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Top Tips for Diagnosing and Managing Rare Diseases

  • Authors: Lucy McKay, MD
  • CME / ABIM MOC / CE Released: 2/17/2022; Reviewed and Renewed: 2/28/2023
  • Valid for credit through: 2/28/2024, 11:59 PM EST
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    Nurses - 0.25 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

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Target Audience and Goal Statement

This activity is intended for pediatricians, primary care physicians, diabetologists and endocrinologists.

The goal of this activity is to shorten the rare disease diagnostic odyssey by increasing familiarity with clinical clues that point to a possibility for a rare disease.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Common red flags across rare diseases
  • Have greater competence related to
    • Recognizing patterns of symptoms suggestive of a possible rare disease diagnosis


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Disclosures for additional planners can be found here.


  • Lucy McKay, MD

    Chief Executive Officer, Medics4RareDiseases
    England and Wales
    United Kingdom


    No relevant financial relationships


  • Pakinam Aboulsaoud, PharmD

    Medical Education Director, Medscape, LLC


    Disclosure: Pakinam Aboulsaoud, PharmD, has no relevant financial relationships.

  • Jason Luis Quiñones, PhD

    Scientific Content Manager, Medscape, LLC


    Disclosure: Jason Luis Quiñones, PhD, has no relevant financial relationships.

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  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP, has no relevant financial relationships.

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Top Tips for Diagnosing and Managing Rare Diseases

Authors: Lucy McKay, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 2/17/2022; Reviewed and Renewed: 2/28/2023

Valid for credit through: 2/28/2024, 11:59 PM EST


Activity Transcript

Lucy McKay, MD: Hello, I'm Dr Lucy McKay the Chief Executive Officer of Medics 4 Rare Diseases in England and Wales. I'm also a steering group member for the Medscape Education Rare Diseases Learning Center. Welcome to this program, titled: "Top Tips for Diagnosing and Managing People with Rare Disease." Today, I want to just give you some top tips for when you might suspect that your patient has an underlying rare condition, and also how you can better manage your patients, independent of whatever role you play in their healthcare. To start up, I'm going to take you through some diagnostic methods and tools that will equip you to know when to suspect your patient has a rare disease.

I have divided these tools into an overarching method falling under "think rare," "think and," "think again." Let's start with "think rare." Unfortunately, some methods of medical education can slightly stifle our curiosity as we learn to pattern match and assign people to groups based on either body systems or demographics. Also, a reliance on performers and pathways can be a real hindrance to those who do not have a common presentation or a common condition. Just by thinking rare you are already breaking down the mental barriers that can leave patients undiagnosed for years.

In order to help you suspect rare disease, attempts have been made to apply the same pattern matching that is used in the rest of medicine within rare disease as a whole. I'll quickly mention 2 examples of these. First, I'm going to start with the Family GENES Red Flags tool, which was developed by Whelan et al. It is used by clinicians all over the world. Also, I'm going to talk about some free online search engines for use by the public and medical professionals, which can suggest some possible diagnoses.

The Family GENES Red Flags tool created by Whelan et al, can be used in primary care or in secondary care. It is not for suspecting a specific rare disease, but rather for rousing your attention that a rare genetic disease may be at play and that you will need to potentially get some assistance to find out what disease it is. First of all, family. Take a 3-generation family history and remember to ask about miscarriage, as well as infant and childhood death. Don't simply ask, does anything run in your family because believe me, if a rare genetic condition runs in their family and they know about it, they're probably likely to mention it already. Ask instead about similar symptoms and long-term conditions in other family members bearing in mind that they, too, may be undiagnosed.

Also remember that only up to 80% of rare diseases have a genetic origin and not all genetic conditions run in families. Many will be de novo, which means it's a new variant in that family, or simply this is just the first person to present. Now, onto the acronym GENES, G stands for a group of congenital anomalies. Common anatomic variations are common. However, having 2 or more anomalies is much more likely to indicate the presence of a syndrome with genetic implications.

