Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis

INTRODUCTION — Hyperimmunoglobulin D syndrome (HIDS; MIM #260920) is a rare, autosomal recessive genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level. Classic HIDS is due to compound heterozygous or homozygous mutation in the mevalonate kinase (MVK) gene. The underlying genetic defect is not known in variant HIDS.

Recurrent fever that is not due to infection is a clinical feature of several disorders that are collectively referred to as autoinflammatory diseases. HIDS is one of the major periodic fever syndromes, a subset of autoinflammatory diseases mediated by inflammasome activation (inflammasomopathies). An overview of periodic and recurrent fevers and other autoinflammatory diseases is presented separately. (See "The autoinflammatory diseases: An overview".)

The clinical manifestations, laboratory features, and diagnosis of HIDS are reviewed here. Pathophysiology and management of HIDS are presented separately. (See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Management".)

EPIDEMIOLOGY — HIDS typically presents during the first year of life [1]. The median age of onset of symptoms was six months in one series (range one week to 10 years of age) [2]. Most patients (78 percent) experienced their first attack within the first year of life.

HIDS is equally common in males and females. More than 60 percent of patients are of Dutch or French ancestry, although HIDS cases have been reported around the world, including in the United Kingdom, Germany, Italy, Turkey, the Czech Republic, the United States, Japan, and the Arabian peninsula [1,3-6].

CLINICAL MANIFESTATIONS — Unremitting fever lasting several days and the presence of lymphadenopathy, splenomegaly, arthralgia/arthritis, abdominal pain, and rash are characteristic of the recurrent episodes that occur in patients with HIDS (table 1) [1,2]. Symptoms vanish as the fever declines. The exception is skin and joint manifestations, which tend to linger, although they still typically resolve before the onset of the next attack. Symptom length can vary greatly by individual.

The interval between attacks is commonly four to eight weeks but can vary significantly even in the same patient [1]. Children and adolescents often have shorter intervals, but no strict periodicity has been identified. Patients are virtually symptom free between attacks. Provocative factors include vaccinations, minor trauma, surgery, and stress, although a trigger is not always apparent.

Fever — HIDS episodes are characterized by the rapid onset of fever, often heralded by chills, and an increase in temperature to over 101.3°F (38.5°C). The febrile episodes typically last four to seven days, and the fever does not remit until the episode concludes [1,2].

Most patients or caregivers can predict the impending onset of fever by recognizing prodromal symptoms that include nasal congestion, sore throat, backache, fatigue, vertigo, headache, and even behavioral changes.

Lymphadenopathy — Over 90 percent of patients have palpable lymphadenopathy during a febrile episode. The cervical region is the most commonly involved site, but almost all lymph node groups may be affected. Nodes are tender and/or rubbery on palpation. Lymph node biopsies show various nonspecific changes including hyperplasia and the presence of plasma cells [1].

Abdominal pain — Aside from fever, abdominal pain may be the cardinal feature of an attack and is seen in approximately 85 percent of patients [2]. The pain may be accompanied by vomiting (71 percent) and/or diarrhea (72 percent). The level of pain may mimic an acute abdomen and has prompted appendectomies and exploratory laparotomies. Inevitably, the appendix is found to be normal. Abdominal adhesions have been found in a few cases and are sometimes extensive enough to cause a mechanical ileus [1].

Splenomegaly — Palpable splenomegaly is noted in approximately 50 percent of patients, most of whom are children [1]. The prevalence of splenomegaly in adults is uncertain.

Arthralgia/arthritis — Eighty percent of patients with HIDS may experience polyarthralgia with a febrile episode. Most of those with arthralgia develop objective signs of arthritis. Larger joints are more commonly affected than smaller ones and often in a symmetrical fashion. Joint involvement has not been seen in the absence of an ongoing or preceding febrile episode. Joint symptoms tend to linger beyond the end of the febrile period. Long-term joint destruction does not appear to occur [1,7].

Mucocutaneous manifestations — Cutaneous manifestations occur in over 80 percent of HIDS patients. An erythematous macular rash is the most commonly noted, followed in frequency by papules, urticaria, erythematous nodules, and petechiae. Eruptions typically consist of multiple lesions, which usually remain separate but may become confluent. Acral lesions occur more frequently than truncal lesions. Skin biopsies typically demonstrate endothelial swelling and perivascular inflammatory infiltrates [1,8].

