Available online at www.sciencedirect.com
Annals of Diagnostic Pathology 12 (2008) 62 – 66
Cloacal dysgenesis sequence Archana Bargaje, MDa,4, John F. Yerger, MDb,1, Adib Khouzami, MDc,2, Carolyn Jones, MD, PhD, FAAP, FAAMGd,3 a
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA b Department of Pathology, Johnstown, PA 15905, USA c Department of Obstetrics and Gynecology, Johnstown, PA 15905, USA d Pediatrics, Pediatric Genetics, Pathology, Loyola University Medical Center, Maywood, IL 60153, USA
Abstract
Cloacal dysgenesis sequence is a rare congenital malformation seen in 1:50 000 to 250 000 neonates. It shows a phallus-like structure, smooth perineum, and absence of urethral, vaginal, and anal openings as primary malformations. We report a case of a 4-day-old preterm female neonate. The prenatal ultrasound showed singleton fetus in breech presentation with echogenic bowel, dilated colon, perineal mass, dilated bladder, and fetal hydrops. The complete autopsy revealed smooth perineum without patent urethral, vaginal, and anal openings, and enlarged wrinkled clitoral-like structure. Other anomalies included renal hydronephrosis, hydroureter, megacolon, and urethral agenesis. The chromosomal analysis showed normal female karyotype. These findings are consistent with cloacal dysgenesis sequence, and it results from the defect in cloaca formation during the first 50 days of gestation. It is usually fatal and should be differentiated from other conditions having better prognosis such as fetal obstructive uropathies and persistent cloaca. D 2008 Elsevier Inc. All rights reserved.
Keywords:
Cloaca; Dysgenesis sequence
1. Introduction
2. Material and methods
Cloacal dysgenesis sequence (CDS) is a rare congenital malformation. It is seen in 1:50 000 to 250 000 neonates [1]. Cloaca is a Latin word and it means sewer. The sequence is defined as a pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor [2]. Cloacal dysgenesis sequence is characterized by a phallus-like structure, smooth perineum, and absence of urethral, vaginal, and anal openings as primary malformations. It is usually associated with abnormalities in other organ systems such as vertebral, pulmonary, and genitourinary tract. There are numerous theories regarding embryogenesis and associated pathology. Hence, these cases are reported in the literature under different terminologies. We present a case report of a single case and we will review the literature and discuss differential diagnosis.
A complete autopsy was performed on a 4 -day-old preterm female neonate born at 29 weeks 6 days. The prenatal ultrasound results and chromosomal analysis results were reviewed. The literature review on similar cases was performed.
4 Corresponding author. Tel.: +1 773 572 8200; fax: +1 708 327 2620. E-mail addresses:
[email protected] (A. Bargaje)8
[email protected] (A. Khouzami)8
[email protected] (C. Jones). 1 Tel.: +1 814 534 9822; fax: +1 814 534 9372. 2
Tel.: +1 814 534 9230; fax: +1 814 534 9465.
3
Tel.: +1 708 327 9085; fax: +1 708 327 9132.
1092-9134/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2006.08.003
2.1. Case report The 4 -day-old female neonate was born preterm (29 weeks 6 days) by caesarian section to a 20-year-old gravida 2, para 1 mother. After delivery, the baby was cyanotic with no respiratory effort and decreased heart rate. She was intubated and responded well with improved color and heart rate. Eventually, her condition deteriorated and the patient died after 3 days. The ultrasound performed at 16 weeks of gestation showed singleton fetus in breech presentation with echogenic bowel, dilated colon, and minimal abdominal ascites. There was a cystic mass arising from the perineum between the lower extremities. The genitalia were not seen (Fig. 1). The 16.6 weeks’ ultrasound showed echogenic kidneys, decreased amniotic fluid, and cloacal anomaly.
