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Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT)
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European Journal of Medical Genetics xxx (2014) 1e7
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Clinical research
Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT) Q5
Claude Stoll*, Beatrice Dott, Yves Alembik, Marie-Paule Roth Laboratoire de Genetique Medicale, Faculte de Medecine, Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 October 2013 Accepted 13 April 2014 Available online xxx
Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563 (34%) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including MeckeleGruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16%) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71% of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: CAKUT Urinary anomalies Kidney anomalies Syndromes Surveillance Ascertainment Etiology
1. Introduction Studies of other defects associated with specific congenital anomalies may be helpful to understand embryonic development, identify the causes of congenital anomalies, determine recurrence risks, and guide expectations for the efficacy of prevention strategies [Stevenson et al., 2004]. Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of diseases with a continuum encompassing kidney anomalies (renal agenesis/ aplasia, multicystic dysplastic kidney, renal dysplasia, ectopic kidney, horseshoe kidney, duplex kidney, and hydronephrosis) and ureter anomalies (ureteropelvic anomalies such as idiopathic
* Corresponding author. Laboratoire de Génétique Médicale, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France. Tel.: þ33 3 68 85 32 07; fax: þ33 3 68 85 31 79. E-mail address: [email protected] (C. Stoll).
megaureter and ureteropelvic junction obstruction, vesicoureteral reflux, posterior urethral valves, anterior urethral obstruction, ureterovesical junction obstruction, duplex collecting system, and exstrophy of the bladder) [Renkema et al., 2011]. CAKUT were defined according to Cuckow et al. [2001]: in renal agenesis there is complete absence of the kidney, whereas in renal dysplasia the kidney is present but malformed and consists of undifferentiated and metaplastic cells surrounding poorly branched ureteric bud derivatives, dysplastic organs often contain cysts. Hypoplastic kidneys, in which the organ is small and has fewer nephrons than normal, should also be included within the dysplastic spectrum. Therefore renal dysplasia includes multicystic dysplastic kidney (MCDK), cystic dysplastic kidney, and hypoplastic kidney. In hydronephrosis there is a dilatation of the renal pelvis which may be associated with reflux or obstruction of the lower urinary tract. Renal dysplasia and/or hypoplasia may co-exist. In ectopic kidney the kidneys fail to ascend from the pelvis. In horseshoe kidney there is an aberrant fusion of the lower poles of the two
http://dx.doi.org/10.1016/j.ejmg.2014.04.014 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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frequency and the type of associated anomalies observed vary considerably among different studies. Using data from our surveillance system of congenital anomalies over a 26-year period, we evaluated the nature and frequency of anomalies that were associated with CAKUT for identifying specific patterns of associated anomalies, which could give hints to the understanding of the pathogenesis of CAKUT and for identifying further recognizable conditions with CAKUT.
Table 1 Isolated and associated malformations in 1678 patients with CAKUT ascertained from 1979 to 2004 in 346,831 consecutive births in Northeastern France.
Associated malformations Non chromosomal Recognized MCAb Chromosomal Total Isolated malformation a b
N
%
Prevalencea
444 168 276 119 563 1115
26 10 16 7 34 66
12.8 4.8 7.9 3.4 16.2 32.1
2. Material and methods
Prevalence per 10.000 births. MCA: multiple congenital anomalies.
Infants with anomalies for this study were derived from 346,831 consecutive births of known outcome, including live births, stillbirths, and terminations of pregnancy after prenatal diagnosis regardless of gestational age, registered by our registry of congenital anomalies described previously [Stoll et al., 1985]. Infants born in 11 hospitals were examined from January 1, 1979, to December 31, 2004. The region of investigation was the city of Strasbourg, northeastern France (an urban area), and the area defined by the Departement du Bas-Rhin, in which Strasbourg is situated (a rural area). All newborns were registered within the first 8 days postpartum, as were all fetuses aborted because of anomalies discovered at prenatal diagnosis. As everywhere in our country, no delivery took place at home in the area under study. Each malformed infant was examined by a clinical geneticist and the type of CAKUT was identified. When a suspected or confirmed case was reported, information was obtained from all available records including prenatal consultation records, maternity files, neonatal unit files, autopsy reports, outpatient clinic files, pediatric and pediatric surgery files. Surveillance for anomalies continued until 2 years of age. For each malformed infant, a complete description was obtained, including photographs, radiographs, ultrasonographic examination, and karyotype. However, this study was performed before the array CGH technology was available. CAKUT diagnoses were identified by renal ultrasound in all patients and, on indication, by voiding cystourethrogram and/or renal scintigraphy and computed tomography. Infants with CAKUT were divided into two groups: isolated when only CAKUT were present, and associated when one or more additional major anomalies were recognized. The infants with associated anomalies were subdivided into those with recognizable conditions (chromosomal or nonchromosomal) and those without recognizable conditions (infants with multiple congenital anomalies e MCA e and in whom the associated anomalies were classified according to the organ system primarily affected). Major renal and urinary tract anomalies within a system were counted as one defect. For example, a case with
kidneys during development. In vesicoureteric reflux (VUR) there is a retrograde flow of urine from the bladder into the ureters and kidney. In megaureter there is an increased ureter size; often coupled with VUR. In ureteropelvic junction (UPJ) obstruction and in the ureterovesical junction (UVJ) obstruction there is a stricture (e.g. stenosis or atresia) at the level of the respective junctions. In posterior urethral valves (PUV) an outflow obstruction in the posterior urethra causes aberrant bladder development. In bladder exstrophy there is a failure of growth of the lower abdominal wall between the allantois and the urogenital membrane, coupled with breakdown of the urogenital membrane which leaves a small, open bladder plate, a low-placed umbilical root and diastasis of the pubic bones. In duplex (multiple) ureter there is formation of several ureters resulting from defective ureter induction, two ureteric buds develop on one side, inducing separate upper and lower renal moieties. CAKUT is one of the most common congenital anomaly, representing approximally 30% of all prenatally diagnosed anomalies [Toka et al., 2010] with a reported birth prevalence varying from 2 to 69 per 10,000 births [Wiesel et al., 2005]. CAKUT occur in as many as 1 in 100 livebirths and in 1 in 500 fetal ultrasonographic examination, constituting the most frequent cause of end-stage renal failure [Renkema et al., 2011]. Many infants with CAKUT will have a coexisting defect involving non-renal or non- urinary tract structures. Individual cases of CAKUT may differ widely in their cause. Specific genetic factors, such as chromosomal abnormalities and inherited mutations in developmental genes, or environmental influences on fetal development [Renkema et al., 2011] i.e. medications [Carta et al., 2007; Uetani and Bouchard, 2009] may form the underlying cause. Although it has long been known that CAKUT are frequently associated with other congenital anomalies, their reported
Table 2 Distribution and prevalence at birth per 10,000 births of CAKUT in all malformed children with CAKUT, in children with isolated CAKUT and in children with associated nonCAKUT anomalies. Type
All CAKUT (%)
Prevalence
Sex ratio (M/F)
486 158 185 121
(28.9) (9.4) (11.0) (7.2)
14.0 4.5 5.3 3.5
352
(20.9)
136 95 57 23 65 1678
