Enlightenment of COVID-19 Treated by Botanical Drugs on the Development of Drugs for Rare Diseases in China

Objective To study the feasibility of developing botanical drugs to treat intractable diseases and play an important role in dealing with major public health crises.Methods From January 1990 to May 2021,a bibliographic search was carried out on the use of botanical drugs,rare disease drugs,related registration management policies and regulations in PubMed and CNKI.The following keywords were searched in the database:Rare disease policies and regulations,orphan drugs,botanical drugs for intractable diseases,botanical drugs for the treatment of new coronary pneumonia,traditional Chinese medicine,and emergency guidelines for major public health crisis.Other data were obtained from“Chinese Pharmacopoeia”and relevant Chinese government websites for sorting and analysis.Results and Conclusion Based on 39 Chinese corresponding policies and regulations,challenges and opportunities of developing and researching drugs for treating rare diseases were found out after the analysis and comparison.Based on the study of national policies on drugs for rare diseases,the priority review and approval procedures in the drug registration,as well as China’s emergency guidelines and policies for major public health events,some problems in the use of drugs for rare diseases are found out.Therefore,it is recommended to actively adopt the property rights protection system,explore the folk prescriptions of traditional Chinese medicine and the potential of hospital preparations,and the registration review strategy of giving priority to the use of botanical drugs for rare diseases.Thus,the international status of botanical drugs for rare disease and the influence of responding to major public health events can be enhanced.

New Treatment Options in Rare Diseases

The term rare disease is used for diseases with a prevalence of ˂ 1 per 2000 people in the community. For the first time in 1990, Sweden became the country that established an information center on rare diseases. Turkey has made the relevant legal arrangements in 2020. The largest group under this common roof is “Hereditary Metabolic diseases”. The number of inherited metabolic diseases has reached a remarkable scope in the light of the rapidly accelerating developments in biochemistry, genetics, pharmacology, electronics sciences in 1902, when this name was first used, “Alkaptonuria” disease. In the light of the information obtained, 4 separate subgroups were created according to their common characteristics in order to produce solutions for this large group. Treatment options for metabolic disorders are both simple and complex. Diet therapy, cofactor therapy, enzyme replacement therapy (ERT), Substrate reduction therapy, chaperone therapy, tissue - organ - stem cell transplantation and gene therapy can be listed as these treatment options. Preimplantation genetics has been a rational solution to preventing disease formation, also supported by our ministry of health.

Current situation and prospect for the diagnosis and treatment of pediatric critical rare diseases in China

The onset of critical rare diseases(RDs)in children is rapid and dangerous,accompanied by a high mortality rate,which brings a heavy burden to both families and society.Multiple malformations,neuromuscular diseases,metabolic diseases,and heart diseases are the most common types of RDs in children of China,often manifesting with multiple organ dysfunction.At present,the diagnosis and treatment of critical RDs in children face challenges such as prolonged diagnosis time,a high misdiagnosis rate,limited treatment modalities,and a significant disease burden.However,with the progress in genetic testing technology,the establishment of multidisciplinary diagnosis and treatment platforms,and the implementation of relevant RD policies in China,children with critical RDs will received enhanced medical services,experience improved prognoses,and reintegrate into social life.

Australian children living with rare diseases:health service use and barriers to accessing care

Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare.We aimed to determine health service utilization by Australian children with rare diseases and barriers to access-ing healthcare.Methods Parents completed an online survey on health professional and emergency department(ED)presentations,hospi-talization,and barriers to accessing services.Potential barriers to service access included residential location(city,regional,remote)and child health-related functioning,determined using a validated,parent-completed measure-of-function tool.Results Parents of 462 children with over 240 rare diseases completed the survey.Compared with the general population,these children were more likely to be hospitalized[odds ratio(OR)=17.25,95%confidence interval(CI)=15.50-19.20]and present to the ED(OR=4.15,95%CI=3.68-4.68)or a family physician(OR=4.14,95%CI=3.72-4.60).Child functional impairment was nil/mild(31%),moderate(48%)or severe(22%).Compared to children with nil/mild impair-ment,those with severe impairment were more likely to be hospitalized(OR=13.39,95%CI=7.65-23.44)and present to the ED(OR=11.16,95%CI=6.46-19.27).Most children(75%)lived in major cities,but children from regional(OR=2.78,95%CI=1.72-4.55)and remote areas(OR=9.09,95%CI=3.03-25.00)experienced significantly more barriers to healthcare access than children from major cities.Barriers included distance to travel,out-of-pocket costs,and lack of specialist medical and other health services.Conclusions Children with rare diseases,especially those with severe functional impairment have an enormous impact on health services,and better integrated multidisciplinary services with patient-centered care are needed.Access must be improved for children living in rural and remote settings.

Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Medical service utilisation, economic burden and health status of patients with rare diseases in China

Many patients with rare diseases not only suffer from more severe conditions but often receive less disease management, which is one significant public health concern globally. Few practice-based surveys focus on the care of patients with rare diseases. In the present study, we aimed to investigate medical service utilization, economic burden and health status of patients with rare diseases in China. A cross-sectional questionnaire survey focusing on patients with rare diseases was conducted. Descriptive analysis was conducted to examine the sociodemographic characteristics, medical service utilization, economic burden and health status. Logistic regression analysis was applied to explore influencing factors of self-rated health. A total of 982 patients with 81 types of diseases were included in this survey. We found that 58.2% of patients experienced misdiagnosis, and 35.2% of the patients were misdiagnosed for at least five times. Moreover, 65.8% of patients traveled to hospitals to seek medical services, and 92.1% of patients paid expenses for their treatment. However, only 1.3% of patients could afford their medical expenditure without debts, and 86.8% of patients regarded their health status as bad or moderate. Significant factors correlated with health status were economic status, gender, age, employment and household size. From this study, the accessibility of medical service utilization, the affordability of medical economic burden, and the condition of health status for patients with rare disease in China were considerably poor. Basic medical insurance did not play its role in improving the utilization of medical services and the affordability of medical costs. Social support should be encouraged to improve patients＇ health status.

Attention Should be Drawn to Rare Diseases and Interpretation of Sequence Variants

The last Monday in February is the ＂Rare Disease Day＂ every year. This year the theme of it is ＂Join us in making the voice of rare diseases heard＂, proposed by World Health Organization （http：//www.rarediseaseday.org）. Rare diseases are a group of serious chronic diseases, with a high morbidity and mortality rates.

Determinants and Equity Evaluation for Health Expenditure Among Patients with Rare Diseases in China

Background： China has not established social security system for rare diseases. Rare diseases could easily impoverish patients and their families. Little research has studied the equity and accessibility of health services for patients with rare diseases in China. This study aimed to explore the factors that influence health expenditure of rare diseases and evaluate its equity. Methods： Questionnaire survey about living conditions and cost burden of patients with rare diseases was conducted. Individual and family information, health expenditure and reimbursement in 2014 of 982 patients were collected. The impact of medical insurance, individual sociodemographic characteristics, family characteristics, and healthcare need on total and out-of-pocket （OOP） health expenditures was analyzed through the generalized linear model. Equity of health expenditure was evaluated by both concentration index and Lorenz curve. Results： Of all the surveyed patients, 11.41% had no medical insurance and 92.10% spent money to seek medical treatment in 2014. It was suggested female （P = 0.048）, over 50 years of age （P = 0.062）, high-income group （P = 0.021）, hospitalization （P- 0.000）, and reimbursement ratio （RR） （P = 0.000） were positively correlated with total health expenditure. Diseases not needing long-term treatment （P = 0.000） was negatively correlated with total health expenditure. Over 50 years of age （P = 0.065）, high-income group （P = 0.018）, hospitalization （P = 0.000） and having Urban Employee Basic Medical Insurance （UEBMI） （P - 0.022） were positively correlated with OOP health expenditure. Patient or the head of the household having received higher education （P = 0.044 and P = 0.08 l） and reimbursement ratio （P = 0.078） were negatively correlated with OOP health expenditure. The equity evaluation found concentration indexes of health expenditure before and after reimbursement were 0.0550 and 0.0539, respectively. Conclusions： OOP health expenditure of patients with UEBMI was significantly more than that of patients without medical insurance. However, for any other medical insurance, there was no difference between OOP health expenditure of the insured patients and patients without insurance. The current reimbursement policies have increased the equity of health expenditure, but are biased toward high-income people.

