Prune Belly Syndrome - Clinical Tree

Prune belly syndrome (PBS), also named Eagle-Barrett syndrome, is a rare multisystem congenital disorder with a triad presentation of urinary tract dilation, deficient abdominal wall musculature ( Fig. 61.1 ), and bilateral undescended testes. Frohlich (1839) first described the distinct abdominal wall, and then Parker (1895) described the full triad of anomalies. The term prune belly syndrome was first coined by Osler in 1901. There is a broad spectrum of severity of the condition, with some patients not surviving the neonatal period to others with minimal abnormalities. PBS affects 3.8 cases per 100,000 live births and is more common in infants of African descent. The proportion of those of African descent with PBS is significantly greater than that of the general population (31% vs 15%). The male-to-female ratio is reported to be 5:1. Females with PBS have abdominal wall muscle deficiency and urinary tract dilation, but no gonadal anomalies. Females represent <5% of PBS cases, and fewer than 30 cases have been described in the literature.

PBS is one the most difficult conditions to manage for pediatric urologists and surgeons. It is a challenge to obtain evidence-based data from clinical experience due to the low number of cases (10–20) seen even at large institutions. The overall initial mortality rate is approximately 50% (20% stillborn, 30% initial hospital stay), and survival has not improved much in the last 50 years despite advances in perinatal and operative management. The perinatal mortality is usually related to prematurity and pulmonary conditions. Surviving patients suffer from high morbidity due to prematurity, varied degrees of urinary tract pathology, and associated cardiovascular, respiratory, orthopedic, and gastrointestinal anomalies. The condition is associated with low self-esteem due to its physical appearance, constipation, impaired physical mobility, and decreased fertility. Many will need multiple operative interventions for reconstruction. In a recent study, it was found that family members and patients had a lower overall quality of life compared with healthy children secondary to lifelong medical disability leading to psychological, financial, and social issues.

Genetics

The etiology of PBS is unknown, yet the higher incidence in males, greater proportion of cases in those of African descent, and high concordance rate in twins (12.2/100,000 live births) suggest that PBS has a genetic basis. Although no specific gene has been identified for PBS, certain genes have emerged as candidates.

HNF1β is a transcription factor that regulates gene expression for mesodermal and endodermal development, including mesonephric duct derivatives. In two cases of sporadic PBS, deletions were found on chromosome 17q12 encompassing HNF1β. However, in another study, it was found the HNF1β mutation was present in only 3% of cases (1/32 PBS patients), and it was observed to be functionally normal.

Another gene that has recently become a candidate is CHRM3 , which encodes the M3 muscarinic acetylcholine receptor, the major receptor mediating bladder contraction during voiding. M3 protein is also found on the urogenital sinus, fetal ureteral epithelia, and nephron precursors. In one report, loss of function mutation of the CHRM3 gene was found in five brothers with PBS-like syndrome. Also, in this family, the HNF1β gene was normal. Sporadic cases of PBS have also been associated with other chromosomal abnormalities, including Turner syndrome and trisomies 13, 18, and 21.

Since the majority of reported cases are males, it has been suggested that the mode of inheritance is sex-linked autosomal recessive. However, others feel it is likely pure autosomal recessive. Most cases of PBS occur sporadically, with only a total of 11 cases of familial PBS reported. Currently, there are no large cohort investigations regarding the genetics of PBS, and therefore, the genetic basis for PBS remains unknown. Because most PBS patients have a normal karyotype, it is thought that associated chromosomal abnormalities are probably the exception rather than the rule.

Embryology

Several theories regarding PBS embryogenesis have been proposed. None of these ideas have universal acceptance, and there is some overlap among them. The most widely accepted mechanism is that of transient urethral obstruction during gestation, which causes a massively distended bladder and ureters. This transient urethral obstruction may then interfere with the descent of the testicles, explaining the presence of bilateral cryptorchidism. The severe urinary tract dilation causes abdominal wall muscle atrophy resulting in the characteristic wrinkled, lax, and thin abdominal wall found in PBS patients. Such obstruction is theorized to have resolved prior to delivery. Delayed canalization of the urethra during the 11th–16th week of gestation has been proposed as the mechanism of cases in which the urethra is patent at birth. Another hypothesis for the urethral obstruction is that it is created by a hypoplastic prostate, which may cause the unsupported urethra to twist or create a flap-like obstruction. This theory is sustained by the generalized presence of prostatic hypoplasia in PBS patients.

The abdominal mesodermal maldevelopment theory implies that between 6 and 10 weeks of gestation an unknown event to the mesoderm prevents normal development of the abdominal wall muscles and urinary tract. Failure of migration of the lateral mesoderm explains the classic abdominal wall appearance. In addition, a defect in the intermediate plate mesoderm is suggested because it would affect the development of the ureters, bladder, prostate, urethra, and gubernaculum, which explains the urinary tract abnormalities seen in PBS. However, an insult to the mesodermal layer should affect other organ systems, but this is not observed in PBS.

Finally, an intrinsic defect in the urinary tract leading to ureteral dilation has also been proposed as a mechanism of PBS.

