Prune-belly syndrome

INTRODUCTION — Prune-belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a congenital disorder defined by a characteristic clinical triad (picture 1):

●Abdominal muscle deficiency

●Severe urinary tract abnormalities

●Bilateral cryptorchidism in males

The term "prune belly" reflects the characteristic wrinkled appearance of the abdominal wall in the newborn due to the complete or partially complete absence of abdominal wall muscles. In adolescent and adult life, the abdomen often assumes a smooth "pot belly" appearance. Contrary to this definition, PBS is in fact a multisystem disease, with patients displaying concomitant cardiopulmonary, gastrointestinal, and musculoskeletal anomalies in varying degree.

PBS, including its pathology, clinical manifestations, diagnosis, management, and prognosis, will be reviewed here.

EPIDEMIOLOGY — The reported incidence of PBS is between 2 and 4 cases per 100,000 births, as illustrated by the following:

●In a report based on data from the Kids' Inpatient Database from 2002, 2003, and 2006, the incidence of PBS in the United States was approximately 3.8 cases per 100,000 live births [1]. In this cohort, approximately 50 percent of affected patients were White, 30 percent Black, and 10 percent Hispanic.

●In the Finnish Register of Congenital Malformations from 1993 to 2015, 31 cases of PBS were identified, corresponding to a total prevalence of 2.28 per 100,000 pregnancies. In 16 of these 31 cases, pregnancy was electively terminated due to PBS and 15 were live births [2].

PBS primarily occurs in males, although there are rare case reports of this disorder in females [1,3]. Interestingly, gonadal abnormalities are not observed in affected females [4].

PATHOGENESIS

●Genetics – The genetic basis of PBS remains unknown. A recessive X-linked defect is suggested by the predominance of affected males. However, this mode of inheritance is precluded by two observations:

•Although rare, the disorder can occur in females [3]

•(Untreated) affected males suffer from azoospermia

PBS has also occurred in association with other chromosomal abnormalities, including trisomy 13, 18, and 21 [5], and a report of large deletion in the long arm of chromosome 6 in a male fetus [6].

Further evidence for a genetic basis of PBS includes a report of two cases of concordant PBS in monozygotic twins [7] and a report of two nontwin brothers [8].

Isolated abdominal wall muscular hypoplasia, without evidence of urinary tract or kidney pathology, has also been described in a family with apparent autosomal dominant or mitochondrial inheritance [9].

●Mesenchymal developmental defect – It has been suggested that the underlying defect in PBS is abnormal mesoderm development [10,11]. In particular, a primary defect in the intermediate and lateral plate mesoderm would affect embryogenesis of the musculature of the abdominal wall, the mesonephric and paramesonephric ducts, and the urinary organs [11].

The underlying mesenchymal defect may be caused by one of the following proposed mechanisms:

•Deletion of the hepatocyte nuclear factor 1 beta (HFN1B) gene on chromosome 17q12 [12-14] – HFN1B is a transcription factor that regulates gene expression and plays a crucial role in embryonic development as it is essential for visceral endoderm specification [15]. HFN1B is expressed in the epithelial cells of kidney, pancreas, liver, genital tract, and intestinal tract [16]. Variants of the HFN1B may lead to abnormal development of the kidneys and genital tract; however, it does not explain all the findings of PBS, such as the lack of abdominal musculature. In a study of 32 patients with PBS (30 males and 2 females), only one missense variant, which was functionally normal, was detected [17].

•Hemizygous missense mutations in the X-linked filamin A gene – Whole-exome sequencing identified three hemizygous missense point variants in the X-chromosome gene filamin A (FLNA) in two related cases and two unrelated sporadic individuals. FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold transmitting signals from the cytoskeleton to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in four affected males [18].

•Pathogenic copy number variants – In a report of 34 PBS patients (30 male, 4 female), 17 novel pathogenic copy number variants were identified [19]. This included duplications at 4q22 overlapping the bone morphogenetic protein receptor type 1B (BMPR1B) gene, the intron of the stromal interaction molecule 1 (STIM1) gene, the gene (NOG) that encodes noggin, and a large deletion including the myocardin (MYOCD) gene. All of these genes are involved in mesodermal, muscle, and urinary tract development and differentiation. Another copy number variant associated with PBS was described in chromosome 16p11.2 encompassing the SH2B1 gene [20].

