This document discusses Hyper IgD Syndrome (HIDS), a rare inherited autoinflammatory syndrome characterized by recurrent fever episodes beginning in infancy accompanied by skin rash, abdominal pain, headaches and enlarged lymph nodes. It is caused by mutations in the mevalonate kinase gene resulting in reduced cholesterol synthesis and increased inflammation. Diagnosis is based on clinical criteria including onset before age 5 and fever episodes lasting less than 14 days, along with elevated IgD levels and urine mevalonic acid during attacks. Treatment aims to reduce inflammation and frequency of attacks, but with variable success. Prognosis is generally good with improvement over time, but amyloidosis can rarely occur.

1. Hyper IgD Syndrome
Prof Ariyanto Harsono MD PhD
SpA(K)

2. Introduction
Hyperimmunoglobulinaemia D with periodic
fever syndrome is more commonly known as
hyper-IgD syndrome or HIDS. It is a rare
inherited autoinflammatory syndrome that
presents with recurrent episodes of fever, skin
rash, abdominal pain, headaches and enlarged
lymph glands that begin in infancy.
Mevalonic aciduria is a severe variant of HIDS.
Prof Ariyanto Harsono MD PhD SpA(K)
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3.  Hyper-IgD syndrome is a rare autosomal recessive disorder
in which recurring attacks of chills and fever begin during
the first year of life. Episodes usually last 4 to 6 days and
may be triggered by physiologic stress, such as vaccination
or minor trauma.
 Hyper-IgD syndrome clusters in children of
Dutch, French, and other Northern European ancestry and
is caused by mutations in the gene coding mevalonate
kinase, an enzyme important for cholesterol synthesis.
Reduction in the synthesis of anti-inflammatory
isoprenylated proteins may account for the clinical
syndrome.
Keywords: higds, mevalonate kinase, IL1, inborn error of
metebolism, recurrent fever
Prof Ariyanto Harsono MD PhD SpA(K)
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4. Etiology
Virtually all patients with the syndrome have
mutations in the gene for mevalonate
kinase, which is part of the HMG-CoA
reductase pathway, an important
cellular metabolic pathway. Indeed, similar
fever attacks (but normal IgD) have been
described in patients with mevalonic aciduria an inborn error of metabolism now seen as a
severe form of HIDS.
Prof Ariyanto Harsono MD PhD SpA(K)
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5. Pathophisiology
 The hyper-IgD syndrome is caused by mutations in the
gene encoding mevalonate kinase (MVK)
 In addition to HMG-CoA reductase, mevalonate kinase
is involved in the biosynthesis of cholesterol and
isoprenoids, and catalyses the conversion of
mevalonate to 5-phospho mevalonic acid in the
mevalonate metabolism. The enzyme mevalonate
kinase is involved in the isoprenoid pathway of
cholesterol biosynthesis. The enzyme deficiency results
accumulation of mevalonic acid and increased
interleukin 1. The mechanism of mevalonate kinase
deficiency to cause hyper IgD is not kown.
Prof Ariyanto Harsono MD PhD SpA(K)
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6. It is not known how mevalonate kinase mutations
cause the febrile episodes, although it is
presumed that other products of the cholesterol
biosynthesis pathyway, the prenylation chains
(geranylgeraniol and farnesol) might play a role.
Prof Ariyanto Harsono MD PhD SpA(K)
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7. Immunoglobulins are proteins produced by certain
white blood cells. There are five classes of
immunoglobulins known as IgA, IgD, IgE, IgG, and
IgM. Immunoglobulins play a role in defending the
body against foreign substances or microorganisms
by destroying them or coating them so they are
more easily destroyed by white blood cells. While
the specific function of other immunoglobulins is
well-known, the specific function of IgD within the
immune system is unknown.
Prof Ariyanto Harsono MD PhD SpA(K)
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8. Clinical Symptoms
In addition to chills and fever, patients may have:
abdominal pain,
vomiting or diarrhea,
headache, and
arthralgias.
Signs include cervical
lymphadenopathy, splenomegaly, arthritis, skin
lesions (maculopapular rash, petechiae, or
purpura), and orogenital aphthous ulcers
Prof Ariyanto Harsono MD PhD SpA(K)
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9.  Cutaneous signs of HIDS
o Skin rash affects up to 80% of patients. A number of skin eruptions or rashes
have been described in this syndrome, and these resolve slowly after the
febrile episode settles.
The rashes seen in HIDS are most commonly described as follows:
 small flat spots (macules)
 raised bumps (small papules or larger nodules)
 measles-like rash (morbilliform)
 hive-like rash (urticarial).
 Less common or rare skin presentations include:
 Henoch-Schönlein purpura
 erythema elevatum diutinum
 petechiae (tiny bleeding spots or purpura)
 erythema nodosum.
o Oral and/or vaginal aphthous ulcers affect 50% of patients.
Prof Ariyanto Harsono MD PhD SpA(K)
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10. Symptom
Features

