Rare Immune Gene Defect Unmasked by Incomplete Kawasaki Disease in a Young Child

A single case report from Malaysia is drawing attention to an unexpected intersection between two rare conditions of childhood: Kawasaki disease, an inflammatory illness of the blood vessels, and a genetic defect known as AICDA deficiency, or hyper-IgM syndrome type 2. Writing in BMC Pediatrics, a team of paediatric immunologists led by Khairoon Nisa Mohamed Nashrudin of Universiti Putra Malaysia describes a six-year-old girl whose first brush with serious illness, at just 18 months of age, took the form of incomplete Kawasaki disease. Only years later, after a trail of recurrent infections and swollen lymph nodes, did genetic testing reveal the underlying inborn error of immunity that had been hiding behind her earlier diagnosis. The case is the first to describe Kawasaki disease as the presenting feature of AICDA deficiency, and it offers clinicians a fresh lesson in how rare immune defects can masquerade as more familiar paediatric conditions.

Kawasaki disease is an acute, febrile vasculitis that primarily affects children under the age of five and ranks among the most common causes of acquired heart disease in children worldwide. Its classical presentation includes prolonged fever together with a constellation of mucocutaneous findings: bilateral conjunctival injection, changes of the lips and oral cavity, a polymorphous rash, swelling of the hands and feet, and cervical lymphadenopathy. Yet a substantial proportion of children never display the full set of features. These patients are classified as having incomplete Kawasaki disease, a diagnostic challenge because the stakes are high. Without timely treatment with intravenous immunoglobulin and aspirin, the coronary arteries can become inflamed and dilate, laying the groundwork for aneurysms and long-term cardiovascular complications. Laboratory markers such as elevated inflammatory indices, leukocytosis, thrombocytosis, anaemia and hypoalbuminaemia, together with echocardiographic findings, often tip the balance toward treatment in ambiguous cases.

That is precisely the path taken with the young patient at the centre of this report. At 18 months of age she presented with persistent fever and enlarged cervical lymph nodes, but without the other classical mucocutaneous features that would have made the diagnosis straightforward. Her laboratory results were striking: markedly elevated inflammatory markers, leukocytosis, thrombocytosis, anaemia and low albumin levels. Echocardiography added a decisive piece of evidence, revealing dilatation of the left anterior descending coronary artery and a mild pericardial effusion. Taken together, these findings satisfied the criteria for incomplete Kawasaki disease, and she was treated with intravenous immunoglobulin and aspirin. Her response was favourable, and follow-up imaging showed that the coronary artery abnormalities normalised, an outcome that underscores how effective standard therapy can be even when the underlying biology of the illness remains obscure.

The story might have ended there, a single episode of vasculitis successfully treated. Instead, the following two years brought a pattern that could no longer be dismissed as bad luck. The girl developed recurrent respiratory infections, suffered an episode of Salmonella gastroenteritis, and the lymphadenopathy in her neck refused to resolve. Persistent lymph node enlargement is a recognised hallmark of AICDA deficiency, in which the immune system’s failure to mature antibodies properly leads to prominent lymphoid hyperplasia. But at the time, the treating team faced a child whose infection history was worrying rather than diagnostic. It was this accumulation of recurrent bacterial infections, stubborn lymphadenopathy and unexplained susceptibility to organisms such as Salmonella that prompted a formal immunological work-up, the kind of evaluation the authors argue should be triggered earlier when such a triad appears.

The results of that work-up painted a coherent picture of a class-switch recombination defect. Immunological testing demonstrated elevated IgM alongside low levels of IgG and IgA, the signature immunoglobulin profile of hyper-IgM syndromes. Her ability to mount antigen-specific antibody responses after vaccination was impaired, and flow cytometry revealed an absence of switched memory B cells, the population of lymphocytes that has undergone the genetic rearrangement needed to produce IgG, IgA and IgE antibodies. Genetic testing then identified compound heterozygous pathogenic variants in the AICDA gene, confirming autosomal recessive AICDA deficiency, historically termed hyper-IgM syndrome type 2. With the diagnosis in hand, her management shifted to immunoglobulin replacement therapy and antimicrobial prophylaxis, to which she responded well, providing her immune system with the protective antibodies it cannot manufacture on its own.

