---
title: "Reconciling Genomic Ambiguity and Clinical Certainty in Refractory Panniculitis — Case Report"
id: "frontiers-in-immunology-11-case-report-reconciling-genomic-ambiguity-with-clinical-certainty-in-refractory"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-case-report-reconciling-genomic-ambiguity-with-clinical-certainty-in-refractory"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906895"
published_at: "2026-09-15T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Reconciling Genomic Ambiguity and Clinical Certainty in Refractory Panniculitis — Case Report
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-case-report-reconciling-genomic-ambiguity-with-clinical-certainty-in-refractory
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906895)
- **Published At:** 2026-09-15T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source material did not include the article body; only Frontiers in Immunology website navigation and metadata were available. - The article title indicates a case report addressing **refractory panniculitis** and the challenge of reconciling **genomic ambiguity** with **clinical certainty**, but the full case details were not present in the source. - No patient demographics, clinical presentation, diagnostic work-up, genomic testing methods or results, treatments, outcomes, or specific conclusions were reported in the supplied content. - The article is hosted by Frontiers in Immunology; the journal's sections include topics relevant to inflammation, autoinflammatory disorders, and microbial/viral immunology, which contextualize the likely scope but do not provide case specifics. - Key bibliographic access points (journal page and article URL) were present in the source; the full text was not included, so exact study data and recommendations cannot be summarized from the supplied material. - For clinical use, obtain the full text (Frontiers in Immunology article DOI 10.3389/fimmu.2026.1906895) to review patient data, genomic findings, diagnostic reasoning, and management details that are not available in the provided source. - Any detailed interpretation of diagnostic methods, genomic variants, therapeutic choices, or outcomes would be speculative without the primary article text and therefore was not reported here.
## Clinical Analysis & Structured Key Points
Frontiers | Case Report: Reconciling genomic ambiguity with clinical certainty in refractory panniculitis G; p.Thr199Ala) and a homozygous HAVCR2 variant (c.290T>C; p.Ile97Thr); the latter has not been reported in a homozygous state in existing genomic databases and is predicted to be deleterious. The coexistence of panniculitis, haemophagocytic lymphohistiocytosis (HLH)-like manifestations, and histologically lymphocytic rather than neutrophilic infiltrates suggests a distinct panniculitis–HLH overlap syndrome associated with the HAVCR2 mutation, which does not fit within the subcutaneous panniculitis-like T-cell lymphoma spectrum. A potential contribution (gene dosage effect) from the heterozygous PSMB9 mutation was uncertain, as parental testing was not feasible. The patient achieved sustained remission on corticosteroids and tacrolimus. This case broadens the phenotypic spectrum of HAVCR2-associated immune dysregulation and documents a novel homozygous HAVCR2 variant (p.Ile97Thr), underscoring the importance of comprehensive genetic evaluation in patients with unexplained recurrent panniculitis."> CASE REPORT article Front. Immunol. , 15 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906895 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Part of a Research Topic Immunology of Skin Health and Disease Submission open 45k views 28 articles Editor & Reviewers Edited by A R Annunziata Raimondo Reviewed by P S Priyanka Setia B K Batuhan Küçükali M K Mikhail Kostik Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Serial laboratory tests and medical records of the patient. View in article CASE REPORT article Front. Immunol. , 15 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906895 Case Report: Reconciling genomic ambiguity with clinical certainty in refractory panniculitis S M Sayan Mukherjee 1 * R K Rajat K. Sahu 2 N M Nidhish M. Chandra 2 U D Urmila Dhakad 2 P K Puneet Kumar 2 1. Department of Clinical Immunology and Rheumatology, Rabindranath Tagore International Institute of Cardiac Sciences (RTIICS), Kolkata, India 2. Department of Clinical Immunology and Rheumatology, King George’s Medical University, Lucknow, India Article metrics View details Abstract Panniculitis in adolescents often poses a diagnostic challenge for physicians. We report an adolescent girl presenting with