Rare diseases (RDs) are considered chronic, progressive, and life-threatening conditions that impact a small percentage of the population, resulting in elevated levels of pain and suffering. These diseases lack effective treatments, and the symptoms exhibit considerable variability among individuals (1, 2). The absence of a universal definition poses a critical constraint in determining the prevalence of rare diseases (3). The lack of a universally accepted definition for rare diseases is the result of both practical challenges and regional economic factors. For instance, the United States applies an absolute number criterion based on the potential profitability of developing orphan drugs, whereas the European Union utilises a relative number criterion that considers its diverse population sizes (4). However, this criterion may not be applicable in areas with varying population sizes or where there are only a limited number of diagnosed rare disease patients. In Latin America, for example, there is no consensus on what constitutes a rare disease (5). Consequently, these differing approaches complicate global efforts to standardize the definition of rare diseases.

Following the adoption of the UN resolution on rare diseases, Rare Diseases International (RDI), a global network representing individuals affected by rare diseases, has played an instrumental role in advocating for a standardized definition of these conditions. Thus, in 2015, RDI proposed a universal definition of rare diseases, aiming to create a more cohesive approach to addressing these conditions across borders. However, despite RDI’s recommendations and the implementation of various global frameworks, each country continues to establish its own criteria for defining rare diseases, primarily based on factors such as disease prevalence, the impact on the population, and the capacity of healthcare systems to provide adequate treatment (6). This lack of uniform adoption has led to challenges in ensuring equitable access to healthcare and treatments for rare disease patients worldwide.

The absence of epidemiological data compounds this challenge, impeding a comprehensive understanding of their incidence and impact on individuals and society. Children with rare diseases face a more complex and uncertain future than children with more common diseases. An estimated 10,000 distinct rare diseases have been identified, with over half afflicting children and contributing to approximately 75% of all cases, primarily driven by genetic mutations accounting for about 80% of cases (7).

Globally, approximately 400 million individuals are impacted by rare diseases, and half of these are children (8, 9). The burden of these diseases encompasses significant implications for patients, their families, and the healthcare system. Furthermore, the absence of efficacious treatments exacerbates the burden, leading to heightened morbidity and mortality. A comprehensive understanding of rare disease burden is imperative for developing effective public health policies and targeted interventions.

The assessment of rare disease prevalence poses challenges due to significant variability across geographic regions. Recent data indicates that approximately 400–475 million individuals are affected by rare diseases, with an estimated 370–500 million being Indigenous people who encounter difficulties in accessing rare disease diagnosis, treatment, and healthcare services (10). A recent study shows an increase in rare disease prevalence from 10.57 to 33.21 cases per 100,000 individuals, reflecting an average annual rise of 19.46% (11). Nearly 75% of rare disease cases manifest in children, and regrettably, 30% of affected children do not survive beyond the age of five. Furthermore, 80% of rare diseases have been attributed to genetic factors (12, 13). To underscore the impact of these statistics, it is notable that half of all rare disease patients are children, three out of ten afflicted children do not reach their fifth birthday, and genetic mutations account for eight out of ten rare diseases (8, 9). The rise in the prevalence of rare diseases is not because the situation is deteriorating but due to advancements in diagnostic techniques, improved access to healthcare, and heightened awareness of these conditions. For instance, in Taiwan, advancements in diagnostic capabilities have led to an increased identification of rare diseases that were previously underdiagnosed (11). This rising prevalence should not be interpreted as a sign of worsening public health; instead, it represents a positive outcome resulting from enhancements in healthcare systems.

Regionally, a significant portion of the EU population, ranging from 27 to 36 million individuals, is impacted by approximately 8,000 rare diseases, with 50–75% of these cases affecting children (14, 15). In the United States, rare diseases are estimated to affect around 25–30 million people, encompassing one in ten Americans (8, 16). Australia is home to an estimated two million individuals affected by rare diseases, including 400,000 children (17, 18). The exact prevalence of rare diseases in China is undetermined, with some affecting fewer than 140,000 individuals and others impacting up to 49–82 million people (19, 20). Estimates suggest that around 50 million Africans, 40–50 million individuals in Latin America, and 25 million people in the Middle East are affected by rare diseases (21).

