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Autoinflammatory diseases, characterized by recurrent systemic inflammation due to innate immune dysregulation, often present with fever, arthritis, abdominal pain, and cutaneous involvement, with elevated acute-phase reactants during flare-ups. These rare conditions, arising from monogenic mutations or environmental triggers, can be challenging to diagnose, yet accurate identification is critical for effective targeted therapy. In 2022, Kanderova et al. reported a heterozygous c.1545C>A (p.Tyr515Ter) HCK gene mutation causing early-onset cutaneous pulmonary vasculitis due to increased kinase activity from a truncated HCK protein, leading to chronic inflammation and fatal progression despite partial suppression with ruxolitinib. HCK, a SRC family tyrosine kinase predominantly expressed in granulocytic and monocytic cells, regulates immune functions like phagocytosis and cytokine production. We report a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and persistent symptoms despite multiple antibiotic treatments for suspected recurrent lower respiratory tract infections since age 1.5 years, treated for presumed recurrent lower respiratory tract infections with multiple antibiotic courses, though symptoms persisted. No cutaneous manifestations were observed during the current admission, but elevated acute-phase reactants and pulmonary findings were noted. Based on clinical and laboratory features, a rare autoinflammatory condition was suspected. No pathogenic variants were identified in an autoinflammatory disease gene panel. Whole-exome sequencing (WES) using next-generation sequencing (NGS) revealed a novel splice site mutation (c.1016-5T>C) in the HCK gene, absent from existing genomic databases. Anti-IL1B targeted therapy achieved complete clinical and laboratory remission. This study identifies a novel HCK gene mutation as the cause of a hereditary autoinflammatory disease with early-onset pulmonary and cutaneous manifestations, consistent with classical autoinflammatory syndromes.
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Introduction
In recent years, the recognition of systemic inflammatory diseases that arise independently of infection or autoimmunity has brought “autoinflammatory diseases” (AIDs) to the forefront as a distinct category within immunopathology [1]. These diseases generally result from dysregulation of the innate immune system and are particularly characterized by the inappropriate activation of inflammatory cytokines [2]. Initially described in childhood, these syndromes have also been reported in adults, often presenting with similar clinical features; even in late-onset cases [3, 4]).
Autoinflammatory diseases are associated with inherited or acquired mutations in proteins involved in key immune system signaling pathways, including the inflammasome, NF-κB, and type I interferons [5]. These mutations lead to uncontrolled inflammatory responses, particularly in myeloid cells such as macrophages and neutrophils [5]. Clinically, they are typically characterized by recurrent fever, serositis, mucocutaneous ulcerations, arthralgia, and myalgia. In some cases, features of autoimmunity, allergy immunodeficiency, or lymphoproliferation may also be present [6, 7].
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These diseases classified as monogenic or polygenic are diagnosed through a combination of clinical suspicion, detailed family history, elevated inflammatory markers during disease flares, and genetic testing [1]. However, the diagnostic process may be delayed, or the disease may present with atypical features [8, 9]. Therefore, in patients with atypical inflammatory presentations, autoinflammatory etiologies should be considered. In undiagnosed cases, descriptive terms such as SURF (syndrome of undifferentiated recurrent fever) or USAID (unclassified systemic autoinflammatory disease) may be used [9].
Recent studies have suggested that gain-of-function mutations in the hematopoietic cell kinase (HCK) gene may be implicated in autoinflammatory diseases. In a case reported by [10] a mutation in the HCK gene (c.1545C > A; p.Tyr515*) was identified in association with early-onset cutaneous and pulmonary vasculitis. This mutation results in the loss of the C-terminal inhibitory tyrosine region of the HCK protein, leading to increased kinase activity. The resulting condition is characterized by chronic inflammation of the cutaneous and pulmonary tissues. The patient, monitored since shortly after birth, presented with petechial rashes, recurrent alveolar hemorrhage, interstitial lung disease, hepatosplenomegaly, anemia, and other systemic inflammatory symptoms.
