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Isolated imperforate anus in monozygotic twins: case report and implications
Journal of Pediatric Surgery (2005) 40, E1 – E4
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Isolated imperforate anus in monozygotic twins: case report and implications Rainer Kubiak*, Vipul Upadhyay Department of Paediatric Surgery, University Children’s Hospital Basel, CH-4005 Basel, Switzerland Index words: Anorectal malformation; Anal anomalies; Monozygotic twins; Imperforate anus
Abstract The authors report a case of isolated imperforate anus with perineal fistula in monozygotic twins. Only 4 other well-documented cases of monozygotic twins concordant for isolated anorectal malformation have been reported in the literature. In all these cases the defect occurred below the levator ani muscle. This case confirms previous reports on the incidence of low anorectal anomalies in monozygotic twins where the defect was isolated. A review of the literature relating to this condition in twins and siblings points toward low anomalies and more severe malformations having different genetic backgrounds. D 2005 Elsevier Inc. All rights reserved.
The incidence of anorectal malformation (ARM) has been variously reported as being from 1 in 2500 to 1 in 5000 live birth [1-3]. Isolated ARM occurs in approximately one third of all cases. Of those, in most cases, the rectal anomaly is located below the level of the levator ani muscle [1,2]. The few reported cases of familial isolated ARM suggest various patterns of inheritance [1,3-9]. We report a case of monozygotic twins concordant for isolate imperforate anus with perineal fistula.
1. Case report Male twins were born at 36 weeks to a 33-year-old, gravida II, para I woman by elective cesarean delivery. Birth weights were 2660 and 2450 g, respectively. Twin B presented in a breech position and that was noted on multiple otherwise normal prenatal ultrasound scans be* Corresponding author. Tel.: +41 0 61 6856565; fax: +41 0 61 6855011. E-mail address: [email protected] (R. Kubiak). 1531-5037/05/4003-0032$30.00/0 D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2004.11.002
tween 23 and 34 weeks’ gestation. The pregnancy was uneventful and there was no family history of congenital malformation. The placenta showed 2 layers of amnion without intervening chorion, corresponding with monochorionic diamniotic placentation. Apgar scores were 9/10 and 10/10 at 1 and 5 minutes, respectively. On physical examination, both of the newborns presented with imperforate anus with perineal fistula but no other obvious anomalies. At 30 minutes, both infants developed mild respiratory distress syndrome and were transferred to the neonatal intensive care unit for observation, but did not require any supplementary oxygen or continuous positive airway pressure. Echocardiography was normal apart from a small, hemodynamically irrelevant ventricular septum defect in twin A. Seven hours post birth the twins remained clinically stable and were admitted to our unit for further investigations. Spinal x-rays showed no vertebral anomalies and the sacral ratio [10] was within normal limits. Renal and spinal ultrasound scans were normal. Both chest x-rays of
E2
Fig. 1 Postoperative appearance of monozygotic twins concordant for imperforate anus with perineal fistula.
the infants showed a slight rather unspecific obscuration of the pulmonary vascular markings, but were otherwise normal. After 24 hours, invertograms were performed. This showed that in both infants the air-filled rectal pouch was well below the pubococcygeal line confirming the appearance of a low form of ARM. At that time, meconium was detected at the perineum discharging from the perineal fistulae. The twins underwent Y-V anoplasty [11] on day 2. At the end of the operation, each anus took Hegar 11 dilators easily (Fig. 1). The postoperative course was uneventful and the twins were discharged on day 13, weighing 2.7 kg each. When last seen at follow-up at 2 months of age the twins were gaining weight and defecation was normal.
