Overview

Cryopyrin-associated periodic syndrome (CAPS) ( Fig. 1 ) is now the preferred term that encompasses 3 separately described autoinflammatory syndromes (familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS], and neonatal-onset multisystem inflammatory disease [NOMID]). In practice, a spectrum of disease severity exists for CAPS, with FCAS being the mildest phenotype and NOMID presenting with the most severe with end-organ damage.

CAPS spectrum of disease. FCAS, familial cold autoinflammatory syndrome; MWS, Muckle-Wells syndrome; NOMID, neonatal onset multisystem inflammatory disease; SNHL, sensorineural hearing loss.

In the spectrum of CAPS, mutations are present in the NLRP3 gene, which encodes the protein cryopyrin. This syndrome is driven by a “gain-of-function mutation” in NLRP3 , of which there is a total reported 139 mutations. Most mutations have been found in exon 3, although mutations have also been reported in exons 4, 5, and 6, as well as introns 1, 2, 4, 6, and 8. The NLRP3 gene encodes cryopyrin, which form an oligomeric complex known as an inflammasome, and it is the inflammasome that is involved in the posttranslational activation of inflammatory caspases. An inflammasome is a high molecular weight complex that converts inactive pro–caspase-1 to active caspase-1. In general, caspases are thought to be involved as initiators or effectors of apoptosis, but caspase-1 functions as a subclass of caspases involved in the inflammatory and specifically proinflammatory response. The active form of caspase-1 cleaves inactive cytokine precursors to a secreted and active form, and in CAPS the mutation in NLRP3 leads to elevated cytokine interleukin (IL)-1β. The elevated IL-1β leads to an inflammatory response with the clinical manifestations of periodic fevers and associated symptoms seen in the spectrum of CAPS.

Diagnosis of CAPS

CAPS encompasses a spectrum of disease severity from mild to severe phenotypes, in which patients present with cold-induced fevers and urticarial-like rash, constitutional symptoms, arthritis, aseptic meningitis, and other types of localized inflammation. The most common initial clinical presentation is an urticarial-like rash starting as early as 2 hours after birth, with most patients presenting before 6 months of age. In addition, patients can present with arthralgias and conjunctival injection, and less commonly they present with constitutional symptoms such as sweating, drowsiness, headache, and thirst.

The rash in CAPS is described as “an atypical urticaria,” with minimal or, more likely, absent pruritus in lesions that are subtle figurate erythematous macules ( Fig. 2 ). The rash most frequently follows a circadian rhythm presentation with little to no rash early in the morning, and worsening symptoms and signs as the day progresses. In view of the non-pruritic urticaria and associated joint pains, often the differential includes urticarial vasculitis. However, the rash in CAPS typically resolves within 24 hours without bruising, unlike the lesions in urticarial vasculitis.

CAPS: urticated plaques and figurate macules.

With CAPS considered a spectrum, the mildest phenotype, FCAS, typically presents with daily attacks of urticaria, arthralgias, and fever after general exposure to the cold. The disease typically presents in infants and usually before 6 months of age. The moderate form of CAPS, referred to as MWS, also presents with atypical urticarial lesions, cold-induced fevers, arthralgias, and additional features, including systemic amyloidosis, sensorineural hearing loss, and conjunctivitis. The most severe presentation, typically referred to as NOMID, involves neonatal onset of urticarial lesions, end-organ damage, rapidly progressive arthropathy, and central nervous system (CNS) involvement, as well as characteristic facial features of frontal bossing and saddleback nose. The severity of the joint involvement may lead the patient to be misdiagnosed with systemic-onset juvenile idiopathic arthritis (SOJIA); however, SOJIA tends to have a later age of onset. The CNS changes of NOMID include papilledema, chronic aseptic meningitis, headache, vomiting, spastic diplegia, or abnormally high muscle tone and impaired cognitive function.

As CAPS progresses in severity from mild to moderate, FCAS to NOMID, high-tone sensorineural hearing loss becomes more frequent. In addition, the severity of hearing loss has been reported as greater in patients with NOMID, with 39% of patients having moderate high-tone hearing loss and 11% having severe high-tone frequency loss, whereas in MWS, 67% had normal hearing and 33% had moderate hearing loss, and none had severe or profound hearing loss at higher frequencies. In addition to hearing loss severity, patients with NOMID present with severe early-onset arthritis, progressing rapidly to deforming arthropathy.