Molecular biomarkers,network biomarkers,and dynamic network biomarkers for diagnosis and prediction of rare diseases

The difficulty of converting scientific research findings into novel pharmacological treatments for rare and life-threatening diseases is enormous.Biomarkers related to multiple biological processes involved in cell growth,proliferation,and disease occurrence have been identified in recent years with the development of immunology,molecular biology,and genomics technologies.Biomarkers are capable of reflecting normal physiological processes,pathological processes,and the response to therapeutic intervention;as such,they play vital roles in disease diagnosis,prevention,drug response,and other aspects of biomedicine.The discovery of valuable biomarkers has become a focal point of current research.Numerous studies have identified molecular biomarkers based on the differential expression/concentration of molecules(e.g.,genes/proteins)for disease state diagnosis,characterization,and treatment.Although technological breakthroughs in molecular analysis platforms have enabled the identification of a large number of candidate biomarkers for rare diseases,only a small number of these candidates have been properly validated for use in patient treatment.The traditional molecular biomarkers may lose vital information by ignoring molecular associations/interactions,and thus the concept of network biomarkers based on differential associations/correlations of molecule pairs has been established.This approach promises to be more stable and reliable in diagnosing disease states.Furthermore,the newly-emerged dynamic network biomarkers(DNBs)based on differential fluctuations/correlations of molecular groups are able to recognize pre-disease states or critical states instead of disease states,thereby achieving rare disease prediction or predictive/preventative medicine and providing deep insight into the dynamic characteristics of disease initiation and progression.

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene,causing it to lose its function of regulating downstream phosphorylated-AMPK(Thr172),which may lead to the development of PJS.The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients.These findings not only offer insights for clinical decision-making,but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

Hepatic amyloidosis in a patient with chronic liver failure:A case report

BACKGROUND Amyloidosis is a rare disorder that can be classified into various types,and the most common type is the systemic light chain type.The prognosis of this disease is extremely poor.In general,amyloidosis mainly affects the kidneys and heart and manifests as abnormal proliferation of clonal plasma cells.Cases in which the liver is the primary organ affected by amyloidosis,as in this report,are less common in clinical practice.CASE SUMMARY A 62-year-old man was admitted with persistent liver dysfunction of unknown cause and poor treatment outcomes.His condition persisted,and he developed chronic liver failure,with severe cholestasis in the later stage that was gradually accompanied by renal injury.Ultimately,he was diagnosed with hepatic amyloidosis through liver biopsy and pathological examination.CONCLUSION Hepatic amyloidosis rarely occurs in the clinic,and liver biopsy and pathological examination can assist in the accurate and effective diagnosis of this condition.

Orphan and Rare Disease Products -The Payer Perspective

The paper is to look at the affordability of orphan medications across the globe and whether payer attitudes to high-price medications are changing in the face of rising healthcare expenditure and tighter budgets. We conducted an online semi-quantitative survey of 10 European markets, the United States and Japan （Q1-Q2 2014） to understand how payers＇ views and attitudes are changing in response to new treatments coming to market for rare and ultra-rare conditions. The payers selected for the survey hold or have held senior positions within their respective market institutions. The United States and Japan were included in the study to provide international context to the European results. Responses were anonymised in accordance with good market research principles. The research shows that 75% of respondents surveyed believe that the current approach to orphan drug pricing is unsustainable in the future and 92% predict a tougher approach from payers going forward. 75% of payers do not believe that patent expiry alone will free up the necessary space for innovative orphan and ultra-orphan products. 83% of the payers surveyed believed that less than half of all orphan and ultra-orphan drugs coming to market are supported by an adequate evidence base for reimbursement. The environment for orphan medicines across the globe is changing; and as the financial performance of countries begins to diverge, so do attitudes towards the funding of orphan medicines. The increasing number of rare diseases, and treatments available, is forcing payers to view orphan drugs in a new light and they are becoming increasingly sceptical about the prices charged in relation to the clinical benefit offered. As rare disease spending becomes a higher proportion of pharmaceutical spending, payers will need to take action to curb this trend.