A recent systematic review has emphasized the varying prevalence of rare diseases based on disease type - metabolic disorders being the most common subgroup, affecting an estimated 1 in 1,458 individuals, while immunological and haematological disorders are reported as the rarest, with an impact of 1 in 6,000 individuals (22, 23). The lack of comprehensive data on rare diseases presents challenges in understanding their precise prevalence and societal impact, especially in paediatric patients.

Most rare diseases are genetic, resulting from mutations in one or more genes. These genetic mutations can be inherited from parents or occur de novo. For example, cystic fibrosis is caused by mutations in the CFTR gene, which can be exacerbated by environmental factors like lung infections, which can worsen the disease (24). In contrast, Duchenne muscular dystrophy is caused by mutations in the DMD gene (25). Some rare diseases result from chromosomal abnormalities, such as deletions, duplications, or translocations. An example is Williams syndrome, caused by a deletion of genetic material on chromosome 7 (26). Many rare diseases are inherited in an autosomal recessive, autosomal dominant, or X-linked manner. For instance, Tay-Sachs disease is inherited in an autosomal recessive pattern (27). Rett syndrome is typically caused by de novo mutations in the MECP2 gene on the X chromosome (28). Some rare diseases result from new (de novo) mutations that occur spontaneously during the formation of reproductive cells or in early embryonic development. Progeria (Hutchinson-Gilford progeria syndrome) often results from a de novo mutation in the LMNA gene (29). Environmental factors can also play a role in the expression and progression of these diseases, although this is less common. Exposure to certain environmental factors during pregnancy can increase the risk of rare diseases. For instance, maternal infections, substance abuse, or exposure to toxins can result in congenital anomalies (30, 31). Exposure to environmental toxins, such as heavy metals or pesticides, can increase the risk of developing rare diseases. This exposure can occur prenatally or during early childhood. Environmental factors can cause epigenetic changes that influence gene expression without altering the DNA sequence (32, 33). These changes can contribute to the development of rare diseases or affect their progression. In some cases, a combination of genetic predisposition and environmental triggers can lead to the onset of a rare disease. Many rare diseases result from a complex interplay between genetic predispositions and environmental influences. For example, in individuals with a genetic susceptibility to a disease, environmental factors such as diet, lifestyle, and exposures can influence the severity and onset of the condition (34, 35).

Understanding both genetic and environmental factors is crucial for diagnosing, managing, and potentially preventing rare diseases in children. This comprehensive approach helps develop targeted therapies and improve the quality of life for affected individuals.

Patients with rare diseases encounter substantial challenges stemming from diagnostic delays. These delays are frequently attributed to initial misdiagnosis, insufficient awareness among healthcare professionals, and restricted access to specialized diagnostic facilities. Prolonged diagnostic timelines can exacerbate the severity of consequences, such as disease progression, irreversible organ damage, and diminished treatment efficacy, underscoring the imperative for heightened medical professional awareness (36, 37). Recent studies have revealed that the average diagnostic journey for rare disease patients exceeds five years (38, 39). Furthermore, another study reported a median duration of 75 months (40). Diagnostic delays and misdiagnosis can be attributed to various factors, including the rare nature of these diseases, which pose challenges in data aggregation, in addition to data heterogeneity and fragmentation with inadequate interoperability, compounded by the absence of a comprehensive repository for rare diseases (41).

A previous study identified inaccessibility and lack of referral as the primary reasons for diagnostic delays, followed by service unavailability and protracted waiting times for affected patients (42). Consequently, the medical journey for rare disease patients entails multiple referrals and extensive testing, occasionally yielding inconclusive diagnoses (37, 43). While common diseases are typically prioritized in the diagnostic process, the low prevalence of rare diseases often results in their being overlooked. Consequently, patients affected by rare diseases must navigate the complexities of their conditions amidst a lack of specialized expertise and knowledge. Furthermore, the absence of targeted health policies contributes to diagnostic delays and restricted access to healthcare services. This combination can lead to significant physical, psychological, and cognitive impairments, and, in certain instances, may result in inadequate or even harmful treatments (36).