Laboratory Diagnosis and Assessment of CAPS

In CAPS, acute-phase reactants are invariably elevated, such as C-reactive protein (CRP); indeed, CRP is almost never normal irrespective of severity of symptomatology. In addition, serum amyloid A (SAA) levels are usually markedly elevated, but this can be difficult to obtain, as the test is generally not commercially available. Leukocytosis, sometimes as high as 36,000/μL and decreased hematocrit with neutrophilia may be seen on complete blood cell count (CBC). The most serious long term sequelae of CAPS is the development of systemic AA amyloidosis, which most frequently adversely affects the kidneys. Therefore, regular monitoring of renal function should be done with urinalysis to detect for proteinuria.

Histologic examination of the affected skin can support a diagnosis of CAPS, with neutrophilic dermal infiltrate in the reticular dermis, which tends to be peri-eccrine and peri-vascular. The infiltrate tends to be neutrophil predominant versus mast cell predominant.

The characteristic clinical presentation includes an early onset in age, an atypical urticarial rash on trunk and extremities, fever, arthralgias, arthropathy (joint enlargement, endochondral ossification, calcifications, and functional disability), and biopsy findings of a neutrophilic dermal infiltrate. The definitive diagnosis includes these characteristic clinical features in combination with genetic analysis, with gene testing showing mutations in the NLRP3 gene .

Treatments for CAPS

With the knowledge of increased IL-1 production, targeted therapies have proven to be most effective at controlling symptoms of CAPS and preventing the uncurbed inflammation that leads to amyloidosis. Specifically, anakinra, an IL-1 receptor antagonist, has been shown to be extremely effective at controlling symptoms and signs of disease activity with normalization of inflammatory markers, such as CRP and SAA. Reports have reflected effectiveness in all phenotypes of CAPS and it has recently been approved for the severe phenotypes/NOMID spectrum by the Food and Drug Administration (FDA). Anakinra has a short half-life of 4 to 6 hours, hence requiring daily subcutaneous injections.

Rilonacept, an IL-1 trap, was the first drug that was approved by the FDA for the treatment of CAPS and with a half-life of 8.6 days, it is typically dosed on a weekly schedule with a generally favorable long-term safety profile. Another targeted therapy for CAPS is canakinumab, an IL-1β monoclonal antibody, which is a medication that is FDA approved for CAPS. Because of its half-life of 26 days, its dosing regimen is every 8 weeks. Patients with CAPS on canakinumab showed minimal disease activity during a double-blind randomized control trial with prevention of urticarial rash, minimal levels of CRP, and SAA. There have been no head-to-head studies comparing these 3 agents, although all appear to be extremely effective at controlling the systemic inflammation associated with CAPS.

Overview

Cryopyrin-associated periodic syndrome (CAPS) ( Fig. 1 ) is now the preferred term that encompasses 3 separately described autoinflammatory syndromes (familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS], and neonatal-onset multisystem inflammatory disease [NOMID]). In practice, a spectrum of disease severity exists for CAPS, with FCAS being the mildest phenotype and NOMID presenting with the most severe with end-organ damage.

CAPS spectrum of disease. FCAS, familial cold autoinflammatory syndrome; MWS, Muckle-Wells syndrome; NOMID, neonatal onset multisystem inflammatory disease; SNHL, sensorineural hearing loss.

In the spectrum of CAPS, mutations are present in the NLRP3 gene, which encodes the protein cryopyrin. This syndrome is driven by a “gain-of-function mutation” in NLRP3 , of which there is a total reported 139 mutations. Most mutations have been found in exon 3, although mutations have also been reported in exons 4, 5, and 6, as well as introns 1, 2, 4, 6, and 8. The NLRP3 gene encodes cryopyrin, which form an oligomeric complex known as an inflammasome, and it is the inflammasome that is involved in the posttranslational activation of inflammatory caspases. An inflammasome is a high molecular weight complex that converts inactive pro–caspase-1 to active caspase-1. In general, caspases are thought to be involved as initiators or effectors of apoptosis, but caspase-1 functions as a subclass of caspases involved in the inflammatory and specifically proinflammatory response. The active form of caspase-1 cleaves inactive cytokine precursors to a secreted and active form, and in CAPS the mutation in NLRP3 leads to elevated cytokine interleukin (IL)-1β. The elevated IL-1β leads to an inflammatory response with the clinical manifestations of periodic fevers and associated symptoms seen in the spectrum of CAPS.

