thickens with t h e appearance in i t of muscular and glandular elements. Conceivably, if the latter are absent or sparse, the wall of t h e urogenital sinus remains thin and, unable to withstand t h e pressure of urine entering its lumen, stretches to form a n infravesical chamber (fig. 3). It is also possible t h a t t h e latter situation in combination with t h e marked transitory angulation of t h e caudal portion of t h e developing prostatic urethra (Glenister, '621, impedes the outflow of urine and leads to dilatation of t h e bladder, ureters, and renal pelves. Nunn and Stevens ('61)also have con-
tended t h a t disturbed development of t h e prostate seems to play a role in the genesis of PBS. The cause of prostatic dysgenesis is not clear but may result from either a basic mesenchymal defect leading to deficiency of its musculature, or to failure of glandular elements to form. It has been suggested (Andren et al., '64) t h a t high levels of maternal estrogen affect the fetal prostate adversely and, conceivably, insensitivity of the urogenital sinus to fetal testosterone might have a similar effect. In this specimen t h e testes were well-formed and with good complements of interstitial cells although t h e functional capacity of t h e latter was indeterminable. In t h e present case, as is usual in PBS, t h e entire urethra was patent but occasionally urethral valves or stenoses are encountered (Lattimer, '58). Such abnormalities, however, are not a n essential part of t h e syndrome as they a r e often seen in cases where t h e anterior abdominal wall is normally formed. Underdevelopment of t h e prostate a n d dilatation of i t s urethra also have been observed in t h e presence of apparently normal abdominal musculature (King, '69; Williams and Taylor, '69) suggesting t h a t for prune belly to arise in such cases, a n additional factor is required. The latter is believed to be ascites (vide infra). Megacystis, megaureter, and hydronephrosis Distension of t h e bladder and upper urinary tract i n PBS likely results from fluid back-pressure in t h e manner described above. Perhaps also a paucity of muscle in t h e walls of these structures, as well as of the prostate, renders them easily distensible although t h e reduction in size of t h e bladder and ureters which may follow surgical drainage suggests t h a t a n y such muscle deficiency is not necessarily severe. Again, i t has been pointed out (Droes, '74) t h a t prostatic musculature forms independently of t h a t of the bladder so t h a t presumably deficiency of t h e former need not mean deficiency of t h e latter. ~
~~
~~~
~
Fig. 5 Cross section. PBS fetus. Several large muscle fibers with centrally-placed nuclei typical of myotubule stage are visible. X 485. Fig. 6 Cross section. Muscle fibers of control fetus. X
485.
Fig. 7 Lonetudinal section. PBS fetus. One large partially disrupted muscle fiber is seen. X 485. Fig. 8 Longitudinal section. PBS fetus. Segment of muscle fiber showing marked attenuation. X 485. Fig. 9 Longitudinal section. Muscle fibers of control fetus. X 485.
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Megaureters and hydronephrosis also occur in association with urethral stenosis or valves but there the bladder is usually thick-walled, t h e abdominal musculature normal, and ascites absent. Although the kidneys in this specimen were markedly hydronephrotic, glomeruli appeared normal and there were no cysts or cartilage. Such findings suggest that development of the kidney proceeded normally until affected by fluid back-pressure. The renal substance, rather than being deficient, seemed stretched out over the heavy deposition of fibrous tissue around the calyces. Urachal fistula, which is said to frequently accompany PBS, was absent in this case. However, the point of contact of the bladder and amnion was so attenuated that had it ruptured, a similar type of channel would have resulted. It is possible t h a t some so-called “urachal” fistulae associated with PBS are actually amnio-vesical fistulae that appear only after the bladder has been distended for some time. Ascites It has been suggested that the combination of distended bladder, ureters, and renal pelves can cause severe stretching of the abdominal wall and damage to the muscle within i t but this seem unlikely. On the other hand, when these abnormalities are accompanied by ascites the pressure on the abdominal wall must be considerably increased and more capable of harmful effect. It is believed that ascites then is the other significant factor in the genesis of prune belly. The source of this fluid was not determinable but most likely was from leakage through the walls of the distended urinary tract. Fetal ascites can result from a variety of causes (Lord, ’53; Leonidas et al., ’70).Although apparently normal abdominal musculature is found in conjunction with ascites, it is possible that developing muscle could be damaged by the pressure of excessive intraperitoneal fluid early in fetal life. If ascites is a feature of all cases of PBS prenatally, then an explanation is required for its resorption towards the end of gestation. As yet, there is no clear reason for this unless improved fetal heart action and increased pressure of uterine contractions as pregnancy advances, aid in the return of ascitic fluid t o the vascular system. Abdominal muscle damage The location of the absent, damaged, and normal muscle within the abdominal wall seems compatible with stretching from intra-abdominal pressure.