The E stands for extreme or exceptional presentation of common conditions. For example, a heart attack in a young female patient with no risk factors may still be a heart attack even if it's not caused by atherosclerosis. The authors also suggest early onset cardiovascular disease, cancer, or renal failure. Did you know that all childhood cancers are considered rare diseases? Unusually severe reactions to infections or metabolic stress, recurrent miscarriage, bilateral primary cancers, impaired organs, and multiple primary cancers of different tissues also fall under this exceptional or extreme presentation.

N stands for neurodevelopmental delay or degeneration or loss of abilities. Developmental delay in the pediatric group carries a very high risk for genetic disorders. Developmental regression in children or early onset dementia in adults should similarly raise suspicion for genetic etiologies. Remember to ask whether your patient has lost any abilities that they used to have. The second E stands for extreme or exceptional pathology. For example, unusual tissue histology; the authors go into more detail. S stands for surprising laboratory results.

This tool could be very useful for you in primary care to help condense and define your suspicions of rare disease and give you the buzz words for making referrals, for example, to a specialist such as a genetic counselor. However, it has a very clinical field of vision and is driven entirely by the clinician. Later I will talk about how active listening to the patient and the family has been an instrumental way to stopping an unnecessary diagnostic odyssey. Next, there are open access tools out there waiting for you -- Medscape has a brand-new rare disease learning center called Pathways in Rare Disease. Then obviously there's PubMed. There's also a site called OMIM, which stands for Online Inheritance of Man and Orphanet, which is a compendium of rare disease information.

More recently, traditional search engines have been optimized to help diagnose rare diseases from signs and symptoms. Patients and clinicians can enter a phenotype and these search engines can return a potential underlying disease. I would suggest using the website FindZebra; it's a good idea to start by using the 2 most specific or standout terms. These tools are only as good as the information you put in them. Remember garbage in, garbage out. It's very important you do the basics well -- When something's not adding up, start at the beginning and put biases aside, and listen actively to the patient and the family. Take a thorough history from birth with a 3-generation family history and perform a thorough examination. Also, a word of caution on some websites, there are websites that we would go to frequently to learn about more common conditions, but because of the nature of rare conditions, they may not be the most accurate place to find information.

Remember to look for those patient advocacy group websites to see what information they have, because often it's very up to date and reliable. Next, we're on to "think and." The tools I've been mentioned so far, very much concentrate on the clinical side of things, looking at the patients through the lens of biomedicine, but this won't give you the full picture. The impact of a rare disease is often pervasive throughout the patient's life. Therefore, a lot can be gleaned from a thorough past medical history, social history, and a proper holistic overview of the patient and their family. The frustrating medical ping-pong between specialties that often ensues in a multi-system rare disease can mean that nobody is looking at the entire patient. Many patients report that they were only finally diagnosed when one doctor listened to their story from beginning to end, and this often coincides with changing areas and having a new doctor in charge of their care.

When you are looking at your patient and you're putting all the pieces together, do you find yourself with a complex patient with a list of symptoms, but no convincing diagnosis? Take a look at this picture here from my colleague and friend. This is from a hospital letter of hers. If you look under diagnosis, there's a list of symptoms that don't help give a true diagnosis. Eventually she went on to be diagnosed with a neurovascular condition called moyamoya. Sarah spent 11 years growing up with an unknown condition before she was finally diagnosed at the age of 18. I very urge you to go check out her full story in her graphic memoir, A Puff of Smoke.

