Abstract
Birth defects involving the kidney and urinary system are often encountered and frequently occur in association with other structural abnormalities. A congenital urinary tract anomaly may provide the first clue to the recognition of multiorgan developmental abnormalities. Nevertheless many renal anomalies remain asymptomatic and undiagnosed. Therefore it is critical, not only for pediatric nephrologists but also for pediatricians in general, to be familiar with the common anomalies involving the kidney and urinary system and the more complex disorders with which they may be associated.
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Introduction
Birth defects involving the kidney and urinary system are often encountered and frequently occur in association with other structural abnormalities. A congenital urinary tract anomaly may provide the first clue to the recognition of multiorgan developmental abnormalities. Nevertheless many renal anomalies remain asymptomatic and undiagnosed. Therefore it is critical, not only for pediatric nephrologists but also for pediatricians in general, to be familiar with the common anomalies involving the kidney and urinary system and the more complex disorders with which they may be associated.
The kidney is a pivotal organ in dysmorphology. Although the number of single malformations involving the kidney is limited, combinations of these malformations in conjunction with anomalies involving other organ systems are found in more than 500 syndromes. In addition, many well-known sequences and associations involve the kidney and urinary tract. This chapter discusses common malformations, sequences and associations involving the kidney and urinary tract, and provides a summary of conditions that have these anomalies as one of their features. In addition, Tables 6-1 – 6-3 summarize more detailed information about a large number of disorders, including their phenotypic features, reported urinary tract anomalies, pattern of inheritance, causative genes and related references. These tables can be used both to provide readily available information about potential urinary tract anomalies for patients with a diagnosed genetic syndrome and to suggest a differential diagnosis when anomalies are identified. Readers interested in additional details about a specific syndrome are referred to standard reference textbooks and databases about syndromes and malformations for further reading (e.g., (5–7)).
To understand the pathophysiologic basis of structural abnormalities, it is important to be familiar with the meaning of certain terms as they are used in describing malformations and syndromes.
Malformation refers to a single structural anomaly that arises from an error in organogenesis. Such an error may be due to the failure of cells or tissues to form, to die (programmed cell death), or to induce others. Examples include renal agenesis, horseshoe kidney, and bladder exstrophy.
Deformation refers to a single structural anomaly that arises from mechanical forces, such as intrauterine constraint. Examples include many cases of metatarsus adductus, torticollis, and congenital scoliosis. The underlying tissue may be normal or abnormal, and sometimes a malformation (e.g., renal agenesis) can predispose patients to a deformation (e.g., Potter’s sequence from oligohydramnios).
Disruption refers to a single structural anomaly, that results from a destructive event after normal morphogenesis. Such events can be caused by lack of vascular supply, an infectious process, or mechanical factors. Examples include limb amputation from amniotic bands and abdominal wall defect from vascular insufficiency related to maternal cocaine use.
Sequence refers to a cascade of abnormalities that result from a single initiating anomaly. Sequences can be malformational, deformational, or disruptive, and they sometimes represent more than one of these categories. Obstruction of urine flow at the level of the ureter during early gestation, for example, can cause malformation of the kidneys, intestines, and abdominal wall – a malformation sequence. At the same time, decreased urine flow will produce oligohydramnios, fetal compression, and multiple deformities of the face, limbs, and chest wall – a deformation sequence.
Syndrome refers to a consistently observed pattern of anomalies found in an individual, whether malformation, deformation, or disruption. Anomalies comprising a syndrome are thought to have a single cause, although in many cases, their causes are still unknown. Examples include Turner syndrome and fetal alcohol syndrome.
Association refers to a constellation of anomalies that occur together more often than expected by chance alone but cannot be explained by a single cause or sequence of events, and so do not represent a syndrome or sequence. VATER association, which is discussed later in this chapter, is a common example.