(8.1) (5.7) (3.4) (1.4) (3.9) (100)
N Hydronephrosis Idiopathic megaureter Vesicoureteric reflux Ureteropelvic junction obstuction Renal dysplasiaa Renal agenesis Unilateral Bilateral Posterior urethral valves Exstrophy of bladder Miscellaneous Total a
Isolated CAKUT
CAKUT with non-CAKUT anomalies
(%)
1.22 1.11 0.91 1.15
358 121 160 106
(73.6) (76.6) (86.5) (87.6)
78 13 7 14
47 18 16 0
3 6 2 1
10.1
1.60
227
(64.5)
24
25
76
3.9 2.7 1.6 0.6 1.8 48.4
1.20 1.27 1.37
43 4 39 6 51 1115
(31.6) (4.2) (68.4) (26.1) (78.5) (66.5)
63 37 16 17 7 276
6 4 2 0 1 119
24 50 0 0 6 168
1.13 1.19
N
Multiple malformations N
Recognized chromosomal N
Syndromes nonchromosomal N
Renal dysplasia including multicystic dysplastic kidney, cystic dysplastic kidney, and hypoplastic kidney.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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hydronephrosis and kidney agenesis was counted once as kidney agenesis. A child with a Mendelian disorder that includes multiple anomalies e.g., MeckeleGruber syndrome (OMIM 249000) was classified as having a recognizable nonchromosomal condition. The concept of recognized constellations depends on the happiness of a system to put such labels to an infant with multiple anomalies - typical examples are the VATER and CHARGE associations. These problems were discussed by Källen et al. [1999], [2001]. 3. Results During the 26-year study period, 1678 infants with CAKUT were registered, representing a prevalence at birth of 48.4 per 10,000 (Table 1). No trends in the frequency of CAKUT were noted during the time frame of the study. The distribution and the prevalence of CAKUT in all malformed children with CAKUT, in children with isolated CAKUT and in children with associated non-CAKUT anomalies as well as the sex ratio are shown on Table 2. 3.1. Associated malformations There were 1115 infants (66%) without congenital anomalies other than CAKUT (isolated CAKUT) and 563 infants (34%) with anomalies other than CAKUT (associated CAKUT; Table 1). In the group of associated CAKUT, 119 (7%) infants had chromosomal anomalies, 168 (10%) infants had nonchromosomal recognizable conditions, and 276 (16%) infants had multiple malformations without a recognized condition (MCA). These 276 infants had 584 malformations, as some children had malformations in more than one site. Table 3 shows the recognizable and non recognizable conditions in 563 patients with associated CAKUT. Hundred nineteen children had chromosomal abnormalities including 33 trisomies 18, 26 trisomies 21, 24 trisomies 13, 11 Turner syndrome, 10 triploidies, 6 autosomal deletions, 5 unbalanced translocations, 3 autosomal duplications, and one ring chromosome 22. Among the 168 children with recognizable nonchromosomal conditions (Table 3), VACTERL association (33%), MeckeleGruber syndrome (21%), and prune belly syndrome (14%), were most often present. Among the 276 infants with associated anomalies classified as nonrecognizable conditions, the most frequent anomalies were musculoskeletal anomalies, digestive system anomalies, cardiac defects, central nervous system anomalies, ear, face and neck anomalies, pulmonary system anomalies, cleft lip/palate, abdominal wall anomalies, and hypospadias (Table 3). Prenatal diagnosis was obtained in 71% of pregnancies. However, when the study period was subdivided into three parts, 1979e 1986, 1987e1996, 1997e2004, prenatal diagnosis was obtained in 55% (271/496), 72% (474/661), and 87% (455/521) of the cases, respectively. Pregnancy was terminated in 53% of the fetuses with CAKUT detected prenatally. Most of these fetuses had chromosomal abnormalities or multiple congenital anomalies.
3
Table 3 Recognizable and non-recognizable conditions in 563 patients with CAKUT and associated malformations ascertained from 1979 to 2004 in 346,831 consecutive births in Northeastern France. Recognizable conditions
n
Chromosomal abnormalities 119 Trisomy 18 33 Trisomy 21 26 Trisomy 13 24 Turner syndrome 11 Triploidy 10 Autosomal deletions 6 Unbalanced translocations 5 Autosomal duplications 3 Ring chromosome 22 1 Recognized nonchromosomal conditions 168 VACTERI association 56 Meckel-Gruber syndrome 36 Prune belly syndrome 23 Othera 53 Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 97 Limb reduction defects 30 Polydactyl 27 Syndactyly 18 Other 22 Digestive system 91 Anal atresia 38 Malrotation 29 Other 24 Congenital heart disease 88 Ventricular septal defect 42 Atrial septal defect 21 Other 25 CNS 60 Spina bifida 21 Encephalocele 15 Microcephaly 8 Anencephaly 6 Other 10 Ear, face and neck 53 Facial dysmorphia 21 Hypertelorism 19 Other 13 Pulmonory system 28 Lung hypoplasia 21 Other 7 Cleft lip and/or palate 23 Abdominal wall 23 Omphalocele 14 Gastroschisis 9 Hypospadias 21 Diaphragmatic hernia 6 Miscellaneous 94 Total 584
% 28 22 20 9 8
33 21 14 31
a (n) Fetal alcohol syndrome (6), BardeteBiedl syndrome (4), de Lange syndrome (4), Di George syndrome (4), CHARGE association (3), oculo-auriculo-vertebral spectrum (3),PradereWilli syndrome (3), BeckwitheWiedemann syndrome (2), chondrodysplasia punctata (2), cystic fibrosis (2), Kabuki syndrome (2), Nail-patella syndrome (2), PallistereHall syndrome (2), SimpsoneGolabieBehmel syndrome (2), SmitheLemlieOpitz syndrome (2), TowneseBrocks syndrome (2) and one each : campomelic dysplasia, caudal regression, Ellis van Creveld syndrome, Kallmann syndrome, KlippeleFeil syndrome, RubinsteineTaybi syndrome, sirenomelia, and Zellweger syndrome.
4. Discussion During the 26-year study period, the overall prevalence at birth of CAKUT was 48.4/10,000. The most frequent CAKUT were, (in parentheses the prevalence at birth per 10,000 and the percentage are given), hydronephrosis (14.0; 29), renal dysplasia (10.1; 21), renal agenesis (6.6; 14), vesicoureteric reflux (VUR) (5.3; 11), and megaureter (4.5; 9). The prevalence per 10,000 births of CAKUT in the previous reports is shown on Table 4. Vast differences in the prevalence of CAKUT appeared between the different studies. The
same variations in prevalence were noted for different categories of CAKUT : renal agenesis, cystic kidney and bladder exstrophy. In our study, 34% of the patients had associated CAKUT. The percentage of associated CAKUT in the other studies is shown on Table 5. There were large regional differences in the percentage of associated anomalies in CAKUT from 24 in Norway [Isaksen et al., 2000] to 37 in Atlanta [Honein et al., 2003], as well as in the different types of CAKUT: the percentage of associated anomalies
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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1 2 3 Q2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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Table 4 Review of literature: total number of cases of CAKUT and prevalence per 10,000 births of all CAKUT, of renal agenesis, cystic kidney and bladder exstrophy.
Total number All CAKUT Renal agenesis Cystic kidney Bladder exstrophy
Q1
[EUROAT]
[International Clearinghouse for Birth Defects Surveillance and Research annual report, 2008]b
[Scott and Renwick, 1993]
[Cocchi et al., 1996]
[Sebastian Calderon and Zarante, 2006]
z2800/year 33.7a 1.18 4.18 0.69
z1400/year
736 11.5f
349 16.6g
83 43.0h 2.0 2.6
0.33 to 7.16c 0.2 to 11.9d 0.0 to 1.33e
[Caiulo et al., 2012]
[Fletcher et al., 2012]
[Melo et al., 2012]
[Adams-Chapman et al., 2013]
This study
Total number
171
147
524
171
1678
All CAKUT Renal agenesis Cystic kidney Bladder exstrophy
96.1i
0.16j
14.8k
45.8l
48.4 6.6 10.8 0.44
a In 20 registries of congenital anomalies from 12 European countries reporting their results to EUROCAT, the prevalence of CAKUT varied from 2 (North East Italy) to 69 (Mainz, Germany). b ICBDSR (International Clearinghouse for Birth Defects Surveillance and Research) registered only renal agenesis, cystic kidney and bladder exstrophy. c Toscany, Italy and Czech Republic. d British Columbia, Canada, North East Italy and Paris, France. e 14 registries out of 37 registries of congenital anomalies around the world and Ireland. f Northern Region of UK. g Emilia-Romagna, Italy. h Colombia. i Ultrasound mass screening at 2 months of age in Salento, Italy. j Prevalence of children <20 years of age over the study period 1996e2006 in Australia and New Zealand. k Tertiary neonatal unit in a referral center for congenital anomalies in Belo Horizonte, Brazil. l Very low birthweigh infants ascertained by the US National Institute of Child Health and Human Development Neonatal Research Network.