The functional studies performed suggest that the HCK mutation enhances myeloid cell activation, promoting excessive cytokine production, increased cell migration, and tissue infiltration. This case represents a newly described monogenic autoinflammatory disease and highlights that HCK mutations can be included within the autoinflammatory disease spectrum.
Autoinflammation with pulmonary and cutaneous vasculitis (APCV) is a rare autosomal dominant condition caused by a heterozygous mutation in the HCK gene. Given its role in immune regulation and disease, HCK has become a focal point in research on autoinflammatory and autoimmune disorders. To date, only one case report has described an autoinflammatory disease associated with HCK mutations. [10] reported a novel disorder resulting from a de novo p.Tyr515* mutation, presenting with cutaneous vasculitis and pulmonary fibrosis.
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The findings of our study contribute to the genetic and clinical literature by illustrating how mutations in the HCK gene may broaden the clinical spectrum of autoinflammatory diseases.
Case presentation
A 6-year-old girl had experienced recurrent febrile episodes approximately every two weeks since the age of 1.5 years, accompanied by cutaneous petechial rashes, chronic cough, and exertional dyspnoea. Based on these symptoms, she was treated for presumed recurrent lower respiratory tract infections with multiple courses of antibiotic therapy at various healthcare facilities, though symptoms persisted (Table 1).
At the age of 4 years, she was admitted to our clinic with high-grade fever, wheezing, and worsening exertional dyspnoea. On examination, her body temperature was 39 °C, and auscultation revealed widespread crepitations and wheezing over the bilateral middle and lower pulmonary zones. The abdominal examination revealed hepatomegaly, palpable 1 cm below the right costal margin. Laboratory tests showed leukocytosis (21,000/μL), hypochromic microcytic anaemia, elevated acute-phase reactants (C-reactive protein (CRP) 95 mg/dL; serum amyloid A (SAA) 984 mg/L), and hypergammaglobulinaemia (Table 1). Abdominal ultrasonography confirmed mild hepatomegaly and splenomegaly.
Although her cutaneous examination was unremarkable at the time of presentation, the parents reported that during previous febrile episodes she frequently developed cutaneous petechial and occasionally maculopapular rashes over the face and lower limbs.
Table. 1
Timeline of the key clinical events.
Her perinatal history was unremarkable. She was born at 40 weeks of gestation via caesarean section with a birth weight of 3500 gram. Developmental milestones were age-appropriate, immunisations were complete according to the national schedule, and she had undergone adenoidectomy at age 4 years. There was no family history of rheumatological or autoinflammatory disorders.
The initial working diagnosis was bronchopneumonia, and empiric antibiotic therapy was commenced. However, on follow-up, she continued to have persistent cough, bilateral crackles on auscultation, and abnormal radiographic findings. Chest radiography demonstrated atelectasis and pericardiac infiltration in the right lung. Contrast-enhanced thoracic CT revealed atelectatic consolidation with volume loss in the medial segment of the right middle and in the posterobasal and superior segments of the right lower lobe. Additional findings included diffuse mosaic attenuation and air trapping in the right lung and the posterobasal segment of the left lower lobe, as well as mild thickening of the right pulmonary bronchial walls (Fig. 1). These findings were considered consistent with sequelae of prior infections and small airway disease.
Fig. 1
Chest CT scan showing atelectatic consolidation and air trapping predominantly in the right lung with key findings highlighted by arrows
Genetic testing for common autoinflammatory syndromes (including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), hyper-IgD syndrome (HIDS), and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) did not detect any pathogenic mutations. Following paediatric pulmonology consultation, flexible bronchoscopy was performed. Bronchoalveolar lavage (BAL) culture yielded Haemophilus influenzae non-type B (1 × 106 CFU/mL). BAL cytology showed 35% macrophages, 60% neutrophils, 4% lymphocytes, and 1% eosinophils.
