Hirschsprung Disease and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Abstract

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.

Mammalian Kidney Development: Principles, Progress, and Projections

“…Loss of Gdnf, Ret, or Gfra1 in the mouse leads to an almost completely penetrant failure of UB outgrowth, and resulting kidney agenesis (Jain et al 2009). Patients with Hirschsprung's disease present with agangliosis of the intestine as a result of mutations in either Gdnf or Ret; the intestinal pathology is coupled with renal agenesis, hypoplasia, or dysplasia (Pini Prato et al 2009). Whereas a total loss of Ret in the mouse results in kidney agenesis, inactivating mutations (such as Y1062F) that remove a specific site of intracellular phosphorylation of the Ret receptor results in renal hypoplasia (Wong et al 2005;Jain et al 2006Jain et al , 2010.…”

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

“…RET, a transmembrane receptor tyrosine kinase (RTK), regulates the development of many organ systems and its aberrant signaling produces phenotypes in mice that are reminiscent of human diseases such as Hirschsprung disease, CAKUT and MEN2 hereditary cancer syndromes (Amiel and Lyonnet, 2001;Amiel et al, 2008;Jain, 2009;Moore, 2006;Ponder and Smith, 1996;Prato et al, 2009;Skinner et al, 2008). In the urinary system, complete loss or misexpression of Ret results in bilateral renal agenesis, dysplasia, defective insertion of the WD into cloaca and defective ureter maturation (Batourina et al, 2002;Chia et al, 2011;Jain et al, 2006b;Jain et al, 2010;Murawski and Gupta, 2008;Schuchardt et al, 1994;Shakya et al, 2005;Uetani et al, 2009).…”

The many faces of RET dysfunction in kidney

“…RET mutations have been reported in patients presenting with MEN2 and HSCR, CAKUT and MEN2, and more recently in patients with isolated CAKUT, or with HSCR and CAKUT. 2,12,13 These observations illustrate the potential for aberrations in RET signaling to predispose for both isolated as well as multisystem defects in urinary and other systems. They have led to increased efforts to understand the mechanisms of RET function at cellular as well as at organ level in hopes of delineating how abnormalities of RET signaling can be associated with multiple syndromes.…”