varied for hydronephrosis from 14 in Europe [Garne et al., 2009] to 35 in Brazil [Melo et al., 2012], for renal agenesis, from 28 in UK [Carter et al., 1979] to 68 in Atlanta [Honein et al., 2003], and for multicystic renal dysplasia (MCDK), from 5 in Bonn [RudnikSchöneborn et al., 1998] and Rotterdam [van Eijk et al., 2002] to 46 in Atlanta [Honein et al., 2003]. The enormous variability in prevalence in different studies depends of methodological differences. For example, surveillance registries differ in whether ascertainment is active or passive. Other reasons that could explain the different frequencies of additional anomalies may be time that the surveillance continued after birth, and all patients were or not taken into consideration, including stillborns and terminations of pregnancy. Other factors were the differences in definitions (for example EUROCAT had not exactly the same definition than the ICBDSR for renal agenesis and cystic kidney) and inclusion/exclusion criteria, the length of time after
birth that patients were examined, the variability of clinical expression of associated anomalies, the difficulty to knew the proportion of patients diagnosed by objective techniques, the selection of patients, the sources of ascertainment, and the sample size. In addition to these factors, autopsies were not always performed, there was not always follow-up, many authors did not report all patients born in a certain geographical area, but instead, patients referred to a certain health care facility, and there are true population differences and changes in frequency over time [EUROAT]. Moreover, many of the estimates of prevalence are uncertain due to small numbers. The same concerns exist for the comparisons of subgroups of associated anomalies. In this study chromosomal abnormalities were observed in 119 (7%) infants with CAKUT. The reported percentages of chromosomal abnormalities in infants with CAKUT vary from 3.7 in Norway [Isaksen et al., 2000] to 24 and 12 in London [Nicolaides et al., 1986,
Table 5 Review of literature: total number of cases of CAKUT and percentage of associated anomalies in all CAKUT and in hydronephrosis, renal agenesis and multicystic dysplastic kidney (MCDK).
Total number All CAKUT Hydronephrosis Renal agenesis MCDK
Total number All CAKUT Hydronephrosis Renal agenesis MCDK
[Carter et al., 1979]
[Wilson and Baird, 1985]
[Macquard-Moulin et al., 1989]
[Al Naimi et al., 2013]
[Cocchi et al., 1996]
[Rudnik-Schöneborn et al., 1998]
[Lazebnik et al., 1999]
[Isaksen et al., 2000]
103
209
164
54
349 30
204
102
112 24
28
1/3 to 1/2 32
18
5
35
[Aubertin et al., 2002]
[van Eijk et al., 2002]
[Honein et al., 2003]
[Wiesel et al., 2005]
[Garne et al., 2009]
[Fletcher et al., 2012]
[Westland et al., 2013]
This study
73
38
169 37 20 68 46
1130 33
3648
524
2684b
1678 34 26 36 12
16
5
14
a
35 63
32
a Chromosomes anomalies were excluded as well as congenital hydronephrosis with posterior urethral valves and congenital hydronephrosis with prune belly syndrome. There were large regional differences ranging, in Europe, from 2 (Poznan, Poland) to 29 (Wales, UK). b A systematic review of 43 published studies of unilateral renal agenesis.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
Q3
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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5
3.3% [Benacerraf et al., 1990], 0.7% [Gunn et al., 1995], 0.3% no risk factors to 1.0% risk factors [Chitty, personal communication to Valentin and Marsal, Valentin and Marsal, 1998], and 0% [Valentin and Marsal, 1998]. Unfortunately, all of these studies were performed before the array CGH technology was available. Many syndromes, sequences, associations and spectrums were reported to be associated with CAKUT [Stoll et al., 1990; Wellesley
1992] respectively (Table 6). In this series the more common chromosomal abnormalities were trisomy 18 (28%), trisomy 21 (22%), trisomy 13 (20%), Turner syndrome (9%), triploidy (8%), and chromosomal structural aberrations (15%). This figure compares well with that in other studies (Table 6). Chromosomal anomalies in fetus with pyelectasis detected at ultrasound examination accounted for 11.6% [Reuss et al., 1988], 3.9% [Morin et al., 1996],
Table 6 Review of literature: total number of cases of CAKUT and percentage of recognized conditions, chromosomal and non chromosomal, and of multiple congenital anomalies (MCA). [EUROAT]
[Carter et al., 1979]b
Total number 17.739 103 Chromosomal anomalies Total 4.3 Trisomie 18 Trisomie 21 Trisomie 13 Turner syndrome Other Non chromosomal recognized conditions Total VACTERL Meckel-Gruber Prune-belly Other MCA MSKa 12 CHDa 15 GIa 11 a CNS 12 Respiratory Ear Orofacial 4 Abdominal wall Diaphragme Genital Other [Lazebnik et al., 1999]d Total number 102 Chromosomal anomalies Total Trisomie 18 Trisomie 21 Trisomie 13 Turner syndrome Other Non chromosomal recognized conditions Total VACTERL MeckeleGruber Prune-belly Other MCA MSKa 26 CHDa 23 a GI 14 a CNS 13 Respiratory Ear 5 Orofacial 10 Abdominal wall 3 Diaphragme Genital 6 Other a b c d e f
[Nicolaides et al., 1986] and [Nicolaides et al., 1992]
[Macquard-Moulin et al., 1989]
[Boue et al., 1988] [Eydoux et al., 1989]c
[EUROFETUS STUDY REPORT et al., 1995]
[Cocchi et al., 1996]
682
164
936
954
349
12 to 24 23 22 21
11 28 19 17
2.9 18 32 14 4 32
5.2
9.5
4
34 45 17 10
2 3
16 9
[Isaksen et al., 2000]
[Aubertin et al., 2002]e
[Wiesel et al., 2005]
[Damen et al., 2005]
[Garne et al., 2009]e,f
[Melo et al., 2012]
This study
112
73
1130
408
3648
524
1678
3.7 35 18 23
3
23
11 25 23 16 13 22
8.6
4.4 10 16 21
57
43
6 23 20 57
17
7
18
12
14 57
7 2 1 2
14
1 4
11
53
7 28 22 20 9 20
11 12 12 50 25
10 33 21 14 31 17 15 16 10 5 9 4 4 1 3 16
MSK ¼ musculoskeletal, CHD ¼ congenital heart disease, GI ¼ gastrointestinal, CNS ¼ central nervous system. Renal agenesis only. Both studies were done in Paris. Multicystic dysplastic kidney (MCDK) only. Unilateral MCDK only. Hydronephrosis only.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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and Howe, 2001]. In our series 168 out of 1678 (10%) infants with CAKUT had non chromosomal recognizable conditions including 56 VACTERL association (33%), 36 MeckeleGruber syndrome (21%), 23 prune belly syndrome (14%), and 53 (31%) other recognizable conditions (Table 3). In the previous reports the percentage of non chromosomal recognizable conditions varied considerably (Table 6) from 6% in the EUROSCAN study [Wiesel et al., 2005] to 11% in Brazil [Melo et al., 2012]. Syndromic forms of renal hypoplasia/dysplasia include rare disorders affecting extrarenal organs such as the eye, the central nervous system, the skin, the limbs, and others. The list of syndromes that include the renal agenesis/hypoplasia/dysplasia phenotype consists of at least 73 clinical conditions. Renalcoloboma syndrome, orofaciodigital syndrome, branchiootorenal syndrome, renal cysts and diabetes syndrome, and Fraser syndrome are the most frequent syndromes associated with renal parenchymal defects [Sanna-Cherchi et al., 2007]. There are no agreements in the literature as to which associated anomalies are most common in infants with CAKUT and MCA. In this study (Table 3) the most common associated anomalies were musculoskeletal, digestive, cardiac, central nervous, ear, face and neck, pulmonary, oral clefts, abdominal wall, and hypospadias. The more common anomalies were for musculoskeletal anomalies limb reduction defects, polydactyly and syndactyly, for digestive system anomalies anal atresia and malrotation, for cardiac defects ventricular septal defect (VSD) and atrial septal defect (ASD), for central nervous system anomalies neural tube defects, for ear, face and neck anomalies facial dysmorphia and hypertelorism, and for pulmonary system anomalies lung hypoplasia. In the literature the percentage of the most common associated anomalies varied greatly (Table 6). However, it is difficult to compare our results with those of other studies as, for example some authors include the patients with isolated CAKUT in the total number of patients. Other reasons for the discrepancies between the reported studies and this study were aforementioned. In order to evaluate patients and to compare studies, it is necessary to standardize the methods of case classification. Congenital anomalies and associated anomalies must be grouped into meaningful syndromes and conditions. Methods for case classification into isolated, multiple and syndrome categories were described [Rasmussen et al., 2003]. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying etiology of congenital anomalies. The causes of CAKUT include [Wellesley and Howe, 2001] chromosomal abnormalities; dominant or recessive genes (“Mendelian inheritance”); familial inheritance in the absence of a Mendelian syndrome; known syndromes, sequences, associations, and related anomalies (i.e., VACTERL association, MeckeleGruber syndrome); teratogenic exposures (i.e. antiepileptic drugs-carbamazepine and phenobarbital [Carta et al., 2007]); subfertility and overweight/obesity [Honein et al., 2003]; and unknown causes. The prenatal exposure to teratogens may be preventable. The molecular basis for CAKUT remains unknown. A large number of monogenic knock-out mouse models have been developed with offspring manifesting a phenotypic spectrum which mimics the human CAKUT complex and numerous candidate genes have been discussed [Weber, 2012]. The potential limitations of the present study include the small number of infants in some categories of CAKUT and the lack of molecular studies of the patients with CAKUT. However, the study was performed in a homogeneous population, and complete ascertainment was obtained. The strength of our study involves a
well-defined population in which all patients were referred to the Registry of Congenital Anomalies including livebirths, stillbirths, and termination of pregnancies, liveborn infants were followed up until 2 years of age, the patients were reported by several sources, every patient was examined by a clinical geneticist, and the registration was active. In conclusion, we have determined a frequency of congenital anomalies associated with CAKUT of 34%. This result was derived from a geographically-based cohort of close to 350,000 births. The associated anomalies underscore the need for thorough evaluation and careful characterization of patients with CAKUT. A multidisciplinary approach is needed to comprehensively cover all aspects of these often complicated cases. A routine screening for other congenital anomalies, especially of the musculoskeletal, digestive, cardiac, central nervous and pulmonary systems need to be considered in patients with CAKUT, and genetic counseling seems warranted in most of these complicated cases. Pediatricians, pediatric nephrologists, geneticists and birth defects surveillance programs should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in 17% of the cases. Conflicts of interest The authors declare there are no conflicts of interest. References Adams-Chapman I, Hansen NI, Shankaran S, Bell EF, Boghossian NS, Murray JC, et al. Ten-year review of major birth defects in VLBW infants. Pediatrics 2013;132: 49e61. Al Naimi A, Baumüller J-E, Spahn S, et al. Prenatal diagnosis of multicystic dysplastic kidney disease in the second trimester screening. Prenat Diagn 2013;33:726e 31. Q4 Aubertin G, Cripps S, Coleman G, et al. Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management. Prenat Diagn 2002;22:388e94. Benacerraf BR, Mandell J, Estroff J, et al. Fetal pyelectasis: a possible association with Down syndrome. Obstet Gynecol 1990;76:58e60. Boue A, Muller F, Briard ML, Boue J. Interest of biology in the management of pregnancies where a fetal malformation has been detected by ultrasonography. Fetal Ther 1988;3:14e23. Caiulo VA, Caiulo S, Gargasole C, et al. Ultrasound mass screening for congenital anomalies of the kidney and urinary tract. Pediatr Nephrol 2012;27:949e53. Carta M, Cimador M, Giuffrè M, Sergio M, Di Pace MR, De Grazia E, et al. Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy. Pediat Nephrol 2007;22:1054e7. Carter CO, Evans K, Pescia G. A family study of renal agenesis. J Med Genet 1979;16: 176e88. Cocchi G, Magnani C, Morini MS, Garani GP, Milan M, Calzolari E. Urinary tract abnormalities (UTA) and associated malformations: data of the EmiliaeRomagna registry. IMER group. EmiliaeRomagna registry on congenital malformations. Eur J Epidemiol 1996;12:493e7. Cuckow PM, Nyirady P, Winyard PJD. Normal and abnormal development of the urogenital tract. Prenat Diagn 2001;21:908e16. Damen HA, De Jong TP, Stigter RH, et al. Congenital renal tract anomalies: outcome and follow-up of 402 cases detected antenatally between 1986 and 2001. Ultrasound Obstet Gynecol 2005;25:134e43. EUROCAT: http://www.eurocat-network.eu/. Eurofetus Study Report. Cost-effectiveness of antenatal screening for fetal malformation by ultrasound. In: Levi S, Grandjean H, Lebrun T, editors. European Union, Direction Generale XII, Brussels, vol. 1; 1995. Eydoux P, Choiset A, Le Porrier N, et al. Chromosomal prenatal diagnosis: study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diagn 1989;9:255e69. Fletcher J, McDonald S, Alexander SI, on behalf of the Australian and New Zealand Pediatric Nephrology Association (ANZPNA). Prevalence of genetic renal disease in children. Pediat Nephrol 2012;28:251e6. Garne E, Loane M, Wellesley D, et al. Congenital hydronephrosis: prenatal diagnosis and epidemiology in Europe. J Pediat Urol 2009;5:47e52. Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: Incidence and outcome. Am J Obstet Gynecol 1995;172:479e86. Honein MA, Moore CA, Watkins ML. Subfertility and prepregnancy overweight/ obesity: possible interaction between these risk factors in the etiology of
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C. Stoll et al. / European Journal of Medical Genetics xxx (2014) 1e7 congenital renal anomalies. Birth Defects Res Part Clin Mol Teratol 2003;67: 572e7. International Clearinghouse for Birth Defects Surveillance and Research annual report. The centre of the international clearinghouse for birth defects surveillance and research. Roma: Italy; 2008. 290 pp. Isaksen CV, Eik-Nes SH, Blaas HG, Torp SH. Fetuses and infants with congenital urinary system anomalies: correlation between prenatal ultrasound and postmortem findings. Ultrasound Obstet Gynecol 2000;15:177e85. Källen K, Robert E, Mastroiacovo P, Castilla EE, Kallen B. Charge association in newborns: a registry-based study. Teratology 1999;60:334e43. Källen K, Mastroiacovo P, Castilla EE, Robert E, Kallen B. Vater non-random association of congenital malformations: study based on data from four malformation registers. Am J Med Genet 2001;101:26e32. Lazebnik N, Bellinger MF, Ferguson JE, et al. Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 1999;19:418e23. Macquard-Moulin G, Julian C, Chapel F, Aymé S. Sensibilité de l’échographie obstétricale dans le diagnostic anténatal des anomalies fœtales majeures. Rev Epidémiol Santé Publique 1989;37:197e205. Melo BF, Aguiar MB, Bouzada MC, et al. Early risk factors for neonatal mortality in CAKUT: analysis of 524 affected newborns. Pediatr Nephrol 2012;27:965e72. Morin L, Cendron M, Crombleholme TM, et al. Minimal hydronephrosis in the fetus: clinical significance and implications for management. J Urol 1996;155:2047e9. Nicolaides KH, Rodeck CH, Gosden CM. Rapid karyotyping in non-lethal fetal malformations. Lancet 1986:283e7. Nicolaides KH, Cheng HH, Abbas A, et al. Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther 1992;7:1e11. Rasmussen SA, Olney RS, Holmes LB, et al. Guidelines for case classification for the national birth defects prevention study. Birth Defects Res A Clin Mol Teratol 2003;67:193e201. Renkema KY, Winyard PJ, Skovorodkin IN, Levtchenko E, Hindryckx A, Jeanpierre C, et al. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT). Nephrol Dial Transpl 2011;26:3843e51. Reuss A, Stewart RA, Wladimiroff JW, et al. Non-invasive management of fetal obstructive uropathy. Lancet 1988:949e51. Rudnik-Schöneborn S, John U, Deget F, et al. Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 1998;157:666e72.
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Sanna-Cherchi S, Caridi G, Weng PL, et al. Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr Nephrol 2007;22:1675e84. Scott JES, Renwick M. Urological anomalies in the northern region fetal abnormality survey. Arch Dis Child 1993;68:22e6. Sebastian Calderon J, Zarante I. Congenital urological anomalies: epidemiological description and associated risk factors in Colombia 2001e2004. Arch Esp Urol 2006;59:7e14. Stevenson RE, Seaver LH, Collins JS, Dean GH. Neural tube defects and associated anomalies in South Carolina. Birth Defects Res A Clin Mol Teratol 2004;70:554e8. Stoll C, Roth M-P. The Northeastern France birth defects monitoring system. In: Marois M, editor. Prevention of physical and mental congenital defects, part B. New York: Alan R. Liss; 1985. pp. 157e62. Stoll C, Alembik Y, Roth MP, et al. Risk factors in internal urinary system malformations. Pediatr Nephrol 1990;4:319e23. Toka HR, Toka O, Harir A, Nguyen HT. Congenital anomalies of kidney and urinary tract. Semin Nephrol 2010;30:374e86. Uetani N, Bouchard M. Plumbing in the embryo: developmental defects of the urinary tracts. Clin Genet 2009;75:307e17. Valentin L, Marsal K. Does the prenatal diagnosis of fetal urinary tract anomalies affect perinatal outcome? Ann N Y Acad Sci 1998;847:59e73. van Eijk L, Cohen-Overbeek TE, den Hollander NS, et al. Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessment. Ultrasound Obstet Gynecol 2002;19:180e3. Weber S. Novel genetic aspects of congenital anomalies of kidney and urinary tract. Curr Opin Pediatr 2012;24:212e8. Wellesley D, Howe DT. Fetal renal anomalies and genetic syndromes. Prenat Diagn 2001;21:992e1003. Westland R, Schreuder MF, Ket JFC, van Wijk JAE. Unilateral renal agenesis: a systematic review on associated anomalies and renal injury. Nephrol Dial Transpl 2013;28:1844e55. Wiesel A, Queisser-Luft A, Clementi M, Bianca S, Stoll C, The Euroscan study group. Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries. Eur J Med Genet 2005;48:131e44. Wilson RD, Baird PA. Renal agenesis in British Columbia. Am J Med Genet 1985;21: 153e69.
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Contents lists available at ScienceDirect
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Clinical research
Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT) Q5
Claude Stoll*, Beatrice Dott, Yves Alembik, Marie-Paule Roth Laboratoire de Genetique Medicale, Faculte de Medecine, Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 October 2013 Accepted 13 April 2014 Available online xxx
Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563 (34%) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including MeckeleGruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16%) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71% of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: CAKUT Urinary anomalies Kidney anomalies Syndromes Surveillance Ascertainment Etiology
1. Introduction Studies of other defects associated with specific congenital anomalies may be helpful to understand embryonic development, identify the causes of congenital anomalies, determine recurrence risks, and guide expectations for the efficacy of prevention strategies [Stevenson et al., 2004]. Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of diseases with a continuum encompassing kidney anomalies (renal agenesis/ aplasia, multicystic dysplastic kidney, renal dysplasia, ectopic kidney, horseshoe kidney, duplex kidney, and hydronephrosis) and ureter anomalies (ureteropelvic anomalies such as idiopathic
* Corresponding author. Laboratoire de Génétique Médicale, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France. Tel.: þ33 3 68 85 32 07; fax: þ33 3 68 85 31 79. E-mail address: [email protected] (C. Stoll).
megaureter and ureteropelvic junction obstruction, vesicoureteral reflux, posterior urethral valves, anterior urethral obstruction, ureterovesical junction obstruction, duplex collecting system, and exstrophy of the bladder) [Renkema et al., 2011]. CAKUT were defined according to Cuckow et al. [2001]: in renal agenesis there is complete absence of the kidney, whereas in renal dysplasia the kidney is present but malformed and consists of undifferentiated and metaplastic cells surrounding poorly branched ureteric bud derivatives, dysplastic organs often contain cysts. Hypoplastic kidneys, in which the organ is small and has fewer nephrons than normal, should also be included within the dysplastic spectrum. Therefore renal dysplasia includes multicystic dysplastic kidney (MCDK), cystic dysplastic kidney, and hypoplastic kidney. In hydronephrosis there is a dilatation of the renal pelvis which may be associated with reflux or obstruction of the lower urinary tract. Renal dysplasia and/or hypoplasia may co-exist. In ectopic kidney the kidneys fail to ascend from the pelvis. In horseshoe kidney there is an aberrant fusion of the lower poles of the two
http://dx.doi.org/10.1016/j.ejmg.2014.04.014 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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frequency and the type of associated anomalies observed vary considerably among different studies. Using data from our surveillance system of congenital anomalies over a 26-year period, we evaluated the nature and frequency of anomalies that were associated with CAKUT for identifying specific patterns of associated anomalies, which could give hints to the understanding of the pathogenesis of CAKUT and for identifying further recognizable conditions with CAKUT.
Table 1 Isolated and associated malformations in 1678 patients with CAKUT ascertained from 1979 to 2004 in 346,831 consecutive births in Northeastern France.
Associated malformations Non chromosomal Recognized MCAb Chromosomal Total Isolated malformation a b
N
%
Prevalencea
444 168 276 119 563 1115
26 10 16 7 34 66
12.8 4.8 7.9 3.4 16.2 32.1
2. Material and methods
Prevalence per 10.000 births. MCA: multiple congenital anomalies.
Infants with anomalies for this study were derived from 346,831 consecutive births of known outcome, including live births, stillbirths, and terminations of pregnancy after prenatal diagnosis regardless of gestational age, registered by our registry of congenital anomalies described previously [Stoll et al., 1985]. Infants born in 11 hospitals were examined from January 1, 1979, to December 31, 2004. The region of investigation was the city of Strasbourg, northeastern France (an urban area), and the area defined by the Departement du Bas-Rhin, in which Strasbourg is situated (a rural area). All newborns were registered within the first 8 days postpartum, as were all fetuses aborted because of anomalies discovered at prenatal diagnosis. As everywhere in our country, no delivery took place at home in the area under study. Each malformed infant was examined by a clinical geneticist and the type of CAKUT was identified. When a suspected or confirmed case was reported, information was obtained from all available records including prenatal consultation records, maternity files, neonatal unit files, autopsy reports, outpatient clinic files, pediatric and pediatric surgery files. Surveillance for anomalies continued until 2 years of age. For each malformed infant, a complete description was obtained, including photographs, radiographs, ultrasonographic examination, and karyotype. However, this study was performed before the array CGH technology was available. CAKUT diagnoses were identified by renal ultrasound in all patients and, on indication, by voiding cystourethrogram and/or renal scintigraphy and computed tomography. Infants with CAKUT were divided into two groups: isolated when only CAKUT were present, and associated when one or more additional major anomalies were recognized. The infants with associated anomalies were subdivided into those with recognizable conditions (chromosomal or nonchromosomal) and those without recognizable conditions (infants with multiple congenital anomalies e MCA e and in whom the associated anomalies were classified according to the organ system primarily affected). Major renal and urinary tract anomalies within a system were counted as one defect. For example, a case with