•Loss-of-function mutation of the CHRM3. In a case report, six brothers of a Turkish family with a prune-belly-like syndrome had inherited the same loss-of-function mutation of the CHRM3 from their unaffected parents. CHRM3 encodes the muscarinic acetylcholine receptor M3 that, apart from its role in detrusor contractions, is present in developing renal epithelia and bladder muscle [14,21].

•Other genes with mutations found in patients with either prune belly or an overlapping disease called megacystis microcolon intestinal hypoperistalsis syndrome include ACTA2 (encodes alpha-smooth muscle actin), ACTG2 (encodes gamma 2 smooth muscle actin), MYH11 (encodes a smooth muscle heavy chain protein), and MYLK (encodes myosin light-chain kinase that modifies myosin chains in smooth muscle cells) [22].

•Alternatively, some investigators have suggested that early urethral obstruction by a valve-like mechanism is the primary abnormality in PBS, which can then lead to the other clinical manifestations [23,24]. However, the observation that patients with congenital posterior urethral valves do not have the other features of PBS casts doubt on this hypothesis [11].

PATHOLOGY — Pathologic involvement of the kidneys, genitourinary tract, and other organ systems results in the variable clinical manifestations of PBS.

Kidneys — The major kidney abnormality in PBS is dysplasia that affects a variable portion of kidney tissue. The dysplasia is manifested by incomplete nephron differentiation and dilatation of tubules, which are lined by immature epithelial cells [25]. Tubular atrophy, interstitial fibrosis, and chronic lymphoplasmacytic infiltrates are present, and glomerulosclerosis is eventually seen. In addition, associated findings include reflux nephropathy and recurrent pyelonephritis, which may result in cortical scars.

Renal dysplastic changes may not be evident before 16 weeks gestation, as demonstrated by a case report from Japan [26]. In this report, a fetus was diagnosed with PBS by ultrasound at 12 weeks gestation with cystomegaly due to urethral obstruction. The pregnancy was terminated at 14 weeks gestation based on fetal urinary electrolyte and beta-2-microglobulin values that indicated a poor kidney prognosis. An autopsy demonstrated abdominal wall defects and severe urethral obstruction consistent with a diagnosis of PBS, but the kidneys were histologically normal without any evidence of dysplasia.

Urogenital tract — Abnormalities of the ureter, prostate, bladder, and testicles are commonly observed. These anomalies may be unilateral or bilateral, thereby resulting in varying degrees of kidney impairment due to vesicoureteral reflux and obstruction.

●Ureters – The ureters are grossly elongated, dilated, and tortuous due to replacement of smooth muscle with fibrous tissue. Ureteral stenoses may occur due to kinking. Peristalsis is ineffective or lacking.

●Bladder – The bladder is usually enlarged and nontrabeculated and has thickened walls (due to collagen deposits) with smooth muscle hypoplasia. The dome of the bladder is frequently capped by a diverticular remnant of the urachus. The trigone is barely discernible, and the ureteral ostia are lateralized (often with a golf hole-like appearance).

Contrary to a widely held belief that urinary obstruction is the cause of bladder distention, intraluminal storage and voiding pressures are abnormally low in patients with PBS. Significant residual urine volumes suggest the presence of defective bladder urodynamics [27].

●Prostate – A hallmark of PBS in males is a markedly hypoplastic or dysplastic prostate, which leads to dilatation of the prostatic urethra. In occasional patients, a valve-like mechanism develops in the membranous part of the urethra and causes urinary obstruction [24]. This may lead to a pressure-induced dysplasia of the prostate [28].

●Testicles – Bilateral undescended testes and an empty scrotum are regularly found in affected male patients. However, spermatogonia are not universally absent. The germ cells are markedly reduced in number, appear atypical, and may predispose to malignant tumors later in life [29,30]. It is presumed that the mechanical obstruction from megacystis and hydroureteronephrosis contributes to the maldescent of the testicles [31].