Of course, like the people that they affect, rare diseases are heterogeneous. However, the more you speak to people living with a rare disease, commonalities reveal themselves. This can help us build up a picture of what a patient with a rare disease might present like just like we have models for the comorbid patient or for the immunocompromised patient. Knowing how a rare disease patient may present will help point you in the right direction. People with rare conditions, but no diagnosis might come to you with, like Sarah did, a long list of symptoms; some may be unusual, but no diagnosis. Multi-system problems that don't seem to be explained by one cohesive, underlying pathology. These diseases can have multiple common diagnoses that span several specialties; rare diseases are also often multi-system diseases and require somebody to join the dots between those symptoms in order to get to the bottom of the patient's problems. Multi-specialist input is also key -- has this one patient seen many specialists in a pursuit for a diagnosis?

When thinking about multi-specialist involvement, remember to include a dentist, optometrist, dietitian, speech and language, physio, OT, and social care on the list. Consider also the following when trying to make a diagnosis: Are there diagnoses that your patient has that either you or the patient are unsatisfied with? Have they got diagnoses of mental health that are refractory to treatment where there's no improvement because the needs remain unmet by them being diagnosed and because they're not receiving an appropriate treatment for their underlying condition? Are there unexplained or refractory behavioral difficulties that may increase your suspicions in the presence of other red flags? Has your patient had multiple visits or admissions without a known cause for their presentation? Is there a pervasive impact on all aspects of their life? Are they having difficulties in education, work, within the family, and socializing with others? More importantly, have parents been dismissed as being anxious, especially mothers? We call this "think and."

When you start putting the whole picture together, you might find yourself with a case with lots of "ands." They've got this problem; they've seen all of these people, the mom has been worried about this child, but she was never worried about that child previously. When you put the picture together and there's no real answer for why the patient or their family are experiencing this, could it be a rare disease, and no one's got to the bottom of it? They may be in this situation because nobody has thought outside the box. Remember that a large portion of rare diseases are invisible conditions -- Someone may look fit and healthy but could be struggling with their health.

Lastly, "think again." Review patient's history and check that labels on clinical records are correct. Patients, clinicians, and knowledge changes over time so it can be wise to review whether a given diagnosis still fits the clinical picture. Remember those pesky diagnostic biases you have learned about I'm sure in medical school. Consider anchoring, which is when you stick with a diagnosis, even when other evidence becomes available, that could shed doubt on the original diagnosis. Rare disease case studies demonstrate that a number of diagnostic biases can hinder the pursuit of an accurate diagnosis. Revisit old diagnoses because times they have changed, and diagnostic techniques may be available now that were not available when the patient originally went through their diagnostic workup.

In the last 20 years, there have been significant advancements in how we can diagnose rare diseases. Just think about the genomic revolution, for example. Even if someone's management isn't likely to change, having an accurate diagnosis would equip you, the patient, and their family with knowledge that can be very empowering. Remember, this will also help the advancement of medical understanding as well.

This is how you can reduce the diagnostic odyssey -- by using the framework of think rare, think and, think again. Now I'm going to try and sum up include in some top tips, on what you can do in terms of managing your patient with rare diseases, whatever role you play in their healthcare. I want to give you some pragmatic tips for managing any patients you come across with a rare disease. First of all, I want to give you some guiding principles that you can stick to when you are managing any patients you have with rare disease. Firstly, listen to your patient and their family to find out what they need and what they're asking for. Rare diseases are often life-long, and a problem-solving approach may not be the right one. Try to approach rare disease management in a way that will allow your patient to live their most fulfilling life they can while they manage the condition from day-to-day.

Think about the basics. Are they in pain? Do they have mental health problems or mobility difficulties? Things like that where small interventions or adjustments may make a big difference to the patient's life. Next is be honest. Of course, we want our medical professionals to be honest, but what I'm talking about here is be honest about what you can and can't do. No one can expect you to know 7000 rare diseases, but they can expect you to say, "I don't know about your rare disease, but I will find out." IT is important to show support and care by saying things like: "I do know that rare diseases can have a great impact on people's lives because of these common challenges. Let me see what I can do to help you."

