By Tom Ulrich

One of a series of posts honoring ‪#RareDiseaseDay (Feb 28, 2015).

Historically, the starting point for making a rare disease diagnosis is the patient’s clinical profile: the set of symptoms and features that together define Diamond Blackfan anemia (DBA), Niemann-Pick disease or any of a thousand other conditions.

For example, anemia and problems absorbing nutrients are features of Pearson marrow pancreas syndrome (PS), whereas oddly shaped fingernails, lacy patterns on the skin and a proneness to cancer point to dyskeratosis congenita (DC).

The resulting diagnoses give the child and family an entry point into a disease community, and is their anchor for understanding what’s happening to them and others: “Yes, my child has that and here’s how it affects her. Does it affect your child this way too?”

But as researchers probe the relationships between genes and their outward expression – between genotype and phenotype – some families are losing that anchor. They may discover that their child doesn’t actually have condition A; rather, genetically they actually have condition B. Or it may be that no diagnosis matches their genetic findings.

What does that mean for patients’ care, and for their sense of who they are? 

What’s in a diagnosis?

Part of the issue lies in how the nature of diagnostics is changing.

“A growing number of functional and genetic tests are available to reinforce clinical impressions and firm up the diagnosis,” says Suneet Agarwal, MD, PhD, a pediatric hematologist/oncologist with Dana-Farber/Boston Children’s Cancer and Blood Disorders Center who studies rare conditions like PS, DBA and DC. “More and more, however, these tests are showing us two things: a large degree of clinical overlap across patients with different genetic mutations, and a huge variation in clinical symptoms amongst patients with the same genetic mutations.

“This raises the question of whether diagnoses should be clinical or test-based,” he adds, “which is even more difficult in rare diseases.”

A paper he published last spring in Blood  – showing that a small number of people diagnosed clinically with DBA actually bear the genetic hallmarks of PS – illustrates the problem’s impact on care.

While the two conditions can start out looking similar clinically, especially at an early age, PS affects different tissues than DBA and requires a different approach to treatment. And while PS is generally thought to arise sporadically, DBA often runs in families – important considerations when counseling families.

The still-murky links between phenotype and genotype, especially in rare diseases, also raise fundamental questions about what it means to be “diagnosed.” For instance, the parent of a DBA patient sometimes turns out to harbor the same mutation as their child, but without any symptoms. Does that parent then “have” DBA?

Or take DC, where a child may have the mutations that define the syndrome but only some of its clinical features. Because they don’t match the canonical criteria, those children aren’t typically diagnosed with DC.

It’s a matter, Agarwal suggests, of accepting that one mutation can, in different patients, make itself known in a wide variety of ways, ways we don’t yet understand and can’t always yet predict.

“For patients diagnosed with a syndrome primarily on clinical criteria, we have to accept that there will be a mixture of distinct biological causes across the group,” he says. “That mixture will be due to the overlap of phenotypes that can result from mutations in different pathways, but which still fall within the definition of that syndrome.”

Who am I now?

The evolving diagnostics debate touches a deeper question – one of identity.

“Say you’ve been diagnosed into a disease category based on clinical findings,” Agarwal muses. “What happens if you end up not being in that disease category anymore 10 years down the road, when a molecular pathway has been described in that syndrome, and you don’t have defects in that pathway?”

Are you still part of that community?

Sharyn Lincoln, a clinical genetic counselor in Boston Children’s Hospital’s Division of Genetics and Genomics and coordinator of the hospital’s Fragile X Program, says situations where a family’s diagnosis changes, or is taken away, can be challenging.

“For families that have been heavily involved in a particular community, and have made that their other family, it can be difficult to say, ‘I don’t fit into that anymore.'” But for some families, she adds, it can actually be good because they recognized that their symptoms or experiences didn’t quite fit with everybody else’s.

“There’s still that sense of loss, because you may feel you’ve lost that community,” she continues, adding that some families may even go through a grieving process. “But at the same time you may fit better with a different community.”

It depends in part, she adds, on how much that diagnosis changes. Families who lose a diagnosis of one bone marrow failure syndrome in favor of another, for instance, can at least identify with the same overall category.

But if a family’s diagnosis is taken away without an alternative, the family can be left adrift without a community. “That causes the most angst and frustration,” Lincoln says.

In such cases, though, counselors and doctors can steer families to support groups, including ones for the undiagnosed like Syndromes Without A Name.

“There are more groups out there now for the rare disease patients, the ones going through the diagnostic odyssey, than ever before,” Lincoln says. “Even among the larger organizations, that might be more general, it doesn’t hurt to get involved because the more patients they have with a particular diagnosis, the more information they can provide to families or clinicians who have patients with that diagnosis.”

Lincoln says one of the most wonderful things she sees is when a family with a rare diagnosis or a changed diagnosis helps bring others together into a new community. “They’re not only helping themselves find that community, but they’re helping others find it also. Families from all over get a lot of benefit when that happens.”