Almost 10 percent of pediatric deaths occur suddenly and without explanation. In this terrible situation, the first question many parents have is “Why?” For most, answers never come.
Childhood deaths that cannot be explained by traditional autopsy and death-scene investigation are referred to as sudden unexplained deaths in pediatrics (SUDP). In children, these deaths are more common than those from either cardiac disease or cancer and typically occur in infancy or early childhood.
Robert’s Program at Boston Children’s Hospital, co-founded by Richard Goldstein, MD, and Hannah Kinney, MD, is adding a genetic approach to the search for answers. The program has, to date, developed a panel of 254 genes linked to potentially fatal conditions that can cause sudden death, providing a starting place for further investigation.
Considering genetic possibilities
Most cases of SUDP, a broad term that includes sudden infant death syndrome (SIDS), have three things in common, explains Goldstein: a vulnerable infant, an external trigger and a critical age in development, when the autonomic nervous system — responsible for breathing, heart rate and digestion — is still developing.
Traditionally, the external trigger has received the most attention. Efforts like the “Back to Sleep Campaign” have reduced the incidence of SUDP, encouraging parents to put infants to bed lying on their backs to avoid the triggers of lowered oxygen or elevated carbon dioxide. But what Goldstein calls “the sleep accident bias” doesn’t fully account for the complexity of SUDP.
Goldstein and his colleagues believe that many cases of SUDP represent undiagnosed diseases, newly recognized diseases or rare diseases in combination with environmental triggers. They developed their genetic panel to better identify these diseases.
Previous genetic panels for sudden death were designed to investigate cardiac deaths in adults. To develop an effective panel for SUDP, the Robert’s Program clinicians reviewed hundreds of case reports, utilized the findings of numerous studies and ultimately included genes linked to cardiac arrhythmia, epilepsy, brain malformations, metabolic disorders and more.
The Robert’s Program process
With families’ consent, Robert’s Program screens deceased children for variants in each of the 254 genes currently included in the panel. If a variation is identified, researchers consider its expected clinical presentation and whether the parents have the same variant. In some instances, the team will delve into family history to look for further answers.The program provides these investigations free of charge, thanks to support from grants and donations.
“Many genes have variable penetrance,” explains Goldstein, “meaning that you can have a genetic variant and not have disease at all, or have a different presentation.”
One investigation, for example, followed a baby who died during sleep. The team found that in the previous generation, an infant had died of pneumonia, and, in the generation before that, a child had died of “galloping pneumonia.” The team deduced that, in fact, they were looking at multi-generational cardiac death.
Caring for the family
Such investigations not only can provide families with answers that help them cope with their loss, but can also help in understanding the risks for their other children. This is especially important for parents of children who died of SIDS, who are six times more likely than other parents to have a second child die of SIDS.
In one girl, for example, the team was able to identify asymmetry of the hippocampus, a structure in the brain associated with emotion, memory and autonomic nervous function. Further investigation revealed that she had a personal and a family history of febrile seizures and likely had a seizure disorder herself. In response to these findings, her twin brother received a brain MRI, which revealed the same vulnerability. He is now followed by a neurologist who has prescribed anti-seizure medication.
There’s power in going through this list and not finding anything.
If no likely causative variations are identified from the genetic screen, parents can still find solace in the knowledge that every currently known gene linked to SUDP has been tested, and that they all came up negative.
“I’ve seen so many couples ask, ‘Are we a bad combination?’” says Goldstein. “There’s power in going through this list and not finding anything.”
So far, results have been communicated to more than 100 families, and are still being compiled for over 200 more.
Evolving standards of practice
Robert’s Program is continually evaluating and updating its genetic panel to reflect the latest findings. Goldstein also hopes to share the program’s method with other pediatricians and pathologists.
“Right now, there’s no widely available medical model for evaluating unexplained deaths,” says Goldstein. “A child dies, the family is investigated for abuse and the autopsy returns negative. That’s all that happens. We replace this with a program that seeks to advise, council and minimize risk.”
Robert’s Program provides free services for families in Massachusetts who have lost a child under age 3 suddenly and unexpectedly. Resources are available for families outside of Massachusetts as well.
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