Orientation & Overview of Enteropeptidase Deficiency

Finding a name for what your child is experiencing is often the end of a long and frightening journey. You may have spent weeks or months watching your baby struggle to gain weight, deal with persistent diarrhea, or experience mysterious swelling (edema) ^[1][2]. This period of poor weight gain or “failure to thrive” is a heavy burden for any parent to carry.

Now that you have a diagnosis, it is important to know that what happened is not a result of how you fed or cared for your baby. Congenital enteropeptidase deficiency (also called enterokinase deficiency) is a rare genetic condition that fundamentally changes how the body processes protein ^[3][4]. While the diagnosis is serious, reported cases show that it is highly responsive to treatment, and children often see substantial improvement once the right medical support is in place ^[2][4].

What is Known and What is Uncertain

Because this condition is exceptionally rare (with only a small number of cases reported in the medical literature), there is no universally validated, standardized protocol that applies to every child.

• What is known: The biological cause is well understood, and treatment with pancreatic enzymes has been shown to rapidly improve symptoms and growth in published case reports.
• What is uncertain: Long-term adult outcomes, neurodevelopmental tracks, and the exact lifelong duration of specific therapies are still being studied. Your child’s care will be highly individualized.

Understanding the Enzyme “Starter Step”

To understand this condition, it helps to think of protein digestion as a falling row of dominoes. Normally, when your child eats protein, the pancreas releases inactive enzymes (proteases) into the small intestine. For these enzymes to start working and break down the protein, they need a “starter” to turn them on.

That starter is an enzyme called enteropeptidase (or enterokinase) ^[3]. It is produced by the lining of the small intestine. Its only job is to flip a switch that turns an inactive enzyme called trypsinogen into its active form, trypsin ^[3]. Once trypsin is active, it goes on to activate all the other protein-digesting enzymes.

In children with this deficiency, the “starter” enzyme is missing or does not function properly ^[1][3]. Because that first domino never falls, the body cannot break down protein into the nutrients it needs to grow ^[1]. This can lead to:

• Hypoproteinemia: Low levels of protein in the blood ^[1][2].
• Steatorrhea: Oily or fatty stools because digestion is disrupted ^[2].
• Anemia and Rashes: Often secondary to broad malnutrition, requiring clinical assessment to rule out iron, zinc, or vitamin deficiencies ^[3][2].

An Exceptionally Rare Condition

If your local doctor or pediatrician seems unfamiliar with this diagnosis, it is because the condition is extraordinarily rare ^[4][2]. Your care team will likely include specialists in pediatric gastroenterology (doctors for children’s digestive systems) and genetics. While you may feel pressure to become an “expert” on your child’s disease, remember that your role is to partner with specialists who can guide the medical decisions.

How It Is Inherited

Congenital enteropeptidase deficiency is caused by variants (mutations) in the TMPRSS15 gene ^[1][2]. This gene provides the instructions for making the enteropeptidase enzyme.

The condition follows an autosomal recessive inheritance pattern ^[4][1]. This means:

• A child must inherit two variant copies of the gene (one from each parent) to have the condition ^[4].
• The parents are typically “carriers”—they have one variant copy and one normal copy, have no symptoms, and often have no idea they carry the variant ^[4].
• When two carriers have a child, there is a 25% chance with each pregnancy that the child will have the condition, a 50% chance the child will be a carrier, and a 25% chance the child will not have the variant at all ^[4].

A Path Toward Growth

The most important thing to know today is that this condition is treatable. Standard care typically involves pancreatic enzyme replacement therapy (PERT). These are prescription supplements taken with feedings that provide the active enzymes the body is failing to activate on its own ^[2]. In recorded cases, infants starting this treatment have shown rapid improvement: diarrhea improves, swelling goes down, and they begin to gain weight and reach developmental milestones ^[2][4]. While the road to a diagnosis may have been exhausting, proper treatment allows your child’s body to finally use the nutrition you have been providing.