Aphthous ulcers are reported to occur with a frequency of 48.5 percent, with or without genital ulcers (frequency not reported) [2]. They can be a very prominent symptom, as evidenced by three patients in a case series of approximately 100 who were initially diagnosed with Behçet syndrome prior to being diagnosed with HIDS [2].

Other manifestations — Up to 12 percent of patients may develop serositis during an attack [9,10]. Orbital tendonitis with tendomyositis was reported in a single patient [11]. Secondary (amyloid A, AA) amyloidosis is a rare but serious long-term complication of HIDS [12-16] (see "Overview of amyloidosis", section on 'Clinical manifestations'). One case of nummular keratopathy successfully controlled with infliximab was also reported [17].

HIDS during pregnancy — There is a paucity of data on HIDS and pregnancy. Two women with HIDS experienced a decrease in frequency of attacks during their pregnancies, had no complications of pregnancy, and had healthy newborns [18]. Another woman had no attacks or complications during three pregnancies [19].

Variant HIDS — Variant HIDS cases differ from classic HIDS in the lack of a known genetic mutation. Such patients can present later in life, even into adulthood, and sometimes manifest less common symptoms such as serositis, hepatomegaly, and splenomegaly (seen in 19, 22, and 32 percent, respectively, in one case series) [2]. In addition, the intervals between attacks tend to be more variable. These patients also have elevated serum IgD and immunoglobulin A (IgA) as diagnostic laboratory findings, although levels may be lower than in patients with classic HIDS [9]. (See "Hyperimmunoglobulin D syndrome: Pathophysiology", section on 'Variant HIDS'.)

Overlap syndromes — Although rare, some patients may develop features that overlap with other periodic fever syndromes. As an example, one case report highlights a 10-year-old boy with tumor necrosis factor receptor 1 associated periodic syndrome (TRAPS) who also had some features suggestive of HIDS including an elevated IgD level [20]. Another patient had mutations in both the gene associated with HIDS (MVK V377I and L234P mutations) and the gene associated with TRAPS (TNFRSF1A R92Q mutation) [14]. This patient developed amyloidosis, which is very rare in HIDS but occurs in approximately 15 percent of patients with TRAPS. In another case report, a patient with a similar mutation combination (MVK V377I and TNFRSF1A R92Q) had mild HIDS-associated clinical features but did not have evidence of TRAPS-associated features including amyloidosis [21]. (See "Hyperimmunoglobulin D syndrome: Pathophysiology", section on 'Overlap syndromes' and "The autoinflammatory diseases: An overview".)

However, the R92Q mutation is present in 3 to 5 percent of the White population, which suggests that it is a benign polymorphism rather than a pathogenic variant. It is also possible that the R92Q mutation is not causative, per se, but may be a genetic modifier of other inflammatory diseases (ie, modifies the presentation of the MVK mutations rather than causing TRAPS in a patient that also has HIDS). (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)", section on 'Genetics'.)

LABORATORY FINDINGS — Elevated serum levels of IgD and IgA are frequently noted (table 1). These levels usually remain elevated even between attacks. Reference ranges for these immunoglobulins vary by age (table 2A-B) [22,23]. Levels of other immunoglobulins are normal.

Immunoglobulin D level — As its name suggests, hyperimmunoglobulin D syndrome is usually characterized by an elevated serum polyclonal IgD greater than 14 mg/dL (100 international units/mL) [1], though normal levels do not exclude the disease [24-26]. In one series, 22 percent of patients had a normal maximum IgD level, even when measured serially over time including during and between attacks [2]. Initially thought to be etiologically linked to the pathophysiology, some now consider elevated IgD levels to be an epiphenomenon secondary to the systemic inflammatory process [27].

An elevated IgD is only suggestive of HIDS in the setting of clinical features consistent with the disorder. Despite the name (hyper-IgD syndrome), an elevated IgD alone does not make the diagnosis. (See 'Causes of elevated immunoglobulin D' below.)

Immunoglobulin A level — The serum IgA level is elevated (>260 mg/dL) in 64 to 80 percent of cases [1,2,28]. The elevation is typically due to an increase in polymeric-IgA1 rather than IgA1 monomer or IgA2 [28].

Acute phase reactants — Other laboratory findings during attacks are those associated with an acute systemic inflammatory process, including elevated levels of the following [1,29]:

●Leukocytes in peripheral blood (predominantly neutrophils)

●Erythrocyte sedimentation rate (ESR)

●C-reactive protein (CRP)

●Ferritin

●Serum amyloid A (SAA)

Forty-five percent of patients may continue to have elevated SAA levels between attacks [30]. The other acute phase reactants typically return to normal or are only mildly elevated between attacks [1,2].