Prevalence of Urinary Tract Anomalies
The true incidence of urinary tract anomalies is difficult to ascertain because many anomalies are asymptomatic and therefore undetected. Many reported statistics have apparent bias of ascertainment because they are derived from symptomatic individuals. Furthermore, inconsistent terminology and clustering of data have decreased the power of much of the epidemiologic data. Long-term analysis of data collected through major national birth defect registries showed increasing prevalence of reported statistics for many congenital birth defects, not only from an actual increment but also from increased tendency to report several isolated and associated anomalies (1–4). For this reason, the practical use of the derived prevalence seems not to be meaningful. However, there currently are quite a number of reliable estimates for prevalence of specific isolated anomalies and of those associated with a specific syndrome. A large number of European birth cohorts during 1996–1998 (EUROSCAN) was prenatally studied and recently reported (4). Table 6-4 shows a comparison of prevalence figures among various studies.
Approach to the Child with a Urinary Tract Anomaly
The approach to the child with a urinary tract anomaly is similar to that for other birth defects. The initial step is to make a specific diagnosis based on history taking, physical examination, and laboratory investigation. A thorough family history for both urinary tract anomalies and for any other type of congenital or developmental anomalies that may have occurred in the family must be obtained. Many genetic disorders have variable expression even within the same family. A careful physical examination looking specifically for major and minor anomalies should be performed. Sometimes, a pattern of multiple anomalies can be recognized immediately as a well-described syndrome. Patterns of anomalies that cannot be recognized may require a literature or database search, or referral to an expert in syndrome recognition, such as a clinical geneticist. The search for a specific diagnosis is optimally accomplished by identifying the least common and most distinctive anomalies, for which the list of differential diagnoses is limited. Many excellent textbooks, atlases, and databases are available (5–7). To aid in this effort, refer to Tables 6-1 – 6-3 in addition to a table listing the differential diagnosis that accompanies the description of each of the major urinary tract anomalies below (Tables 6-5 – 6-15 ). For example, it is preferable to search for syndromes with urethral agenesis (22 syndromes) rather than renal dysplasia (more than 80 syndromes) when the two anomalies coexist. A search based on the more common anomalies can be performed if the first search does not reveal a match. Even after careful evaluation, a substantial number of children with multiple congenital anomalies remain undiagnosed.
When a suspected syndrome is known to be caused by a gene mutation, confirmatory molecular genetic testing can be performed. DNA-based test is currently available on either a clinical service or research basis. Knowledge regarding a pathogenic mutation specific for each proband may potentially be useful for genetic counseling and future reproductive option in order to avoid intra-familial recurrence. Tables 6-1 and 6-2 list currently known causative gene(s) for each of the disorder.
A chromosome analysis is indicated in any child who has at least two major congenital anomalies or one isolated anomaly that is a pertinent feature of a chromosome abnormality, such as aniridia (microdeletion 11p). Growth or developmental delay and dysmorphic features or lack of familial resemblance should also prompt a chromosome analysis. Chromosome abnormalities are found in approximately 10–12% of all renal anomalies (3, 8). Table 6-3 lists common and distinct chromosomal disorders with their reported urinary tract anomalies.
For a child with no known urinary tract anomaly, findings that should prompt an evaluation of the urinary tract are oligohydramnios, undefined abdominal mass, abnormal genitalia, aniridia, hypertension, preauricular pits or tags, branchial cleft cyst or sinus, imperforate anus, or symptoms indicative of renal dysfunction, urinary tract infection, or obstructive uropathy (3). For patients with known syndromes, the type of potentially associated urinary tract anomalies are listed in Tables 6-1 and 6-2 .
The best initial evaluation to screen for urinary tract anomalies in general is an ultrasound examination because this study is noninvasive and gives good anatomic information about the urinary tract. It is also the only method routinely used for the prenatal diagnosis of urinary tract anomalies. Specific investigations such as intravenous pyelogram, voiding cystourethrogram, radionuclide renal and urinary system scan, and specialized genetic testing may then be used, depending on the working diagnosis. The type of anomaly generally guides treatment. Corrective or reparative treatments are available for many anomalies (stenosis or atresia, bladder exstrophy, duplication. diverticula, and tumors). Symptomatic treatment for complications is often necessary.
Families who have a child with a urinary tract anomaly should be informed of the diagnosis when possible. A search for a related anomaly in first-degree relatives is automatically indicated only when the proband has renal agenesis by ultrasound examination (9). Otherwise, the decision to investigate family members should be based on a thorough family history and/or physical examination, and whether the child’s disorder is a well described inherited syndrome. Genetic counseling should be provided to the family and should include a discussion of the manifestations of the disorder, the natural history, complications, available treatments, cause, and recurrence risk when these are known. Reproductive options should be discussed in a nondirective fashion. For an isolated anomaly without a family history of similar or related anomalies, an empiric risk can be provided. Accurate risk figures can be determined for Mendelian disorders, and estimated risks are available for associations.
