J Cancer Res Clin Oncol. 2022 Aug 12. doi: 10.1007/s00432-022-04223-7. Online ahead of print.

ABSTRACT

PURPOSE: Anaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival.

METHODS: Using individualized patient data derived from our systematic review of literature and our single center study (n = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study (n = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC.

RESULTS: Pooled cohort study showed surgery (p < 0.001), RT ≥ 30 Gy (p < 0.001), ChT (p < 0.001) and multimodal treatment (p = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162-3.433], p = 0.012) and RT ≥ 30 Gy (1.877 [1.232-2.843], p = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment (n = 445) total thyroidectomy (p = 0.031), administration of ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy (p = 0.031), ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS (p < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002).

CONCLUSIONS: Surgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease.

PMID:35960373 | DOI:10.1007/s00432-022-04223-7

Pan Afr Med J. 2022 May 18;42:48. doi: 10.11604/pamj.2022.42.48.29515. eCollection 2022.

NO ABSTRACT

PMID:35949470 | PMC:PMC9338714 | DOI:10.11604/pamj.2022.42.48.29515

J Comp Eff Res. 2022 Oct;11(14):999-1010. doi: 10.2217/cer-2022-0120. Epub 2022 Aug 10.

ABSTRACT

Scientific advancements, new US FDA approval pathways and limited competition have contributed to rapid growth in the number of approved rare disease treatments in recent years. While the rising numbers of orphan drug approvals are a sign of success, the rapid growth in approved rare disease treatments has created concerns about the pricing of orphan drugs and their cumulative affordability to the health system. To support efforts to build a policy and practice infrastructure that drives innovation within a platform that is affordable to patients and the health system, this paper provides an analysis of potential risks as well as advantages of reform options related to drug development, pricing and coverage.

PMID:35946484 | DOI:10.2217/cer-2022-0120

JMIR Mhealth Uhealth. 2022 Aug 10;10(8):e38331. doi: 10.2196/38331.

ABSTRACT

BACKGROUND: Large gaps exist in understanding the symptomatic and functional impact of sarcoidosis, a rare multisystem granulomatous disease affecting fewer than 200,000 individuals in the United States. Smartphones could be used for prospective research, especially for rare diseases where organizing large cohorts can be challenging, given their near ubiquitous ownership and ability to track objective and subjective data with increasingly sophisticated technology.

OBJECTIVE: We aimed to investigate whether smartphones could assess the quality of life (QoL) and physical activity of a large cohort of individuals with sarcoidosis.

METHODS: We developed a mobile app (Sarcoidosis App) for a prospective, cross-sectional study on individuals with sarcoidosis. The Sarcoidosis App was made available on both Apple and Android smartphones. Individuals with sarcoidosis were recruited, consented, and enrolled entirely within the app. Surveys on sarcoidosis history, medical history, and medications were administered. Patients completed modules from the Sarcoidosis Assessment Tool, a validated patient-reported outcomes assessment of physical activity, fatigue, pain, skin symptoms, sleep, and lungs symptoms. Physical activity measured by smartphones was tracked as available.

RESULTS: From April 2018 to May 2020, the App was downloaded 2558 times, and 629 individuals enrolled (404, 64.2% female; mean age 51 years; 513, 81.6% White; 86, 13.7% Black). Two-thirds of participants had a college or graduate degree, and more than half of them reported an income greater than US $60,000. Both QoL related to physical activity (P<.001, ρ=0.250) and fatigue (P<.01, ρ=-0.203) correlated with actual smartphone-tracked physical activity. Overall, 19.0% (98/517) of participants missed at least 1 week of school or work in an observed month owing to sarcoidosis, and 44.4% (279/629) reported that finances "greatly" or "severely" affected by sarcoidosis. Furthermore, 71.2% (437/614) of participants reported taking medications for sarcoidosis, with the most common being prednisone, methotrexate, hydroxychloroquine, and infliximab. Moreover, 46.4% (244/526) reported medication side effects, most commonly due to prednisone.

CONCLUSIONS: We demonstrate that smartphones can prospectively recruit, consent, and study physical activity, QoL, and medication usage in a large sarcoidosis cohort, using both passively collected objective data and qualitative surveys that did not require any in-person encounters. Our study's limitations include the study population being weighted toward more educated and wealthier individuals, suggesting that recruitment was not representative of the full spectrum of patients with sarcoidosis in the United States. Our study provides a model for future smartphone-enabled clinical research for rare diseases and highlights key technical challenges that future research teams interested in smartphone-based research for rare diseases should anticipate.

