CASE A 17-month-old female with a history of congenital deformity of the right hand and wrist, gross motor delay and hypotonia presented to the clinic for acute bilateral wrist and ankle swelling, intermittent fever and rash. She was admitted to the hospital for further investigation. Prior to this presentation, the infant had experienced 3 other episodes of fever, each lasting 2–4 days in duration without associated symptoms over the past 2 months. During these isolated episodes of fevers, there was no definite etiology as the patient had no associated notable infectious symptoms such as congestion, nausea, vomiting or cough. The family had no pets or recent travel history. On admission, her weight and height were at the first and second percentiles, respectively, and she appeared in no acute distress. Her temperature was 39°C, heart rate was 48 beats per minute, respiratory rate was 48 breaths per minute and blood pressure was 99/61 mm Hg. Her physical examination was normal except for the musculoskeletal system. Edema and tenderness were noted of both wrists and ankles with the right wrist showing significantly more soft tissue swelling proximal to the wrist joint. There was erythema overlying the posterior ankles bilaterally near the insertion of the Achilles tendon, as well as adjacent to the lateral malleoli and overlying both wrists. Laboratory studies on admission included a complete blood count that demonstrated a normocytic anemia with hemoglobin of 8 g/dL (ref range, 10.5–13.5 g/dL), white blood cell count of 15.4 103/uL (ref range, 6–17.5×103/uL), markedly elevated erythrocyte sedimentation rate at 109 mm/h and an elevated C-reactive protein of 8.5 mg/dL (ref range, <1.2 mg/dL). Further lab evaluation included a normal comprehensive metabolic panel, urinalysis, LDH, uric acid, CK, ferritin and a minimally elevated stool calprotectin. Respiratory PCRs for virus panel (coronavirus, human metapneumovirus, rhino/enterovirus, influenza, parainfluenza, RSV, bordetella, Chlamydia pneumonia), M. pneumoniae and SARS-CoV-2 and blood PCRs for human herpesvirus 6, adenovirus, parvovirus and entero/parechovirus; Epstein-Barr virus and Bartonella henselae were negative, as were Lyme serologies and blood culture. Echocardiogram and EKG were both within normal limits. An MRI demonstrated multifocal synovitis of the right wrist, right elbow, right glenohumeral joint and right epitrochlear and axillary lymphadenopathy. Chest radiograph and abdominal ultrasound were negative for adenopathy. Biopsy of a right axillary lymph node revealed a reactive lymph node with multifocal necrosis, paracortical hyperplasia and sinus histiocytosis. Cultures and universal PCRs for bacteria, mycobacteria and fungi were negative. Additional laboratory studies were obtained, which led to the diagnosis. DENOUEMENT Shortly after admission, our patient defervesced without intervention. Serum immunoglobulin levels showed a markedly elevated IgD of 44.1 mg/dL (≤15.3 mg/dL), elevated IgA at 255 mg/dL (19–118 mg/dL), elevated IgG at 1520 mg/dL (248–1337 mg/dL) and normal IgM at 105 mg/dL (13–108 mg/dL). The urine MA level was elevated at 38.45 mg/g creatinine [normal reference for <2 y, 0.57 ± 0.33 (SD)]. A primary immunodeficiency and autoinflammatory genetic panel (Invitae) showed that our patient possessed a pathogenic mutation identified in the mevalonate kinase (MVK) gene, associated with autosomal recessive MVK deficiency and a variant of unknown significance in the same gene. The patient was discharged with ibuprofen for pain control, and at follow-up with rheumatology 1 month after discharge, she remained fever free, and the areas of erythema had resolved. However, she continued to have swelling and pain of her right wrist. Given the clinical presentation of reported periodic fevers, arthritis and adenopathy, combined with an elevated urine MA level and a pathogenic mutation in the MVK gene, a diagnosis of hyperimmunoglobulin D syndrome (HIDS) was made. Based on recent reports of potentially effective therapies, the patient was started on the long-acting anti–IL (interleukin)-1 monoclonal antibody canakinumab (150 mg/mL) at 4 mg/kg by subcutaneous injection every 4 weeks. Since initiation of canakinumab, the patient has remained fever free with improvement in the synovitis and use of her right wrist while playing and crawling. Systemic autoinflammatory disorders are rare disorders of innate immunity characterized by seemingly random episodes of inflammation in the absence of autoantibodies. Since the initial discovery of the underlying genetic defect in familial mediterranean fever (FMF) in 1997, rheumatologists have identified the underlying mechanisms in many other autoinflammatory disorders.1 With many physicians not familiar with these diseases, there is often a diagnosis delay with diseases such as MVK deficiency having an average diagnosis delay of 7.1 years.2 These disorders are characterized by their periodic patterns of fever and symptoms associated with inflammation during the episodes. During these bouts of recurrent