3 DISCUSSION
HIDS is an autoinflammatory disorder determined by recurrent and periodic fever episodes occurring since early childhood. Fever episodes generally related to wide range of symptoms such as joint pain, abdominal pain, headache, enlargement of lymph nodes, diarrhea and skin involvement (13, 14). In the current study, we reported the clinical manifestations of a girl with a mutation in the MVK gene, which is consistent with a diagnosis of HIDS. Patients with MVK gene reveal first fever episodes in early childhood (under one year old) (15). In our patient, the onset of fever occurred at the age of 3 years old, which is rather late. The presentation of HIDS in this case occurred at a later age than typically observed, emphasizing the importance of considering this condition even in older patients. The nonspecific nature of the symptoms and the overlap with other conditions pose a diagnostic challenge, underscoring the need for increased awareness among healthcare professionals. Similar to our report, Yoshimura et al. reported a boy having periodic fever since 3 years and 2 months (16).
In the study of Tsitsami et al, the recurrent and periodic nature of the disease in a 7-year period indicated periodic fever syndrome. A number of periodic fever syndromes were excluded based on a combination of laboratory findings, genetic testing, and clinical features. Serum IgD values were more than 11 mg/dL on more than two occasions with an interval of one month. Although this does not fully confirm the diagnosis of HIDS, the patient’s fever patterns and clinical symptoms suggested the HIDS for the patient. Contrary to our patient, and based on a complete analysis of the MVK gene, no mutation was found (17).
The skin lesions of HIDS are generally erythematous maculopapular rashes, urticarial and aphthous ulcers mimicking Behçet’s disease(18).
It is significant to differentiate the skin rash associated with HIDS from other skin diseases that show similar manifestations of fever and rash. The initial diagnosis for our study patient was a skin disease, and the patient was treated accordingly. In study by Omoyinmi et al. a 2-year-old boy who had suffered from frequent episodes of fever since early infancy with maculopapular/petechial rashes lasting 2–6 days every 2 weeks was reported. Moreover, WES demonstrated heterozygous mutation in MVK c.928G > A and c.1129G >A(19). In the study by Aygun et al. a 16-month-old boy was presented with recurrent fever episodes, maculopapular rash and cervical lymphadenopathy. Similar to our report, he had heterozygote mutation of MVK gene, and he was diagnosed as HIDS (18).
In addition, in patients with mevalonate kinase deficiency-hyper IgD syndrome (MKD-HIDS), the enzymatic activity can vary significantly, whereas patients with mevalonate aciduria (MKD-MA) consistently exhibit very high concentrations of mevalonic acid in their urine. However, the correlation between the severity of MVK mutations and loss of mevalonate kinase enzyme activity remains unclear (20). In a study conducted by Jerold Jeyaratnam et al., the diagnostic value of measuring urinary mevalonic acid in patients suspected of having mevalonate kinase deficiency (MKD) was evaluated; while MKD is highly unlikely in patients with normal mevalonic acid excretion, it cannot be completely ruled out. On the other hand, a positive result of urinary mevalonic acid excretion still requires further confirmation through MVK analysis to establish the diagnosis of MKD. Therefore, the detection of urinary mevalonic acid should not be mandatory before genetic testing. However, in situations where genetic testing is not widely available or affordable, measuring urinary mevalonic acid can be a reasonable approach to select patients for MVK gene analysis or enzyme assay (21). Furthermore, in their study, Jeyaratnam et al. reported that measuring urinary mevalonic acid demonstrated a sensitivity of 92%, specificity of 90%, positive predictive value of 71%, and negative predictive value of 98% (21). Therefore, the presence of consistently high mevalonate urine levels in our case aligns with previous studies highlighting the utility of this biomarker in diagnosing mevalonate kinase deficiency and distinguishing it from other febrile syndromes and these findings underscore the importance of measuring mevalonate urine levels as a diagnostic tool in suspected cases of mevalonate kinase deficiency, allowing for timely intervention and appropriate management strategies.
Cases with severe skin involvement such as those we report here are rare and may lead to misdiagnosis of HIDS as another inflammatory or infectious disorder (22). Considering the rarity of HIDS, increasing awareness among healthcare professionals about its clinical presentation, diagnostic criteria, and management is crucial. This will enable early recognition, appropriate intervention, and improved outcomes for patients affected by this syndrome.
Treatment options for Hyper-IgD syndrome with periodic fever (HIDS) have been a subject of ongoing research and exploration. Although there is currently no known curative therapy for this fever syndrome, various treatment approaches have been investigated to manage symptoms and improve the quality of life for affected individuals (18). One of the commonly used treatment strategies for HIDS involves the use of corticosteroids, such as methylprednisolone or prednisolone, to suppress inflammation and control fever episodes. These medications have shown effectiveness in reducing the frequency and severity of fever episodes in many patients. However, long-term use of corticosteroids may be associated with potential side effects, necessitating careful consideration of their use and close monitoring of patients (23). In recent years, the use of biologic agents targeting interleukin-1 (IL-1) has emerged as a promising therapeutic approach for HIDS. Anakinra, an IL-1 receptor antagonist, has demonstrated favorable outcomes in reducing disease activity and improving symptoms in HIDS patients (18,23). Studies have reported significant improvements in fever control and reduction in systemic inflammation with the use of Anakinra (23). Other IL-1 inhibitors, such as canakinumab and rilonacept, have also shown efficacy in managing HIDS symptoms (24). The choice of treatment may depend on various factors, including the severity of symptoms, individual patient characteristics, and response to therapy (23). The decision to initiate biologic therapy should be made on a case-by-case basis, considering the potential benefits and risks associated with these medications (18,23). It is important to note that while biologic agents targeting IL-1 have shown promise in managing HIDS symptoms, further research is needed to evaluate their long-term efficacy, safety, and optimal dosing strategies. Additionally, the cost and accessibility of these medications may pose challenges in certain healthcare settings (23,24). Therefor, the treatment of HIDS remains a challenge, with symptomatic management being the primary approach. Corticosteroids have been widely used to control fever episodes, while biologic agents targeting IL-1, such as Anakinra, have shown promising results in improving symptoms and reducing inflammation. Further research and clinical trials are warranted to establish standardized treatment guidelines and explore novel therapeutic options for individuals with HIDS.