International Rare Disease Day: A Day That Must Not Be Forgotten

Every year on 28 February, the world observes International Rare Disease Day. For many, rare diseases remain abstract entities confined to textbooks. As medical teachers repeatedly reminded us, one must first consider common differentials; so much so that, in practice, contemplating a rare diagnosis almost felt forbidden, lest a more frequent condition be overlooked. Consequently, rare disorders are often reduced to statistical entries in journals, occasional case reports, or distant headlines announcing breakthrough therapies developed elsewhere. For us working in pediatrics - especially hematology-oncology and blood and marrow transplantation, however, rare diseases are not rare encounters, especially in recent years. They are daily realities.

Rare, or “orphan,” diseases are traditionally defined by low population prevalence, affecting fewer than 1 in 2,000 individuals in the European Union and fewer than 200,000 people in the United States; yet they are often associated with delayed diagnosis, inappropriate management, chronic disability, and premature mortality. While each condition is individually uncommon, together nearly 8,000 such disorders affect millions worldwide, reminding us that rare diseases are collectively common and that many “small drops” together form a vast and neglected ocean of unmet medical need. Disease prevalence alone is an imperfect measure of rarity, as it fails to account for population dynamics, regional variation, degrees of rarity, and the feasibility of systematic clinical study. We confront inherited bone marrow failure syndromes, ultra-rare bleeding disorders, inborn errors of immunity, congenital thrombotic microangiopathies, cancer predisposition syndromes, and rare metabolic disorders—each associated with distinct diagnostic and therapeutic challenges, where delays in recognition and intervention are often dismal and carry profound clinical consequences.

As I reflect on our experiences over the past few years, which have underscored both the vulnerabilities and the resilience of our systems, a single fundamental truth emerges for anyone working in this space. Our greatest vulnerability is, paradoxically, also our greatest strength—the sheer volume of patients we serve. In this context, what is considered “rare” elsewhere is no longer rare in absolute terms. With this scale comes responsibility, and with responsibility comes opportunity. The true power lies in systematically generated, high-quality data.

When Rare Is Invisible

For most families, the journey begins with symptoms that do not fit into common diagnostic frameworks. Few months ago, a 19-year-old with recurrent bleeding and abdominal pain from early children who had received multiple transfusions was evaluated. He has been to more than 20 medical centers, received countless treatments for pain in the abdomen, before being diagnosed with Glanzmann thrombasthenia, a rare bleeding disorder which would have caused repeated bleeding into his gut.

An infant with severe anemia was repeatedly evaluated and treated for presumed nutritional deficiency before molecular testing revealed a rare cobalamin metabolism disorder. This condition, the inborn cblF defect caused by pathogenic variants in LMBRD1 (lysosomal cobalamin transporter), has been reported only exceptionally in the medical literature, with approximately 20 genetically confirmed cases described worldwide to date.

Another infant we encountered presented after the family had already lost an earlier child with similar complaints, without ever having received a definitive diagnosis. The reality of blended phenotypes is no longer theoretical. We described the first reported coexistence of Wiskott–Aldrich syndrome and Ghoshal hematodiaphyseal dysplasia, a dual genetic diagnosis uncovered through next-generation sequencing, representing an uncommon amalgamation of two individually rare disorders. The absence of timely recognition in earlier siblings underscores the devastating consequence of missed diagnosis in rare genetic disorders, where each missed opportunity represents not only a clinical failure, but also a profound human loss.

Diagnostic delay is not benign at all. In congenital afibrinogenemia, an extremely rare congenital bleeding disorder, we observed a median diagnostic delay of over eight years in a prospective Indian cohort, with one child losing vision due to delayed recognition and inappropriate therapy. Three of these four children whom we reported, were initially misdiagnosed as hemophilia; a “commoner” rare disease. The consequences of misclassification in rare diseases are profound—irreversible morbidity, avoidable mortality, and avoidable cost.

Cancer predisposition syndromes represent another rare but important group of inherited genetic disorders, in which germline mutations confer a heightened risk of malignancy, often affecting multiple members within the same family. These conditions carry profound clinical implications, influencing not only the choice and intensity of cancer therapy, but also the need for structured surveillance for secondary or recurrent malignancies for the same person. Equally important are the ramifications for unaffected siblings and relatives, who may harbor the same pathogenic variants in an asymptomatic state, and for potential stem cell donors, in whom unrecognized germline mutations could compromise transplant outcomes. The mother who has already lost one child to cancer and seeks treatment for relapsed, high-risk leukemia in her second child is inconsolable. Early identification thus helps not only optimize individualized treatment but guides family counseling and safe donor selection.

When Diagnosis Is Not Enough

Rare diseases often converge at the transplant unit. Bone marrow failure syndromes, immunodeficiencies, inherited metabolic disorders, and certain ultra-rare leukemias require hematopoietic stem cell transplantation as definitive therapy. Many of these conditions are potentially curable, provided they are recognized in time before irreversible organ damage has set in.

There are however, no large, randomized trials to tell us how to treat them. Conditioning regimens are extrapolated. Toxicity profiles often differ. Coexisting issues such as predisposition to infections, immune dysregulation and sensitivity to certain drugs adds complexity. We often adopt and adapt regimes to local challenges. These nuanced adaptations are rarely codified in guidelines; they emerge from experience. Thus, successes in this sphere are not routine; they are the product of meticulous planning, aggressive supportive care, and multidisciplinary coordination.