2. Discussion Anorectal malformation is a complex condition, which can be subdivided into a high, intermediate, and low form according to the level of termination of the rectum or anal canal in relation to the levator ani muscle [12]. For an alternative classification accentuating anatomy and functional outcome, see Pena [10]. From a genetic point of view, ARM can be divided into 2 main groups: ARM as part of a definite syndrome or in association with other anomalies, and isolated ARM [5]. Considerable effort has gone toward understanding the abnormal process that produces ARM, yet, to date, neither normal nor abnormal development of the hindgut and cloacal is fully understood [13]. There is debate whether isolated ARM is of different origin to those associated with other anomalies [2]. As this case involved an isolated ARM a literature review was performed to establish if this condition is more commonly found in twins or siblings. The first reported case of anorectal anomalies in siblings dates back to 1885 when Hadra described 2 cousins with banus vestibularisQ [14]. Each of these index cases had a sibling who died shortly after birth because of an apparently more severe form of ARM. Apart from the
R. Kubiak, V. Upadhyay difficulty in obtaining the original paper in the above case, some reports on familial ARM are often not precise enough to compare accurately. Norris et al [15] reported on 52 cases with anorectal anomalies. In their study, a pair of sisters with similar anomalies is mentioned, although it is not clear whether the reported abnormalities occurred in isolated form or in association with other problems. Furthermore, although the authors used the classification according to Ladd and Gross [16], the exact type of anomaly could not be deduced accurately. Weinstein [8] reported on brothers with imperforated anus in 3 families and suggested a sex-linked recessive pattern for this anomaly. Similarly to the above case [15] the level of anomaly was not described. Because of the classification uncertainty, both reports [8,15] have not been included in the review described below. The literature, including this case, identifies 19 families with 2 or more siblings (n = 41) having isolated ARM [1,3,4,6,7,9,14,17-20] (Table 1). Of the patients, 22 were males and 17 were females. According to the Wingspread classification [12] there were 26 low and 15 intermediate or high ARM. Although in column 2 of Table 1 most cases show the same anomaly, there are siblings with phenotypically different types of ARM. In approximately one third of the cases (n = 8) (Table 1) there were other unaffected siblings in the family. In 10 cases other family members suffered from anorectal anomalies of which in 9 instances one affected person belonged to another generation. Various forms of inheritance were proposed: autosomal dominant [1,3,5,6], autosomal recessive [4,7,9], and x-linked [4,8]. Schwoebel et al [3] suggested that if ARM occurs as an isolated malformation, possibly combined with minor additional malformations of the hands, feet and/or ears, it mostly follows the multifactorial mode of inheritance. Multifactorial means influenced by more than one gene (polygenic) and modified through (intra- and extrauterine) environmental factors [3]. The frequency for atresia or stenosis of the large intestine and anus has been reported to be higher in twins [21,22]. The concordance rate for early malformations in monozygotic twins lies between 10% and 20% [22]. There are also reports on affected twins, including conjoined twins, with isolated ARM [2,22], although it is not always clear whether one or both twins were affected. In 1969, Tu¨nte [23] reported a series of 18 twins and siblings with anal atresia. Apart from 2 cases, the ARM described was either discordant or associated with other anomalies ranging from major (eg, sirenomelia) to minor (eg, partial duplication of the thumb). Of the 2 cases identified above, Feggetter [19] reported on monozygotic male twins with isolated anal stenosis (see Table 1). Another case reported by Tu¨nte [23], supported by only limited clinical details, describes the occurrence of isolate imperforate anus in twins. Because of the unclear circumstances, this instance has been disregarded in this study.
Isolated imperforate anus in monozygotic twins: case report and implications Table 1
E3
Isolated ARM in siblings
Authors
Sex/classification of ARMa
Relationship
ARM in other family members/generations
Feggetter [19] Seitz and Bautze [14] Cochran [18] Kaijser and Malmstrfm-Groth [20] VanGelder and Kloepfer [7]
Monozygotic twins Sisters Brothers Sistersd Siblings
No Yes (mother) No Yes (mother) No
Manny et al [6] Schwoebel et al [3]
M/AS (L)-M/AS (L) F/anterior perineal anus (L)-F/anterior perineal anus (L) M/IA (I)-M/IA (I)b F/IA + rectovaginal fistulac (I)-F/IA + anocutaneous fistula (L) M/IA + anocutaneous fistula (L)-M/IA + rectourethral fistula (H)-F/IA + rectovaginal fistulac (I)-F/IA + rectovaginal fistulac (I) M/AS (L)-M/AS (L) F/AS (L)-F/AS (L) M/AS (L)-F/AS (L) M/AS (L)-M/AS (L) M/AS (L)-M/RAe (H) M-M-M/RAe (H) F/IA + rectovaginal fistulac (I)-F/IA + rectovaginal fistulac (I) F/anterior perineal anus (L)-F/anterior perineal anus (L) Mf/IA + rectovesical fistula (H)-M/RA (H) M/anorectal stenosis (I)-Fg/IA + anocutaneous fistula (L)
Monozygotic twins Monozygotic twins Siblings Brothers Brothersd Brothersd Sistersd Sistersd Brothersd Siblingsd
Boocock and Donnai [1] Christensen et al [17] Current study
M/AS (L)-F/anterior perineal anus (L) M/AS (L)-M/AS (L) F/IA (L)e-F/IA (L)e M/IA + anocutaneous fistula (L)-M/IA + anocutaneous fistula (L)
Siblingsd Half brothers (paternal) Monozygotic twins Monozygotic twins
No Yes ? (maternal aunt) Yes (aunt, cousin) Yes (aunt, cousins) Yes (aunt, cousins) Yes (niece) No No Yes (father) Yes (uncle ?, cousin, second cousin) Yes (mother) No No No
Cozzi and Wilkinson [4]
Winkler and Weinstein [9]
M indicates male; F, female; AS, anal stenosis; IA, imperforated anus; RA, rectal atresia; L, low; I, intermediate; and H, high. a According to Wingspread classification [12]. b Originally classified as type III according to Ladd and Gross [16]. c Report suggests rectovestibular rather than rectovaginal fistula. d Other unaffected siblings in the family. e Malformation not specified. f Bifid scrotum noted in this patient. g Hemi-os-coccygeum noted in this patient.
