Pediatr Surg Int DOI 10.1007/s00383-014-3529-3
ORIGINAL ARTICLE
Congenital anomalies of the kidney and urinary tract (CAKUT) associated with Hirschsprung’s disease: a systematic review Alejandro D. Hofmann • Johannes W. Duess Prem Puri
•
Accepted: 18 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Congenital anomalies of the kidney and urinary tract (CAKUT), a term introduced in the late 1990s accounts for 30–50 % of cases of end-stage renal disease in children. The association of urogenital anomalies and Hirschsprung’s disease (HSCR) based on the common genetic background of enteric nervous system and human urinary tract development has been well described in the literature. However, the reported prevalence of HSCR associated with CAKUT seems to be underestimated. The aim of this systematic review was to determine the prevalence of this association and show its relationship to other syndromes. Methods A systematic literature search was conducted for relevant articles published between 1955 and 2014. Two online databases were searched for the terms ‘‘Hirschsprung’s disease’’, ‘‘congenital anomalies of the kidney and urinary tract’’, ‘‘urogenital anomalies’’ and ‘‘urological anomalies’’. All published studies containing adequate clinical data were included. Resulting publications were reviewed for epidemiology, genetic testing, operative treatment and morbidity. Reference lists were screened for additional cases. Results A total of 32 articles reported 222 cases of HSCR associated with either CAKUT, ‘‘urological’’ or
A. D. Hofmann J. W. Duess P. Puri (&) National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland e-mail: [email protected] J. W. Duess P. Puri School of Medicine and Medical Science and Conway Institute of Biomedical Research, University College Dublin, Dublin, Ireland
‘‘urogenital’’ anomalies from 1955 to 2014. Gender was reported in a total of 68 cases, with 54 (79 %) males and 14 (21 %) females. Extent of aganglionosis was reported in 67 cases and included classical rectosigmoid disease in 38, long-segment aganglionosis in 12, total colonic aganglionosis in 12 and total intestinal aganglionosis in 5 patients. 18 articles reported 204 cases of either CAKUT, ‘‘urological’’ or ‘‘urogenital’’ anomalies in a case series of 5.693 HSCR patients, resulting in an overall prevalence of 3.6 % of this association. Within this collective of 18 studies only seven were, regardless of the date of publication compatible with CAKUT criteria introduced and published in the late 1990s. These seven studies reported a total of 72 patients with associated CAKUT among 757 HSCR patients resulting in a prevalence of 9.5 %. After introduction of the CAKUT acronym, only three studies specifically investigated the association of HSCR and CAKUT stating a prevalence of 14.3 % resulting in an almost fivefold increase compared to the reported prevalence of HSCR and associated urological and urogenital anomalies. The remaining 14 publications reported 18 single cases of HSCR patients with associated CAKUT phenotypes. Of these 18 cases, 11 (61 %) cases were associated with other syndromes or syndromatic features or reported chromosomal anomalies. Conclusion This review confirms that the recognition of CAKUT in HSCR patients has been underestimated in the past. The results suggest that when confronted with HSCR in a patient, a thorough urological investigation may be indicated. The high prevalence of associated syndromes in HSCR with CAKUT may further suggest a syndromic association. Keywords Hirschsprungs’s disease CAKUT Congenital urological anomalies
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Introduction Hirschsprung’ disease (HSCR) is a congenital malformation of the hindgut occurring in 1/5,000 live births which is characterised by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses [1]. Based on a common genetic background of the enteric nervous system and kidney development, the association of congenital urological anomalies and HSCR has been well described in the literature [2–4]. First evidence that linked these two morbidities was the discovery that mice with deletions of Rearranged after Transfection (RET) [5] or glial cell line-derived neurotrophic factor (GDNF) [6] genes had abnormalities in enteric innervation and renal morphogenesis. This RET–GDNF signalling pathway has not only been linked to the pathogenesis of HSCR, but is also known to be responsible for the fusion of the ureteric bud and metanephric blastema playing a crucial role in the correct development of the kidney and urinary tract [7–9]. In the late 1990s, uncertainty in the clinical classification of congenital urological anomalies and the growing