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Abstract
We present a case of a girl in her early childhood with a background of chromosomal deletion 10q21.2, hypothyroidism, second-degree atrioventricular block, developmental delay, gastroesophageal reflux disease, constipation and recurrent fevers. She had subcutaneous nodules, which represented panniculitis. Diagnosis of fever of unknown origin (FUO) associated with panniculitis was very challenging despite the involvement of geneticist, dermatologist, rheumatologist and paediatrician. To detect possible malignant cases and start treatment plans promptly, the case emphasises the need for a comprehensive diagnostic examination, which includes an early biopsy of nodular lesions. To maximise patient outcomes in complicated paediatric presentations, it emphasises the need for continual multidisciplinary teamwork and close monitoring. This case adds to the body of knowledge on the treatment of panniculitis and FUO in paediatric patients, highlighting the need of a comprehensive approach to treatment.
- Infectious diseases
- Immunology
- Genetics
- Rheumatology
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Background
The term fever of unknown origin (FUO) was first used by Petersdorf and Beeson at Yale University in the 1960s. They studied 100 patients with a body temperature above 38.3°C for over 3 weeks without diagnosis despite a week of hospital evaluation.1 Most panniculitides present similarly, with tender, erythematous subcutaneous nodules, typically where fatty tissue is prominent (eg, legs, thighs, buttocks and cheeks). Subtypes of panniculitis are linked to infections, trauma, cancer and inflammatory illnesses.2 Diagnosing panniculitis is challenging due to its rarity and similar clinical presentations. Diagnosis requires thorough clinical examination, considering patient risk factors, lesion distribution and related symptoms (eg, ulceration, sclerosis and atrophy). Histopathologic evaluation can aid diagnosis, but requires careful clinical correlation to avoid inaccuracies. The challenge increases with FUO, necessitating a comprehensive assessment. We describe a young child with panniculitis and recurring fevers, highlighting the diagnostic challenges and need for a multidisciplinary approach
Case presentation
The patient presented with a constellation of medical background, including a confirmed chromosomal deletion 10q21.2, hypothyroidism, second-degree atrioventricular block, developmental delay and constipation. She had a history of dermatological issues, which initially began as problems in the right upper arm consisting of asymptomatic, red scaly lesion just above the elbow which was unresponsive to topical antifungal treatment and subsequent linear lesions on the back of the right hand involving the right middle finger with associated nail dystrophy. The history and changes of these were in keeping with lichen striatus. Concurrently, they developed skin nodules, sporadic joint pains and ongoing daily fevers that were made worse by a recent COVID-19 infection. Imaging showed extensive lymphadenopathy, moderate hepatomegaly and splenomegaly, which indicated a possibility of panniculitis. There is a maternal family history of psoriatic arthritis, autoimmune autonomic ganglionopathy, type 2 diabetes, psoriatic arthritis and ankylosing spondylitis.
After the above skin changes, the patient had persistent daily fevers, varying from 37.9°C to 39°C, which were significantly worsened when she was reported to have confirmed COVID-19 infection. Over the next 4 weeks, in addition to the fevers, she was noted to have skin changes on the lower legs consisting of firm lumps 1–1.5 cm maximum size, which are most marked when the fevers are at their highest (figure 1). The overlying skin appeared normal and did not ulcerate or scar, however, the lumps were tender on palpation. Although the lump sizes varied, they never completely disappeared.
Multiple skin lesions seen across lower limb (arrow).
Investigations
Along with normal results from other screens, investigations revealed aberrant results in respiratory virus panels, echocardiography and blood tests. Thenceforth, the patient was scheduled for a bone marrow biopsy and an extra diagnostic skin biopsy. Multiple subcutaneous nodules on the thighs and lower legs, considered panniculitis, were discovered during a subsequent dermatological examination. Other findings included keratosis pilaris and café au lait macules. An MRI showed widespread panniculitis/fasciitis. Given the complexity of her presentation, a multidisciplinary approach, including genetics, rheumatology, dermatology and paediatrics, was necessary. Symptomatic therapy consisting of prednisolone 5 mg once daily and methotrexate 12 mg once weekly had to be maintained while the results of a biopsy were being obtained, as well as genetic testing for R413 panel from the national amyloidosis centre.
Treatment
Treatment for panniculitis and FUO focused on both pharmacological and supportive measures to manage symptoms and address underlying inflammation. Pharmacological therapy included the initiation of prednisolone and methotrexate, tailored to mitigate inflammatory processes and modulate the immune response. Prednisolone, a corticosteroid, was administered orally at a starting dose of 5 mg once daily, with adjustments based on clinical response and adverse effects. The dosage was carefully titrated to balance efficacy in reducing inflammation with minimising side effects commonly associated with long-term corticosteroid use in paediatric patients. Methotrexate was prescribed at an initial weekly dose of 12 mg. The treatment plan involved close monitoring of liver function tests and haematological parameters due to methotrexate’s potential hepatotoxicity and myelosuppressive effects. Dosage adjustments were made as necessary to maintain therapeutic efficacy, while ensuring patient safety. Non-pharmacological supportive care included regular follow-up visits to monitor disease progression, assess treatment response and manage potential adverse effects of medications. Patient education and counselling were integral to promote adherence to treatment and enhance overall patient and caregiver understanding of the disease course. Surgical intervention was not indicated in this case, as the management primarily focused on medical therapy to address underlying inflammatory processes. The treatment approach was guided by current clinical guidelines and multidisciplinary consensus, emphasising the need for a comprehensive and individualised approach to optimise therapeutic outcomes.
Outcome and follow-up
Following initiation of treatment, the patient showed gradual improvement in clinical symptoms and overall health during the subsequent follow-up period. Comprehensive follow-up data were obtained over a 12-month period post initiation of therapy. Concerns regarding health aspects showed improvement in the resolution of daily fevers and the size and tenderness of subcutaneous nodules. Serial assessment of inflammatory indices and imaging examinations further supported the trend of decreasing disease activity and resolution of the systemic manifestations, such as lymphadenopathy, hepatomegaly and splenomegaly. The patient was able to get back to a normal routine at home and school with little interference from their illness. Other supportive cares incorporated regular follow-up of liver function tests and haematological profile for methotrexate, to maintain therapeutic effectiveness with minimal toxicity.
Follow-up was done with regular dermatological examinations, laboratory tests and imaging to capture any sign of relapse early. Compliance with treatment and patient information contributed to the improvement of outcomes and overall quality of life. Surveillance guidelines called for follow-up every 3 months in the first year and increasing to 6 monthly depending on clinical safety. Expansion of treatment compliance and multidisciplinary teamwork to keep the disease mild and away from developing complications. Thus, no side effects or complications due to the treatment were noted during the follow-up period, indicating the effectiveness and safety of the therapeutic approach used. The patient’s long-term prospects seem good, but it is crucial to continue the evaluation to achieve and maintain remission and provide comprehensive care. The R413 autoinflammatory panel had returned normal. She is now awaiting whole genome sequencing (WGS) including R27 paediatric super panel and R29 intellectual disability and development delay panel. While awaiting the WGS, paediatric rheumatology has advised to perform an interferonopathy screen to rule out aberrant interferon production and signalling for the ongoing recurrent fevers.
Discussion
Based on aetiology, panniculitis is a relatively rare process in children and is among many diseases that cause panniculitis.3 Other forms of childhood panniculitis include, poststeroidal panniculitis, neonatal scleroderma, cold panniculitis, newborn subcutaneous fat necrosis among others. There are very few reports of panniculitis in children that are well described in adults. The most common type is erythema nodosum, a septal panniculitis without vasculitis, which is clinically defined as the appearance of painful and inflammatory cutaneous nodules that primarily affect the pretibial region of the lower limbs. These nodules typically resolve on their own in 1–6 weeks without ulceration or cutaneous atrophy. It is a pluriaetiological condition that usually develops because of a hypersensitivity response linked to paediatric enteric, tuberculosis or streptococcal infections, as well as beta-lactam and macrolide use.4 The patient in this instance had subcutaneous nodules, a fever and systemic symptoms, all of which were clinical signs of panniculitis and called for a thorough diagnostic evaluation. Clinically, panniculitis manifests as deep plaques or nodules, irrespective of the aetiology. To arrive at an accurate diagnosis, it is thus important to supplement its investigation with a histological study.3 Nevertheless, given the restricted capacity of adipose tissue to respond with various patterns, its histology is not easily interpreted.5 It is the physician’s responsibility to decide when to do a skin biopsy, which is the most effective diagnostic tool. It is important to perform the biopsy early on to prevent the lesion from evolving into one with less specific histological changes.5
Furthermore, panniculitis linked to malignant illness is discussed, although very uncommon, this should be considered when presenting with unusual lesions or linked to constitutional symptoms.4 The diagnostic process was made more difficult by the patient’s medical history, which included developmental delay, hypothyroidism and the confirmed chromosomal deletion 10q21.2. Chromosomal deletion 10q21.2 is a rare genetic anomaly with limited prevalence data. It typically presents developmental delays, intellectual disabilities, craniofacial dysmorphisms and possible congenital malformations including genitourinary and cardiac malformations. This emphasises the significance of taking underlying genetic predispositions and related comorbidities into account in paediatric patients with complex presentations. A helpful clinical history was also given by the mother, including a family history of autoimmune diseases and recent COVID-19 positive results, both of which can affect the immune system and the progression of the disease in the patient. In this case, the differential diagnosis of panniculitis involves a range of inflammatory, viral autoimmune and neoplastic diseases, and thus, significant efforts were made to exclude each of them. Further elucidation of the underlying disease and the tailored therapeutic approach were to be further clarified by a bone marrow biopsy as well as a diagnostic skin biopsy. However, the complexity of the patient’s clinical picture underlines the appropriateness of continuous multidisciplinary collaboration and close monitoring to ensure timely diagnosis and adequate management.