Such action conceivably damages muscle tissue not only directly, but also indirectly from interference with blood supply and nerve conduction. The finding of ruptured muscle fibers seems to support the former contention; however, the possibility that these were the result of handling a t the time of delivery, or arose from agonal contractions, cannot be excluded. In regions where muscle damage was evident, many fibers appeared not to have developed beyond the myotubule stage which can be attained without innervation, and i t is of interest that many such fibers were also observed in the abdominal wall of a case of PBS born after 32 weeks gestation (O’Kell, ’69). Perhaps loss of nerve conduction from stretching results in persistence of myotubules which only resume differentiating when abdominal distension lessens and nerve function is restored. Such a sequence might account for the clinical improvement shown by some cases of PBS as they get older. Also, of note, was the marked increase in diameter of many muscle fibers, mostly of the myotubule type, in areas of the abdominal wall intermediate between those with no muscle and those with normal muscle. It is possible that this was the result of hypertrophy in an effort to combat stretching. Incomplete descent of the testes in PBS is usually attributed to interference by the greatly distended bladder and ureters although perhaps lack of gubernacula sometimes may be a factor. Sterlility, said to occur in all cases of PBS (Burkholder et al., ’70), may well be the result of intrinsic testicular abnormality, however, disruption of the ductus deferentes may be the primary cause in some instances. Conceivably, in this case, the latter situation arose from overstretching by excessive distension of the prostate and bladder. Abnormal location of the gut is common in PBS (Silverman and Huang, ’50) but whether this is due to malrotation, as sometimes stated, or to displacement by pressure from the distended urinary tract and the accompanying ascites, is not certain. Prune belly is rare in females (Rabinowitz and Schillinger, ’77) and then usually is associated with less severe abnormalities of the urinary tract than in the opposite sex. Its genesis in such cases is obscure but may involve a combination of defective development of the urogenital sinus and transient ascites, as seems to occur in males.
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I t is hoped t h a t these thoughts on the genesis of the abnormalities encountered in PBS will be a stimulus to further research on this puzzling subject. ACKNOWLEDGMENTS
The authors express their gratitude to the late Dr. J. Yerushalmy, and to Dr. B. J. van den Berg, Child Health and Development Studies, University of California, Berkeley, for providing the specimen and the case history, respectively. They are also indebted to Dr. D. A. Riley for helpful advice and criticism, to Messrs J. Morgan and H. Borsting for technical guidance, and to Mr. D. R. Akers for photography. LITERATURE CITED Afifi, A. K., J. Rebeiz, J. Mire, S. J. Adonian and V. M. Der Kaloustian 1972 The morphology of the prune belly syndrome. J. Neurol., 25: 153-165. Adren, L., L. Bjersing and J. Lagergren 1964 Congenital aplasia of the abdominal muscles with urogenital malformations. Acta Radiol., IDiagn.1 (Stockh.), 2: 298-304. Burkholder, G. V., R. C. Harper and P. D. Beach 1970 Congenital absence of t h e abdominal muscles: a clinicopathologic correlation. Am. J. Clin. Pathol., 53: 602-608. Drces, J. Th. P. M. 1974 Observations on the musculature of the urinary bladder and urethra in the human fetus. Br. J. Urol., 46: 179-185. Eagle, J. F.. andG. S. Barrett 1950 Congenital deficiency of abdominal musculature with associated genitourinary abnormalities: a syndrome. Pediatrics, 6: 721-736. Glenister. T. W. 1962 The development of the utricle and of the so-called “middle” or “median” lobe of the human prostate. J. Anat., 96: 443-455. Guthrie, L. 1896 Case of congenital deficiency of the abdominal muscles, with dilation and hypertrophy of the bladder and ureters. Tr.Path. Soc. London, 47: 139-145.
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Harley, L. M.. Y. Chen and W. H Rattner 1972 Prune belly syndrome. J. Urol., 208: 174-176. Housden, L. G. 1934 Congenital absence of abdominal muscles. Arch. Dis. Child., 9: 219-232. King, L. R. 1969 Idiopathic dilatation of the posterior urethra in boys without bladder outlet obstruction. J. Urol.. 102: 783-787. Lattimer, J. K. 1958 Congenital deficiency of the abdominal musculature and associated genitourinary anomalies: a report of 22 cases. J. Urol., 79: 343-352. Leonidas, J. C., E. Leiter and D. Gribetz 1970 Congenital urinary tract obstruction presenting with ascites a t b i r t h : roentgenographic diagnosis. Radiology, 96 111-112. Lord, J. M. 1953 Foetal ascitea. Arch. Dis. Child., 28: 398-403. Nunn, I. N., and F. E. Stephens 1961 The triad syndrome: A composite anomaly of t h e abdominal wall, urinary system, and testes. J. Urol., 86: 782-794. OKell, R. T. 1969 Embryonic abdominal musculature associated with anomalies of the genitourinary and gastrointestinal systems. Am. J. Obstet. Gynecol., 205. 1283-1284. Osler, W. 1901 Congenital absence of abdominal muscles, with distended and hypertrophied urinary bladder. Bull. Johns Hopkins Hosp., 22: 331-333. Rabinowitz, R., and J. F. Schillinger 1977 Prune belly syndrome in the female subject. J. Urol., 218: 454-456. Silverman, F. N., and N. Huang 1950 Congenital absence of abdominal muscles. Am. J. Dis. Child., 80: 91-124. Stumme, E. G. 1903 Ueber die symmetrischen kongenitalen, Bauchmuskeldefekte und uber die Kombination derselben mit anderen Bildungsanomalien des Rumpfes. Mitt. Grenzgeb. Med. Chir.. 22: 548-590. Warkany, J. 1971 Congenital Malformations: Notes and Comments, Chicago: Year Book, pp. 1026-1029. Welch, K. J., and G. P. Kearney 1974 Abdominal musculature deficiency syndrome: prune belly. J. Urol., 2 2 1 : 693-700. Wigger, H. J., and W. A. Blanc 1977 The prune belly syndrome. Path. Annu., 12: 17-39. Williams, D. I., and J. S. Taylor 1969 A rare congenital uropathy: vesico-urethral dysfunction with upper tract anomalies. Brit. J. Urol., 41: 307-313.
ABSTRACT A case of prune belly syndrome (PBS) in a 22 week male fetus is described. All t h e features characteristic of t h e syndrome were present: absence of abdominal muscle; dilatation of t h e bladder, ureters, and renal pelves; and undescended testes. In addition, there was marked ascites. The rectus abdominis muscles were entirely absent whereas other abdominal muscles were only absent centrally. Between regions of normal and absent musculature muscle fibers were sparse, enlarged, frequently disrupted, and mostly in t h e myotubule stage. The prostate was thin-walled and its urethra greatly expanded. The testes lay close to t h e corresponding ureters and each ductus deferens was only partially present. I t is considered t h a t prostatic dysgenesis and fetal ascites a r e key factors in t h e causation of PBS. Prune belly syndrome (PBS) is charac- fetus. Some comments are offered on t h e possiterized by absence of abdominal wall muscula- ble genesis of prune belly and of t h e other abture, marked dilatation of the bladder and normalities comprising t h e syndrome. ureters, and incompletely descended testes; MATERIALS AND METHODS occasionally, i t is accompanied by clubfoot, spina bifida, or abnormalities of the carThe intact male fetus along with its cord diovascular or urogenital systems. Details of and placenta was aborted by a 16 year-old the various pathological and clinical features mother after a gestation period estimated at of PBS have been amply described elsewhere 22 weeks and when received by us had been (Housden, '34; N u n n a n d Stephens, '61; preserved in formalin for about 9 years. The Warkany, '71; Welch and Kearney, '74). A history was brief and unremarkable. For commodified and usually less severe form of t h e parison, a normal-appearing male fetus of syndrome has been reported in a few females similar length and time of preservation was (Rabonowitz and Schillinger, '77; Wigger and selected as a "control." Blanc, '77). Both fetuses were dissected and selected The genesis of PBS has been much disput- organs removed and weighed. Portions of t h e ed with disagreement centering mainly on abdominal wall, several muscles, and some whether t h e absence of abdominal muscula- other organs were excised, embedded i n parture is a primary defect (Osler, '01; Afifi e t affin, and cut at 7 to 10 Fm. Sections were al., '72) or a secondary defect due to pressure stained with hematoxylin and eosin, Malloryfrom t h e distended bladder and ureters alone Azan, or Verhoeff-van Gieson, as considered (Sturnme, '03; Eagle and Barrett, '50), or in appropriate. In addition, small portions of t h e combination with ascites (Guthrie, 1896; abdominal wall were removed, teased in glyHousden, '34).The suggestion t h a t a deficien- cerin, and examined in t h e unstained s t a t e to cy of autonomic ganglion cells innervating t h e determine t h e location of muscle. bladder and ureters might be involved has not RESULTS found much support. While genetic factors may play a role in PBS, no clear-cut evidence The fetus was normal in appearance except of inheritance has yet been demonstrated for marked distension of t h e abdomen. It mea(Warkany, '711, In a few cases, chromosomal sured 165 mm crown-rump, weighed 450 gm, abnormalities have been observed (Harley et and had a greatest abdominal girth of 235 mm al., '72). (fig. 1). The control fetus measured 162 mm The following account concerns PBS accomReceived Apr. 21. '78. Accepted Aug. 1 1 , '78. panied by marked ascites in a 22 week-old TERATOLOGY(1979)19: 111-118.
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n
Fig. 1 Male fetus with PBS showing marked distension of the abdomen. X - area where thinned bladder wall is in intimate contact with amnion.
crown-rump weighed 348 gm, and had a greatest abdominal girth of 125 mm. The remarks which follow refer to the abnormal fetus unless otherwise indicated. The skin of the abdominal wall was tense and smooth, except for some fine creases, with subcutaneous hemorrhages in the circum- and infra-umbilical regions. The cord contained two arteries and one vein and flared slightly a t its attachment to the body wall. The abdominal cavity contained 46 ml of fluid and was dominated by the greatly distended bladder, ureters, and kidneys (fig. 21, all of which, when drained, yielded 44 ml of urine. Both fluids were similar in appearance
and on standing each presented a clear colorless supernatant and an equal amount of precipitated debris. No sophisticated chemical tests were attempted in view of the long period of preservation. After removal of fluid the fetus weighed 360 gm which was close to that of the control. The latter contained no measurable fluid in either the peritoneal cavity or the ureters, and had only 0.6 ml of urine in the bladder. The abdominal wall, lax and folded after the removal of fluid, was extremely thin and when examined under a dissecting microscope showed complete absence of the rectus abdominis muscles. The other abdominal muscles were absent centrally but detectable laterally. Intercostal nerves were traceable in the abdominal wall and visible in areas with and without muscle fibers. Microscopic examination of teased preparations and of sections of the abdominal wall confirmed the gross findings. Absent muscle was replaced by fibrous tissue and extravasated blood. Where muscle was sparse, individual fibers varied greatly in diameter, many being quite large with centrally-placed nuclei characteristic of myotubules (fig. 5 ) . In the same regions, disrupted muscle fibers were common (figs. 7, 8),while farther laterally, although sparse, they were normal in appearance and similar to those in the psoas and sartorius muscles. Sections of corresponding muscles in t h e control showed n o abnormalities nor were myotubules seen (figs. 6,9). The greatly enlarged bladder extended to the umbilicus where it came into contact with the amnion (fig. 1 ) ; inferiorly its ventral wall lay in close contact with the thin abdominal wall but was easily separated from it. The urachus could not be identified. The umbilical arteries pursued normal courses (fig. 2). The bladder wall was thinnest (1 mm) ventrally, and thickest (4 mm) infero-dorsally with a lining smooth and free from trabeculations. Inferiorly, it communicated with a smaller chamber formed by the greatly expanded prostatic urethra and this, in turn, opened into the membranous urethra which was of normal caliber (figs. 3, 4). Sections of the bladder revealed a sparsity of muscle except in the trigonal region where bundles of muscle fibers were interwoven with masses of connective tissue. Nerves and ganglion cells were clearly visible near the terminations of the ureters, in the bladder wall, and inferiorly on the outer aspect of the prostate.
