PLoS One. 2024 Dec 3;19(12):e0312936. doi: 10.1371/journal.pone.0312936. eCollection 2024.

ABSTRACT

BACKGROUND: In clinical research, the most appropriate way to assess the effect of an intervention is to conduct a randomized controlled trial (RCT). In the field of rare diseases, conducting an RCT is challenging, resulting in a low rate of clinical trials, with a high frequency of early termination and unpublished trials. The aim of the EPISTOP trial was to compare outcomes in infants with tuberous sclerosis (TSC) who received vigabatrin preventively before the seizures onset with those who received it conventionally after. The study was designed as a prospective, multicentre, randomized clinical trial. However, ethics committees at four centres did not approve this RCT design, resulting in an open-label trial (OLT) in these four centres and an RCT in the other six centres. In this paper, we re-analyse the data from the EPISTOP trial using methods to investigate the influence of allocation bias on the results of the EPISTOP trial.

METHOD: A bias-corrected analysis is used to support and strengthen the published results. We included a term representing the effect of selection bias as an influencing factor on the corresponding endpoint in the statistical model. Thus, the treatment effect estimates for the primary endpoint of time to first seizure and additional secondary endpoints are adjusted for the bias effect.

RESULT: The bias-corrected analyses for the primary endpoint show that the estimated hazard ratio and associated confidence intervals are in a very similar range (original analysis: HR 2.91, 95%-CI [1.11 to 7.67], p-value 0.0306; bias-corrected analysis: HR 2.89, 95%-CI [1.10 to 7.58], p-value 0.0316). This was also the case for the secondary endpoints.

CONCLUSION: The statistical re-analysis of the raw trial data therefore supports the published results and confirms that there is no additional bias introduced by randomization, thereby increasing the value of the results. However, this highlights that this aspect needs to be considered in future trials, especially in rare diseases, to avoid additional biases in an already small sample size where it may be difficult to reach significance.

PMID:39625912 | DOI:10.1371/journal.pone.0312936

Pulmonology. 2025 Dec 31;31(1):2429911. doi: 10.1080/25310429.2024.2429911. Epub 2024 Dec 3.

ABSTRACT

Alpha-1 Antitrypsin Deficiency (AATD) is a co-dominant condition associated with an increased risk of lung and liver disease. Since it is commonly thought that 95% of severe cases of AATD have PI*ZZ genotype, most studies about AATD have been focused on the Z variant. Nevertheless, over 500 single nucleotide variations in the SERPINA1 gene have been identified. We investigated the clinical presentation of subjects with severe AAT deficiency due to rare genotypes of the SERPINA1 gene. We enrolled patients from the Italian Registry for AATD (RIDA1) with the following inclusion criteria: diagnosis of severe AATD; age >18 years; full clinical data available at diagnosis; three years of follow-up respiratory function data. A total of 281 patients were enrolled from the RIDA1 Registry and subdivided into 3 cohorts: PI*ZZ genotype (n = 160), PI*SZ genotype (n = 54), and rare genotypes PI*R (n = 67). We did not observe any statistical differences among the cohorts regarding sex, smoking habits, occupational exposure and age at diagnosis. Patients with severe AATD due to rare genotypes have clinical characteristics and respiratory profiles similar to PI*ZZ subjects, and differed from the PI*SZ patient group. Early and accurate diagnosis of PI*R subjects is therefore important for their appropriate clinical management.

PMID:39624947 | DOI:10.1080/25310429.2024.2429911

NPJ Genom Med. 2024 Dec 2;9(1):60. doi: 10.1038/s41525-024-00441-9.

ABSTRACT

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

PMID:39622807 | DOI:10.1038/s41525-024-00441-9

Clin Chim Acta. 2025 Jan 30;566:120065. doi: 10.1016/j.cca.2024.120065. Epub 2024 Nov 29.