All children with congenital anomalies need long-term, periodic follow-up to detect new abnormalities or complications of their birth defects. This is especially the case for children with undiagnosed multiple congenital anomalies, for whom follow-up examination may lead to a specific diagnosis. Additional relevant family information should be specifically sought for any newly affected member. Finally, for patients with a urinary tract anomaly who reach reproductive age, the recurrence risk for their offspring and reproductive options should be discussed.
The remainder of this chapter contains descriptions of the major types of urinary tract anomalies, including the etiology, pathogenesis, and associated disorders. First, a review of the embryology of the normal urinary tract will be useful in understanding structural urinary tract abnormalities.
Overview of Normal Embryogenesis of the Urinary System
Renal organogenesis is reviewed in chapter 1. Embryogenesis of the lower urinary tract includes development of the mesonephric duct and urogenital sinus. The mesonephric duct from which the ureteric bud arose inserts into the lower allantois, just above the terminal part of the hindgut, the cloaca. During the fourth to seventh weeks, mesoderm proliferates and forms the transverse mesodermal ridge, the urorectal septum that divides the cloaca into the anterior portion, the primitive urogenital sinus, and the posterior portion, the cloacal sinus or anorectal canal. The mesonephric ducts open into the urogenital sinus and later become the ureters. The urorectal septum develops caudally and fuses with the cloacal membrane, dividing it into the urogenital membrane (anterior) and the anorectal membrane (posterior) by the end of the seventh week. The primitive perineal body forms at the site of fusion.
The primitive urogenital sinus develops primarily into the urinary bladder. The superior portion, originally continuous with the allantois, later becomes a solid fibrous cord, the urachus or median umbilical ligament, which connects the bladder to the umbilicus. The inferior portion of the urogenital sinus in the male divides into a pelvic portion, containing the prostatic and membranous urethra, and the long phallic portion, containing the penile urethra. The inferior portion in the female forms a small portion of the urethra and the vestibule. At the same time, the distal portion of the mesonephric ducts is incorporated into the endodermal vesicoureteral primordium, forming the trigone of the bladder. A part of the distal end of both mesonephric ducts just proximal to the trigone develops into the seminal vesicles and ductus deferens in the male. Finally, at the end of the twelfth week, the epithelium of the superior portion of the prostatic urethra proliferates to form buds that penetrate the surrounding mesenchyme. In the male, these buds form the prostate gland; in the female, they form the urethral and paraurethral glands.
Anomalies Involving the Urinary Tract
Kidney Defects
Renal Agenesis
By definition, renal agenesis refers to complete absence of one of both kidneys without identifiable rudimentary tissue. Renal agenesis is usually associated with agenesis of the ipsilateral ureter. The pathogenesis of renal agenesis is failure of formation of the metanephros. Causal heterogeneity has been shown, by both animal studies and human observations (10–12), including failure of ureteric bud formation, failure of the bud to reach the metanephric blastema, or failure of the bud and the metanephric blastema to create mutual inductive influence on one another. In addition, interruption in vascular supply and regression of a multicystic kidney can lead to renal agenesis in the fetal period (11).
Unilateral renal agenesis is usually asymptomatic and found incidentally, whereas bilateral renal agenesis results in severe oligohydramnios and fetal or perinatal loss. Renal agenesis can occur in either side without predilection. Birth prevalence in the United States for renal agenesis/hypoplasia ranges between 0.30 and 9.61 per 10,000 live births (3). Several studies have demonstrated that unilateral renal agenesis is associated with an increased frequency of anomalies in the remaining kidney (9, 13). Moreover, renal agenesis is often detected in conjunction with anomalies of other organ systems. These anomalies can occur both in contiguous structures (e, g., vertebrae, genital organs, intestines, and anus) and also in noncontiguous structures (e.g., limbs, heart, trachea, ear, and central nervous system). The diagnosis of renal agenesis is made by abdominal ultrasound. Care must be taken to exclude the possibility of ectopic kidney. Intravenous pyelography, computerized tomography scan, and radionuclide studies can be helpful in equivocal cases.
