Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.

OBJECTIVE: Congenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing. DESIGN: We performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies. RESULTS: We identified novel de novo missense mutations in GUCY2C, the gene encoding receptor guanylate cyclase C (GC-C) in 4 patients with CSD. One patient developed severe, early-onset IBD and chronic arthritis at 4 years of age. GC-C is an intestinal brush border membrane-bound guanylate cyclase, which functions as receptor for guanylin, uroguanylin and Escherichia coli heat-stable enterotoxin. Mutations in GUCY2C were present in different intracellular domains of GC-C, and were activating mutations that enhanced intracellular cyclic guanosine monophosphate accumulation in a ligand-independent and ligand-stimulated manner, following heterologous expression in HEK293T cells. CONCLUSIONS: Dominant gain-of-function GUCY2C mutations lead to elevated intracellular cyclic guanosine monophosphate levels and could explain the chronic diarrhoea as a result of decreased intestinal sodium and water absorption and increased chloride secretion. Thus, mutations in GUCY2C indicate a role for this receptor in the pathogenesis of sporadic CSD.

Influence of Lateral Sitting Wedges on the Rasterstereographically Measured Scoliosis Angle in Patients Aged 10-18 Years with Adolescent Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional axial deviation of the spine diagnosed in adolescence. Despite a long daily sitting duration, there are no studies on whether scoliosis can be positively influenced by sitting on a seat wedge. For the prospective study, 99 patients with AIS were measured with the DIERS formetric III 4D average, in a standing position, on a level seat and with three differently inclined seat wedges (3°, 6° and 9°). The rasterstereographic parameters 'scoliosis angle' and 'lateral deviation RMS' were analysed. The side (ipsilateral/contralateral) on which the optimal correcting wedge was located in relation to the lumbar/thoraco-lumbar convexity was investigated. It was found that the greatest possible correction of scoliosis occurred with a clustering in wedges with an elevation on the ipsilateral side of the convexity. This clustering was significantly different from a uniform distribution (p < 0.001; chi-square = 35.697 (scoliosis angle); chi-square = 54.727 (lateral deviation RMS)). It should be taken into account that the effect of lateral seat wedges differs for individual types of scoliosis and degrees of severity. The possibility of having a positive effect on scoliosis while sitting holds great potential, which is worth investigating in follow-up studies.