ABSTRACT

With the rapid development of massive sequencing technologies, the analysis of genetic variants for clinical diagnosis has exponentially escalated, particularly in the context of Rare Diseases (RDs). Diagnosing them involves identifying the genetic variants responsible for the underlying pathology development. In 2015, the American College of Medical Genetics (ACMG) established a set of recommendations to assess the evidence associated with each variant, aiming to achieve a standardized five tier classification. Over the past 5 years, ClinGen, the NIH-funded Clinical Genome Resource, has reviewed these criteria in order to make variant classification a more reproducible and rigorous process. This paper examines the impact of ClinGen-Rev modifications on variant classification, comparing them with the ACMG-2015 original recommendations. After analyzing sets of genetic variants, extracted from VCFs samples, using both criteria, we observed a change in 8.0 % of the clinical verdicts for these variants. ClinGen-Rev modifications correctly categorized 89.2 % of the curated variants, representing a significant improvement compared to the 65.6 % achieved by ACMG-2015. We also analyzed the modifications impact in a real like clinical setting, showing a significant overall reduction of VUS variants and thus potential reduction in analysis time. Finally, we discuss the underlying reasons for the most relevant changes in terms of specific labels and present their implications on the prioritization and selection process of variants, identifying some recommendations of key significant importance.

PMID:39615735 | DOI:10.1016/j.cca.2024.120065

Orphanet J Rare Dis. 2024 Nov 29;19(1):446. doi: 10.1186/s13023-024-03377-6.

ABSTRACT

BACKGROUND: Rare disease (RD) management and orphan drug development in India face various hurdles regarding the implementation and adoption of comprehensive policies, lack of dedicated regulatory frameworks, and absence of epidemiological data. Current rare disease policy focuses more on strengthening the diagnostics and lacks a proper comprehensive treatment framework to ensure favorable clinical outcomes. Indian patients are largely excluded from global orphan drug clinical trials. This further alienates patients from access to rare disease treatment and available treatments come at high cost. This review-based study assesses the landscape of health policies and programs in India through a review of literature and guidelines, to identify strategic opportunities and recommendations for enhancing the overall care and support for the Rare Disease (RD) patient population and improving the orphan drug research ecosystem in India.

DISCUSSION: The absence of specific regulations, shortage of healthcare resources, budget constraints, competing health priorities, lack of patient data, and insufficient research incentives discourage orphan drug development and global clinical trial inclusion, resulting in treatment inaccessibility and high costs. The Indian Government introduced the National Policy for Treatment of Rare Diseases (NPRD) to address these challenges. Several initiatives have been introduced to attract stakeholders with government-funded research, grants, incentives, and accelerated regulatory approvals of novel therapies that can ensure timely prevention and treatment of rare diseases. The National RD Registry by the Indian Council of Medical Research (ICMR) aims to provide prevalence data. Innovative approaches are required to improve rare disease management and promote orphan drug research. This will ensure the accessibility and affordability of life-saving therapeutics for India's rare disease patients.

CONCLUSION: An integrated RD management and orphan drug research framework focusing on robust data management, patient-oriented policies to improve the treatment landscape, flexible regulations, strengthening rare disease registry with clinical and diagnostic data, and a favorable research ecosystem to promote indigenous research catering to the Indian population, will improve the treatment landscape and orphan drug research and development in India. This will ensure timely availability of therapeutics at affordable prices.

PMID:39614301 | DOI:10.1186/s13023-024-03377-6

Orphanet J Rare Dis. 2024 Nov 29;19(1):443. doi: 10.1186/s13023-024-03462-w.

ABSTRACT

BACKGROUND: Mass spectrometry-based quantitative proteomics has a demonstrated utility in increasing the diagnostic yield of mitochondrial disorders (MDs) and other rare diseases. However, for this technology to be widely adopted in routine clinical practice, it is crucial to accurately estimate delivery costs. Resource use and unit costs required to undertake a proteomics test were measured and categorized into consumables, equipment, and labor. Unit costs were aggregated to obtain a total cost per patient, reported in 2023 Australian dollars (AUD). Probabilistic and deterministic sensitivity analysis were conducted to evaluate parameter uncertainty and identify key cost drivers.

RESULTS: The mean cost of a proteomics test was $897 (US$ 607) per patient (95% CI: $734-$1,111). Labor comprised 53% of the total costs. At $342 (US$ 228) per patient, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was the most expensive non-salary component. An integrated analysis pipeline where all the standard analysis are performed automatically, as well as discounts or subsidized LC-MS/MS equipment or consumables can lower the cost per test.