The recurrence risk for renal agenesis can be provided if the pattern of inheritance is known or if the proband has a recognizable syndrome. For nonsyndromic renal agenesis, an empiric risk of 3% can be used for families in which renal anomalies in first-degree relatives (siblings, parents) have been excluded (3). First-degree relatives of patients with nonsyndromic renal agenesis have an increased prevalence of related urogenital anomalies. In one study, 9% of first- degree relatives of infants with agenesis or dysgenesis of both kidneys had a related urogenital anomaly, and 4.4% had an asymptomatic renal malformation (13). In another recent retrospective review, empiric risks were 7% in offspring, 2.5% in siblings and 4.5% in parents (14). Moreover, offspring of an individual with unilateral agenesis is at a slightly increased risk for bilateral renal agenesis. Therefore renal ultrasound is recommended for the first-degree relatives of the proband unless renal agenesis in the proband is clearly sporadic or a specific cause without an increased recurrence risk is identified.
Tables 6-5 and 6-6 list the syndromes commonly associated with unilateral and bilateral renal agenesis, respectively. See also Tables 6-1 – 6-3 for more information about these disorders and other less known conditions with renal agenesis.
Ectopic Kidney
The ectopic kidney derives from an error of ascent. Most are pelvic kidneys that fail to ascend out of the pelvic cavity. Rare case reports of thoracic kidney exist (15). Ectopic kidney can be unilateral or bilateral. In bilateral pelvic kidneys, the kidneys often fuse into a midline mass of renal tissue, with two pelves and a variable number of ureters, which is referred to as a pancake or discoid kidney. Fused pelvic kidney may in fact be due to fusion of ureteric buds or metanephric blastema. Crossed renal ectopia refers to an ectopic kidney whose ureter crosses the midline. It often fuses with the normal kidney. The embryogenesis of crossed renal ectopia is not well understood, but presumably involves abnormal migration of the ectopic kidney to the contralateral side. An ectopic kidney is usually hypoplastic, is rotated, and has numerous small blood vessels and associated ureteric anomalies. Ectopic kidneys may be asymptomatic and incidentally found, but complications from ureteral obstruction, infection, and calculi can occur. In a recent study, ectopic kidney without hypoplasia or hydronephrosis seems not to be associated with an appreciable increase frequency of associated anomaly and complication thus making further urologic investigation such as vesicourethrography unnecessary (16). Table 6-7 provides a list of syndromes that include ectopic kidney. These are described in Tables 6-1 – 6-3 .
Horseshoe Kidney
Horseshoe kidney refers to a condition in which both kidneys are fused at the lower poles with a renal parenchymal or, less commonly, fibrous isthmus. The embryogenesis of horseshoe kidney with parenchymal isthmus is thought to be migration of nephrogenic cells across the primitive streak before the fifth gestational week. Horseshoe kidney with fibrous isthmus is believed to originate from mechanical fusion of the two developing kidneys at or after the fifth week before renal ascent (17). The concept of a narrow vascular fork leading to approximation and fusion of the two kidneys is no longer considered valid. Most horseshoe kidneys are located in the pelvis or at the lower lumbar vertebral level because ascent is further prevented when the fused kidney reaches the junction of the aorta and inferior mesenteric artery.
Complications of horseshoe kidneys include obstructive uropathy primarily related to ureteropelvic junction obstruction, calculi and urinary tract infection. Similar to other urinary tract anomalies, a horseshoe kidney is often associated with other genitourinary anomalies. In addition, there is an increased risk of various types of renal tumors developing in the horseshoe kidney compared with the normal kidney (18). Renal cell carcinoma is the most common, but Wilms’ tumor, adenocarcinoma, transitional cell carcinoma, malignant teratoma, oncocytoma, angiomyolipoma, and carcinoid have all been reported. Horseshoe kidneys also carry an increased risk for renal pelvis carcinoma and higher proportion of squamous cell carcinoma than those in normal kidneys (19).
Table 6-8 lists syndromes associated with horseshoe kidney. See Tables 6-1 and 6-2 for more details of these disorders.