Diagnosis of CAPS

CAPS encompasses a spectrum of disease severity from mild to severe phenotypes, in which patients present with cold-induced fevers and urticarial-like rash, constitutional symptoms, arthritis, aseptic meningitis, and other types of localized inflammation. The most common initial clinical presentation is an urticarial-like rash starting as early as 2 hours after birth, with most patients presenting before 6 months of age. In addition, patients can present with arthralgias and conjunctival injection, and less commonly they present with constitutional symptoms such as sweating, drowsiness, headache, and thirst.

The rash in CAPS is described as “an atypical urticaria,” with minimal or, more likely, absent pruritus in lesions that are subtle figurate erythematous macules ( Fig. 2 ). The rash most frequently follows a circadian rhythm presentation with little to no rash early in the morning, and worsening symptoms and signs as the day progresses. In view of the non-pruritic urticaria and associated joint pains, often the differential includes urticarial vasculitis. However, the rash in CAPS typically resolves within 24 hours without bruising, unlike the lesions in urticarial vasculitis.

CAPS: urticated plaques and figurate macules.

With CAPS considered a spectrum, the mildest phenotype, FCAS, typically presents with daily attacks of urticaria, arthralgias, and fever after general exposure to the cold. The disease typically presents in infants and usually before 6 months of age. The moderate form of CAPS, referred to as MWS, also presents with atypical urticarial lesions, cold-induced fevers, arthralgias, and additional features, including systemic amyloidosis, sensorineural hearing loss, and conjunctivitis. The most severe presentation, typically referred to as NOMID, involves neonatal onset of urticarial lesions, end-organ damage, rapidly progressive arthropathy, and central nervous system (CNS) involvement, as well as characteristic facial features of frontal bossing and saddleback nose. The severity of the joint involvement may lead the patient to be misdiagnosed with systemic-onset juvenile idiopathic arthritis (SOJIA); however, SOJIA tends to have a later age of onset. The CNS changes of NOMID include papilledema, chronic aseptic meningitis, headache, vomiting, spastic diplegia, or abnormally high muscle tone and impaired cognitive function.

As CAPS progresses in severity from mild to moderate, FCAS to NOMID, high-tone sensorineural hearing loss becomes more frequent. In addition, the severity of hearing loss has been reported as greater in patients with NOMID, with 39% of patients having moderate high-tone hearing loss and 11% having severe high-tone frequency loss, whereas in MWS, 67% had normal hearing and 33% had moderate hearing loss, and none had severe or profound hearing loss at higher frequencies. In addition to hearing loss severity, patients with NOMID present with severe early-onset arthritis, progressing rapidly to deforming arthropathy.

Laboratory Diagnosis and Assessment of CAPS

In CAPS, acute-phase reactants are invariably elevated, such as C-reactive protein (CRP); indeed, CRP is almost never normal irrespective of severity of symptomatology. In addition, serum amyloid A (SAA) levels are usually markedly elevated, but this can be difficult to obtain, as the test is generally not commercially available. Leukocytosis, sometimes as high as 36,000/μL and decreased hematocrit with neutrophilia may be seen on complete blood cell count (CBC). The most serious long term sequelae of CAPS is the development of systemic AA amyloidosis, which most frequently adversely affects the kidneys. Therefore, regular monitoring of renal function should be done with urinalysis to detect for proteinuria.

Histologic examination of the affected skin can support a diagnosis of CAPS, with neutrophilic dermal infiltrate in the reticular dermis, which tends to be peri-eccrine and peri-vascular. The infiltrate tends to be neutrophil predominant versus mast cell predominant.

The characteristic clinical presentation includes an early onset in age, an atypical urticarial rash on trunk and extremities, fever, arthralgias, arthropathy (joint enlargement, endochondral ossification, calcifications, and functional disability), and biopsy findings of a neutrophilic dermal infiltrate. The definitive diagnosis includes these characteristic clinical features in combination with genetic analysis, with gene testing showing mutations in the NLRP3 gene .