Urinary mevalonic acid — Excretion of mevalonic acid in the urine may be minimally elevated during febrile episodes but are typically normal between episodes [31]. In contrast, urinary mevalonic acid levels are chronically elevated, and usually to higher levels, in patients with mevalonic aciduria. Mevalonic acid excretion is assessed by determining the ratio of mevalonic acid to creatinine in an untimed sample of urine. An elevated ratio (>20 mmol/mol creatinine) is suggestive of HIDS [32]. However, techniques and sensitivities for measuring urinary mevalonic acid levels vary widely [33]. Thus, we do not recommend the use of the urinary mevalonic acid-to-urine creatinine ratio as a confirmatory test for HIDS. (See 'Mevalonic aciduria' below.)

Urinary LTE4 — Urinary leukotriene E4 (LTE4) excretion may be elevated during febrile episodes, as illustrated in a study of seven children with HIDS. During flares, affected children had urinary LTE4 levels of 46 to 199 nmol/mol creatinine with a mean of 92 (normal <40 nmol/mol creatinine) compared with levels of 30 to 40 nmol/mol creatinine with a mean of 36 during asymptomatic intervals [34]. Urinary LTE4 levels were undetectable in 20 other children without HIDS who had bacterial or viral illnesses. Further studies and standardization of testing techniques are required before urinary LTE4 levels are ready for use as a diagnostic tool for HIDS.

DIAGNOSIS — HIDS should be suspected in patients with unremitting fever lasting several days that is accompanied by one or more of the following: lymphadenopathy, splenomegaly, arthralgia/arthritis, abdominal pain, and rash (table 1). If the diagnosis is suspected on clinical grounds, serum IgD should be measured (IgA is also typically measured but is not required for diagnosis) (algorithm 1). The finding of elevated serum IgD with or without an elevated IgA level is sufficient to confirm the diagnosis [35]. Normal values for IgD and IgA differ by age in children and should be taken into consideration (table 2A-B). Suspected cases of classic, but not variant, HIDS with normal serum IgD and IgA levels can be diagnosed by genetic testing [24,25]. Genetic testing is otherwise not required to confirm the diagnosis. However, it is useful for establishing a family pedigree, and it is the most definitive diagnostic test if a mutation is identified. (See 'Genetic testing' below.)

The median period from disease onset to diagnosis is approximately 14 years in patients who lack a family history of HIDS, and approximately one-third of patients are initially misdiagnosed with another disorder [2]. This delay in diagnosis is due to the fact that symptoms manifested by patients with HIDS are typical of more common illnesses that are usually excluded before rarer diagnoses are considered. The periodic pattern of symptom recurrence is often the clue that finally leads to the correct diagnosis. Given the rarity of serious, long-term complications, the rationale for confirming the diagnosis of HIDS is to minimize the morbidity associated with extensive workups and unnecessary surgeries [33].

Genetic testing — At least 63 mutations in the MVK gene have been noted in association with HIDS [31,32,36,37]. The finding of a compound heterozygous or homozygous previously reported MVK mutation in a patient with clinical suspicion of HIDS establishes the diagnosis. Identification of the V377I mutation (most common) is confirmatory [35]. In the absence of this mutation, genetic sequencing of the MVK gene may be requested if the clinical suspicion of HIDS is high but IgD and IgA levels are normal (table 3). A negative genetic analysis should not dissuade the clinician from the diagnosis in the face of other positive clinical and laboratory findings consistent with HIDS, since there are most likely other mutations unidentified as of yet. Nearly one-quarter of patients with compatible clinical symptoms, physical findings, and immunoglobulin levels do not have MVK mutations and are categorized as having variant HIDS. (See 'Variant HIDS' above.)

Genetic testing for HIDS is unlikely to be positive in patients whose febrile attacks began at ≥5 years of age, last more than 14 days, and do not have associated joint pain [38]. Patients with these features are more likely to have variant HIDS.