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Fig. 2 Diagram showing distended bladder and ureters, along with some related structures. The bladder has been tilted forwards and opened to display the expanded prostatic urethra and its connection with the membranous urethra. The umbilical arteries course along the bladder wall. Fig. 3 Diagram depicting bladder and lower urinary tract. The proximal penile urethra is moderately dilated. The relationship of the left ductus deferens to the ureter and bladder is indicated. Fig. 4 Diagram showing the dorsal wall of the greatly expanded prostatic urethra. The fine midline crest is visible. Key: A, aorta; B, bladder; C, sigmoid colon; D, left ductus deferens; E, ejaculatory duct openings; LK, left kidney; LU, left ureter; M, membranous urethra; P, prostatic urethra: R, rectum: RK, right kidney; T, testis; V, inferior vena cava.
The prostatic urethra had very thin walls, and a smooth lining except dorsally where numerous delicate folds extended at right angles from a fine midline crest (fig. 4). The prostatic utricle was not visible but two small depressions indicated the openings of the ejaculatory ducts. The proximal portion of each ductus (vas) deferens was absent and there was no trace of either seminal vesicle. Microscopic examination of the prostatic wall revealed few muscle fibers or gland elements. In contrast, serial sections of the membranous and penile portions of the urethra showed these to be of normal composition and patent throughout with some moderate expansion of the latter channel proximally. The ureters were greatly distended and saccular (figs. 2, 3) but narrowed towards the bladder wall; only their most caudal portions contained muscle fibers. Both kidneys were m a r k e d l y hydronephrotic and larger and heavier than those of the control. In each, the pelvis and calyces were greatly expanded, and the medulla reduced in width. Their cortices, on the other
hand, contained well-formed glomeruli slightly fewer in number but comparable in size to those of the control. Collecting tubules, however, were sparse and mostly dilated while a thick layer of fibrous tissue separated the calyces from the adjoining renal substance; the latter was devoid of cysts or cartilage. Experitoneally, the perinephric tissue had a gelatinous appearance quite unlike that of the control. Each testis and epididymis lay dorsal to the bladder and in contact with the corresponding ureter (fig. 2). The left ductus deferens was traceable caudally for a short distance before terminating blindly but the right ductus did not extend beyond the tail of the epididymis (fig. 3). Neither the gubernacula nor the inguinal folds could be identified in microscopic sections. In the control, each testis lay close to the internal inguinal ring. The combined weights of the testes and epididymides were slightly greater than those of the control. Leydig (interstitial) cells were numerous in the testes of both fetuses. The large and small intestines were smaller
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in diameter than those of t h e control but showed no abnormality which could be a t tributed with certainty to malrotation. Ganglion cells were present in t h e walls of the sigmoid colons of both fetuses. The remaining thoracic and abdominal viscera weighed less and were smaller t h a n those of the control but did not differ in appearance either grossly or microscopically. Sections of the spinal cord were similar in both fetuses. Diagnosis: Prune belly syndrome accompanied by ascites. DISCUSSION