awareness of long-term effects of chronic kidney disease resulted in the summary of different clinical entities under the popular single-label acronym CAKUT (congenital anomalies of the kidney and urinary tract). CAKUT is a major cause of morbidity and collectively accounts for 30–50 % of cases of end-stage renal disease (ESRD) in children and young adults [10–13]. Resembling an aggregation of different clinical entities, the literature has included morbidities such as renal agenesis, renal dysplasia, multicystic kidney disease (MCKD), hydronephrosis, ureteropelvic junction obstruction (UPJO), vesicoureteral reflux (VUR), duplex collecting system, megaureter, posterior urethral valves (PUV) and horseshoe kidney. The reported prevalence of HSCR associated with CAKUT appears to be underestimated [4]. Moore et al. reviewed more than 4800 HSCR patients from 18 separate series and described an overall incidence of 6.05 % of genitourinary anomalies [14]. This overall incidence was comprised of CAKUT compatible diagnoses as well as a broad spectrum of genitourinary anomalies, such as hypospadias, undescended testis and disorders of bladder function. Similar incidences for urogenital anomalies were also reported by two other studies reviewing a total of 462 HSCR patients [7, 15]. A more recent prospective study, however, screened their HSCR patients specifically for the presence of CAKUT and revealed a surprisingly high prevalence of 25 % of associated CAKUT with HSCR. They concluded that HSCR patients have a 3- to 18-fold higher risk of having associated CAKUT than the normal population and suggested a thorough urological workup when confronted with a new diagnosis of HSCR [16].
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The aim of this systematic review was to determine the prevalence of CAKUT phenotypes in a population of HSCR patients and show its relationship to other syndromes.
Materials and methods A systematic search of the literature was performed to identify articles that reported cases of HSCR associated with CAKUT or urological anomalies. Two common electronic databases, Pubmed and the Cochrane Library were searched in March 2014 using a combination of the following terms: ‘‘Hirschsprung’’’ or ‘‘congenital megacolon’’ and ‘‘CAKUT’’ or ‘‘urological anomalies’’ or ‘‘urogenital anomalies’’. Reference lists of identified articles were screened for additional publications of interest. Retrospective as well as prospective studies and single case reports published between 1955 and 2014 matching the search terms were eligible for inclusion. All identified articles were independently assessed by each of the three authors. Series referring to results of already selected cohorts were excluded. The current study included following 10 abnormalities that had previously been published as CAKUT phenotypes: renal agenesis, renal dysplasia, multicystic kidney disease, ureteropelvic junction obstruction, hydronephrosis, vesicoureteral reflux, nonobstructed, nonrefluxing primary megaureter, duplex collecting system, posterior urethral valves and horseshoe kidney. The extracted data consisting of study-related characteristics (author names, study design, study period, cohort size) and patientrelated characteristics (male-to-female ratio, associated syndromes, types of HSCR, procedure type for correction of HSCR, additional comorbidities) were extracted into an electronic datasheet in a standardised manner. There were no language restrictions.
Results A total of 32 articles reported 222 cases of HSCR associated with either CAKUT, urological or urogenital anomalies from 1955 to 2014. The male-to-female ratio was 3.8:1. Gender was reported in total of 68 cases, with 54 (79 %) males and 14 (21 %) females. Extent of aganglionosis was reported in 67 cases and included classical rectosigmoid disease in 38, long-segment aganglionosis in 12, total colonic aganglionosis in 12 and total intestinal aganglionosis in five patients. Eighteen articles reported 204 cases of either CAKUT, urological or ‘‘urogenital’’ anomalies in a case series of
Pediatr Surg Int Table 1 Definition of CAKUT and classification of data analysis
Clinical entities
Classification of data analysis Urological or urogenital anomalies 11 studies n = 132 [14, 15, 17, 18, 20, 21, 26, 27, 29–31]
1
Renal agenesis
2
Renal dysplasia
3
Hydronephrosis
4
VUR
5
Duplex collecting system
6
Horseshoe kidney
7
PUV
8
Megaureter
9
UPJO
10
MCKD
11
Megacystis
12
Hypospadia
13
Cryptorchism
14
Inguinal hernia
15 16
Rotational kidney anomaly Ectopic kidney
17
Bladder diverticulum
18
Urethral diverticulum
19
Ureteropelvic duplication
20
Recto-urethral fistula
21
Vaginal atresia
