Although it is well known that RET mutation causes multiple endocrine neoplasia type 2A (MEN2A), thus far only 3 individuals have been reported to have MEN2A and renal agenesis/dysgenesis.
It is possible that subtle malformations in the ENS may result from RET dysfunction which then predisposes the individual to environmental influences which initiate the later onset of muscle degeneration.
Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET-null mice.
Hirschsprung disease (HSCR) is a congenital developmental defect of the enteric nervous system known to be associated with the RET-protooncogene and other candidates.
Germline mutations of RET cause a dominantly inherited dysgenesis of the enteric nervous system known as Hirschsprung's disease (HSCR; aganglionosis megacolon).
Transgenic mice with the highest levels of DbetaH-RET(MEN2B) expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations in the Ret gene.
Thus, the two 'faces' of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect.