Prune Belly Syndrome

In addition to the abnormalities of the abdominal musculature and cryptorchidism, prune belly syndrome may comprise abnormalities of any of the following:

• Urethra
• Ureters
• Bladder
• Skeletal system
• Cardiovascular system
• Gastrointestinal tract

Urethra

Anterior urethral abnormalities, which range from urethral atresia to megalourethra, are common in patients with prune belly syndrome. Patients with urethral atresia or microurethra commonly have a patent urachus, which allows escape of urine and enables survival; early deaths usually occur in those who do not have a patent urachus.

Both scaphoid and fusiform megalourethra are associated with prune belly syndrome. The fusiform type is associated with deficient corpora cavernosa and more severe renal defects. Scaphoid megalourethra is associated with deficiency of the corpus spongiosum with a normal glans and fossa navicularis. The mesenchymal developmental arrest, which accounts for the major features of the syndrome, may also explain the urethral abnormalities.

Infravesical obstruction or obstruction at the prostatic urethra was originally thought to be due to a type I posterior urethral valve. This theory has been replaced by the notion that the obstruction may be caused by severe angulation at the prostatic and membranous urethral junction. This may be due to a lack of striated muscle in the membranous urethra or urogenital diaphragm; alternatively, hypoplasia of the prostate may result in a ring of obstructive tissue that acts as a flap valve, creating a ballooning of the prostatic urethra.

In these patients, studies have also shown that the smooth muscle in the prostate is reduced and the connective tissue content is increased, which may lead to a functional obstruction. This abnormality in the prostatic urethra can be similar to a valve created by anterior urethral diverticulum. Stephens describes this configuration as a type IV valve in patients with prune belly syndrome, in which the dilated prostatic urethra joins the membranous urethra in various configurations that cause obstruction. ^[7] However, these theories have not been supported by urodynamic studies, which fail to demonstrate either mechanical or functional outlet obstruction in most cases. 

Ureters

Prune belly syndrome is characterized by elongated, dilated, and tortuous megaureters, which affect 81% of patients. Studies indicate that the more distal lower ureter is abnormal in several ways, while the more proximal portion of the ureter is more anatomically normal. Histologically, the ureter has a smooth muscle deficiency with fibrous degeneration and a poor blood supply. In addition, a decrease in nerve plexuses is reported, with irregularity in degeneration of nonmyelinated Schwann fibers.

Herniation of the bladder is prevalent in patients with prune belly syndrome because the bladder is large and redundant.

Bladder

Typically, patients with prune belly syndrome have megacystis. The bladder is routinely enlarged, although trabeculations are rarely present and muscular hypertrophy is inconsistent. The bladder can be fixed to the umbilicus via urachus, giving it an hourglass configuration radiographically. Bladder-voiding pressures are frequently near-normal, and residual urine volume is insignificant. Snyder et al describe a typical shift to the right on filling cystometrograms, and some patients with prune belly syndrome can void normally. ^[8]  

Skeletal system

Orthopedic anomalies can affect 50% of patients. Scoliosis and congenital hip dislocations are common. Abnormalities associated with oligohydramnios also are observed.

Cardiovascular system

Patients with prune belly syndrome  have an increased incidence of tetralogy of Fallot and ventriculoseptal defects. Cardiac anomalies are reported in 10% of patients. 

Alhawsawi et al reported a hepatic arterial aneurysm in a patient with prune belly syndrome. This is a rare defect that may be associated with inflammation or trauma to the arteries of the liver. Atherosclerosis, arthritis, and collagen vascular disease are the most common etiologies of inflammation that result in such aneurysms. The authors postulate that the mesodermal defect may account for the aneurysm. ^[9]

Gastrointestinal tract

Gastrointestinal abnormalities, which include malrotation, atresia, stenosis, and volvulus, affect 30% of patients. All may be due to a persistence of the embryonic wide mesentery, with absent fixation to the posterior abdominal wall. The same defect allows the spleen to wander widely and can lead to splenic torsion. Imperforate anus, anorectal agenesis, omphalocele, and gastroschisis are uncommon but have been reported. Chronic constipation has been attributed to a decrease in abdominal wall pressure, which is necessary to aid in evacuation.

In 1903, Strumme proposed that prune belly syndrome may be caused by in utero bladder obstruction, stating that dilatation of the urinary tract in utero leads to secondary-pressure atrophy of the abdominal wall and the subsequent clinical findings. More recent theories focus on a functional obstruction due to prostatic hypoplasia that leads to a conformational change in the prostatic urethra during voiding, thereby causing obstruction. The most recent theories suggest a transient obstruction at the junction of the glanular and penile urethra. This would explain the high incidence of megalourethra observed in cases of prune belly syndrome.

