Three additional cases of the congenital hypothalamic “hamartoblastoma” (Pallister‐Hall) syndrome

Abstract

The cause of this syndrome remains unknown. Epidemiologic studies should be done by experts. The first two cases above gave a "muddy" history for possible teratogens--a "recall bias"--one of a vaginal foam spermicide, one of exposure over several days to a heavy residue of aviation diesel fuel exhaust. We do not think these are pertinent but they do point to the problem of getting a meaningful history. In addressing this problem (in a letter of 5/27/82) R.J. Berry, M.D., medical epidemiologist, Centers for Disease Control, Atlanta, Georgia, wrote "... a designed study providing standardized interview forms with controls could be designed if cases continue to appear." Since this seems to be the case, perhaps this approach should be embraced. A teratogen(s) appears to be a good bet since the condition was recognized suddenly with the first Montana case in February, 1978. Even though no record has been found in the files of the Armed Forces Institute of Pathology, Children's Hospital Automated Medical Programs (CHAMP), Montreal or Wisconsin and one or two other places, it might be worthwhile to look back at all cases of imperforate anus which have come to autopsy for possible associated CNS lesions. We may be deluding ourselves in considering the condition as "new." Chromosomes were usually studied in lymphocytes, once on the tumor and once or twice on marrow. It might be well to do more than one tissue in all new cases. Once again there appears to be no "obligatory" finding for any one syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

GLI3 repressor controls functional development of the mouse ureter

“…Hh signaling has been previously implicated in ureteral smooth muscle development (5,7,8,37,38). Here, using application of Rarb2-Cre to analyze Hh signaling in the ureter mesenchyme, we have identified what we believe to be a novel additional requirement for Hh signaling in unidirectional and coordinated ureter contractions via regulation of 2 distinct cell populations believed to be important in electrical activity initiation and transmission.…”

Mammalian Kidney Development: Principles, Progress, and Projections

“…As loss of Gli3 results in inappropriate Hedgehog pathway activation in any responsive cell type, some phenotypes likely reflect neomorphic actions rather than the normal action of hedgehog signals. Consistent with the important silencing function of Gli3, mutations in GLI3 in patients with Pallister-Hall syndrome can result in renal agenesis, hypoplasia, or hydronephrosis (Hall et al 1980;Pallister et al 1989). …”

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

“…Intriguingly, deletion of both Gli3 and Shh rescues the renal phenotype observed in Shh conventional mutants as well as the expression of Pax2, Sall1, Cyclin D1, N-Myc, Gli1, and Gli2 [Gill and Rosenblum, 2006]. Inappropriate activation of the Shh-Gli signaling pathways occurs in several human cancers [Ok et al, 2012] and renal malformations [Pallister et al, 1989;Tsanev et al, 2009;McPherson and Cold, 2013;Blake et al, 2016]. Genetic elimination of Ptc1 in the ureteric cell lineage resulted in increased ectopic Shh signaling activity in the cortical collecting ducts and the UB tips of the developing kidney.…”

“…These data demonstrated that Gli3R has a multifunctional role in the functional development of the mouse ureter, being required for normal smooth muscle cell development and differentiation. Also, it is well known that Pallister-Hall syndrome (PHS) is caused by a genetic mutation of Gli3 that produces the transcriptional repressor Gli3R [Pallister et al, 1989]. Urogenital malformation in PHS exhibits renal aplasia, renal hypoplasia, and hydroureter [Pallister et al, 1989;Tsanev et al, 2009;McPherson and Cold, 2013;Blake et al, 2016].…”

“…Also, it is well known that Pallister-Hall syndrome (PHS) is caused by a genetic mutation of Gli3 that produces the transcriptional repressor Gli3R [Pallister et al, 1989]. Urogenital malformation in PHS exhibits renal aplasia, renal hypoplasia, and hydroureter [Pallister et al, 1989;Tsanev et al, 2009;McPherson and Cold, 2013;Blake et al, 2016]. Studies using mutant mice with Gli3R and Gli3 null alleles have demonstrated that Gli3R alters the normal Shh signaling domain in the caudal embryo and that Gli3R impairs nephric duct patterns, renal branching morphogenesis, and nephrogenic mesenchyme self-renewal.…”