The painful puzzle of diseases that have no name

"It's all in your mind."

Helene Cederroth has lost count of the number of times doctors have said this to her. Yet she knew, soon after her son Wilhelm was born in 1983, that something wasn't quite right with her second child.

"He looked like a perfect baby with red cheeks," says Helene. "Everyone at the hospital thought he was perfectly healthy."

But by the time he reached one year old, Wilhelm had developed epilepsy and chronic stomach problems. By the age of three, he developed an inflammation of the upper airways known as false croup, and his family was told he had asthma.

Helene was far from satisfied. She wanted to know more. What was causing these medical conditions, specifically? Were they related? And could they be cured?

Helene was seeking what is known in the medical world as a causative diagnosis: one unifying diagnosis that could explain all of Wilhelm's health issues. She says this was the only way to get a better understanding of the course of Wilhelm's disease – and of his chances of a recovery.

Sadly, Wilhelm's experience was only the start of his family's fraught journey with the enigma of undiagnosed diseases.

Mystery conditions

An undiagnosed disease is a medical condition without a known cause, despite extensive evaluation. While undiagnosed diseases are relatively rare, they still affect millions. Up to 350 million people around the world have an "undiagnosed" or "rare" condition (a rare condition is defined as affecting less than one in 2,000 of the general population in the European Union or fewer than 200,000 people in the US).

Children under the age of five are disproportionately affected: they make up 50% of cases, 30% of whom will die before the age of five, according to one report. In the UK alone, 6,000 children are born each year with "syndromes without a name” (Swanis).

Dealing with a child's medical challenges is hard enough. But going without a diagnosis opens up a myriad of added challenges for clinicians and families. That’s something Anna Jewitt, a clinical nurse specialist for Swan children at the Great Ormond Street Hospital in London, knows well. Without an explanation for their child's health, parents are left feeling lost and alone.

Sometimes, despite their concerns, caregivers are told their child is "normal". Yet this "is often the worst word for a parent with a child with an undiagnosed condition", says Jewitt.  

One difficulty is that most children who present with a symptom do not have a serious disease. Generally, it's more likely to be something minor or temporary. As a result, most parents need reassurance that their child is fine – not dozens of laboratory tests and weeks of additional medical investigation.

"If you were to take 100 parents who come in with complaints, most of them do need the reassurance that nothing is going on," says William Gahl, a senior investigator at the National Human Genome Institute in Bethesda, Maryland.

But in some cases, that tactic can backfire – as it did with Wilhelm. Physicians reassured Helene and her husband Mikk that there was nothing sinister going on with their baby's health, just a bad-luck hand of epilepsy, asthma and false croup together. Unconvinced, the couple pressed on with medical investigations.

In the meantime, life went on. "Wilhelm was great in school with lots of friends. He was a kind boy. The teachers in the school said he would be the United Nations General Secretary," remembers Helene. "He was fun. He was like a normal boy."

Like most normal kids, Wilhelm and his elder sister would come home from school with pesky bugs and infections. But for Wilhelm, recovery was beginning to take longer than usual. Helene was met with the same response from doctors: "for some children, that's just the way it is".

One afternoon when Wilhelm was five, he went out to pick raspberries. When he came inside, he had a cough so intense his eyes became bloodshot. His face swelled, followed by a high fever. Doctors had never seen a raft of symptoms quite like this, but they also couldn't find anything wrong.

Helene was assured by the doctors that whatever was causing Wilhelm's various symptoms, it wasn't hereditary or genetic. When Wilhelm was eight years old, Helene and Mikk went on to have their third child, Hugo.

In fact, up to 80% of undiagnosed and rare conditions are genetic. But as Gahl points out, most physicians are not geneticists. "Part of the issue is physicians want to reassure the parents that they can have a second child. When they don't know what the genetic cause is, they can't put an estimate on the percentage recurrence rate," he says. "Sometimes the default will be to say, 'We don't think it is genetic' – and the basis for that is that there is no known genetic cause." Gahl says that "it's not the best default" answer to give parents.

Living with uncertainty

In her third trimester with Hugo, Helene felt a strange movement: an erratic kick that reminded her of young children with epilepsy. It was something she'd never felt before with Wilhelm or his older sister. The doctors told her it was the baby hiccupping.

Hugo was born on 27 December 1991. At six hours old he had his first seizure. Helene's suspicions were right – Hugo had epilepsy.

Hugo spent the first six months of his life in hospital. To make the family's trauma worse, his medical team became suspicious that Mikk was shaking Hugo.

"That's still in my husband's head today," Helene says. "In some ways you are afraid to go to the hospital." Helene remembers having her parenting monitored by the team. "It was the most horrible thing I've ever gone through," she says.

Fear of judgement is something Jewitt hears in her conversations with the many families she tries to reassure. For some parents it's "feeling like people don't believe them, and being called an overanxious mother", she says. "Others who don't come from privileged backgrounds might feel like they are being judged."

There were moments of hope for the family. When Hugo was 18 months old, Helene was told he would never walk or sit by himself. The same day they went home from hospital, a determined Hugo propped himself up on a corner sofa. "He turned around and walked eight steps, proving the doctors wrong," she says. He went on to not only walk, but run.