5.693 HSCR patients, resulting in an overall prevalence of 3.6 % of this association [2, 4, 14, 15–30]. Eleven [14, 15, 17, 18, 20, 21, 26, 27, 29–31] of theses 18 studies consisted of a mix of 132 cases of urological, urogenital and CAKUT phenotypes among 4,936 HSCR patients (Table 1). The remaining seven studies [2, 4, 16, 19, 23–25] were, regardless of date of publication, compatible with the CAKUT criteria published by Pope et al. [13] and reported a total of 72 patients with associated CAKUT among 757 HSCR patients (Table 1). This resulted in a prevalence of 9.5 % stating that 1 in 10.5 HSCR patients has an associated CAKUT. Five patients had two or more coexisting CAKUT. In these seven studies, a total of 73 anomalies were identified comprising the following CAKUT phenotypes: 32 renal dysplasia, 17 hydronephrosis, 15 VUR, five duplex collecting systems, two posterior urethral valves, one horseshoe kidney and one renal agenesis. After introduction of the CAKUT acronym in the late 1990s, only three studies [4, 7, 16] specifically investigated the association of HSCR and CAKUT. In this collective review of 350 patients with HSCR, 50 cases of associated CAKUT were identified giving a prevalence of 14.3 % suggesting that one in seven HSCR patients has an associated CAKUT. The remaining 14 publications reported 18 single case reports of HSCR patients with associated CAKUT phenotypes [32–45]. There was a clear male preponderance with
CAKUT 7 studies n = 72 [2, 4, 16, 19, 23–25]
a male-to-female ratio of 10:1 in the reported single cases. Extent of aganglionosis was stated in 13 of the 17 reported cases: 4 cases of total intestinal aganglionosis, classical rectosigmoid disease, long-segment aganglionosis and total colonic aganglionosis were reported each in 3 cases. CAKUT phenotypes were reported in all 18 patients and consisted of: 7 renal agenesis, 6 renal dysplasia, 4 VUR, 1 hydronephrosis and 1 horseshoe kidney. Two patients had two coexisting CAKUT (renal agenesis and VUR). Associated syndromes, syndromatic features or chromosomal anomalies were reported in 11 patients (61 %) of the reported 18 single cases. The most common syndrome encountered was the IFAP/BRESHEK syndrome, which was seen in 6 patients, followed by Bardet–Biedel syndrome in 1 patient. Dysmorphic features and chromosomal anomalies were reported in 4 cases.
Discussion The association of urological anomalies in HSCR has been well described in the literature. Especially before the introduction of the term CAKUT in the late 1990s urological comorbidities associated with HSCR were reported in a very heterogeneous manner [13, 14, 18, 28, 31, 46]. Our systematic review identified up to 20 reported clinical entities summarised as urological or urogenital anomalies
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associated with HSCR in studies published before the introduction of CAKUT (Table 1). Many of these studies were limited by small sample size of the populations studied or attention was mainly focused on major malformations that required surgical repair, not on detailed dysmorphic description of HSCR patients [19]. It was not until the introduction of the CAKUT acronym that the focus shifted towards long-term outcome of chronic kidney disease of affected patients. Although CAKUT may be used for a general classification it does not represent a classified clinical entity. The popular acronym CAKUT results from an uncertainty in clinical classification and resembles an aggregation of different genetic, anatomical and clinical entities making it difficult to use from an epidemiological perspective [16, 47]. In the 18 studies investigated, the total number of CAKUT and urological cases was 204 giving an overall prevalence of 3.6 %. The CAKUT criteria were compatible in 125 of the cases, whereas 79 cases were summarised as urological or urogenital cases. Regardless of date of publication, seven studies exclusively met the CAKUT criteria suggested by Pope et al. [13] (Table 1). The prevalence of CAKUT in these seven studies that solely reported CAKUT phenotypes associated with HSCR was 9.5 %, stating that one in ten HSCR patients has an associated CAKUT anomaly. Although the CAKUT acronym was established in the late 1990s, only three studies published after 1999 specifically investigated the association of HSCR and CAKUT. These three studies identified 50 cases of associated CAKUT among a collective of 350 HSCR patients resulting in an almost fivefold increase in prevalence of 14.2 % compared to the overall prevalence in our study [4, 7, 16]. The two most recent studies published by Prato et al. were the first prospective studies investigating the association of HSCR and CAKUT reporting an even