kidneys during development. In vesicoureteric reflux (VUR) there is a retrograde flow of urine from the bladder into the ureters and kidney. In megaureter there is an increased ureter size; often coupled with VUR. In ureteropelvic junction (UPJ) obstruction and in the ureterovesical junction (UVJ) obstruction there is a stricture (e.g. stenosis or atresia) at the level of the respective junctions. In posterior urethral valves (PUV) an outflow obstruction in the posterior urethra causes aberrant bladder development. In bladder exstrophy there is a failure of growth of the lower abdominal wall between the allantois and the urogenital membrane, coupled with breakdown of the urogenital membrane which leaves a small, open bladder plate, a low-placed umbilical root and diastasis of the pubic bones. In duplex (multiple) ureter there is formation of several ureters resulting from defective ureter induction, two ureteric buds develop on one side, inducing separate upper and lower renal moieties. CAKUT is one of the most common congenital anomaly, representing approximally 30% of all prenatally diagnosed anomalies [Toka et al., 2010] with a reported birth prevalence varying from 2 to 69 per 10,000 births [Wiesel et al., 2005]. CAKUT occur in as many as 1 in 100 livebirths and in 1 in 500 fetal ultrasonographic examination, constituting the most frequent cause of end-stage renal failure [Renkema et al., 2011]. Many infants with CAKUT will have a coexisting defect involving non-renal or non- urinary tract structures. Individual cases of CAKUT may differ widely in their cause. Specific genetic factors, such as chromosomal abnormalities and inherited mutations in developmental genes, or environmental influences on fetal development [Renkema et al., 2011] i.e. medications [Carta et al., 2007; Uetani and Bouchard, 2009] may form the underlying cause. Although it has long been known that CAKUT are frequently associated with other congenital anomalies, their reported
Table 2 Distribution and prevalence at birth per 10,000 births of CAKUT in all malformed children with CAKUT, in children with isolated CAKUT and in children with associated nonCAKUT anomalies. Type
All CAKUT (%)
Prevalence
Sex ratio (M/F)
486 158 185 121
(28.9) (9.4) (11.0) (7.2)
14.0 4.5 5.3 3.5
352
(20.9)
136 95 57 23 65 1678
(8.1) (5.7) (3.4) (1.4) (3.9) (100)
N Hydronephrosis Idiopathic megaureter Vesicoureteric reflux Ureteropelvic junction obstuction Renal dysplasiaa Renal agenesis Unilateral Bilateral Posterior urethral valves Exstrophy of bladder Miscellaneous Total a
Isolated CAKUT
CAKUT with non-CAKUT anomalies
(%)
1.22 1.11 0.91 1.15
358 121 160 106
(73.6) (76.6) (86.5) (87.6)
78 13 7 14
47 18 16 0
3 6 2 1
10.1
1.60
227
(64.5)
24
25
76
3.9 2.7 1.6 0.6 1.8 48.4
1.20 1.27 1.37
43 4 39 6 51 1115
(31.6) (4.2) (68.4) (26.1) (78.5) (66.5)
63 37 16 17 7 276
6 4 2 0 1 119
24 50 0 0 6 168
1.13 1.19
N
Multiple malformations N
Recognized chromosomal N
Syndromes nonchromosomal N
Renal dysplasia including multicystic dysplastic kidney, cystic dysplastic kidney, and hypoplastic kidney.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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hydronephrosis and kidney agenesis was counted once as kidney agenesis. A child with a Mendelian disorder that includes multiple anomalies e.g., MeckeleGruber syndrome (OMIM 249000) was classified as having a recognizable nonchromosomal condition. The concept of recognized constellations depends on the happiness of a system to put such labels to an infant with multiple anomalies - typical examples are the VATER and CHARGE associations. These problems were discussed by Källen et al. [1999], [2001]. 3. Results During the 26-year study period, 1678 infants with CAKUT were registered, representing a prevalence at birth of 48.4 per 10,000 (Table 1). No trends in the frequency of CAKUT were noted during the time frame of the study. The distribution and the prevalence of CAKUT in all malformed children with CAKUT, in children with isolated CAKUT and in children with associated non-CAKUT anomalies as well as the sex ratio are shown on Table 2. 3.1. Associated malformations There were 1115 infants (66%) without congenital anomalies other than CAKUT (isolated CAKUT) and 563 infants (34%) with anomalies other than CAKUT (associated CAKUT; Table 1). In the group of associated CAKUT, 119 (7%) infants had chromosomal anomalies, 168 (10%) infants had nonchromosomal recognizable conditions, and 276 (16%) infants had multiple malformations without a recognized condition (MCA). These 276 infants had 584 malformations, as some children had malformations in more than one site. Table 3 shows the recognizable and non recognizable conditions in 563 patients with associated CAKUT. Hundred nineteen children had chromosomal abnormalities including 33 trisomies 18, 26 trisomies 21, 24 trisomies 13, 11 Turner syndrome, 10 triploidies, 6 autosomal deletions, 5 unbalanced translocations, 3 autosomal duplications, and one ring chromosome 22. Among the 168 children with recognizable nonchromosomal conditions (Table 3), VACTERL association (33%), MeckeleGruber syndrome (21%), and prune belly syndrome (14%), were most often present. Among the 276 infants with associated anomalies classified as nonrecognizable conditions, the most frequent anomalies were musculoskeletal anomalies, digestive system anomalies, cardiac defects, central nervous system anomalies, ear, face and neck anomalies, pulmonary system anomalies, cleft lip/palate, abdominal wall anomalies, and hypospadias (Table 3). Prenatal diagnosis was obtained in 71% of pregnancies. However, when the study period was subdivided into three parts, 1979e 1986, 1987e1996, 1997e2004, prenatal diagnosis was obtained in 55% (271/496), 72% (474/661), and 87% (455/521) of the cases, respectively. Pregnancy was terminated in 53% of the fetuses with CAKUT detected prenatally. Most of these fetuses had chromosomal abnormalities or multiple congenital anomalies.
3
Table 3 Recognizable and non-recognizable conditions in 563 patients with CAKUT and associated malformations ascertained from 1979 to 2004 in 346,831 consecutive births in Northeastern France. Recognizable conditions
n
Chromosomal abnormalities 119 Trisomy 18 33 Trisomy 21 26 Trisomy 13 24 Turner syndrome 11 Triploidy 10 Autosomal deletions 6 Unbalanced translocations 5 Autosomal duplications 3 Ring chromosome 22 1 Recognized nonchromosomal conditions 168 VACTERI association 56 Meckel-Gruber syndrome 36 Prune belly syndrome 23 Othera 53 Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 97 Limb reduction defects 30 Polydactyl 27 Syndactyly 18 Other 22 Digestive system 91 Anal atresia 38 Malrotation 29 Other 24 Congenital heart disease 88 Ventricular septal defect 42 Atrial septal defect 21 Other 25 CNS 60 Spina bifida 21 Encephalocele 15 Microcephaly 8 Anencephaly 6 Other 10 Ear, face and neck 53 Facial dysmorphia 21 Hypertelorism 19 Other 13 Pulmonory system 28 Lung hypoplasia 21 Other 7 Cleft lip and/or palate 23 Abdominal wall 23 Omphalocele 14 Gastroschisis 9 Hypospadias 21 Diaphragmatic hernia 6 Miscellaneous 94 Total 584
% 28 22 20 9 8
33 21 14 31
a (n) Fetal alcohol syndrome (6), BardeteBiedl syndrome (4), de Lange syndrome (4), Di George syndrome (4), CHARGE association (3), oculo-auriculo-vertebral spectrum (3),PradereWilli syndrome (3), BeckwitheWiedemann syndrome (2), chondrodysplasia punctata (2), cystic fibrosis (2), Kabuki syndrome (2), Nail-patella syndrome (2), PallistereHall syndrome (2), SimpsoneGolabieBehmel syndrome (2), SmitheLemlieOpitz syndrome (2), TowneseBrocks syndrome (2) and one each : campomelic dysplasia, caudal regression, Ellis van Creveld syndrome, Kallmann syndrome, KlippeleFeil syndrome, RubinsteineTaybi syndrome, sirenomelia, and Zellweger syndrome.
4. Discussion During the 26-year study period, the overall prevalence at birth of CAKUT was 48.4/10,000. The most frequent CAKUT were, (in parentheses the prevalence at birth per 10,000 and the percentage are given), hydronephrosis (14.0; 29), renal dysplasia (10.1; 21), renal agenesis (6.6; 14), vesicoureteric reflux (VUR) (5.3; 11), and megaureter (4.5; 9). The prevalence per 10,000 births of CAKUT in the previous reports is shown on Table 4. Vast differences in the prevalence of CAKUT appeared between the different studies. The
same variations in prevalence were noted for different categories of CAKUT : renal agenesis, cystic kidney and bladder exstrophy. In our study, 34% of the patients had associated CAKUT. The percentage of associated CAKUT in the other studies is shown on Table 5. There were large regional differences in the percentage of associated anomalies in CAKUT from 24 in Norway [Isaksen et al., 2000] to 37 in Atlanta [Honein et al., 2003], as well as in the different types of CAKUT: the percentage of associated anomalies
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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1 2 3 Q2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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Table 4 Review of literature: total number of cases of CAKUT and prevalence per 10,000 births of all CAKUT, of renal agenesis, cystic kidney and bladder exstrophy.