over 40C

preceding chills and malaise

affects up to 80%

various presentations (see below)
Headache

nonspecific
Enlarged lymph nodes in neck

characteristic

bilateral

painful

severe

diarrhoea and vomiting

peritonitis

arthralgia (pain) or arthritis (swelling)

most common in young patients

affects large joints

symmetrical, polyarticular, non-destructive

symptoms occur with abdominal pain and settle slowly

affects 50% of children
Fever
Skin rash
Abdominal pain
Joint pain
Enlarged liver and spleen (hepatosplenomegaly)
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Tendonitis

11. Trigger
Acute episodes may be triggered by:
o Vaccinations – more than 50% report at least
one episode in childhood following an
immunisation
o Infection
o Physical and emotional stress
o Trauma, including surgery
Prof Ariyanto Harsono MD PhD SpA(K)
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12. Diagnosis
The characteristic recurrent acute febrile attacks
without a clear infectious or autoimmune
cause, suggest the need for investigation.
 Clinical criteria
In addition to the the of febrile attacks outlined
above, clinical diagnostic criteria should include:
o Onset before the age of 5 years
o Episodes last less than 14 days
o MVK gene mutations are unlikely if these features are
not present.
Prof Ariyanto Harsono MD PhD SpA(K)
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13. IgD levels
Raised levels of IgD can be found in many but not
all patients, especially in children under 3 years of
age. Levels are raised not only during an attack
but between attacks. Elevations of IgD levels can
occur in other periodic fever syndromes such
as familial Mediterranean fever and TRAPS, and
other chronic inflammatory conditions, so it
should be interpreted with caution.
Prof Ariyanto Harsono MD PhD SpA(K)
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14.  Other useful tests
o Urine organic acids measured during an acute attack usually
show raised levels of mevalonic acid.
o During an attack:
 leukocytosis,
 Increase erythrocyte sedimentation rate (ESR),
 increaseC-reactive protein (CRP) and serum amyloid A (SAA).
 Serum IgA levels may also be increased.
o Radiometric assay testing can demonstrate reduced
mevalonate kinase activity in white blood cells or cultured
fibroblasts.
o Skin biopsy may show a mild vasculitis which may extend
deeply. Changes may resemble Sweet disease or cellulitis.
Prof Ariyanto Harsono MD PhD SpA(K)
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15. DNA analysis
DNA analysis showing two disease-linked
mutations in the MVK gene is used to confirm the
diagnosis of HIDS. In most cases the patient has
two different mutations, called compound
heterozygosity.
Prof Ariyanto Harsono MD PhD SpA(K)
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16. Treatment of HIDS
Many treatments have been tried in HIDS, none with uniform
success:
 Colchicine – is generally unhelpful although there are case
reports of its successful use
 Non-steroidal anti-inflammatory drugs (NSAID)
 Statins – such as simvastatin, inhibit HMGCoA-reductase
resulting in reduced production of mevalonic acid
 Systemic corticosteroids – a single dose at the start of an
attack may reduce the severity and duration (1mg/kg)
Prof Ariyanto Harsono MD PhD SpA(K)
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17. Dapsone
Ciclosporin
Thalidomide
Intravenous immunoglobulin (IVIG)
Biologic agents– including anakinra (interleukin-1
receptor antagonist) and etanercept (tumour
necrosis factor alfa inhibitor) have been reported
to reduce the frequency and/or severity of attacks
in 80%. However there have also been cases
where these agents have increased the frequency
and/or prolonged attacks.
Prof Ariyanto Harsono MD PhD SpA(K)
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18. Prognosis
 There is a tendency to improve with age, with
less frequent and less severe attacks by
adulthood. Between episodes, health is normal.
 A small subgroup of affected patients develop
neurologic abnormalities in adulthood, similar to
mevalonic aciduria.
 Unlike familial Mediterranean fever, amyloidosis
is rarely seen in HIDS, affecting less than 3%.
 Life expectancy is usually normal, however this
can be affected by renal failure due to
amyloidosis or severe infections.
Prof Ariyanto Harsono MD PhD SpA(K)
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19. Mevalonic aciduria
Mevalonic aciduria involves the same gene and
enzyme as HIDS, however the resulting enzyme
deficiency is virtually complete. The condition is also
called mevalonate kinase deficiency. The gene
mutations so far identified have been localised to
one end of the enzyme. Mevalonic aciduria results
in neurological effects that mainly arise because of
inadequate cholesterol, which is required for brain
and nerve development.
Prof Ariyanto Harsono MD PhD SpA(K)
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20.  Patients with mevalonic aciduria suffer the same
febrile episodes as in HIDS, but in addition develop
profound developmental delay, retinal dystrophy
(visual defects) and cataracts, mild facial
deformities, and liver/spleen enlargement. Those less
severely affected have mental retardation, failure to
thrive, progressive cerebellar ataxia (unsteadiness) and
anaemia. In childhood and adolescence, eye problems
develop, including cataracts and uveitis. Myopathy
(muscle weakness) can occur. In those severely
affected, mevalonic aciduria is commonly fatal in
infancy/childhood.
Prof Ariyanto Harsono MD PhD SpA(K)
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21. High levels of mevalonic acid are detected in
the urine at all times.
Genetic counselling should be performed for
families with an affected child and prenatal
testing should be considered.
Prof Ariyanto Harsono MD PhD SpA(K)
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22. Periodic fever syndromes
Prof Ariyanto Harsono MD PhD
SpA(K)