recurrent steroid-responsive lymphocytic septal panniculitis, genital ulcer, and constitutional symptoms, later complicated by macrophage activation syndrome and steatohepatitis. Extensive evaluation excluded infectious, autoimmune, and malignant causes. Histopathology revealed septal panniculitis without vasculitis or atypical lymphoid cells. Whole-exome sequencing identified a heterozygous PSMB9 variant (c.595A>G; p.Thr199Ala) and a homozygous HAVCR2 variant (c.290T>C; p.Ile97Thr); the latter has not been reported in a homozygous state in existing genomic databases and is predicted to be deleterious. The coexistence of panniculitis, haemophagocytic lymphohistiocytosis (HLH)-like manifestations, and histologically lymphocytic rather than neutrophilic infiltrates suggests a distinct panniculitis–HLH overlap syndrome associated with the HAVCR2 mutation, which does not fit within the subcutaneous panniculitis-like T-cell lymphoma spectrum. A potential contribution (gene dosage effect) from the heterozygous PSMB9 mutation was uncertain, as parental testing was not feasible. The patient achieved sustained remission on corticosteroids and tacrolimus. This case broadens the phenotypic spectrum of HAVCR2 -associated immune dysregulation and documents a novel homozygous HAVCR2 variant (p.Ile97Thr), underscoring the importance of comprehensive genetic evaluation in patients with unexplained recurrent panniculitis. Introduction Panniculitis refers to inflammation of the subcutaneous adipose tissue and can be histologically classified into septal or lobular types based on the predominant site of involvement. The aetiology of panniculitis varies across age groups, and a broad spectrum of diseases can present with recurrent episodes. Accurate diagnosis relies on histopathological evaluation, taking into account the pattern of involvement, the predominant type of inflammatory cell infiltrate, and the presence or absence of associated vasculitis. In children and adolescents, panniculitis may result from infections, connective tissue diseases, or autoinflammatory disorders, with or without underlying immunodeficiencies ( 1 , 2 ). Erythema nodosum (EN) is the most common form of panniculitis across all age groups, with a peak incidence during adolescence and no clear sex predilection ( 3 ). In children, lesions typically involve the anterior thighs, upper limbs, trunk, and face. Streptococcal and gastrointestinal infections are the most frequently identified triggers, though up to 40% of paediatric cases remain idiopathic. Histologically, EN in children resembles the adult form, displaying a predominantly septal panniculitis. The inflammatory infiltrate varies with lesion age: acute lesions are neutrophil-rich, while chronic lesions show a predominance of mononuclear cells and histiocytes. Miescher’s radial granulomas—stellate aggregates of histiocytes—may aid diagnosis but are not consistently present ( 1 ). We present a diagnostically challenging case of refractory panniculitis complicated by haemophagocytic lymphohistiocytosis (HLH), in which genomic interrogation revealed a novel variant of uncertain significance. Although the genetic findings did not meet established criteria for pathogenicity, meticulous clinical phenotyping and a mechanistic understanding of the underlying immune dysregulation facilitated syndrome recognition and therapeutic intervention. The resultant sustained remission underscores the critical importance of integrating genomic data with clinical and biological context, particularly when variant interpretation remains inconclusive. This case highlights the evolving paradigm of precision immunology, where pathogenic inference and therapeutic decision-making are guided not solely by genotype but by the convergence of molecular, clinical, and immunological evidence. Case presentation A 14-year-old girl presented with a 1-year history of intermittent high-grade fever, 10 months of recurrent painful erythematous cutaneous nodules, and a 6-month history of a painful solitary vulval ulcer. The fever was insidious and intermittent, lacked diurnal variation, and responded poorly to antipyretics. Cutaneous lesions began as well-circumscribed, tender nodules over the buttocks, spreading to the trunk within 1 month and subsequently to the extremities. Lesions healed with hyperpigmentation without ulceration and spared the face. Over the preceding 8 months, some gluteal lesions developed superficial ulceration. She was initially treated for a gluteal abscess with multiple antibiotic courses without improvement. Empirical antitubercular therapy was initiated for suspected erythema nodosum but discontinued due to