Clinical Features

Genitourinary Anomalies

Bladder

Usually the bladder in PBS patients will be massively enlarged and smooth walled without trabeculations. Histologically muscle fibers are replaced by collagen and fibrous tissue. This loss of muscle fibers will cause the bladder to bulge in multiple directions, which gives the appearance of a pseudodiverticulum at the bladder dome ( Fig. 61.2 ). A patent urachus is present in 25–30% of PBS patients. In the presence of urethral atresia, a patent urachus will allow bladder emptying in utero. The trigone is wider and the bilateral ureteral orifices are displaced more lateral than usual, which likely contributes to the presence of vesicoureteral reflux (VUR) in 75–80% of patients. Also, the bladder neck is poorly defined and opens into a dilated, elongated prostatic urethra. As the prostatic urethra becomes membranous, it will taper due to redundant folds of mucosa, which may give the impression of obstruction on imaging. On urodynamic studies, PBS patients typically demonstrate a normal compliance. However, a very large bladder capacity and delay in the first sensation to void are often seen. In addition, PBS bladders demonstrate poor detrusor contractions and incomplete emptying. The ability to empty the bladder is variable, with around 50% of PBS patients voiding spontaneously with normal voiding pressures, normal flow rates, and low post void residual (PVR). Regardless of the voiding pattern, all PBS patients should be closely followed because their ability to empty the bladder may change.

Ureters

As stated previously, the wide bladder trigone with bilateral ureteral orifices displaced more lateral than usual may contribute to the presence of VUR in up to 80% of patients ( Fig. 61.3 ). The ureters are tortuous and severely dilated. The degree of ureteral pathology can vary and has been shown to be segmental, with the distal ureter being the most affected ( Fig. 61.4 ). Distally, the ureter has shown a greater decrease in muscle fibers and an increase in collagen and connective tissue fibers. This causes inefficient ureteral peristalsis and the development of upper tract urinary stasis and system dilation. This is important to identify prior to surgical reconstructions because the proximal ureter is typically a better substrate when compared with the distal ureter. Although definite obstruction is not common, it has been reported at the ureterovesical junction (UVJ) and ureteropelvic junction (UPJ). As the child grows and the ureters elongate, spontaneous improvement may occur in the ureteral appearance and function.

Fig. 61.4, This photograph shows marked dilation of the distal ureter (asterisk), which is often found in a child with prune belly syndrome.

It is interesting to note that, in many cases, the flaccidity of the abdominal wall is not related to the degree of dilation of the urinary tract. However, in a recent study, a direct correlation was observed between the flaccidity of the abdominal wall to the severity of the urinary tract dilation in which those with a severely wrinkled abdomen had marked dilation, whereas those with partial wrinkling had minimal dilation. This association continues to be studied.

Kidneys

PBS is characterized by a low-pressure dilated urinary system from the urethra to the renal pelvis. The etiology of the renal abnormalities remains unknown. The pathogenesis has been hypothesized to be from early urethral obstruction or from an abnormal interaction between the metanephric blastema and ureteral bud. Renal abnormalities range from completely normal to severely dysplastic kidneys. Dysplasia is present in 50% of PBS cases. In some cases, one kidney may be affected, with a normal contralateral kidney. The presence of hydronephrosis is also quite variable, and the degree of hydronephrosis does not correlate with the degree of dysplasia. Despite severe ureteral and renal pelvis dilation, calyceal morphology is often well preserved. Hydronephrosis, when present, is typically nonobstructive.

Progressive uropathy is known to occur, and nearly 20–30% of PBS patients will progress to renal failure. The most accurate predictor of progression to end-stage renal disease (ESRD) is a nadir creatinine >0.7 mg/dL in the first 8 months of life. The degree of urinary system dilation is not a prognostic factor for renal function. Renal infection provides the greatest risk to renal function. Early progression to ESRD may be attributed to severe renal dysplasia, but later progression is attributed to renal damage from repeated infections and obstruction. Many patients with PBS will ultimately require renal transplantation.

Urethra

The anterior urethra of PBS patients is usually normal. However, several anomalies have been described, including urethral atresia and megalourethra. Urethral atresia is usually fatal unless associated with a patent urachus. On the other hand, PBS is associated with two types of megalourethra. Scaphoid megalourethra is the deficiency of corpus spongiosum with intact bilateral corpora cavernosa ( Fig. 61.5 ). This is the most common and less severe form. Fusiform megalourethra occurs when there is complete absence of corpus cavernosum and corpus spongiosum. With the fusiform megalourethra, when the patient voids, the entire penis will enlarge, while with the scaphoid megalourethra, only the anterior urethra dilates with voiding. Megalourethra is more commonly seen in PBS than any other syndromes, with 50% of cases associated to PBS.

Prostate and Accessory Sex Organs

As mentioned, PBS children have hypoplasia of the prostate that causes dilation of the posterior urethra ( Fig. 61.6 ). The normal prostatic smooth muscle and epithelium are replaced by connective tissue. The prostatic urethra tapers as it becomes membranous due to redundant folds of mucosa that may give the impression of obstruction on imaging. Although rare, actual obstructive lesions of the distal posterior urethra have been described in 20% of cases. These lesions include urethral atresia, valves, urethral stenosis, and urethral diverticulum.

Fig. 61.6, Posterior urethral dilation (asterisk) is often found in children with PBS. This dilation is similar to that seen in boys with posterior urethral valves.

Adult men with PBS usually will have infertility that is multifactorial in etiology due to cryptorchidism, prostate secretory disorders, and retrograde ejaculation. Ejaculatory failure may occur due to the lack of normal prostatic tissue. Retrograde ejaculation can result from the incompetent bladder neck. In addition, the vas and the seminal vesicles typically have atresia, but dilation of these structures has also been described. Furthermore, there may be poor attachment between the testis and epididymis and between the efferent duct and the rete testis.

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