The utilization of genomic sequencing has seen a significant rise in the diagnosis of a wide array of diseases, including rare ones (40, 44). In recent years, there has been a paradigm shift in diagnosing rare diseases of epigenetic origin (RDEOs) owing to the transformative impact of next-generation sequencing techniques. High-throughput sequencing has proven effective in detecting and uncovering genetic variants, particularly in rare genetic diseases (8, 32, 45, 46). It has been observed that whole genome sequencing yields a higher diagnosis rate than exome sequencing alone (18, 47, 48). Notable technological progress has significantly enhanced the diagnostic paradigm (Table 1), facilitated by advanced diagnostic tools (49–52). Early screening of newborns is pivotal for the appropriate implementation of medical interventions and future decision-making (53). The combination of single-cell genome amplification technology and deep sequencing holds promise in elucidating the pathogenesis of additional genetic diseases, thereby enabling high-throughput screening and diagnosis of congenital disabilities and rare diseases (54). Long-read RNA sequencing is also applicable in disorders related to rare diseases (8). However, it is imperative to acknowledge the existence of ethical issues and parental concerns surrounding genomic sequencing (55). One of the primary concerns revolves around informed consent. Parents must comprehensively understand the implications of genetic testing, which may involve discovering incidental findings unrelated to their child’s condition. Such findings could include genetic predispositions to other diseases, which can lead to emotional distress and challenging decisions regarding additional testing and disclosure (56, 57). Furthermore, the potential misuse of genetic information—particularly in employment or insurance contexts—raises significant issues of privacy and discrimination that must be thoughtfully considered (58, 59). Parental views on genomic sequencing are diverse. While some parents regard genetic testing as an essential tool for gaining clarity and accessing specific treatments, others express concerns about the psychological burden it may create. The uncertainty associated with genomic sequencing results—whether they will yield a definitive diagnosis or uncover unknown risks—can provoke feelings of anxiety and helplessness (60, 61). In some instances, parents grapple with the moral dilemma of seeking such testing, fearing they may uncover information they are unprepared to handle, mainly when effective treatments are unavailable (58, 62). Noteworthy attention has been directed toward the application of artificial intelligence (AI) in the diagnosis of rare diseases in recent years (63, 64).

Establishing a Clinical Decision Support System (CDSS) utilising Information Retrieval (IR) to aid in the diagnosis of Rare Diseases (RD) presents specific challenges (65). These challenges include catering to physicians’ precise informational needs and ensuring the involvement of domain experts in user-centric development and evaluation (66). Subsequent research endeavors are essential to assess the practical utility of these CDSS in clinical settings. Although tools and resources exist to decipher rare disease variants, aiming to expedite diagnosis and the implementation of timely management strategies, challenges arise in the comprehensive and accurate adoption of specific diagnostic methodologies and in appraising their cost-effectiveness (67, 68). Furthermore, parents encounter difficulties in comprehending the significance of these diagnostic parameters, and reservations and uncertainties exist concerning the application of select diagnostic tools in paediatric cases (69–71).

There is currently no effective treatment for most rare diseases. Out of the 10,000 reported rare diseases globally, only 5% can be managed with pharmaceutical interventions, underscoring the critical need to enhance patient access to orphan drugs (72). Due to the scarcity of these conditions, the requisite expertise for their management is often limited, resulting in numerous undiagnosed cases and suboptimal treatment regimens among children with rare diseases (73). The rarity of these diseases also complicates the recruitment of an adequate number of patients for clinical trials, posing challenges to the development of effective treatments and cures for many rare diseases (74, 75). Additionally, issues such as low prevalence, limited knowledge of disease progression, and phenotype heterogeneity hinder drug development for rare diseases (76). Other contributing factors include disease severity and the absence of therapeutic alternatives (77). Meanwhile, inadequate healthcare services, unstructured or complex healthcare facilities, and bureaucratic policies hinder access to appropriate medical care or orphan drugs in certain regions. Nonetheless, advancements in prenatal diagnosis and screening hold promise for enhancing diagnostic accuracy and formulating preventive and treatment strategies for paediatric patients with rare diseases (54).

