What Are the Chances Our Next Child Will Have HI?

When a family has a child with congenital hyperinsulinism, a question often arises: Will any future child also have HI?

The answer, like many things concerning HI, is “It depends.” The type of HI in the first child and the parents’ genetics are important factors. And chance plays a big role.

Vicki Sanders, MS, LCGC, the genetic counselor in CHOP’s Congenital Hyperinsulinism Center, is available to review your family’s specific circumstances, but here are the basics.

Recessive Forms of HI

Most children with diffuse HI inherited it from a recessive gene. With this type of HI, both parents are carriers, and each parent passes on the gene for HI to the child. So, while the parents don’t have HI themselves, they carry the gene. For every pregnancy, there is a 1-in-4 chance the child will have HI, a 2-in-4 chance the child will be an unaffected carrier and a 1-in-4 chance the child will not be a carrier or have HI.

It should be stressed that each pregnancy has the same odds. Having one child with HI does not improve the chances that the next child will be a carrier or be unaffected. Imagine you were to flip a coin and it came up heads six times in a row. It’s unlikely, but it could happen.

There are multiple recessive forms of HI, with KATP-HI (caused by changes in the ABCC8 or KCNJ11 genes) being the most common type of recessive HI.

Dominant Forms of HI

If the child with HI has a dominant type, as a lesser number of children with diffuse HI do, they may have inherited it from one parent (who also has the dominant gene) or their HI mutation may have happened spontaneously, or “de novo.”

If it is a de novo mutation, there is only a tiny chance (about 1%) any additional children in the family will have HI.

However, if one parent has the same form of HI, even if they have mild or subtle symptoms and may not have previously recognized they were affected, each subsequent pregnancy has a 50% chance the child will inherit HI. It’s impossible to predict if the child’s HI will be on the mild or more severe end of the spectrum.

There are multiple dominant forms of HI, including some types of KATP-HI, hyperinsulinism/hyperammonemia (HI/HA), glucokinase, HNF1-alpha and HNF4-alpha, as some examples.

Focal Disease Is Special

The inheritance of the focal form of congenital hyperinsulinism is more complicated. Children with focal HI inherit one copy of the gene change from their father, who is unaffected, and a normal copy of the same gene from their mother. For focal HI to happen, the normal gene that was inherited from the mother is lost, and the gene with the change from the father makes a copy of itself. This means the child now has two copies of the genetic change with no normal copy of the gene. Only some cells in the pancreas have the two copies of the gene change. Therefore only some beta cells release too much insulin.

The chance that a subsequent pregnancy would inherit focal HI is less than half of 1%.

Decisions on Future Pregnancies

Families have a range of options if they chose to pursue a HI-free pregnancy or find out if a fetus has HI. “Families will make the very personal decision on how they choose to proceed,” Sanders says.

The most technologically advanced way is for the family to work with a fertility clinic and plan an in vitro fertilization (IVF) pregnancy. When the fertilized egg (embryo) is six or eight cells, one cell is removed for genetic testing. Only embryos testing negative would be implanted.

Some families choose prenatal genetic testing either with chorionic villus sampling (CVS), a biopsy of tissue from the placenta at 10 to 12 weeks, or amniocentesis, when a fine needle is used to withdraw a small amount of amniotic fluid at 15 to 20 weeks. Both procedures have a slight risk of miscarriage.

In addition to the options outlined above (pre-implantation genetic testing with IVF or prenatal testing), additional reproductive options include using a donor egg or sperm (depending on the parents’ genetics) in subsequent pregnancies or adoption. If a couple that is at higher risk to have a child with HI chooses not to do any testing before birth, they would need to make a plan with Endocrinology to monitor the child for HI right after birth until a diagnosis is confirmed or ruled out.

Sanders recommends that unaffected siblings wait until they are adults to have a genetic test, when they can make the decision themselves. If an unaffected sibling does test positive for being a carrier, their partner should also be tested to better understand if any of their children could have HI or be a carrier.

Delivering a Baby Known to Have HI

Knowing in advance a baby will have HI allows families to make a birth plan with the knowledge the newborn may have hypoglycemia (low blood sugar) at birth. The HI Center provides families an informative letter to give to their birth hospital that outlines steps for blood glucose testing and management of hypoglycemia.

The letter is also helpful for families that have declined prenatal genetic testing so the birth hospital has the protocols to keep babies safe if they do have low blood sugar. Directions for genetic testing, if that is needed, can also be provided. The HI Center is always available to consult with endocrinologists in hospitals all over the country — all over the world — if HI is suspected and/or confirmed.

Some families carrying a baby with diagnosed HI, especially those from across the United States, choose to give birth in the Garbose Family Special Delivery Unit (SDU) at CHOP, the nation’s first delivery unit in a pediatric hospital for babies with prenatally diagnosed birth abnormalities. There, the baby comes under the care of HI experts from the very beginning.

Sanders and the HI Center’s geneticist Jennifer M. Kalish, MD, PhD, will help you understand your family’s case and discuss options for the future.