higher prevalence of 24–25 % (Table 1). These two studies not only suggest an underestimation of this association in the literature, but also support the concept of a novel syndromic association between the two conditions [4, 16]. The concept of a syndromic association between HSCR and CAKUT is not new, since it was already suggested by various authors [2, 14, 15]. Regarding the common genetic background and the fact that a high percentage (61 %) of the reported single cases were associated with syndromes, syndromic features or chromosomal anomalies strengthen the hypothesis of a syndromic association. The four to sixfold increase in prevalence of CAKUT in HSCR patients in the Prato studies compared with previous reports in the literature [7, 14, 33] most probably originated from the prospective nature of the studies although the authors included only six of the ten CAKUT phenotypes we identified in our systematic review and that are reported in the literature [13]. Although we identified up to 20 different clinical entities (Table 1) in studies published before the introduction of
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the CAKUT acronym, reported prevalence of urological or urogenital anomalies associated with HSCR was only between 2 and 7.3 % [2, 14, 15]. An explanation for underestimation of prevalence in these studies in the past may have been because of heterogeneous inclusion and diagnostic criteria or that certain CAKUT variants remain asymptomatic for years, being discovered as unexpected incidental findings [16]. Another reason for the heterogeneity of the reported prevalence may be the lack of a homogeneous classification of CAKUT [47]. This makes it difficult to separate the different subphenotypes of congenital anomalies and perform comparative studies. As the literature lacks prospective studies investigating the rare association of HSCR and CAKUT, it would be favourable to implement further prospective multicentre research projects. This shortage of prospective studies is also one of the limitations of this systematic review and larger case series of patients might strengthen the results of the two existing prospective studies and their suggested implementation of prevention strategies and timely adequate rehabilitation treatments [4, 16].
Conclusion The review confirms that the recognition of CAKUT in HSCR patients has been underestimated in the past. Although the term CAKUT can be useful for a general classification, it may not be useful from an epidemiological perspective and lacks a homogeneous classification. The results suggest that when confronted with HSCR in a patient, a thorough urological investigation may be indicated. The high prevalence of associated anomalies in HSCR with CAKUT may further suggest a syndromic association.
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30. Suita S, Taguchi T, Ieiri S, Nakatsuji T (2005) Hirschsprung’s disease in Japan: analysis of 3852 patients based on a nationwide survey in 30 years. J Pediatr Surg 40:197–201. doi:10.1016/j. jpedsurg.2004.09.052 (discussion 201-2) 31. Ikeda K, Goto S (1986) Additional anomalies in Hirschsprung’s disease: an analysis based on the nationwide survey in Japan. Zeitschrift fu¨r Kinderchirurgie 41:279–281 32. Sampson MG, Coughlin CR II, Kaplan P et al (2010) Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease. Am J Med Genet 152A:2618–2622. doi:10.1002/ajmg.a.33628 33. Sinnassamy P, Yazbeck S, Brochu P, O’Regan S (1986) Renal anomalies and agenesis associated with total intestinal aganglionosis. Int J Pediatr Nephrol 7:1–2 34. Virdi VS, Cheema AS (2003) Neonatal Hirschsprung disease with multicystic dysplastic kidneys presenting as multiple gastrointestinal perforations. Trop Gastroenterol 24:99–101 35. Cherian MP, Al-Sanna’a NA (2009) Clinical spectrum of BardetBiedl syndrome among four Saudi Arabian families. Clin Dysmorphol 18:188–194 36. de Maeyer VMDS, Kestelyn PAFA, Shah AD et al (2013) Extraskeletal osteosarcoma of the orbit: A clinicopathologic case report and review of literature. Indian J Ophthalmol [Epub ahead of print] 37. Hurst JA, Markiewicz M, Kumar D, Brett EM (1988) Unknown syndrome: Hirschsprung’s disease, microcephaly, and iris coloboma: a new syndrome of defective neuronal migration. J Med Genet 25:494–497. doi:10.1136/jmg.25.7.494 38. Naiki M, Mizuno S, Yamada K et al (2011) MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet 158A:97–102. doi:10.1002/ajmg.a.34373 39. Santos H, Mateus J, Leal MJ (1988) Hirschsprung disease associated with polydactyly, unilateral renal agenesis, hypertelorism, and congenital deafness: a new autosomal recessive syndrome. J Med Genet 25:204–205 40. Martino F, D’Eufemia P, Pergola MS et al (1992) Child with manifestations of dermotrichic syndrome and ichthyosis follicularis–alopecia–photophobia (IFAP) syndrome. Am J Med Genet 44:233–236. doi:10.1002/ajmg.1320440222 41. Oeffner F, Fischer G, Happle R et al (2009) IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet 84:459–467. doi:10.1016/j.ajhg.2009. 