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

Half-precessional dynamics of monsoon rainfall near the East African equator: Implications for Indian Ocean ITCZ migration over the past 25,000 years

We present a detailed reconstruction of hydrological changes near the equator in East Africa from before the LGM to the present, using proxies extracted from the sediment record of Lake Challa on the lower east slope of Mt. Kilimanjaro (3° S, 36° E). Our results show that monsoon rainfall in this region varied at half-precessional (~11,500-year) intervals, because the southeasterly and northeasterly Indian Ocean monsoons, which together create the bimodal seasonal distribution of equatorial rainfall, were strengthened in alternation when the inter-hemispheric insolation gradient was maximized. Dry conditions prevailed when neither monsoon was particularly strong, and minima in local March or September insolation weakened the rain season that followed. The distinct timing of late-glacial drought on the equator (20.5-16.5 ka BP) does not fit well with NH glaciation being its primary driver. It is best attributed to partial failure of the short rain season due to modest local September insolation, perhaps exacerbated by the southeasterly monsoon being weakened by northern cooling still affecting the North African land mass. Our data further highlight that orbital-scale ITCZ ‘migration’, or shifts in its mean annual latitudinal position, mainly relates to variation in how far the ITCZ is displaced into the NH or SH during summer and winter; the cross-equatorial position of the East African region with twice-annual ITCZ passage is not much affected. On (sub)millennial time scales the temporal pattern of hydrological change on the East African equator bears clear signatures of northern high-latitude climate variability, but on the orbital time scale it mainly responded to low-latitude insolation forcing. Important keys to this history are the low-latitude position of its continental regions of convergence and its relative isolation from the Atlantic Ocean domain, where strong meridional overturning circulation more tightly coupled tropical climate regimes to high-latitude climate dynamics

Risk of hip fracture with hip or knee osteoarthritis: a systematic review

Osteoarthritis (OA) and hip fracture are two common musculoskeletal disorders associated with substantial societal and personal burden. The objective of this systematic review was to determine the association between hip or knee OA and risk of hip fractures in people aged 45 years and older as compared to people aged 45 years and older who do not have OA. We searched CINAHL, Cochrane Database of Systematic Reviews, Embase, OVID Medline, PUBMED, and SCOPUS for studies published up to July 2010 and conducted forward searches of included studies using Web of Science. Two reviewers independently screened articles for inclusion, extracted data, and evaluated the risk of bias of included studies using the Newcastle-Ottawa Scale. Eleven articles were included. Three investigated individuals with knee OA, two included adults with knee or hip OA, and six investigated adults with hip OA. We did not combine the hip OA or the knee OA studies in a meta-analysis due to the heterogeneity in: study populations and covariates adjusted for in estimates of association. Hip OA may be related to a decreased risk of hip fracture when considering crude estimates of association or estimates of association adjusted for a limited number of covariates, although not all studies found support for the presence of this association. The association between knee OA and hip fracture remains unclear. The presence of OA in the hip or knee should not act as an indication that assessment for hip fracture risk is unnecessary