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

The prevalence of leprosy in school-students and evaluation of school-based screening for leprosy: a Systematic Review

Leprosy is a Neglected Tropical Disease (NTD) causing significant physical and functional disabilities around the world. The objective of this systematic review was to evaluate school-based leprosy screening as a means of identifying early leprosy cases. Using a structured search method, 30 suitable publications were identified. Whilst all studies included in this review were found to identify cases of leprosy through school-based screening, sample sizes were high and numbers detected were small, raising concerns about the feasibility and sustainability of school-based screening as a stand-alone intervention for leprosy detection. For school-based screening programmes to become a sustainable intervention, the inclusion of both capacity building and health education components into school-based screening and intervention programmes should be further explored. More research is needed to consider alternate methods which maximise the efficiency of school-based approaches in the early case detection of leprosy. Also, cases found at school may be used to find further active cases via family and friends. School-based screening could be an effective solution for the early identification of leprosy particularly in areas of high endemicity, however to date there is limited data on its effectiveness compared with other interventions

The prevalence of leprosy in school-students and evaluation of school-based screening for leprosy: a Systematic Review

Leprosy is a Neglected Tropical Disease (NTD) causing significant physical and functional disabilities around the world. The objective of this systematic review was to evaluate school-based leprosy screening as a means of identifying early leprosy cases. Using a structured search method, 30 suitable publications were identified. Whilst all studies included in this review were found to identify cases of leprosy through school-based screening, sample sizes were high and numbers detected were small, raising concerns about the feasibility and sustainability of school-based screening as a stand-alone intervention for leprosy detection. For school-based screening programmes to become a sustainable intervention, the inclusion of both capacity building and health education components into school-based screening and intervention programmes should be further explored. More research is needed to consider alternate methods which maximise the efficiency of school-based approaches in the early case detection of leprosy. Also, cases found at school may be used to find further active cases via family and friends. School-based screening could be an effective solution for the early identification of leprosy particularly in areas of high endemicity, however to date there is limited data on its effectiveness compared with other interventions

Functional disconnection of the substantia nigra pars compacta from the pedunculopontine nucleus impairs learning of a conditioned avoidance task

The pedunculopontine tegmental nucleus (PPTg) targets nuclei in the basal ganglia, including the substantia nigra pars compacta (SNc), in which neuronal loss occurs in Parkinson's disease, a condition in which patients show cognitive as well as motor disturbances. Partial loss and functional abnormalities of neurons in the PPTg are also associated with Parkinson's disease. We hypothesized that the interaction of PPTg and SNc might be important for cognitive impairments and so investigated whether disrupting the connections between the PPTg and SNc impaired learning of a conditioned avoidance response (CAR) by male Wistar rats. The following groups were tested: PPTg unilateral; SNc unilateral; PPTg-SNc ipsilateral (ipsilateral lesions in PPTg and SNc); PPTg-SNc contralateral (contralateral lesions in PPTg and SNc); sham lesions (of each type). SNc lesions were made with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine HCl (MPTP, 0.6micromol); PPTg lesions with ibotenate (24nmol). After recovery, all rats underwent 50-trial sessions of 2-way active avoidance conditioning for 3 consecutive days. Rats with unilateral lesions in PPTg or SNc learnt this, however rats with contralateral (but not ipsilateral) combined lesions in both structures presented no sign of learning. This effect was not likely to be due to sensorimotor impairment because lesions did not affect reaction time to the tone or footshock during conditioning. However, an increased number of non-responses were observed in the rats with contralateral lesions. The results support the hypothesis that a functional interaction between PPTg and SNc is needed for CAR learning and performance