23. Periodic fever syndromes are conditions in which the
patient experiences recurrent episodes of fever with
associated inflammatory symptoms, in the absence of
infection, allergy, malignancy, immunodeficiency or
autoimmune conditions. They are one category
of autoinflammatory syndromes.
Familial Mediterranean fever (FMF) is the most
common and best known of the hereditary periodic
fever syndromes. Inherited (genetic) forms of periodic
fever syndromes are also known as hereditary recurrent
fever syndromes. Nonfamilial syndromes have also
been described.
Prof Ariyanto Harsono MD PhD SpA(K)
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24. Periodic fever syndromes can be genetic conditions.
Therefore some periodic fever syndromes are seen
predominantly in specific racial groups. Familial
Mediterranean fever, for example, affects races
originating from around the eastern Mediterranean
area.
The hereditary periodic fever syndromes can be
classified by the type of inheritance:
Autosomal recessive
 Autosomal dominant
Prof Ariyanto Harsono MD PhD SpA(K)
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25. Autosomal recessive periodic fever syndromes
Genetic conditions with this type of inheritance require two
copies of the abnormal gene; one copy inherited from each
parent. Although the defective gene is usually the same in
each parent, the actual mutation may be
different, i.e., heterogeneous homozygotes or compound
heterozygotes. The parents are asymptomatic carriers of the
defect.
Autosomal recessive periodic fever syndromes with skin
involvement include:
 Familial Mediterranean fever (FMF)
 Hyperimmunoglobulinaemia D syndrome (hyperIgD
syndrome, HIDS)
Prof Ariyanto Harsono MD PhD SpA(K)
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26. Autosomal dominant periodic fever syndromes
Only a single copy of the defective gene is required to develop
symptoms and signs of an autosomal dominant periodic fever
syndrome. Therefore the condition is usually inherited from an
affected parent or, less commonly, is due to a spontaneous
mutation in the affected child.
Autosomal dominant periodic fever syndromes with skin
involvement include:
 Tumour necrosis factor receptor-associated periodic fever
(TRAPS)
 Cryopyrin-associated periodic syndromes (CAPS)
 Familial cold autoinflammatory syndrome (FCAS)
 Muckle-Wells syndrome (MWS)
Prof Ariyanto Harsono MD PhD SpA(K)
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27. Molecular biology of periodic fever syndromes
The defective gene has been identified for these
hereditary periodic fever syndromes. The defective
gene is different for each of the syndromes with the
exception being the three clinically distinct syndromes
that are now clustered as the cryopyrin-associated
periodic syndromes (CAPS).
All periodic fever syndromes result in overstimulation
of the innate immune system, usually due to overactivity of interleukin 1.
Prof Ariyanto Harsono MD PhD SpA(K)
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28. Nonhereditary periodic fever syndromes with
skin involvement include:
PFAPA syndrome
Schnitzler syndrome
The cause of these syndromes is not yet known.
Prof Ariyanto Harsono MD PhD SpA(K)
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29. Symptoms
The one clinical feature in common between all the
periodic fever syndromes is the recurrent episodes of
fever in the absence of infection, autoimmune disease
or malignancy.
The frequency of febrile attacks can vary between
individuals and syndromes from daily to once every ten
years. The duration of the fever during an attak may be
hours or be virtually continuous, but is usually typical
for a particular syndrome. The height of the fever may
range from a slight elevation of temperature to over 40
degrees Celsius.
Prof Ariyanto Harsono MD PhD SpA(K)
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30. The age at which the febrile attacks begin is also
highly variable between the different syndromes
with some beginning at or shortly after birth but
others being delayed even as late as middle age.
In some periodic fever syndromes there are wellrecognised triggers for a febrile attack, such as
generalised exposure to cold triggering a fever in
familial cold autoinflammatory syndrome (FCAS) But
in others no trigger is identified.
Prof Ariyanto Harsono MD PhD SpA(K)
