Pathogenesis of the Prune-Belly Syndrome: A Functional Urethral Obstruction Caused by Prostatic Hypoplasia

(1)

Pathogenesis

of the Prune-Belly

Syndrome:

A Functional

Urethral

Obstruction

Caused

by

Prostatic

Hypoplasia

Philippe

Moerman,

MD, Jean-Pierre

Fryns,

MD,

Paul Goddeeris,

MD,

and Joseph

M Lauweryns,

MD, PhD

From the Departments of Pathology I and Human Biology, Division of Human Genetics, Kathoileke Universiteit Leuven, Belgium

ABSTRACT. Abdominal muscle deficiency, urinary tract

abnormalities, and cryptorchidism are the three major

features of the prune-belly syndrome, also referred to as

triad syndrome or Eagle-Barrett syndrome. The etiology

is unclear and the pathogenesis a subject of continuing

debate. Clinical and pathologic experience with seven

cases of prune-belly syndrome is reviewed. Findings

in-dicate that the urogenital anomalies can be attributed to

a functional urethral obstruction which in turn is the

result of prostatic hypoplasia. The histology of the ab-dominal wall is that of atrophy-ie, the degeneration of

already formed muscle-and not of primitive muscle.

This observation supports the theory that the abdominal

muscle hypoplasia is a nonspecific lesion, resulting from

fetal abdominal distension of various causes. Transient

fetal ascites may be an important feature of the

prune-belly syndrome. Pediatrics 1984;73:470-475; prune belly,

urethral obstruction, prostatic hypopkisia.

The prune-belly syndrome (PBS) represents an

intriguing constellation of anomalies which could

not fail to elicit the curiosity of many investigators.

The association of abdominal muscle defects with

urogenital anomalies was first described by Parker

in 1895.’ Today, PBS is a well-established entit?

but the significance of urethral obstruction is still

an unsettled question. Several patients with PBS

were reported to have urethral valves, stenosis, or

atresia, but in the majority of cases an obstructive

lesion could not be identified anatomically.3 In

these infants the nature of the obstructive lesion

Received for publication March 21, 1983; accepted June 10,

1983.

Reprint requests to (P.M.) Department of Pathology I,

Univer-sity Hospital St-Rafael, Minderbroedersstraat 12, B-3000,

Leu-yen, Belgium.

American Academy of Pediatrics.

may be functional. From our observations and

oth-ers it appears that the theory of a primary

meso-dermal defect is no longer tenable and that the PBS

can be caused by different types ofurethral

obstruc-tion.

SUBJECTS

Seven cases of PBS were seen in a consecutive

series of 940 pediatric autopsies, performed over a

6-year period. Special emphasis was placed on the

microscopic anatomy of the abdominal muscles and

urinary tract. The urethra, which had been removed

en bloc in each patient, was serially sectioned at 4

m and every fifth section was mounted and

his-tologically examined. The abdominal musculature

from a case of massive fetal ascites without

associ-ated malformations, was studied for comparison.

Likewise, the urethras from three infants with pos-tenor urethral valves were serially sectioned.

His-tologic preparations were stained by

hematoxylin-eosin and Masson’s trichrome.

All seven patients were male and white. Prenatal

diagnosis of severe obstructive uropathy was

estab-lished by ultrasonography in two cases. Fetal

kar-yotypes were normal in all patients.

RESULTS

Clinical Observations

The pertinent clinical data are summarized in

Table 1. Gestational age ranged between 25 and 40

weeks. Pregnancy was complicated by severe

oh-gohydramnios in five cases. The resulting infants

exhibited the nonrenal features of Potter’s

syn-drome and died very soon after birth in extreme

respiratory distress. The two other patients (cases

(2)

. ‘I

I..

,

,,

‘ :.j

TABLE 1. Clinical Data

Case

No.

