“Rare” but Not Uncommon: The Hidden Crisis of Rare Diseases

A recent national survey of 2,000 US adults living in households with a member with a rare disease weighted to reflect our population found 8% reporting that they or a household member have been diagnosed with a rare disease. While estimates of healthcare expenditures are problematic, the GAO estimated spending on rare diseases in 2019 was roughly $966 billion, 23% of the spending on chronic illness.

Among those expenditures were

• More frequent visits with clinicians - 19% had 7⁺ in-person visits in the past year vs. 9% in non-rare-disease households
• More visits with mental health support – both online (29% vs. 18%) and in person (28% vs. 19%)
• More use of telehealth – 63% vs. 45% in non-rare-disease households

“To have a rare disease is often to have a condition that goes undiagnosed for years while concerned physicians who have never seen the condition before may offer one diagnosis and then search for another when new or advancing symptoms belie the original diagnosis. Once accurately diagnosed, patients with rare conditions may be treated by physicians who have little evidence or guidance to help them—physicians who may experience the frustration imagined by the patient quoted above. Particularly when a condition is extremely rare, patients and families frequently travel long distances to consult with the few experts experienced in treating and studying their rare diseases; patients and their families may even relocate to make access easier.”  

Because our definition of a rare disease is based simply on the number of individuals affected [1], it is a mixed bag of demographics, symptoms, and treatments. Rare disease afflicts all ages, ethnicities, and demographics – it is an equal-opportunity disease. It can be an acute or chronic illness, often resulting in debilitating symptoms and an ongoing fear of death. Some are inevitably fatal; some are now treatable or curable; however, most have no therapy that cures or modifies the disease. 
 

How many of us are there? 

The epidemiology of rare diseases is inexact. Government estimates correspond to 25 to 30 million patients, but those estimates come with a wide degree of uncertainty. The Institute of Medicine reports that of the approximately 2,000 known rare diseases, 70% consist “only of case reports for individuals or families.” 

An unintended side effect of a definition based solely on numbers involved makes a designation as a rare disease changeable. For example, AIDS was initially a rare disease, but as treatment turned a death sentence into a long, healthful lifespan, it outgrew that designation. On the other hand, a common disease through “curative” treatment can become a rare disease, as is the case of measles and those shunning vaccination. 

Why did this happen to me?

Some diseases, such as cystic fibrosis or sickle cell disease, have known causes. Despite years of investigation, other diseases have indeterminate causes, and in some instances, there is no “smoking gun” but multiple underlying causes. 

Most rare diseases, 80% or more, have genetic origins. Some are due to a single defect in a gene with additional mutations in the same gene, resulting in varying severity and presentation. Muscular dystrophy has multiple variants, each caused by a defect in a different gene. Duchenne’s muscular dystrophy is the most widely known. Marfan syndrome, often mentioned as a possible disease in President Lincoln, is an inherited rare disease, except up to 25% of cases arise from chance mutation. Sarcoidosis appears inherited, but no specific genetic mutation has been identified. Finally, multiple genes may be at play, with “modifier” genes influencing the course of the illness. 

Infectious diseases underlie certain rare diseases. Rabies and botulism come readily to mind. Hantavirus currently has some national attention. Tuberculosis, while a rare disease in the US, remains a concern in countries with fewer public health resources. Toxins may account for rare diseases. Mercury poisoning, which resulted in being Mad as a Hatter, was a rare disease of the 19^th century. Radium Girls were poisoned by radium from watch dials in the 20^th century, and today, we are still haunted by mesothelioma resulting from asbestos exposure. The FDA has approved orphan designation for the treatment of snakebites. 

There are some real outliers among rare diseases. Damar Hamlin of the Buffalo Bills experienced Commotio cordis when a tackle led to ventricular fibrillation. A few classic nutritional deficiencies, such as beriberi due to thiamine deficiency, may be seen in impoverished countries. Vitamin A deficiency, the leading cause of blindness, is not considered a rare disease because of the large number of individuals affected. Golden Rice could make it a rare disease. 

What can I do?

While some rare diseases are preventable, many are not. Cures exist for a few conditions; some have therapies that modify the disease to allow for a near-normal life, and for others, “the impact on morbidity and mortality may be very modest.”  

Primary Prevention - seeks to eliminate or reduce risk factors that cause disease. It is the mainstay of control for infectious diseases involving basic public health sanitation measures for our drinking water and waste disposal, as well as individual actions, including hand washing, masking, and immunization. We have instituted federal regulations to control or ban exposure to toxic agents, including asbestos and mercury, and clean up contaminated locations – the ongoing EPA cleanup of the Palisades fire or Ohio train derailment are examples. 

Medications are a special case. Thalidomide, associated with birth defects in the late 50s, is approved by the FDA for the treatment of multiple myeloma and erythema nodosum leprosum “with special precautions to limit the chance of fetal exposure.” Folic acid is prescribed “for women of childbearing age to prevent neural tube defects in their children.”