The most striking aspect of this case is the combination of PBS and marked ascites which is not a feature of full term infants with this syndrome. The latter finding confirms t h e suggestion of Guthrie (1896), some eighty years ago, t h a t fetal ascites was t h e most likel y cause of stretching of t h e abdominal wall and of damage to t h e muscle within it. This, however, seems to be t h e first time t h a t t h e predicted combination has been observed and reported. Absence of a midline defect suggests t h a t abnormality of the anterior abdominal wall occurred after t h e tenth week when it is fully formed and t h e midgut loop derivatives have returned to the peritoneal cavity. Considering all of t h e findings, it is felt t h a t PBS in this instance resulted from a series of developmental disturbances which took place in the following order: prostatic dysgenesis; dilatation of t h e bladder, ureters and renal pelves; transient ascites; and severe stretching of the anterior abdominal wall. The case for such a hypothesis is now presented. Prostatic dysgenesis This is believed to be t h e key developmental disturbance which leads to PBS and explains why i t is confined almost entirely to males. The prostate forms mainly d u r i n g t h e fourth month when t h e wall of t h e urogenital sinus thickens with t h e appearance in i t of muscular and glandular elements. Conceivably, if the latter are absent or sparse, the wall of t h e urogenital sinus remains thin and, unable to withstand t h e pressure of urine entering its lumen, stretches to form a n infravesical chamber (fig. 3). It is also possible t h a t t h e latter situation in combination with t h e marked transitory angulation of t h e caudal portion of t h e developing prostatic urethra (Glenister, '621, impedes the outflow of urine and leads to dilatation of t h e bladder, ureters, and renal pelves. Nunn and Stevens ('61)also have con-
tended t h a t disturbed development of t h e prostate seems to play a role in the genesis of PBS. The cause of prostatic dysgenesis is not clear but may result from either a basic mesenchymal defect leading to deficiency of its musculature, or to failure of glandular elements to form. It has been suggested (Andren et al., '64) t h a t high levels of maternal estrogen affect the fetal prostate adversely and, conceivably, insensitivity of the urogenital sinus to fetal testosterone might have a similar effect. In this specimen t h e testes were well-formed and with good complements of interstitial cells although t h e functional capacity of t h e latter was indeterminable. In t h e present case, as is usual in PBS, t h e entire urethra was patent but occasionally urethral valves or stenoses are encountered (Lattimer, '58). Such abnormalities, however, are not a n essential part of t h e syndrome as they a r e often seen in cases where t h e anterior abdominal wall is normally formed. Underdevelopment of t h e prostate a n d dilatation of i t s urethra also have been observed in t h e presence of apparently normal abdominal musculature (King, '69; Williams and Taylor, '69) suggesting t h a t for prune belly to arise in such cases, a n additional factor is required. The latter is believed to be ascites (vide infra). Megacystis, megaureter, and hydronephrosis Distension of t h e bladder and upper urinary tract i n PBS likely results from fluid back-pressure in t h e manner described above. Perhaps also a paucity of muscle in t h e walls of these structures, as well as of the prostate, renders them easily distensible although t h e reduction in size of t h e bladder and ureters which may follow surgical drainage suggests t h a t a n y such muscle deficiency is not necessarily severe. Again, i t has been pointed out (Droes, '74) t h a t prostatic musculature forms independently of t h a t of the bladder so t h a t presumably deficiency of t h e former need not mean deficiency of t h e latter. ~
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Fig. 5 Cross section. PBS fetus. Several large muscle fibers with centrally-placed nuclei typical of myotubule stage are visible. X 485. Fig. 6 Cross section. Muscle fibers of control fetus. X
485.
Fig. 7 Lonetudinal section. PBS fetus. One large partially disrupted muscle fiber is seen. X 485. Fig. 8 Longitudinal section. PBS fetus. Segment of muscle fiber showing marked attenuation. X 485. Fig. 9 Longitudinal section. Muscle fibers of control fetus. X 485.
