In clinical trials for rare diseases, small patient populations constrain recruitment, limiting data collection. Expert elicitation, the process of extracting expert beliefs into quantitative expressions, can act as a source of evidence in a setting with limited data. Expert judgement can be combined with trial data through the prior distribution in a Bayesian trial. This approach makes the most use out of the available information and possible trial recruitment, unlike conventional approaches that rely on trial data alone. Previous elicitations for rare disease trial prior distributions have used ad hoc approaches, rather than an established protocol designed to limit biases in judgement. This practical guide introduces rare disease clinical investigators to expert elicitation using the IDEA (Investigate, Discuss, Estimate, Aggregate) protocol. IDEA is a structured elicitation technique where experts individually estimate quantities, discuss their answers, then revise their estimates before aggregation into a final distribution. In an elicitation for a trial, experts can either estimate the control arm response or the treatment effect. The elicitation estimates then inform the design and analysis of the trial. IDEA has previously been described in a general context, but this paper provides tailored recommendations for conducting an elicitation for a clinical trial for a rare disease. By outlining practical steps to using IDEA, we aim to promote more structured, transparent practices that will increase the uptake and acceptance of expert elicitation to improve clinical trials for rare diseases.
Glycogen storage disease type VI (GSD VI) (also known as Hers disease) caused by biallelic variants in the PYGL gene results in the deficiency of hepatic glycogen phosphorylase enzyme and commonly presents during early childhood. Celiac disease is a systemic immune-mediated disorder triggered by the ingestion of dietary gluten in genetically-predisposed individuals also presenting in early childhood. Herein, we report an extremely rare case of genetically confirmed GSD VI, diagnosed in association with celiac disease in a 4.2-year-old Libyan girl with non-consanguineous parents. To our knowledge, celiac disease has never been reported previously in association with GSD VI. The patient was initially diagnosed with celiac disease at the age of 3 years and showed partial improvement on a strict gluten-free diet. However, her abdominal distention persisted due to marked hepatomegaly and for this she was referred for consultation at Cairo University Children Hospital, Cairo, Egypt. A liver biopsy was subsequently performed at the age of 4.2 years and was consistent with the diagnosis of GSD. Whole exome sequencing confirmed the diagnosis of GSD VI through the detection of two heterozygous likely pathogenic PYGL variants: a previously reported NM_002863.5:c.1499T > G; p.(Leu500Arg), and a novel variant NM_002863.5:c.1736T > C; p.(Leu579Ser). The patient was promptly prescribed uncooked cornstarch alongside the continued gluten-free diet. At the age of 6 years, abdominal ultrasonography showed a 4.4 cm reduction in the liver size along the mid-clavicular line and improved laboratory studies. We came to the conclusion that in pediatric practice, a definitive diagnosis of one disease should not deter from searching for other disease(s) particularly if the symptoms and/or signs are not adequately explained.
Abstract Background Ovarian involvement by T-cell lymphoid neoplasms is exceptionally rare and can closely mimic advanced epithelial ovarian carcinoma. Distinguishing between them is clinically important because lymphoid neoplasms require subtype-specific systemic therapy rather than ovarian cytoreductive surgery; therefore, adequate tissue diagnosis should be pursued by the least invasive feasible method when lymphoma is considered. Case presentation A 43-year-old woman presented with progressive asthenia, a 12-kg weight loss, abdominal distension, and pain. Physical examination revealed a large abdominopelvic mass. Laboratory findings included elevated CA-125 (195 U/mL), markedly elevated LDH (1,482 IU/L), elevated C-reactive protein, and hypoalbuminaemia. Imaging showed a 17-cm left adnexal mass, ascites, peritoneal thickening, splenomegaly, and a bulky retroperitoneal nodal conglomerate causing bilateral hydroureteronephrosis, raising strong suspicion of advanced ovarian carcinoma while also prompting consideration of lymphoma. Diagnostic laparoscopy revealed no macroscopic peritoneal carcinomatosis or omental caking. A left adnexectomy was performed for decompressive and diagnostic purposes after image-guided biopsy had been considered but was unavailable. Histopathology demonstrated an aggressive T-cell lymphoid neoplasm, with diffuse strong CD3 expression and negative CD20 and pancytokeratin AE1/AE3; no definitive lymphoma subtype could be assigned because ancillary studies were not completed. Before complete staging and lymphoma-directed systemic therapy could be initiated, the patient rapidly deteriorated and died on postoperative day 25; the immediate cause of death was not established. Conclusion Aggressive lymphoid neoplasms presenting as an adnexal mass can visually and radiologically mimic advanced ovarian carcinoma. Markedly elevated LDH, bulky retroperitoneal lymphadenopathy, ureteric encasement, splenomegaly, and discordance between imaging and laparoscopic findings should raise suspicion for a lymphoid malignancy but are not pathognomonic. Rapid acquisition of adequate tissue for comprehensive pathological and haematopathological assessment is important, and definitive surgery should be avoided when a less invasive diagnostic approach is feasible.
Cardiovascular involvement has been described in patients with neurofibromatosis type 1 (NF1), including congenital cardiac abnormalities, hypertension, and vascular lesions; however, clinically significant valvular disease requiring cardiac surgery is rarely reported. We report a case of severe aortic regurgitation (AR) in a patient with NF1 and highlight the perioperative evaluation, surgical decision-making, and management considerations relevant to cardiac surgery in this multisystem disorder. A 67-year-old female with NF1 presented with progressive dyspnea and was diagnosed with severe aortic regurgitation. Following comprehensive cardiovascular and perioperative evaluation, she successfully underwent bioprosthetic aortic valve replacement (AVR) with an uneventful recovery. Severe aortic regurgitation in patients with NF1 should be evaluated and managed according to established guidelines for valvular heart disease. Given the possibility of multisystem involvement, a thorough perioperative evaluation of patients with NF1 undergoing cardiac surgery remains paramount. A multidisciplinary and individually tailored approach is important, given the diverse systemic manifestations. Not applicable.
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variant in GBA1, resulting in deficient glucocerebrosidase activity and accumulation of glycosylceramide-laden macrophages. It is most reported among the Ashkenazi Jewish population. Reported cases in Sri Lanka are rare and have largely been confined to the paediatric population, with adult presentations being exceptionally uncommon. Adult recognition may be difficult where specialist investigations and disease-specific therapies are difficult to access. A 52-year-old Buddhist monk presented with generalized tonic-clonic epilepsy since 12 years of age presented after a further seizure while taking sodium valproate 500 mg daily. He also complained of abdominal discomfort and had a one-month history of mild cognitive impairment. On examination, he showed pallor, and splenomegaly without hepatomegaly or lymphadenopathy. Investigations revealed pancytopenia and 20 cm spleen with multiple low-attenuation splenic gaucheromas, an isolated lytic skull lesion, peripheral retinal bone-spicule-like pigmentation, and biclonal IgG-kappa paraproteins. Bone marrow examination showed macrophages morphologically consistent with Gaucher cells. Fluorometric dried-blood-spot testing demonstrated reduced beta-glucosidase activity of 0.67 nmol/hr/mL (laboratory reference interval 2.3–18.4). Confirmatory leukocyte or fibroblast enzyme testing, GBA1 analysis, PSAP analysis, and disease-specific biomarkers were unavailable in the country. No gaze palsy, oculomotor apraxia, ataxia, pyramidal signs, parkinsonism, or peripheral neuropathy was identified; The clinical phenotype classified as neuronopathic Gaucher disease with existing clinical evidence. Disease-specific therapy was considered at a multidisciplinary meeting but was not initiated because of patient preference, limited access, cost and uncertainty regarding benefit for the longstanding epilepsy. The patient continued symptomatic treatment with clinical and hematological surveillance. Gaucher disease is rare in adulthood. The disease may involve multiple organ systems, while ocular manifestations are uncommon. Close clinical follow-up is important for early detection of complications. The potential systemic benefits of treatment must be distinguished from its limitations for neurological disease. This case illustrates the challenges of recognizing, confirming and treating Gaucher disease in a resource-limited setting. Not applicable.