Total number All CAKUT Renal agenesis Cystic kidney Bladder exstrophy
Q1
[EUROAT]
[International Clearinghouse for Birth Defects Surveillance and Research annual report, 2008]b
[Scott and Renwick, 1993]
[Cocchi et al., 1996]
[Sebastian Calderon and Zarante, 2006]
z2800/year 33.7a 1.18 4.18 0.69
z1400/year
736 11.5f
349 16.6g
83 43.0h 2.0 2.6
0.33 to 7.16c 0.2 to 11.9d 0.0 to 1.33e
[Caiulo et al., 2012]
[Fletcher et al., 2012]
[Melo et al., 2012]
[Adams-Chapman et al., 2013]
This study
Total number
171
147
524
171
1678
All CAKUT Renal agenesis Cystic kidney Bladder exstrophy
96.1i
0.16j
14.8k
45.8l
48.4 6.6 10.8 0.44
a In 20 registries of congenital anomalies from 12 European countries reporting their results to EUROCAT, the prevalence of CAKUT varied from 2 (North East Italy) to 69 (Mainz, Germany). b ICBDSR (International Clearinghouse for Birth Defects Surveillance and Research) registered only renal agenesis, cystic kidney and bladder exstrophy. c Toscany, Italy and Czech Republic. d British Columbia, Canada, North East Italy and Paris, France. e 14 registries out of 37 registries of congenital anomalies around the world and Ireland. f Northern Region of UK. g Emilia-Romagna, Italy. h Colombia. i Ultrasound mass screening at 2 months of age in Salento, Italy. j Prevalence of children <20 years of age over the study period 1996e2006 in Australia and New Zealand. k Tertiary neonatal unit in a referral center for congenital anomalies in Belo Horizonte, Brazil. l Very low birthweigh infants ascertained by the US National Institute of Child Health and Human Development Neonatal Research Network.
varied for hydronephrosis from 14 in Europe [Garne et al., 2009] to 35 in Brazil [Melo et al., 2012], for renal agenesis, from 28 in UK [Carter et al., 1979] to 68 in Atlanta [Honein et al., 2003], and for multicystic renal dysplasia (MCDK), from 5 in Bonn [RudnikSchöneborn et al., 1998] and Rotterdam [van Eijk et al., 2002] to 46 in Atlanta [Honein et al., 2003]. The enormous variability in prevalence in different studies depends of methodological differences. For example, surveillance registries differ in whether ascertainment is active or passive. Other reasons that could explain the different frequencies of additional anomalies may be time that the surveillance continued after birth, and all patients were or not taken into consideration, including stillborns and terminations of pregnancy. Other factors were the differences in definitions (for example EUROCAT had not exactly the same definition than the ICBDSR for renal agenesis and cystic kidney) and inclusion/exclusion criteria, the length of time after
birth that patients were examined, the variability of clinical expression of associated anomalies, the difficulty to knew the proportion of patients diagnosed by objective techniques, the selection of patients, the sources of ascertainment, and the sample size. In addition to these factors, autopsies were not always performed, there was not always follow-up, many authors did not report all patients born in a certain geographical area, but instead, patients referred to a certain health care facility, and there are true population differences and changes in frequency over time [EUROAT]. Moreover, many of the estimates of prevalence are uncertain due to small numbers. The same concerns exist for the comparisons of subgroups of associated anomalies. In this study chromosomal abnormalities were observed in 119 (7%) infants with CAKUT. The reported percentages of chromosomal abnormalities in infants with CAKUT vary from 3.7 in Norway [Isaksen et al., 2000] to 24 and 12 in London [Nicolaides et al., 1986,
Table 5 Review of literature: total number of cases of CAKUT and percentage of associated anomalies in all CAKUT and in hydronephrosis, renal agenesis and multicystic dysplastic kidney (MCDK).
Total number All CAKUT Hydronephrosis Renal agenesis MCDK
Total number All CAKUT Hydronephrosis Renal agenesis MCDK
[Carter et al., 1979]
[Wilson and Baird, 1985]
[Macquard-Moulin et al., 1989]
[Al Naimi et al., 2013]
[Cocchi et al., 1996]
[Rudnik-Schöneborn et al., 1998]
[Lazebnik et al., 1999]
[Isaksen et al., 2000]
103
209
164
54
349 30
204
102
112 24
28
1/3 to 1/2 32
18
5
35
[Aubertin et al., 2002]
[van Eijk et al., 2002]
[Honein et al., 2003]
[Wiesel et al., 2005]
[Garne et al., 2009]
[Fletcher et al., 2012]
[Westland et al., 2013]
This study
73
38
169 37 20 68 46
1130 33
3648
524
2684b
1678 34 26 36 12
16
5
14
a
35 63
32
a Chromosomes anomalies were excluded as well as congenital hydronephrosis with posterior urethral valves and congenital hydronephrosis with prune belly syndrome. There were large regional differences ranging, in Europe, from 2 (Poznan, Poland) to 29 (Wales, UK). b A systematic review of 43 published studies of unilateral renal agenesis.
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Q3
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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3.3% [Benacerraf et al., 1990], 0.7% [Gunn et al., 1995], 0.3% no risk factors to 1.0% risk factors [Chitty, personal communication to Valentin and Marsal, Valentin and Marsal, 1998], and 0% [Valentin and Marsal, 1998]. Unfortunately, all of these studies were performed before the array CGH technology was available. Many syndromes, sequences, associations and spectrums were reported to be associated with CAKUT [Stoll et al., 1990; Wellesley
1992] respectively (Table 6). In this series the more common chromosomal abnormalities were trisomy 18 (28%), trisomy 21 (22%), trisomy 13 (20%), Turner syndrome (9%), triploidy (8%), and chromosomal structural aberrations (15%). This figure compares well with that in other studies (Table 6). Chromosomal anomalies in fetus with pyelectasis detected at ultrasound examination accounted for 11.6% [Reuss et al., 1988], 3.9% [Morin et al., 1996],
Table 6 Review of literature: total number of cases of CAKUT and percentage of recognized conditions, chromosomal and non chromosomal, and of multiple congenital anomalies (MCA). [EUROAT]
[Carter et al., 1979]b
Total number 17.739 103 Chromosomal anomalies Total 4.3 Trisomie 18 Trisomie 21 Trisomie 13 Turner syndrome Other Non chromosomal recognized conditions Total VACTERL Meckel-Gruber Prune-belly Other MCA MSKa 12 CHDa 15 GIa 11 a CNS 12 Respiratory Ear Orofacial 4 Abdominal wall Diaphragme Genital Other [Lazebnik et al., 1999]d Total number 102 Chromosomal anomalies Total Trisomie 18 Trisomie 21 Trisomie 13 Turner syndrome Other Non chromosomal recognized conditions Total VACTERL MeckeleGruber Prune-belly Other MCA MSKa 26 CHDa 23 a GI 14 a CNS 13 Respiratory Ear 5 Orofacial 10 Abdominal wall 3 Diaphragme Genital 6 Other a b c d e f
[Nicolaides et al., 1986] and [Nicolaides et al., 1992]
[Macquard-Moulin et al., 1989]
[Boue et al., 1988] [Eydoux et al., 1989]c
[EUROFETUS STUDY REPORT et al., 1995]
[Cocchi et al., 1996]
682
164
936
954
349
12 to 24 23 22 21
11 28 19 17
2.9 18 32 14 4 32
5.2
9.5
4
34 45 17 10
2 3
16 9
[Isaksen et al., 2000]
[Aubertin et al., 2002]e
[Wiesel et al., 2005]
[Damen et al., 2005]
[Garne et al., 2009]e,f
[Melo et al., 2012]
This study
112
73
1130
408
3648
524
1678
3.7 35 18 23
3
23
11 25 23 16 13 22
8.6
4.4 10 16 21
57
43
6 23 20 57
17
7
18
12
14 57
7 2 1 2
14
1 4
11
53
7 28 22 20 9 20
11 12 12 50 25
10 33 21 14 31 17 15 16 10 5 9 4 4 1 3 16
MSK ¼ musculoskeletal, CHD ¼ congenital heart disease, GI ¼ gastrointestinal, CNS ¼ central nervous system. Renal agenesis only. Both studies were done in Paris. Multicystic dysplastic kidney (MCDK) only. Unilateral MCDK only. Hydronephrosis only.
