Hirschsprung disease and congenital anomalies of the kidney and urinary tract (CAKUT): a novel syndromic association.
Congenital anomalies of the kidney and urinary tract (CAKUT) can be associated with Hirschsprung disease (HSCR). Based on the common genetic background of enteric nervous system and kidney development, the reported association of CAKUT and HSCR seems underestimated. Therefore, we designed a prospective study aimed at determining the prevalence of CAKUT in HSCR patients and at identifying RET, glial cell line-derived neurotrophic factor (GDNF), and GDNF family receptor alpha1 (GFRalpha1) mutations or haplotypes associated with this subset of HSCR patients. Eighty-four HSCR patients consecutively admitted to our department between July 2006 and July 2007 underwent interviews, notes review, ultrasound screening (further investigation according to detected anomaly), urinalysis, and DNA extraction for molecular genetics study. Another 27 patients with isolated CAKUT were included as a control group for the molecular genetics study. Twenty-one patients (25%) with HSCR had associated CAKUT, with hydronephrosis and hypoplasia being the most frequent diagnoses. Nine of 21 CAKUT were symptomatic. Six additional patients had other non-CAKUT anomalies (for example, stones, Barter syndrome) that were excluded from association and molecular genetics analysis to avoid bias of inclusion criteria. RET mutations were found in 5 patients (4 HSCR, 1 HSCR + CAKUT, 0 CAKUT) and GDNF mutations in 3 (2 HSCR, 1 CAKUT, 0 HSCR + CAKUT). No GFRalpha1 mutations were found. Finally, the HSCR-predisposing T haplotype of RET proto-oncogene was found in 64% of HSCR, 50% of HSCR + CAKUT, and in 24% of CAKUT patients. The incidence of CAKUT in HSCR patients is 4- to 6-fold higher than expected. Therefore, a patient with HSCR has a 3- to 18-fold higher risk of developing a CAKUT, particularly hydronephrosis or hypoplasia. If we consider that the proportion of predisposing haplotype in HSCR + CAKUT patients resembles that of other syndromic HSCR, we can conclude that HSCR + CAKUT has to be considered a novel syndromic association. These results need to be confirmed in a larger series. At present, we strongly suggest considering ultrasound screening of the urinary tract in every patient with a diagnosis of HSCR.
Prato
Alessio Pini
AP
From Department of Pediatric Surgery (APP, GM, CG, VJ) and Molecular Genetics Laboratory (IC), Giannina Gaslini Institute, Genoa; Division of Nephrology, Dialysis and Transplantation (MM, GMG), Giannina Gaslini Children's Hospital, Genoa; and University of Genoa (GM, CG, VJ), Genoa, Italy.
Musso
Marco
M
Ceccherini
Isabella
I
Mattioli
Girolamo
G
Giunta
Camilla
C
Ghiggeri
Gian Marco
GM
Jasonni
Vincenzo
V
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D003952:Diagnostic Imaging; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000150:complications* / Q000235:genetics; D006801:Humans; D006869:Hydronephrosis / Q000150:complications; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D014551:Urinary Tract / Q000002:abnormalities*; D014718:Vesico-Ureteral Reflux / Q000150:complications
C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human