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31. Most periodic fever syndromes have associated
symptoms and signs of inflammation at the same
time as the fever. Commonly these affect the serosal
surfaces, joints, eyes and skin. In some forms the
predominant associated symptom is severe
abdominal pain often leading to unnecessary
exploratory surgery. In others, joint or neurological
involvement can result in major disability.
Prof Ariyanto Harsono MD PhD SpA(K)
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32. Quality of life can be severely impacted, particularly
if febrile attacks are frequent or in those forms of
periodic fever syndrome that develop joint or
neurological complications.
Secondary systemic amyloidosis develops in some
periodic fever syndromes and this can result in lifethreatening complications.
Prof Ariyanto Harsono MD PhD SpA(K)
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33. Diagnosis
Periodic fever syndromes should be suspected
clinically when the patient presents with recurrent
episodes of fever associated with other
inflammatory symptoms. However this can be
difficult if the attacks are very infrequent, such once
every few years, or continuous. A family history of
such episodes is not always present, but is helpful if
known.
Prof Ariyanto Harsono MD PhD SpA(K)
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34. Periodic fever syndromes can only be considered
after infections, allergies, malignancy,
immunodeficiencies and autoimmune diseases are
excluded.
In children, it can be difficult to distinguish
hereditary periodic fevers from the much
commoner PFAPA syndrome as there are
overlapping clinical features. The Gaslini score may
help identify those most likely to benefit from
genetic testing, and then to determine the order in
which genes should be sequenced.
Prof Ariyanto Harsono MD PhD SpA(K)
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35. Some specific periodic fever syndromes can be
diagnosed on biochemical testing or challenge with
the known trigger. An example of the former
is HIDS, which typically is associated with a very high
level of IgD in the blood. Triggering of an attack
within hours of generalised exposure to cold
in FCAS is an example of the latter category.
Prof Ariyanto Harsono MD PhD SpA(K)
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36. Genetic testing is often definitive if positive, but not
all mutations are known or easily tested for. A
negative test does not exclude the diagnosis. In
these cases, the diagnosis must be reached on
clinical criteria. Genetic testing of the
MEFV, TNFRSF1A and MVK genes detects a mutation
in 20% of patients with clinical symptoms suggestive
of a periodic fever syndrome.
Prof Ariyanto Harsono MD PhD SpA(K)
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37. A rapid and complete response to a trial of therapy
may support the clinical diagnosis. Familial
Mediterranean fever (FMF) responds to colchicine in
over 90% of cases. Interleukin-1 blockade
with biologic agents results in dramatic resolution of
symptoms within hours of the first injection in some
specific syndromes.
Prof Ariyanto Harsono MD PhD SpA(K)
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38. Treatment
Acute attacks of hereditary periodic fever
syndromes are usually treated with bed rest, antiinflammatory agents, analgesics and
sometimes systemic corticosteroids. The fever does
not respond to aspirin or paracetamol.
Avoidance of triggers, where known, can reduce the
frequency of attacks. Sufferers of familial coldassociated syndrome (FCAS) often move to
temperate climates to avoid cold winters and hot
summers, for example.
Prof Ariyanto Harsono MD PhD SpA(K)
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39. To prevent febrile episodes, improve quality of life
and minimise longterm complications, continuous
treatment may be required for some forms. Apart
from colchicine for familial Mediterranean fever,
treatment of the hereditary periodic fever
syndromes is with biologic agents such as anakinra,
given by subcutaneous injection. Treatment should
be started as early as possible to prevent the
development of life-threatening complications in
such periodic fever syndromes.
Prof Ariyanto Harsono MD PhD SpA(K)
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40. Autoinflammatory syndromes
Prof Ariyanto Harsono MD PhD
SpA(K)

