Mol Genet Metab. 2024 Mar 18;142(1):108453. doi: 10.1016/j.ymgme.2024.108453. Online ahead of print.

ABSTRACT

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

PMID:38522179 | DOI:10.1016/j.ymgme.2024.108453

EMBO Mol Med. 2024 Mar 21. doi: 10.1038/s44321-024-00054-w. Online ahead of print.

ABSTRACT

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

PMID:38514794 | DOI:10.1038/s44321-024-00054-w

Hum Genomics. 2024 Mar 21;18(1):28. doi: 10.1186/s40246-024-00595-8.

ABSTRACT

BACKGROUND: In the process of finding the causative variant of rare diseases, accurate assessment and prioritization of genetic variants is essential. Previous variant prioritization tools mainly depend on the in-silico prediction of the pathogenicity of variants, which results in low sensitivity and difficulty in interpreting the prioritization result. In this study, we propose an explainable algorithm for variant prioritization, named 3ASC, with higher sensitivity and ability to annotate evidence used for prioritization. 3ASC annotates each variant with the 28 criteria defined by the ACMG/AMP genome interpretation guidelines and features related to the clinical interpretation of the variants. The system can explain the result based on annotated evidence and feature contributions.

RESULTS: We trained various machine learning algorithms using in-house patient data. The performance of variant ranking was assessed using the recall rate of identifying causative variants in the top-ranked variants. The best practice model was a random forest classifier that showed top 1 recall of 85.6% and top 3 recall of 94.4%. The 3ASC annotates the ACMG/AMP criteria for each genetic variant of a patient so that clinical geneticists can interpret the result as in the CAGI6 SickKids challenge. In the challenge, 3ASC identified causal genes for 10 out of 14 patient cases, with evidence of decreased gene expression for 6 cases. Among them, two genes (HDAC8 and CASK) had decreased gene expression profiles confirmed by transcriptome data.

CONCLUSIONS: 3ASC can prioritize genetic variants with higher sensitivity compared to previous methods by integrating various features related to clinical interpretation, including features related to false positive risk such as quality control and disease inheritance pattern. The system allows interpretation of each variant based on the ACMG/AMP criteria and feature contribution assessed using explainable AI techniques.

PMID:38509596 | PMC:PMC10956189 | DOI:10.1186/s40246-024-00595-8

Int J Equity Health. 2024 Mar 19;23(1):64. doi: 10.1186/s12939-024-02137-z.

ABSTRACT

BACKGROUND: China has implemented policies to make rare diseases more affordable. While previous studies evaluated overall affordability, few have examined affordability differences across regions and disease types. Given the vastness of China and varying medical policies across cities, this study assesses the affordability of rare diseases based on China's First List of Rare Diseases (CFLRD), National Reimbursement Drug List (NRDL), and outpatient chronic and special disease policies in each prefecture.

METHOD: Six rare diseases were selected and the average annual treatment cost of all relevant drugs in NRDL was calculated for each disease. Based on the WHO/HAI standardized approach, the study analyzed 289 cities with outpatient chronic and special disease policies, measured the security levels by the actual reimbursement ratio of Basic Medical Insurance (BMI) and affordability by the ratio of individual expenses after reimbursement to the annual disposable income of urban residents in the province. The security levels and affordability differences across disease types and provinces were analyzed using the Mann-Whitney U test and the K-W test.

RESULT: The affordability of rare diseases varied significantly on the disease types and annual treatment cost. Diseases with an annual treatment cost below 100 000 yuan are affordable to all prefectures even with low reimbursement rates, while those with a higher treatment cost were not affordable in at least 80% of prefectures even though the reimbursement ratio is high. The affordability of the same disease varies significantly across provinces and municipalities. Outpatient chronic and special diseases insurance and critical illness insurance, and the inconsistencies between them, result in regional differences.

CONCLUSION: Although China has made progress in improving the affordability of rare diseases, significant differences persist between cities and diseases. The study suggests the optimization of the BMI system and explores independent funds and innovative insurance models to enhance the affordability of rare diseases, particularly those with extremely high treatment costs.

PMID:38504266 | PMC:PMC10953120 | DOI:10.1186/s12939-024-02137-z

Cell. 2024 Mar 11:S0092-8674(24)00227-7. doi: 10.1016/j.cell.2024.02.025. Online ahead of print.