For several severe genetic conditions, such as cystic fibrosis and Tay-Sachs [2], we have genetic counseling, which raises ethical questions. However, these very personal decisions are effective, with the incidence of Tay-Sachs dropping by 90% once genetic testing and counseling became available. 

Secondary Prevention - screening or testing to identify a condition so that effective treatments can be initiated. This involves newborn screening, where blood tests can identify genetic disorders and begin treatment before debilitating symptoms develop. Unfortunately, while all states have newborn screening, they vary in the core tests done. [3]  

Diagnosis 

“For many patients, diagnosis comes a frustratingly long time after symptoms first become evident. It follows countless tests and visits limited historically by imprecise, cumbersome, or expensive testing and by limitations on physician and patient access to the most up-to-date information about rare diseases (including diagnostic criteria) and other diagnostic resources.”

Surveys have shown that for patients

• “One in three reported that obtaining a diagnosis took from 1 to 5 years and one in seven reported that it took 6 years or more.”
• “Forty percent of respondents reported their first diagnosis was wrong, and 25 percent reported waiting between 5 and 30 years for a correct diagnosis.”

Physicians are often ill-trained in the diagnosis of rare diseases. (Many Texas physicians are getting refresher information on diagnosing measles, a disease of little concern during their medical training.) The diagnostic dilemma is made worse by the protean manifestations of rare diseases, often with symptoms associated with more common diseases or involvement of many organ systems, which our highly specialized (and fractured) care is not designed to identify. While genetic testing may be diagnostic, ordering the tests requires physicians to consider the possibility of the illness first. 

Treatments

Curative treatments are rare but available for diseases caused by nutritional deficiencies and some rare poisonings or infections, e.g., snakebites and rabies. There are surgical cures for some genetic anatomic defects, such as heart transplantation for hypoplastic left heart syndrome or repairs for abnormal vascular connections (the transposition of the great vessels). 

In most instances, all we have to offer is symptomatic treatment. While vital in maintaining a good quality of life, this falls short of being free from the healthcare system for any length of time. In the cases in which pain plays a significant symptomatic role, the push by the CDC to restrict opioid use has created substantial and unwarranted suffering. Symptomatic treatment can also help prevent complications, e.g., sickle cell disease’s anemia or the pneumonia associated with cystic fibrosis. 

The community formed by those suffering from rare diseases has been a significant force in transforming healthcare. They were key in passing the Orphan Drug Act and have been leaders in developing patient-led registries, internet disease-related communities, and telehealth. The latter has been an outgrowth of the need for specialized care and centers. While there are a few specialized centers, the geographic dispersion of patients makes in-person access difficult, if not impossible. Telehealth reduces that distance. Additionally, specialized centers can act as consultants to on-the-ground clinicians, bringing needed expertise to the patient. 

Emotional and Financial Toll

“Rare diseases take their toll on all involved, from affected individuals and their families and friends to the health professionals who care for them, their communities, and the larger society.”

Rare conditions often have devastating functional disabilities that prove a constant strain on patients and caregivers, which are frequently family. For less severe diseases, there is the isolation that accompanies rarity and the uncertainty of the course and possible treatment for the condition. And premature death for children and young adults remains an unfortunate possibility – with lifelong effects on both the patient and their family. 

In addition to the emotional cost, there is often a more significant financial burden. Among the drivers

• The long search for a diagnosis is time-consuming and expensive
• Medications for rare diseases can be costly
• Patients often require long-term supportive care
• The time needed for caregiving is often experienced as lost wages

For patients with rare diseases, the struggle isn’t just about surviving; it’s about navigating a healthcare system that often wasn’t built for them. From misdiagnoses and delayed diagnoses to the financial and emotional burdens of long-term care, these patients and their families are forced to become relentless advocates for their health. Yet, despite the challenges, they’ve pioneered online communities, telehealth, and patient-led research—proving that even in the rarest of circumstances, resilience is anything but uncommon.

[1] FDA designates “orphan” or rare disease status to drugs indicated for fewer than 200,000 people in the US, and in the case of devices, a Humanitarian Device Exemption for conditions affecting fewer than 4,000 people.

[2] A rare, inherited neurodegenerative disorder in infants and young children caused by a gene mutation causing progressive nerve cell damage and destruction.

[3] Newborn conditions fall into five broad categories: organic acid metabolism disorders, fatty acid oxidation disorders, amino acid metabolism disorders, hemoglobinopathies, and other disorders. Four conditions (three hemoglobin disorders and congenital hypothyroidism) accounted for approximately 60 percent of this total; nine of the screened conditions accounted for an estimated 15 or fewer cases.

Sources: Rare Disease in the US 2025 Society for Social Responsibility in Science

Rare Diseases and Orphan Products: Accelerating Research and Development Institute of Medicine NIH