A. Bargaje et al. / Annals of Diagnostic Pathology 12 (2008) 62 – 66
63
Table 1 Final anatomic diagnoses Organ system
Findings
Fetal
Hydrops fetalis Oligohydramnios Premature female newborn (weight, 2230 g) Renal hydronephrosis Hydroureter Urethral agenesis Ovaries present Anorectal atresia Partial colon atresia Imperforate anus Megacolon Absent vaginal opening Smooth perineum Clitoral-like structure Hyaline membrane disease Pulmonary atelectasis Pulmonary edema and hemorrhage
Genitourinary tract
Gastrointestinal
External genitalia
Respiratory
The 20.3 weeks’ ultrasound showed cloacal anomaly, oligohydramnios (amniotic fluid index [AFI] = 4 cm), hepatomegaly, megacystis, fluid in the uterine cavity, and dilated echogenic bowel (Fig. 2). The amniocentesis showed normal female karyotype. Cytomegalovirus, parvovirus, and Toxoplasma (IgG and IgM), in addition to cystic fibrosis carrier tests, were negative. The patient was counseled about the poor prognosis and the likelihood of pulmonary hypoplasia. She wanted to continue the pregnancy. The 27.7 weeks’ ultrasound showed worsening of the ascites and thin membranous septations in the fetal abdominal cavity suggestive of adhesions. The rectum and bladder were dilated (Fig. 2). The placenta was thickened (8.57 cm); there was pleural effusion and scalp edema consistent with fetal hydrops. A calcification was present in the lower abdomen, which may be due to the exposure of meconium to urine. A small thorax (chest circumference, 18 cm, 25th percentile) was seen. The middle cerebral artery peak velocity was 72 cm/s, consistent with fetal anemia. There was anhydramnios, and the fetus was in the breech presentation. The patient was admitted to labor and
Fig. 1. Antenatal ultrasound at 16 weeks of gestation showing soft tissue mass in clitoral region.
Fig. 2. Antenatal ultrasound at 20.3 weeks showing uterus (U), urinary bladder (B), and colon (C).
delivery. The result of the Kleihauer-Betke test was negative. She was in labor. The cervix changed to 2 cm. She wanted everything done to optimize the outcome of the pregnancy. Cesarean was performed for breech presentation. A baby girl was delivered from the complete breech presentation. Apgar scores were 4 and 8, and umbilical artery pH was 7.33. The chest x-ray of the neonate showed ground glass opacification consistent with respiratory distress syndrome of a newborn. 3. Results The complete autopsy was performed. On gross examination, the female infant weighed 2230 g and measured 37.5 cm in length from head to heel. The ears were low-set. The genitalia were grossly abnormal. The perineum was smooth without patent urethral, vaginal, and anal openings. The external genitalia were ambiguous, with an enlarged wrinkled clitoral-like structure. No labia majora and minora were identified (Fig. 3). The peritoneal cavity showed 40 mL of serosanguinous free fluid. The small intestine showed multiple fibrinous adhesions. The lumen of the large intestine showed meconium-stained fecal material. The
Fig. 3. Autopsy of a 4-day-old female neonate showing imperforate anus and perineal swelling.
64
A. Bargaje et al. / Annals of Diagnostic Pathology 12 (2008) 62 – 66
terminal portion of the colon was dilated and ended blindly on the anterior structure in the pelvic cavity. No normal urogenital structures were identified. There were 2 saccular structures in the pelvic cavity. The anterior structure showed 2 dilated stenosed ureters and a fibrotic terminal portion of the colon (Fig. 4). The posterior wall of the anterior structure showed tan-gray oval structures. The posterior structure was thick walled with the lumen. No definitive ovaries and fallopian tubes were identified on gross examination. The combined weight of the kidneys was 11 g (normal, 12.3 F 8.5 g). On section, the cortices and medullae were thin and well demarcated. The renal calyces were severely dilated. The ureters were dilated and the ureteral openings in the bladder wall were partially stenotic (Table 1). On microscopy, the anterior structure was lined mostly by a nonkeratinized squamous epithelium, an endometrium, and a transitional-like epithelium in focal sites (Fig. 5). The supporting stroma showed collections of ganglion cells and nerve fibers. A section from the blindly ending colonic structure showed glandular colonic mucosa. Section from posterior structure showed transitional mucosa and hypertrophied smooth muscle wall. Sections from oval structure on the posterior wall of the anterior sac showed fallopian tube and numerous primordial follicles in the stroma consistent with the ovary. The perineal swelling was lined by squamous epithelium with underlying fibrous stroma. 4. Discussion It is important to review embryology to understand the pathogenesis of CDS. The genitourinary system develops mostly from intraembryonic mesoderm and ectoderm (cloacal membrane) [3]. The intraembryonic mesoderm is formed by the third to fourth week, consisting of 3 divisions — paraxial, intermediate, and lateral plate. The primitive hindgut (endoderm) lying adjacent to the cloacal membrane forms an expanded structure called cloaca. The cloaca is divided into anterior primitive urogenital sinus and posterior anorectal canal by growing urorectal septum
Fig. 4. Dissection of pelvic organs showing 2 pelvic structures and partially stenosed ureters.
Fig. 5. Anterior pelvic structure showing squamous epithelium, transitional epithelium, and endometrial lining (hematoxylin and eosin, medium power).