transaminitis. Concurrently, a vulval papule progressed to a deep ulcer with undermined edges. A thigh lesion subjected to incision and drainage subsequently ulcerated and failed to heal. 5 months prior, she was evaluated at our center and diagnosed with undifferentiated vasculitis. Treatment with prednisolone (0.5 mg/kg/day) and methotrexate was initiated; however, methotrexate was discontinued due to recurrent transaminitis and replaced with colchicine. Following steroid tapering to < 10 mg/day, she developed a relapse, necessitating dose escalation and the addition of azathioprine. She then presented with a 15-day history of persistent fever and recurrence of nodular skin lesions over the trunk and lower limbs, accompanied by severe fatigue and diffuse arthralgia. She reported adherence to prednisolone (5 mg/day) and azathioprine (100 mg/day), with no new drug exposures. Figure 1 summarizes the timeline of clinical events. Figure 1 Timeline of events. D, present day; m, months; D-12 m, episode 12 months previously; and the remaining time points are similarly defined. GC, glucocorticoid; MTX, methotrexate; AZA, azathioprine. There was no significant past medical or surgical history apart from vasculitis, and no family history of tuberculosis or autoimmune disease. No known genetic conditions or consanguinity were recorded in the family. She had normal developmental milestones, had not yet attained menarche, and had experienced anorexia, fatigue, and a 5 kg weight loss over 6 months. She had previously performed well academically and was fully immunized as per national guidelines. A comprehensive review of systems was otherwise unremarkable. On examination, the patient appeared to be of average build but poorly nourished, with a body mass index (BMI) of 16 kg/m². She was pale and febrile (102°F) but haemodynamically stable. Cutaneous examination revealed multiple erythematous, tender, subcutaneous nodules measuring 1–2 cm in diameter, distributed over the abdomen, buttocks, thighs, legs, and upper limbs. The lesions were in various stages of healing; several showed induration and hyperpigmentation. A single, well-defined, erythematous, tender vulval ulcer with an undermined edge and serous discharge was present. Otherwise, her systemic examination was unremarkable. Serial laboratory parameters ( Table 1 ) demonstrated iron-deficiency anemia, transaminitis, markedly elevated alkaline phosphatase, and raised inflammatory markers at the initial presentation. Hepatic dysfunction was initially attributed to possible granulomatous hepatitis in the context of suspected tuberculosis, supported by clinical features; abdominal ultrasound showed mild hepatomegaly without parenchymal disease. Liver enzymes further worsened following the initiation of antitubercular therapy. Subsequent evaluation led to a working diagnosis of vasculitis, and she was treated with glucocorticoids and methotrexate. Skin biopsy revealed septal panniculitis without vasculitis, and immunohistochemistry demonstrated a mixed CD4/CD8 T-cell infiltrate without clonality ( Figure 2 ). Methotrexate was later discontinued due to suspected drug-induced transaminitis and replaced with colchicine. Although anemia partially improved, a disease flare necessitated the initiation of azathioprine. Table 1 Serial laboratory tests and medical records of the patient Therapeutic intervention offered Methotrexate Colchicine Azathioprine TAC Glucocorticoids ATT Pulse MP x3d +2unit PRBC IV antibiotics Timeframe D-10m D-9m D-7m D-6m D-6m D-5m D-4m D-2m D-1m D D+15 Hb 8.8 9.0 9.8 9.2 – 10.2 11.8 11.5 11.8 6.9 9.8 TLC 6000 5900 6100 5791 – 18200 8600 6800 6000 2870 4600 PLT 3.3 3.5 4.6 3.2 – 3.04 1.56 1.67 1.08 0.77 1.32 N%/L% 70/25 72/25 – – – – 73/12 69/25 80/16 90/06 88/10 MCV 81 82 – – – – 84 – 79 88 80 ESR – 60 – 22 – 9 32 – 22 10 19 CRP – 30.8 26 16.28 – 8.6 5.6 12.2 – 25 8 Total Bilirubin 0.27 0.63 1.28 1.27 – – – 1.9 – Direct Bilirubin 0.17 0.24 0.9 0.94 – – – 0.8 – SGPT 104 97 131 230 86 192 23 89 42 105 58 SGOT 240 240 246 470 92 221 88 56 37 82 46 ALP 3433 2861 3715 2623 1782 692 372 164 – 246 – Creatinine 0.4 0.5 0.6 0.5 – 0.52 0.73 0.55 – 0.8 0.7 Urea 18 20 – – – – 29 24 – 22 – Total protein – – – 5.6 – 5.7 – – – 6.4 – Albumin – – – 2.3 – 3.4 – – – 3.2 – Ferritin 26 – – – – – – – – 1008 582 Fibrinogen – – – – – – – – – 280 – Triglyceride – – – – – – – – – 390 – Procal. – – – – – – – – – 0.09 0.04 Autoimmune profile • ANA by IIF (1:100): Negative • ENA: Negative • MSA (IP): Negative • AntidsDNA-Elisa: <20 • C3:176 • C4: 96.2 • Anti-LKM-1: Negative • Anti-SLA: Negative • AMA: Negative • Anti-PR3: Negative • Anti-MPO: Negative • Fecal calprotectin: <45μg/mg