Be open to working with your patient and to be being educated by your patient who are likely to know more than you about their condition, unless you are the top specialist, but even then, they're the ones living with it. Check in with families, check in with your patient especially after a diagnosis. A diagnosis of a chronic, life-long or debilitating disease is breaking bad news. Imagine that patient has nowhere to go for support afterwards -- that can be the case in rare disease in which patients and families report a free fall after diagnosis with no safety net -- If you can be the person to check in, do it.

Keep your patients informed, just keep them up to date because they're probably dealing with a huge amount of care coordination themselves. I know you'll have a lot of patients and you would love to keep them all up to date, but just try and put yourself in the patient or the family's shoes coordinating so much care for themselves. Then that obviously leads onto coordinating with other healthcare professionals and services. Make sure there's a named healthcare professional who's going to be the person who liaises or keeps the patient up to date; try to make all the appointments coincide. Can you do a multidisciplinary clinic instead of asking the patient and their family to go to lots of different appointments?

Collaborate with patient advocacy groups, bring them in if the patient is welcoming it. Work with them in partnership because they will be able to support you and support the patient. Make sure you sign post to supportive groups and tools, and also think about the specific needs of your patient. Maybe they're young and they don't necessarily want to talk about their particular condition, but what it's like to live as a young person with a rare condition and there's groups out there like Rare Youth Revolutions, available to provide care support. These are very important principles -- Work in partnership, know your limits and ask for help.

Now for some practical tips, just have a think about what ongoing care you were to give to someone following a cancer diagnosis. Cancer is also a large area of medicine made up of a collection of heterogenous conditions that can affect anyone and anybody system. If we can do it for cancer, we can apply it to rare disease. Ensure that your patient's physical, practical, emotional, and social needs are identified and addressed at the earliest opportunity. Seek out mental health support for them, because this is very likely to be ongoing. Engage with a patient advocacy group relevant to that patient. Not only to find information for them, but also for yourself. Work with specialists involved to create a diagnosis summary and a management plan, make sure this is front of their notes and that everyone is aware of it.

You can include valuable information, including treatments, potential side effects, signs, and symptoms of deteriorating disease and contact details to address any concerns to. Also, it is very important to know what to do in an emergency and when a specialist needs to be called. This is helpful for both the patient, the family doctor, and the larger MDT and emergency services. Perform an annual review with all the patients on your caseload that have a rare disease. This would be a discussion between the patient and their designated healthcare profession, about their long-term condition. It helps a person to discuss any concerns and changes in their conditional situation. You can anticipate things like family planning decisions, prevent mental health decline, and also deal with that period where a patient might be going from pediatric to adult care, which we know as transition of care.

Is also is a very good opportunity to scope out any appropriate clinical trials that may be newly available because research might be the only option for this patient in terms of treatment. There is so much evidence in the rare disease community that patients are open to the idea of research and would like to know more. Here's another good tip: tidy up their electronic health records or their paper records. Mark their records that this patient has a rare disease. Make sure that contact information for the specialist and the advocacy group are readily available. Many rare diseases can cause serious problems for the patient when it comes to communicating. If your patient has impediments that prevent them from being able to use the usual communication techniques, then make sure this is obvious on their records to whomever might be trying to contact them. For example, it can be frustrating for one of my colleagues whose adult son is nonverbal to be told that she cannot speak on his behalf and he will have to come to the phone.

All of these measures may prevent unnecessary attendances, better disease management, holistic care, but it'll also start working towards greater equity of care. All patients with rare disease will receive a basic healthcare provision regardless of what condition they have -- Arguably primary care is an obvious home for rare disease because of its place in the community and its whole person perspective. Thank you for listening to my top tips on diagnosing and managing rare disease.

I now just want to tell you my goal and Medics 4 Rare Diseases' goal. In an ideal world, a patient with a rare disease would receive a timely diagnosis, mental health support care in a specialist center with excellent communication with their local hospital and their family doctor, and be backed up with the support of the patient group and the hope provided by research opportunities. You can play your part in making this happen. You just need to know what role you have to play. Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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