When a Juvenile Idiopathic Arthritis is not a Juvenile Idiopathic Arthritis: An overview of the mimics 29o Συνέδριο Παγκρήτιας Παιδιατρικής Εταιρείας

1. When is JIA not JIA?
R Cimaz
AOU Meyer Firenze

2. Permission to show these pictures has been obtained.

3. Can this be anything else other than JIA?
1. Absolutely yes
2. Absolutely no
3. Need more clinical and laboratory data to decide
4. Impossible to say with only a photo
Q

4. Case study
• Normal past medical history
• Myopia diagnosed at 4 years of age
• Bilateral retinal detachment (right eye at 12 yrs,
left eye at 15 yrs)
• Height 75º centile
• Pain and stiffness of joints (knees ++)
• Hypermobile in some joints (elbow ++)

5. What is the more likely diagnosis?
1. Blau syndrome
2. Cogan syndrome
3. Stickler syndrome
4. Mucolipidosis type III
Q

6. COL2A1 (12q13.11-q13.2) precursor
alpha chain collagen type II
Tripeptides Gly-X-Y containing
high # of proline residues,
involved in the formation of
homotrimers that assemble on
a triple helix structure
Canty EG, et al. J Cell Sci. 2005;118:1341–1353.

7. • Hypoplasia middle portion of face
• Depression nasal bridge
• Antiversion nostrils
• Cleft palate, uvula bifida, micrognatia
• (incomplete Pierre Robin)
• Myopia
• Strabismus
• Early-onset cataract
• Vitreo-retinal or chorio-retinal degeneration
• Chronic uveitis
• Retinal detachment
• Neurosensorial or transmissive hearing loss
• Hypermobility tympanic membrane

8. When to suspect Stickler syndrome in a
child with arthropathy?
• Characteristic facial features
• Ocular and hearing abnormalities
• Joint laxity
• No laboratory abnormalities
Rose PS, et al. Am J Med Genet. 2005;138A:199–207.
Family history

9. Vincenzo
• ♂ - born full-term, vaginal delivery, normal pregnancy
─ Birth weight 3.450 kg, length 51 cm
• Negative family hx
• Normal psychomotor development
• Age 7 mo.: hip ultrasound “abnormal” (??) – double
diaper until 13 mo.
• Walking age 2½ years
─ At that time starts to complain of left hip pain

10. Vincenzo
• At 11 yrs: pain, walking difficulties and articular
functional limitation worsens
• New admission
• Elbow flexion 15º, not complete extension
─ Pronosupinates only by 2/3
• Hips flexion contracture, stiffness and painful
• Knees flexion 10, not full extension

11. Permission to show these pictures has been obtained.

12. What test should you order ?
1. ANA
2. Genetic counselling
3. Slit lamp
4. Urinary GAGs
Q

14. The diagnostic challenge of progressive pseudorheumatoid dysplasia
(PPRD): A review of clinical features, radiographic features, and
WISP3 mutations in 63 affected individuals
Nuria Garcia Segarra, Laureane Mittaz, Ana Belinda Campos-Xavier1,Cynthia F. Bartels2, Beyhan
Tuysuz3, Yasemin Alanay4, Rolando Cimaz5, Valerie Cormier-Daire6, Maja Di Rocco7, Hans-
Christoph Duba8,Nursel H. Elcioglu9, Francesca Forzano10, Toni Hospach11, Esra Kilic12, Jasmin
B. Kuemmerle-Deschner13, Geert Mortier14, Sonja Mrusek15, Sheela Nampoothiri16, Ewa
Obersztyn17, Richard M. Pauli18, Angelo Selicorni19, Romano Tenconi20, Sheila Unger21, G. Eda
Utine12, Michael Wright22, Bernhard Zabel23, Matthew L. Warman24, Andrea Superti-Furga25, PD
Dr. Luisa Bonafé1,*
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
Special Issue: New Topics in the Skeletal Dysplasias
Volume 160C, Issue 3, pages 217–229, 15 August 2012

16. A difficult case
• CR, male, born 1984
• 6 yrs: difficulty writing and diminished hand function, with
stiffness in metacarpophalageal and interphalangeal
joints
• In the following months, worsening of the symptoms,
with flexion contractures of the hands and progressive
involvement of all joints, functionally limited but not
swollen nor tender
• Laboratory: wnl
• Working diagnosis of JCA
• No response to NSAIDs
• Carpal tunnel syndrome (bilateral)

17. What is the more likely diagnosis ?
1. Mucopolysaccharidosis type II
2. Mucopolysaccharidosis type IV
3. Mucopolysaccharidosis type VI
4. Mucopolysaccharidosis type I
Q

18. Classification of MPS
DS = dermatan sulfate, HS = heparan sulfate, CS = chondroitin sulfate, KS = keratan sulfate, HA= Hyaluronan
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:3421–3452.
11 known
enzyme
deficiencies
Storage of
GAGs
7 main MPS
types

19. MPS: joint and skeletal disease
• Caused by progressive storage of GAGs in synovium,
periarticular tissues, and bone
• Outcomes
─ Joint stiffness and joint contractures without inflammation
(hands++, shoulders)
─ Joint pain
─ Severe skeletal deformity
─ Significant loss of mobility and functional independence

20. Skeletal abnormalities
(dysostosis multiplex)
• Gibbus
• Spinal deformity
• Poorly formed pelvis
• Abnormal clavicles
and ribs
• Hip dysplasia
• “Knock knees”
• Joint stiffness
• Growth retardation
Courtesy of Sanofi Genzyme.