Significant progress has been made in the treatment of rare diseases, particularly those resulting from genetic mutations (Table 1). Advancements encompass CRISPR/Cas9-based gene therapy (78–80), gene therapies (81, 82), RNA-based therapies (83, 84), genetic silencing techniques (85, 86), stem cell therapies (87), immunotherapy (88), molecular-targeted therapies (89, 90), and enzyme replacement therapies (91–94). Personalized medicine is pivotal in addressing rare diseases, with multidisciplinary collaboration holding the potential for tailoring treatments to specific rare diseases (95–97). For instance, there is notable progress in the personalized treatment of Batten’s disease using nusinnersen (98). Additionally, digital health platforms and telemedicine are being explored to expand patients’ treatment accessibility (99, 100).

These developments mirror a rapidly evolving landscape in the rare diseases sphere initiated by state-of-the-art technologies and collaborative endeavors. They offer the prospect of enhancing treatments and overall quality of life for rare disease patients, ushering in renewed hope and improved outcomes. However, their application in paediatric patients with rare diseases remains to be explored.

In addition to traditional funding models for orphan drugs, alternative approaches such as value-based healthcare (VBHC) are increasingly gaining attention (101, 102). Under a value-based model, treatment costs are directly linked to the outcomes achieved, promoting a more efficient allocation of resources and ensuring both efficacy and accessibility of treatments. This model can potentially enhance access to orphan drugs, particularly in resource-constrained settings where the high costs of these treatments can pose significant barriers (103, 104). By focusing on the clinical benefits and long-term outcomes associated with rare disease treatments, value-based healthcare may provide a sustainable solution to the financial burdens linked to rare disease care. Studies, such as those by Fuchs et al., have demonstrated promising results in treating sarcoma patients (105). Furthermore, several countries have reported similar encouraging outcomes when adopting these models (106).

Thus, VBHC signifies a profound transformation in the way healthcare systems approach the management of rare diseases. By prioritising patient-centred outcomes and encouraging collaborative practices, VBHC has the potential to enhance both the quality and effectiveness of care for individuals facing the unique challenges posed by rare conditions. Although challenges in implementation persist, a steadfast commitment to value-based principles can lead to significant improvements in patient outcomes, ultimately benefiting not just individuals but society as a whole (107).

The pharmaceutical industry’s historically limited focus on orphan drugs has shifted, with a growing recognition of their importance due to market dynamics and technological progress (16). This evolving landscape has prompted diverse business strategies in this expanding sector (108). Orphan drugs are indispensable therapeutic options for individuals with rare conditions, such as cystic fibrosis (CF) (109) and Dunne muscular dystrophy (DMD) (110). Nevertheless, their notably higher costs compared to non-orphan drugs have prompted inquiries into their cost-effectiveness and accessibility. For instance, expenditure on orphan drugs in the United States has surpassed 10%, a figure five times greater than that of non-orphan drugs (111). The utilization of respiratory syncytial virus (RSV) prophylactic programmes for CF patient care generated specific incremental cost-effectiveness ratios and annual budget impacts (112). Treatment of spinal muscular atrophy (SMA) patients with particular drugs led to increased annual costs (113). Consequently, the pricing of select rare disease drugs exceeds international reference prices, rendering most drugs financially unattainable for rare disease patients (114, 115). Apart from the elevated cost of certain orphan drugs, challenges persist in conducting clinical trials for orphan drug research (116).