ABSTRACT

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

PMID:38503282 | DOI:10.1016/j.cell.2024.02.025

J Perinatol. 2024 Mar 18. doi: 10.1038/s41372-024-01935-1. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate patterns of genetic testing among infants with CHD at a tertiary care center.

STUDY DESIGN: We conducted a retrospective observational cohort study of infants in the NICU with suspicion of a genetic disorder. 1075 of 7112 infants admitted to BCH had genetic evaluation including 329 with CHD and 746 without CHD. 284 of 525 infants with CHD admitted to CMHH had genetic evaluation. Patterns of testing and diagnoses were compared.

RESULTS: The rate of diagnosis after testing was similar for infants with or without CHD (38% [121/318] vs. 36% [246/676], p = 0.14). In a multiple logistic regression, atrioventricular septal defects were most high associated with genetic diagnosis (odds ratio 29.99, 95% confidence interval 2.69-334.12, p < 0.001).

CONCLUSIONS: Infants with suspicion of a genetic disorder with CHD had similar rates of molecular diagnosis as those without CHD. These results support a role for genetic testing among NICU infants with CHD.

PMID:38499751 | DOI:10.1038/s41372-024-01935-1

BMJ Case Rep. 2024 Mar 18;17(3):e256608. doi: 10.1136/bcr-2023-256608.

ABSTRACT

Ductal carcinoma in situ is very rare in male patients, accounting for approximately 5%-7% of all male breast cancers. We present a case of a man in his early 70s who presented with bloody nipple discharge and gynaecomastia and was subsequently diagnosed with ductal carcinoma in situ (DCIS). We discuss his management with surgical resection and the consideration of adjuvant treatment. We also review the existing literature on the presentation, diagnosis and management of DCIS in men.

PMID:38499353 | DOI:10.1136/bcr-2023-256608

Ann Child Neurol Soc. 2023 Sep;1(3):228-238. doi: 10.1002/cns3.20038. Epub 2023 Sep 12.

ABSTRACT

OBJECTIVE: To determine the longitudinal distribution of hand function skills in individuals with classic Rett Syndrome (RTT), an X-linked dominant neurodevelopmental disorder, and correlate with MECP2 variants.

METHOD: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus in this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups.

RESULTS: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C-terminal truncations) compared to groups composed of individuals with more severe variants.

CONCLUSIONS: These temporal variations in hand use represent specific considerations which could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

PMID:38496825 | PMC:PMC10939125 | DOI:10.1002/cns3.20038

Innov Clin Neurosci. 2024 Mar 1;21(1-3):52-60. eCollection 2024 Jan-Mar.

ABSTRACT

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

PMID:38495603 | PMC:PMC10941866

Lancet. 2024 Mar 30;403(10433):1279-1289. doi: 10.1016/S0140-6736(23)02843-X. Epub 2024 Mar 13.

ABSTRACT

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.

METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window).

FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases.

INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand.

FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

PMID:38492578 | DOI:10.1016/S0140-6736(23)02843-X

Lancet. 2024 Mar 30;403(10433):1211-1213. doi: 10.1016/S0140-6736(24)00198-3. Epub 2024 Mar 13.

NO ABSTRACT

PMID:38492577 | DOI:10.1016/S0140-6736(24)00198-3

J Neurodev Disord. 2024 Mar 15;16(1):10. doi: 10.1186/s11689-024-09518-z.