Treatments for CAPS

With the knowledge of increased IL-1 production, targeted therapies have proven to be most effective at controlling symptoms of CAPS and preventing the uncurbed inflammation that leads to amyloidosis. Specifically, anakinra, an IL-1 receptor antagonist, has been shown to be extremely effective at controlling symptoms and signs of disease activity with normalization of inflammatory markers, such as CRP and SAA. Reports have reflected effectiveness in all phenotypes of CAPS and it has recently been approved for the severe phenotypes/NOMID spectrum by the Food and Drug Administration (FDA). Anakinra has a short half-life of 4 to 6 hours, hence requiring daily subcutaneous injections.

Rilonacept, an IL-1 trap, was the first drug that was approved by the FDA for the treatment of CAPS and with a half-life of 8.6 days, it is typically dosed on a weekly schedule with a generally favorable long-term safety profile. Another targeted therapy for CAPS is canakinumab, an IL-1β monoclonal antibody, which is a medication that is FDA approved for CAPS. Because of its half-life of 26 days, its dosing regimen is every 8 weeks. Patients with CAPS on canakinumab showed minimal disease activity during a double-blind randomized control trial with prevention of urticarial rash, minimal levels of CRP, and SAA. There have been no head-to-head studies comparing these 3 agents, although all appear to be extremely effective at controlling the systemic inflammation associated with CAPS.

Overview

Tumor necrosis factor (TNF)-receptor–associated periodic syndrome (TRAPS) is an autosomal dominantly inherited autoinflammatory condition, with recurrent fevers lasting 1 to 3 weeks. Mutations are present in the gene TNFRSF1A (TNF receptor Superfamily 1A), located on chromosome 12p13 coding for the 55-kDa TNF 1, which can lead to improper folding and shedding or clearance of TNFR1. One hypothesis on disease pathogenesis includes improper shedding of the TNF receptor leading to increased inflammatory response due to TNF, but other etiologies of pathogenesis include decreased apoptosis, increased nuclear factor kappaB (NF-kB), defective receptor trafficking, and increased reactive oxygen species leading to increased mitogen-activated protein kinase (MAPK) activity. The condition was initially coined familial Hibernian fever by Williamson and colleagues in 1982, when describing an Irish/Scottish family with recurrent fevers, abdominal pain, localized myalgias, and erythematous skin lesions. Recurrent fever, abdominal pain, myalgia, and arthralgia are the most common manifestations of TRAPS, followed by tender erythematous skin lesions, migratory rash with underlying myalgias and arthralgias, chest pain, conjunctivitis, periorbital edema, testicular pain, headaches, lymphadenopathy, and amyloidosis.

Diagnosis of TRAPS

TRAPS is characterized by recurrent fever episodes, which typically last from 1 to 3 weeks, and can occur every 5 to 6 weeks. The intervals between fevers vary, and are longer than those seen in other hereditary systemic autoinflammatory diseases, although variability in frequency and presentation is perhaps the greatest in TRAPS. Recurrent inflammatory episodes occur either spontaneously or after minor triggers, such as local injury, minor infection, stress, exercise, or hormonal changes. The median age of onset of TRAPS is 3 years old, with a range from 2 weeks to 53 years of age; therefore, TRAPS may not be diagnosed until adolescence or adulthood.

Initially, an individual will present with muscle cramps or myalgias that migrate in a centrifugal pattern. Myalgia is nearly always present in patients with TRAPS, and is usually a harbinger of an attack, and typically presents in conjunction with fever. Affected muscles can be tender and warm to palpation, and can be followed by overlying skin manifestations. Abdominal symptoms include cramping and nausea, with vomiting present in 92% of patients. In addition, genitourinary symptoms, such as scrotal pain and testicular pain, have also been reported. Ocular manifestations, including periorbital edema/pain and conjunctivitis, are common and uveitis and pulmonary symptoms of pleuritis are seen in 32% of patients.

The most common dermatologic manifestation is a centrifugal migratory erythematous rash ( Figs. 3 and 4 ), overlying an area affected by myalgia, which can be painful and warm to the touch. In 1997, McDermott and colleagues reported cutaneous manifestations in 69% of individuals followed with TRAPS, which included erythematous patches and indurated lesions. In an evaluation of 25 patients with TRAPS, cutaneous manifestations were present in 84% of patients, which lasted from a range of 4 to 21 days, with a mean duration of 13 days, with lesions, including large annular patches, erythematous dermal macules and patches, and generalized erythematous reticulated patches and plaques ranging in size from 1 to 28 cm. Migration of the lesions to a distal extremity was also a distinctive feature. In this review of patients with TRAPS, 44% presented with ocular symptoms, including conjunctival pain and redness and/or periorbital edema.