PMID:35947439 | DOI:10.2196/38331

Genome Med. 2022 Aug 9;14(1):85. doi: 10.1186/s13073-022-01094-y.

ABSTRACT

BACKGROUND: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.

METHODS: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.

RESULTS: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10-13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10-13). We constructed an interactive resource highlighting demographic information ( http://www-personal.umich.edu/~mattpat/rareDiseases.html ) and demonstrate transferability by applying our mapping to a medical claims database.

CONCLUSIONS: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.

PMID:35945607 | DOI:10.1186/s13073-022-01094-y

Am J Physiol Cell Physiol. 2022 Aug 8. doi: 10.1152/ajpcell.00356.2021. Online ahead of print.

ABSTRACT

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category are monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations which may be germline (e.g. deficiency of ADA2 or GATA2 deficiency) or somatic (e.g. VEXAS syndrome). The second category are the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-gamma, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. While this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, non-invasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and under-recognized diseases.

PMID:35938681 | DOI:10.1152/ajpcell.00356.2021

Int J Rheum Dis. 2022 Aug 8. doi: 10.1111/1756-185X.14418. Online ahead of print.

ABSTRACT

Pachydermoperiostosis (PDP) is a rare disorder characterized by skin thickening, acropachia, and periostosis. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is also an orphan disease featured by different dermatological and osteoarthritic manifestations. Herein, we report the first case of an adolescent male diagnosed with both PDP and SAPHO syndrome, presenting with digital clubbing, polyarthralgia, ostealgia, pachydermia and acne on his face, chest and back. Furthermore, we distinguish the characteristics of both diseases and explore the potential pathological mechanism for this coexistence in one patient. Further investigations are needed to establish the detailed pathophysiological association of these 2 diseases.

PMID:35938529 | DOI:10.1111/1756-185X.14418

Front Public Health. 2022 Jul 19;10:915438. doi: 10.3389/fpubh.2022.915438. eCollection 2022.

ABSTRACT

Patient involvement (PI) in determining medical research priorities is an important way to ensure that limited research funds are allocated to best serve patients. As a disease area for which research funds are limited, we see a particular utility for PI in priority-setting for medical research on rare diseases. In this review, we argue that PI initiatives are an important form of evidence for policymaking. We conducted a study to identify the extent to which PI initiatives are being conducted in the rare disease field, the features of such initiatives, the trends in the priorities elicited, and the extent to which translation into policy is reported in the academic literature. Here, we report the results of this exploratory review of the English-language literature gathered through online databases and search engines, with the aim of identifying journal articles published prior to December 2020, describing PI initiatives focused on determining priorities for medical research funding in the rare disease field. We identified seven recently-published articles and found that the majority made use of structured methodologies to ensure the robustness of the evidence produced, but found little reported practical implementation or concrete plans for implementation of the results of the initiatives. We conclude that priority-setting initiatives are meaningful mechanisms for involving patients in determining research directions. However, we highlight the importance of translation into policy as a necessary next step to fully utilize the results and move beyond well-intentioned exercises. Finally, we draw attention to the benefits of involving patients throughout this process.

PMID:35928485 | PMC:PMC9343727 | DOI:10.3389/fpubh.2022.915438

Mol Cell. 2022 Aug 4;82(15):2735-2737. doi: 10.1016/j.molcel.2022.07.005.

ABSTRACT

Rensvold, Shishkova, et al. (2022) apply an integrated systems biology approach spanning proteomics, lipidomics, and metabolomics to a collection of CRISPR knockout cells targeting 116 distinct human mitochondrial proteins, revealing new mitochondrial biology and guiding orphan disease diagnosis.

PMID:35931038 | DOI:10.1016/j.molcel.2022.07.005

J Antimicrob Chemother. 2022 Aug 5:dkac269. doi: 10.1093/jac/dkac269. Online ahead of print.

ABSTRACT

BACKGROUND: Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes.

METHODS: Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7 days, in duplicate units. Total bacterial burden versus AUC/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment.

RESULTS: The mean CRS0540 intracellular/extracellular AUC0-24 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0 log10 cfu/mL. The free drug AUC0-24/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC/MIC was described by a quadratic function, with resistance amplification at an AUC/MIC of 54.8 and resistance suppression at an AUC/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100 mg/kg achieved PTAs of >90% at MICs up to 1.0 mg/L.

CONCLUSIONS: CRS0540 is a promising orphan drug candidate for listeriosis. Future PK/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients.

