Mars Skae

Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth

3-M syndrome, a primordial growth disorder, is associated with mutations in CUL7 and OBSL1. Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome. CCDC8 is a widely expressed gene that is transcriptionally associated to CUL7 and OBSL1, and coimmunoprecipitation indicates a physical interaction between CCDC8 and OBSL1 but not CUL7. We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth.

The association of cardiac ventricular hypertrophy with congenital hyperinsulinism.

OBJECTIVE Ventricular hypertrophy (VH) has been observed in children with congenital hyperinsulinism (CHI), a condition of hypoglycaemia characterised by dysregulated insulin secretion, but the prevalence is not known. PATIENTS AND METHODS Cardiac assessment was performed in children (n=49) with CHI at diagnosis and follow-up. Two dimensional and Doppler echocardiography studies were used to assess cardiac structures, while M-mode study was used to measure left ventricular (LV) dimensions, subsequently converted to Z scores. Where possible, LV hypertrophy was confirmed by LV mass index (g/m(2.7)) >95th centile. RESULTS Cardiac structural lesions were found in 14 (28%) children. At initial echocardiography, VH was present in 31 (65%) children with median (range) LV posterior wall dimension in diastole Z scores of +1.6 (-2.4 to +5.8) and interventricular septal wall dimension in end diastole Z scores of +1.9 (-1.7 to +17.2). At follow-up echocardiography, performed after an interval of 178 (45-390) days, VH persisted in 16 (33%) children. In regression analysis, the presence of VH (odds ratio (95% confidence intervals) 1.1 (1.0-1.2), P=0.04) at initial echocardiography was correlated with maximum glucose requirement at diagnosis, indicating that severity of CHI at presentation may play a role in the pathogenesis of VH. CONCLUSIONS A significant proportion of children with CHI have cardiac structural lesions. A majority also have VH, which may be associated with the severity of CHI at diagnosis. VH may persist in some children, which requires careful long-term cardiac review.

Islet cell proliferation is inappropriately maintained in the pancreas of children with congenital hyperinsulinism in infancy

o s te r T e m p la te ro m w w w .m a n c h e s te .a c .u k /p h o to g ra p h ic s Age (months) Congenital Hyperinsulinism of Infancy (CHI) is a potentially lethal condition of profound hypoglycaemia caused by unregulated insulin release in the neonatal period and early infancy. CHI mainly arises due to mutations in ATPsensitive K-channel genes (ABCC8 and KCNJ11) which can manifest in all islets cells – diffuse CHI (CHI-D), or can be localised to a focal lesion, focal CHI (CHI-F). Increased rates of cell proliferation have been reported in the CHI-D and this may be liked to ABCC8 and KCNJ11 defects. Here, we examined the proliferative index (PI) of islet cells in CHI-D patients and compared this with focal CHI (CHI-F), which is caused by loss of cell cycle repression in β-cells specifically within the focal domain. We also examined islet PI in patient tissues with severe CHI unrelated to defects in ABCC8 and KCNJ11, atypical CHI (CHI-A). Background