Abdominal wall musculature — A constant feature of PBS is partial aplasia or hypoplasia of the abdominal muscles (which may be unilateral or asymmetric), leading to the prune-belly appearance (picture 1). Electron microscopy of affected abdominal muscles reveals dystrophy with loss of coherence in the Z bands, clumping of glycogen granules, and mitochondrial abnormalities [32].

CLINICAL MANIFESTATIONS

Clinical triad — PBS is composed of a characteristic clinical triad:

●Abdominal muscle deficiency (picture 1), leading to the characteristic wrinkled appearance of the abdominal wall ("prune belly")

●Severe kidney and urinary tract abnormalities

●Bilateral cryptorchidism in males

The severity of renal dysplasia and urinary tract abnormalities along with the presence of pulmonary hypoplasia are the two principal characteristics that determine the eventual outcome among patients with PBS. These abnormalities may result in recurrent episodes of urinary tract infections, urosepsis, varying degrees of renal and respiratory insufficiency, and other manifestations of the disorder [33].

Abdomen — Prune-belly appearance (picture 1) is due to aplasia or hypoplasia of the abdominal muscles (which may be unilateral or asymmetric). Later in life, intraabdominal organs may prolapse and lead to a "pot-belly" appearance.

Other gastrointestinal malformations can occur and include [34]:

●Malrotation of the midgut and persistence of the embryonic wide mesentery, resulting in cecum mobile, elongation of the colon, and volvulus. (See "Intestinal malrotation in children".)

●Hindgut abnormalities, leading to anorectal malformations (eg, persistence of the embryonic cloaca, agenesis of rectum and anus, and congenital pouch colon).

Kidney — Approximately one-half of the patients surviving infancy will develop chronic kidney disease in childhood or adolescence [33]. Findings of bilaterally abnormal kidneys (as determined by ultrasound or renal scan), a serum creatinine concentration greater than 0.7 mg/dL (62 mcmol/L), and episodes of clinical pyelonephritis appear to predict the eventual development of chronic kidney disease [35]. Other patients with the least severe form of the syndrome experience either no or only mild impairment of kidney function.

The severity and timing of onset of kidney impairment may reflect the degree of renal dysplasia (see 'Kidneys' above). One study, for example, correlated histologic findings with the severity and onset of kidney dysfunction [25]. At autopsy, six of nine children who had died in infancy or as neonates had severe and diffuse renal dysplasia. By comparison, dysplastic changes were observed in less than 25 percent of the renal parenchyma in 10 surviving patients, all of whom had varying degrees of kidney dysfunction. Kidney failure in these patients was thought to be due to pyelonephritis and obstruction, not renal dysplasia.

Individuals with deformed appearance of the urinary tract on kidney ultrasonography and voiding cystourethrogram often have surprisingly good kidney function. Thus, radiologic techniques are not always reliable in assessing obstruction [36].

Data are limited regarding kidney failure in patients with PBS. Review of data from the European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry identified a cohort of 88 children with PBS who progressed to kidney failure [37]. Age at kidney replacement therapy (KRT) onset varied, with 15, 25, 22, and 26 patients starting KRT at <0.5 years, 0.5 to 5 years, 6 to 10 years, and ≥11 years, respectively. Initial KRT included peritoneal dialysis (n = 44), preemptive kidney transplantation (n = 29), and hemodialysis (n = 15).

Urogenital — Most patients have urologic abnormalities. This was illustrated in a review of 46 patients (44 boys and 2 girls) cared for at a tertiary center in the United States, which reported bilateral hydroureteronephrosis in 45 patients (98 percent) and vesicoureteral reflux in 34 cases (78 percent) [33].

In most affected males, bilateral undescended testes and an empty scrotum are typical findings. Male adolescent patients usually experience normal erections and orgasm, but retrograde ejaculation is frequent [38]. Owing to early orchiopexy, there are case reports of successful paternity by aspirated sperm retrieval and in vitro fertilization [39]. In addition, hypoplastic or dysplastic prostate leads to prostatic urethral dilation, which may cause urinary obstruction [24].

In a postpubertal cohort study of fifteen male patients with PBS, all of whom had orchiopexy at a mean age of 18 months, 14 patients had normal and orthotopic kidneys at a mean age of 19.2 years. In five of eight patients who had analysis of their semen, spermatozoa were detected, with motile sperm in four [40]. Two-thirds of the cohort had hypoplastic prostates and unilateral seminal vesicle absence.

