1. A 3-year-old male child presented with joint pain, fever, and skin rash for 6 months. His mother had a similar history since childhood of inflammatory joint pain, skin lesions, and eye issues. 2. Examination found joint swelling and tenderness, skin papules, and the mother had hand deformities. Investigations for both were normal. 3. A differential diagnosis of Blau syndrome or familial early onset sarcoidosis was made given the familial pattern. Genetic testing found a pathogenic NOD2 variant consistent with Blau syndrome.

1. PID case- Blau syndrome
2.12.2020

2. Rheumatology OPD - Patient information
• 3 year old male child
• Resident of Karimnagar
• First visit on 21.1.2019
Reviewed in rheumatology OPD after the birth of second child

3. Chief complaints
• Joint pain for 6 months
• Fever for same duration
• Papular skin rash over limbs for same duration

4. History
• Pain and swelling in small and large joints of upper and lower limb
• High grade fever – on and off associated with chill
• Papular skin rash in upper limb and trunk for 6 months
• No H/O redness of eye , blurring of vision , oral or genital ulcer .

5. Examination
• Skin - Multiple small papular lesions over upper limb , trunk with
xerosis
• MSK – Tender & swelling in B/L PIP 2-5 , restricted movement in
ankle and wrist .

6. Investigation
• CBP – 10.4/13800/3.59 , ESR – 6 , CUE – Normal
• IgM-RF- Neg
• ANA-IF –Neg
• Anti CCP ab – Neg

7. Mother also had significant history from childhood
• Since age 5 – inflammatory pain and swelling in small and large joints
of upper & lower limb
• Deformity in hand since 10 years
• History of papular skin rash over dorsum of hand since childhood
• Since childhood , recurrent redness of eyes with spontaneous
resolution

8. Camptodactyly

9. Papular lesions over upper limb

10. Investigation findings in mother
• CBP- 13/6300/2.4
• ESR – 21, CRP- neg
• IgM-RF – NEG
• ANA-IF – NEG
• Anti CCP – Neg

11. Female child of 1 year also started symptoms
• She was born in 2019.
• At 9 month of her age , she developed multiple white papular spots
over both leg – nonpainful , non-pruritic

12. Papular eruption over lower limb

13. PEDIGREE
LMP: 08/05/2018
POG:17 weeks 1 day
P
Polyarthritis
Excessive eye watering
Fever, Skin rashes
3 years
29 years
Non consanginously married couple.
Mother and son with similar presenting complaints- more in favour of autosomal dominant pattern of inheritance
No other family member with similar history

14. Summary
• Mother – since child hood inflammatory deforming arthritis , papular
skin lesion , recurrent red eyes
• Ist male child ( 5 yr age ) – inflammatory arthritis recurrent fever with
papular skin eruption in upper limb and trunk
• 2nd female child ( 9 m) – papular eruption over the bilateral lower
limb

15. Differential diagnosis
• Familial early onset sarcoidosis or Blau syndrome
• Juvenile idiopathic arthritis
• Familial periodic fever syndrome

16. PRESENTED IN MEDICAL GENETICS
• 29 year old lady presented with history of suspected rheumatoid
arthritis in her and her previous offspring
• Mother:
• Small joints arthritis, Joint pains, stiffness and deformity
• Pterygium surgery- multiple episodes of ?conjunctivitis with spontaneous
resolution
• Papular rashes with pigmentation over the skin
• 1st Son:
• Recurrent fevers
• small joint pain
• dryness of skin
• morning stiffness with joint pain
Mrs Swapna Rani was pregnant 17 weeks 1 day and was concerned for
similar symptoms in her present child

17. • Juvenile onset inflammatory polyarthritis
• Episodes of fever and eye watering
• Skin rash – multiple erythematous papular healed with pigmentation
• Autosomal dominant/ ? familial clustering with low penetrance
AD FMF
Blau syndrome – triad of ocular, skin and cutaneous symptoms
• Next generation sequencing based clinical or whole exome sequencing
• Prenatal testing was not offered in view of advanced period of gestation and
exact genetic pathogenic variant was not ascertained in the proband

18. Gene (Transcript) Location Variant Zygosity Disease
(OMIM)
Inheritance
NOD2
NM_022162.3
Exon 4 c.1000C>T
p.Arg334Trp
Heterozygous Blau
syndrome(186580)
Yao
syndrome(617321)
Autosomal
Dominant
Whole Exome sequencing done from CCMB

19. Database Reports Prediction Scores
1000
Genomes
EVS* ExAC# dbSNP In-house
exome
database†
HGMD ClinVar SIFT Polyphen 2 Mutation
taster
Intervar
Absent Absent Absent Present Absent Absent Present Damaging Damaging Disease
causing
Pathogenic
MAF:NA Frequency:N
A
MAF:NA RS:10489
5462
Frequency:
NA
Frequency:
NA
IC:VC00000
4696.3
• Not present in population databases – 1000G, EVS, gnomAD, in house database
• Previously reported variant – Clinvar
• In silico predictions damaging
• Conserved across species
Pathogenic variant by intervar according to ACMG/Amp guidelines 2015

20. LITERATURE SEARCH
• Multiple papers with same variant - ocular , joint and skin
involvement

21. SKIN MANIFESTATION

22. BLAU VS YAO
BLAU YAO
Onset in first 2 decades of life Onset 3rd to 4th decade of life
Granulomatous arthritis, iritis, and skin rash Arthritis or arthralgia, skin manifestations;
weight loss, episodic self-limiting fever, and/or
gastrointestinal (GI) symptoms, dry eyes and
mouth ,chest pain pulmonary parenchymal
disease
Uveitis is common Uveitis not seen
Granulomatous dermatitis Spongiotic dermatitis
GI symptoms less common GI symptoms more common
Chronic joint involvement with camptodactyly Joint deformity not characteristic

23. Further testing
• Skin biopsy – granulomatous lesion
• Complete ophthalmic evaluation – granulomatous uveitis
• Targeted testing of the variant in mother and younger sibling – for
confirmation
• Prenatal testing can now be offered at 12-14 weeks through CVS and
> 16 weeks through amniocentesis – if the family desires.

24. Basics on Blau syndrome
• Blau Syndrome is an autosomal dominant auto-inflammatory disorder
• It affects the skin, eyes, and joints predominantly
• It is caused by a mutation in the NOD2 (CARD15) gene
• Symptoms usually begin before the age of 4 years
• Disease manifests as early onset cutaneous manifestations , arthritis, and uveitis.

26. Published in BMJ – 2020