ABSTRACT

We describe a multidisciplinary teamwork approach known as "Operation IDD Gene Team" developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College of Medicine. This initiative brings families affected by rare genetic diseases that cause intellectual and developmental disability together with physicians, basic scientists, and their trainees. At team meetings, family members share their child's medical and personal history, physicians describe the broader clinical consequences of the condition, and scientists provide accessible tutorials focused on the fundamental biology of relevant genes. When appropriate, possible treatment approaches are also discussed. The outcomes of team meetings have been overwhelmingly positive, with families not only expressing deep gratitude, but also becoming empowered to establish foundations dedicated to their child's specific condition. Physicians, and in particular the scientists and their trainees, have gained a deeper understanding of challenges faced by affected families, broadening their perspective on how their research can extend beyond the laboratory. Remarkably, research by the scientists following the Gene Team meetings have often included focus on the actual gene variants exhibited by the participating children. As these investigations progress and newly created foundations expand their efforts, national as well as international collaborations are forged. These developments emphasize the importance of rare diseases as windows into previously unexplored molecular and cellular processes, which can offer fresh insights into both normal function as well as more common diseases. Elucidating the mechanisms of and treatments for rare and ultra-rare diseases thus has benefits for all involved-families, physicians, and scientists and their trainees, as well as the broader medical community. While the RFK IDDRC's Operation IDD Gene Team program has focused on intellectual disabilities affecting children, we believe it has the potential to be applied to rare genetic diseases impacting individuals of any age and encompassing a wide variety of developmental disorders affecting multiple organ systems.

PMID:38491427 | PMC:PMC10941544 | DOI:10.1186/s11689-024-09518-z

BMJ Case Rep. 2024 Mar 15;17(3):e259192. doi: 10.1136/bcr-2023-259192.

ABSTRACT

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder which typically manifests with muscle weakness. However, despite late-onset MADD being treatable, it is often misdiagnosed, due in part to the heterogeneity of presentations. We report a case of late-onset MADD manifesting first as a sensory neuropathy before progressing to myopathic symptoms and acute metabolic decompensation. Early diagnostic workup with acylcarnitine profiling and organic acid analysis was critical in patient outcome; metabolic decompensation and myopathic symptoms were completely reversed with riboflavin supplementation and dietary modification, although sensory neuropathy persisted. Clinical consideration of MADD as part of the differential diagnosis of neuropathy with myopathy is crucial for a timely diagnosis and treatment of MADD.

PMID:38490702 | DOI:10.1136/bcr-2023-259192

Sci Rep. 2024 Mar 14;14(1):6186. doi: 10.1038/s41598-024-56240-w.

ABSTRACT

Acromegaly is a rare disease characterized by a diagnostic delay ranging from 5 to 10 years from the symptoms' onset. The aim of this study was to develop and internally validate machine-learning algorithms to identify a combination of variables for the early diagnosis of acromegaly. This retrospective population-based study was conducted between 2011 and 2018 using data from the claims databases of Sicily Region, in Southern Italy. To identify combinations of potential predictors of acromegaly diagnosis, conditional and unconditional penalized multivariable logistic regression models and three machine learning algorithms (i.e., the Recursive Partitioning and Regression Tree, the Random Forest and the Support Vector Machine) were used, and their performance was evaluated. The random forest (RF) algorithm achieved the highest Area under the ROC Curve value of 0.83 (95% CI 0.79-0.87). The sensitivity in the test set, computed at the optimal threshold of predicted probabilities, ranged from 28% for the unconditional logistic regression model to 69% for the RF. Overall, the only diagnosis predictor selected by all five models and algorithms was the number of immunosuppressants-related pharmacy claims. The other predictors selected by at least two models were eventually combined in an unconditional logistic regression to develop a meta-score that achieved an acceptable discrimination accuracy (AUC = 0.71, 95% CI 0.66-0.75). Findings of this study showed that data-driven machine learning algorithms may play a role in supporting the early diagnosis of rare diseases such as acromegaly.

PMID:38485706 | PMC:PMC10940660 | DOI:10.1038/s41598-024-56240-w

Tex Heart Inst J. 2024 Mar 14;51(1):e238209. doi: 10.14503/THIJ-23-8209.

ABSTRACT

Portopulmonary hypertension is a rare condition with a poor prognosis. Prompt management is essential for liver transplantation eligibility, a potentially curative option. This report presents a case of severe portopulmonary hypertension that resolved with a conservative therapeutic regimen of tadalafil, macitentan, and inhaled treprostinil, which ultimately enabled successful liver transplantation. There was no recurrence of pulmonary hypertension after transplantation, and the patient was weaned off most pulmonary arterial hypertension therapies. This case report is the first to provide evidence that inhaled treprostinil is a safe and effective alternative to continuous intravenous prostacyclins in portopulmonary hypertension.