Dysplasia and Polycystic Kidney
Renal dysplasia is the most common congenital urinary tract anomaly and the most common cause of an abdominal mass in children (3). Unilateral dysplasia is reported to occur in 1:1,000, whereas the prevalence of bilateral disease is estimated to be 1:5,000 (20). It may be unilateral or bilateral, and diffuse, segmental, or focal. Symptoms are variable from silent in unilateral or focal dysplasia to progressive renal dysfunction in diffuse or bilateral dysplasia. Dysplasia refers to abnormal differentiation or organization of cells in the tissue. Renal dysplasia is characterized histologically by the presence of primitive ducts and nests of metaplastic cartilage (20, 21). Although cysts are not always present in a dysplastic kidney, the dysplastic process often results in the formation of cysts that are variable in size and number. Several hypotheses are proposed for the embryogenesis of the dysplastic kidney. The most likely pathogenesis is an error of the mutual induction between the ureteric bud and the metanephric blastema. The molecular pathogenesis of cystic kidney, especially polycystic kidney, has been one of the most extensively studied aspects of nephrology and recent studies discovered few genes and pathways critical for renal cyst formation such as TCF2/hepatocyte nuclear factor 1ss (HNF1beta), PAX2 and uroplakins. Dysplastic kidneys are usually identified as enlarged bright kidneys on prenatal ultrasonography. If there is associated functional renal impairment, alteration in amniotic fluid volume could potentially be detected and signifies a poor prognosis. (22) Unilateral dysplasia carries an overall better postnatal prognosis than that of bilateral disease. However, up to 30–50% of those with unilateral dysplasia have associated contralateral urinary anomalies (22). Multicystic renal dysplasia is the most common among many causes of renal dysplasia and it is usually unilateral. Polycystic kidney diseases, both autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms, are in general far more common than other syndromic causes of renal dysplasia. Table 6-9 summarizes well-known syndromes with renal dysplasia/cystic kidney. See also Tables 6-1 – 6-3 .
Obstruction and Hydronephrosis
Urinary obstruction is a complication of a primary anomaly, which can be stenosis or atresia of the ureteropelvic junction, ureter, or urethra; a poorly functional bladder causing reflux; a malformed dilated ureteral end (ureterocele); or extrinsic compression by other structures, such as anomalous blood vessels or tumors. Hydronephrosis and pyelectasis (dilated renal pelvis) are the most common urinary tract abnormalities on prenatal ultrasound examination. Early diagnosis of collecting system dilatation can be achieved by ultrasound examination in the second trimester (23). Persistent dilatation almost always indicates an underlying anomaly. Isolated obstructive uropathies diagnosed prenatally may not require antenatal or immediate postnatal surgical intervention. Postnatally diagnosed obstructive uropathies are almost always symptomatic and require thorough investigation to delineate the anatomy of the urinary tract and to exclude associated anomalies.
Table 6-10 provides a list of syndromes commonly associated with obstruction and hydronephrosis. See also Tables 6-1 – 6-3 .
Ureter Defects
Duplication
Double ureters or collecting systems are caused by duplication of the ureteric bud. Early duplication results in duplicated kidney, which is usually smaller and fused with the ipsilateral kidney and has ureters that enter into the bladder separately. Duplication that occurs later results in double ureters that may have separate openings into the bladder or may join each other before the opening. On rare occasion, one of the ureters may have an ectopic opening into the vagina, vestibule, or urethra. In most double ureters, the two ureters cross each other, and that from the higher pelvis enters the bladder more caudally. Duplication anomalies are common but usually asymptomatic; therefore they often remain undetected. One autopsy study reported the prevalence of duplication anomalies to be as high as 1 in 25, with females about four times more likely to be affected than males (24). Unilateral duplication is five to six times more common than bilateral duplication (3). Double ureters are commonly associated with vesico-ureteral reflux due to their ectopic opening into the urinary bladder and/or the ureterocele (23). In addition, ureteric obstruction can occur at the level of vesico-ureteric junction or that of uretero-pelvic junction.
Table 6-11 summarizes syndromes associated with duplication, and Tables 6-1 – 6-3 provide clinical information about these disorders.
Hydroureter
Hydroureter, or magaloureter, is caused by distal obstruction and is usually found with hydronephrosis, except in ureteropelvic junction obstruction. Hydroureter has the same etiology as hydronephrosis (see Obstruction and Hydronephrosis).