Urinary tract infections, including recurrent episodes of cystitis and pyelonephritis, are common, occasionally resulting in urosepsis [33].

Pulmonary hypoplasia — Pulmonary hypoplasia is the most significant extra-urogenital complication in PBS. It is caused by oligohydramnios in the first one-half of gestation due to lack of sufficient urine production, which promotes mechanical compression of the fetus and inhibits thoracic expansion. Without amniotic fluid entering the airways, the lungs remain hypoplastic. In addition, thoracic cage deformities and paradoxical movement of the abdomen during respiration may predispose affected patients to mechanical restriction, thereby explaining their susceptibility to impaired cough mechanism, recurrent bronchitis and pneumonia, and respiratory depression following anesthesia [41].

Cases of congenital cystic adenomatoid malformations in patients with PBS have also been reported, suggesting a possible association between these two disorders [42]. (See "Congenital pulmonary airway malformation".)

Other manifestations — Other manifestations include:

●Chronic constipation is a common feature of PBS [33,43]. (See "Functional constipation in infants, children, and adolescents: Clinical features and diagnosis".)

●Impaired exercise tolerance in older children and adults due to paradoxical motion of the abdomen during respiration [41].

●Poor growth occurs in up to one-third of cases [44].

●Anorectal malformations have been described in children with PBS including imperforate anus [45], anorectal agenesis [46], or congenital pouch colon [47].

●Splenic torsion may occur due to intestinal malrotation and wandering spleen [48].

●Musculoskeletal anomalies are numerous and include clubfoot, dislocated hip, kyphoscoliosis, polydactyly, torticollis, and pectus excavatum [33,44]. Some of these abnormalities are deformations due to severe reduction of amniotic fluid (oligohydramnios). (See "Lower extremity positional deformations".)

●Complex cardiac anomalies can occur rarely [49].

Imaging — Imaging by ultrasound is the preferred modality as it can identify the following findings:

●Dilatation of urinary bladder and ureters (megacystis, megaureters)

●Hydronephrosis with or without echodense kidney parenchyma

●Polycystic or dysplastic kidneys

●Hypoplastic lungs

Antenatal ultrasound imaging may identify any of the above findings as well as detect oligohydramnios and fetal ascites.

Magnetic resonance urography appears to be a promising technique for evaluation of the upper urinary tract in patients with PBS. In a retrospective series of 13 boys (median age 29.3 months, range 6 to 97 months), urologic abnormalities beyond hydroureteronephrosis were easily detected and included renal dysplasia, scarring, calyceal diverticula, and thickened bladder [50].

DIAGNOSIS — The diagnosis of PBS is made clinically with the identification of the characteristic clinical triad of abdominal muscle deficiency, severe kidney and urinary tract abnormalities, and bilateral cryptorchidism in males. The syndrome is most often recognized at birth or in early childhood by the peculiar appearance of the abdominal wall, cryptorchism in males, and identified urogenital abnormalities by ultrasound. PBS occasionally presents later in life as a rare cause of end-stage kidney failure in the adult [51,52].

Antenatal diagnosis may be made by routine ultrasonographic examination of the fetus between weeks 20 and 30 gestation. High-end vaginal sonography allows visualization of the kidneys and the urinary drainage system as early as 11 to 13 weeks gestation [53]. In some cases, it may be difficult to differentiate posterior urethral valves from PBS in utero as both may present with antenatal ultrasound findings of a dilated bladder and bilateral hydronephrosis. In the rare cases of in utero intervention, patients with PBS have a better prognosis than those with posterior urethral valves. (See "Clinical presentation and diagnosis of posterior urethral valves", section on 'Prenatal' and "Management of posterior urethral valves", section on 'Outcome'.)

MANAGEMENT

Antenatal management — Antenatal intervention may be required in severe cases of obstructive uropathy (ie, when midgestational oligohydramnios is present). In this setting, placement of a vesicoamniotic shunt may prevent an otherwise fatal neonatal course, due primarily to pulmonary hypoplasia [54-56]. (See "Fetal hydronephrosis: Etiology and prenatal management", section on 'Fetal surgery'.)