03.014 42. Lore´ F, Talidis F, Di Cairano G, Renieri A (2001) Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations. J Intern Med 250:37–42 43. Winkelman J (1967) Coexistent megacolon and megaureter. Report of a case with normal vesical autonomic innervation. Pediatrics 39:258–262 ´ gueda S, Monteiro G et al (2013) Expanding the 44. Corujeira S, A phenotype of IFAP/BRESECK syndrome: A new case with severe hypogammaglobulinemia. Eur J Med Genet 56:603–605. doi:10.1016/j.ejmg.2013.09.005 45. Reish O, Gorlin RJ, Hordinsky M et al (1997) Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome? Am J Med Genet 68:386–390 46. Moore SW, Rode H, Millar AJ et al (1991) Familial aspects of Hirschsprung’s disease. Eur J Pediatr Surg 1:97–101. doi:10. 1055/s-2008-1042468 47. Sanna-Cherchi S, Ravani P, Corbani V et al (2009) Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int 76:528–533. doi:10.1038/ki.2009.220
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ORIGINAL ARTICLE
Congenital anomalies of the kidney and urinary tract (CAKUT) associated with Hirschsprung’s disease: a systematic review Alejandro D. Hofmann • Johannes W. Duess Prem Puri
•
Accepted: 18 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Congenital anomalies of the kidney and urinary tract (CAKUT), a term introduced in the late 1990s accounts for 30–50 % of cases of end-stage renal disease in children. The association of urogenital anomalies and Hirschsprung’s disease (HSCR) based on the common genetic background of enteric nervous system and human urinary tract development has been well described in the literature. However, the reported prevalence of HSCR associated with CAKUT seems to be underestimated. The aim of this systematic review was to determine the prevalence of this association and show its relationship to other syndromes. Methods A systematic literature search was conducted for relevant articles published between 1955 and 2014. Two online databases were searched for the terms ‘‘Hirschsprung’s disease’’, ‘‘congenital anomalies of the kidney and urinary tract’’, ‘‘urogenital anomalies’’ and ‘‘urological anomalies’’. All published studies containing adequate clinical data were included. Resulting publications were reviewed for epidemiology, genetic testing, operative treatment and morbidity. Reference lists were screened for additional cases. Results A total of 32 articles reported 222 cases of HSCR associated with either CAKUT, ‘‘urological’’ or
A. D. Hofmann J. W. Duess P. Puri (&) National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland e-mail: [email protected] J. W. Duess P. Puri School of Medicine and Medical Science and Conway Institute of Biomedical Research, University College Dublin, Dublin, Ireland
‘‘urogenital’’ anomalies from 1955 to 2014. Gender was reported in a total of 68 cases, with 54 (79 %) males and 14 (21 %) females. Extent of aganglionosis was reported in 67 cases and included classical rectosigmoid disease in 38, long-segment aganglionosis in 12, total colonic aganglionosis in 12 and total intestinal aganglionosis in 5 patients. 18 articles reported 204 cases of either CAKUT, ‘‘urological’’ or ‘‘urogenital’’ anomalies in a case series of 5.693 HSCR patients, resulting in an overall prevalence of 3.6 % of this association. Within this collective of 18 studies only seven were, regardless of the date of publication compatible with CAKUT criteria introduced and published in the late 1990s. These seven studies reported a total of 72 patients with associated CAKUT among 757 HSCR patients resulting in a prevalence of 9.5 %. After introduction of the CAKUT acronym, only three studies specifically investigated the association of HSCR and CAKUT stating a prevalence of 14.3 % resulting in an almost fivefold increase compared to the reported prevalence of HSCR and associated urological and urogenital anomalies. The remaining 14 publications reported 18 single cases of HSCR patients with associated CAKUT phenotypes. Of these 18 cases, 11 (61 %) cases were associated with other syndromes or syndromatic features or reported chromosomal anomalies. Conclusion This review confirms that the recognition of CAKUT in HSCR patients has been underestimated in the past. The results suggest that when confronted with HSCR in a patient, a thorough urological investigation may be indicated. The high prevalence of associated syndromes in HSCR with CAKUT may further suggest a syndromic association. Keywords Hirschsprungs’s disease CAKUT Congenital urological anomalies