21. M S
U K
S E
C L
U E
L T
O A
L
L
U
N
G
G
I
C
A
R
D
I
A
C
Symptomsperorgansystem
?
Valvular
disease
N
E
U
R
O
Joint stiffness
33 yExtensive GI tract investigation & liver biopsy
34 yExertional dyspnoea
Difficult intratracheal intubation
34yBilateral dysesthesia & weakness in hands
38 yExertional pain in the legs
Laminectomy for spinal cord compression C2 – C7
Low back pain
35 yDisabled due to chronic fatigue
DIAGNOSISOFMPSI
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 400 years
Case report attenuated phenotype of MPS I
Hepatomegaly
Cardiac murmur
Age >
Chronic diarrhoea
40 y
40 y

22. Possible MPS I disease presentation
from early childhood to adulthood
• Physical appearance: Facial dysmorphisms, large abdomen,
short stature
• Corneal clouding
• Chronic rhinitis, sinusitis, otitis, “glue ear”
• Skeletal deformities, joint stiffness without inflammation,
trigger fingers, restricted mobility, walking problems
• Hip dysplasia
• Scoliosis
• Carpal tunnel syndrome
• Limited endurance
• Diarrhoea
• Cardiac murmur: aortic/mitral valve disease
• Cognitive decline (only most severe MPS I)

23. Disease progression: attenuated MPS I
Courtesy of Sanofi Genzyme.
3 years 24 years 31 years 54 years

25. What is the more specific feature for
MPS I in a child ?
1. Joint contractures
2. Carpal tunnel syndrome
3. Valvular heart disease
4. Cervical spine involvement
Q

26. Case #
(country)
S Family
history
Age at onset of
symptoms (years)
Symptoms at onset Carpal tunnel
syndrome
Age at dx
(yrs.)
1 (Italy) M 6 Stiffness hands (metacarpophalangeal,
proximal interphalangeal)
+ 7
2 (Italy) M 8 Stiffness and pain in the hands 54
3 (Italy) F 3 Stiffness finger 53
4 (UK) F 7 Flexion contractures hands + 13
5 (UK) F 3 Flexion deformity fingers + 10
6 (UK) F 1 Limp; stiff hands; stiff neck + 4
7 (Germ) M + 5 Flexion contracture hands + 9
8 (Germ) M + 5 Flexion contracture hands + 5
9 (Germ) M 6 Contracture finger + 6
10
(France)
M 1 Flexion contracture hands; inguinal
hernia; frequent otitis
+ 33
11
(France)
F 7 days Hip dysplasia + 21
12
(France)
F 1 Flexion contracture hands + 4
13
(France)
F + 8 Shoulder movement restriction 41
Cimaz R. et al. Clin Exp Rheumatol. 2006;24:196-202.

27. Other common disease manifestations
of MPS I
• Fatigue, general malaise
• Short stature
• Excess coarse hair
• Thick coarse skin
• In less severe types, normal to
near-normal intelligence,
no primary CNS involvement
• ENT recurrent infections
• Inguinal/umbilical hernias
Courtesy of Sanofi Genzyme.
1.47

28. Misdiagnoses/differential diagnosis
• Juvenile arthritis
• Rheumatoid arthritis
• Other MPSs
• Muscular dystrophy
• Trigger fingers
• Obstructive airways disease
• Post streptococcal endocarditis
• Hip dysplasia
• Arthrogryposis
• Acute rheumatic fever

30. Differential diagnosis with Juvenile
Idiopathic Arthritis

31. MPS VI clinical manifestations: hands
• Bone and joint abnormalities
• Short, thickened fingers
• Fixed flexion
• Typical claw hand deformity
• Trigger finger abnormality
• Loss of dexterity
• Carpal tunnel syndrome
Courtesy of Biomarin

32. MPS VI is often under-diagnosed
• Patients with a rapidly progressing clinical presentation
of MPS VI are usually diagnosed by 1–5 years of age
• Those with the more slowly progressing disease may be
misdiagnosed because presenting symptoms may
mimic other common diseases
• As the disease progresses, and depending on the
degree of enzyme deficiency, patients experience severe
disabilities and early death – factors underscoring the
importance of early diagnosis

33. Conclusion / key findings
• Joint contractures without inflammation are the
hallmark of storage disorders – e.g., MPS.
Carpal tunnel syndrome in children is also
very suspicious
• In doubtful cases order urinary GAG
• Some patients may present to rheumatologists/paediatric
rheumatologists since these can be the presenting
symptoms
• Extraskeletal manifestations may be absent at onset and
occur much later (many years) during the disease
course, or, even if present, may be overlooked