Postnatal management — The appropriate therapy of PBS in early childhood remains controversial. Severely affected patients require early surgery (supravesical diversion or primary reconstruction) to provide adequate urinary drainage and avoid recurrent infections [57]. In some patients, the insertions of a cystostomy button may facilitate bladder drainage and improve quality of life [58].

By comparison, others may reach adult life with only a minor degree of chronic kidney impairment, and, therefore, require only minimal early intervention. Furthermore, as the progression of the kidney impairment in childhood and adolescence is primarily due to recurrent pyelonephritis and reflux nephropathy, adequate antibiotic therapy including antibiotic prophylaxis and, in rare cases, surgical intervention may prevent or delay progression to kidney failure [25]. (See "Clinical presentation, diagnosis, and course of primary vesicoureteral reflux".)

Kidney failure

Transplantation — Kidney transplantation has been successfully performed in PBS and is the preferred treatment for kidney failure, either as preemptive therapy or following dialysis. Long-term outcome is excellent and is similar to other causes of kidney failure [37,59,60]. However, extensive pretransplant urologic tract preparation may be necessary to reduce the postvoid residual volume to a minimum [61,62].

There also may be rare complications of transplantation intrinsic to this syndrome, such as acute torsion of the transplant [63]. In some cases when the native bladder is unsuitable, successful drainage of the transplanted kidney into a urinary conduit or augmented bladder has been performed [64].

Dialysis — Maintenance hemodialysis and continuous ambulatory peritoneal dialysis are equally effective in the management of kidney failure in PBS [65]. Children with PBS who are initially treated with peritoneal dialysis have similar complication rates as patients with other causes of kidney failure [37,63].

In the previously mentioned study from European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry, 8 of the 44 patients who started on peritoneal dialysis were switched to hemodialysis because of technical difficulties [37]. However, this was a similar rate as other patients with kidney failure due to obstructive uropathy and renal hypodysplasia. (See "Overview of kidney replacement therapy for children with chronic kidney disease" and "Chronic peritoneal dialysis in children" and "Hemodialysis for children with chronic kidney disease".)

Other genitourinary interventions — Additional therapeutic interventions may also be required for other manifestations of PBS. These include:

●Ureteral reimplantation for high-grade vesicoureteral reflux or patients who fail medical management for vesicoureteral reflux. (See "Management of vesicoureteral reflux".)

●Reduction cystoplasty may help improve voiding and minimize infection, although bladder capacity is not reduced and voiding dynamics are not improved [66]. To assure sufficient bladder drainage, a cutaneous vesicostomy or appendicovesicostomy (Mitrofanoff procedure) may be necessary.

●Urethrotomy may often improve bladder emptying, even if there is no anatomical obstruction ("functional obstruction") [67].

●The intraabdominal testes in males have been successfully brought to the scrotum laparoscopically or by a Fowler-Stephens orchiopexy [68,69]. This procedure should not be delayed until adolescence. In a retrospective series of 41 male adults with PBS who had undergone Fowler-Stephens orchiopexy in childhood, 38 (93 percent) achieved sufficient testicular function to induce puberty and maintain satisfactory sexual function in adult life [70]. (See "Undescended testes (cryptorchidism) in children: Management", section on 'Timing of surgery'.)

Abdominal wall reconstruction — The abdominal wall may be reconstructed for cosmetic and psychosocial reasons by excision of the redundant skin while preserving the umbilicus [71-73]. In addition, this may improve bladder function, with reduction of postvoid residual urine volume, as well as bowel function and facilitate the development of more normalized walking and breathing [74].

In those who do not require a concurrent intraabdominal procedure, an abdominoplasty can be performed by an extraperitoneal plication of fascial folds, obviating the need for a fascial incision and/or entrance into the peritoneal cavity; this technique produces cosmetically excellent results with a decreased recovery time [75]. This reconstruction may be done by laparoscopy that potentially decreases morbidity and complications associated with an open surgical procedure [76].

To improve the functional status of the abdominal wall, muscle transposition from the thigh musculature has been performed, which may prevent the loss of spinal stability and development of kyphoscoliosis [77,78].