Considering current knowledge regarding high-pressure voiding and reflux, the theories involving urethral abnormalities can also explain the upper tract deformities that this syndrome can include. High-pressure voiding has been discovered to lead to reflux in patients without prune belly syndrome. The obstructive process that occurs may impart a similar effect that mimics the dyssynergic voiding in persons with reflux. This high-pressure voiding thereby leads to changes in the location of the ureter, as well as the deleterious effects of the water-hammer effect on the renal tissue. Therefore, this abnormal high-pressure voiding process could explain reflux that is encountered along with renal dysplasia. The overdistended bladder could result in the abnormal development of the abdominal wall musculature and prevent the descent of the testis.

The histopathology of the abdominal wall muscles demonstrates a pattern of developmental arrest rather than one of atrophy. This is also suggested by a lack of any aponeurotic layers.

Fetal ascites, which may be transient because the urine is reabsorbed before birth, may explain the abdominal wall defects.

The prevailing theory is mesodermal arrest, which would explain the involvement of the genitourinary tract, the testis, and the abdominal wall. A noxious insult would have to occur between the 6th and 10th weeks of gestation. Some place the insult at 3 weeks of embryogenesis, which may explain the prostatic hypoplasia and poor glandular development.

The mesodermal arrest theory is supported by the histologic findings in the abdominal wall, the urinary tract, and the male genital system. The abundance of fibrous tissue, collagen, and connective tissue with sparsely placed smooth muscle throughout the urinary tract indicates more of a mesodermal differentiation problem than one of obstruction.

The yolk-sac theory is based on the overdevelopment of the allantoic diverticulum that grows out from the yolk sac contiguous with the body stalk. If it becomes enlarged, it is incorporated into the urinary tract as a redundant enlarged urachus, bladder, and prostatic urethra. Unfortunately, this theory does not explain the abnormalities in the development of the upper urinary tract or male genital tract.

The etiology of prune belly syndrome (PBS) is largely unresolved. Although PBS often presents as a sporadic condition, familial cases of PBS as well as occurrence with chromosomal defects, suggest a genetic contribution. Specifically, PBS has been associated with chromosomal anomalies including trisomy 21 and large deletions in the long arm of chromosome 6. Additionally, several reports have shown that PBS occurs in both twin and non-twin siblings, as well as in successive generations. ^[10]

Boghossian et al screened the genome of 34 PBS cases (30 males and 4 females) for copy number variants (CNVs) and identified 17 candidate autosomal CNVs, including the following ^[10] :

• A 158-Kb duplication at 4q22 that overlaps the  BMPR1B gene
• Duplications of different sizes carried by two cases in the intron of  STIM1 gene
• A 67-Kb duplication 202 Kb downstream of the  NOG gene
• A 1.34-Mb deletion including the  MYOCD gene

The identified rare CNVs spanned genes involved in mesodermal, muscle, and urinary tract development and differentiation, which might help in elucidating the genetic contribution to PBS. Whether these CNVs were de novo or inherited is unknown. ^[10]

Prune belly syndrome affects 1 per 30,000-40,000 live births. Approximately 3-5% of all prune belly syndrome cases occur in females. ^[6] Twinning is associated with prune belly syndrome; 4% of all cases are products of twin pregnancies.

The prognosis in patients with prune belly syndrome varies. The spectrum runs from stillbirth to undescended testicles with a minimal degree of abdominal wall laxity. The mortality rate associated with prune belly syndrome is 20%. 

The authors conducted an anonymous Internet- and postal-based survey of the members of the Prune Belly Syndrome Network, which is a nonprofit organization dedicated to the support of patients with prune belly syndrome. The survey was designed to query adult patients with prune belly syndrome regarding physical, social, and sexual aspects of their lives. General health–related quality of life was assessed with the RAND 36-Item Health Survey 1.0 (SF-36), which is a self-administered 36-item questionnaire that was designed to evaluate and to quantify general health–related quality of life based on 8 scales to rate physical function, role limitations due to physical problems, social functioning, pain, emotional well-being, role limitations due to emotional problems, energy/fatigue, and general health perceptions.

The SF-36 has been widely tested and validated. Each of the 8 scales is scored from 0-100, with a higher score representing a better outcome. The scores themselves have been scaled such that they can be compared with scores from a general US adult population cohort without a chronic medical illness. The average score in the general population is 50.