(mesoderm) in 4 to 6 weeks. The urorectal septum fuses with cloacal membrane giving rise to an anterior urogenital membrane and a posterior anal membrane. These 2 membranes rupture in the seventh week to form the external urogenital sinus and the anus. The point of fusion between the urorectal septum and the cloacal membrane becomes the perineum. In males, the primitive urogenital sinus develops into the bladder, the pelvic urethra, and the penile urethra. In females, it develops into the bladder, the membranous urethra, and the vestibule of vagina. Thus, any insult during the seventh week will result into CDS. Cloacal dysgenesis sequence is one of the many causes of stillbirth and immediate neonatal death. The most common causes of death in these cases are pulmonary hypoplasia and renal failure. In some cases of CDS associated with normal lung and kidney development, infants can survive [4-6]. In the literature where babies have survived, all had urinary outlet in the form of patent urachus or perforated bladder. Cloacal dysgenesis sequence can be diagnosed prenatally by ultrasound. Ultrasound findings include megacystis, oligohydramnios, perineal mass, hydronephrotic, or dysplastic kidney. Some cases show intracolonic calcifications due to calcified meconium [6,7]. The calcified meconium is seen because of the presence of communication between urinary and gastrointestinal tract. This finding is seen in different types of cloacal malformations [8]. Initially, it was thought that CDS is only seen in female patients, but later, it was also described in male patients [9]. It is associated with normal karyotype in most cases described in the literature, including our case. The first report of female fetus with isochromosome 18q associated with CDS and other anomalies was published in 1998 [10]. The 2 pelvic structures were lined by different epithelia, namely, squamous, transitional, and endometrial, suggesting improper development of bladder and uterus. Hence, on microscopy, these structures could not be identified definitively, although they look like bladder and uterus on
A. Bargaje et al. / Annals of Diagnostic Pathology 12 (2008) 62 – 66
ultrasound and on gross examination. These histopathologic findings were not described in the literature before. Robinson and Tross [11] studied 5 infants with absent anal, genital, and urinary orifices, and attributed these cases to agenesis of cloacal membrane. They found out 7 reported cases with identical changes in publications over the last 54 years from 1926 to 1980. They categorized systemic findings in 3 types—primary malformations of genitourinary system, fetal malformations due to external compression, and anomalies involving other systems of uncertain relationships. They also evaluated genetic and teratogenic factors and concluded that embryological exposure to doxylamine succinate was certain within the first 50 days of the pregnancy in 3 cases and was probable in 2 cases. Gardner and Nelson [12] reported 2 newborns with genital malformations and vertebral anomalies, who died on the third day after delivery. They proposed that an aberrant migration of axial mesoderm in caudal region resulted in these anomalies. They also proposed a presence of bcloacal dysgenesis spectrumQ with associated defects at the clinical level. They speculated from a mouse model of mesodermal dysplasia that abnormality in cell surface molecule might cause these caudal malformations. Our case did not show any vertebral anomaly or limb deformities. Escobar et al [5] studied 6 female infants with ambiguous genitalia, lack of perineal opening, lack of anal opening, and mqllerian and urinary tract anomalies. They also compared their cases with 11 cases described in the literature. Seven of 11 cases had cystovaginorectal fistula. Our case did not have any fistula, which explains the presence of dilated bladder. In the same study, 94% patients showed one of the mqllerian tract anomalies, such as agenesis or malformation of uterus and/or vagina. They proposed the term urorectal septum malformation sequence (URSMS) because they believe that these anomalies result because of a failure of migration and/or fusion of the urorectal septum with the cloacal membrane. This in turn causes persistence of the cloaca and cloacal membrane and failure of normal differentiation of external genitalia with absent perineal openings. They suggest that the URSMS is a recognizable pattern of dysmorphogenesis, which falls under cloacal dysgenesis spectrum as mentioned by Gardner and Nelson. Pauli [9] studied 17 infants of both sexes with similar genitourinary anomalies as in our case in addition to axial skeletal system anomalies. He proposed it as blower mesodermal defects sequenceQ because all these structures arise from lower mesoderm. We think that CDS is a distinct entity that can be included under an umbrella of lower mesodermal defect sequence. Wheeler et al [13] suggested that external genitalia abnormalities result because of failure to breakdown urogenital and anal membranes in the seventh week of gestation. It is important to differentiate CDS from other treatable conditions such as the fetal obstructive uropathies (FOUs) and persistent cloaca. Qureshi et al [14] reviewed 8 autopsy cases over an 11-year period for CDS and focused on