To appreciate why this diagnosis matters, it helps to understand the molecular machinery involved. Activation-induced cytidine deaminase, the enzyme encoded by AICDA, is expressed in activated B cells within germinal centres of lymphoid tissue. Its job is to initiate both class-switch recombination, the process by which a B cell changes the constant region of its antibody from IgM to IgG, IgA or IgE, and somatic hypermutation, which fine-tunes antibody affinity for its target. When biallelic pathogenic variants disable the enzyme, B cells remain stuck producing IgM, the antibody class that dominates early immune responses but lacks the tissue penetration, complement activation profile and memory characteristics of the switched classes. The consequences are recurrent infections with encapsulated and enteric bacteria, poor vaccine responses, and, as in this patient, enlarged lymph nodes driven by hyperplastic germinal centres that churn out unswitched B cells in a futile attempt to respond.

What makes the case scientifically provocative is the temporal relationship between the Kawasaki disease episode and the later recognition of the immune defect. The authors are careful to state that a causal relationship cannot be established from a single case. Kawasaki disease itself is thought to arise in genetically susceptible children following exposure to environmental triggers, possibly infectious, that set off a hyperinflammatory cascade affecting medium-sized arteries. AICDA deficiency, for its part, is increasingly recognised to involve immune dysregulation beyond simple antibody failure. The possibility raised by this report is that the immune dysregulation associated with AICDA deficiency may contribute to susceptibility to hyperinflammatory vasculitis of the Kawasaki type. If that hypothesis holds up in larger cohorts, it would suggest that some children diagnosed with Kawasaki disease, particularly those with atypical or recurrent features, may carry an underlying inborn error of immunity that shapes their inflammatory response.

The practical message for clinicians is embedded in the case’s chronology. The combination of recurrent bacterial infections, persistent lymphadenopathy and a hyper-IgM immunoglobulin profile should raise suspicion of AICDA deficiency and prompt timely immunological evaluation, including assessment of switched memory B cells and, where indicated, genetic testing. Early diagnosis changes the trajectory of the disease. Immunoglobulin replacement replenishes missing antibody classes, prophylactic antimicrobials reduce the burden of breakthrough infections, and families receive genetic counselling appropriate to an autosomal recessive condition. Conversely, a delayed diagnosis leaves children exposed to repeated infections, unnecessary courses of empiric treatment and the risk of chronic organ damage. The authors also note that the diagnostic criteria for incomplete Kawasaki disease, which lean heavily on laboratory markers and echocardiography, functioned well in this patient, but they could not by themselves reveal the deeper immunological story unfolding beneath the vasculitis.

For the research community, the case adds a new entry to the growing catalogue of immune dysregulation phenomena associated with inborn errors of immunity. Over the past two decades, the boundaries between classical immunodeficiency and autoinflammatory or autoimmune disease have blurred considerably, as genes once thought to govern only one aspect of immunity turn out to have pleiotropic effects. AICDA deficiency presenting with a Kawasaki-like vasculitis fits this pattern, hinting that defective antibody maturation may alter the way the innate immune system responds to common triggers, tilting the balance toward excessive inflammation in the vessel wall. Testing that idea will require systematic collection of vasculitis cases in patients with class-switch defects, and of immune evaluations in children with severe or atypical Kawasaki disease, work that single case reports like this one help to catalyse.

In the meantime, the girl at the centre of the report is doing well on replacement therapy and prophylaxis, her coronary arteries having recovered fully from the episode that first brought her to medical attention. Her case stands as a reminder that a diagnosis, however confident, is sometimes only the first layer of the truth. A fever and swollen lymph nodes in a toddler can signal a familiar vasculitis, a hidden genetic defect, or both in sequence. Paediatricians who hold both possibilities in mind, and who pursue immunological evaluation when infections recur and lymph nodes persist, stand the best chance of finding the deeper answer before the complications find the patient.

Subject of Research: AICDA deficiency presenting as incomplete Kawasaki disease in a paediatric patient

Article Title: Incomplete Kawasaki disease preceding the diagnosis of AICDA deficiency (hyper-IgM syndrome type 2)

Article References: Nashrudin, K. N. M., Bukhari, N. H., Jamaluddin, J., Latiff, A. H. A., Sham, M. M., Siniah, S., Abidin, M. A. Z., & Ismail, I. H. (2026). Incomplete Kawasaki disease preceding the diagnosis of AICDA deficiency (hyper-IgM syndrome type 2). BMC Pediatrics. https://doi.org/10.1186/s12887-026-07847-7

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07847-7

Keywords: AICDA deficiency, hyper-IgM syndrome type 2, Kawasaki disease, inborn error of immunity, class-switch recombination, lymphadenopathy, paediatric immunology, coronary artery dilatation, immunoglobulin replacement, switched memory B cells, vasculitis, case report