1) Hereditary periodic fever syndromes (HPFS) are a group of genetic autoinflammatory disorders characterized by recurrent episodes of fever along with inflammation in various organs. 2) The underlying causes of HPFS and autoimmune diseases are both immune system malfunctions, but HPFS involve dysregulation of the innate immune system and its inflammatory cytokines like IL-1 and TNF-α, while autoimmune diseases involve issues with the adaptive immune system and autoantibodies. 3) Common HPFS include Familial Mediterranean Fever (FMF), Hyperimmunoglobulin D Syndrome (HIDS), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS),

1. HERIDITERY PERIODIC FEVER
SYNDROMES
Dr.Vinod. p

2. • Introduction
• What are included in HPFS
• Approach to intermittent prolonged fever
• Approach to hereditary periodic fever

3. Are both same?
• Auto inflammatory = Autoimmune

4. • Auto inflammatory = Malfunction in the
Innate Immune System
• Autoimmune = Malfunction in the Adaptive
Immune System

5. Similarities and differences
• Both do have an immune system malfunction
as the underlying cause of the symptoms.
• And both share some of the same symptoms,
such as joint pain and swelling, rash, and
fatigue.
• BUT the underlying cause or mechanism of
the immune disregulation is different.

6. Some basics
• The acquired immune system- Once exposed
to a pathogen, the acquired immune system
learns from it and remembers it.
• Targets of the adaptive immune system are
specific

7. • The innate immune system - uses white blood
cells and acute inflammation to attack
pathogens.
• May be activated by triggers.

8. Autoinflammatory
• Genetic mutation causing disease leads to
activation of the innate immune system
• leading to dysregulation of inflammatory
cytokines, such as IL-1 and TNF-alpha and
others that are over produced.
• Not the autoantibodies driving the inflammation

9. • Fever, becomes the most common symptom
in addition to involvement of other organs.

10. Autoinflmmattion
• Genetic mutation leads to activation of the
innate immune system
• Dysregulation of inflammatory cytokines
• IL-1 and TNF-alpha etc are over produced.
• Rather autoantibodies driving the inflammation

11. Does the difference matter?
Symptoms may be same, but the common
treatments will not hold good because the
cause is different.
To best treat each condition- understand the
cause and target that specific mechanism of
the innate immune system that is overactive .

12. Hereditary periodic fevers
• Monogenic diseases that present with
• Recurrent bouts of fever and associated
• Pleural and/or peritoneal inflammation
• Arthritis
• Various types of skin rash

13. • Episodes of inflammation, without the
• High titer auto antibodies
• Antigen-specific T cells like in autoimmune
diseases ( SLE, RA)

14. .
.
HEREDITARY PERIODIC FEVER SYNDROMES
AUTO RECESSIVE AUTO DOMINANT
FMF ( Familial Mediterranean
fever)
HIDS ( Hyper IG D syndrome)
PAPA (pyogenic arthritis with
pyoderma gangrenosum and acne )
TRAPS( TNF receptor ass periodic fever)
CAPS ( Cryopyrin ass periodic fever)
Familial cold auto inflammatory syndrome
Muckle wells syndrome,
NOMIDS or CINCA( Neonatal onset multisystem inflammatory
disease or chronic Infantile neurologic cutaneous and articular
syndrome)

15. Other mendelian autoinflammatory diseases that
present in childhood and are not considered
hereditary periodic fever syndromes.
• Pyogenic arthritis with pyoderma gangrenosum
and acne PAPA
• Deficiency of the interleukin 1 (IL-1) receptor
antagonist (DIRA)
• Blau syndrome (early-onset sarcoidosis)
• Chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature
(CANDLE)

16. • Autoinflammation with phospholipase Cγ2-
associated antibody deficiency and immune
dysregulation (APLAID)
• Deficiency of adenosine deaminase-2 (DADA2)
• Congenital sideroblastic anemia with B-cell
immunodeficiency, periodic fevers and
developmental delay (SIFD)

17. • Autoinflammatory disorders with a complex
mode of inheritance.
• Periodic fever with aphthous stomatitis,
pharyngitis, and adenitis (PFAPA)
• chronic recurrent multifocal osteomyelitis
(CRMO)

18. FMF
• Onset is before the age of 20 yrs
• It occurs in Jewish, Armenian, Arab, Turkish,
Greek and Italian populations
• MEFV gene located on the short arm of
chromosome 16 encoding a 781 amino acid
protein called pyrin.
• Gain-of-function and IL-1β– dependent
inflammation

19. • frequent mutations (M694V, V726A, V680I,
E148Q, and V694I)
• M694V mutation is associated with a more
severe phenotype
• Homozygosity for M694V carries a higher risk
of amyloidosis.

20. Clinical features
• Recurrent 1-3 day self-limited fever
• Serositis
• Mono- or pauciarticular arthritis
• Erysipeloid rash
• Diagnostic criteria well established for adults,
but less specific for the diagnosis in children

21. Complications
• The most common presenting sign of
amyloidosis is proteinuria.
• Untreated amyloidosis in FMF progress to
renal failure, often within 3–5 yr

22. Diagnosis
• A study in Turkish children where prevalence of
FMF is high (1per 1000) has proposed the
following criteria:
• 3 or more attacks in one yr + at least 2 of the
following:
• fever, abdominal pain, chest pain, arthritis and
family history of FMF.
• Sensitivity and specificity of 86.5% and 93.6%,
respectively

23. Treatment
• Daily colchicine prevents attacks and
amyloidosis.
• Complete remission - 50–65% and partial
remission in 30% .
• Steroids - for prophylaxis, and for control of
myalgia.
Intolerance or resistant to colchicine (5–10%),
Rilonacept an IL-1 inhibitor
Anakinra IL-1 receptor antagonist.