65
prenatal diagnosis on ultrasound to differentiate these cases from other FOUs. Intraluminal calcifications in the colon with abnormalities of external genitalia were fairly definitive evidence of CDS. The phallic enlargement was not seen on the ultrasound examination in their cases in contrast to our case. They suggested that prenatal diagnosis of CDS is important to differentiate from other FOUs because some FOUs are amenable to intrauterine surgical procedures, whereas CDS is not. Thus, CDS can be differentiated from other FOUs by the presence of abnormal phallic structure and colonic calcifications. The persistent cloaca or classic cloacal anomaly is an anomaly with a single urogenital sinus and must be considered under a differential diagnosis. There is a single perineal opening. The bladder terminates into the sinus anteriorly, the rectum posteriorly, and the vagina commonly 1 on each side [15]. The basic defect is due to failure of complete descent of urorectal septum. The urethra is absent or drains into urogenital sinus or is normal. The bladder drains into the anal canal or vagina or it is normal. The major complication is either incontinence of urine because of incompetent urethral sphincter mechanism or overflow incontinence associated with neurogenic bladder. The vagina and uterus are single or duplex and drain either into urogenital sinus or into the bladder. The external genitalia show phallic-like structure or are normal. The initial surgical treatment includes decompressive techniques such as colostomy or vaginostomy followed by planned reconstructive surgery. Thus, it is important to differentiate persistent cloacal anomaly from CDS because the latter is usually fatal. To conclude, CDS is a rare congenital malformation. It is seen in 1:50 000 to 250 000 neonates. It is characterized by a phallus-like structure, smooth perineum, and absence of urethral, vaginal, and anal openings as primary malformations. It is usually associated with abnormalities in other organ systems such as vertebral, pulmonary, and genitourinary tract. This abnormality results from the defect in cloaca formation during the first 50 days of gestation. It is usually fatal and it should be differentiated from other conditions with better prognosis such as FOUs and persistent cloaca. Ultrasound examination is an important prenatal diagnostic tool showing phallic enlargement and intracolonic calcifications.
References [1] Escobar LF, Weaver DD, Bixler D, Hodes ME, Mitchell M. Urorectal septum malformation sequence: report of six cases and embryological analysis. Am J Dis Child 1987;141:1021 - 4. [2] Spranger J, Bernirschke K, Hall JG, et al. Errors of morphogenesis: concepts and terms. J Pediatrics 1982;100:160 - 5. [3] Larsen WJ. The third week. Human embryology. New York (NY)7 Churchill Livingstone; 2001. p. 55 - 8. [4] Liang X, Ioffe OB, Sun CC. Cloacal dysgenesis sequence: observations in four patients including three fetuses of second trimester gestation. Pediatr Dev Pathol 1987;7(4):457 - 66.
66
A. Bargaje et al. / Annals of Diagnostic Pathology 12 (2008) 62 – 66
[5] Escobar LF, Weaver DD, Bixler D, et al. Urorectal septum malformation sequence. Report of six cases and embryological analysis. Am J Dis Child 1987;141(9):1021 - 4. [6] Sahinoglu Z, Mulayim B, Ozden S. The prenatal diagnosis of cloacal dysgenesis sequence in six cases: can the termination of pregnancy always be the first choice? Prenat Diagn 2004;24:10 - 6. [7] Kramer RL, Johnson MP, Qureshi F. Concordance for cloacal dysgenesis. Fetal Diagn Ther 1997;12(5):279 - 82. [8] Chaubal N, Dighe M, Shah M, et al. Calcified meconium: an important sign in the prenatal sonographic diagnosis of cloacal malformation. J Ultrasound Med 2003;22(7):727 - 30. [9] Pauli RM. Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 1994;50:154 - 72. [10] Chen CP, Chern SR, Lee CC, Town DD. Isochromosome 18q in a fetus with congenital megacystis, intra-uterine growth retarda-
[11] [12]
[13]
[14] [15]
tion and cloacal dysgenesis sequence. Prenat Diagn 1998;18(10): 1068 - 74. Robinson HB, Tross K. Agenesis of cloacal membrane. Perspect Pediatr Pathol 1984;1:79 - 96. Gardner RJM, Nelson MM. An association of caudal malformations arising from a defect in the daxial mesodermT developmental field. Am J Med Genet 1986;(suppl 2):37 - 44. Wheeler PG, Weaver DD, Obeime MO, et al. Urorectal septum malformation sequence. Report of thirteen additional cases and review of the literature. Am J Med Genet 1997;73:456 - 62. Qureshi F, Jacques SM, Yaron Y, et al. Prenatal diagnosis of cloacal dysgenesis sequence. Fetal Diagn Ther 1998;13(2):69 - 74. Allen TD, Hunsmann DA. Cloacal anomalies and other urorectal septal defects in female patients: a spectrum of anatomical abnormalities. J Urol 1991;145:1034 - 9.