Gesta-tional Age (wk)

Pregnancy Corn-plicated by Severe

Oligohydrarnnios

Ultrasound Diagnosis Birth weight (g)

Age at Death

1 38 - ... 3,050 8mo

2 25 + Fetal ascites, small cystic kidneys,

hydroureters, huge megacystis

1,145 Perinatally (P)

3 40 - ... 3,150 2mo

4 32 + Huge cyst in right hemiabdomen, left hydronephrosis, massively distended ureters, large thick

un-nary bladder

2,410 P

5 33 + . . . 1,440 P

6 35 + . . . 2,540 P

7 40 + . . . 4,485 P

Both infants developed renal insufficiency and suf-fered from recurrent urinary infections. In all in-stances the abdomen was massively dilated. In four cases (cases 1, 3, 6, and 7) the abdominal wall showed the characteristic wrinkled prune-belly

ap-pearance.

Pathologic Findings

Urethra and Prostate. Invariably, the prostatic

urethra was cystically dilated. Especially its dorsal wall was thinned and markedly expanded, resem-bling a diverticulum (Figs 1 to 3). In all seven infants, microscopic examination disclosed severe

prostatic hypoplasia (Fig 4). The stroma of the

prostatic wall was practically devoid of smooth

muscle fibers and the tubuloalveolar glands were markedly reduced in number, at times even corn-pletely absent. In four cases, sections at the level of the verurnontanurn showed few major prostatic ducts surrounding the prostatic utricle. Normal

ejaculatory duct endings were identified in all cases.

Serial sections disclosed that the membranous

ure-thra was often narrow but never actually atretic.

There were no abnormalities of the penile urethra.

For comparison, histologic examination was

made of the prostates from three patients with

posterior urethral valves. In these cases the

pros-tatic strorna contained a normal amount of smooth

muscle bundles. The glandular parenchyma was

compressed but normally developed.

Ureters and Urinary Bladder. Ureteral dilation

and tortuosity were prominent features in all cases.

Several patients showed impressive megaureters

reaching the size of intestines. In general, the

dis-tension was most marked in the distal parts of the

ureters. Ureteral obstruction was never

encoun-tered, the ureteral orifices were always widely

pat-ent. Microscopic examination of the ureteral walls

revealed a decrease in the amount of smooth muscle

with replacement by dense collagen. Again, these changes were most pronounced in the lower

por-Fig 1. Large urinary bladder in case 1. Note especially sacculated pnostatic urethra (arrow), forming infravesicle

chamber. Membranous urethra is patent. Abbreviations

‘used are: U, ureteral orifices; BN, widened bladder neck.

tions of the ureters. A megacystis, attached to the umbilicus, was present in cases 2 and 6. In the other patients, thickening of the bladder wall was more

outstanding then the dilation. Microscopically,

there was an increase in smooth muscle. A widened

and hypertrophic bladder neck was evident in all

cases. In case 4, a cystically dilated urachal remnant

(3)

Fig 2. Dissection specimen from case 4 with right

kid-ney exhibiting huge cyst. Note urachal remnant (arrow) at dome of hypertrophied bladder and sacculated pros-tatic urethra (asterisk).

Kidneys. In most patients, the kidneys were

con-genitally small and severely dysplastic. As a rule, the dysplastic changes involved both cortex and medulla although there was preservation of the general renal architecture. The outer cortex showed cystic dysplasia: small glomerular and tubular cysts were observed under the capsule both grossly and histologically. The medulla was delta-like and con-sisted of primitive collecting ducts surrounded by excessive fibrous connective tissue. Osathanondh and Potter4 classified this type of dysplasia as their

type 4 of renal cystic disease.

In case 4, the right kidney exhibited a peculiar

pattern. The organ weighed 412 g; the renal paren-chyma was spread over the medial side of a huge thin-walled cyst (Fig 2). The dysplastic changes were less pronounced in the two patients who sur-vived the perinatal period (cases 1 and 3). In these cases, pyelonephritis was an outstanding feature. Hydronephrosis was not evident in cases 2, 3, and

6.

Abdominal Muscle. The abdominal musculature

was abnormal in every patient of the present series.

Fig 3. Dysplastic kidneys and distended urinary tract in case 5. Prostatic urethra (asterisk) is markedly ex-panded dorsally.