Genetic testing for other periodic fever syndromes is indicated if there are overlapping features or an atypical presentation [10]. Identification of known mutations is considered diagnostic only in the face of typical clinical manifestations since the genetic penetrance is less than 100 percent [39]. (See 'Differential diagnosis' below and 'Overlap syndromes' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HIDS includes other causes of recurrent or periodic fever or of recurrent, severe abdominal pain. Other diseases should be suspected in the setting of an elevated IgD without other clinical features suggestive of HIDS. Even when there is a family history of HIDS, alternative diagnoses, particularly infectious diseases and surgical emergencies, must be considered and excluded when a child or adult presents with fever and abdominal pain. Among them are the following:

●Surgical emergencies (eg, appendicitis, intussusception, perforated peptic ulcer) (see "Acute appendicitis in children: Clinical manifestations and diagnosis" and "Intussusception in children" and "Overview of complications of peptic ulcer disease", section on 'Perforation')

●Relapsing pancreatitis (see "Clinical manifestations and diagnosis of acute pancreatitis")

Causes of recurrent or periodic fever — For the patient with recurrent or periodic fever in whom an infectious etiology has been excluded, other syndromes of unknown etiology or rare, heritable diseases may be considered. The length of the febrile episodes and the interval from episode to episode are helpful in differentiating between the periodic fever syndromes (this can be determined by having the caregivers/patient keep a fever diary), as is the age at onset, certain clinical features, and response to particular treatments. The Eurofever classification criteria can be used to help determine which periodic fever syndrome is most likely [40]. The periodic fever syndromes are briefly reviewed here. An overview of the causes of periodic and recurrent fevers is presented in detail separately. (See "The autoinflammatory diseases: An overview".)

Familial Mediterranean fever — The typical manifestations of familial Mediterranean fever (FMF) are recurrent attacks of severe pain (due to serositis at one or more sites) and fever lasting one to three days and then resolving spontaneously. In between attacks, patients feel entirely well. Colchicine prevents attacks in most patients, an effect that is not seen in HIDS. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)

Tumor necrosis factor receptor-1 associated periodic syndrome — The febrile episodes of tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS) generally last longer than those of HIDS. They may continue for up to two weeks. Other clinical features of TRAPS that are not typically seen in HIDS include conjunctivitis, periorbital edema, and myalgias. Abdominal pain may be prominent in both diseases, but arthritis in TRAPS is uncommon and, when present, is typically monoarticular. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

Periodic fever with aphthous stomatitis, pharyngitis and adenitis syndrome — The periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a disease of unknown etiology and uncertain pathogenesis. It presents in childhood and is characterized by periodic fevers at regular intervals of four to six weeks and stereotypical symptoms of pharyngitis, aphthous ulcers, and cervical adenitis. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

Muckle-Wells syndrome — The Muckle-Wells syndrome is a rare, periodic syndrome characterized by an urticarial rash, fever, arthralgia/arthritis, and sensorineural hearing loss beginning in childhood. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Muckle-Wells syndrome'.)

Familial cold autoinflammatory syndrome — Formerly called familial cold urticaria, familial cold autoinflammatory syndrome (FCAS) is an unusual condition in which exposure to generalized cold results in fever, an urticarial rash, conjunctival injection, and arthralgia. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Familial cold autoinflammatory syndrome'.)

Mevalonic aciduria — Mevalonic aciduria (MEVA; MIM #610377) is also associated with mutations in both alleles of the MVK gene. However, the phenotype of MEVA is more severe and often lethal in infancy. In addition to experiencing febrile episodes and HIDS-like features of recurrent fever, lymphadenopathy, and skin rash, infants with MEVA can also present with developmental delay, ataxia, failure to thrive, dysmorphic features, hepatosplenomegaly, cytopenias, myopathy, and cataracts [41,42]. Very little or no MVK enzyme activity is present in affected children (<0.5 percent activity compared with normal controls), and large amounts of mevalonic acid are excreted in the urine [31,32]. Patients are often homozygous for certain mutations, such as H20P, I268T, and A334T [43]. Structural analysis suggests that these mutations interfere with the active sites of the MVK enzyme, thereby significantly reducing or inhibiting its activity [44].

Some experts feel that MEVA and HIDS are simply two points on a spectrum of disease, termed mevalonate kinase deficiency (MKD) [42,45,46]. Support for this view includes the observations that IgD is not elevated in all cases of HIDS and it is elevated in some patients with MEVA [6,47,48]. Other experts disagree and maintain that HIDS and MEVA are clinically distinct diseases [49].

Causes of recurrent severe abdominal pain — The differential diagnosis of acute abdominal pain in children and adults is very broad and is discussed in detail elsewhere. Nonsurgical causes of recurrent, severe abdominal pain that should be considered in the differential diagnosis include hereditary or acquired angioedema and acute intermittent porphyria. (See "Causes of acute abdominal pain in children and adolescents" and "Causes of abdominal pain in adults".)