Natural Nanoskin ACT Management of the Rare Disease as Burnt Patient with Epidermolysis Bullosa and Stevens-Johnson

Epidermolysis Bullosa (EB) is a group of rare genetic skin conditions, which is characterised by extremely fragile skin and recurrent blister formation, resulting from minor mechanical friction or trauma. Sufferers of EB have compared the sores to third-degree burns. Stevens-Johnson syndrome is a rare but very serious skin problem, which causes the appearance of reddish lesions throughout the body and other changes, such as difficulty in breathing and fever, which can endanger the life of the affected person. The aim of this study was to show efficacy of a NANOSKIN ACT, AND NANOSKIN ACT SOFT wound dressing on the wound care management in patients with EB AND Stevens-Johnson syndrome (SJS).

The Enlightenment of EU Real-World Evidence Supporting the Inclusion of Rare Disease Drugs in Medical Insurance Decisions to China

Objective To study the use of real-world evidence by EU and its member states for establishing a strategy for rare diseases and provide references for the inclusion of orphan drugs in China’s medical insurance.Methods A case analysis method was used to introduce the EU’s decision to include rare disease drugs in medical insurance by using real-world evidence because clinical data of rare diseases were difficult to obtain.Results and Conclusion China can use real-world evidence to make medical insurance decisions based on the experience of the EU and continue to invest more in rare diseases,which can solve the problem of few drugs for patients with rare disease.

基于史密斯政策执行过程模型的国家医保药品目录准入谈判罕见病药品落地问题及路径研究

目的基于史密斯政策执行过程模型的国家医保药品目录准入谈判(以下简称“国谈”)罕见病药品落地的关键和难点,探索罕见病药品在进入国家基本医疗保险和工伤保险药品目录后政策实施过程中存在的问题并提出对策建议。方法通过文献复习和政策梳理、专家访谈、焦点小组访谈收集资料,结合史密斯政策执行过程模型的理论框架从多角度探索国谈罕见病药品政策执行情况的现状、问题以及解决方案。结果目前我国罕见病药品行业管理尚处于初级阶段;医疗服务提供方在意识、管理等方面仍存在不足;罕见病药品保障渠道有待优化,医疗保险支付机制尚不完善。结论建议进一步加强行业管理,提升罕见病用药保障;加强医疗服务提供方能力建设,取消罕见病用药考核限制;畅通罕见病用药保障渠道,完善医疗保险支付机制。

Understanding neurodevelopmental proteasomopathies as new rare disease entities:A review of current concepts,molecular biomarkers,and perspectives

The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis,allowing for rapid identification of hundreds of genes causing human diseases.This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3%of individuals worldwide are monogenic dis-eases.Strikingly,a substantial fraction of the mendelian forms of intellectual disability is asso-ciated with genes related to the ubiquitin-proteasome system,a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis.Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate"neurodevelopmen-tal proteasomopathies".Besides cognitive impairment,these diseases are typically associated with a series of syndromic clinical manifestations,among which facial dysmorphism,motor delay,and failure to thrive are the most prominent ones.While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes,the mo-lecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined.In this re-view,we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis,management,and potential treatment of these new rare disease entities.

