Variantă cu pierdere a funcției genei IFIH1 la un copil cu sindrom inflamator recurent și BTAI – prezentare de caz

Introduction

This case report presents a 5-year-and-11-month-old male patient with a complex clinical phenotype of recurrent in­flammatory episodes, hyper-IgE, and suspected autoimmune thyroid disease (AITD). Genetic testing identified a he­te­ro­zygous nonsense mutation [(c.688C>T, p.(Gln230*)] in the IFIH1 gene, a variant reclassified from a variant of un­cer­tain significance (VUS) to likely pathogenic (LP). This case is unique as it provides an example of the potential over­lap between recurrent inflammatory syndrome, autoim­mune thyroid disease, and genetic predisposition mediated by an IFIH1 loss-of-function (LOF) variant. Given the role of IFIH1 in viral immunity, inflammatory regulation and autoimmune disease susceptibility, this case shows the complex interaction between innate and adaptive immunity^(1,2).

Case presentation

Patient’s information

The patient is a 5-year-and-11-month-old male presenting for suspected autoimmune thyroid disease at the endocrinology office. At the time, he exhibited hypertriglyceridemia, vitamin D deficiency and hyper-IgE (635 IU/mL). He had a significant personal history of recurrent inflammatory episodes and infections, leading to an investigation for possible genetic causes of autoinflammatory syndrome.

Medical and family history

Family history was notable for autoimmune thyroid disease (AITD) in close relatives. The child was born from a twin pregnancy with pathological evolution, born by caesarean section at 32 weeks, weighing 1650 grams, and he required neonatal interventions, including antibiotic therapy and tent oxygen. He had a history of frequent respiratory infections, including bronchitis associated with respiratory syncytial virus (RSV), multisystem inflammatory syndrome (MIS-C) post-COVID-19 with kidney and heart involvement, and recurrent pyelonephritis with E. coli. The patient also experienced prolonged febrile syndromes following infections.

Clinical presentation

The physical examination revealed a height of 114 cm (-0.6 SD) and weight of 24 kg (the 95^th percentile). He was afebrile at the time of evaluation, with normal hydration, and displayed discreetly pale skin, with no edema or rashes. No hepatosplenomegaly or palpable kidney enlargement was detected. The laboratory tests showed no inflammatory, nitrogen retention, or hepatic cytolysis syndromes, with normal levels of glucose, protein, albumin and calcium. Hypovitaminosis D and elevated IgE (635 IU/mL) were noted. Urinalysis and urine culture were unremarkable. For the moment, the investigations ruled out autoimmune, oncologic and infectious conditions, including tuberculosis (QuantiFERON negative) and Bartonella henselae and Toxocara canis serologies, both negative.

Genetic evaluation and testing results

The patient’s history of recurrent severe infections and prolonged febrile syndromes raised concerns about a potential innate immune deficiency or systemic inflammatory dysfunction. This suspicion was further supported by the repeated involvement of immune response mechanisms to viral (RSV, COVID-19) and bacterial (E. coli) infections, suggesting a possible genetic dysregulation of immunological pathways. As a result, the patient was referred for genetic evaluation and testing to explore the possibility of an autoinflammatory syndrome.

The genetic analysis identified a heterozygous variant [c.688C>T, p.(Gln230*)] in the IFIH1 gene, previously reported as a variant of uncertain significance (VUS) in the 2023 genetic report. A reevaluation based on ACMG-AMP guidelines⁽³⁾ and data from platforms such as Varsome and Franklin suggests reclassification of this variant as likely pathogenic (LP)^(4,5). The variant is a point mutation resulting in a glutamine-to-stop codon substitution (nonsense mutation), predicted to result in nonsense-mediated decay (NMD), and is absent in control populations. Given the gene’s role in inflammatory regulation, this variant may contribute to the patient’s recurrent inflammatory episodes; however, its classification and clinical relevance are limited by the lack of extensive clinical and functional data to confirm its pathogenicity (Table 1).

Table 1 summarizes the analysis of relevant ACMG criteria and their justification. Based on strong evidence (PVS1) and additional support (PM2), the variant was reclassified as likely pathogenic. However, the lack of extensive clinical and functional data requires cautious interpretation^(3-5).

Diagnostic assessment

The laboratory investigations revealed no significant abnormalities in the blood count, inflammatory markers, nitrogen retention markers, or indicators of hepatocellular damage. Glucose, total protein, albumin and calcium levels were all within normal ranges, ruling out significant metabolic disturbances. However, notable findings included hypovitaminosis D and elevated serum IgE levels (635 IU/mL), consistent with a hyper-IgE state.

The urinalysis was unremarkable, with no evidence of infection or abnormalities. Urine cultures were sterile, excluding urinary tract infections. These findings suggested no active systemic inflammatory or infectious process at the time of evaluation.

Extensive investigations were performed to exclude potential autoimmune, oncological or infectious causes of the patient’s recurrent febrile syndromes. Oncological causes were excluded based on non-suggestive blood smear results and normal lung imaging conducted during previous hospitalizations, which showed no evidence of tumor masses. Furthermore, infectious conditions, including Mycobacterium tuberculosis, were ruled out, with two negative QuantiFERON tests. Serology for Bartonella henselae was negative, and infection with Toxocara canis was also excluded.

Genetic testing provided critical insights, identifying a heterozygous c.688C>T, p.(Gln230*) variant in the IFIH1 gene. This nonsense mutation, initially classified as a variant of uncertain significance (VUS) in 2023, has been reclassified as likely pathogenic (LP), as it is predicted to result in a truncated protein product. The IFIH1 gene plays a critical role in inflammatory regulation, and this variant may contribute to the patient’s clinical presentation of recurrent inflammatory episodes.

Endocrinological evaluation revealed a longilineal skeleton and Tanner stage G1P1, with a penile length of approximately 6 cm, within normal limits for age. A medium-sized, homogeneous goiter was observed, clinically euthyroid, with no evidence of laterocervical adenopathy. Thyroid function tests were within normal limits, including TSH, free T4 and free T3 levels. However, the presence of thyroid peroxidase antibodies (anti-TPO) and thyroglobulin antibodies (anti-Tg) confirmed an underlying autoimmune thyroid disease (ATID), consistent with the family history of ATID. These findings highlight the need for ongoing endocrinological monitoring to assess potential progression to clinical hypothyroidism or other thyroid dysfunctions.

Therapeutic intervention, follow-up and outcomes

The therapeutic plan for this patient focuses on addressing recurrent inflammation, hyper-IgE and autoimmune thyroid disease (AITD) through a multidisciplinary approach. Preventive measures include ensuring updated immunizations, such as influenza and pneumococcal vaccines, and considering RSV prophylaxis due to the history of severe respiratory infections. Symptomatic management involves anti-inflammatory medications for febrile episodes and supportive care for viral infections. 

Regular endocrinological evaluations are recommen­ded for monitoring thyroid function and antibody levels, aiming to detect early thyroid dysfunction. For the moment, there is no need for pharmacologic intervention as the patient remains clinically euthyroid. Vitamin D supplementation was initiated to correct the deficiency. 

Genetic counseling was also provided to discuss the implications of the identified IFIH1 mutation for the patient and family. Additional genetic testing, including parental analysis, was advised to clarify inheritance patterns and the significance of the IFIH1 mutation. Functional studies were also suggested to confirm the pathogenicity of the variant. Future management may include targeted therapies, such as immunomodulatory treatments, to address the underlying immune dysregulation based on emerging clinical and genetic evidence.

Hyper-IgE levels will be monitored over time, and a referral for allergology reassessment was recommended to evaluate potential atopic or immune-related causes. Monitoring infections, autoimmune markers and inflammation through multidisciplinary follow-up is crucial for conducting proper management and enhancing long-term results.

Discussion

The IFIH1 gene, located on chromosome 2q24.3, encodes the melanoma differentiation-associated protein 5 (MDA5), a cytosolic RNA sensor that plays a critical role in antiviral immunity. MDA5 recognizes viral double-stranded RNA (dsRNA) and triggers the production of type I interferons (IFN-I), leading to apoptosis of virally infected cells and the activation of both innate and adaptive immune responses. Mutations in IFIH1 can lead to either gain-of-function (GOF) or loss-of-function (LOF) effects, contributing to a spectrum of immune-related diseases^(1,6).

GOF mutations in IFIH1 are associated with autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS7) and Singleton-Merten syndrome (SMS), where overactive MDA5 leads to excessive IFN-I production and chronic inflammation. In contrast, LOF mutations impair MDA5 function, resulting in reduced antiviral responses and susceptibility to viral infections, particularly severe respiratory tract infections and infections such as those with SARS-CoV-2. These mutations have also been linked to autoimmune diseases, including type 1 diabetes (T1D), multiple sclerosis (MS) and autoimmune thyroid diseases (AITDs), although their effects are heterogeneous and influenced by environmental and genetic factors^(2,6-8).

In this case, the nonsense mutation (c.688C>T) in IFIH1 introduces a premature STOP codon, likely resulting in nonsense-mediated decay (NMD) and impaired protein function. This LOF variant could contribute to the patient’s history of recurrent respiratory infections, such as RSV-associated bronchitis and pyelonephritis, by disrupting MDA5’s ability to clear viral infections effectively⁽²⁾.

The child’s history of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection is consistent with the established role of IFIH1 LOF variants in increasing susceptibility to severe viral infections and dysregulated immune responses. LOF mutations in IFIH1 impair type I interferon (IFN-I) signaling, a critical pathway in antiviral defense, and this dysfunction is central to the pathogenesis of conditions like MIS-C. Recent findings demonstrate that patients with LOF variants in IFIH1 are more susceptible to infections such as those with SARS-CoV-2, with clinical phenotypes varying significantly among individuals, possibly due to environmental and genetic factors^(8,9).

Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), along with type 1 diabetes (T1D) are among the most common autoimmune disorders in children. These conditions arise from the loss of immune tolerance to tissue-specific antigens, leading to immune-mediated destruction of the thyroid gland in AITDs and pancreatic beta cells in T1D. Viral infections are known as environmental triggers for autoimmune diseases, including T1D and AITDs. LOF mutations in IFIH1 can create a proinflammatory environment by failing to clear viral infections, potentially compromising the immune tolerance and promoting autoreactive T-cell activation^(10,11).

In this case, the child’s history of recurrent infections and elevated thyroid antibodies (anti-TPO and anti-Tg) is consistent with immune dysregulation linking viral triggers to autoimmune thyroid disease. The presence of a family history of AITD further supports the role of genetic predisposition in this clinical presentation^(9-11).

The connection between viral infections and AITDs further supports the involvement of IFIH1. Chronic or unresolved viral infections, coupled with genetic susceptibility, may create a proinflammatory environment that breaks the immune tolerance and promotes autoantibody production^(10,12). However, evidence for IFIH1’s role in AITDs remains inconsistent. Some studies report significant associations between IFIH1 polymorphisms and Graves’ disease, while others fail to establish a link, suggesting that these effects may vary across populations or be less pronounced compared to T1D^(1,10,13).

Variants in IFIH1, such as the rs1990760 single nucleotide polymorphism (SNP), a nonsynonymous change resulting in an alanine-to-threonine substitution, have been associated with autoimmune diseases, including Graves’ disease (GD) and type 1 diabetes (T1D)^(1,10). While the role of IFIH1 in AITDs remains less consistent, with some studies linking specific polymorphisms to GD and others reporting no significant association, its function in regulating innate immunity and type I interferon responses suggests that it may contribute to disease susceptibility, especially in the context of unresolved viral infections^(1,13,14). This demonstrates IFIH1’s dual function as a modulator of immune tolerance and a viral sensor, connecting its genetic variation to the broader spectrum of immune dysregulation in AITDs^(1,12). The significant genotypic and phenotypic heterogeneity of IFIH1-related disorders is highlighted by the interaction of autoinflammation, autoimmunity and infection susceptibility⁽⁸⁾.

The relationship between the innate and adaptive immune systems is characterized by a complex interplay where dysfunction in one often impacts the other, particularly evident in conditions like IFIH1 LOF. The innate immune system, acting as the first line of defense, utilizes pattern recognition receptors to initiate rapid responses, while the adaptive immune system provides specificity and memory through B and T cells⁽¹⁵⁾. IFIH1, encoding MDA5, is crucial for early viral detection; its LOF leads to immunodeficiency and increased susceptibility to infections, including severe COVID-19 and inflammatory diseases. This dysregulation highlights how innate immune deficiencies can compromise adaptive responses, as seen in patients with recurrent infections and elevated inflammatory markers⁽⁸⁾. Deficiencies or imbalances in initial innate immune responses can significantly contribute to the dysregulation that underlies autoimmune diseases⁽¹⁶⁾.

The 5-year-and-11-month-old boy with a loss-of-function (LOF) mutation in the IFIH1 gene had a distinct immunological profile characterized by recurrent infections and immune dysregulation, rather than the classic features of gain-of-function (GOF) mutations in IFIH1 (seen in SMS or AGS). GOF mutations typically result in hyperactive MDA5 function and excessive production of type I interferon, leading to autoinflammatory phenotypes such as vasculopathy and neurological complications. In contrast, this patient’s LOF mutation likely impaired MDA5-mediated antiviral responses and contributed to recurrent viral infections such as RSV-associated bronchitis and MIS-C post-COVID-19, as well as the observed immune dysregulation. The presence of elevated IgE levels and thyroid autoantibodies also suggested a complex interplay between innate immune deficiency and adaptive immune activation, supporting the hypothesis that LOF mutations in IFIH1 predispose to a spectrum of immune disorders, including susceptibility to autoimmune thyroid diseases.

Conclusions

This case highlights the importance of considering genetic contributions such as IFIH1 mutations in patients with recurrent infections, immune deficiencies and suspected autoimmune diseases. The identified loss-of-function mutation in IFIH1 highlights how impaired antiviral immunity can lead to recurrent inflammatory episodes and create a proinflammatory state that disrupts immune tolerance and potentially leads to autoimmune thyroid disease. The gene’s role in autoimmune thyroid disease remains unclear, highlighting the need for further research to clarify its contribution to immune dysregulation and to develop targeted therapies. It demonstrates the need for a multidisciplinary approach to diagnosis and management that integrates genetic, immunological and endocrinological investigations to effectively adapt care.

Autor corespondent: Diana-Monica Preda E-mail: diana_monica_preda@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.