Diagnosing children with IgG4-RD requires flexibility, study finds

Diagnosing IgG4-related disease (IgG4-RD) in children may require a flexible framework involving many kinds of tests, as the disease often looks different in children than in adults, according to a review study from researchers in Italy.

While IgG4-RD in adults usually affects multiple organs over time, in children it is often seen in areas around the eyes. This can make it difficult to obtain tissue samples or biopsies, which help confirm an IgG4-RD diagnosis.

“Given the challenges in obtaining biopsies in pediatric patients, particularly in delicate anatomical sites, a multidisciplinary approach integrating clinical, serological [blood], and radiological findings is often necessary for diagnosis,” the researchers wrote.

The review study, “IgG4-Related Disease in Childhood: Clinical Presentation, Management, and Diagnostic Challenges,” was published in Children.

In IgG4-RD, immune cells infiltrate tissues, leading to noncancerous masses, enlargements, and/or inflammation in one or more organs that can cause organ damage and scarring (fibrosis).

Symptoms vary; pediatric cases rare

IgG4-RD symptoms vary depending on the affected tissues. The disease most often affects the pancreas, head, neck, or abdomen, but it can manifest in virtually any organ. People with IgG4-RD often, but not always, have elevated levels of the antibody IgG4 in their blood.

Pediatric cases of IgG4-RD are rare and most often involve adolescents. Contrary to what’s observed in adults, a young patient will typically experience disease-related changes in a single area of the body.

Diagnosing IgG4-RD can be complex, partly because of the variability in symptoms and the need to rule out other potential causes. In addition, adult diagnostic criteria may not be appropriate for children.

“Due to these challenges, a multidisciplinary approach involving [several specialists] is often necessary to achieve an accurate diagnosis, especially in pediatric cases where the disease is rare and may present atypically,” the team wrote.

The researchers reviewed cases of pediatric IgG4-RD to better understand common features and identify diagnostic challenges. Their analysis involved 103 cases of children and adolescents with confirmed IgG4-RD diagnoses and two cases from their clinic with possible diagnoses.

The children presented with symptoms at an average age of 11 (range 1-18). Most (68%) had a localized form of the disease involving one organ or body part, with the rest showing involvement of multiple systems.

In 40% of cases, the disease affected the bony areas around the eye, called the orbits, and this was the only affected area in 28%. Other commonly affected organs were the pancreas, liver, kidneys, and lungs.

Constitutional symptoms, or generalized disease symptoms, like fever, fatigue, and unexplained weight loss, were seen in about half of the participants (52%). “In adults, constitutional symptoms are rare,” the researchers wrote.

Most pediatric cases (80%) had elevated IgG4 levels, and 52% had high levels of inflammatory markers. As the researchers only included cases with histopathological findings, or those obtained from microscopic evaluation of tissue samples, consistent with IgG4-RD, all children in the literature review part of the study met this diagnostic criterion.

To illustrate the complexity of diagnosing IgG4-RD in children, the team provided detailed reports of two probable pediatric IgG4-RD cases at their clinical center that challenged diagnostic criteria.

“The description of these two cases, despite the lack of definitive histopathological confirmation, illustrates the real-world difficulties in clinical practice,” the researchers wrote.

In one case, a 12-year-old girl experienced fluctuating swelling and redness in one of her eyelids for about six months. Blood testing revealed elevated blood IgG4 levels. Imaging scans showed that the sinuses and other tissues near the eye were also involved.

Antibiotics failed to resolve her symptoms, suggesting a bacterial infection wasn’t the cause.

To obtain more information and address her sinus symptoms, clinicians performed a minimally invasive procedure to collect samples from the orbital bone and the sinus lining. Histological examination of these samples was inconclusive, but based on her overall presentation, the team suspected IgG4-RD over other possible diagnoses. Glucocorticoids, the first-line IgG4-RD treatment, successfully resolved her symptoms.

The other case involved a 14-year-old boy who had had an inflamed tear-producing gland for three years. Although glucocorticoids and antibiotics initially helped, symptoms kept recurring. An MRI scan showed abnormalities, including enlargement of the tear gland.

Although most of the boy’s blood work was normal, he had elevated IgG4 levels. The family didn’t consent to a biopsy of the affected tear gland, but the clinicians suspected IgG4-RD.

“These cases illustrate the complexity of diagnosing IgG4-related disease in children and highlight the need for a thorough, multidisciplinary approach when histological confirmation is not feasible,” the researchers wrote. “These challenges underline the need for further studies to better shape diagnostic criteria in this population.”