Yet access to bone marrow transplantation remains uneven. Financial constraints, lack of matched donors and late referrals complicate outcomes. For bleeding disorders access to new drugs such as non-factor replacement therapies is transformative—but still limited in many regions. Gene therapy trials for immunodeficiencies and hemoglobinopathies are underway globally, yet access is constrained by cost, regulatory pathways, and limited trial sites.

Diagnostic capacity has improved dramatically in recent years, driven by the rapid expansion of genetic technologies and providers. Next-generation sequencing is no longer confined to a few apex institutions; it has increasingly reached the bedside, even in tier-2 and tier-3 cities. Families no longer need to endure months of trial-and-error testing or send samples abroad in search of answers. Consequently, they can no longer be left with only broad, phenotype-based labels—such as “transfusion-dependent anemia,” “undiagnosed bleeding disorder,” or “unclassified immunodeficiency” in place of precise molecular diagnoses. With contemporary genomic tools now widely available, definitive etiological classification is increasingly achievable and should be regarded as an essential component of high-quality rare disease care.

Therapeutic advances in the cell and gene therapy space are also expanding rapidly. With growing indigenous research capacity, manufacturing infrastructure, and clinical expertise, India is well positioned to develop and deliver affordable, high-quality cellular and gene-based therapies. In the coming years, this has the potential not only to transform care for patients within the country, but also to provide cost-effective solutions for rare diseases to the rest of the world.

Access to treatment has also improved. With an increasing number of novel therapies in the development pipeline and growing interest from the pharmaceutical industry in rare diseases, there is renewed hope for more effective and accessible treatments for orphan disorders. Sustained collaboration between clinicians, researchers, industry, and policymakers will be essential to ensure that these advances translate into equitable patient care.

The Rare Disease Policy of the Government of India has been a step forward. It has provided funding mechanisms for certain conditions and catalyzed awareness. However, coverage remains selective. Many ultra-rare conditions fall outside predefined lists. For families, the financial toxicity of rare disease management—diagnostics, hospitalizations, travel, loss of wages—is overwhelming.

Families in Isolation

Rare diseases are not only biologically rare; they are socially isolating.

Diagnosis without access to treatment can be ethically distressing. It converts uncertainty into certainty but does not necessarily alter the outcome. Families frequently report that no one in their community has heard of their child’s condition. In their search for information, they often encounter misinformation or resources relevant only to high-income settings, offering little practical guidance. Educational institutions often refuse admission or re-entry to children with a diagnosis and are reluctant to accommodate medical needs. In one recent instance, a school demanded a “fitness certificate” from a healthy child who had donated stem cells to his sister, reflecting a profound misunderstanding of donor safety.

Families benefit immensely from meeting others with the same condition. Peer networks reduce anxiety, improve adherence, and empower advocacy. Structured patient support groups—integrated with hospital-based registries—should be considered part of standard care. Longitudinal follow-up is therefore not optional—it is central. Rare diseases are chronic. Transplantation does not end surveillance.

India’s Unique Opportunity: Strength in Numbers

Globally, rare diseases suffer from small sample sizes. Trials struggle with recruitment. Natural history data are sparse. Genotype–phenotype correlations remain incomplete.

India, paradoxically, has an advantage.

With a population exceeding 1.4 billion, even diseases with a prevalence of 1–2 per million translate into substantial absolute numbers. Consanguinity in certain regions increases the visibility of autosomal recessive disorders. Referral centers in metropolitan regions see concentrated volumes of rare hematologic and genetic disease.

If systematically captured, such data can shape global knowledge. India can emerge as a hub for:

1.     Rare Disease Registries
Multicenter, standardized registries capturing demographics, genotype, phenotype, interventions, and outcomes.

2.     Natural History Studies
Longitudinal cohorts clarifying disease trajectory, complications, and quality of life.

3.     Genomic Databases
Population-specific variant repositories improving interpretation of novel mutations.

4.     Clinical Trials
Accelerated recruitment for targeted therapies, gene therapies, and novel biologics.

5.     Translational Research
Collaboration between clinicians, molecular biologists, and data scientists.

But this requires infrastructure: interoperable electronic records, data governance frameworks, biobanking, and ethical oversight.

The Power Is in Data

Rare diseases cannot be advanced through anecdote alone. Anecdotal reports are important—but registries transform isolated experiences into evidence. Systematically collected data enable accurate estimation of disease prevalence, identification of diagnostic delays, benchmarking of outcomes across centers, evaluation of cost-effectiveness, advocacy for inclusion in national funding schemes, and meaningful engagement with pharmaceutical partners for clinical trial inclusion.

As clinicians, our commitment to rare disease is both scientific and human. We have seen children who, with timely treatment, return to school and lead normal lives. We have also witnessed preventable morbidity due to delayed diagnosis or lack of access to therapy. Each rare disease case is a reminder that medicine must extend beyond probability; it must embrace possibility.

Rare diseases test health systems. They test clinical acumen. They test compassion.

India stands at a pivotal moment. With expanding genomic capacity, growing transplant expertise, increasing pharmaceutical investment in rare disorders, and greater participation in global clinical trials, our population—once seen as a burden—has become a powerful research advantage. If harnessed responsibly, it can drive a rare disease revolution and transform outcomes for generations to come.

On 28 February, let us reaffirm that rare diseases are not rare people. They are children, families, and communities whose futures depend on our collective resolve; to diagnose early, treat equitably, study rigorously, and care compassionately.

Rare—but not unaware.