PMID:38483473 | DOI:10.14503/THIJ-23-8209

Dermatol Online J. 2023 Dec 15;29(6). doi: 10.5070/D329663003.

ABSTRACT

Orofacial granulomatosis is a rare disorder that is heterogeneously defined in the published literature. Herein, we describe a patient with orofacial granulomatosis with clinical and histologic evidence, discuss differential diagnoses, and offer clinical pearls for diagnosing and assessing this disorder. Our case provides support that orofacial granulomatosis is a distinct disorder as opposed to a sequela of other systemic granulomatous diseases. This information will aid dermatologists in decision making and diagnosing the disorder.

PMID:38478674 | DOI:10.5070/D329663003

Tremor Other Hyperkinet Mov (N Y). 2024 Mar 6;14:10. doi: 10.5334/tohm.851. eCollection 2024.

ABSTRACT

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX.

METHODS: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented.

RESULTS: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis.

DISCUSSION: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

PMID:38476584 | PMC:PMC10929277 | DOI:10.5334/tohm.851

Orphanet J Rare Dis. 2024 Mar 12;19(1):117. doi: 10.1186/s13023-024-03111-2.

ABSTRACT

BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency's feedback on its strengths and key challenges.

RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients' baseline characteristics, missing information, and potential bias and measurement errors.

CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

PMID:38475874 | PMC:PMC10936002 | DOI:10.1186/s13023-024-03111-2

Int J Surg Case Rep. 2024 Mar 5;117:109462. doi: 10.1016/j.ijscr.2024.109462. Online ahead of print.

ABSTRACT

INTRODUCTION: With the rapid improvement of magnetic resonance imaging (MRI), mucoid degeneration (MD) of the anterior cruciate ligament (MD-ACL) has become an established disease entity and mechanical factors, such as increased posterior tibial tilt and intercondylar notch impingement, have been proposed. However, symptomatic MD of the posterior cruciate ligament (MD-PCL) remains an orphan disease without any established etiology.

PRESENTATION OF CASE: A man in his 60s exhibited restricted range of motion with knee pain. MRI revealed PCL enlargement with high-signal intensity and tram-track appearance on T2-weighted sagittal images and lipoma arborescens (LA) in the suprapatellar pouch. On gadolinium-enhanced MRI, the distal PCL was not contrasted. Arthroscopy revealed an almost normal expanded appearance with partial loss of the envelope synovium. Debulking operation was performed. Pathological findings revealed intravascular thrombus formation in early lesions of MD, and intraligamentous vascular degeneration and severity of MD were proportional.

DISCUSSION: ACL is susceptible to mechanical external forces from surrounding tissues because of its anatomical features that induce protease expression, resulting in MD-ACL with denatured large aggregating proteoglycans deposition. Conversely, occlusion of nutrient vessels within the ligament was observed in this case of MD-PCL. Coexisting LA likely provoked an inflammatory response with hypercoagulability, resulting in thromboembolism of the envelope synovial nutrient vessel.

CONCLUSION: MD-CL is a disease entity comprising multiple pathologies. Although symptomatic MD-ACL is mainly caused by mechanical factors with a relatively high morbidity rate, nutrient vessel dysfunction can contribute to symptomatic MD-PCL with coexisting LA in middle-aged adults with an extremely low morbidity rate.

PMID:38479129 | DOI:10.1016/j.ijscr.2024.109462

BMJ Case Rep. 2024 Mar 12;17(3):e259763. doi: 10.1136/bcr-2024-259763.

ABSTRACT

Klippel-Trenaunay syndrome (KTS) is a rare, congenital disorder typically emerging in early infancy or childhood. The classic presentation of KTS is distinguished by a triad of clinical features: a port-wine stain, early-onset varicosities and limb overgrowth. However, a notable variant of KTS has been documented, characterised by limb shortening rather than lengthening, occasionally referred to as 'inverse KTS'. This report details two cases that display this unusual presentation-both patients had classical features of port-wine stain and varicose veins but both experienced shortening of the affected limb. Whether these cases represent a variant of KTS or a new clinical syndrome altogether is uncertain. They however offer valuable insights into the nuances and breadth of clinical manifestations associated with this syndrome.

PMID:38471707 | PMC:PMC10936486 | DOI:10.1136/bcr-2024-259763