BackgroundCraniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing.MethodsWe used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative.ResultsWe identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3).ConclusionsThis substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

In our experience, GFD showed short-term benefits by reducing GI symptoms and severe hypoglycaemia while the insulin requirement increased significantly.

Objective: To investigate long-term mortality rates and causes of death in individuals diagnosed with type 1 diabetes before the age of 15 years during the period 1989-2012 or known to paediatric diabetes teams in 1989, in Northern Ireland.Methods: A cohort of 3129 patients from the Northern Ireland Childhood Diabetes Register was linked to death registrations and underlying causes, coded according to ICD-9 or ICD-10.Standardized mortality ratios (SMRs) were calculated as the ratio of observed to expected deaths by sex, attained age, time since diagnosis, calendar period, and cause of death.Results: Subjects were followed to December 31, 2012 giving 39 764 person-years of follow-up (median 12.1 years). In total, 59 subjects had died (1.5 per 1000 person-years) compared with 19.9 deaths expected, an SMR of 296 (95% confidence interval (CI) 229-382).Women had a significantly higher excess risk of mortality than men with SMRs of 535 (95% CI 361-764) and 203 (95% CI 136-291), respectively. Over half of the deaths (56%) were judged to be related or possibly related to diabetes with most of these due to acute (n = 24) or late (n = 6) complications.Conclusions: Subjects with type 1 diabetes diagnosed less than 15 years of age had 3 times the mortality risk of the general population. Over half of the deaths were related to acute or chronic complications of diabetes. K E Y W O R D Smortality, standardized mortality ratio, type 1 diabetes

Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.

SummaryObjectiveLoss‐of‐function mutations in IGSF1 result in X‐linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred.Design, Patients and MeasurementsA novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype‐phenotype correlations were investigated in the wider kindred.ResultsThe mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH‐based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed.ConclusionsAs observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where TSH‐based CH screening programmes may fail to detect CeCH at birth.