To the best of our knowledge, the present case is the fifth clearly reported case of monozygotic twins concordant for isolated ARM. Of these 5 instances of twin pairs (3 male twins, 2 female twins), all presented with a low anomaly (see Table 1). Apart from one case where a maternal aunt of 2 female twins may have been similarly affected [4], all twins had no other affected siblings or family members. There are reports of monozygotic twins concordant for ARM associated with other anomalies, for example, the omphalocele-exstrophy-imperforated anus-spinal defects complex [24]. Apart from one pair of twins concordant for cloacal extrophy [25], we are not aware of any cases reporting concordance of monozygotic twins for an isolated high form of ARM. The epidemiology of isolated anal anomalies was described by Cuschieri et al [2]. Of 4.6 million birth recorded in 33 Eurocat registries, there were 1846 cases of anal anomalies, of which 672 (36%) were isolated. This report [2] highlighted the fact that the morphologic subdivision comprises supralevator and infralevator anal atresia, with and without fistula, ectopic anus, congenital anal fistula and persistence of the cloacal, and that each was epidemiologically distinct. Furthermore, the report [2] suggested that the differences in epidemiologic characteristics between the different types of anal atresia could indicate that anal atresia is heterogeneous in its pathogenesis and etiology.
The small number of cases available notwithstanding, isolated ARM appears to occur more often in the group of low anomalies where associated defects are less common. There are several contributing factors that might explain this occurrence, namely, artifactual and genetic. Artifactual differences could be due to problems in accurate identification, description, and coding of type of anal anomaly [2]. An example of the former is provided by Levi [26], whose ultrasonic assessment revealed a significant number of singleton births that had previously (before 10 weeks’ gestation) been diagnosed as twins. The connection between genetics and the occurrence of ARM has been documented. The nature of the underlying clinical processes that give rise to conditions of greater or lesser severity is as yet not fully understood. Martı´nez-Frı´as et al [27] used the developmental field theory to differentiate between the etiology of isolated ARM and those associated with other anomalies. According to this theory, the entire embryo during blastogenesis is the primary field that reacts in an integrated and organized manner [28]. In contrast to multiple, midline defects (eg, VACTERL association, caudal dysgenesis sequence), isolated anal anomalies may arise because of developmental disturbance occurring during formation of the progenitor fields or during the later stages of blastogenesis. Such a disturbance during late blastogenesis may produce a milder monotopic defect, resulting in a single anomaly possibly
E4 because of the buffering capacity of the embryo during early development [27]. Our review, particularly the 5 cases of monozygotic twins, draws together genetic causation in relation to isolated low forms of ARM. An additional insight into the possible genetic causation of ARM is firmly established through the association of Down’s syndrome and imperforate anus without fistula [29]. The clinical condition of Down’s syndrome and the patients in this study is different except generally patients present with low anomalies. This lends a measure of support to the view that in both groups the anomaly was caused by a bhitQ at the same stage of embryogenesis. Clearly, genetic implications in this disease need further clarification. Further reports on detailed cases of familial ARM will help to explain the exact pattern of inheritance in different types of anomalies. There is also a need for further critical studies to delineate the etiology of different types of anal anomalies. We hope to further this cause by contributing our cases to the literature.
