Published on in HI Hope
Children’s Hospital of Philadelphia has long been on the forefront of genetics when it comes to hyperinsulinism.
Now, CHOP’s Congenital Hyperinsulinism Center, which treats more children with hyperinsulinism (HI) than any center in the world, has added a dedicated genetic counselor to its multidisciplinary team.
Victoria Sanders, MS, LCGC, is available to meet with families from their first visit, throughout the child’s initial treatment and into the future.
Pediatric geneticist Jennifer M. Kalish, MD, PhD, has been part of the HI Center team for years, consulting and educating families and guiding them through genetic testing. Kalish continues to be available for families; Sanders’ presence offers another layer of expertise.
Genetics plays a large role in managing HI. Determining if a child has diffuse or focal disease is critical in determining treatment options.
Diffuse disease, when the affected beta cells are found throughout the pancreas, usually requires combination of medical and/or surgical therapies to control the hypoglycemia. With focal disease, the affected beta cells are concentrated in one spot, so only that area of the pancreas needs to be removed, sparing the rest. CHOP pioneered the 18F-DOPA PET scan that helps determine the location of the focal lesion, making the surgery more precise.
Two Tiers for Genetic Testing
The Tier 1 genetic panel, which looks for mutations in the four genes most commonly associated with HI, is indicated for children who are unresponsive to diazoxide. It is very predictive of diffuse vs. focal disease, as a genetic mutation is identified in 90% of diazoxide-unresponsive cases. Some patient families may have already begun genetic testing by the time they arrive in Philadelphia; others have not. For those without prior genetic testing, Sanders will explain the process and coordinate the test.
For children who are responsive to diazoxide, or children with negative Tier 1 testing, Sanders will arrange for a Tier 2 test. This test includes nine genes currently, including the four genes on the Tier 1 test, and will soon be expanding to include more. About half of patients will have negative Tier 2 testing and have a genetic mutation that is yet to be identified.
For all families, parents are also tested to see if they are carriers of the mutation, even if they don’t have HI symptoms themselves. In about 10% of cases, the mutation is “de novo,” meaning it happened spontaneously during fetal development and was not inherited from a parent.
“If we find a genetic cause, what does that mean for that patient?” Sanders says. “In addition to guiding treatment, it raises other issues. For example, will future pregnancies for the family be impacted? Siblings — and even aunts and uncles and cousins — may need to be tested to see if they have a mild form that doesn’t present symptoms, but that they could pass on, in a more severe form, to their children.”
Sanders works with teens and young adult patients who have questions as they are thinking about their future families. “They ask: ‘Are our kids going to be at risk?’ ’’ Sanders says. “Their testing may have been done while ago when we knew less or perhaps it was under a research protocol. We re-do their tests in a clinical lab to confirm the genetic mutation and counsel them as appropriate.”
HI genetic mutations come in recessive and dominate forms. Some are passed down from a parent who had a milder presentation and might not even know they had it. “There can be identical genetics but variations in presentation,” Sanders says. “There are environment influencers that may come into play. There’s a lot of education involved.”
For children among the 50% without a known gene mutation for HI, families may choose to have whole exome sequencing done. This is to find out if the child has any of the various syndromes, such as Beckwith-Wiedemann syndrome, Turner syndrome, Soto syndrome or Kabuki syndrome, which sometimes feature HI as a component.
The HI Center researchers are also actively searching for additional genes that could cause HI. Families are asked if they want to participate by allowing their blood samples to be part of the research database.
CHOP understands that learning your child has hyperinsulinism can be overwhelming, and Sanders sees her role as helping to demystify the genetic component, providing answers when they’re available and reassurance when they are not.