Infection profile • HbsAg/ Anti-HCV: Non-reactive • Anti-HAV IgM/ Anti-HEV IgM: Non-reactive • HIV1&2: Non-reactive • CMV/EBV/Parvo B19 PCR- Negative • Urine R&M: NAD • Urine culture: No growth • Blood c/s: No growth • Serial wound swab c/s: No growth • Vulval swab c/s: Pseudomonas sp. • Mantoux test : 2mm x 4mm (Negative) Imaging • US abdomen and pelvis: NAD • Chest X ray: NAD • Contrast enhanced CT chest and abdomen: hepatomegaly Biopsy reports Skin biopsy: Septal panniculitis without any granuloma or vasculitis ( Figure 2 ) Final Dx: Erythema nodosum Liver biopsy: Hepatocytes show micro and macro vesicular steatosis with mild peri-portal lymphocytic inflammation with preserved parenchymal architecture. No evidence of rosette or necroinflammation or fibrosis. Final Dx: Steatohepatitis Bone marrow biopsy: Haematopoiesis with evidences of Hemophagocytosis and histiocytosis. Final Dx: Hemophagocytosis Serial laboratory tests and medical records of the patient. HB, Hemoglobin(g/dl); TLC, total leukocyte count(per mm 3 ); PLT, platelet count(X10 9 per mm 3 ); N%/L%, neutrophil & Lymphocyte(%); MCV, Mean corpuscular volume(fl); ESR, Erythrocyte sedimentation rate(mm/1 st hour); CRP, C reactive protein(mg/L); SGPT, Serum Glutamic-Pyruvic Transaminase(IU/L); SGOT, Serum Glutamic-Oxaloacetic Transaminase(IU/L); ALP, Alkaline phosphatase(U/L); Procal, Procalcitonin(ug/L). Expression units: Ferritin (ug/L), triglyceride(mg/dl), creatinine(mg/dl), fibrinogen(mg/dl) and protein & albumin (g/dl). TAC, Tacrolimus; ANA, anti-nuclear antigen; ENA, extractable nuclear antigen; MSA, Myositis specific antibody; dsDNA, double stranded deoxyribonucleic acid; C3, complement protein3; C4, complement protein4; Anti-LKM-1, Liver kidney microsome type1 antibody; SLA, Soluble liver antigen; AMA, anti-mitochondrial antibody; IIF, indirect immunofluorescence; IP, Immunoprecipitation; Elisa, Enzyme linked immunosorbent assay; HbsAg, Hepatitis B surface antigen; HCV, Hepatitis C virus; HAV, Hepatitis A virus; HEV, Hepatitis E virus; HIV, Human immunodeficiency virus; CMV, Cytomegalo virus; EBV, Epstein Barr virus; NAD, No abnormality detected. Figure 2 (A) Section shows skin with subcutaneous septal fibrosis and chronic inflammation (asterisk), extending into surrounding lobular fat (arrow). Haematoxylin and eosin, ×25; (B) section shows subcutaneous fat with septal fibrosis and a septal infiltrate of lymphocytes, histiocytes, and few eosinophils (asterisk). Haematoxylin and eosin, ×200; (C) section shows subcutaneous fat with a scattered infiltrate of CD3-positive T lymphocytes (arrows). Adipocytic rimming is not seen. Diaminobenzidine, ×100; (D) section shows subcutaneous fat with a scattered infiltrate of CD4-positive T lymphocytes (arrows). Diaminobenzidine, ×100; (E) section shows subcutaneous fat with a scattered infiltrate of CD8-positive T lymphocytes (arrows). Diaminobenzidine, ×100. At this presentation, she developed acute pancytopenia, transaminitis, hyperferritinaemia, and hypertriglyceridaemia, consistent with macrophage activation syndrome in the setting of a disease flare. Infectious triggers were excluded, and imaging showed no evidence of occult infection or malignancy. Bone marrow examination confirmed haemophagocytosis, while liver biopsy demonstrated non-specific steatosis. She was managed with a packed red cell transfusion and intensive immunosuppression, resulting in clinical and biochemical improvement over 2 weeks. Case summary An adolescent girl presented with steroid-responsive recurrent septal panniculitis (erythema nodosum), a genital ulcer, and constitutional symptoms and was admitted with a cutaneous flare, haemophagocytosis, and steatohepatitis. Differential diagnosis A broad differential diagnosis was considered for recurrent septal panniculitis with systemic manifestations. Behçet’s disease was initially considered in view of erythema nodosum-like lesions and genital ulcers; however, the absence of oral aphthae, negative pathergy, modest inflammatory markers, and lack of vasculitis on histopathology, together with peripheral haemophagocytosis, argued against this diagnosis. Systemic lupus erythematosus was deemed unlikely given the negative serology and the presence of septal rather than lobular panniculitis. Subcutaneous panniculitis-like T-cell lymphoma remains a diagnostic consideration; however, the relapsing course, steroid responsiveness, and absence of classical peri-adipocyte rimming are atypical for this entity. Monogenic autoinflammatory disorders, including haploinsufficiency of A20 (HA20), were considered less likely due to the absence of mucocutaneous, gastrointestinal, and ocular