The findings ranged in degree from thinning out of the muscles to complete absence of muscle fibers. Usually, the muscles overlying the distended un-nary bladder were most severely affected. Micro-scopic examination of these lower regions of the abdominal wall revealed severe muscle atrophy:

only a few scattered shrunken fibers, embedded

within fibrous tissue were found. At times, the muscle was totally replaced by dense wavy collagen, occasionally containing foci of metaplastic carti-lage. In the upper and lateral portions ofthe

abdom-ma! wall, the musculature was nearly intact. Sec-tions from intermediate regions revealed a marked

dystrophic appearance (Fig 5). There was abnormal variability in fiber size. Atrophic fibers alternated

with hypentrophic ones, showing centrally placed and degenerated nuclei, fiber splitting, and hyalin-ization with loss of cross-striation. Occasionally the fiber centers were unstained. Group atrophy, char-acteristic of neurogenic atrophy, did not occur. Blood vessels, nerves, and muscle spindles appeared normal. There was no inflammatory reaction nor macrophage response.

(4)

.

“

,

Zw41;:i-’-’

I.. :t

Fig 5. Dystrophic changes in abdominal muscle in case

7(hematoxylin-eosin, x200).

t

- i:’’-#{149}

-‘--,-‘ 4 I.-. - ;

__#.#{149}.‘#{149}_#{149}-‘.

..

#{149}‘#{149}-- .-. .

..

.w,---.

...

. . . .. .‘

,.

...‘.. ,.. .. ‘

:‘ . ., .‘ , “:#{149};:.J::.. ,.; ‘ . -.

;;‘ ,

f:’:’

:

‘

..

- ‘. .‘ .-,‘

.

‘__i

,.-.“ (#{149}#{149}1 ‘

\

,,

\

. ;.‘I ‘‘

Fig 4. Wall of prostatic urethra in case 6 is markedly thinned and shows complete absence of glandular

struc-tures. Two ejaculatory ducts (arrows) are unusually

prominent (hematoxylin-eosin, x50).

described above, were observed in one of our au-topsy cases, in which massive fetal ascites of un-known origin and not associated with urinary tract abnormalities were seen.

Testes. Cryptorchidism was a constant finding.

The testes were found in an intra-abdominal

posi-tion, fixed to the anterior walls of the enlarged

ureters or displaced to the lateral sides of the

dis-tended bladder. Testes and excurrent duct systems

were histologically normal.

Associated Anomalies. Associated malformations

are summarized in Table 2. Pulmonary hypoplasia

secondary to oligohydramnios and incomplete

in-testinal rotation with nonfixation of the dorsal

mesentery were the most frequently encountered

associated anomalies; these occurred in five and

four cases, respectively.

DISCUSSION

For many decades, the pathogenesis of PBS has

been the subject of considerable debate. Two major

theories have been proposed. The first of these

theories states that all the changes of PBS are the

TABLE 2. Associated Malformations

Case No. Associated Findings at Autopsy

1 Intestinal malrotation

2 Massive ascites, pulmonary hypoplasia, per-sistent left superior vena cava connecting to right atrium, intestinal malrotation

3 Bronchopulmonary dysplasia, necrotizing

en-terocolitis

4 Pulmonary hypoplasia

5 Pulmonary hypoplasia

6 Pulmonary hypoplasia, hypoplastic left yen-tricular syndrome with aortic and mitral

valve atresia, total anomalous pulmonary ye-nous connection to left innominate vein, an-nular pancreas, intestinal malrotation

7 Pulmonary hypoplasia, hyaline membrane

dis-ease, intestinal malrotation

result of an early mesodermal defect; the second

theory holds that there is a primary urethral

ob-struction with consequent early bladder distension,

giving rise to abdominal distention and other

sec-ondary anomalies, which Pagon et al5 termed the

urethral obstruction malformation complex. Our

(5)

for a primary functional obstruction at the level of

the prostatic urethra.