24. HIDS
• Known to occur in French and other European
children.
• Mevalonate kinase deficiency
• Conversion of mevalonic acid to 5-
phosphomevalonic acid in the biosynthesis of
cholesterol and nonsterol isoprenoids

25. Clinical features
• Starts in the first year of life.
• Immunizations triggers first attack in
significant numbers of small children.
• Fevers -4 to 8 wks, last for 3–7 days with
• Polyarthralgia ,Abdominal pain &Diarrhea
• Tender cervical lymphadenopathy
• Maculopapular rash in 2/3. ( utricarial/
erythema nodosum)

26. • 50% - splenomegaly during an attack
• Aphthous ulcers - mouth and also on the
genital area.

27. Diagnosis
• MVK gene mutations
• Mevalonate kinase in blood
• Mevalonic acid in the urine during an attack
• All are expensive and complicated to do
• Hyper IG d is epiphenomenon, not present
always

28. International HIDS study group guidelines

29. • Mild disease- steroids
• Colchicine-not much response
• Etaneracept and anakinra -promising

30. TRAPS
• Misfolded TNFR1 aggregates intracellularly
resulting in the release of proinflammatory
cytokines IL-1β and TNF-α.

33. Clinical features
• Mean age of 10 yrs.
• Febrile episodes usually last more than 1 wk.
• Abdominal pain (88%), pleurisy (40%),
migratory myalgia (80%), arthralgia (52%)
• Generalised serpiginous erysipelas-like rash
and periorbital oedema.
• AMYLOIDOSIS OCCURS in 30%

34. CAPS
• Includes FCAS, MWS, NOMID/CINCA
• Cryopyrinopathies are really a continuum, and
that patients may present with overlap
syndromes that do not fit neatly into a single
diagnosis
• Mutation in cryopyrin or NLRP3.

35. • characterized by recurrent fevers and an
urticaria-like rash that develops early in
infancy.
FCAS MWS
UTRICARIAL RASH
Starts in infancy
COLD induced
SNHL
AMYLOIDOSIS

36. NOMIDS/ CINCA
• .
CNS SKIN
BONES

37. NOMIDS / CINCA
• Neonatal onset
• Diffuse urticarial rash
• Daily fevers
• Dysmorphic features.
• Significant joint deformities (bony overgrowth
of the epiphyses )

38. • Chronic aseptic meningitis
• > ICP, optic disc edema, visual impairment,
progressive sensorineural hearing loss, and
intellectual disability.

39. • Anakinra, IL-1 receptor antagonist- life-
changing for NOMID patients, not only for
symptom control , but also preventing end-
organ damage.
• Rilonacept, canakinumab, are effective in
both FCAS and MWS

40. • Aggressive IL-1 blockade has resulted in
attenuation of amyloidosis in
cryopyrinopathies.

45. Frequency/Periodicity of Various
Periodic Fever Syndromes
Frequency
of Episodes
PFAPA Cyclic
Neutropenia
FMF HIDS TRAPS
Range q 3-6 weeks q 2-8 weeks q 3-4
months
q 4-8 weeks q weeks to
years
‘Classic’ q 28 days q 21 days
(90%)
None None None

46. Duration of Febrile Episodes in
Various Periodic Fever Syndromes
– .
PFAPA Cyclic
Neutropenia
FMF HIDS TRAPS
3-5 days 5-7 days 1-3 days 3-7 days 2 days-weeks

47. Flowchart for the Initial Evaluation of a Child with Periodic Fevers and No Suspicion of
Recurrent Viral Infections
Verify Fever
Well in-between
Episodes with no weight
loss and normal
inflammatory markers?
Age onset <1
year?
Assess
Frequency of
Fever
Evaluate for more serious etiology
(e.g. Rheumatologic, Oncologic)
Yes
Cyclic Neutropenia
Hyper IgD Syndrome
Findings Fit?
Neutropenia q 3 weeks,
Fevers q 21 days, oral ulcers,
Recurrent bacterial infections
Abdominal pain, rash,
diarrhea, splenomegaly
No
Findings Fit? Findings Fit?
Regular Irregular
q 21 days
q 3-6 weeks
q 4-8 weeks
q 4-8 weeks
Weeks to months
Weeks to years
Cyclic Neutropenia
PFAPA
Hyper IgD Syndrome
Neutropenia q 3 weeks,
fevers q 21 days, oral ulcers,
recurrent bacterial infections
Pharyngitis, cervical adenitis, oral
ulcers
Abdominal pain, rash, diarrhea
splenomegaly
Abdominal pain, rash, diarrhea,
splenomegaly
Abdominal pain, rash, arthritis
Abdominal pain, rash, periorbital
edema, arthritis
Hyper IgD Syndrome
FMF
TRAPS
No
Yes

48. References
• HEREDITARYPERIODICFEVER JOOSTP.H. DRENTH, M.D.
N Engl J Med, Vol. 345, No. 24 December 13,
2001
• Fevers and the Rheumatologist Prudence Joan
Manners & Robin Guttinger Indian J Pediatr (2010)
77:1173–1181
• NELSON TEXT BOOK OF PEDIATRICS