References [1] Boocock GR, Donnai D. Anorectal malformation: familial aspects and associated anomalies. Arch Dis Child 1987;62:576 - 9. [2] Cuschieri A, EUROCAT Working Group. Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million birth in Europe. Am J Med Genet 2001;103:207 - 15. [3] Schwoebel MG, Hirsig J, Schinzel A, et al. Familial incidence of congenital anorectal anomalies. J Pediatr Surg 1984;19:179 - 82. [4] Cozzi F, Wilkinson AW. Familial incidence of congenital anorectal anomalies. Surgery 1968;64:669 - 71. [5] Landau D, Mordechai J, Karplus M, et al. Inheritance of familial congenital isolated anorectal malformations: case report and review. Am J Med Genet 1997;71:280 - 2. [6] Manny J, Schiller M, Horner R, et al. Congenital familial anorectal anomaly. Am J Surg 1973;125:639 - 40. [7] VanGelder DW, Kloepfer HW. Familial anorectal anomalies. Pediatrics 1961;27:334 - 6. [8] Weinstein ED. Sex-linked imperforated anus. Pediatrics 1965;35: 715 - 8.
R. Kubiak, V. Upadhyay [9] Winkler JM, Weinstein ED. Imperforated anus and heredity. J Pediatr Surg 1970;5:555 - 8. [10] Pena A. Anorectal malformations. Semin Pediatr Surg 1995;4:35 - 7. [11] Paidas CN, Pena A. Rectum and anus. In: Oldham KT, Colombani RP, Foglia RP, editors. Surgery of infants and children, chap 83. Philadelphia (Pa)7 Lippincott-Raven; 1997. p. 1323 - 62. [12] Kiely EM, Pena A. Anorectal malformations. In: O’Neill Jr JA, Rowe MI, Grosfeld JL, et al, editors. Pediatric Surgery, chap 95, 5th ed. St. Louis (Mo)7 Mosby; 1998. p. 1425 - 48. [13] Qi BQ, Beasley SW, Frizelle FA. Clarification of the processes that lead to anorectal malformations in the ETU-induced rat model of imperforated anus. J Pediatr Surg 2002;37:1305 - 12. [14] Seitz A, Bautze HJ. Famili7rer anus vestibularis. Zentralbl Gynaecol 1951;73:1543 - 5. [15] Norris WJ, Brophy III TW, Brayton D. Imperforated anus. Surg Gynecol Obstet 1949;88:623 - 34. [16] Ladd WE, Gross RE. Abdominal surgery in infancy and childhood. Philadelphia7 WB Saunders Co; 1941. p. 166 - 87. [17] Christensen K, Madsen CM, Hauge M, et al. An epidemiological study of congenital anorectal malformations: 15 Danish birth cohorts followed for 7 years. Paediatr Perinat Epidemiol 1990;4: 269 - 75. [18] Cochran JL. Imperforate anus in brothers. Am J Dis Child 1955;89:350. [19] Feggetter S. Imperforated anus in identical twins. Newcastle Med J 1939;19:20 - 1. [20] Kaijser K, Malmstrfm-Groth A. Ano-rectal abnormalities as a congenital familial incidence. Acta Paediatr 1957;46:199 - 200. [21] Doyle PE, Beral V, Botting B, et al. Congenital malformations in twins in England and Wales. J Epidemiol Community Health 1990;45:43 - 8. [22] Schinzel AA, Smith DW, Miller JR. Monozygotic twinning and structural defects. J Pediatr 1979;95:921 - 30. [23] Tqnte W. Anal atresia in twins. Z Kinderheilk 1969;106:21 - 32. [24] Lee DH, Cottrell JR, Sanders RC, et al. OEIS complex (omphaloceleexstrophy-imperforated anus-spinal defects) in monozygotic twins. Am J Med Genet 1999;84:29 - 33. [25] Redman JF, Seibert JJ, Page BC. Cloacal extrophy in identical twins. Urology 1981;17:73 - 4. [26] Levi S. Ultrasonic assessment of the high rate of human multiple pregnancy in the first trimester. J Clin Ultrasound 1976;4:3 - 5. [27] Martı´nez-Frı´as ML, Frı´as JL, Opitz JM. Errors of morphogenesis and developmental field theory. Am J Med Genet 1998;76:291 - 6. [28] Opitz JM. The developmental field concept in clinical genetics. J Pediatr 1982;101:805 - 9. [29] Torres R, Levitt MA, Tovilla JM, et al. Anorectal malformations and Down’s syndrome. J Pediatr Surg 1998;33:194 - 7.
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Isolated imperforate anus in monozygotic twins: case report and implications Rainer Kubiak*, Vipul Upadhyay Department of Paediatric Surgery, University Children’s Hospital Basel, CH-4005 Basel, Switzerland Index words: Anorectal malformation; Anal anomalies; Monozygotic twins; Imperforate anus
Abstract The authors report a case of isolated imperforate anus with perineal fistula in monozygotic twins. Only 4 other well-documented cases of monozygotic twins concordant for isolated anorectal malformation have been reported in the literature. In all these cases the defect occurred below the levator ani muscle. This case confirms previous reports on the incidence of low anorectal anomalies in monozygotic twins where the defect was isolated. A review of the literature relating to this condition in twins and siblings points toward low anomalies and more severe malformations having different genetic backgrounds. D 2005 Elsevier Inc. All rights reserved.
The incidence of anorectal malformation (ARM) has been variously reported as being from 1 in 2500 to 1 in 5000 live birth [1-3]. Isolated ARM occurs in approximately one third of all cases. Of those, in most cases, the rectal anomaly is located below the level of the levator ani muscle [1,2]. The few reported cases of familial isolated ARM suggest various patterns of inheritance [1,3-9]. We report a case of monozygotic twins concordant for isolate imperforate anus with perineal fistula.
1. Case report Male twins were born at 36 weeks to a 33-year-old, gravida II, para I woman by elective cesarean delivery. Birth weights were 2660 and 2450 g, respectively. Twin B presented in a breech position and that was noted on multiple otherwise normal prenatal ultrasound scans be* Corresponding author. Tel.: +41 0 61 6856565; fax: +41 0 61 6855011. E-mail address: [email protected] (R. Kubiak). 1531-5037/05/4003-0032$30.00/0 D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2004.11.002
tween 23 and 34 weeks’ gestation. The pregnancy was uneventful and there was no family history of congenital malformation. The placenta showed 2 layers of amnion without intervening chorion, corresponding with monochorionic diamniotic placentation. Apgar scores were 9/10 and 10/10 at 1 and 5 minutes, respectively. On physical examination, both of the newborns presented with imperforate anus with perineal fistula but no other obvious anomalies. At 30 minutes, both infants developed mild respiratory distress syndrome and were transferred to the neonatal intensive care unit for observation, but did not require any supplementary oxygen or continuous positive airway pressure. Echocardiography was normal apart from a small, hemodynamically irrelevant ventricular septum defect in twin A. Seven hours post birth the twins remained clinically stable and were admitted to our unit for further investigations. Spinal x-rays showed no vertebral anomalies and the sacral ratio [10] was within normal limits. Renal and spinal ultrasound scans were normal. Both chest x-rays of
E2
Fig. 1 Postoperative appearance of monozygotic twins concordant for imperforate anus with perineal fistula.
the infants showed a slight rather unspecific obscuration of the pulmonary vascular markings, but were otherwise normal. After 24 hours, invertograms were performed. This showed that in both infants the air-filled rectal pouch was well below the pubococcygeal line confirming the appearance of a low form of ARM. At that time, meconium was detected at the perineum discharging from the perineal fistulae. The twins underwent Y-V anoplasty [11] on day 2. At the end of the operation, each anus took Hegar 11 dilators easily (Fig. 1). The postoperative course was uneventful and the twins were discharged on day 13, weighing 2.7 kg each. When last seen at follow-up at 2 months of age the twins were gaining weight and defecation was normal.
