Autoinflammation with Infantile Enterocolitis

Periodic fever-infantile enterocolitis-autoinflammatory syndrome, AIFEC, NLRC4-related autoinflammatory syndrome with MAS, NLRC4-related macrophage activation syndrome, NLRC4-related infantile enterocolitis-autoinflammatory syndrome

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Autoinflammation with infantile enterocolitis is a rare genetic disorder that causes life-threatening episodes of inflammation beginning in the first weeks or months of life, affecting the intestines and other body systems.

Table of contents

• What is autoinflammation with infantile enterocolitis?
• Signs and symptoms
• What causes the disease
• How the disease is inherited
• What can trigger disease flares
• Diagnosis and testing
• Disease course over time

What is autoinflammation with infantile enterocolitis?

Autoinflammation with infantile enterocolitis is a rare genetic disorder that causes the immune system to attack the body’s own tissues without a clear reason. This condition is part of a group of diseases called autoinflammatory disorders, which occur when the body’s natural defense system becomes overactive and causes inflammation even when there is no infection or injury.^[1]

The disease typically starts very early in life, during the newborn period or in the first few months after birth. It causes repeated episodes of severe inflammation that can affect multiple organs and systems in the body. The condition gets its name from one of its most prominent features: inflammation of the intestines, known as enterocolitis, which occurs during infancy.^[2]

This is an extremely rare condition, affecting fewer than 1 in 1,000,000 people worldwide.^[5]

Signs and symptoms

The symptoms of autoinflammation with infantile enterocolitis appear very early in life and can be severe. The condition affects multiple parts of the body, with symptoms that may vary between individuals but follow a general pattern.^[2]

Early infancy symptoms

In the first weeks or months of life, babies with this condition typically develop inflammation of the intestines. This manifests as severe watery diarrhea, sometimes called secretory diarrhea, which means the intestines release excess fluid. Affected infants may also experience vomiting and fever. These digestive problems are often accompanied by poor growth and failure to gain weight appropriately, a condition doctors call failure to thrive.^[2][4]

During this early period, blood tests show clear signs of inflammation throughout the body. Laboratory findings typically include elevated levels of substances that indicate inflammation, such as C-reactive protein (a protein the liver makes in response to inflammation) and ferritin (a protein that stores iron). Some infants also develop problems with their blood cells and blood clotting.^[2]

Recurring fever episodes

After the initial intestinal symptoms, children with this condition experience repeated episodes of fever. These febrile episodes are often accompanied by an enlarged spleen, a condition called splenomegaly. During these flares, patients may develop skin rashes that look like hives (urticaria-like rashes), joint pain called arthralgia, and muscle pain known as myalgia.^[5][9]

Serious complications

Some individuals experience severe complications during disease flares. These can include disseminated intravascular coagulation (a serious condition where blood clots form throughout the body while bleeding occurs at the same time), pancytopenia (a dangerous reduction in all types of blood cells), and activation of certain immune cells called macrophages. Laboratory tests may show increased levels of specific inflammatory molecules, including IL-18, IL-1B, and soluble IL2R.^[2][4]

In the most severe cases, particularly in early infancy, the condition can lead to organ failure and death if not treated promptly. Some infants have died from complications such as bleeding in the lungs.^[2][4]

What causes the disease

Autoinflammation with infantile enterocolitis is caused by changes, called mutations, in a gene named NLRC4. This gene is located on chromosome 2 at position 2p22.3. The NLRC4 gene provides instructions for making a protein that plays an important role in the immune system’s response to infections and other threats.^[1][3]

The mutations that cause this disease are called gain-of-function mutations, which means they make the NLRC4 protein work too much rather than too little. When this protein becomes overactive, it triggers excessive inflammation even when there is no real threat to the body. Specifically, the overactive protein causes the release of inflammatory molecules and leads to a type of inflammatory cell death called pyroptosis.^[2][13]