41. Autoinflammatory syndromes are defined as
conditions caused by an exaggerated innate immune
system response resulting in episodes of
spontaneous inflammation affecting multiple organs.
An autoinflammatory syndrome can only be
diagnosed when infective
conditions, malignancy, allergic
and immunodeficiency conditions have been
excluded. Compared to classical autoimmune
diseases, autoinflammatory syndromes lack
pathogenic autoantibodies and antigen-specific T
cells.
Prof Ariyanto Harsono MD PhD SpA(K)
41

42. Classification of autoinflammatory syndromes
Autoinflammatory syndromes may be inherited
through mutations to a single gene (monogenic
autoinflammatory syndromes), or, more
commonly, are polygenic immune conditions that
resemble autoimmune collagen disorders. The
number of conditions included is increasing as
molecular and genetic studies reveal disease
mechanisms.
A classification system, with examples of syndromes
with dermatologic manifestations, follows.
Prof Ariyanto Harsono MD PhD SpA(K)
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43. Hereditary fever syndromes
Familial Mediterranean fever (FMF)
Tumour necrosis factor receptor-associated
periodic fever syndrome (TRAPS)
Hyper-IgD syndrome (HIDS)
Prof Ariyanto Harsono MD PhD SpA(K)
43

44.  Other monogenic autoinflammatory syndromes
 Cryopyrin-associated periodic syndromes (CAPS)
o Familial cold autoinflammatory syndrome ( FCAS)
o Muckle-Wells syndrome (MWS)
o Neonatal onset multisystem inflammatory disease/chronic
Infantile neurologic cutaneous arthropathy syndrome
(NOMID/CINCA)
 Syndrome of pyogenic arthritis, pyoderma gangrenosum
and acne (PAPA syndrome, PAPAS, PAPGA syndrome)
 Juvenile systemic granulomatosis (Blau syndrome, early
onset sarcoidosis)
 Deficiency of interleukin-1 receptor antagonist (DIRA)
 Mevalonic aciduria
 Majeed syndrome
Prof Ariyanto Harsono MD PhD SpA(K)
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45. Nonhereditary or polygenic disorders
 Schnitzler syndrome
 Crohn disease
 Behcet disease
 Psoriatic arthritis
 Syndrome of periodic fever, aphthous stomatitis,
pharyngitis and adenitis (PAPAS, PFAPA syndrome)
Systemic-onset juvenile idiopathic arthritis
 Adult-onset Still disease
Prof Ariyanto Harsono MD PhD SpA(K)
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46. Treatment
Treatment varies with the actual syndrome. In many
forms, systemic corticosteroids have only a modest
effect. Biologic agents such as anakinra (which
targets IL-1) result in a dramatic and consistent
improvement in those syndromes where a clear link
to IL-1 has been shown. There is less consistent
benefit in other conditions where a direct link with
IL-1 has not been found.
Prof Ariyanto Harsono MD PhD SpA(K)
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47. Thank you
Prof Ariyanto Harsono MD PhD SpA(K)
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