Hypoplasia of the prostate and dilation of the

prostatic urethra, observed in each patient of the

present series, are now recognized as essential

fea-tures of the PBS. We assume that prostatic

mal-development, especially absence of its smooth

mus-cle component, causes weakness of the prostatic

wall with resultant sacculation of the prostatic

ure-thra. This bulging is most marked dorsally and

caudally. Consequently, the implantation of the

membranous urethra upon the dilated prostatic

urethra faces more frontally and becomes oblique

(Figs 2 and 3), creating a flap valve mechanism

with hindrance of the urinary outflow. The

mem-branous urethra is often narrow as could be

ex-pected when there was no passage of urine, which

is necessary for its expansion. The belief that

pros-tatic hypoplasia is the cause and not the effect of

dilation is based on comparative pathology: the

prostatic urethra is equally distended in patients

with posterior urethral valves but the prostate is

histologically normal, although compressed. Thus,

our findings are supportive of the theory that

pros-tatic hypoplasia is the basic developmental defect

in most cases of PBS.9 Although the etiology of the

prostatic defect is unknown, this interpretation

ex-plains why PBS occurs almost exclusively in males

and above all why the urethra is usually

anatomi-cally patent in these infants.3”0

Our observations are also consistent with the

theory that the abdominal muscle deficiency in

PBS is caused by atrophy secondary to abdominal

distension.4”2 In the present series, the histology

of the abdominal wall showed severe dystrophic

muscle changes similar to those described by Pagon

et al.5 Pinto et al’3 suggested that the muscle

atro-phy was the result of venous infarction due to

overdistension of the abdominal wall. This

comple-mentary explanation also pleads against a primary

mesodermal defect.

The fetal abdominal distension in PBS is caused

by enlargement of the ureters and urinary bladder,

and in some cases (case 2 of this series) by

accom-panying massive fetal ascites. Massive fetal ascites

is most frequently due to obstructive uropathy,’4

but has only sporadically been described in

PBS.8”’7 This apparent contradiction could be

explained by the transient nature of the ascites

with resorption toward the end of gestation.9

Regression of the ascites and eventual loss of urine

from the distended urinary tract would then

ac-count for the lax, wrinkled appearance of the

col-lapsed abdominal wall. The role of fetal ascites in

the pathogenesis of PBS is further emphasized by

the fact that abdominal muscle deficiency also

oc-curs in cases of massive fetal ascites without

asso-ciated urinary tract abnormalities.4”8

The renal cystic dysplasia occurring in PBS is

similar to that observed in male infants with

pos-tenor urethral valves. It is now agreed that this

type of renal damage is the result of early urinary

obstruction with increased retrograde pressure,

in-terfering with further nephron induction.4 The

de-gree of dysplasia varies and determines the

prog-nosis of those patients surviving the perinatal

pe-nod. The cases in which pregnancy is complicated

by severe oligohydramnios (five infants of our

se-ries) show marked renal dysplasia with rare

first-generation nephrons, which is incompatible with

postnatal life.

Distal obstruction is the only satisfactory

expla-nation for the fact that the bladder wall

hypertro-phy is due to an increase in smooth muscle. Early

bladder distension apparently prevents testicular

descent and normal intestinal rotation and explains

why the hydroureters are most marked distally.

Since the inauguration of ultrasonography, PBS

can readily be discovered prenatally. The recent

development of fetal therapy in utero opens new

perspectives. In cases of fetal urethral obstruction,

surgical intervention in utero has been justified by

the thought that drainage of the distended urinary

tract might reduce progressive damage to the

de-veloping kidneys and lungs. Until now there has

been little experience with such cases and success

has been himited.’7”9’#{176} In instances in which fetal

urethral obstruction leads to severe

ohigohydram-nios, advanced irreversible renal and pulmonary

damage has already occurred before 20 weeks of

gestation. This is important because prenatal

di-agnosis is usually not established until after 20

weeks of gestation. Finally, it should be stressed

that PBS can occur as part of a broader syndrome,

eg, trisomy 18.21 A thorough evaluation of the fetus

is thus essential, in order to avoid unnecessary

interventions.