Please cite this article in press as: Stoll C, et al., Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT), European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.014
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C. Stoll et al. / European Journal of Medical Genetics xxx (2014) 1e7
and Howe, 2001]. In our series 168 out of 1678 (10%) infants with CAKUT had non chromosomal recognizable conditions including 56 VACTERL association (33%), 36 MeckeleGruber syndrome (21%), 23 prune belly syndrome (14%), and 53 (31%) other recognizable conditions (Table 3). In the previous reports the percentage of non chromosomal recognizable conditions varied considerably (Table 6) from 6% in the EUROSCAN study [Wiesel et al., 2005] to 11% in Brazil [Melo et al., 2012]. Syndromic forms of renal hypoplasia/dysplasia include rare disorders affecting extrarenal organs such as the eye, the central nervous system, the skin, the limbs, and others. The list of syndromes that include the renal agenesis/hypoplasia/dysplasia phenotype consists of at least 73 clinical conditions. Renalcoloboma syndrome, orofaciodigital syndrome, branchiootorenal syndrome, renal cysts and diabetes syndrome, and Fraser syndrome are the most frequent syndromes associated with renal parenchymal defects [Sanna-Cherchi et al., 2007]. There are no agreements in the literature as to which associated anomalies are most common in infants with CAKUT and MCA. In this study (Table 3) the most common associated anomalies were musculoskeletal, digestive, cardiac, central nervous, ear, face and neck, pulmonary, oral clefts, abdominal wall, and hypospadias. The more common anomalies were for musculoskeletal anomalies limb reduction defects, polydactyly and syndactyly, for digestive system anomalies anal atresia and malrotation, for cardiac defects ventricular septal defect (VSD) and atrial septal defect (ASD), for central nervous system anomalies neural tube defects, for ear, face and neck anomalies facial dysmorphia and hypertelorism, and for pulmonary system anomalies lung hypoplasia. In the literature the percentage of the most common associated anomalies varied greatly (Table 6). However, it is difficult to compare our results with those of other studies as, for example some authors include the patients with isolated CAKUT in the total number of patients. Other reasons for the discrepancies between the reported studies and this study were aforementioned. In order to evaluate patients and to compare studies, it is necessary to standardize the methods of case classification. Congenital anomalies and associated anomalies must be grouped into meaningful syndromes and conditions. Methods for case classification into isolated, multiple and syndrome categories were described [Rasmussen et al., 2003]. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying etiology of congenital anomalies. The causes of CAKUT include [Wellesley and Howe, 2001] chromosomal abnormalities; dominant or recessive genes (“Mendelian inheritance”); familial inheritance in the absence of a Mendelian syndrome; known syndromes, sequences, associations, and related anomalies (i.e., VACTERL association, MeckeleGruber syndrome); teratogenic exposures (i.e. antiepileptic drugs-carbamazepine and phenobarbital [Carta et al., 2007]); subfertility and overweight/obesity [Honein et al., 2003]; and unknown causes. The prenatal exposure to teratogens may be preventable. The molecular basis for CAKUT remains unknown. A large number of monogenic knock-out mouse models have been developed with offspring manifesting a phenotypic spectrum which mimics the human CAKUT complex and numerous candidate genes have been discussed [Weber, 2012]. The potential limitations of the present study include the small number of infants in some categories of CAKUT and the lack of molecular studies of the patients with CAKUT. However, the study was performed in a homogeneous population, and complete ascertainment was obtained. The strength of our study involves a
well-defined population in which all patients were referred to the Registry of Congenital Anomalies including livebirths, stillbirths, and termination of pregnancies, liveborn infants were followed up until 2 years of age, the patients were reported by several sources, every patient was examined by a clinical geneticist, and the registration was active. In conclusion, we have determined a frequency of congenital anomalies associated with CAKUT of 34%. This result was derived from a geographically-based cohort of close to 350,000 births. The associated anomalies underscore the need for thorough evaluation and careful characterization of patients with CAKUT. A multidisciplinary approach is needed to comprehensively cover all aspects of these often complicated cases. A routine screening for other congenital anomalies, especially of the musculoskeletal, digestive, cardiac, central nervous and pulmonary systems need to be considered in patients with CAKUT, and genetic counseling seems warranted in most of these complicated cases. Pediatricians, pediatric nephrologists, geneticists and birth defects surveillance programs should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in 17% of the cases. Conflicts of interest The authors declare there are no conflicts of interest. References Adams-Chapman I, Hansen NI, Shankaran S, Bell EF, Boghossian NS, Murray JC, et al. Ten-year review of major birth defects in VLBW infants. Pediatrics 2013;132: 49e61. Al Naimi A, Baumüller J-E, Spahn S, et al. Prenatal diagnosis of multicystic dysplastic kidney disease in the second trimester screening. Prenat Diagn 2013;33:726e 31. Q4 Aubertin G, Cripps S, Coleman G, et al. Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management. Prenat Diagn 2002;22:388e94. Benacerraf BR, Mandell J, Estroff J, et al. Fetal pyelectasis: a possible association with Down syndrome. Obstet Gynecol 1990;76:58e60. Boue A, Muller F, Briard ML, Boue J. Interest of biology in the management of pregnancies where a fetal malformation has been detected by ultrasonography. Fetal Ther 1988;3:14e23. Caiulo VA, Caiulo S, Gargasole C, et al. Ultrasound mass screening for congenital anomalies of the kidney and urinary tract. Pediatr Nephrol 2012;27:949e53. Carta M, Cimador M, Giuffrè M, Sergio M, Di Pace MR, De Grazia E, et al. Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy. Pediat Nephrol 2007;22:1054e7. Carter CO, Evans K, Pescia G. A family study of renal agenesis. J Med Genet 1979;16: 176e88. Cocchi G, Magnani C, Morini MS, Garani GP, Milan M, Calzolari E. Urinary tract abnormalities (UTA) and associated malformations: data of the EmiliaeRomagna registry. IMER group. EmiliaeRomagna registry on congenital malformations. Eur J Epidemiol 1996;12:493e7. Cuckow PM, Nyirady P, Winyard PJD. Normal and abnormal development of the urogenital tract. Prenat Diagn 2001;21:908e16. Damen HA, De Jong TP, Stigter RH, et al. Congenital renal tract anomalies: outcome and follow-up of 402 cases detected antenatally between 1986 and 2001. Ultrasound Obstet Gynecol 2005;25:134e43. EUROCAT: http://www.eurocat-network.eu/. Eurofetus Study Report. Cost-effectiveness of antenatal screening for fetal malformation by ultrasound. In: Levi S, Grandjean H, Lebrun T, editors. European Union, Direction Generale XII, Brussels, vol. 1; 1995. Eydoux P, Choiset A, Le Porrier N, et al. Chromosomal prenatal diagnosis: study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diagn 1989;9:255e69. Fletcher J, McDonald S, Alexander SI, on behalf of the Australian and New Zealand Pediatric Nephrology Association (ANZPNA). Prevalence of genetic renal disease in children. Pediat Nephrol 2012;28:251e6. Garne E, Loane M, Wellesley D, et al. Congenital hydronephrosis: prenatal diagnosis and epidemiology in Europe. J Pediat Urol 2009;5:47e52. Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: Incidence and outcome. Am J Obstet Gynecol 1995;172:479e86. Honein MA, Moore CA, Watkins ML. Subfertility and prepregnancy overweight/ obesity: possible interaction between these risk factors in the etiology of
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