Notwithstanding these high-cost challenges, several case studies highlight the potential for positive outcomes in the treatment of rare diseases through the application of innovative interventions. For example, the development of CFTR modulators, such as Ivacaftor and Orkambi (Lumacaftor/Ivacaftor), has significantly transformed the treatment landscape for children with cystic fibrosis (CF). Research has shown that these medications improve lung function and nutritional status, resulting in a better quality of life and fewer hospitalisations (117). Another important case is Nusinersen (Spinraza), an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA) in children. Clinical trials have provided evidence that Nusinersen can significantly enhance motor function in infants diagnosed with SMA, contributing to greater independence in their daily activities, enabling them to reach developmental milestones that would have been impossible without treatment (118). Additionally, Idursulfase (Elaprase) represents an enzyme replacement therapy developed for Hunter syndrome (Mucopolysaccharidosis Type II), further illustrating the positive impact of innovative treatments for rare diseases. Clinical studies have shown that idursulfase can enhance walking ability, reduce organ enlargement, and improve the overall quality of life for affected children (119). The approval of these therapies marks a significant advancement in the field of orphan drug development, demonstrating the effectiveness of targeted treatments in enhancing patient outcomes.

Patient organizations and advocacy groups have been instrumental in raising awareness and advocating for access to treatments such as Dornase alfa and Ivacaftor, spearheaded by the Cystic Fibrosis Association of South Africa, which have significantly improved diagnosis rates and the management of cystic fibrosis (CF) patients, resulting in better lung function and a higher quality of life (120). Moreover, the Brazilian Ministry of Health developed a national screening programme for phenylketonuria (PKU), which included access to dietary products and healthcare support for affected families. This initiative has successfully reduced the incidence of cognitive disabilities among treated individuals, highlighting the potential of targeted public health strategies to markedly improve health outcomes (121).

Rare diseases can significantly impact the quality of life of individuals, leading to physical, emotional, and social stress that detrimentally affects their daily functioning and overall well-being (122–124). The scarcity of these diseases often results in challenges for patients in accessing specialized medical care, treatments, and support services. Furthermore, many rare diseases carry a heightened risk of morbidity and mortality as a result of inadequate and unavailable treatments (124).

The United Nations (UN) recognises the disproportionate impact of rare diseases on individuals, particularly in relation to poverty, discrimination, and work-related adversities (125). This discrimination can significantly affect young individuals, notably in terms of education and social integration. Efforts have been made to establish an economic framework aimed at ameliorating the burden of rare diseases, along with the regulation of orphan drug usage in children (126–128). Yet, individuals living with rare diseases may still face enduring psychological, social, and economic vulnerabilities, encountering specific challenges in education, employment, and social engagements.

The impact of rare diseases on patients’ quality of life (QoL) is pervasive and often profound. Individuals with rare diseases frequently endure considerable morbidity and mortality, leading to a reduced life expectancy (177, 178). In the case of paediatric patients, they may encounter health-related stigma, bullying, and mental health challenges (174). The intricate nature of rare diseases, delayed diagnoses, and the absence of effective treatments often engender feelings of isolation and psychological distress among patients and their families (126, 179). Assessing health-related quality of life in rare diseases presents unique challenges, but innovative approaches can enhance measurement and clinical outcomes (179). Numerous studies have demonstrated that children with rare diseases exhibit lower quality of life scores than children without chronic diseases (161, 170, 180). As delineated earlier, these diminished quality of life scores are frequently associated with the physical, emotional, and social burdens accompanying rare diseases.

Moreover, the impact of rare diseases on families and caregivers should not be underestimated, as caring for a loved one with a rare disease can be emotionally and financially taxing, often necessitating significant investments of time and resources (131). Parents tending to a child with a rare disease often harbor unmet needs, encompassing dissatisfaction with healthcare professionals’ knowledge, lack of support, financial hardships, social seclusion, and emotional strain (181, 182). Many of these children are susceptible to short- and long-term neurodevelopmental sequelae that can compound adverse psychological quality of life outcomes.