Bladder Defects
Anomalies of the bladder are rare. These include agenesis, hypoplasia, diverticulae, and dilatation or megacystis caused by distal obstruction or by non-obstructive causes. Agenesis of the bladder is usually associated with severe developmental anomalies of the urinary tract, such as in sirenomelia and caudal regression syndrome. Hypoplastic bladder can be found in conditions associated with bilateral renal agenesis because no urine is produced. Bladder diverticulae have heterogeneous causes. They result from an intrinsic defect in the bladder wall, such as in cutis laxa, or Ehlers-Danlos, Ochoa, occipital horn, and Williams syndromes. They can also be caused by increased intravesicular pressure from distal obstruction or by persistent urachus. See Tables 6-1 – 6-3 for information about specific syndromes associated with bladder diverticulae.
Bladder Exstrophy
Bladder exstrophy refers to a urinary bladder that is open anteriorly because of the lack of an abdominal wall closure. It is usually associated with anomalies of the contiguous structures including epispadias and separation of the pubic rami. This anomaly is thought to result from an overdeveloped cloacal membrane that interferes with inferolateral abdominal mesenchymal closure. Therefore, when the cloacal membrane ruptures, the inferior abdominal wall has not completely closed and the bladder cavity is exposed. It has been suggested that bladder exstrophy belongs to the spectrum of omphalocele-cloacal exstrophy-imperforate anus-spinal dysraphism (OEIS) complex (25–27). The extent of anomalies is determined by the timing of the cloacal membrane rupture. Rupture that occurs after the separation of cloaca by the urorectal septum results in bladder exstrophy, whereas one that occurs before the separation results in the more severe cloacal exstrophy and OEIS complex. Bladder exstrophy is six times more common in males.
Table 6-12 lists syndromes associated with bladder exstrophy, and Tables 6-1 – 6-3 provide information about these disorders.
Urethral Defects
Agenesis and Atresia
Urethral agenesis is rare, and its predominant occurrence in males probably reflects the greater complexity of embryogenesis of the male urethra. Urethral agenesis is often associated with bladder obstruction sequence. Table 6-13 lists syndromes associated with urethral agenesis, and clinical information about these disorders is summarized in Tables 6-1 – 6-3 .
Duplication
Duplication refers to complete or partial duplication of the urethra, which is a rare anomaly found only in a few syndromes. Those syndromes associated with urethral duplication are listed in Table 6-14 and their findings are provided in Tables 6-1 – 6-3 .
Posterior Urethral Valves
Posterior urethral valves refer to abnormal mucosal folds that function as a valve to obstruct urine flow. This is the most common childhood cause of obstructive uropathy leading to renal failure. Posterior urethral valves can be suspected prenatally when a dilated bladder is seen in association with obstructive uropathy. A “keyhole” sign has been demonstrated in prenatal ultrasound of fetuses with subsequently confirmed posterior urethral valves (28). A voiding cystourethrogram or endoscopy is usually required for a definitive diagnosis. The embryogenesis of posterior urethral valves is unknown. Proposed hypotheses include an overdeveloped posterior urethral fold, a remnant of the mesonephric duct, and an anomalous opening of the ejaculatory duct. Table 6-15 lists syndromes in which posterior urethral valves can be seen, and the other findings in these disorders are provided in Tables 6-1 – 6-3 .
Associations and Sequences Involving the Urinary Tract
A number of associations and sequences involve anomalies of the urinary tract that may be important to both diagnosis and management. For this reason, such conditions are described in more detail in this section, in addition to the information presented in Tables 6-1 and 6-2 .