General questions were asked regarding the number and types of surgeries the respondents had undergone. A current medication profile was obtained. The survey included items pertaining to educational and employment achievements, as well as to participation in various types of physical activities.

The Brief Male Sexual Inventory (BMSI) scale assessed sexual quality of life and sexual function. This questionnaire is an 11-item instrument designed to evaluate sexual drive, erection, ejaculation, and perceptions of problems in these areas, as well as overall sexual satisfaction. Additional questions were asked regarding patient fertility and whether they had children (biological or adopted).

The authors received responses to the survey from 23 patients (20 men, 3 women); the mean age was 32 years (range, 14-62 y). All 20 men surveyed acknowledged a history of undescended testicles. Twelve of these men had undergone some form of orchidopexy. Four men who reported having undergone orchidopexy also reported having undergone unilateral or bilateral orchiectomy. Two men who had not undergone orchidopexy underwent at least one orchiectomy. Fourteen of the 23 respondents reported a history of vesicoureteral reflux. Eleven of these persons went on to undergo some form of ureteral reimplantation. Eight patients went on to undergo at least one nephrectomy. Seven patients (6 men, 1 woman) experienced renal failure and underwent kidney transplantation (mean age at the time of survey, 36.3 y).

Four patients acknowledged having undergone some form of abdominal wall reconstruction for their muscle laxity. Three patients reported wearing a scoliosis-type brace, presumably as a noninvasive means of affording abdominal wall support.

Health-related quality of life was determined based on the SF-36. Twenty-two patients responded to the SF-36 portion of the questionnaire. The scores were scaled so that they may be compared with a standard reference population of US adults. The average domain score in the standard population is 50. Above-average scale scores were reported for physical function (13/22), lack of limitations due to physical problems (14/22), lack of limitations due to emotional problems (16/22), energy (15/22), mental health/sense of emotional well-being (15/22), social function (14/22), bodily pain (13/22), and general health perceptions (8/22) versus established norms for the standard population. The 7 patients who required renal transplantation had significantly lower scores (P < 0.05, Student's T-test) on scales of physical function, general health perceptions, social function, and mental health compared with patients who did not require renal transplantation.

Eighteen patients (16 men, 2 women) responded to the BMSI. Eight of the 16 men noted in their responses that they either have retrograde ejaculation or are anejaculatory. Only 2 of these men reported this as bothersome. Twelve respondents (11 men, 1 woman) reported that they are mostly or very satisfied with their sex lives.

Six respondents (5 men, 1 woman) reported having used artificial reproductive techniques to attempt conception. Three of the male patients reported having children secondary to artificial reproductive techniques. Two of the men fathered children with their own sperm and some form of artificial insemination. Both of these men had undergone some form of undescended testis surgery. One man's wife conceived with the use of donor sperm and artificial insemination.

Twenty-two of those surveyed responded to questions regarding employment status. Of these, 3 are unemployed, 3 are retired, 3 are full-time students, and 13 are currently employed.

Two of the respondents are currently in high school, 2 are in college, 2 did not finish high school, 6 received a high school or equivalency diploma, 7 have a bachelor's or associate's degree, and 3 have a Master's degree.

Prune belly syndrome, along with its associated long-term medical issues, does not necessarily result in long-term perceived physical, psychosocial, or sexual distress or problems. The vast majority of the patients who responded to the authors' survey seemed to function physically and emotionally at levels as high or higher than the standard normative study population on the SF-36. Interestingly, perceived levels of general health were, for the most part, lower than the levels reported by the standard normative study population on the SF-36.

The differences between the authors' study group and the standard population are all the more striking considering the patients who underwent kidney transplantation. Only 1 of 7 transplant recipients reported a general health scale score higher than that of the normative population, whereas 7 of 15 respondents who did not require a transplantation reported a higher general health scale score than the normative population (P < 0.05, Student's T-test). This finding corresponds with the general trend that patients who require kidney transplantation are not as healthy overall as those who do not need renal replacement. These differences were also significant on the physical function, social function, and mental health scales.

The authors were somewhat surprised that only 14 men had undergone some type of testis surgery (orchidopexy alone, 8; orchidopexy and orchiectomy, 4; orchiectomy alone, 2) considering that all men reported having a history of undescended testicles. Two men (ages 49 and 53 y) had bilateral intra-abdominal testicles and underwent bilateral orchiectomies. One of these men is currently taking testosterone supplementation. Conceivably, orchidopexy may not have been attempted due to unavailability of a surgeon with orchidopexy expertise for intra-abdominal testes or due to the belief at that time that fertility was impossible in these patients.