When discussing the diagnostic challenges of FUO and clinical implications in children with panniculitis only a few works are available.6 A young boy presented with subcutaneous nodular lesions and persistent fever and required hospitalisation and detailed investigation to exclude immunological and infective aetiology. More biopsy established that subcutaneous panniculitis-like T-cell lymphoma was among the FUO causes and led to the conclusion that nodular lesions in FUO patients require early biopsy to prevent complications and delays in treatment.6 By presenting this case, a team approach and analysis can be applied to address paediatric patients who may present with obscure manifestation of FUO and therefore improving clinical results and efficacy of the patients. It can be labile to diagnose mesenteric panniculitis sometimes mainly in cases of FUO and abdominal surgical history.7 Further studies were required in this clinical case because of recurrent fevers, fatigue and increased urinary frequency in a woman in her 40s with thalassemia and history of surgeries in the abdomen. In the imaging studies, it was described as misty mesenteric appearance with enlarged nodes pointing more towards the chronic MP. The biopsy result was negative which in essence eliminated cancer and confirmed the medical diagnosis. In the case of treatment choices of FUO which relates to mesenteric panniculitis, the requirement for complex and personalised approach and specific management interventions, such as steroids or methotrexate, have emerged. As pointed in the literature focused here, it is important for differential diagnosis of FUO for a patient who has had an abdominal surgery in the past to consider mesenteric panniculitis as possible cause. For that reason, more emphasis must be directed to the suitable evaluation and differentiated, individually chosen therapy to optimise the patient’s result.
The case study by Lombana et al emphasises how crucial it is to rule out mesenteric panniculitis when making a differential diagnosis for FUO. An elderly man was described as having lost 3 months’ worth of weight, had bewilderment and had periods of fever.8 The diagnosis of mesenteric panniculitis was made just 2 weeks before hospitalisation, despite a battery of diagnostic tests, including a CT scan of the abdomen. There may be a connection between the patient’s symptoms and mesenteric panniculitis if fevers go down over a few weeks after discharge. This example highlights the need for doctors to assess patients with FUO with a high index of suspicion for unusual illnesses, such as mesenteric panniculitis, especially when standard diagnostic procedures are unable to provide a diagnosis.
Patient’s perspective
As a mother, watching my daughter struggle with her health has been incredibly challenging. From an early age, she faced numerous medical issues, which already made life complicated. The fevers were relentless, peaking unpredictably and making her feel miserable. Visiting multiple specialists, from dermatologists to rheumatologists, each contributing their expertise but leaving us with more questions than answers.
Treatment with prednisolone and methotrexate offered some relief, but managing the side effects and ensuring she stayed on track with her medications required constant vigilance. Regular follow-ups and tests became a part of our routine, and while we saw gradual improvements, the fear of relapse lingered. Despite these challenges, my daughter showed remarkable resilience, returning to her daily activities with a determination that inspired us all.
Through this journey, the importance of comprehensive, coordinated care became clear. However, the 2 year wait for whole genome sequencing has been a significant source of anxiety for our family. The uncertainty of what the results might reveal and the prolonged period without definitive answers weighs heavily on us every day. Through this journey, we have learnt that a simple fever should never be taken for granted. It can be a sign of something much more serious, and we urge other parents to seek thorough medical evaluation if their child experiences persistent unexplained fevers. Today, while she continues to face health challenges, the improvement in her symptoms and the ability to attend school and play bring immense relief and joy to our family.
Learning points
Persistent or unexplained fevers in paediatric patients should not be taken lightly as they can indicate a more serious underlying condition, with the hunt for a diagnosis taking us down to our molecular genomics
Early biopsy of nodular lesions is crucial in detecting potentially malignant or serious conditions, facilitating timely treatment.
Diagnosing conditions with overlapping and non-specific symptoms, such as recurrent fevers and skin nodules, requires a comprehensive and multidisciplinary approach.
Continuous monitoring and regular follow-ups are critical for assessing treatment response and ensuring patient safety.
Ethics statements
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Footnotes
X @DhanushanG
Contributors DG and TA were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content. AM and KM gave final approval of the manuscript. DG, as the guarantor, takes full responsibility for the integrity of the work and the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.