2. Discussion Anorectal malformation is a complex condition, which can be subdivided into a high, intermediate, and low form according to the level of termination of the rectum or anal canal in relation to the levator ani muscle [12]. For an alternative classification accentuating anatomy and functional outcome, see Pena [10]. From a genetic point of view, ARM can be divided into 2 main groups: ARM as part of a definite syndrome or in association with other anomalies, and isolated ARM [5]. Considerable effort has gone toward understanding the abnormal process that produces ARM, yet, to date, neither normal nor abnormal development of the hindgut and cloacal is fully understood [13]. There is debate whether isolated ARM is of different origin to those associated with other anomalies [2]. As this case involved an isolated ARM a literature review was performed to establish if this condition is more commonly found in twins or siblings. The first reported case of anorectal anomalies in siblings dates back to 1885 when Hadra described 2 cousins with banus vestibularisQ [14]. Each of these index cases had a sibling who died shortly after birth because of an apparently more severe form of ARM. Apart from the
R. Kubiak, V. Upadhyay difficulty in obtaining the original paper in the above case, some reports on familial ARM are often not precise enough to compare accurately. Norris et al [15] reported on 52 cases with anorectal anomalies. In their study, a pair of sisters with similar anomalies is mentioned, although it is not clear whether the reported abnormalities occurred in isolated form or in association with other problems. Furthermore, although the authors used the classification according to Ladd and Gross [16], the exact type of anomaly could not be deduced accurately. Weinstein [8] reported on brothers with imperforated anus in 3 families and suggested a sex-linked recessive pattern for this anomaly. Similarly to the above case [15] the level of anomaly was not described. Because of the classification uncertainty, both reports [8,15] have not been included in the review described below. The literature, including this case, identifies 19 families with 2 or more siblings (n = 41) having isolated ARM [1,3,4,6,7,9,14,17-20] (Table 1). Of the patients, 22 were males and 17 were females. According to the Wingspread classification [12] there were 26 low and 15 intermediate or high ARM. Although in column 2 of Table 1 most cases show the same anomaly, there are siblings with phenotypically different types of ARM. In approximately one third of the cases (n = 8) (Table 1) there were other unaffected siblings in the family. In 10 cases other family members suffered from anorectal anomalies of which in 9 instances one affected person belonged to another generation. Various forms of inheritance were proposed: autosomal dominant [1,3,5,6], autosomal recessive [4,7,9], and x-linked [4,8]. Schwoebel et al [3] suggested that if ARM occurs as an isolated malformation, possibly combined with minor additional malformations of the hands, feet and/or ears, it mostly follows the multifactorial mode of inheritance. Multifactorial means influenced by more than one gene (polygenic) and modified through (intra- and extrauterine) environmental factors [3]. The frequency for atresia or stenosis of the large intestine and anus has been reported to be higher in twins [21,22]. The concordance rate for early malformations in monozygotic twins lies between 10% and 20% [22]. There are also reports on affected twins, including conjoined twins, with isolated ARM [2,22], although it is not always clear whether one or both twins were affected. In 1969, Tu¨nte [23] reported a series of 18 twins and siblings with anal atresia. Apart from 2 cases, the ARM described was either discordant or associated with other anomalies ranging from major (eg, sirenomelia) to minor (eg, partial duplication of the thumb). Of the 2 cases identified above, Feggetter [19] reported on monozygotic male twins with isolated anal stenosis (see Table 1). Another case reported by Tu¨nte [23], supported by only limited clinical details, describes the occurrence of isolate imperforate anus in twins. Because of the unclear circumstances, this instance has been disregarded in this study.
Isolated imperforate anus in monozygotic twins: case report and implications Table 1
E3
Isolated ARM in siblings
Authors
Sex/classification of ARMa
Relationship
ARM in other family members/generations
Feggetter [19] Seitz and Bautze [14] Cochran [18] Kaijser and Malmstrfm-Groth [20] VanGelder and Kloepfer [7]
Monozygotic twins Sisters Brothers Sistersd Siblings
No Yes (mother) No Yes (mother) No
Manny et al [6] Schwoebel et al [3]
M/AS (L)-M/AS (L) F/anterior perineal anus (L)-F/anterior perineal anus (L) M/IA (I)-M/IA (I)b F/IA + rectovaginal fistulac (I)-F/IA + anocutaneous fistula (L) M/IA + anocutaneous fistula (L)-M/IA + rectourethral fistula (H)-F/IA + rectovaginal fistulac (I)-F/IA + rectovaginal fistulac (I) M/AS (L)-M/AS (L) F/AS (L)-F/AS (L) M/AS (L)-F/AS (L) M/AS (L)-M/AS (L) M/AS (L)-M/RAe (H) M-M-M/RAe (H) F/IA + rectovaginal fistulac (I)-F/IA + rectovaginal fistulac (I) F/anterior perineal anus (L)-F/anterior perineal anus (L) Mf/IA + rectovesical fistula (H)-M/RA (H) M/anorectal stenosis (I)-Fg/IA + anocutaneous fistula (L)
Monozygotic twins Monozygotic twins Siblings Brothers Brothersd Brothersd Sistersd Sistersd Brothersd Siblingsd
Boocock and Donnai [1] Christensen et al [17] Current study
M/AS (L)-F/anterior perineal anus (L) M/AS (L)-M/AS (L) F/IA (L)e-F/IA (L)e M/IA + anocutaneous fistula (L)-M/IA + anocutaneous fistula (L)
Siblingsd Half brothers (paternal) Monozygotic twins Monozygotic twins
No Yes ? (maternal aunt) Yes (aunt, cousin) Yes (aunt, cousins) Yes (aunt, cousins) Yes (niece) No No Yes (father) Yes (uncle ?, cousin, second cousin) Yes (mother) No No No
Cozzi and Wilkinson [4]
Winkler and Weinstein [9]
M indicates male; F, female; AS, anal stenosis; IA, imperforated anus; RA, rectal atresia; L, low; I, intermediate; and H, high. a According to Wingspread classification [12]. b Originally classified as type III according to Ladd and Gross [16]. c Report suggests rectovestibular rather than rectovaginal fistula. d Other unaffected siblings in the family. e Malformation not specified. f Bifid scrotum noted in this patient. g Hemi-os-coccygeum noted in this patient.