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Introduction Hirschsprung’ disease (HSCR) is a congenital malformation of the hindgut occurring in 1/5,000 live births which is characterised by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses [1]. Based on a common genetic background of the enteric nervous system and kidney development, the association of congenital urological anomalies and HSCR has been well described in the literature [2–4]. First evidence that linked these two morbidities was the discovery that mice with deletions of Rearranged after Transfection (RET) [5] or glial cell line-derived neurotrophic factor (GDNF) [6] genes had abnormalities in enteric innervation and renal morphogenesis. This RET–GDNF signalling pathway has not only been linked to the pathogenesis of HSCR, but is also known to be responsible for the fusion of the ureteric bud and metanephric blastema playing a crucial role in the correct development of the kidney and urinary tract [7–9]. In the late 1990s, uncertainty in the clinical classification of congenital urological anomalies and the growing awareness of long-term effects of chronic kidney disease resulted in the summary of different clinical entities under the popular single-label acronym CAKUT (congenital anomalies of the kidney and urinary tract). CAKUT is a major cause of morbidity and collectively accounts for 30–50 % of cases of end-stage renal disease (ESRD) in children and young adults [10–13]. Resembling an aggregation of different clinical entities, the literature has included morbidities such as renal agenesis, renal dysplasia, multicystic kidney disease (MCKD), hydronephrosis, ureteropelvic junction obstruction (UPJO), vesicoureteral reflux (VUR), duplex collecting system, megaureter, posterior urethral valves (PUV) and horseshoe kidney. The reported prevalence of HSCR associated with CAKUT appears to be underestimated [4]. Moore et al. reviewed more than 4800 HSCR patients from 18 separate series and described an overall incidence of 6.05 % of genitourinary anomalies [14]. This overall incidence was comprised of CAKUT compatible diagnoses as well as a broad spectrum of genitourinary anomalies, such as hypospadias, undescended testis and disorders of bladder function. Similar incidences for urogenital anomalies were also reported by two other studies reviewing a total of 462 HSCR patients [7, 15]. A more recent prospective study, however, screened their HSCR patients specifically for the presence of CAKUT and revealed a surprisingly high prevalence of 25 % of associated CAKUT with HSCR. They concluded that HSCR patients have a 3- to 18-fold higher risk of having associated CAKUT than the normal population and suggested a thorough urological workup when confronted with a new diagnosis of HSCR [16].
123
The aim of this systematic review was to determine the prevalence of CAKUT phenotypes in a population of HSCR patients and show its relationship to other syndromes.
Materials and methods A systematic search of the literature was performed to identify articles that reported cases of HSCR associated with CAKUT or urological anomalies. Two common electronic databases, Pubmed and the Cochrane Library were searched in March 2014 using a combination of the following terms: ‘‘Hirschsprung’’’ or ‘‘congenital megacolon’’ and ‘‘CAKUT’’ or ‘‘urological anomalies’’ or ‘‘urogenital anomalies’’. Reference lists of identified articles were screened for additional publications of interest. Retrospective as well as prospective studies and single case reports published between 1955 and 2014 matching the search terms were eligible for inclusion. All identified articles were independently assessed by each of the three authors. Series referring to results of already selected cohorts were excluded. The current study included following 10 abnormalities that had previously been published as CAKUT phenotypes: renal agenesis, renal dysplasia, multicystic kidney disease, ureteropelvic junction obstruction, hydronephrosis, vesicoureteral reflux, nonobstructed, nonrefluxing primary megaureter, duplex collecting system, posterior urethral valves and horseshoe kidney. The extracted data consisting of study-related characteristics (author names, study design, study period, cohort size) and patientrelated characteristics (male-to-female ratio, associated syndromes, types of HSCR, procedure type for correction of HSCR, additional comorbidities) were extracted into an electronic datasheet in a standardised manner. There were no language restrictions.