Timing of urinary tract reconstruction and abdominoplasty remains a matter of discussion. Early simultaneous correction of PBS anomalies seems advisable to preserve kidney function and improve quality of life [33,79,80].

Spinal procedures — In rare cases of marked scoliotic spine deformities, orthopedic surgery is warranted to correct the underlying defect [81].

PROGNOSIS

Mortality — Patients with PBS have had a generally poor prognosis. In older reports, 20 percent of affected children were said to be stillborn and 50 percent did not survive to the age of two years [82]. However, early diagnosis and appropriate therapy have led to improved survival. In a subsequent series of 50 patients, the overall mortality was 32 percent, with the majority of deaths confined to the perinatal period [83].

Paternity — Although affected untreated males suffer from azoospermia, and thus are infertile by definition, viable spermatozoa may be found in testes after orchiopexy. Intracytoplasmic sperm injection and transfer of a single expanded blastocyst, performed three times in an otherwise infertile couple, has led to three singleton pregnancies [84]. Outcomes included nonviable fetus (gestational age 18 weeks) and two healthy male infants, one of whom was born prematurely. Sperm retrieval may be done intraoperatively by microdissection testicular sperm extraction for cryopreservation and in vitro fertilization [85].

Pregnancy — Women's reproductive systems are rarely affected by PBS, and little is known regarding reproductive potential. In one case report, a 25-year-old female patient diagnosed with (incomplete) PBS delivered a healthy child after an uneventful pregnancy [86]. Labor and delivery were, however, complicated by a prolonged second stage of labor and need for vacuum-assisted vaginal delivery.

SUMMARY AND RECOMMENDATIONS

●Introduction – Prune-belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a congenital disorder defined by a characteristic clinical triad that includes abdominal muscle deficiency, severe urinary tract abnormalities, and bilateral cryptorchidism in males (picture 1).

●Epidemiology – The reported incidence is between 2 and 4 cases per 100,000 births. Males are primarily affected, although there are rare cases in females. (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of PBS remains unknown. It is thought to be due to a genetic defect in mesenchymal development. (See 'Pathogenesis' above.)

●Kidney pathology – The severity of kidney pathology is the primary factor that affects the clinical manifestations of PBS. Dysplasia is the main kidney abnormality of PBS, and it is manifested by incomplete nephron differentiation and dilatation of the tubules. Approximately one-half of patients have severe dysplasia, develop kidney failure, and require kidney replacement therapy (KRT). (See 'Kidney' above.)

●Clinical manifestations

•The clinical triad that defines PBS includes include prune-belly appearance due to aplasia or hypoplasia of the abdominal muscles, impaired kidney function, and cryptorchidism in males. (See 'Clinical manifestations' above.)

•Pulmonary hypoplasia due to severe oligohydramnios resulting in maldevelopment of the lungs is the most severe finding associated with PBS.

•Other findings include gastrointestinal malformations (eg, malrotation of the midgut or anorectal malformations) and skeletal abnormalities (eg, clubfoot). (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of PBS is made clinically with the identification of the characteristic features of abdominal muscle deficiency, severe urinary tract abnormalities, and bilateral cryptorchidism in males. The diagnosis may be made by antenatal ultrasonographic examination between weeks 20 and 30 gestation, or at birth or in early childhood by clinical recognition of the syndrome. (See 'Diagnosis' above.)

●Management – The management of PBS depends on the severity of the clinical findings:

•In rare cases, antenatal intervention has been performed to reduce the risk and severity of pulmonary hypoplasia. (See 'Antenatal management' above.)

•Postnatal surgical intervention may be needed to provide adequate urinary drainage and avoid urinary tract infections in some patients. (See 'Postnatal management' above.)

-Kidney failure is managed with dialysis or kidney transplantation. (See 'Kidney failure' above.)

-Other interventions include additional genitourinary procedures to improve bladder control and capacity, orchiopexy, abdominal wall reconstruction, and, in rare cases, orthopedic surgery for skeletal deformities.

●Prognosis – Although the survival rate has improved for PBS with earlier diagnosis and intervention, the mortality rate still remains at approximately 30 percent, with the majority of deaths occurring in the perinatal period due to pulmonary insufficiency. (See 'Prognosis' above.)