Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.

Objectives Frailty has been suggested to take part in the recently demonstrated link between olfactory dysfunction and overall mortality risk. Preoperative assessment of frailty is essential to detect the most vulnerable patients scheduled for surgery. The aim of this study was to evaluate whether olfactory dysfunction is a reliable predictor of preoperative frailty and postoperative outcome. Design This was a single-center prospective observational study conducted between July and October 2020 in Brussels, Belgium. Setting And Participants 155 preoperative patients aged from 65 years old and scheduled for elective non-cardiac surgery. Measurements Olfactory function was examined using the Sniffin’ Sticks 12-item identification test. Frailty was assessed using the Edmonton Frail Scale (EFS) and handgrip strength. The clock drawing test (CDT) from the EFS was also analyzed separately to evaluate cognitive function. Patients were followed for postoperative complications and mortality over one year. Results Olfactory dysfunction was significantly associated with the EFS score, anosmic patients having a higher median EFS score than normosmic patients (6[4–7] vs 4[2–5], p =.025). Anosmic patients had an increased odds of being frail after adjusting for possible confounding factors (OR: 6.19, 95% CI: 1.65–23.20, p =.007) and were more at risk of poor postoperative outcome (including complications and death) (OR: 4.33, 95% CI: 1.28–14.67, p =.018). Conclusions Olfactory dysfunction is associated with preoperative frailty determined by the EFS and with poor post-surgical outcome at one-year.

Hypotrichosis‐lymphedema‐telangiectasia syndrome (HLTS) is a rare condition caused by pathogenic variants in the SOX18 gene. SOX18 plays a key role in angio‐ and lymphangiogenesis due to its expression in venous endothelial cells from which the lymphatic system develops. It is also expressed in embryonic hair follicles, heart, and vascular smooth muscle cells. The main clinical symptoms of HLTS include sparse hair, alopecia totalis, lymphedema, most often affecting lower limbs, and telangiectatic lesions. Only 10 patients with a SOX18 pathogenic variant have been described that presented with additional features such as hydrocele, renal failure, arterial or pulmonary hypertension, aortic dilatation, and facial dysmorphism. Here, we summarize these phenotypic variations and report an additional HLTS patient, with a 14‐nucleotide de novo duplication in SOX18 and congenital ileal atresia, a feature not previously associated with HLTS.

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