Cutaneous findings in TRAPS. Migrating erythematous macular rash during an inflammatory attack in a patient with TRAPS.

( From van der Hilst JCH, van der Meer JWM, Drenth JPH. Autoinflammatory fever syndromes. In: Rich R, Fleisher T, Shearer E, et al. editors. Clinical Immunology: Principles and Practice. third edition. Philadelphia: Elsevier/Mosby; 2008; with permission.)

Cutaneous findings in TRAPS. Migratory, erythematous macular rash on the abdomen and chest of a patient with TRAPS. The rash extends from the midline to the right lateral chest wall. Notice the surgical scars from previous exploratory laparotomies.

( From Brydges S, Athreya B, Kasther DL. Periodic Fever Syndromes in Children. In: Cassidy JT, Petty RE, editors. Textbook of Pediatric Rheumatology. fifth edition. Philadelphia: Elsevier Saunders; 2005; with permission.)

Histology showed perivascular lymphocytes and monocytes, and no biopsy specimens showed granulomatous or leukocytoclastic vasculitis.

Treatment for TRAPS

Providing patients with effective therapy has been challenging, although symptomatic relief may be seen with high-dose nonsteroidal anti-inflammatory drugs (NSAIDs). During an attack, patients typically require prednisone, typically useful in dosages greater than 20 mg per day, although, because there can be side effects with long-term use of high doses of corticosteroids, a short course of steroid started at 1 mg/kg per day tapered over a course of 7 to 10 days during an attack can be used. Patients typically fail to respond to treatment with colchicine, and this lack of response can help to differentiate TRAPS from other conditions that do respond to colchicine (such as FMF). With the various proposed methods of pathogenesis, various and diverging responses to treatment exist after lack of response to NSAIDs and prednisone. TNF-α blockade with etanercept has shown symptomatic improvement and reduction in acute-phase reactants. Notably, there has been a paradoxic reaction in patients with other TNF-α inhibitors, infliximab or adalimumab, with an increase in proinflammatory cytokines, so these treatments are less in favor. However, not all patients will respond to etanercept, and in those individuals with TRAPS, anakinra has been show to prevent short-term and long-term relapses. Canakinumab, which is a monoclonal antibody to IL-1β, has also showed amelioration of inflammation severity in patients not responding to etanercept. Treatment with canakinumab brought resolution of clinical manifestations and in normalizing markers of inflammation as well.

Overview

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare autosomal recessively inherited autoinflammatory disease characterized by recurrent fevers and elevated polyclonal immunoglobulin D (IgD). Mutations in the MVK gene encoding mevalonate kinase, an enzyme involved in the biosynthesis of cholesterol and isoprenoids, leads to a spectrum of clinical manifestations collectively termed mevalonate kinase deficiency (MKD), which includes recurrent febrile attacks seen in HIDS to a more severe phenotype, mevalonic aciduria (MA). The severe phenotype of MA includes the febrile attacks of HIDS and also includes psychomotor retardation, facial dysmorphia, cataracts, and failure to thrive. For MA, most mutations occur in cluster in the C-terminal region of the protein, whereas most patients with HIDS are compound heterozygotes for a missense mutation in the MVK gene, with more than 80% of patients presenting with the V3371 mutation. Thus, the genotype and phenotype correlate such that patients with MA have no mevalonate kinase activity and have a severe phenotype, whereas patients with HIDS may have residual enzyme activity of up to 5% to 15% and a less severe phenotype, reflecting the phenotypic differences seen in HIDS versus MA.

Diagnosis of HIDS

In addition to recurrent fevers and an elevated serum polyclonal IgD level, associated episodes typically occur with lymphadenopathy, abdominal pain, arthralgias, vomiting and diarrhea, and aphthous ulcers. For a febrile episode of HIDS, typical provocations can include vaccinations, infections, minor trauma, or surgery and other physical or emotional stress, although an episode can occur without any trigger at all with the mean age of initial attack occurring at 6 months of age (range 0–120 months). In HIDS, the febrile attacks and other symptoms of abdominal pain start in infancy, and can occur with or without triggers with episodes lasting between 3 and 7 days, with periods of 4 to 6 weeks between attacks, and, as the patient ages, the frequency of attacks can decrease and the severity of attacks may decrease as well. Data obtained from 103 patients with HIDS showed that febrile episodes can be accompanied by presence of lymphadenopathy, splenomegaly, arthralgias, abdominal pain, aphthous ulcers, and cutaneous lesions, and long-term complications were rare, although an infrequent complication was amyloidosis (2.9%). Lymphadenopathy, reported in 90% of patients, is a defining feature of HIDS, which typically involves cervical lymph nodes and can include axillary and inguinal localization as well.