Hereditary or acquired angioedema — Patients with hereditary or acquired angioedema due to abnormalities in the level or function of the regulatory C1 inhibitor (C1-Inh) protein may develop bowel wall swelling that can result in severe abdominal pain, nausea, and vomiting. Such symptoms can mimic other acute abdominal syndromes but are distinguished from the abdominal pain of HIDS by the absence of mechanistically associated fever. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

Acute intermittent porphyria — Acute intermittent porphyria (AIP) typically begins after puberty and is more common in females than males. Abdominal pain, often severe, may be generalized or localized and may be accompanied by fever. There are no cutaneous manifestations of AIP. Peripheral neuropathy and anxiety or other psychiatric disorders are relatively common features of AIP that are not typically seen in HIDS. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

Causes of elevated immunoglobulin D — An elevated IgD level alone is not pathognomonic for HIDS, despite the name. In the absence of clinical features suggestive of HIDS, patients should be evaluated for other causes of an elevated IgD (though not always polyclonal). These include:

●Hodgkin disease (see "Overview of Hodgkin lymphoma in children and adolescents")

●Sarcoidosis (see "Overview of extrapulmonary manifestations of sarcoidosis")

●Tuberculosis (see "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis")

●Aspergillosis (see "Epidemiology and clinical manifestations of invasive aspergillosis")

●Ataxia-telangiectasia (see "Ataxia-telangiectasia")

●Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (see "Pediatric HIV infection: Classification, clinical manifestations, and outcome" and "Acute and early HIV infection: Clinical manifestations and diagnosis")

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Unremitting fever lasting four to seven days and the presence of palpable tender lymphadenopathy, splenomegaly, arthralgia/arthritis, abdominal pain, and rash are characteristic of the recurrent episodes that occur in patients with hyperimmunoglobulin D syndrome (HIDS). Symptoms and signs of an episode of HIDS typically resolve along with the fever. An exception is arthralgia or arthritis, which may linger a bit longer but does not cause joint damage. The rash seen in HIDS is usually an erythematous macular eruption but may be papular, urticarial, nodular, or petechial in nature. Half of patients also have aphthous ulcers. (See 'Clinical manifestations' above.)

●Laboratory findings – Laboratory findings suggestive of HIDS include elevated age-specific serum immunoglobulin D (IgD) and/or immunoglobulin A (IgA) levels, elevation of acute phase reactants, and urinary excretion of mevalonic acid during, but not between, attacks. (See 'Laboratory findings' above.)

●Diagnosis – If the diagnosis of HIDS is suspected based upon clinical features, we suggest measurement of serum IgD (algorithm 1). The diagnosis is established if an elevated age-specific level of IgD is detected. IgA levels are typically measured at the same time but are not required for diagnosis. (See 'Diagnosis' above.)

●When to perform genetic testing – If the IgD level is not elevated, but HIDS is still suspected, we suggest genetic testing for the presence of a mutation in the mevalonate kinase (MVK) gene as an aid to diagnosis. Genetic testing can identify individuals with classic, but not variant, HIDS. (See 'Genetic testing' above and 'Variant HIDS' above and "Hyperimmunoglobulin D syndrome: Pathophysiology", section on 'Genetics'.)

●Differential diagnosis – The differential diagnosis of HIDS includes other causes of recurrent or periodic fevers or of recurrent severe abdominal pain. Even when there is a family history of HIDS, alternative diagnoses, particularly infectious diseases and surgical emergencies, must be considered and excluded when a child or adult presents with fever and abdominal pain. Other diseases should be suspected in the setting of an elevated IgD without other clinical features suggestive of HIDS. (See 'Differential diagnosis' above.)

•Recurrent or periodic fever – For the patient with recurrent or periodic fever in whom an infectious etiology has been excluded, other syndromes of unknown etiology or rare heritable diseases should be considered. Among these are the periodic fevers with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, tumor necrosis factor receptor 1 associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), Muckle-Wells syndrome, familial cold autoinflammatory syndrome (FACS), and mevalonic aciduria (MEVA). (See 'Causes of recurrent or periodic fever' above.)

•Recurrent, severe abdominal pain – Nonsurgical causes of recurrent severe abdominal pain include hereditary or acquired angioedema and acute intermittent porphyria (AIP). (See 'Causes of recurrent severe abdominal pain' above and "Causes of acute abdominal pain in children and adolescents" and "Causes of abdominal pain in adults".)

•Elevated IgD – Elevated serum IgD is not specific for HIDS and can occur in patients with certain neoplastic, infectious, heritable, and idiopathic disorders. (See 'Causes of elevated immunoglobulin D' above.)