Repeated Childhood Illness? Think Genetics and Autoinflammatory Diseases - Dr Pallavi Pimpale

When a child falls ill repeatedly, parents often assume the cause is frequent infections. However, when symptoms persist or occur frequently, especially from early childhood and without any clear cause, it may indicate something far more complex. Such patterns can sometimes point to a group of conditions called inborn errors of immunity, including a major subgroup known as autoinflammatory diseases, in which the immune system becomes overactive, leading to unexplained inflammation and recurring symptoms. These “mystery illnesses” can be baffling for families, but timely diagnosis and treatment can change a child’s life.

The following are two cases of autoinflammatory diseases treated at Narayana Health SRCC Children’s Hospital, Mumbai. They highlight how early intervention and treatment can improve outcomes.

Case 1: Three Strokes Before Age Three

A three-year-old boy had his first stroke at just 10 months of age. Over the next two years, he suffered two more strokes, despite extensive testing showing normal clotting and no evidence of infection. Mild anemia was the only persistent finding. He was initially managed by a pediatric neurologist. The rarity of recurrent strokes in such a young child prompted referral to a pediatric rheumatologist.

Given the very early onset of symptoms and that both parents belonged to the same community (an endogamous marriage—which can increase the risk of inherited genetic conditions when there is distant shared ancestry), genetic testing was advised. The results revealed a mutation in the ADA2 gene, confirming Deficiency of Adenosine Deaminase 2 (DADA2), a hereditary autoinflammatory disease. He was started on a TNF blocker to control inflammation. Since then, he has had no further strokes and has steadily regained strength and function with ongoing treatment and physiotherapy.

Case 2: Recurrent Fevers Since Infancy

A five-year-old girl, born to parents who are second cousins, had experienced recurrent fevers since she was just one month old. These episodes occurred every 35 to 50 days, lasted four to seven days, and were accompanied by rashes, loose stools, and irritability—sometimes severe enough to require hospitalization for dehydration.

Despite multiple evaluations, all infection-related tests and cultures were negative. Her inflammatory markers were consistently elevated during episodes and normal in between. With no clear diagnosis, she was referred to a pediatric rheumatologist. Considering the periodic fevers, very early onset, and parental consanguinity, genetic testing was recommended.

This confirmed Mevalonate Kinase Deficiency, a rare autoinflammatory disorder. She was started on colchicine and disease-modifying medications, which have helped control her symptoms, although the ideal treatment—anti–IL-1 therapy—is not yet readily available in India.

Understanding Autoinflammatory Diseases: Key Features

Autoinflammatory diseases are caused by specific genetic defects that make the immune system behave like a malfunctioning alarm, triggering repeated inflammation even without infection. Children commonly present with irritability, recurrent fevers, skin rashes, abdominal pain, loose stools, oral ulcers, joint pain or swelling, and persistently elevated inflammatory markers despite normal cultures. Symptoms often begin very early in life and may follow predictable cycles. To date, more than sixty autoinflammatory diseases have been identified worldwide.

Why This Matters for Indian Families

India carries a higher risk of developing potential hereditary conditions because of the prevalence of community-based marriages and consanguinity in many regions. Many of these families, unknowingly, may carry genetic traits that are associated with autoinflammatory diseases. In 2017, The New York Times described South Asian communities as a “living lab for genetic disease,” heavily undermining the importance of awareness and early diagnosis.

When children do experience frequent and unexplained symptoms, it becomes increasingly important to look beyond the scope of common infections. Though autoinflammatory diseases are not common, they have been increasingly identified and detected in India. With timely diagnosis and appropriate treatment, many children can achieve disease control, avoid unnecessary investigations, and prevent complications. Advances in genetic testing and targeted therapies are now offering families clarity and renewed hope.

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