CONCLUSIONS: Proteomics testing provide a lower-cost option and wider application compared to respiratory chain enzymology for mitochondrial disorders and potentially other functional assays in Australia. Our analysis suggests that streamlining and automating workflows can reduce labor costs. Using PBMC samples may be a cheaper and more efficient alternative to generating fibroblasts, although their use has not been extensively tested yet. Use of fibroblasts could potentially lower costs when fibroblasts are already available by avoiding the expense of isolating PBMCs. A joint evaluation of the health and economic implications of proteomics is now needed to support its introduction to routine clinical care.

PMID:39609890 | DOI:10.1186/s13023-024-03462-w

BMJ Open. 2024 Nov 27;14(11):e083044. doi: 10.1136/bmjopen-2023-083044.

ABSTRACT

INTRODUCTION: In 2020, the Australian Medical Services Advisory Committee (MSAC) recommended new proton beam therapy (PBT) item numbers be added to the Medicare Benefits Schedule. During the MSAC 1638 application process, MSAC recognised the uncertainties inherent in the cost-utility modelling of PBT. To address these uncertainties, MSAC proposed the establishment of a national registry with the intention to gather evidence to validate the claim of PBT's superior toxicity outcomes and cost-effectiveness compared with conventional photon radiation therapy.

METHODS AND ANALYSIS: The Australian Particle Therapy Clinical Quality Registry is a prospective, observational, longitudinal registry collecting national data on paediatric, adolescent young adult and adult patients with rare tumours receiving any form of radiation therapy for a defined group of diseases, specified by the MSAC 1638 Public Summary Document. Eligible patients undergoing radiation therapy at participating institutions will be provided with information about the registry, including the opt-out procedure. The registry has no enrolment cap and will persist either indefinitely or until the conclusion of the study.The study design was informed by the Australian Metadata Online Repository and contains a core set of minimum data elements. Representing baseline participant demographics, assessment, diagnosis and treatment; incorporating radiation and systemic therapies, with a specific focus on long-term follow-up, treatment toxicities and specific organ-at-risk testing.

ETHICS AND DISSEMINATION: There will be no identifying data used in any reports or presentations of data. Additionally, all identifiable data will be safeguarded according to standard practices and available only to the host institution submitting the data to the registry. Aggregated data for the purposes of research will be stripped of identifiers. The registry has been approved under the National Mutual Agreement by the Central Adelaide Local Health Network Human Research Ethics Committee-HREC: 2021/HRE00394.

TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622000026729p.

PMID:39609005 | DOI:10.1136/bmjopen-2023-083044

Oncoimmunology. 2024 Dec 31;13(1):2432062. doi: 10.1080/2162402X.2024.2432062. Epub 2024 Nov 27.

ABSTRACT

Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients.

PMID:39604816 | DOI:10.1080/2162402X.2024.2432062

Exp Neurol. 2025 Feb;384:115073. doi: 10.1016/j.expneurol.2024.115073. Epub 2024 Nov 25.

ABSTRACT

Primary mitochondrial disorders (PMDs) are an extraordinarily complex group of rare disorders caused by impairment of the mitochondrial electron transport chain, or respiratory chain. Studying genotype-phenotype relationships in PMDs is a complex task. The clinical variability is large even in individuals with the same genotype, and the statistical power is low in single-center studies because of their rarity. To better define the clinical phenotypes associated with PMDs, in the last 15 years a significant multicenter effort has led to nation-wide studies on large cohorts of patients. Many national registries of mitochondrial patients have been developed in recent years, and now there is a strong effort towards international (and even global) registries. This review will revise the notable advances obtained with such studies in recent years, and will discuss the actual developments and future perspectives.

PMID:39603485 | DOI:10.1016/j.expneurol.2024.115073

J Pediatr. 2024 Nov 25:114422. doi: 10.1016/j.jpeds.2024.114422. Online ahead of print.

ABSTRACT

OBJECTIVE: To characterize clinical, hemodynamic, imaging, and pathologic findings in children with pulmonary arterial hypertension (PAH) and variants in SOX17, a novel risk gene linked to heritable and congenital heart disease-associated PAH.