The NLRC4 protein is part of a structure called an inflammasome, which is like an alarm system inside cells. When working properly, this system helps protect against infections. However, when mutations make it overactive, the inflammasome triggers inflammation constantly, leading to the symptoms of the disease.^[8][13]

In some cases, the mutation is not present in all cells of the body but only in some cells, a condition called somatic mosaicism. This means the mutation occurred after conception rather than being inherited from a parent.^[13]

How the disease is inherited

Autoinflammation with infantile enterocolitis follows an autosomal dominant pattern of inheritance. This means that only one copy of the changed NLRC4 gene (out of the two copies everyone has) is needed to cause the disease.^[1][3]

In autosomal dominant inheritance, an affected person has a 50% chance of passing the genetic change to each of their children. Both males and females can inherit and pass on the condition equally. The disease has been reported in families where a father and his children were all affected, showing that it can be passed from one generation to the next.^[2]

However, not all cases are inherited from a parent. Some individuals are the first in their family to have the condition, meaning the genetic change occurred as a new mutation. In some instances, the mutation may only be present in some of the body’s cells rather than all of them, which is called mosaicism.^[13]

What can trigger disease flares

After the initial period of intestinal inflammation in infancy, individuals with this condition experience recurring episodes or flares of inflammation throughout their lives. These flares do not occur randomly but are often triggered by specific events or circumstances.^[2][4]

Common triggers for disease flares include viral infections, which activate the immune system and can set off the overactive inflammasome. Physical or emotional stress can also provoke episodes of inflammation. Overexertion or excessive physical activity is another recognized trigger that can lead to a flare of symptoms.^[2][5][9]

Understanding and avoiding these triggers when possible can help reduce the frequency and severity of inflammatory episodes, though this is not always feasible, particularly with unavoidable situations like viral infections.^[2]

Diagnosis and testing

Diagnosing autoinflammation with infantile enterocolitis can be challenging because its symptoms overlap with other conditions that cause intestinal inflammation and fever in infants. The diagnosis requires careful evaluation by specialists familiar with autoinflammatory diseases.^[7]

A key clue to the diagnosis is an elevated level of IL-18 in the blood. This inflammatory molecule is typically much higher than normal in people with this condition, and measuring it can help distinguish this disease from other disorders. Blood tests also typically show increased C-reactive protein, elevated ferritin, and sometimes abnormalities in blood cell counts.^[2][13]

The definitive diagnosis is made through genetic testing that identifies mutations in the NLRC4 gene. This involves analyzing a sample of the patient’s DNA, usually from blood, to look for changes in this specific gene. Several types of genetic tests are available, including tests that read the entire sequence of the gene, tests that look for specific known mutations, and tests that detect deletions or duplications of genetic material.^[1]

Because the disease is so rare and can appear similar to other conditions, there may be delays in reaching the correct diagnosis. Medical professionals may need to rule out other causes of early-onset enterocolitis and recurrent fever before considering this specific autoinflammatory disorder.^[7]

Disease course over time

The course of autoinflammation with infantile enterocolitis changes significantly as affected individuals grow older. The disease has a characteristic pattern that evolves from infancy through later childhood and adulthood.^[2]

The most severe intestinal symptoms occur during infancy, particularly in the newborn period and first months of life. This is when the inflammation of the intestines is most prominent, causing diarrhea, vomiting, and poor growth. For those who survive this critical early period, the intestinal symptoms tend to improve and eventually resolve as the child gets older.^[2][4][5]

After infancy, individuals who have survived typically no longer experience significant intestinal problems. However, they continue to have recurring episodes of fever and systemic inflammation throughout their lives. These later episodes may include fever, enlarged spleen, joint pain, muscle pain, and skin rashes, but the severe intestinal inflammation that characterized early infancy usually does not return.^[5][9][12]

This age-related difference in symptoms suggests that the developing infant intestine is particularly vulnerable to the effects of the overactive inflammasome, while the mature intestine in older children and adults is more resistant. Understanding this pattern helps doctors anticipate what symptoms to expect at different ages and tailor treatment accordingly.^[8][12]