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.