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Primary Healthcare Workers and the Diagnosis of Rare Disease

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It takes years, and usually more than 7 different physicians, before most people with a rare disease are correctly diagnosed1.

As outlined in our blog ‘Shortening the time to diagnosis’, strides are being taken to empower families in the battle against the ‘diagnostic odyssey’. Primary healthcare workers such as physicians, dentists, opticians, and health visitors represent another group of people who need to be empowered to “think rare” before rapid diagnosis can become a reality for all.

The role of primary healthcare workers in rare-disease diagnosis

One of the hardest, and most essential tasks that primary healthcare workers undertake in the diagnosis of rare disease is becoming aware of the subtle patterns and ‘flags’ which indicate that a non-standard condition should be considered2.

This is incredibly difficult - in a UK General Practitioner’s (GP’s) career they will see many thousands of people and yet only a handful of those will have rare conditions. In addition, the majority of early symptoms experienced by people with rare diseases have gradual onset and mimic those of conditions physicians see far more frequently.

Practitioners on the front-line of healthcare have a unique opportunity as they are the interface between home-life and medicine. They have the opportunity to ask about family lifestyle and changes in symptoms over time, as well as helping patients and their families collect information that may be needed for diagnosis (for example, keeping a diary, taking photos, or scoring levels of pain).

In addition to this critical insight, in some countries, GPs hold the entirety of the medical record for patients in their care and are especially skilled at interpreting diffuse problems based on the minimal information most people present with. Even so, with short appointment times, and so many other possible explanations, it takes great skill and awareness to be able to filter through the vast array of information and consider alternative (rarer) conditions.

Indeed, recent research carried out by Swii.ch suggests that even if education in one rare condition is afforded to GPs, it is a tall order to expect them to become familiar with all 7,000 conditions that exist.

A more manageable approach that was identified may be to use educational and online symptom tools to help GPs identify common symptom clusters and enhance the proportion of HCPs who “think rare”.

After suspecting a diagnosis, GPs then need to identify the correct expert network and rapidly refer the patient through so that secondary care specialists and others can help them further – ensuring at the same time that the referral notes contain all the relevant contextual information.

Often this includes a standard medical history, all the symptoms and signs they’ve observed, plus all the information that patients and their families have collected and shared. This latter information is often missed or even overlooked. Such rapid referral can really make a difference – as ably demonstrated when a young boy called James was taken to a routine appointment with an optician3. Steven Crawford, the optician, noticed unusual retinalscarring and, following immediate referral, James was quickly diagnosed with the rare condition Coats disease.

As Mr Crawford states “Early detection is key because identifying the problem early on gives us a far better chance of slowing the deterioration down and hopefully the more advanced operation can provide relief.” For James’s Mum this came as a total surprise “We were shocked when we found out. We knew he was short sighted, but he had no other symptoms showing that his blood vessels were leaking.”

Although there is no therapy for the blindness that Coats disease ultimately causes, the family can now assess advanced options such as ophthalmic surgery. In addition, understanding what was happening while James was still a child has helped the family maximise the years of sight that James still experiences, whilst also giving them maximum time to prepare and transition their lives as his eyesight changes. This case also highlights the important role that professions allied to medicine can also play in the early identification and support of people who live with rare conditions.

What training in rare conditions do primary physicians normally receive?

In order to support rapid diagnosis, primary care physicians and other HCPs need a good awareness of rare diseases, easy to find information sources, systems to help them spot rare patterns of events, and good knowledge of expert networks and their referral pathways.

Two recent studies were conducted to explore physicians’ own views on their current awareness and requirements. The first of these was in 2019, when Vandeborne and colleagues conducted an online survey of 295 primary care physicians in Belgium4. Most GPs (75%) were unaware of any specific rare disease information sources and 80% of them stated that their training was either ‘insufficiently useful’ or ‘not useful at all’ for helping them spot ‘flags’ or diagnose rare disease.

Less than a third of physicians received training in rare diseases during their undergraduate or postgraduate years.
Ramalle-Gómara et al., 2020. https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1285-0

These same messages were reflected in 2020 by Ramalle-Gómara and colleagues’ survey of 132 primary-care physicians and 37 hospital specialists in Spain5. Less than a third of these physicians had received training in rare diseases during their undergraduate or postgraduate years.

What’s being done?

The group Medics 4 Rare Disease6 is a charity that is doing a huge amount to change the medical communities attitude to rare through working with physicians in training - providing materials and opportunities to help increase awareness of rare disease and how to spot flags and ‘think rare’. As CEO of the society Dr Lucy McKay sums up brilliantly “We would like all doctors to have an appreciation that together rare diseases are common, and they share common challenges, therefore they need to #daretothinkrare.”7

Machine Learning and AI to Accelerate Diagnosis in Rare 

Another major change in recent years has been the robust collection of integrated clinical and genetic information into databases that are used for machine-driven physician support systems. This means that, instead of a primary-care physician relying solely on their own medical knowledge (where they may have had limited experience identifying rare conditions), they can instead enhance this with a search into alternative explanations for the patient’s condition and – in doing so – use the wisdom generated by that millions of pieces of rare-data knowledge8.

This is an evolving field that holds great promise, however, in addition to validation of the system, physicians themselves need to get involved and take on the responsibility for developing the care pathways that seamlessly integrate these into clinicaldecision making processes9.

Indeed, in some cases Physicians need to know what they are looking for in terms of “thinking rare” before accessing this sophisticated technology.  Investing the time and preparation into care pathway optimisation as these tools develop is likely to rapidly show benefit for reducing the diagnostic odyssey10.

An example of a physician-targeted search engine that maps phenotypes and genotypes for rare diseases is Mendelain (backed by a collaboration between innovate UK, The Crick Institute, KQ LAbs, Eastern Academic Health Science Network and Imperial College London)11. Doctors can enter the symptom clusters they’re seeing into the Mendelain website and ‘behind the scenes’ the system uses semantic analysis and data algorithms to code and rank potential causative genetic mutations that may underpin the patient’s disease.

Having these options prioritised and returned in seconds helps the doctor to rapidly consider the correct referral routes and linking well with the specialist insight that may be needed to further support the patient. Mendelain is also a good example of using such databases for complementary tasks such as identifying patients who are eligible for clinical trials of new potential therapies; or, as in the east of England in 2019, to review more than 90,000 patients’ health records and assess them for undiagnosed rare disease12.

These types of search facilities are being integrated with networks of expert organisations, and educational resources. For example, the Genetic And Rare Diseases (GARD) Information centre are linking specialist clinical and patient referral pathways, research announcements, and literature review summaries, with the online machine-learning powered symptom search engine ‘FindZebra’ 13, 14, 15.

The Manchester Centre for Genomic Medicine (MCGM), who are a centre of excellence for rare diseases, have opened their doors to simplify the ordering of diagnostic tests, provide easier access to their clinical genetics expert hub, speed up referral processes (for diagnosis, care, or genetic counselling) and provide training courses in spotting rare diseases for local primary physicians16.

Professions Allied to Medicine

Professions allied to medicine are important in the contributions to rare diagnoses and Dental and Orofacial malformations centres have worked together to systematically improve and publish referral routes and clinical pathways for those on the front-line trying to detect dentalcraneofacial manifestations associated with rare disease17, 18.

An example of these are Ectodermal dysplasias (EDs) that represent about 150 different genetic rare conditions and are characterised by key characteristics that may be picked up by a dentist. Some of these are included in Table 1 below, which is adapted from Luo and colleagues 2019 publication17.

Table 1. Key manifestations of EDs that may help dentists ‘think rare’17.

Rare diseases Origin Major manifestations Dental-cranio-facial manifestations Incidencea Onsetb
Congenital ectodermal dysplasiac Changes in ectodermc structure Excessively fragile and twisted hair; thick, brittle or discoloured nails; red or brown pigmentations on skin; overheating; respiratory infections Missing, peg-shaped, or pointed teeth. Abnormal molar growth, thin tooth enamel and reduced secretion of saliva 80%30.2% ChildhoodChildhood
Williams syndrome Geneticdeletion ofchromosome7q11.23 Intellectual disability; cardiovascular defects; failure to thrive; lack of social inhibition Small jaw, wide mouth with full lips; teeth not positioned correctly when jaw is shut (usually teeth are widely spaced), missing teeth and enamel defects 75%–91%38%–93% ChildhoodEarly childhood
Congenital erythropoietic porphyria Geneticmutations in chromosome 10q25.2-q26.3 Thickened skin with hyperpigmentation and bullae formation; anaemia; dry eyes Scabs and scars on the face. Teeth have a reddish reddishbrown discoloration with a sharply defined margin (and reddishflourescence), and changes in the upper and lower jaw bonese 47%73%41% Early childhoodChildhoodAdulthood

a Incidence of dental-craniofacial manifestations

b Onset period of dental-craniofacial manifestationsAdapted from17 c Ectoderm: there is a time between fertilisation of the egg, and being a foetus - in this time the baby-to-be is a small ball of cells. The outer layer of these cells is the ectoderm. Someone’s hair, nails, teeth, and sweat glands usually come from this layer.

What Does the Future Hold?

With improved community access to integrated clinical phenological and symptom searching, the enhanced learning opportunities and resources and awareness that Medics 4 Rare Diseases have created, and linkage through to international organisations that provide networks of clinical and patient experts, the rare disease community are on the cusp of making life-changing improvements in the battle to reduce time-to-diagnosis for the many thousands of people around the world living with undiagnosed rare disease.


1 Shire. Rare disease impact report: insights from patients and the medical community. 2013. Available from: https://globalgenes.org/wp-content/uploads/2013/04/ShireReport-1.pdf.

2 Rare Disease: The GP’s Role. https://www.youtube.com/watch?v=1CNGk5lovv4

3 Specsavers latest news. https://www.specsavers.co.uk/news-and-information/latestnews/optician-picks-up-rare-eye-condition-for-youngster

4 Vandeborne et al., 2019. https://ojrd.biomedcentral.com/articles/10.1186/s13023-0191075-8

5 Ramalle-Gómara et al., 2020. https://ojrd.biomedcentral.com/articles/10.1186/s13023019-1285-0

6 Medics 4 Rare Diseasehttps://www.m4rd.org/

7 Rare Disease Series by Swii.ch: Introducing Medics 4 Rare Diseases https://youtu.be/tlVvzajXZ1M

8 Diagnosing rare diseases with AI and machine learning. https://www.physicianspractice.com/technology/diagnosing-rare-diseases-ai-and-machinelearning

9 Machine Learning in healthcare: A physician’s perspective.


10 Shortening Diagnostic Delay of Rare Pituitary Disease in Primary Care. https://www.isendo.org/course/shortening-diagnostic-delay-of-rare-pituitary-disease-inprimary-care/

11 Mendelian main website. https://www.mendelian.co/

12 Eastern AHSN and Mendelian working together to help to help identify undiagnosed patients. https://www.mendelian.co/blog/eastern-ahsn-and-mendelian 13 FindZebra main website. https://www.findzebra.com/

14 Radu Dragusin et al., 2013. https://www.sciencedirect.com/science/article/abs/pii/S1386505613000166

15 How can GARD help healthcare professionals? https://rarediseases.info.nih.gov/guides/pages/97/healthcare-professionals

16 Manchester centre for genomic medicine. https://www.mangen.co.uk/mcgm/raredisease/

17 Luo et al., 2019. https://www.nature.com/articles/s41368-018-0041-y

18 Boy-Lefe`vre et al., 2014. https://www.jdaojournal.org/articles/odfen/pdf/2014/01/odfen2014171p102.pdf

19 NORD free physician guides. https://rarediseases.org/for-patients-andfamilies/information-resources/physician-guides/

A non-exhaustive list of useful links

Information type Example Link
Symptom search tools for physicians FindZebra  https://www.findzebra.com/
Mendelian https://www.mendelian.co/
Phenomizer http://compbio.charite.de/phenomizer_o rphanet/
Information and network linkage portals GARD Information centre https://rarediseases.info.nih.gov/
Genetics Alliance Australia (central repository for genetic resources) www.geneticalliance.org.au
NORD Physician guides19 https://rarediseases.org/for-patientsand-families/informationresources/physician-guides/
Medics 4 Rare Disease https://www.m4rd.org/
Online Mendelian Inheritance in Man (OMIM) https://omim.org/
Orphanet https://www.orpha.net/
Unique: understanding rare chromosome and gene disorders  https://www.rarechromo.org/
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