The management of rare diseases necessitates a comprehensive public health strategy that incorporates policy development, resource allocation, and the active involvement of diverse stakeholders, including healthcare providers, researchers, and patient advocacy groups (208, 209). Public health policy is vital for the adequate care and management of rare diseases, particularly in ensuring that sufficient resources are earmarked for diagnosis, treatment, and long-term care.

In recent years, international frameworks have emerged to advance the rights of individuals with rare diseases. A notable milestone was the passage of the United Nations General Assembly resolution A/RES/78/173 in 2021, which calls for heightened attention to the global challenges posed by rare diseases. This resolution encourages member states to formulate national plans for rare diseases, improve access to diagnostic tools, and foster research into treatments. Furthermore, it emphasises the crucial need for international collaboration and the sharing of information to tackle the public health challenges associated with rare diseases (210). These initiatives underscore the significance of integrating considerations for rare diseases into public health policy to ensure that individuals with these conditions are not marginalized. Furthermore, value-based healthcare models, which focus on patient outcomes and cost-effectiveness, can be instrumental in facilitating access to essential treatments, including orphan drugs (103, 211). Implementing educational initiatives designed to raise awareness of rare diseases among healthcare professionals and the general public is critical for reducing diagnostic delays and enhancing care (107).

Patient advocacy groups are essential in influencing public health policy regarding rare diseases. These organizations offer invaluable insights into patient needs, promote awareness, and advocate for policy changes that emphasize research and funding for rare diseases (212). Collaborative efforts between advocacy groups and governmental bodies can significantly improve the quality of care and support available to families affected by rare diseases.

Successful policy models in countries such as the USA and members of the European Union demonstrate that integrating rare disease management into national health systems is not only feasible but can also lead to significant improvements in patient outcomes (213–215). Recently, Latin America has introduced policies and recommendations aimed at enhancing access to equitable healthcare services for patients with rare diseases (216). These models typically involve the establishment of national registries, coordination among healthcare providers, and the formation of public-private partnerships to ensure sustainable access to care and treatment. For instance, initiatives like the European Reference Networks (ERNs) create platforms for sharing best practices and fostering collective learning among healthcare providers across Europe (217). By prioritising cooperation, countries can collaborate to promote data sharing, advance clinical research, and develop innovative treatment options that extend beyond their borders.

Investing in registry-based research can yield valuable insights into rare diseases by enabling the systematic collection of data that informs policy decisions. These registries facilitate longitudinal studies that evaluate treatment outcomes and patient experiences, thereby generating the essential evidence needed to develop informed guidelines and optimize resource allocation (218, 219). While data scarcity and healthcare disparities persist, significant opportunities exist for improvement and innovation (220). Therefore, public health policies play a crucial role in enhancing the circumstances of children with rare diseases. By focusing on accessibility, advocacy, funding, and education, public health initiatives can improve the quality of life for affected families and promote advancements in research and treatment. A coordinated global effort that prioritises rare diseases will be vital in addressing the ongoing challenges faced by this vulnerable population.

Rare diseases pose a significant global challenge for individuals, families, and the healthcare system (Table 2) (221). The heterogeneity of epidemiological approaches and inconsistent reporting constrained the identification of high-quality population-based studies and data collection. The generalisability of results to other regions may be compromised by including solely global, European, or American data (22, 123).