Two men underwent attempted orchidopexy followed by orchiectomy. One man reported having undergone bilateral orchiectomies after attempted orchidopexy for bilateral intra-abdominal testicles. He is taking testosterone supplementation. Another patient reported having had one testicle removed after failed orchidopexy. His other testis is intrascrotal. Nine of the 12 men in the orchidopexy group report having one or both testicles in the scrotum. Of the remaining men, one man has palpable pubic testicles, one still has bilateral intra-abdominal testicles, and one man underwent bilateral orchiectomies after failed orchidopexy.

Four of the 6 men who have not undergone testicular surgery reported having bilateral intra-abdominal testis. All of these men are postpubertal (age range 29-47 y). The literature quotes at least 4 cases of germ cell malignancy in patients with prune belly syndrome. The authors do not know how these men are being monitored for potential malignancy.

At one time, all patients with prune belly syndrome were believed to be infertile. All men with prune belly syndrome seen by Woodhouse et al were found to have Sertoli cell–only patterns on their testicular biopsy samples. ^[11]  Massad et al found germ cells present, but abnormal, in testis biopsy samples of children younger than 1 year with prune belly syndrome. ^[12]  Woodard et al reported viable sperm in the postejaculate urine in a patient who had undergone orchidopexy as a young child. ^[13]

With advances in assisted reproductive technologies come reports of sperm retrieval and intracytoplasmic sperm injection in patients with prune belly syndrome. Five of the authors' male respondents tried some means of assisted reproductive with sperm retrieval and artificial insemination. Two of these men have successfully fathered children.

Given that some men with prune belly syndrome seem to be capable of fathering children, albeit with the help of assisted reproductive technologies, surgery should be attempted early in patients with prune belly syndrome to preserve fertility. Using current techniques, laparoscopic orchidopexy is apparently an ideal treatment for intraabdominal testis in persons with prune belly syndrome.

Intuitively, with intact Leydig cell function, men with prune belly syndrome should have normal testosterone levels and, therefore, a normal libido. Woodard reported that, following puberty, the average serum testosterone level was higher in patients with prune belly syndrome following prepubertal rather than postpubertal orchidopexy. ^[13]  Erection and orgasm are apparently normal. However, retrograde ejaculation secondary to prostatic hypoplasia and an open bladder neck is common. This reported finding was also seen in the authors' patients. Despite findings of retrograde ejaculation and difficulties with fertility, 11 of 16 men who responded were mostly or very satisfied with their sex lives.

Repair of the abdominal wall defect (from which prune belly syndrome derives its name) should be considered to be not only cosmetic but also potentially functional. Smith et al reported improvement in voiding function in patients with prune belly syndrome after abdominal wall reconstruction. ^[14]  Woodard and colleagues reported improved pulmonary function after abdominal wall plication. ^[15]  Therefore, surprisingly, only 4 patients had undergone some form of abdominal wall reconstruction. If an external support device can be considered as tantamount to a noninvasive approach to abdominal wall management, more than two thirds of those surveyed did not undergo definitive treatment of their abdominal wall defect.

Prune belly syndrome presents with a wide spectrum of severity. Seven of the authors' patients (30%) ultimately required kidney transplantation. This number parallels previous estimates regarding the development of renal failure in this population. Noh et al found several factors as prognostic for renal failure, including bilateral abnormal kidneys revealed by imaging studies, nadir serum creatinine levels of greater than 0.7 mg/dL, and clinical pyelonephritis. ^[16]  The authors did not ask about these factors in their survey. Of their patients who went on to undergo transplantation, 4 had undergone some form of ureteral reimplantation, 4 had undergone vesicostomy (3) or suprapubic tube (1), and one had an ileal conduit. The role of extensive urinary tract reconstruction in patients with prune belly syndrome is controversial. The authors do not know the chronology of when lower urinary tract reconstructions were attempted relative to the onset of renal failure.

The findings in the authors' study seem to indicate that adults with prune belly syndrome are happy and well-adjusted and are participating in conventional physical, sexual, emotional, educational, and employment roles.

The authors' study has limitations. The data represent the responses of only 23 adults with prune belly syndrome. Whether a larger sample size would have altered the outcome is unknown. Additionally, the BMSI is not specifically designed or validated to answer questions about female sexuality. A questionnaire designed to address female sexuality may have been better to include.

In conclusion, many individuals with prune belly syndrome appear to function at a high level, with good health-related quality of life and good social and sexual function. Persons who require kidney transplantation score significantly lower on many indices of health-related quality of life. Artificial reproductive technology appears to be required to conceive children but is possible, contrary to prior beliefs.