The combination of early onset of febrile attacks lasting for days that are initially separated by approximately a month, along with abdominal pain, vomiting, and diarrhea, can also be accompanied by joint and cutaneous symptoms ( Fig. 5 ). In an analysis of 35 patients with HIDS, 79% of patients had skin lesions during a febrile episode with the most common lesions being erythematous macules followed by papules, typically 0.5 to 2.0 cm, but some patients also presented with urticarial lesions, annular erythema, and palpable purpura. Patients tended to present with a consistent pattern during subsequent attacks, with lesions localized primarily to trunk and extremities lasting for the length of the attack (5–10 days), but resolving between febrile attacks. However, the histopathology on cutaneous lesions in patients with HIDS was more variable, with findings ranging from mainly vasculitis, varying numbers of polymorphonuclear neutrophils (PMNs), and sometimes Sweet syndrome–like, and rarely a deep vasculitis picture on biopsy. However, almost all biopsy specimens showed perivascular inflammatory infiltrates composed of a variable number of lymphocytes and PMNs.

HIDS: erythematous macules and papules on trunk and extremities.

( From Brydges S, Athreya B, Kasther DL. Periodic Fever Syndromes in Children. In: Cassidy JT, Petty RE, editors. Textbook of Pediatric Rheumatology. fifth edition. Philadelphia: Elsevier Saunders; 2005; with permission.)

In addition to fever, abdominal pain is a characteristic feature, with accompanying diarrhea and vomiting that can resemble an acute abdomen. There are reports of patients undergoing exploratory surgery for concerns of appendicitis. In some reports, finding that adhesions were present suggested sterile peritonitis as the cause of the abdominal pain.

The definitive diagnosis of HIDS requires either a mutation in both alleles of the MVK gene or the finding of reduced function of the MVK enzyme. Most patients are compound heterozygous for missense mutations in the MVK gene, resulting in reduced activity of the MVK enzyme. In addition, the MVK gene reveals a mutation, and urinary mevalonic acid can also be slightly elevated, although usually not to the extent of the more severe MA.

Laboratory Assessment of HIDS

At the start of an attack, along with fevers, patients may have elevated acute-phase reactants: ESR, CRP, and SAA. During an attack, acute-phase reactants increase, with CRP reported at a median of 163 (range, 36–404 mg/L), as well as leukocytosis. Between attacks, there was occasionally an increase in these inflammatory markers, although less than during the attack.

Normal serum IgD (in those without HIDS) measured by radioimmunoassay varies in the literature, ranging between 0.2 and 121.0 mg/L, with mean reported at different levels from 25 mg/L to 50 mg/L. In HIDS, patients typically have 3 times the normal range, with the median IgD concentration in patients elevated to 400 U/mL (range of <0.8–5300 IU/mL), with patients typically having consistently elevated IgD levels of higher than 60 mg/L. This was not universally present in patients, as in 22% of patients the highest concentration of IgD was less than 60 mg/L; therefore, a low IgD level does not exclude the diagnosis of HIDS. In addition to elevated IgD, there is also possible concomitant elevation of serum IgA, which tends to increase with IgD as a patient ages. Also, patients with HIDS tended to have slightly elevated levels of mevalonic acid in urine, with a median value of 17 mmol/mol creatinine (normal <1) with a range from 2.8 to 10,000, and usually these numbers normalized, but the values were rarely as elevated as in patients with MA. So checking urinary mevalonic acid levels can assist in a diagnosis of HIDS, but detecting the MVK gene mutation is the definitive test.

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  Physician Orders:

  
  
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  CBC (showing leukocytosis)

  
  
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  CRP, ESR

  
  
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  SAA

  
  
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  IgD

  
  
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  Urinary mevalonic acid

  
  
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  MVK gene mutation

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