To the best of our knowledge, the present case is the fifth clearly reported case of monozygotic twins concordant for isolated ARM. Of these 5 instances of twin pairs (3 male twins, 2 female twins), all presented with a low anomaly (see Table 1). Apart from one case where a maternal aunt of 2 female twins may have been similarly affected [4], all twins had no other affected siblings or family members. There are reports of monozygotic twins concordant for ARM associated with other anomalies, for example, the omphalocele-exstrophy-imperforated anus-spinal defects complex [24]. Apart from one pair of twins concordant for cloacal extrophy [25], we are not aware of any cases reporting concordance of monozygotic twins for an isolated high form of ARM. The epidemiology of isolated anal anomalies was described by Cuschieri et al [2]. Of 4.6 million birth recorded in 33 Eurocat registries, there were 1846 cases of anal anomalies, of which 672 (36%) were isolated. This report [2] highlighted the fact that the morphologic subdivision comprises supralevator and infralevator anal atresia, with and without fistula, ectopic anus, congenital anal fistula and persistence of the cloacal, and that each was epidemiologically distinct. Furthermore, the report [2] suggested that the differences in epidemiologic characteristics between the different types of anal atresia could indicate that anal atresia is heterogeneous in its pathogenesis and etiology.
The small number of cases available notwithstanding, isolated ARM appears to occur more often in the group of low anomalies where associated defects are less common. There are several contributing factors that might explain this occurrence, namely, artifactual and genetic. Artifactual differences could be due to problems in accurate identification, description, and coding of type of anal anomaly [2]. An example of the former is provided by Levi [26], whose ultrasonic assessment revealed a significant number of singleton births that had previously (before 10 weeks’ gestation) been diagnosed as twins. The connection between genetics and the occurrence of ARM has been documented. The nature of the underlying clinical processes that give rise to conditions of greater or lesser severity is as yet not fully understood. Martı´nez-Frı´as et al [27] used the developmental field theory to differentiate between the etiology of isolated ARM and those associated with other anomalies. According to this theory, the entire embryo during blastogenesis is the primary field that reacts in an integrated and organized manner [28]. In contrast to multiple, midline defects (eg, VACTERL association, caudal dysgenesis sequence), isolated anal anomalies may arise because of developmental disturbance occurring during formation of the progenitor fields or during the later stages of blastogenesis. Such a disturbance during late blastogenesis may produce a milder monotopic defect, resulting in a single anomaly possibly
E4 because of the buffering capacity of the embryo during early development [27]. Our review, particularly the 5 cases of monozygotic twins, draws together genetic causation in relation to isolated low forms of ARM. An additional insight into the possible genetic causation of ARM is firmly established through the association of Down’s syndrome and imperforate anus without fistula [29]. The clinical condition of Down’s syndrome and the patients in this study is different except generally patients present with low anomalies. This lends a measure of support to the view that in both groups the anomaly was caused by a bhitQ at the same stage of embryogenesis. Clearly, genetic implications in this disease need further clarification. Further reports on detailed cases of familial ARM will help to explain the exact pattern of inheritance in different types of anomalies. There is also a need for further critical studies to delineate the etiology of different types of anal anomalies. We hope to further this cause by contributing our cases to the literature.
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