Results A total of 32 articles reported 222 cases of HSCR associated with either CAKUT, urological or urogenital anomalies from 1955 to 2014. The male-to-female ratio was 3.8:1. Gender was reported in total of 68 cases, with 54 (79 %) males and 14 (21 %) females. Extent of aganglionosis was reported in 67 cases and included classical rectosigmoid disease in 38, long-segment aganglionosis in 12, total colonic aganglionosis in 12 and total intestinal aganglionosis in five patients. Eighteen articles reported 204 cases of either CAKUT, urological or ‘‘urogenital’’ anomalies in a case series of
Pediatr Surg Int Table 1 Definition of CAKUT and classification of data analysis
Clinical entities
Classification of data analysis Urological or urogenital anomalies 11 studies n = 132 [14, 15, 17, 18, 20, 21, 26, 27, 29–31]
1
Renal agenesis
2
Renal dysplasia
3
Hydronephrosis
4
VUR
5
Duplex collecting system
6
Horseshoe kidney
7
PUV
8
Megaureter
9
UPJO
10
MCKD
11
Megacystis
12
Hypospadia
13
Cryptorchism
14
Inguinal hernia
15 16
Rotational kidney anomaly Ectopic kidney
17
Bladder diverticulum
18
Urethral diverticulum
19
Ureteropelvic duplication
20
Recto-urethral fistula
21
Vaginal atresia
5.693 HSCR patients, resulting in an overall prevalence of 3.6 % of this association [2, 4, 14, 15–30]. Eleven [14, 15, 17, 18, 20, 21, 26, 27, 29–31] of theses 18 studies consisted of a mix of 132 cases of urological, urogenital and CAKUT phenotypes among 4,936 HSCR patients (Table 1). The remaining seven studies [2, 4, 16, 19, 23–25] were, regardless of date of publication, compatible with the CAKUT criteria published by Pope et al. [13] and reported a total of 72 patients with associated CAKUT among 757 HSCR patients (Table 1). This resulted in a prevalence of 9.5 % stating that 1 in 10.5 HSCR patients has an associated CAKUT. Five patients had two or more coexisting CAKUT. In these seven studies, a total of 73 anomalies were identified comprising the following CAKUT phenotypes: 32 renal dysplasia, 17 hydronephrosis, 15 VUR, five duplex collecting systems, two posterior urethral valves, one horseshoe kidney and one renal agenesis. After introduction of the CAKUT acronym in the late 1990s, only three studies [4, 7, 16] specifically investigated the association of HSCR and CAKUT. In this collective review of 350 patients with HSCR, 50 cases of associated CAKUT were identified giving a prevalence of 14.3 % suggesting that one in seven HSCR patients has an associated CAKUT. The remaining 14 publications reported 18 single case reports of HSCR patients with associated CAKUT phenotypes [32–45]. There was a clear male preponderance with
CAKUT 7 studies n = 72 [2, 4, 16, 19, 23–25]
a male-to-female ratio of 10:1 in the reported single cases. Extent of aganglionosis was stated in 13 of the 17 reported cases: 4 cases of total intestinal aganglionosis, classical rectosigmoid disease, long-segment aganglionosis and total colonic aganglionosis were reported each in 3 cases. CAKUT phenotypes were reported in all 18 patients and consisted of: 7 renal agenesis, 6 renal dysplasia, 4 VUR, 1 hydronephrosis and 1 horseshoe kidney. Two patients had two coexisting CAKUT (renal agenesis and VUR). Associated syndromes, syndromatic features or chromosomal anomalies were reported in 11 patients (61 %) of the reported 18 single cases. The most common syndrome encountered was the IFAP/BRESHEK syndrome, which was seen in 6 patients, followed by Bardet–Biedel syndrome in 1 patient. Dysmorphic features and chromosomal anomalies were reported in 4 cases.
