Severe lower limb defects in exstrophy of the cloaca

INTRODUCTION

Cloacal exstrophy is characterized by the lack of closure of the lower abdominal wall. It commonly is associated with omphalocele, incompletely formed external genitalia, imperforate anus, and a skin-covered lumbosacral spina bifida (hydromyelia). Occasionally, exstrophy of the cloaca is associated with cardiac, gastrointestinal, renal and limb abnormalities, and neurologic deficiencies [Moore and Weaver, 1990].

We report here a case of typical exstrophy of the cloaca with severe and unusual lower limb anomalies. We also review the literature on limb anomalies associated with this condition and propose a hypothesis that accounts for the co-occurrence of cloacal exstrophy and limb defects.

CLINICAL REPORT

The patient (Fig. 1) was diagnosed by prenatal ultrasound to have multiple congenital anomalies. Prenatal chromosomal analysis was 46,XY with an unreported band resolution level. He was born to a G2P0Ab1 25-year-old mother at 32 weeks of gestation by Caesarian section due to preterm labor. The mother denied any recognized prenatal exposure to teratogenic compounds. The parents are unrelated. Apgar scores were 8 and 9 at 1 and 5 min, respectively. Birth weight was 1,860 g (40th centile) and occipitofrontal circumference was 30 cm (25th centile). A meaningful length could not be obtained due to the severe lower limb defects. The parents decided to raise the patient as a male.

Physical defects included omphalocele, exteriorization of the bladder and cloaca, bifid scrotum and penis, imperforate anus, pelvic deformities, hydromyelia, scoliosis, and limb anomalies. He had right oligodactyly with one section of the right foot containing two fused toes (first and second) and the other a single fifth toe (Fig. 2), left oligodactyly with attachment of the lower half of the left leg and a two-toed (first and fifth) left foot at nearly a right angle to the mid left thigh (Fig. 3) and absence of this part from the left lower leg. Radiographs in the newborn period indicated that the right fibula and tibia, while being present, were widely separated distally with the articulation of the foot predominately with the fibula (Fig. 4). The fibula was also proximately dislocated (Fig. 4). On the left side, the proximal two-thirds of the tibia and the entire fibula were missing (Fig. 5). Radiographs of both feet at 6 months showed reduced numbers of ossified bones; the right foot had nine ossified bones including the calcaneus, three metatarsals, and five poorly visualized phalanges, and the left foot had five ossified bones with the only identifiable ones being the calcaneus and a single metatarsal. The upper limbs were normal to physical exam. An echocardiogram and postnatal chromosomal analysis (band resolution—495) were also normal. At 4 months, an abdominal ultrasound indicated right hydroureteronephrosis and a slightly hypoplastic right kidney (length 4 cm; normal 4.6–7.5 cm). The left kidney and ureter were normal. Spinal radiographs showed multiple pelvic and vertebral anomalies, including a myelomeningocele, absence of the left lumbar and sacral pedicles, hypoplastic sacrum, multiple vertebral body segmentation anomalies beginning at T4 distally, dextroscoliosis, flaring of the iliac bones and abnormal appearing sacroiliac joints (Fig. 6). An Arnold–Chiari malformation was present on an MRI of the head. However, the propositus has not required a ventriculoperitoneal shunt.

Treatments of the patient have included right orchiopexy and repair of the omphalocele, bladder exstrophy, bilateral inguinal hernias, and spina bifida. At 7 months of age, the propositus had a left knee disarticulation and a Syme amputation of the right leg. Prolapse of an initial colostomy lead to resection of the colon and formation of an ileostomy. At 3 years of age, the ileostomy prolapsed as well. The patient now has been fitted with lower limb prostheses, and he can stand easily but walks with some difficulty. The walking difficulties presumably are due to his congenital pelvic deformities. He has normal cognitive development. At age 3, his height is less than the 5th centile (91 cm), measured with prosthetics, and his weight is at the 10th centile (12.25 kg) without prosthetics.

DISCUSSION

We present a patient with classic exstrophy of the cloaca complicated by severe leg anomalies. The limb anomalies include split foot and lower leg defects on the right, attachment of the lower half of the left leg and foot at the left mid thigh, and bilateral oligodactyly of the foot. Although cognitively normal, the patient has poor lower limb coordination while using his prosthetics, although he can stand and walk with these appliances.