involvement and the later disease onset. Other autoinflammatory syndromes (RELopathies—ELF4/ REL ) which involve nuclear factor kappa B (NF-κB) signalling and cell death pathway (tumor necrosis factor (TNF) receptor pathway— OTULIN /HA20) dysregulation were also deemed less significant due to lack of a neutrophilic driver, a classical disease phenotype, and an association with HLH. Inflammatory bowel disease and sarcoidosis were effectively excluded based on unremarkable imaging and the absence of granulomatous inflammation. Proteasome-associated autoinflammatory syndromes remained within the differential but are not typically associated with haemophagocytosis or steatohepatitis. Overall, idiopathic panniculitis was considered less plausible in the context of prominent systemic and mucosal involvement. The patient’s course The patient presented with a flare of panniculitis complicated by HLH-like features and was promptly started on high-dose corticosteroids. Oral tacrolimus was introduced 2 weeks later as a steroid-sparing agent, resulting in rapid clinical improvement and progressive normalization of laboratory parameters. In view of recurrent, idiopathic panniculitis in an adolescent, whole - exome sequencing was undertaken. This identified a heterozygous variant in PSMB9 (exon 6) and a homozygous variant in HAVCR2 (exon 2), both classified as variants of uncertain significance ( Figure 3A ). While PSMB9 mutations are implicated in proteasome-associated autoinflammatory syndromes, which may present with panniculitis, they are not typically associated with HLH-like manifestations. In contrast, HAVCR2 variants have been reported in subcutaneous panniculitis-like T-cell lymphoma and are more strongly linked to HLH-like presentations. The precise driver of HLH in this case remains uncertain; an unrecognized or unidentified viral trigger could not be excluded, and a potential gene dosage effect of the HAVCR2 variant was also considered. Figure 3 (A) whole-exome sequencing of the index patient with two identifiable variants of uncertain significance. (B, C) normal and altered protein structures associated with the HAVCR2 index mutation, respectively. Persistent transaminitis prompted a liver biopsy, which demonstrated non-specific steatohepatitis that was likely multifactorial—associated with prolonged corticosteroid and immunosuppressive exposure and/or systemic inflammatory activation rather than HLH alone. Although the acute dysfunction was predominantly attributable to HLH, its persistence indicated steatosis possibly secondary to medication use. The patient was discharged on tapering corticosteroids with adjunctive tacrolimus. Over 6 months, prednisolone was successfully reduced to < 5 mg/day, while tacrolimus was maintained at 3 mg/day in divided doses, guided by therapeutic trough levels (5–8 ng/mL). She has remained in sustained clinical remission for 24 months, including over 12 months without corticosteroids, with no recurrence or disease flare. Discussion In our case, the patient presented with recurrent episodes of panniculitis and fever, and was found to have a heterozygous PSMB9 variant and a homozygous HAVCR2 variant, in the absence of any overt or classical features of immunodeficiency. Parental genetic analysis may have provided valuable insights, but it was not performed due to financial constraints. Genomic analys
## Related Clinical Research

- [Market landscape of penicillin for syphilis and rheumatic heart disease in WHO South‑East Asia Reg](https://medichelpline.com/clinical-feed/pubmed-42676699.md) (DOI: 10.2471/BLT.25.295053)
- [Case report: ADMIO type 1 linked to de novo STAT3 gain-of-function mutation](https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-a-case-report-of-admio-type-1-caused-by-a-de-novo-stat3-gain-of-function.md)
- [Predictors of Healthcare Costs for Commercially Insured Adults with Tuberculosis in the US (2013–2](https://medichelpline.com/clinical-feed/medrxiv-0-predictors-of-healthcare-costs-among-commercially-insured-persons-with.md)
- [Mortality and Predictors Among People Living with HIV Newly Enrolled in Care at Bamenda Regional H](https://medichelpline.com/clinical-feed/medrxiv-11-mortality-and-associated-factors-among-people-living-with-hiv-newly-initiated.md)
- [ANCA testing in a large teaching hospital: decade-long single-centre experience and strategy impli](https://medichelpline.com/clinical-feed/plos-one-22-anca-testing-strategies-a-single-centre-experience-over-the-past-decade-in-a.md)

## Navigation
- [← Back to Infectious Disease Feed](https://medichelpline.com/clinical-feed/infectious-disease.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.