The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype–phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia

Muscle strengthening intervention for boys with haemophilia: Developing and evaluating a best-practice exercise programme with boys, families and health-care professionals

Background: Muscle strengthening exercises have the potential to improve outcomes for boys with haemophilia, but it is unclear what types of exercise might be of benefit. We elicited the views of health-care professionals, boys and their families to create and assess a home-based muscle strengthening programme. Objective: To design and develop a muscle strengthening programme with healthcare professionals aimed at improving musculoskeletal health, and refine the intervention by engaging boys with haemophilia and their families (Study 1). Following delivery, qualitatively evaluate the feasibility and acceptability of the exercise programme with the boys and the study's physiotherapists (Study 2). Design: A person-based approach was used for planning and designing the exercise programme, and evaluating it post-delivery. The following methods were utilized: modified nominal group technique (NGT) with health-care professionals; focus group with families; exit interviews with boys; and interviews with the study's physiotherapists. Results: Themes identified to design and develop the intervention included exercises to lower limb and foot, dosage, age accommodating, location, supervision and monitoring and incentivization. Programme refinements were carried out following engagement with the boys and families who commented on: dosage, location, supervision and incentivization. Following delivery, the boys and physiotherapists commented on progression and adaptation, physiotherapist contact, goal-setting, creating routines and identifying suitable timeframes, and a repeated theme of incentivization. Conclusions: An exercise intervention was designed and refined through engagement with boys and their families. Boys and physiotherapists involved in the intervention's delivery were consulted who found the exercises to be generally acceptable with some minor refinements necessary

Feasibility, safety and acceptability of select outcome measures in a physiotherapy study protocol for boys with haemophilia.

BACKGROUND: There is a lack of functional performance measures for children and young people with haemophilia (CYPwH) with associated control data from typically developing boys (TDB). The literature advocates development of a core set of outcome measures for different chronic conditions. As medical treatment improves, CYPwH are experiencing better outcomes; therefore, more challenging measures are required to monitor physical performance. Such testing is not performed routinely, due to practical and safety concerns. AIM: Evaluate the feasibility, safety and acceptability of select outcome measures as part of a study protocol testing CYPwH; including myometry, 10 metre incremental shuttle walk test (10-m ISWT), iSTEP (an incremental step test, with data from TDB), and 1 week of accelerometry-wear at home. METHODS: Sixty-six boys aged 6-15 years with mild, moderate or severe haemophilia A or B (including inhibitors) attending routine clinics at Great Ormond Street Hospital were approached to participate. Descriptive statistics and content analysis were used to assess outcomes of feasibility, safety and acceptability, which included recruitment/retention rates, protocol completion within routine appointment timeframes, performance testing without serious adverse events/reactions (SAE/SARs), and acceptability to CYPwH of high-level performance measures. RESULTS: Outcomes were met: 43 boys completed testing at clinic review (Jan-Nov 2018) within a 10-month timeframe, retention was 95% at completion of protocol and no SAE/SARs were reported throughout testing. CONCLUSION: Feasibility, safety and acceptability of the study protocol have been established in this population. Both high-level performance tests, iSTEP and 10-m ISWT, were an acceptable addition to boys' routine clinic appointments and could be safe, acceptable choices of outcome measure as part of a core set of tests for CYPwH. Further investigation of the psychometric properties for the iSTEP is now justified, in order for it to be used as a standardised, validated, reliable outcome measure in clinical or research settings. TRIAL REGISTRATION: Retrospectively registered on September 3, 2019, on ClinicalTrials.gov (ID: NCT04076306 )

Muscle strengthening intervention for boys with haemophilia: Developing and evaluating a best-practice exercise programme with boys, families and health-care professionals

Background: Muscle strengthening exercises have the potential to improve outcomes for boys with haemophilia, but it is unclear what types of exercise might be of benefit. We elicited the views of health-care professionals, boys and their families to create and assess a home-based muscle strengthening programme. Objective: To design and develop a muscle strengthening programme with health-care professionals aimed at improving musculoskeletal health, and refine the intervention by engaging boys with haemophilia and their families (Study 1). Following delivery, qualitatively evaluate the feasibility and acceptability of the exercise programme with the boys and the study's physiotherapists (Study 2). Design: A person-based approach was used for planning and designing the exercise programme, and evaluating it post-delivery. The following methods were utilized: modified nominal group technique (NGT) with health-care professionals; focus group with families; exit interviews with boys; and interviews with the study's physiotherapists. Results: Themes identified to design and develop the intervention included exercises to lower limb and foot, dosage, age accommodating, location, supervision and monitoring and incentivization. Programme refinements were carried out following engagement with the boys and families who commented on: dosage, location, supervision and incentivization. Following delivery, the boys and physiotherapists commented on progression and adaptation, physiotherapist contact, goal-setting, creating routines and identifying suitable timeframes, and a repeated theme of incentivization. Conclusions: An exercise intervention was designed and refined through engagement with boys and their families. Boys and physiotherapists involved in the intervention's delivery were consulted who found the exercises to be generally acceptable with some minor refinements necessary

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma

Fight For Sight Fellowship, UK; National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHSFoundation Trust and UCL Institute of Ophthalmology. J.W. and C.C. acknowledge support from Cancer Research UK Centre of Excellence Award to Barts Cancer Centre [C16420/A18066

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets

The relationship between target joints and direct resource use in severe haemophilia

Objectives Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. Methods Data on haemophilia patients without inhibitors was drawn from the ‘Cost of Haemophilia across Europe – a Socioeconomic Survey’ (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. Results Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1–10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). Conclusions Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients

The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors