Group of rare conditions that cause children to have regular fevers alternating with periods of wellness

1. PERIODIC FEVER SYNDROMES

2. PERIODIC FEVER SYNDROMES
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3. TYPES OF PERIODIC FEVER SYNDROMES

4.  Periodic fever syndromes can be genetic. Therefore some periodic
fever syndromes are seen predominantly in specific racial groups.
 The hereditary periodic fever syndromes can be classified by the
type of inheritance:
Autosomal recessive
Autosomal dominant

5. 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 (hyper lgD
syndrome, HIDS)

6. 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:
Tumor necrosis factor receptor-associated periodic
fever(TRAPS)
Cryopyrin-associated periodic syndromes (CAPS)
Pfapa Syndrome
Muckle-Wells syndrome (MWS)

7.  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 10 years.
 The duration of the fever during an attack may be hours or be
virtually continuous, is usually typical for a particular syndrome.
 The height of the fever may range from a slight elevation of
temperature to over 40degrees Celsius.

8. GASLINI SCORE
 The Gaslini diagnostic score is used to
assess periodic fever syndromes. It is
calculated on the following:
Age at onset – the younger the onset
the more likely to be genetic
Positive family history of periodic fever
- more likely to be genetic
Chest pain
Abdominal pain
Diarrhea
Mouth ulcers

9.  The presence of any of the clinical symptoms increases the likelihood of a genetic basis.
Clinical symptoms are graded as never, sometimes, often, always. A score of 1.32 or higher in
this system determined a child with PFAPA-like febrile attacks to be at high risk of having one
of the three hereditary forms of non-CAPS periodic fever syndromes and therefore appropriate
for genetic testing.
 Of those PFAPA-like children deemed to be at high risk of having an inherited periodic fever,
the clinical features that helped direct the order of gene testing were:
Mean duration of fever
Vomiting
Enlarged spleen (splenomegaly)
 The duration of fever discriminated between TRAPS and FMF, but not between FMF and HIDS,
which were then separated by vomiting and splenomegaly which were more likely to be
present in HIDS than FMF.

11. PFAPA SYNDROME
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12. CLINICAL FEATURES
OF PFAPA
SYNDROME
 A child with PFAPA
syndrome presents with
recurrent episodes every
2-6 weeks which, in 60%,
occur with clockwork
regularity.
 The episodes last for 3-6
days and there
are symptom-free
intervals of 3-5 weeks.
Between episodes the
child is well with normal
growth and development.
 The major feature of an
episode is fever with
spikes ranging 38.5-
41C.
Aphthous
stomatitis
1-5 ulcers
small not keratinised
rapidly self-healing
oral and/or genital
oral lesions are located on the lip side of gums
Skin involvement
rare
erythema, mainly on the trunk
palmoplantar macules or purpura
Pharyngitis
follicular exudative tonsillitis
negative cultures
occur at higher frequency than in genetically-positive
PFAPA-like syndrome
Adenitis cervical lymph nodes enlarged and tender
Other features
headache
general malaise
arthritis
nausea/vomiting
Splenomegaly

13. Aphthous stomatitis and
pharyngitis
White patches on the tonsils

14. DIAGNOSIS
 Diagnosis of PFAPA syndrome is clinical, with exclusion of other causes. It is based on
recurrent fever of early onset (<5years) and at least one of the following associated features:
Aphthous stomatitis
enlarged tender lymph nodes in the neck
pharnygitis
 In the absence of:
respiratory tract infections
cyclical neutropaenia
monogenic periodic fever

15. TREATMENT OF PFAPA SYNDROME

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18. CLINICAL FEATURES OF TRAPS
 The most distinctive features of an attack are fever and migratory myalgia and swelling in the
extremities. The overlying skin is erythematous and tender.
 Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation,
nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males
are prone to developing inguinal hernias.
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19. DIAGNOSIS OF TRAPS
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20. TREATMENT OF TRAPS
Corticosteroids
Anakinra and canakinumab
 Short-term nonsteroidal anti-inflammatory drugs may be used for mild attacks. However,
inflammatory attacks usually require corticosteroids (eg, prednisone). The dosage of
corticosteroids may need to be increased over time and this therapy may, over time,
paradoxically lead to more prolonged flare-ups.
 Prophylactic therapy includes anakinra once a day and canakinumab every 4
weeks. Etanercept has proved to be only partially effective and is generally considered a
second-line prophylactic agent.

22.  It represent a spectrum of clinically overlapping autoinflammatory diseases due to mutations
in the NLRP3 gene encoding the protein cryopyrin mediating inflammation and IL-1 beta
processing
 Cryopyrin activity is augmented, triggering increased release of IL-1 beta from the NLRP3
inflammasome; the result is inflammation and fever.
Familial cold autoinflammatory syndrome (FCAS) typically causes a cold-induced urticarial
rash accompanied by fever, conjunctivitis, and sometimes arthralgias. The condition often
appears in the first year of life.
Muckle-Wells syndrome (MWS) causes intermittent fevers, urticarial rash, joint pain, and
progressive sensorineural hearing loss; 25% of patients develop renal amyloidosis.
Neonatal-onset multisystem autoinflammatory disease (NOMID) tends to cause joint and limb
deformities, facial deformities, chronic aseptic meningitis, cerebral atrophy, uveitis, papillary
edema, delayed development, and amyloidosis, in addition to fever and a migratory urticarial
rash. As many as 20% of patients die by age 20 if untreated.

23. CLINICAL
FEATURES

24. DIAGNOSIS AND TREATMENT
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27. )
 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.
 This rare genetic condition is also known as Mevalonate Kinase-
Associated Periodic Fever Syndrome.
 Symptoms usually start in the first year of life. It typically begins with
an abrupt onset of high fever (up to 104).

28. PATHOPHYSIOLOGY
 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 in accumulation of mevalonic acid and increased
interleukin 1.
 The mechanism of mevalonate kinase deficiency to cause hyper IgD is not known.

29.  It is not known how mevalonate kinase mutations cause the febrile
episodes, although it is presumed that other products of the
cholesterol biosynthesis pathway, the prenylation
chains(geranylgeraniol and farnesol) might play a role.

30.  Acute episodes may be triggered by:
Vaccinations - more than 50% report at least one episode in childhood
following an immunization
Infection
Physical and emotional stress
Trauma, including surgery

31. CLINICAL FEATURES
 In addition to chills and fever,
symptoms of hyper-IgD syndrome may
include abdominal pain, vomiting or
diarrhea, headache, and arthralgias.
 Signs of hyper-IgD syndrome include
cervical lymphadenopathy,
splenomegaly, arthritis, skin lesions
(maculopapular rash, petechiae, or
purpura), and orogenital aphthous
ulcers.

32. DIAGNOSIS
Clinical evaluation
Sometimes genetic testing
 Diagnosis of hyper-IgD syndrome is based on history, examination, and a serum IgD level
of > 100 units/L; however, up to 20% of patients have normal serum IgD levels.
 Nonspecific abnormalities include leukocytosis and elevated acute-phase reactants during
fever; elevated urinary mevalonic acid during attacks helps confirm the diagnosis.
 Genetic testing is available but is negative in 25% of patients.

33. TREATMENT
For preventing attacks, anakinra or canakinumab
For symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and anakinra
 Anakinra once a day and canakinumab every 4 weeks are proved to prevent attacks (1).
Patients can expect to have recurrent bouts of fever throughout their life, although episodes
tend to become less frequent after adolescence.
 NSAIDs and corticosteroids may help relieve symptoms during attacks. On-demand treatment
of symptoms with anakinra has been used successfully

35. REFERENCES
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