VATER Association
VATER association is an acronym used to designate a non-random occurrence of Vertebral defects, imperforate Anus, Tracheo-Esophageal fistula, Radial and Renal anomalies (29, 30). An acronym VACTERL has been proposed to broaden the spectrum of VATER to include Cardiac defects and Limb anomalies. The term VATER is not a diagnosis per se, but the designation provides clues for potentially associated anomalies and for recurrence risk counseling when no specific syndromic diagnosis can be made. Patients with VATER association need a careful physical examination and investigation for potential multiorgan anomalies. A specific diagnosis should be sought. Causes of VATER association include: chromosomal disorders, such as trisomy 18; genetic syndromes, such as Goldenhar and Holt-Oram syndromes; and teratogenic exposures, such as infants of diabetic mothers and fetal alcohol syndrome. A family with a mitochondrial DNA mutation was identified in which the daughter was born with VACTERL association, and her mother and sister had classic mitochondrial cytopathy (31). Thus all patients suspected to have VATER association should have a chromosome analysis, a careful family and prenatal exposure history, and a thorough examination for dysmorphic features. The spectrum of anomalies seen in VATER is broad. Associated renal anomalies are usually agenesis, ectopy, or obstruction (29, 30).
Because there is apparent causal heterogeneity for VATER association, the inheritance pattern and recurrence risk vary with the cause. VATER association is usually sporadic with an empirical recurrence risk of 1 to 3% when a specific cause cannot be identified (32). Autosomal recessive and X-linked inheritance have been reported for subsets of patients, such as for VATER with hydrocephalus, and recurrence risk in these families can be as high as 25% (32).
CHARGE Syndrome (CHARGE Association)
CHARGE syndrome – previously designated as an association but now recognized to have a major causative gene- is an acronym used to designate an association of Coloboma of iris, choroid or retina, Heart defects, Atresia choanae, Retarded growth and development, Genital anomalies or hypogonadism, and Ear anomalies or deafness (33–36). In addition, unilateral facial palsy is a common finding. Renal anomalies occasionally found in CHARGE syndrome include ectopy, dysplasia, renal agenesis, and ureteric anomalies. The presence of two or more anomalies associated with CHARGE syndrome should prompt a search for the others. To prevent overuse of the term, it was suggested that at least three anomalies are required for the term CHARGE to be applied, and one of the anomalies should be either coloboma or choanal atresia (34). To date, consistent features in CHARGE syndrome have been ocular coloboma, choanal atresia and semicircular canal hypoplasia (37). Conditions with anomalies in the spectrum of CHARGE include trisomy 13, trisomy 18, and Wolf-Hirschhorn (deletion 4p), cat-eye, Treacher-Collins, velocardiofacial, Apert, Crouzon, and Saethre-Chotzen syndromes. Therefore, a careful physical examination for malformations and dysmorphic features should be conducted. Recently, CHD7 mutation has been found by an array CGH study to be the cause of this syndrome in about 60 percent of typical patients thus making a molecular confirmation possible. In those without CHD7 mutation, chromosome analysis including specific fluorescence in situ hybridization (FISH) probes for velocardiofacial syndrome (deletion 22q) and 4p deletion should be performed. Because most cases of CHARGE association are sporadic, the empirical recurrence risk in sibling is low (33, 36).
MURCS Association
MURCS association refers to a rare occurrence of Mullerian duct aplasia, Renal aplasia and Cervicothoracic Somite dysplasia (38). Anomalies include absence of the proximal two thirds of the vagina; uterine hypoplasia or aplasia; unilateral renal agenesis; ectopic kidney; renal dysplasia; C5-T1 vertebral anomalies (hypoplasia of vertebrae, fusion, hemivertebrae, and butterfly vertebrae); and short stature. Additional anomalies are common, including rib defects, facial asymmetry, limb anomalies, hearing loss, and brain anomalies, such as encephalocoele and cerebellar cyst (39).
The pathogenesis of MURCS association is unknown, but is thought to be related to defects in the paraxial mesoderm, which gives rise to the cervicothoracic somites and the adjoining intermediate mesoderm. Most patients are diagnosed because of primary amenorrhea or infertility associated with normal secondary sexual characteristics, followed by recognition of reproductive organ atresia. MURCS association is usually sporadic. A report of vertebral and renal anomalies associated with azoospermia was proposed to represent the male version of MURCS association (40).