PMID:35929190 | DOI:10.1093/jac/dkac269

Inn Med (Heidelb). 2022 Jul;63(7):791-797. doi: 10.1007/s00108-022-01350-8. Epub 2022 Jun 2.

ABSTRACT

BACKGROUND: Patients with an unclear diagnosis and suspected rare disease pose special challenges to physicians, among others.

AIM OF THE STUDY (RESEARCH QUESTION): The ZSE-DUO project aims to establish whether patient care under the joint supervision of a somatic expert and a mental health expert can improve diagnostic efficacy and precision, as well as shorten the time to diagnosis.

MATERIAL AND METHODS: ZSE-DUO has successfully recruited more than 1000 patients at eleven national centres for rare diseases in a control and an intervention group. The findings are being analysed by three evaluating institutions.

RESULTS AND DISCUSSION: The study is currently in its final phase. The results will be published in further papers.

PMID:35925266 | DOI:10.1007/s00108-022-01350-8

Hum Mol Genet. 2022 Aug 4:ddac182. doi: 10.1093/hmg/ddac182. Online ahead of print.

ABSTRACT

Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.

PMID:35925862 | DOI:10.1093/hmg/ddac182

J Genet Couns. 2022 Aug 2. doi: 10.1002/jgc4.1616. Online ahead of print.

ABSTRACT

Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine-guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch-Nyhan syndrome (LNS) and is inherited in an X-linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self-mutilating behaviors. Here, we present the case of a male infant who was diagnosed with LNS at 3 weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally inherited deletion of at least 1.3 Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents' values that guided the decision-making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity of discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family toward making an informed decision.

PMID:35916015 | DOI:10.1002/jgc4.1616

Eur Urol Focus. 2022 May;8(3):657-659. doi: 10.1016/j.euf.2022.07.006. Epub 2022 Jul 30.

ABSTRACT

Prediction of treatment response has attracted growing attention in cancer research to improve clinical outcomes via individualized treatment regimens. Patient-derived organoids and xenografts are novel preclinical model systems that recapitulate the genetic and phenotypic features of parental tumors for this purpose. Organoid culture has been successfully established in multiple cancers and used for assessment of drug and immunotherapy responses. Patient-derived xenograft (PDX) models provide insights into in vivo tumor growth and metastatic potential. Continued improvements in these model systems to better maintain tumor architecture and microenvironment will advance patient-specific targeted therapies. PATIENT SUMMARY: This mini review describes up-to-date organoid and xenograft models of bladder cancer created using patient-derived tissue. These models are important for research and may provide information on mutations and expression patterns for cancer-related genes that are unique to each patient, and could facilitate personalized therapy for individual patients.

PMID:35915037 | DOI:10.1016/j.euf.2022.07.006

Dis Model Mech. 2022 Jul 1;15(7):dmm049788. doi: 10.1242/dmm.049788. Epub 2022 Aug 1.

ABSTRACT

Neuromuscular disorders (NMDs) are a heterogenous group of rare inherited diseases that compromise the function of peripheral nerves and/or muscles. With limited treatment options available, there is a growing need to design effective preclinical studies that can lead to greater success in clinical trials for novel therapeutics. Here, I discuss recent advances in modelling NMDs to improve preclinical studies as well as two articles from this issue that work in parallel to enable a deeper understanding of a particularly rare NMD, known as X-linked myotubular myopathy.

PMID:35912512 | DOI:10.1242/dmm.049788

Orphanet J Rare Dis. 2022 Jul 29;17(1):297. doi: 10.1186/s13023-022-02459-7.

ABSTRACT

BACKGROUND: Bibliometric have been widely applied to the evaluation of academic productivity. However, those of individuals or institutions on a specific disease have not been explored. The aim of the present study is to conduct a bibliometric analysis of particular rare disease and investigate whether those doctors and hospitals with higher index screened by this method specialize in this disease.

METHODS: A representative rare disease, Wilson disease (WD), was searched on Clarivate Analytics' Web of Science and Elsevier's Scopus, which was published in English between 1 January 2001 and 31 December 2020. Clinical authors and medical institutions with the most papers were screened, and their total number of publications and citations, h-index and g-index were computed and then ranked by h-index.

RESULTS: A total of 6856 and 6193 papers and 200 and 160 authors were got from WoS and Scopus, respectively. Scopus provided 160 institutions. The above bibliometric indices were calculated in 100 researchers and 80 institutions, and top 30 authors (Top-30a) and top 20 institutions (Top-20i) of them based on the h-index were listed in the tables. Top-30a came from seven specialties and 13 countries whose median (interquartile range) h-index was 14 (12-19.5) (range 10-28) which was located between associate and full professors in some other disciplines. Top-20i was distributed in 13 countries whose mean ± standard deviation of the h-index was 15 ± 4.9 (range 10-27).