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Megaureters and hydronephrosis also occur in association with urethral stenosis or valves but there the bladder is usually thick-walled, t h e abdominal musculature normal, and ascites absent. Although the kidneys in this specimen were markedly hydronephrotic, glomeruli appeared normal and there were no cysts or cartilage. Such findings suggest that development of the kidney proceeded normally until affected by fluid back-pressure. The renal substance, rather than being deficient, seemed stretched out over the heavy deposition of fibrous tissue around the calyces. Urachal fistula, which is said to frequently accompany PBS, was absent in this case. However, the point of contact of the bladder and amnion was so attenuated that had it ruptured, a similar type of channel would have resulted. It is possible t h a t some so-called “urachal” fistulae associated with PBS are actually amnio-vesical fistulae that appear only after the bladder has been distended for some time. Ascites It has been suggested that the combination of distended bladder, ureters, and renal pelves can cause severe stretching of the abdominal wall and damage to the muscle within i t but this seem unlikely. On the other hand, when these abnormalities are accompanied by ascites the pressure on the abdominal wall must be considerably increased and more capable of harmful effect. It is believed that ascites then is the other significant factor in the genesis of prune belly. The source of this fluid was not determinable but most likely was from leakage through the walls of the distended urinary tract. Fetal ascites can result from a variety of causes (Lord, ’53; Leonidas et al., ’70).Although apparently normal abdominal musculature is found in conjunction with ascites, it is possible that developing muscle could be damaged by the pressure of excessive intraperitoneal fluid early in fetal life. If ascites is a feature of all cases of PBS prenatally, then an explanation is required for its resorption towards the end of gestation. As yet, there is no clear reason for this unless improved fetal heart action and increased pressure of uterine contractions as pregnancy advances, aid in the return of ascitic fluid t o the vascular system. Abdominal muscle damage The location of the absent, damaged, and normal muscle within the abdominal wall seems compatible with stretching from intra-abdominal pressure.
Such action conceivably damages muscle tissue not only directly, but also indirectly from interference with blood supply and nerve conduction. The finding of ruptured muscle fibers seems to support the former contention; however, the possibility that these were the result of handling a t the time of delivery, or arose from agonal contractions, cannot be excluded. In regions where muscle damage was evident, many fibers appeared not to have developed beyond the myotubule stage which can be attained without innervation, and i t is of interest that many such fibers were also observed in the abdominal wall of a case of PBS born after 32 weeks gestation (O’Kell, ’69). Perhaps loss of nerve conduction from stretching results in persistence of myotubules which only resume differentiating when abdominal distension lessens and nerve function is restored. Such a sequence might account for the clinical improvement shown by some cases of PBS as they get older. Also, of note, was the marked increase in diameter of many muscle fibers, mostly of the myotubule type, in areas of the abdominal wall intermediate between those with no muscle and those with normal muscle. It is possible that this was the result of hypertrophy in an effort to combat stretching. Incomplete descent of the testes in PBS is usually attributed to interference by the greatly distended bladder and ureters although perhaps lack of gubernacula sometimes may be a factor. Sterlility, said to occur in all cases of PBS (Burkholder et al., ’70), may well be the result of intrinsic testicular abnormality, however, disruption of the ductus deferentes may be the primary cause in some instances. Conceivably, in this case, the latter situation arose from overstretching by excessive distension of the prostate and bladder. Abnormal location of the gut is common in PBS (Silverman and Huang, ’50) but whether this is due to malrotation, as sometimes stated, or to displacement by pressure from the distended urinary tract and the accompanying ascites, is not certain. Prune belly is rare in females (Rabinowitz and Schillinger, ’77) and then usually is associated with less severe abnormalities of the urinary tract than in the opposite sex. Its genesis in such cases is obscure but may involve a combination of defective development of the urogenital sinus and transient ascites, as seems to occur in males.
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I t is hoped t h a t these thoughts on the genesis of the abnormalities encountered in PBS will be a stimulus to further research on this puzzling subject. ACKNOWLEDGMENTS
The authors express their gratitude to the late Dr. J. Yerushalmy, and to Dr. B. J. van den Berg, Child Health and Development Studies, University of California, Berkeley, for providing the specimen and the case history, respectively. They are also indebted to Dr. D. A. Riley for helpful advice and criticism, to Messrs J. Morgan and H. Borsting for technical guidance, and to Mr. D. R. Akers for photography. LITERATURE CITED Afifi, A. K., J. Rebeiz, J. Mire, S. J. Adonian and V. M. Der Kaloustian 1972 The morphology of the prune belly syndrome. J. Neurol., 25: 153-165. Adren, L., L. Bjersing and J. Lagergren 1964 Congenital aplasia of the abdominal muscles with urogenital malformations. Acta Radiol., IDiagn.1 (Stockh.), 2: 298-304. Burkholder, G. V., R. C. Harper and P. D. Beach 1970 Congenital absence of t h e abdominal muscles: a clinicopathologic correlation. Am. J. Clin. Pathol., 53: 602-608. Drces, J. Th. P. M. 1974 Observations on the musculature of the urinary bladder and urethra in the human fetus. Br. J. Urol., 46: 179-185. Eagle, J. F.. andG. S. Barrett 1950 Congenital deficiency of abdominal musculature with associated genitourinary abnormalities: a syndrome. Pediatrics, 6: 721-736. Glenister. T. W. 1962 The development of the utricle and of the so-called “middle” or “median” lobe of the human prostate. J. Anat., 96: 443-455. Guthrie, L. 1896 Case of congenital deficiency of the abdominal muscles, with dilation and hypertrophy of the bladder and ureters. Tr.Path. Soc. London, 47: 139-145.
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Harley, L. M.. Y. Chen and W. H Rattner 1972 Prune belly syndrome. J. Urol., 208: 174-176. Housden, L. G. 1934 Congenital absence of abdominal muscles. Arch. Dis. Child., 9: 219-232. King, L. R. 1969 Idiopathic dilatation of the posterior urethra in boys without bladder outlet obstruction. J. Urol.. 102: 783-787. Lattimer, J. K. 1958 Congenital deficiency of the abdominal musculature and associated genitourinary anomalies: a report of 22 cases. J. Urol., 79: 343-352. Leonidas, J. C., E. Leiter and D. Gribetz 1970 Congenital urinary tract obstruction presenting with ascites a t b i r t h : roentgenographic diagnosis. Radiology, 96 111-112. Lord, J. M. 1953 Foetal ascitea. Arch. Dis. Child., 28: 398-403. Nunn, I. N., and F. E. Stephens 1961 The triad syndrome: A composite anomaly of t h e abdominal wall, urinary system, and testes. J. Urol., 86: 782-794. OKell, R. T. 1969 Embryonic abdominal musculature associated with anomalies of the genitourinary and gastrointestinal systems. Am. J. Obstet. Gynecol., 205. 1283-1284. Osler, W. 1901 Congenital absence of abdominal muscles, with distended and hypertrophied urinary bladder. Bull. Johns Hopkins Hosp., 22: 331-333. Rabinowitz, R., and J. F. Schillinger 1977 Prune belly syndrome in the female subject. J. Urol., 218: 454-456. Silverman, F. N., and N. Huang 1950 Congenital absence of abdominal muscles. Am. J. Dis. Child., 80: 91-124. Stumme, E. G. 1903 Ueber die symmetrischen kongenitalen, Bauchmuskeldefekte und uber die Kombination derselben mit anderen Bildungsanomalien des Rumpfes. Mitt. Grenzgeb. Med. Chir.. 22: 548-590. Warkany, J. 1971 Congenital Malformations: Notes and Comments, Chicago: Year Book, pp. 1026-1029. Welch, K. J., and G. P. Kearney 1974 Abdominal musculature deficiency syndrome: prune belly. J. Urol., 2 2 1 : 693-700. Wigger, H. J., and W. A. Blanc 1977 The prune belly syndrome. Path. Annu., 12: 17-39. Williams, D. I., and J. S. Taylor 1969 A rare congenital uropathy: vesico-urethral dysfunction with upper tract anomalies. Brit. J. Urol., 41: 307-313.
