Objective: The neurotrophin receptor TrkB has been implicated in the regulation of energy homeostasis in rodents. We have previously identified four rare missense mutations in the gene encoding TrkB, NTRK2, in 198 severely obese children with developmental delay. We have now undertaken a more detailed analysis of the in vitro functional consequences of the mutations identified: I98V, P660L, T821A and Y722C. Design: Wild-type and mutant TrkB receptor constructs were stably transfected into PC12 cells and the signaling responses to the endogenous ligand, brain-derived neurotrophic factor (BDNF), were examined by Western blotting of cell lysates. In the case of Y722C, PC12 cells stably expressing this mutant were studied for their ability to respond to BDNF by promoting neurite outgrowth and cell survival. Results: Further functional characterization of the previously reported Y722C TrkB mutation reveals impaired activation of mitogen-activated protein kinase, phospholipase C-g and Akt, as well as reduced BDNF-induced neurite outgrowth and cell survival in stably transfected PC12 cell lines. However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type. Conclusion: We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF. Thus, impaired hypothalamic neurogenesis may contribute to the severe hyperphagia and obesity seen in the individual harboring the Y722C variant. The other three rare TrkB variants do not show reduced autophosphorylation or impaired downstream signaling in vitro and, as yet, it is unclear whether these variants contribute to obesity in these patients.

BACKGROUNDGNAS encodes the Gα s (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODSWe performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTSAlmost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, −0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONSBecause pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.

Young patients with diabetes are particularly vulnerable to long‐term complications, and require a carefully planned transition to adult diabetes care. As clinic non‐attendance has been identified as an issue for transitional clinics, we audited our well established clinic to look at non‐attendance rates, and to examine the characteristics of those who miss transitional clinic appointments.We conducted a retrospective analysis of audit data from the diabetes transitional clinic in January to December 2004, and September 2007 to September 2008.The results showed that 40/53 patients missed at least one appointment in 2004, compared to 19/61 in 2007–8 (p<0.0001). There was no reduction in HbA1c in this group (2004: median HbA1c 9.4% [range 6.8–13.2%]; 2007–8: median HbA1c 9.7% [range 5.7–14.0%[). In 2007–8, the non‐attender group had higher HbA1c (full attenders: median [range] HbA1c 8.9% [5.7–12.7%]; those who missed at least one appointment: HbA1c 10.3% [7.7–14.0%]; p<0.001), and were older (non‐attenders mean [SD] 18.0 [1.10] years, full attenders 17.3 [1.17] years). Sex and type of diabetes did not affect ‘did not attend’ rates.Those who miss diabetes transitional clinic appointments have poorer glycaemic control, although non‐attendance is complex and may be due to a variety of reasons. New strategies to help young people deal with their diabetes are needed. Copyright © 2010 John Wiley & Sons.

A 3 week old infant presented with persistent hypoxaemia and was diagnosed with pulmonary arteriovenous malformations. Her family history was positive for hereditary haemorrhagic telangiectasia. She was treated successfully with coil embolotherapy at the age of 4 months. Transcatheter embolisation may be considered the primary treatment for pulmonary arteriovenous malformations in infancy.H ereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant mucocutaneous and visceral vascular dysplasia, characterised by the occurrence of telangiectasia and arteriovenous malformations (AVMs). Patients are usually recognised by the presence of telangiectasia, recurrent epistaxis, and a positive family history. Clinical symptoms usually appear after puberty.First reports appear to be from around 1864 when Sutton and Babington described patients with recurrent epistaxis and vascular abnormalities. Rendu, Osler, and Weber later recognised the combination of epistaxis in a familial pattern with telangiectasia. Pulmonary AVM is the most dangerous localisation of HHT because of the risk of paradoxical septic embolism.1 In 1897, the first pulmonary AVM was found at the postmortem examination of a 12 year old boy.2 Reported series of patients with pulmonary AVM, however, indicate that such findings are uncommon in children.3-6 To our knowledge, only 12 cases of pulmonary AVM diagnosed during the first year of life have been described from 1975 onwards, the last one being reported in 2000.6 Most of the previously described cases were treated primarily with surgery. We report on a 3 week old infant who presented with persistent hypoxaemia as a result of pulmonary AVM. CASE REPORTA 3 week old Dutch Antillean girl was admitted after an apparently life threatening event. The pregnancy was uncomplicated, and the patient was born term with a birth weight of 2420 g (p13). Apgar scores were 8 and 9 after one and five minutes respectively. There had been no remarkable events until the day of admission, when she had an apnoeic episode after several coughs. The pregnancy had been the mother's seventh. Two older children originate from another relationship; four pregnancies were terminated by legal abortion. The history later revealed the occurrence of HHT in the family, with a confirmed mutation in the gene coding for endoglin on chromosome 9. This family, 3655, and the mutation have been described previously.7 The patient's mother has been diagnosed recently with HHT, and the presence of the same mutation is under investigation.Physical examination at admission showed a healthy and alert black neonate without fever. Besides mild tachypnoea and a persistent percutaneous oxygen saturation of 87%, vital signs were stable. Auscultation of the chest showed normal heart sounds with a slight early systolic murmur, maximal at the upper left sternal border, attributed to a persistent ductus arteriosus as evidenced by cardiac ultrasonography. On revision three weeks later, it was no longer audible o...

There were a large number of admissions and the majority were emergencies. Parents generally felt that they receive good care, although with some lack of knowledge amongst the ward staff. There were an unacceptable number of adverse incidents reported. We recommend that education of ward staff in diabetes is carried out regularly with reference to the standards of care.