CONCLUSIONS: The related specialists and medical institutions of WD screened by specific disease bibliometric analysis are eminent and credible and benefit WD patients to obtain reliable medical treatment. This model may be suitable for other rare diseases.

PMID:35906666 | PMC:PMC9335981 | DOI:10.1186/s13023-022-02459-7

Orphanet J Rare Dis. 2022 Jul 29;17(1):295. doi: 10.1186/s13023-022-02439-x.

ABSTRACT

BACKGROUND: Systemic mastocytosis is a rare genetic disease characterized by aberrant proliferation and/or activation of mast cells, resulting in multi-organ, allergy-like symptoms. Mast cell activation syndrome (MCAS) is a clinically similar, but more prevalent disease with unclear etiology. In this study, the health-related quality of life (HRQOL) and health literacy of people suffering from SM and MCAS were assessed.

RESULTS: Two validated questionnaires (QLQ-C30/QLQ-INFO25) from the European Organisation for Research and Treatment of Cancer (EORTC) were used to analyze HRQOL and level of information of SM and MCAS patients. In addition, a control group without any health issues was included. Data were analyzed by ANOVA and linear regression to detect significant differences. Questionnaire data from 66 patients with MCAS (83% female, mean 44 years), 32 patients with SM (78% female, mean 53 years) and 52 healthy participants (67% female, mean 48 years) resident in Germany were analyzed. HRQOL as measured by the Global health status was significantly worse in patients suffering from MCAS or SM compared to control group. Individuals with MCAS showed a slightly, but insignificantly lower score on Global health status, and a significantly lower score with respect to role function and fatigue. Patients with the rare disease SM felt significantly better informed on their disease compared to MCAS patients. Linear regression performed separately for both groups showed a direct influence of the level of information on patients' HRQOL.

CONCLUSION: Overall, our study showed a significant negative impact on the HRQOL of both diseases, but only a small difference in quality of life and severity of symptoms between patients with MCAS and the supposedly more severe form, the rare disease SM. Our results demonstrate that the level of information patients receive impacts HRQOL, and that this is not only an issue in rare diseases, but also diseases with unclear etiology and pathology. Our data shows that even slight improvements in the patient's level of information can have a positive effect on their quality of life, further highlighting the importance of gaining more knowledge on rare and incompletely understood diseases and communicating these insights to patients.

PMID:35906626 | PMC:PMC9336039 | DOI:10.1186/s13023-022-02439-x

BMJ Open. 2022 Jul 29;12(7):e062126. doi: 10.1136/bmjopen-2022-062126.

ABSTRACT

INTRODUCTION: Rare diseases (RDs) are often chronic and progressive life-threatening medical conditions that affect a low percentage of the population compared with other diseases. These conditions can be treated with medications known as orphan drugs (ODs). Unfortunately, there is no universal definition of RDs or ODs. This systematic review (SR) will identify the quantitative and qualitative criteria and the underlying rationale used internationally to define RDs and ODs.

METHODS AND ANALYSIS: This protocol follows the conventions for the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (2015 guidelines). A SR will be conducted, including a search of the following databases: PubMed, MEDLINE, EMBASE, Scopus, Web of Science, GreyLit and OpenGrey. Eligible publications will be selected based on predetermined inclusion criteria. Extracted data will be analysed using thematic and content analyses of qualitative descriptors, whereas quantitative data will be analysed descriptively and reported in the form of frequencies and percentages.

ETHICS AND DISSEMINATION: No ethical approval is required since this SR focuses on the secondary analysis of data retrieved from the scientific literature. The outcomes of this SR will be published as part of a PhD thesis, presented at conferences, and published in peer-reviewed journals.

PROSPERO REGISTRATION NUMBER: CRD42021252701.

PMID:35906057 | DOI:10.1136/bmjopen-2022-062126

Lancet Oncol. 2022 Aug;23(8):e367. doi: 10.1016/S1470-2045(22)00453-3.

NO ABSTRACT

PMID:35901828 | DOI:10.1016/S1470-2045(22)00453-3

Ned Tijdschr Geneeskd. 2022 Jul 18;166:D6860.

ABSTRACT

A 6-month-old girl with an isolated bald spot was seen at the general practice. We diagnosed aplasia cutis congenita, a rare disorder with a wide variation in clinical symptoms. Most lesions can be managed conservatively. Larger defects, however, require surgery.

PMID:35899755