Numerous obstacles hinder rare disease research, such as an inadequate understanding of rare diseases’ pathophysiology and natural history, along with a lack of incentives to fund the development of orphan drugs for small populations (222). Furthermore, innovative treatments may not be readily available to the general population due to factors including pricing and reimbursement decisions and the limited commercial interest of some pharmaceutical companies in investing in new orphan drug research (13, 195). An additional challenge arises in developing innovative approaches to clinical trials and health technology assessment methods in small populations, as well as the absence of aggregated primary data for estimating the reliable economic burden of rare diseases (223, 224). For instance, many African countries do not maintain national registries for rare diseases, complicating efforts to track their prevalence and fully understand the issue (225, 226). Many regions lack essential diagnostic tools, such as genomic sequencing, which can result in misdiagnoses or delays in diagnosing children with rare diseases (227, 228). Healthcare systems in numerous Latin American countries face similar challenges due to insufficient data on rare diseases, lengthy waiting times for diagnostic tests, and limited public awareness (5, 229). As a result, families often struggle to navigate the myriad medical and social challenges posed by rare diseases. Disparities in the quality of care and access to treatment for rare diseases persist across social classes and communities, even in developed economies with advanced rare disease policies, budgets, and clinical guidelines (21). Variations in the availability and accessibility of medical treatment between rural and urban areas may necessitate long-distance travel for treatment. This socio-economic divide between urban and rural areas exacerbates these challenges, as rural families have less access to medical services. There is also minimal public health education regarding rare diseases, leading to misconceptions and stigma within local communities (135, 226, 230). The development of orphan drugs for rare diseases also encounters notable challenges (231). The cost of certain available orphan drugs is prohibitively high, and many countries lack adequate insurance coverage for rare diseases, preventing families from accessing vital treatments (232).

Accessing social benefits and financial support for rare diseases has presented challenges for many individuals, particularly concerning the high costs of specialized care and treatment, especially for children diagnosed with rare diseases. Those suffering from rare diseases often experience pain, loneliness, and susceptibility to misinformation throughout the diagnosis and treatment process (36). One significant barrier to effective care in regions like Latin America is the limited access to specialized healthcare professionals (216), lack of communication between care professionals and uncoordinated appointments (233). Specialized paediatricians play a pivotal role in identifying, diagnosing, and treating children with rare diseases. It is alarming that a mere 5.3% of surveyed doctors in China were found to be knowledgeable about rare diseases (234). Similarly, a study in Australia attributed approximately 30% of diagnostic delays among families to a lack of knowledge among health professionals (167); with similar findings in Poland, where parents complained about doctors’ lack of knowledge (235). The aforementioned lack of awareness extends beyond healthcare professionals to include families, caregivers, education professionals, and peer groups, all of whom possess a limited understanding of rare diseases and their impact on the quality of life and socioeconomic burden in children (173, 236).

Therefore, comprehensive support systems are essential to address these challenges. These may encompass financial assistance, mental health services, educational support, and access to advanced therapies (Table 3). Additionally, increased research funding and policy changes are imperative to better cater to the needs of patients with rare diseases and their families, ultimately alleviating their disease burden and enhancing their overall quality of life.

By implementing these recommendations, healthcare systems can significantly enhance the diagnosis and treatment of rare diseases, thereby improving the quality of life for patients and their families.

Several strategies and policies have been established to enhance awareness of rare diseases and facilitate the dissemination of pertinent information within the healthcare community, particularly within the EU (166, 223). These initiatives encompass the development of rare disease registries (17, 76), active involvement of patients in research decision-making (237), application of health utility estimation techniques (238), creation of a regulatory framework and initiatives for the development of orphan drugs (127, 239), as well as the establishment of advocacy groups (240). Despite these advancements, the practical implementation of these strategies and policies remains a challenge. Therefore, it is imperative for stakeholders and policymakers to take actionable steps to implement these policies (Table 4). These actionable policy initiatives include but are not limited to:

Rare diseases present a considerable global burden, impacting millions of individuals worldwide, with children constituting the most affected demographic. Inadequacies in disease prevalence estimates underscore significant gaps in our understanding of the epidemiology of rare diseases, particularly within the paediatric cohort. The persistent nature of numerous rare diseases imposes substantial physical, emotional, and social burdens on affected children and their families, profoundly affecting their quality of life. These challenges are further exacerbated by the absence of suitable and accessible treatments for various rare diseases, resulting in numerous children remaining undiagnosed or receiving suboptimal care. The profound ramifications for the quality of life of affected children and their families underscore the imperative to develop efficacious treatments and enhance healthcare accessibility to alleviate the disproportionate burden imposed by these conditions.