Whole-exome sequencing (WES) was subsequently undertaken using DNA extracted from peripheral blood. Library preparation was performed with MGIEasy FS DNA Library Prep Kit, exome capture with MGIEasy Exome Capture V4 and Twist WES Probes, and sequencing on the MGI DNBSEQ-G400 platform (MGI Tech Co., Ltd.). Analysis identified a previously unreported heterozygous splice-site mutation in intron 9 (position −5) of the HCK gene (NM_002110.5), designated c.1016-5T > C (Fig. 2), which was confirmed by Sanger sequencing (Fig. 3). No record of this variant was found in major genomic databases, and it was classified as novel. According to ACMG guidelines and in silico analysis, it was initially interpreted as of uncertain significance. However, similarities in clinical phenotype—particularly pulmonary involvement and cutaneous lesions—between our patient and those reported by Kanderova et al. suggested a possible pathogenic role through dysregulated immune activation and chronic inflammation. Given the autosomal dominant inheritance pattern, a single mutated allele could plausibly explain the phenotype.
Fig. 2
Schematic representation of the HCK gene structure and protein domains showing the c.1016-5T > C variant location. a) Region surrounding the variant, showing intron 9–10 and exon 10 (ENSE00003662889). The c.1016-5T > C variant is located at the −5 position of intron 9, near the splice acceptor site of exon 10. B) Domain structure of the HCK protein, highlighting the tyrosine kinase catalytic (TYRKC, aa 262–525) domain. The variant may disrupt splicing at the exon 9–10 boundary, directly affecting the 339th amino acid (glycine, gga) within the TYRKC domain. C) Enlarged view of the exon 9–10 splice region showing the tccag → cccag substitution; this change may impair canonical splicing, potentially compromising the structural and functional integrity of the TYRKC domain
Genetic analysis by next-generation sequencing (NGS) was performed on the patient. Visualization of NGS data using integrative genomics viewer (IGV) software (alignment of enriched swquences to the human reference genome Hg19/GRCh37) revealed a novel heterozygous splice-site variant in the HCK (GenBank accession no. NM_002110.5), c.1016-5T > C. The variant was confirmed by Sanger sequencing
A diagnosis of HCK-associated autoinflammatory disease with pulmonary involvement was made, and treatment with the IL-1 receptor antagonist anakinra 2 mg/kg/day was initiated. Within weeks, acute-phase reactants normalised, and fever and rash resolved. However, by the end of the first month, she developed local erythema and pruritus at injection sites, attributed to anakinra. Treatment was switched to the IL-1β monoclonal antibody canakinumab 2 mg/kg/dose, administered every four weeks. Clinical symptoms resolved completely, and inflammatory markers normalised. Given the favourable response, the patient showed sustained clinical remission with IL-1β – targeted therapy.
Discussion
In this study, we describe a case exhibiting typical autoinflammatory features, including early-onset recurrent febrile episodes since age 1.5 years, cutaneous petechial rashes, chronic cough, and exertional dyspnoea.
The novel c.1016-5T > C splice site mutation in the HCK gene, identified for the first time by our team, is associated with an autosomal dominant inheritance pattern and a clinical presentation characterized by autoinflammatory disease with recurrent fever, cutaneous and pulmonary vasculitis.
HCK is a member of the SRC family of cytoplasmic tyrosine kinases. The gene is located on the long arm of chromosome 20 and spans approximately 50 kb [11]. It is expressed in myeloid and B-lymphocyte lineages and exists in two isoforms: p61HCK (525 amino acids) and p59HCK (504 amino acids) [12]. HCK is activated by bacterial lipopolysaccharide (LPS), cytokines such as IL-2 and IL-6, and GM-CSF receptors [13].
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The SRC family kinases (SFKs) comprise nine non-receptor tyrosine kinases [14]. While SRC, YES, and FYN are broadly expressed, others—such as HCK, LCK, FGR, BLK, LYN, and YRK—are more cell- and tissue-specific [12]. Like other SFKs, HCK shares a conserved domain structure, and its kinase activity is regulated by SH2 and SH3 domains [15, 16]. These regulatory regions activate numerous signaling pathways essential for modulating immune responses [17, 18].
The relationship between this splice-site mutation and the patient’s clinical findings is evaluated in light of existing literature. HCK, a myeloid cell-specific tyrosine kinase, regulates immune functions such as phagocytosis, cytokine production, and neutrophil migration.
Studies in HckF/F mice demonstrate that HCK mutations lead to exaggerated innate immune responses, including widespread eosinophilic and mononuclear cell infiltration in pulmonary parenchyma, emphysema, and pulmonary fibrosis, alongside systemic features such as weight loss and hypothermia following lipopolysaccharide (LPS) stimulation [19]. These systemic effects underscore HCK’s role in not only localized pulmonary damage but also broader physiological stress responses, potentially contributing to chronic tissue injury.
Paradoxically, HCK deficiency reduces neutrophil accumulation in some tissues while promoting neutrophilia, suggesting that HCK mutations modulate neutrophil behavior in tissue-specific contexts [20]. It is hypothesized that HCK mutations may contribute to vascular inflammation in pulmonary and cutaneous tissues by altering neutrophil migration [21].
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HCK activation enhances the release of proinflammatory cytokines (TNFα, IL1β, IL6) from macrophages, sustaining inflammation, and promotes podosome formation, increasing phagocytic and migratory capabilities [12]. In HckF/F mice, neutrophils exhibit increased migratory capacity and superoxide production, contributing to chronic inflammation [19]. Additionally, HCK polymorphisms may modulate neutrophil activity, potentially increasing susceptibility to chronic obstructive pulmonary disease (COPD) [11]. Studies have demonstrated that mice expressing a constitutively active form of HCK develop severe pulmonary inflammation, with granulocytes showing heightened sensitivity to integrin-mediated stimuli [19, 22]. These findings emphasize the crucial role of HCK in the pathogenesis of autoimmune diseases and vasculitis.
In HCKCA mice, continuous HCK activation has been linked to lung adenocarcinomas, suggesting a broader role in disease pathogenesis [12].
In models of systemic inflammation, hck-/- fgr-/- neutrophils show impaired migration to the liver and reduced early recruitment to airways in response to LPS, indicating HCK’s role in coordinating immune cell trafficking [21, 23]. In allergic inflammation, Fgr deficiency reduces eosinophil accumulation in pulmonary tissues, underscoring HCK’s contribution to inflammatory processes [21]. HCK hyperactivation can lead to congenital pneumonia and vasculitis by enhancing myeloid cell activation and effector functions [24]. Activating mutations in the COOH-terminal region of the c-Src gene have been associated with various diseases [25, 26]. HCK has also been proposed as a potential susceptibility locus for inflammatory conditions [19, 27].
A prior case reported by [10] identified a p.Tyr515* HCK mutation causing early-onset cutaneous and pulmonary vasculitis, with chronic inflammation unresponsive to ruxolitinib, supporting our findings of HCK-driven autoinflammatory disease. HCK inhibition, as shown in immunotherapy studies, enhances CD8+ T cell recruitment, suggesting potential therapeutic applications [24].
In conclusion, our identification of a novel HCK mutation causing autoinflammatory disease with early-onset pulmonary cutaneous vasculitis aligns with the proinflammatory role of HCK. The therapeutic potential of tyrosine kinase inhibitors, such as ruxolitinib, warrants further investigation for managing pulmonary inflammation in such cases, alongside targeted therapies like anti-IL1β, which achieved remission in our patient.
Conclusion
In summary, our study reveals that a new mutation of HCK is a cause of a new hereditary autoinflammatory disease characterized by early-onset pulmonary and cutaneous manifestations. Despite the lack of available literature on this specific mutation, our patient showed a remarkable response to anti-IL1B treatment.
Acknowledgements
Not applicable.
Declarations
Ethics approval
As this study is a case report, it does not require ethics committee approval. Written consent was obtained from the patient/legal guardian.
Consent to publish
Written informed consent for publication of this case report (and any accompanying images) was obtained from the patient’s parent/guardian. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare no competing interests.
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