The evening before he died, Hogan Teem stayed in. It was December 12, 2012, and the teenager played cards with his mother at their home in Clayton, North Carolina. His girlfriend spent Wednesdays with her family, and card games had become a weekly tradition. This time they settled down to a session of Phase 10. Hogan beat his mother, closing the gap in their running score, now at 13 matches to 11. Around 9.30pm, he went to bed; the following day was a busy day of high school, ending with baseball practice. There was no indication that it would be his last.
Hogan was physically fit, spending long summer days mowing lawns in the North Carolina heat. He played American football, basketball, baseball and golf. He loved swimming, hiking and fishing. He went on mission trips with his church. He never suffered illness or missed a day of school. To all intents and purposes, he was a perfectly healthy 17-year-old.
Baseball practice on December 13 had been business as usual. Participating in light conditioning work, Hogan took it easy so as not to put strain on his ankle, which he had sprained a couple of weeks earlier. Then, midway through practice, he approached one of his coaches, saying: “Coach, I don’t feel right.” Before the coach could respond, Hogan blacked out and fell to the ground. The coaches administered CPR. An ambulance arrived almost instantly, and paramedics discerned a faint heartbeat. Hogan’s parents, Allyson and David Teem, arrived at the school, and Allyson travelled in the ambulance. On the way to the hospital, paramedics lost Hogan’s heartbeat. After several minutes of frantic work at the roadside they recovered it and sped on towards the emergency room.
In an effort to keep her son awake, Allyson taunted him about the card game. “I was yelling, ‘You cheated! You owe me a card game,’” she says. “Then I said, ‘OK, you won fair and square, but it’s still 13-11!’” Despite Allyson’s efforts to rouse her son, Hogan was unresponsive by the time they arrived at the hospital. Medical staff worked on him but, after 45 minutes, admitted there was nothing more they could do.
Hogan had suffered an acute cardiac event, brought on by a rare and previously undiagnosed genetic condition known as an arrhythmogenic right ventricular cardiomyopathy, or ARVC. There had been no reason to suspect that Hogan was at risk, and doctors don’t commonly run tests for ARVC. The tragedy was unforeseeable.
For patients in the grip of rare and potentially life-ending conditions that mystify one doctor after another, there is new hope: the collaborative sleuthing of the Undiagnosed Diseases Network
Hogan had been adopted when he was five weeks old. Seventeen years later, his biological parents were raising three children of their own – two sons and a daughter, all full siblings to Hogan. Allyson regularly sent the family letters and pictures of Hogan, but they had no direct contact; the protocol was to send documents via the adoption agency. After Hogan’s death, Allyson realised that the siblings could well carry the same genetic disorder and wrote to his biological parents, urging them to get the family checked.
Due to bureaucratic procedures, it took nine months to get the message through. The two boys, their sister and parents underwent cardiac imaging to look for signs of ARVC. The results came back normal, and the family breathed a collective sigh of relief.
Then, four years later, the youngest sibling, Ethan White – then 14 – complained of chest pains while playing basketball at church. He called his mother, who arrived to find him grey and clammy, complaining of pain in his jaw and arm – symptoms of a heart attack. His mother rushed him to hospital where his heart rate was discovered to be 263 beats per minute. The medical staff thought there was an error with the reading – the average heart rate fluctuates between 60-100bpm. Ethan’s condition worsened. Doctors tried medications but none could be found that alleviated his condition. Just as medical staff were preparing to defibrillate him, Ethan vomited and his heart rate lowered.
His condition stabilised, and Ethan was transferred to Duke University Hospital, the major medical centre in that part of North Carolina, where he was monitored and fitted with an inbuilt defibrillator. It was clear to staff that Ethan had also experienced an acute cardiac event consistent with ARVC and that another attack was likely. The defibrillator was designed to restart his heart in the event of another attack. An MRI scan of his brother, Austin, confirmed he also had ARVC. The two brothers had inherited the same genetic problem as Hogan, despite all the tests finding nothing to indicate a genetic cause. Yet how else could three brothers raised in different families, in different parts of the state, develop the same condition?
With local medical staff stumped, and no further avenues of investigation available, Ethan and Austin were referred to the Undiagnosed Diseases Network (UDN), a group of 12 clinical research hubs designed to delve into chronic illnesses that have previously been undiagnosed, misdiagnosed or simply written off as psychosomatic. Bringing together experts in neurology, immunology, cardiology, endocrinology, genetics, rheumatology and more, the UDN had been custom-built to delve into just such a medical mystery.
In July, in North Carolina, the tree-lined avenues of Duke University are a furnace of mid-summer heat. The university is part of the famed "Research Triangle", a multi-county area linking Duke with North Carolina State University and the University of North Carolina at Chapel Hill. Duke University, based in Durham, boasts a formidable campus, with more than 100 buildings, 1,600 medical students, 2,400 clinical staff – and Dr Vandana Shashi, principal investigator for the Duke UDN site.
Shashi, 60, speaks with a calm and benevolent authority. She has worked at Duke for around ten years. “I’m a clinical geneticist and a paediatrician, so I have seen patients who were difficult to diagnose my entire life,” she says.
In 2011, Shashi found herself discussing the difficulty of diagnosing genetic diseases with a colleague, Dr David Goldstein. At that time, just 50 per cent of patients with genetic diseases received a diagnosis. Together, they started working with new gene-sequencing technology, and in 2012 they published work demonstrating the efficacy of this tool in helping to reach a diagnosis.
Two years later, Shashi heard that the National Institutes of Health – a research centre affiliated with the US Department of Health – was looking to expand a small programme aimed at helping the most difficult to diagnose patients, and set up research centres at clinical sites across the country. Shashi immediately applied, and Duke was accepted in 2014 as one of the first clinical sites alongside UCLA, Stanford, Vanderbilt, Baylor and a co-ordinating centre based at Harvard. This was the first iteration of the UDN.
The Duke site took on its first patients in 2015. To date, it has accepted 199 applicants and made 79 diagnoses. As of 2019, the UDN as a whole has received 3,601 patient applications, 1,372 of which it has been able to accept. It has reached a diagnosis in 323 cases.
“The mission of the UDN was and is to provide diagnostic services to patients who have had difficulty getting a diagnosis, and also to be able to have the patients participate in research activities,” Shashi explains.
In the US, a rare disease is defined as something that affects fewer than 200,000 people, and an ultra-rare disease as affecting fewer than 2,000 people. By their very nature they are hard to diagnose, simply because so few patients are available to study, and are often misdiagnosed. Without any reason to suspect otherwise, doctors have to rely on what they know. In many cases, like that of Ethan and Austin, they know what the problem is but fail to unearth genetic evidence for it – a vital component in identifying at-risk family members and formulating a treatment plan. Frustrated by months or years of disjointed medical testing, a doctor may suggest patients apply to the UDN in a final bid for answers.
The Duke team reviews applications in a meeting every Tuesday. In order for a patient to be eligible, they must have an "objective finding" – a first clue or loose thread for the team to begin unravelling. “There is a perception that ‘undiagnosed’ also means ‘functional’, so the two can be confused,” explains Shashi. “So if you have symptoms like pain or fatigue, yes you can be undiagnosed, but that doesn’t mean you have a true objective undiagnosed disease. These symptoms could be due to pre-existing functional diseases.”
A functional disease is one that exhibits symptoms – nausea, say, or light-headedness – and affects functionality. Because such symptoms are common, they are often easy to diagnose as caused by common illnesses. A UDN patient may display these symptoms, but it is the objective finding – the first unusual clue – that makes them suitable.
Once a patient has been accepted, representatives from each of the UDN sites join a call to share suggestions regarding possible diagnoses or tests. This culture of collaboration means specialists can confer in real time, working together to find a diagnosis. The network has the resources to examine a patient’s history in detail and formulate a working hypothesis based on this data, leading to a suite of tests tailored around the specific condition, a large part of which involves closely examining genetic data for rare or unusual variants or changes.
To date, the UDN has discovered and published papers on two new disease genes, NACC1 and IRF2BPL. After identifying these genes in children, they were able to track down other patients affected by the same diseases. They have also diagnosed a patient with a variant in the KCNC1 gene, known to cause progressive myoclonic epilepsy. Due to that diagnosis, the patient is now enrolling in a clinical trial at another institution that could lead to a drug trial specific to her gene variant.
The majority of UDN patients come from the United States, but international patients are accepted as long as they can afford to travel. Patients apply with suspected auto-immune diseases, infectious diseases, rheumatological diseases, genetic diseases and neurological diseases – although it is not often clear which category they fit into when they first visit the UDN.
Photo credit: Jeremy M. Lange