Simultaneous thyroglossal duct cyst with parathyroid cyst: A case report

BACKGROUND Thyroglossal duct cysts(TDC)are common congenital deformities.Most of them are cysts formed by the thyroglossal ducts that do not disappear and degenerate in the early embryonic stage.TDC exists alone and is rarely complicated by other congenital embryonic malformations.Only a few reports of TDC with branchial cleft cysts,thyroid cancer,thyroid hematoma,and epidermoid cysts have been reported.Therefore,we report a patient with TDC and parathyroid cyst(PC),a rare disease that has never been reported.CASE SUMMARY A 47-year-old woman presented to clinic in April 2021 with a neck tumor which she had noticed 5 d earlier.We perfected the relevant examinations,such as ultrasound and computed tomography,and resected the tumor.After surgical treatment,the pathology revealed a cervical thyroglossal duct cyst and a left lobe parathyroid cyst.The patient was followed up for 1 year without significant recurrence.CONCLUSION We report a patient with a simultaneous TDC and a PC to explore the correlation between the two congenital anomalies.

121种罕见病特异性生命质量量表的研制与应用现状

以《第一批罕见病目录》121种疾病名称为基础,检索中英文数据库(中国知网、万方数据库、PubMed和Web of Science)和患者报告的临床结局和生存质量量表的数据库(PROQOLID),收集并评价罕见病特异性生命质量(quality of life,QoL)量表的研制、测量性能测评及应用文献。现有罕见病特异性生命质量量表50个,其中9个是汉化量表,仅1个量表为国内研制;大部分量表(86.0%)研究对象为成年患者;量表反应度和灵敏度测评较少。建议应加强罕见病生命质量量表尤其是未成年特异性生命质量量表的研制与应用,在量表测量性能评价时重视对反应度和灵敏度的研究。

Genitourinary melanoma:An overview for the clinician

Genitourinary (GU) melanoma is a rare presentation of melanoma accounting for approximately 0.5% of all melanomas.GU melanomas include primary melanomas of the vulva,vagina,uterine cervix,ovary,penis,scrotum,urethra,bladder,ureter,and kidney.These melanomas are often diagnosed in advanced stages and stigma is thought to contribute to delays in presentation.As the likely diagnosing provider,it is imperative that dermatologists,urologists,and gynecologists are aware of these uncommon sites of presentation.While there have been major advances in the treatment of melanomas as a whole in the last 10 years,their applications to GU melanomas have often been overlooked.GU melanomas have not been included in many of the major phase II clinical trials which brought contemporary advanced treatments to market and the prognoses for GU melanomas remain poor.Due to the rarity of GU melanomas,much of the literature provides gener alized recommendations across multiple different organs affected by GU melanomas or omits certain topics,making it difficult to appreciate the funda-mentals of the individual presentations.This review aimed to provide background information on the pathogenesis and epidemiology of the different sites of GU melanomas and categorize data specific to the presentation,staging,treatment,and prognosis of each type of GU melanoma to guide the clinician.It was also meant to encourage a multidisciplinary approach to the management of these patients as it spans the expertise of surgical oncologists,medical oncologists,radiation oncologist,dermatologists,urologists,and gynecologists.

Chilaiditi syndrome in pediatric patients - Symptomatic hepatodiaphragmatic interposition of colon: A case report and review of literature

BACKGROUND Chilaiditi syndrome is a rare disorder characterized by the hepatodiaphragmatic interposition of the intestine.CASE SUMMARY Here we report a case of a 12-year-old male who was admitted to the pediatric intensive care unit secondary to abdominal pain and severe respiratory distress.He was treated conservatively but the symptoms persisted requiring a surgical approach.While there have been several cases of Chilaiditi syndrome reported in adults,there is a scarcity of cases reported in the pediatric population.Our review of the literature found only 30 pediatric cases,including our reported case,with Chilaiditi syndrome,19(63%)of which were male.The median age of diagnosis was 4.5 years old with an interquartile range of 2.0-10.0 years.In our review,we found that the most common predisposing factors in children are aerophagia(12/30 cases)and constipation(13/30 cases).Ninety percent of the cases presented with complete intestinal interposition,in 100%of which,the colon was involved.Three of the 30 cases were associated with volvulus.CONCLUSION In the pediatric population,conservative(21/30 cases)and surgical(8/30 cases)treatment approaches have produced satisfactory outcomes for all the patients,regardless of approach.