Lower limb defects have been stated to occur commonly in patients with exstrophy of the cloaca [Moore and Weaver, 1990]. To determine the accuracy of this statement, we reviewed the literature on exstrophy of the cloaca for lower limb defects. Of 178 reviewed cases, including the one we presented here, 63 reportedly had normal lower limbs [Hurwitz et al., 1987; Meglin et al., 1990; Evans et al., 1994; Chen et al., 1997; Liang et al., 1998; Mathews et al., 1998; Hamada et al., 1999; Keppler-Noreuil, 2001; Reddy et al., 2003], 43 gave no information about the status of the lower limbs [Hayden et al., 1973; Diamond and Jeffs, 1985; Fujiyoshi et al., 1987; McLaughlin et al., 1995; Meizner et al., 1995; Pinette et al., 1996; Kano and Ichimura, 1997; Austin et al., 1998; Nye et al., 2000], 17 had clubfeet with no further status of the lower limb given [Diamond and Jeffs, 1985; Zarabi and Rupani, 1986; Fujiyoshi et al., 1987; McLaughlin et al., 1995; Robin et al., 1996; Bruch et al., 1996; Pinette et al., 1996; Girz et al., 1998; Silver et al., 1999], 24 had clubfeet as the only lower limb anomaly [Hurwitz et al., 1987; Meglin et al., 1990; Chen et al., 1997; Liang et al., 1998; Mathews et al., 1998; Keppler-Noreuil, 2001], and 31 had major malformations of the lower limbs [Ogden, 1976; Balog and Skinner, 1984; Hurwitz et al., 1987; Meglin et al., 1990; Pfeiffer et al., 1990; Evans et al., 1994; Chen et al., 1997; Liang et al., 1998; Mathews et al., 1998; Evans and Chudley, 1999; Keppler-Noreuil, 2001; Shanske et al., 2003]. If one assumes that no information given about lower limb status indicates normal lower limbs and that the clubfoot deformities were secondary to the associated meningomyeloceles and/or intrauterine positioning, then the frequency of lower limb deformities would be 31/178 (17%). However, if one discards the cases where lower limb status was not given, the frequency would be 31/118 (26%).

A subset of patients reported with exstrophy of the cloaca and lower limb defects have had either amelia or hypoplasia of the legs. Mathews et al. [1998] reported 11 cases of lower limb defects associated with cloacal exstrophy, and stated that there was an absence or shortening of limbs. One of these patients had a club foot and split lower leg on the left and attachment of the distal leg and foot to the mid thigh, a similar pattern to the patient reported here. These authors gave no further details about the limb defects on the 10 other patients. Evans et al. [1994] reported six cases of whom four had hypoplasia and two had amelia of a lower limb. One of these patients had transverse defects. Meglin et al. [1990] and Keppler-Noreuil [2001] each reported a single case of a hypoplastic/dysplastic lower extremity. Hurwitz et al. [1987] reported four cases. Two of these children had lower limb agenesis and two were minimally described as having severe deformity of the leg and foot. A second subset of exstrophy patients have had transverse limb defects. Chen et al. [1997] described a case of cloacal exstrophy, hypoplastic femur, and agenesis of the right tibia, fibula, and foot. Liang et al. [1998] reported a case of exstrophy of the cloaca with external rotation of both legs, right leg agenesis with rudimentary tibia and fibula, and right absent foot. Shanske et al. [2003] report a case where a left two-digit foot is attached to the left thigh and there is complete absence of the lower leg. A third subset of exstrophy patients has been reported with duplication of the femur and tibial hemimelia. For instance, Balog and Skinner [1984] described a patient with cloacal exstrophy, unilateral complete duplication of the femur, and tibial hemimelia. Ogden [1976], and Evans and Chudley [1999] each described a patient with duplicated distal femur and absent tibia in conjunction with exstrophy of the cloaca. Pfeiffer et al. [1990] reported a patient with femoral and fibular duplication in a single leg with a single tibia. These reports indicate that unilateral tibial hemimelia is a common finding in those with cloacal exstrophy and severe lower limb defects.

The estimated frequency of limb defects in patients with exstrophy of the cloaca is likely higher than the actual values of lower limb defects in this condition because of bias in publication of severe limb defects. Even so, it appears that limb malformations occur in association with exstrophy of the cloaca at a relatively low rate, but when present tend to be severe.

Mesodermal deficiency in the caudal region of the developing embryo is generally thought to cause exstrophy of the cloaca and associated problems [Pauli, 1994]. Since the internal structures of limbs are mostly formed from mesoderm, we postulate that the limb deficiencies reported in the patient here and in other patients with exstrophy of the cloaca are also caused by mesodermal deficiency and that the etiology of the mesodermal deficiency in both is the same. These polytopic set of birth defects suggest an error during blastogenesis resulting in multiple mesoderm anomalies [Martinez-Frias et al., 1998]. Mutations in distal HOX genes, specifically HOX10, HOX11, HOX12, and HOX13, are hypothesized to be involved in a subset of cloacal exstrophy cases associated with femoral duplication and tibial hemimelia [Evans and Chudley, 1999]. However, it is also possible that inappropriate expression of mesodermal differentiation signals, such as FGF-8 and BMP-4, or environmental factors [Shum et al., 2003] could be the cause of lower limb dysmorphology in patients with exstrophy of the cloaca.

We recommend that in further case reporting of cloacal exstrophy that the status of lower limbs be noted and any malformations present be characterized fully. Doing so may aid our understanding of the pathogenesis of cloacal exstrophy/limb defects, and lead to a more accurate frequency of their association.