Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Microbial Mannan As A Cause Of Phagocyte Dysfunction In Crohn's Disease

Crohn's disease (CD) is a granulomatous condition that is mimicked by rare inherited disorders of phagocyte function and has clinical features compatible with an underlying impaired' defence against the gut microbiota. Crohn's'disease patients commonly have circulating antibodies (ASCA) against a mannan present in baker's yeast (Saccharomyces cerevisiae). I have investigated the possibility that S.cerevisiae mam?-ans may induce defects in phagocyte function. Saccharomyces cerevisiae mannan is shown to inhibit several of the functions of normal human peripheral blood neutrophils, monocytes and monocyte-derived macrophages including chemiluminescence and killing of phagocytosed bacteria. CD mucosa-associated E. coli isolates, that are less readily killed following internalization within adherent monocytes than a control ATCC259222 E. coli strain, undergo net replication inside adherent monocytes in the presence of S.cerevisiae mannan. S.cerevisiae mannan similarly enhanced survival of S. aureus within adherent monocytes. The epitope for ASCA is a mannose al-3 mannose disaccharide that binds snowdrop (Galanthus nivalis) lectin (GNA). A range of putative Crohn's diseaseassociated organisms was screened by GNA lectin blotting. The ASCA epitope was expressed by Mycobacterium avium paratuberculosis but not by M tuberculosis or E. coli. Crohn's disease may arise in part as a consequence of the suppression of mucosal phagocyte function by shed microbial mannans.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease

Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer compared with the general population. This review assesses the evidence that endoscopic surveillance may prolong life by allowing earlier detection of colon cancer or its pre-cursor lesion, dysplasia, in patients with inflammatory bowel disease