STUDY DESIGN: We assembled a multi-institutional cohort of children with PAH and SOX17 variants enrolled in the Pediatric Pulmonary Hypertension Network (PPHNet) and other registries. Subjects were identified through exome and PAH gene panel sequencing. Data were collected from registries and retrospective chart review.

RESULTS: We identified 13 children (8 female, 5 male) aged 1.6 to 16 years at diagnosis with SOX17 variants and PAH. Seven patients had atrial septal defects (ASD) and two had patent ductus arteriosus. At diagnostic cardiac catheterization, patients had severely elevated mean pulmonary artery pressure (mean 78, range 47-124 mmHg) and markedly elevated indexed pulmonary vascular resistance (mean 25.9, range 4.9-55 WU*m2). No patients responded to acute vasodilator testing. Catheter and CT angiography imaging demonstrated atypical pulmonary artery anatomy including severely dilated main pulmonary arteries, lack of tapering in third and fourth order pulmonary arteries, tortuous 'corkscrewing' pulmonary arteries, and abnormal capillary 'blush.' Several children had pulmonary artery stenoses and two had systemic arterial abnormalities. Histologic examination of explanted lungs from three patients disclosed plexiform arteriopathy and extensive aneurysmal dilation of alveolar septal capillaries.

CONCLUSIONS: SOX17-associated PAH is a distinctive genetic syndrome characterized by early onset severe PAH, extensive pulmonary vascular abnormalities, and high prevalence of congenital heart disease with intracardiac and interarterial shunts, suggesting a role for SOX17 in pulmonary vascular development.

PMID:39603521 | DOI:10.1016/j.jpeds.2024.114422

Mult Scler J Exp Transl Clin. 2024 Nov 26;10(4):20552173241293921. doi: 10.1177/20552173241293921. eCollection 2024 Oct-Dec.

ABSTRACT

BACKGROUND: The prevalence of multiple sclerosis (MS) in Latin America is generally considered low to moderate. However, accurate data regarding MS epidemiology in Colombia is lacking.

OBJECTIVE: This study aims to discuss the situation of MS in Colombia.

RESULTS: Analysis reveals a lack of accurate data regarding MS epidemiology in Colombia, however, there have been notable improvements in diagnosis and ultimately leading to better access to treatment for MS patients. While ethnic diversity may potentially influence MS prevalence, there is currently no strong data supporting this claim. MS treatment in Colombia, focuses on early disease-modifying therapy, nevertheless, MS is considered an orphan disease in Colombia, contributing to MS patients not receiving comprehensive evaluation in MS centers. Regional efforts are ongoing to improve diagnostic access and access to treatment for MS patients.

CONCLUSION: Despite the challenges in accurately defining MS epidemiology in Colombia, an increase in neurological training, diagnostic capabilities, and access to treatment has been observed. However, the status of MS as an orphan disease in Colombia poses challenges to comprehensive care for affected individuals. Further studies are needed to elucidate risk factors and improve care conditions for MS patients in the region.

PMID:39600996 | PMC:PMC11590136 | DOI:10.1177/20552173241293921

Orphanet J Rare Dis. 2024 Nov 26;19(1):438. doi: 10.1186/s13023-024-03429-x.

NO ABSTRACT

PMID:39593137 | DOI:10.1186/s13023-024-03429-x

Respir Res. 2024 Nov 26;25(1):416. doi: 10.1186/s12931-024-03040-5.

ABSTRACT

BACKGROUND: Pulmonary lymphangiomatosis (PL) is an ultrarare disease characterized by diffuse infiltration of the lung, pleura and/or mediastinum by abnormal lymphatic proliferation. Consented diagnostic or treatment approaches are not established. We therefore aimed to collect data on diagnostics and treatments in a cohort of patients with PL from a tertiary center for rare lung diseases.

METHODS: Clinical, radiological and outcome data from PL patients were collected retrospectively.