fevers, children may present with a myriad of symptoms including fever, oral ulcers, abdominal pain, vomiting, diarrhea, rash, synovitis, lymphadenopathy and elevation in inflammatory markers (erythrocyte sedimentation rate, C-reactive protein and ferritin). Often, these patients are followed by primary care providers or infectious disease physicians for months to years with serial diagnoses of viral illnesses before eventually being diagnosed with a periodic systemic autoinflammatory process.3 These episodes are generally separated by intervals of overall well-being. Common periodic fever syndromes in children include periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome, FMF, cryopyrin-associated periodic fever syndrome, tumor necrosis factor receptor-associated periodic syndrome and HIDS/MKD.4 Since many of the systemic autoinflammatory disorders are caused by a genetic defect and can overlap with immune deficiencies and immune dysregulation disorders, there is value in utilizing genetic panels and investigating the immune system in the evaluation of these conditions.5 HIDS, first described in 1984, is the milder phenotype of the disease process MKD.6 The more severe phenotype is mevalonate aciduria, which in addition to the usual symptoms of HIDS is characterized by dysmorphic features, neurologic symptoms, mental retardation and failure to thrive.7 Our patient had some evidence of global developmental delay but no other neurological signs or dysmorphic features on presentation. This rare condition is generally inherited in an autosomal recessive manner with 60% of affected individuals being of Dutch or French heritage. The fever pattern noted in HIDS is variable. Some individuals have an episode monthly, some more and others less frequently. Each episode generally lasts 3–7 days. Associated symptoms typically include chills, fatigue, rash, lymphadenopathy, abdominal pain and arthralgias/arthritis. Additional symptoms may include headaches, nausea/vomiting, diarrhea, cough, mucosal ulcers, pharyngitis and hepatosplenomegaly.8 Our patient’s immunodeficiency and autoinflammatory disease genetic panel (Invitae) resulted in the detection of a pathogenic variant in the MVK gene, which encodes the enzyme MVK, involved in the mevalonate pathway that produces isoprenoids such as vitamin K, cholesterol and steroid hormones.9 With decreased MVK activity, there is an accumulation of the substrate MA during fever episodes.10 This substrate is renally excreted, resulting in elevated urinary levels of MA in these patients as noted in our patient. Due to a lack of nonsterol isoprenoid end products, there is in turn an increase in IL-1 via caspase 1 activation,11 which results in the symptoms of fever and inflammation. Standard therapies, including nonsteroidal anti-inflammatory medications and steroids, have resulted in some benefit to those with mild symptoms and infrequent episodes. Of note, colchicine, which has been effective in other periodic fever syndromes, has been found ineffective. Currently, anakinra, a short-acting recombinant IL-1 receptor antagonist, and 2 long-acting IL-1β blocking agents, rilonacept and canakinumab, are approved by the US Food and Drug Administration for treatment of cryopyrin-associated periodic fever syndrome. Phase III trials of the use of canakinumab in treating tumor necrosis factor receptor–associated periodic syndrome, HIDS and colchicine resistant FMF have also been promising.12 Other investigational therapies include tumor necrosis factor inhibitors and tocilizumab (an IL-6 inhibitor). The only curative therapy for individuals with MKD is an allogeneic hematopoietic stem cell transplantation. However, this is reserved for those with serious complications, specifically children with mevalonate aciduria, because of the associated morbidity and mortality.10 The most significant long-term complications of untreated disease are secondary to amyloidosis, including renal failure, joint damage, vision loss and neurological damage.13 Systemic reactive amyloidosis is a severe complication of periodic fever disorders, being higher in patients with FMF and tumor necrosis factor receptor–associated periodic syndrome.14 There is minimal literature describing its incidence in HIDS. One such study of 114 cases from the Eurofever registry found autoimmune amyloidosis in 5 patients—a higher prevalence than was initially expected.15 Most of these patients presented with delayed diagnosis of HIDS and had complications of end-stage renal disease at presentation, requiring dialysis or kidney transplant. Because general pediatricians and pediatric infectious disease physicians often deal with children with recurrent fevers, it is important for them to be aware of the clinical presentation and initial diagnostic workup of periodic autoinflammatory disorders in children. This case highlights the clinical features, role of genetic testing and potential therapies for periodic fever syndromes such as HIDS.
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Apr 15, 2024
Yuefan Liu + 9