Discussion The association of urological anomalies in HSCR has been well described in the literature. Especially before the introduction of the term CAKUT in the late 1990s urological comorbidities associated with HSCR were reported in a very heterogeneous manner [13, 14, 18, 28, 31, 46]. Our systematic review identified up to 20 reported clinical entities summarised as urological or urogenital anomalies
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associated with HSCR in studies published before the introduction of CAKUT (Table 1). Many of these studies were limited by small sample size of the populations studied or attention was mainly focused on major malformations that required surgical repair, not on detailed dysmorphic description of HSCR patients [19]. It was not until the introduction of the CAKUT acronym that the focus shifted towards long-term outcome of chronic kidney disease of affected patients. Although CAKUT may be used for a general classification it does not represent a classified clinical entity. The popular acronym CAKUT results from an uncertainty in clinical classification and resembles an aggregation of different genetic, anatomical and clinical entities making it difficult to use from an epidemiological perspective [16, 47]. In the 18 studies investigated, the total number of CAKUT and urological cases was 204 giving an overall prevalence of 3.6 %. The CAKUT criteria were compatible in 125 of the cases, whereas 79 cases were summarised as urological or urogenital cases. Regardless of date of publication, seven studies exclusively met the CAKUT criteria suggested by Pope et al. [13] (Table 1). The prevalence of CAKUT in these seven studies that solely reported CAKUT phenotypes associated with HSCR was 9.5 %, stating that one in ten HSCR patients has an associated CAKUT anomaly. Although the CAKUT acronym was established in the late 1990s, only three studies published after 1999 specifically investigated the association of HSCR and CAKUT. These three studies identified 50 cases of associated CAKUT among a collective of 350 HSCR patients resulting in an almost fivefold increase in prevalence of 14.2 % compared to the overall prevalence in our study [4, 7, 16]. The two most recent studies published by Prato et al. were the first prospective studies investigating the association of HSCR and CAKUT reporting an even higher prevalence of 24–25 % (Table 1). These two studies not only suggest an underestimation of this association in the literature, but also support the concept of a novel syndromic association between the two conditions [4, 16]. The concept of a syndromic association between HSCR and CAKUT is not new, since it was already suggested by various authors [2, 14, 15]. Regarding the common genetic background and the fact that a high percentage (61 %) of the reported single cases were associated with syndromes, syndromic features or chromosomal anomalies strengthen the hypothesis of a syndromic association. The four to sixfold increase in prevalence of CAKUT in HSCR patients in the Prato studies compared with previous reports in the literature [7, 14, 33] most probably originated from the prospective nature of the studies although the authors included only six of the ten CAKUT phenotypes we identified in our systematic review and that are reported in the literature [13]. Although we identified up to 20 different clinical entities (Table 1) in studies published before the introduction of
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the CAKUT acronym, reported prevalence of urological or urogenital anomalies associated with HSCR was only between 2 and 7.3 % [2, 14, 15]. An explanation for underestimation of prevalence in these studies in the past may have been because of heterogeneous inclusion and diagnostic criteria or that certain CAKUT variants remain asymptomatic for years, being discovered as unexpected incidental findings [16]. Another reason for the heterogeneity of the reported prevalence may be the lack of a homogeneous classification of CAKUT [47]. This makes it difficult to separate the different subphenotypes of congenital anomalies and perform comparative studies. As the literature lacks prospective studies investigating the rare association of HSCR and CAKUT, it would be favourable to implement further prospective multicentre research projects. This shortage of prospective studies is also one of the limitations of this systematic review and larger case series of patients might strengthen the results of the two existing prospective studies and their suggested implementation of prevention strategies and timely adequate rehabilitation treatments [4, 16].
Conclusion The review confirms that the recognition of CAKUT in HSCR patients has been underestimated in the past. Although the term CAKUT can be useful for a general classification, it may not be useful from an epidemiological perspective and lacks a homogeneous classification. The results suggest that when confronted with HSCR in a patient, a thorough urological investigation may be indicated. The high prevalence of associated anomalies in HSCR with CAKUT may further suggest a syndromic association.
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