RESULTS: 12 patients were diagnosed between 1996 and 2022 in our center. PL was diagnosed more commonly in female (58%), never smokers (75%) and younger patients (mean age 42 years). Main clinical symptoms comprised haem- and chyloptysis (58%) and dyspnea on exertion (83%). Pulmonary function was mostly restrictive (mean VC 59%) with impaired DLCO (mean 65%). Radiological assessment mainly showed mediastinal involvement (83%), and pleural effusion (67%), pleural thickening (67%) and bronchial wall thickening (67%) while interstitial changes were rare. Diagnosis was confirmed by surgical or transbronchial cryobiopsy. 8 patients were treated with sirolimus, 3 of these combined with a surgical intervention and in one case surgical intervention was necessary 9 months after initiation of sirolimus. Clinical and radiological improvement was demonstrated for all patients treated with sirolimus. 1 patient received a lung transplant due disease progression. Survival rates were 90% after a mean follow up of at least 3 months.

CONCLUSION: This case series illustrates the variability of the clinical presentation of PL. Among our patients, those treated with sirolimus showed significant clinical, functional and radiological improvement. However, further investigation is needed to understand the pathogenesis of lymphangiomatosis in order to establish therapeutic approaches.

PMID:39593123 | DOI:10.1186/s12931-024-03040-5

J Ayub Med Coll Abbottabad. 2024 Jan-Mar;36(1):229-231. doi: 10.55519/JAMC-01-12868.

ABSTRACT

Scleredema Diabeticorum (SD) is a rare condition characterized by diffuse, symmetrical induration along with non-pitted swelling mostly on the upper back as a result of mucin being deposited in the dermis. It can also involve posterior neck, shoulders, and scalp. We report a case of 48 years old female patient from Pakistan, with uncontrolled diabetes mellites type 2 for the last 15 years, presenting with thickened skin at the back of the neck resulting in difficulty in neck and shoulder movements. This led to decreased functional class from I to II causing her to develop insomnia and depression. Scleredema diabeticorum is a difficult disease to manage as it runs a long and debilitating course with little propensity of remission with available treatments.

PMID:39585292 | DOI:10.55519/JAMC-01-12868

Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:3946320241300137. doi: 10.1177/03946320241300137.

ABSTRACT

Pyoderma gangrenosum (PG) is a rare noninfectious neutrophilic dermatosis characterized by recurrent, painful ulcers that commonly affect the lower extremities but can also involve other parts of the body. Over half of patients with PG have concomitant systemic immune diseases, with the association of PG with systemic sclerosis (SSc) being extremely rare. Treatment of PG primarily involves local therapy, steroids, and immunosuppressants, with an increasing emphasis on biologic agents. Among these, tumor necrosis factor-alpha (TNF-α) antagonists are considered effective. The patient in this report was an elderly female with a history of systemic sclerosis for many years and initially presented with gangrenous ulcers on the fingertips. After inconclusive conventional treatment, adalimumab was added for 5 weeks, resulting in disease suppression, a reduction in ulcer size, and re-epithelialization of the skin lesions after 6 months.

PMID:39584543 | DOI:10.1177/03946320241300137

Mol Biol Rep. 2024 Nov 22;52(1):7. doi: 10.1007/s11033-024-10085-8.

ABSTRACT

BACKGROUND: Spinocerebellar ataxia with axonal neuropathy type 1 (OMIM: 607250) is an extremely rare autosomal recessive disorder caused by a mutation in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene. Only a single missense variant (p.His493Arg) in this gene has been reported. This variant was found in three Arab families with a possible common founder effect.

METHODS AND RESULTS: We report a female patient born to a consanguineous Pakistani family segregating autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1. The patient presents additional clinical features distinct from previously reported Arab families including congenital onset of the disease. We performed whole exome sequencing with the patient's DNA and identified a novel missense variant (NC_000014.9:g.89991982C > T; p.His478Tyr) in exon 13 of the TDP1 gene. Sanger sequencing was performed to verify the autosomal recessive segregation of the p.His478Tyr variant in the family.

CONCLUSION: The current study expands both the clinical and mutation spectrum of the TDP1 associated spinocerebellar ataxia with axonal neuropathy type 1 and increases the body of evidence that supports the pathogenic role of TDP1 in cerebellar ataxias with peripheral neuropathy.

PMID:39576382 | DOI:10.1007/s11033-024-10085-8

Mo Med. 2024 Jul-Aug;121(4):284-288.

ABSTRACT

The world of genetic testing continues to evolve as new technologies provide insight into previously unchartered territories. Access to genetic testing, especially for complex medical patients, could potentially improve the lives of thousands of individuals with undiagnosed conditions. Barriers to testing include financial and physical limitations, along with the emotional and social fortitude that is at times needed for vulnerable populations to agree to testing and participation in research. As healthcare providers, it is imperative that we adopt a wholistic approach to care so that we can arm our patients with the necessary resources to navigate their medical journey.

PMID:39575078 | PMC:PMC11578571

Mo Med. 2024 Jul-Aug;121(4):304-309.

ABSTRACT

DeSanto-Shinawi (DESSH) syndrome is a rare autosomal dominant condition caused by pathogenic variants in the WAC gene. DESSH syndrome was first identified in 2015 in six patients, but has since been diagnosed in more than 200 individuals worldwide. Patients exhibit a variable degree of developmental delay (DD), intellectual disability (ID), hypotonia, gastrointestinal and eye abnormalities, epilepsy, behavioral difficulties, and recognizable facial features. In order to educate families and address the complex medical needs of the increasing number of patients with DESSH syndrome, we established a new multidisciplinary clinic at Washington University in St. Louis. The first clinic was held in September 2022 and attended by 15 patients and their families. Herein, we report the structure of the clinic and present the main clinical findings of these patients. This pilot experience highlights the utility of a multidisciplinary approach to evaluating individuals with rare genetic diseases and the value of collaborating with family support groups to establish multidisciplinary clinics for these disorders, and provides guidance for future clinic planning.

PMID:39575070 | PMC:PMC11578572

Clin Chem. 2025 Jan 3;71(1):169-184. doi: 10.1093/clinchem/hvae183.

ABSTRACT

BACKGROUND: Exome- or genome-based panels-also known as slices or virtual panels-are now a popular approach that involves comprehensive genomic sequencing while restricting analysis to subsets of genes based on patients' phenotypes. This flexible strategy enables frequent gene updates based on novel disease associations as well as reflexing to analyzing other genes up to the whole exome or genome. With recent improvements addressing limitations associated with virtual panels, the advantages of this approach, relative to static custom-based panels, remain to be systematically characterized.

METHODS: Here we perform slice testing on 1014 patients (50.5% females; average age 17 years) referred from multiple pediatric clinics within a single center in the Middle East (83% Arab population).

RESULTS: Initial analysis uncovered molecular diagnoses for 235 patients for a diagnostic yield of 23% (235/1014). "On the fly" focused analysis in most negative cases (N = 779) identified clinically significant variants correlating with patients' presentations in genes outside the originally ordered panel for another 35 patients (3.5% or 35/1024) increasing the overall diagnostic yield to 27%. The pathogenic variants underlying the additional cases (13% of all positive cases) were excluded from the original "panel" gene list, mainly as result of issues related to panel selection, novel gene-disease associations, phenotype spectrum broadening, or gene lists variability. The additional findings led to changes in clinical management in most patients (94%).

CONCLUSIONS: Our findings support slice testing as an efficient and flexible platform that facilitates updates to gene lists to achieve high clinical sensitivity and utility.

PMID:39569808 | DOI:10.1093/clinchem/hvae183

J Pediatr Ophthalmol Strabismus. 2024 Nov-Dec;61(6):e59-e62. doi: 10.3928/01913913-20240911-01. Epub 2024 Nov 1.

ABSTRACT

The authors report a case of a 66-year-old man with sudden-onset diplopia and redness in the left eye. The examination revealed left hypotropia with exotropia and limited elevation. Contrast-enhanced computed tomography and histopathology suggested inferior rectus myositis with fibrosis. The patient was treated with steroid pulse therapy, followed by slow tapering. Later, the patient underwent surgical strabismus correction. He remained diplopia-free with an excellent cosmetic outcome and minimal elevation deficit 12 months postoperatively. [J Pediatr Ophthalmol Strabismus. 2024;61(6):e59-e62.].

PMID:39569718 | DOI:10.3928/01913913-20240911-01