REFERENCES

1. Parker RW: Absence of abdominal muscles in an infant.

Lancet 1895;1:1252-1254

2. Wigger HJ, Blanc WA: The prune-belly syndrome. Pathol

Anna 1977;12:17-39

3. Belman AB, Kaplan GW: Genitourinary Problems in Pedi-atrics. Philadelphia, WB Saunders Co, 1981, pp 254-260 4. Osathanondh V, Potter EL: Pathogenesis of polycystic

kid-ney, type 4 due to urethral obstruction. Arch PathOl

1964;77:510-513

5. Pagon RA, Smith DW, Shephard TH: Urethral obstruction malformation complex: A cause of abdominal muscle

defi-ciency and the “prune-belly.” J Pediatr 1979;94:900’-906 6. Nunn IN, Stephens FE: The triad syndrome: A composite

anomaly of the abdominal wall, urinary system, and testes.

J Umi 1961;86:782-794

(6)

boys without bladder outlet obstruction. J Urol 1969;

102:783-787

8. Deklerk DP, Scott WW: Prostatic maldevelopment in the prune-belly syndrome: A defect in prostatic

stromal-epithe-hal interaction. J Urni 1978;120:341-344

9. Monie 1W, Monie BJ: Prune-belly syndrome and fetal

as-cites.Teratology 1979;19:111-118

10. Mogg HA: Congenital anomalies of the urethra. Br J Urni 1968;40:638-645

11. King CR, Prescott G: Pathogenesis of the prune-belly

an-omalad. J Pediatr 1978;93:273-274

12. Pramanik AK, Altshuler 0, Light IJ, et al: Prune-belly syndrome associated with Potter (renal nonfunction)

syn-drome. Am J Dis Child 1977;131:672-674

13. Pinto T, Baithur SI, Giwan YAM, at al: The prune-belly

syndrome: A possible pathogenesis. Diogn Histopathol 1982;

5:197-203

14. Lord JM: Foetal ascites. Arch Dis Child 1953;28:398-403 15. Guthrie L: Case of congenital deficiency of the abdominal

muscles, with dilatation and hypertrophy ofthe bladder and ureters. Trans Pathol Soc Lond 1896;47:139-145

16. Symonds DA, Driscoll SG: Massive fetal ascites, urethral atresia and cytomegalic inclusion disease. Am J Dis Child 1974;127;895-897

17. Golbus MS, Harrison MR, Filly BA, et al: In utero treatment of urinary tract obstruction. Am J Obstet Gynecol 1982; 142:383-386

18. Lubinsky M, Rapoport P: Transient fetal hydrops and “prune-belly” in one identical female twin. N Engi J Med 1988;306:591-593

19. Berkowitz RL, Glickman MG, Smith GJW, et al: Fetal urinary tract obstruction: What isthe role of surgical

inter-vention in utero? Am J Obstet Gynecol 1982;144:367-375

20. Harrison MR, Golbus MS, Filly RA, et al: Fetal surgery for congenital hydronephrosis. N EnglJ Med 1982;306:591-593

21. Moerman Ph, Fryns JP, Goddeeris P, et al: Spectrum of

clinical and autopsy findings in trisomy 18 syndrome. J

Genet Hum 1982;30:17-38

HUGH SCHOOL

COMPUTER

CALLS

HOMES

TO CUT

DOWN

TRUANCY

At West Hill High School (Connecticut), the truant officer is kept in a box.

Actually, it is a desk-top computer, called Telsol by school officials and the

telephone robot by students. It is equipped with recorders and a timer so that

when it is activated it can telephone the home of an absent teenager in the

evening, when parents who are difficult to reach during the day are more likely

to be home.

It calls back twice if there is no answer, if the home telephone is hung-up

before the end of its recorded 40-second message or if it encounters an answering

machine.

Its message can be changed for other purposes, such as informing parents of

school events.

Since the $5,000 Digital computer began operating three weeks ago, the

average absentee rate among the school’s 1,900 students has declined from 9

percent to 7 percent.

(7)

1984;73;470

Pediatrics

Philippe Moerman, Jean-Pierre Fryns, Paul Goddeeris and Joseph M Lauweryns

Caused by Prostatic Hypoplasia