Oligohydramnios Sequence
Oligohydramnios of whatever cause leads to a recurrent pattern of abnormalities that has been called the oligohydramnios sequence (3, 6). Oligohydramnios may be caused by decreased production of fatal urine from bilateral renal agenesis or dysplasia or by urinary obstruction, or it can result from amniotic fluid leakage. When the oligohydramnios is prolonged and severe, the condition is lethal because of pulmonary hypoplasia. Moderate oligohydramnios from amniotic fluid leakage may result in a liveborn child with multiple congenital anomalies. These anomalies are both malformations and deformations. Intrauterine constraint leads to mechanical compression that leads to the characteristic flat facial profile (Potter’s facies), limb deformities (e.g., talipes equinovarus), and intrauterine growth retardation (IUGR). Decreased fetal movement as a result of intrauterine constraint causes multiple joint contractures (arthrogryposis). Breech presentation is common. Pulmonary hypoplasia can be the consequence of compression of the chest cavity coupled with decreased inspiration of amniotic fluid. Liveborns have respiratory distress caused by pulmonary hypoplasia, and the lungs may have insufficient volume to support life.
Because the initial defect has many causes, recurrence risk is based on the underlying defect. When oligohydramnios is due to nonsyndromic bilateral renal agenesis or dysgenesis, related renal malformations occur at an increased frequency in first-degree relatives (13), and recurrence risk can be as high as 4–9%. The recurrence risk can be as high as 25% for an autosomal recessive disorder causing bilateral renal agenesis or dysplasia.
Urethral Obstruction Sequence
The initial defect in this sequence is obstruction of the urethra leading to dilation of the proximal urinary tract, bladder distension, and hydroureter (3, 6, 41). Obstruction of urine flow interferes with normal nephrogenesis, resulting in renal dysplasia. Other potential anomalies related to bladder distension include cryptorchidism, malrotation of colon, persistent urachus, and limb deficiency caused by iliac vessel compression. In addition, oligohydramnios results from lack of urine and leads to the oligohydramnios sequence.
Prune-belly syndrome (41, 42) is a rare entity referring to a constellation of anomalies that includes megacystis, abdominal wall muscle deficiency, hydroureter, renal dysplasia, and characteristic wrinkled abdominal skin. This condition, previously thought to be a form of urethral obstruction sequence, is in fact a non-obstructive cause of bladder distension that results from a malformation, thus now being properly designated a syndrome (28).
The most common cause of urethral obstruction is posterior urethral valves, but urethral agenesis/atresia or bladder neck obstruction can also be the cause. This anomaly occurs mostly in males, with a male: female ratio of 20:1. Survival is rare in fetuses with complete obstruction, and severe urinary tract dysfunctions are always present in those that are liveborn. Prenatal diagnosis by ultrasound examination can detect the abnormally dilated bladder at the beginning of the second trimester (43), and intrauterine urinary decompression procedures, such as vesicoamniotic shunts, are options for treatment in order to decrease the occurrence of pulmonary hypoplasia, although their benefits have not been unequivocally shown (44, 45).
Sirenomelia Sequence
Sirenomelia is a malformation characterized by the presence of a single lower extremity with posterior alignment of the knees and feet, sacral agenesis and other lower vertebral defects, imperforate anus and rectal agenesis, and absence of external and internal genitalia (46). The current view of the embryogenesis is that sirenomelia results from a vascular steal phenomenon (47). This is supported by the presence of abnormal vasculature in the caudal part of affected embryos. A single large vessel originating from the aorta, a derivative of the vitelline artery complex, connects the iliac arteries to the placenta rather than the two normal umbilical arteries. The area caudal to the origin of this vessel has minimal blood supply because of the lack of aortic branches. Therefore, a “vascular steal phenomenon” is generated, leading to a vascular disruption sequence. Alternatively, since sirenomelia shares a number of anomalies with caudal regression syndrome, it is thought to potentially be causally similar and represent different patterns in the same spectrum.
Sirenomelia is a rare condition and has a broad spectrum of anomalies. Virtually any urinary tract anomaly can occur in sirenomelia sequence. Renal agenesis occurs in two-thirds of cases and a variable degree of renal dysplasia is present in one-third of cases (3). Absence of the ureter and bladder are common. All cases of sirenomelia are sporadic and almost uniformly fatal because of pulmonary hypoplasia. Sirenomelia has been noted with an increased frequency among monozygotic twins in which only one of the twins in usually affected.
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Limwongse, C. (2009). Syndromes and Malformations of the Urinary Tract. In: Avner, E., Harmon, W., Niaudet, P., Yoshikawa, N. (eds) Pediatric Nephrology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-76341-3_6
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