Helene became pregnant again with her fourth child. She was a daughter, and this gave her parents additional hope: their oldest, a girl, had good health, and Helene was told the symptoms Wilhelm and Hugo were experiencing (such as epilepsy) only impacted boys.

Emma was born on 24 January 1994. At 30 minutes old, she had her first seizure.

'Nature's cruel lottery'

Over the next several years, Emma grew into a mischievous character who loved to make her parents laugh. Like Hugo, she adored animals. Despite the children's challenges, which included autism and sleep apnoea in addition to epilepsy, family life continued as best it could – as is common among many families with children who have chronic undiagnosed illnesses.

So did the hunt for answers. What, Helene and Mikk wondered, was the overall cause linking all the symptoms affecting Wilhelm, Hugo and Emma?

The family met with specialists at Great Ormond Street Hospital in London, UK and John Hopkins University in Baltimore, Maryland. Doctors were unable to unravel what was happening, describing the children's condition as "nature's cruel lottery".

Then Wilhelm reached the age of 12 and his condition started to deteriorate. There was now a new cause for concern: childhood dementia. He forgot how to ride his bike. He would run into stinging nettles without recognising the risk. Homework became a battle. And while he previously had played with Hugo and Emma like an elder brother, he began to play with them like they were peers. When Wilhelm didn't recognise his grandmother one day, Helene realised he was regressing.

In Austria, Wilhelm underwent specialist treatment with the permission of the country's medical ethics committee. This was followed in 1997-98 by a Franco-Swiss research team who investigated whether the three siblings might have a mitochondrial disease. Helene and the children underwent DNA sequencing, but it offered no answers.

The family might have different results if they were undergoing the process today: the Human Genome Project, which aimed to identify the order of all DNA bases to obtain the "genetic blueprint" of humans, launched in 1990. Completed in 2003, it has radically improved our understanding of how new diseases form. Exome testing, which looks specifically at  a genome's protein-coding regions (making up about 2% of the whole genome), has become especially helpful, says Gahl.

But in the 1990s genome sequencing was too primitive to help Wilhelm. By the time he was 15 years old, it became clear he would not recover. He was brought home for palliative care with the support of a nursing team.

He died on 2 September 1999, aged just 16. An autopsy found no clear cause of death.

In the wake of losing Wilhelm, Helene and Mikk faced a catalogue of new challenges.

Their youngest, Emma, fell into her first coma three weeks after Wilhelm's funeral, where they believe she had picked up a virus. She recovered but continued to experience intermittent comas in the months that followed, until doctors decided there was nothing they could do. Emma died at home on 20 December 2000, surrounded by her loved ones. She was six years old.  

Not quite two years later, on 8 December 2002, the family lost Hugo just before his 11th birthday. He had developed lung problems and complications with his epilepsy.

As Hugo's health failed, his father asked a local construction company for a favour. They agreed to park their digger outside Hugo's window. Carrying his backpack with an intravenous solution, Mikk would take Hugo out to drive and dig together.

Just like Emma and Wilhelm before him, Hugo's parting words to Helene were "thank you, Mum".

None of the three children ever received a causative diagnosis explaining their conditions, or identifying the links between them. Again, had they been born later they may have learned more. In the UK in 2023, thousands of children with severe developmental disorders finally received a diagnosis, via a study that found 60 new diseases.

In the US, the Undiagnosed Diseases Network – a consortium of 12 research teams and clinical centres across the country – is also working to solve these medical mysteries. In 2018, just two years after it had been established, the consortium had identified 31 new syndromes and had diagnosed 132 patients. Today it has evaluated more than 2,220 patients and successfully diagnosed 676 of them. It has described a total of 53 new conditions. Funding for this kind of work, however, continues to be a problem and support for the Undiagnosed Diseases Network from the National Institutes of Health Common Fund is due to end this year.

Helene acknowledges that an overall diagnosis may not have kept her children alive. However, she believes it would have at least offered an explanation for what was happening to their bodies. In addition, says Jewitt, a diagnosis can "open doors", if only to "simple things like applying to a charity for support".

After their children's deaths, Helene and Mikk turned their attention to fundraising, launching their charity the Wilhelm Foundation. They had been frustrated by the lack of collaboration between the doctors around the world who treated their children. Recognising this, as well as the additional challenges faced by families in middle and lower income countries (such as access to resources), in 2014 they brought together top experts for a world congress on undiagnosed diseases. The annual gathering continues to this day.

Wilhelm, Hugo and Emma all died in the build-up to Christmas, and this time of year continues to be difficult for Helene and Mikk. Emma especially loved the festive season. She always said she wanted to paint Santa's beard blue, her favourite colour.

In her final days in a coma, Emma was visited by a blue-bearded Santa Claus. Helene is confident she heard Emma make a gleeful sound when she sensed him entering the room. "Or maybe," she says, "that was in our mind."

Two years ago, Helene and Mikk were approached by a top diagnostic geneticist who believed that their children probably had a new disease. The couple have since submitted genetic samples for whole-genome sequencing. Sadly, it is too late to help Wilhelm, Hugo or Emma. But there is still time, they say, to use what they've learned about their family to save another child’s life.

-bbc