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Year : 2019  |  Volume : 64  |  Issue : 5  |  Page : 400-403
Blau syndrome associated with nucleotide-binding oligomerization domain containing 2 mutation in a baby from Malaysia

1 Department of Pediatrics, Institute of Pediatric, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50586, Malaysia
2 Department of Research, National Skin Center, Singapore 308205, Singapore
3 Institute of Molecular and Cell Biology, A*Star, Proteos, Singapore 138673; Singapore Bioprocessing Technology Institute, Singapore 138668; Department of Pharmacology, National University of Singapore, Singapore 117660, Singapore

Date of Web Publication5-Sep-2019

Correspondence Address:
Zacharias Aloysius Dwi Pramono
Department of Research, National Skin Center, 1 Mandalay Road, Singapore 308205
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijd.IJD_44_18

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Blau syndrome (BS) is a very rare autosomal dominant juvenile inflammatory disorder caused by mutation in nucleotide-binding oligomerization domain containing 2 (NOD2). Usually, dermatitis is the first symptom that appears in the 1styear of life. About 220 BS cases with confirmed NOD2 mutation have been reported. However, the rarity and lack of awareness of the disease, especially in the regions where genetic tests are very limited, often result in late diagnosis and misdiagnosis. Here, we report a de novo BS case from Malaysia, which may be the first report from southeast Asia. PCR and DNA sequencing of peripheral blood mononuclear cells were performed to screen the entire coding region of NOD2 gene. A heterozygous c.1000C>T transition in exon 4, p. R334W, of the NOD2 gene was identified in the patient. This report further reaffirms the ubiquitousness of the disease and recurrency of p. R334W mutation.

Keywords: Blau syndrome, Malaysia, nucleotide-binding oligomerization domain containing 2, southeast Asia

How to cite this article:
Leong KF, Sato R, Khim Oh GG, Surana U, Dwi Pramono ZA. Blau syndrome associated with nucleotide-binding oligomerization domain containing 2 mutation in a baby from Malaysia. Indian J Dermatol 2019;64:400-3

How to cite this URL:
Leong KF, Sato R, Khim Oh GG, Surana U, Dwi Pramono ZA. Blau syndrome associated with nucleotide-binding oligomerization domain containing 2 mutation in a baby from Malaysia. Indian J Dermatol [serial online] 2019 [cited 2023 Feb 9];64:400-3. Available from:

   Introduction Top

Blau syndrome (BS), first described in 1985 by Dr. Blau and Dr. Jabs, is an inflammatory disorder characterized by noncaseating granulomatous arthritis, dermatitis, and uveitis that is often inherited in autosomal dominant pattern.[1],[2] BS and early-onset sarcoidosis (EOS) are the same genetic disorders of familial and sporadic forms, respectively, caused by gain-of-function mutation of nucleotide-binding oligomerization domain containing 2 (NOD2) gene.[3]

BS is a very rare disease with prevalence to be fewer than 1 in 1,000,000 live births. Here, we report a BS case from Malaysia. To the best of our knowledge, this is the first report of BS in southeast Asia (SEA).

   Case Report Top

An 18-month-old Chinese–Malaysian girl presented with the development of multiple red papules that first became evident at the age of 10 months. The erythematous papules started on her face and subsequently spread to the entire body surface, sparing only palms and soles. She had been initially treated as lichen nitidus by private dermatologist with topical corticosteroids, but her skin condition had worsened and was unresponsive to the treatment. She was the only child of nonconsanguineous parents. Her parents were healthy with no evidence of uveitis and arthritis. On examination, the baby had erythematous papules present on the entire body surface, sparing only palms and soles [Figure 1]. Morphologically, there were multiple erythematous papules that were pinhead size, flat-topped, and slightly scaly. Most of the papules were discrete over her body and extremities. The confluence of papules occurred only on the face. Articular involvement was found with boggy synovial thickening of both ankle joints, wrists, and all the fingers [Figure 2], reported to develop from the age of 12 months. Neither hepatosplenomegaly nor lymphadenopathy, or uveitis was detected.
Figure 1: Pinhead size, flat-topped and slightly scaly, multiple erythematous papules are present on patient's body and extremities

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Figure 2: Patient's fingers show boggy synovial thickening

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Histologic examination of a papule showed well-circumscribed, noncaseating granulomas with sparse lymphocyte infiltrate at the periphery within the upper dermis [Figure 3].
Figure 3: Histology of the papule shows well-circumscribed, noncaseating granulomas with sparse lymphocyte infiltrate at the periphery within the upper dermis, a (H and E, ×40), b (H and E, ×100)

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Currently, her condition had remained under control with oral prednisolone and weekly methotrexate.

Genetic mutation analysis revealed a heterozygous c.1000C>T transition in exon 4 of the NOD2 gene. The mutation resulted in an arginine to tryptophan substitution at position 334, p. R334W, of the coding sequence [Figure 4]. The mutation was not detected in the patient's parents.
Figure 4: Electropherogram shows sequence of heterozygous c.1000C>T transition in exon four of the nucleotide-binding oligomerization domain containing 2 gene in the patient's DNA specimen

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   Discussion Top

Among about 220 BS and EOS patients carrying CARD15/ NOD2 mutations that have been reported, 80% had involvement of the residue at position 334, either p.R334Q or p.R334W.[3],[4] However, whether the type and/or location of the NOD2 mutation affect the clinical features of BS is still unclear.

Granulomatous arthritis represents the most frequent BS manifestation, occurring in almost all patients in pediatric age as a polyarticular “boggy” synovitis and tenosynovitis. It is usually symmetrical involving proximal interphalangeal joints of hands and feet, ankles, knees, and wrists. Despite the chronicity of exuberant arthritis, joint destruction is not commonly reported and range of motion is relatively well preserved, especially in the larger joints.[5] Skin rash is usually the first to appear in the 1st year of a BS patient's life. Dermatitis in the form of dark red, slightly scaly, maculopapular, or eczematoid-like or lichenoid-like rash may occur frequently on the trunk and/or extremities. The rash could be misdiagnosed as atopic dermatitis, or when desquamation is intense, as ichthyosis vulgaris.[6]

In our patient, erythematous papules were the earliest and prominent symptom that first appeared at the age of 10 months. It was only after 2 months of treatment that her condition did not improve together with the development of boggy synovial thickening in both ankle joints, wrists, and fingers; BS was then suspected. Genetic analysis revealed heterozygous R334W mutation which appeared to arise de novo since both her parents did not carry the mutation. Thus, the diagnosis of BS on the patient was confirmed at the age of 20 months. Three other BS families of Chinese ethnicity carrying R334W mutation have been reported previously from the People's Republic of China (PRC). Despite the autosomal dominant inheritance pattern shown in the families, the patients were only genetically diagnosed in their adulthood.[7],[8]

Granulomatous uveitis is a frequent manifestation (70%–80%), often bilateral and with a chronic recurrent course. Our patient did not have uveitis; however, it might be yet to manifest due to her young age. One of the patients from PRC who carried the same p.R334W mutation developed bilateral anterior uveitis at the age of 13 and eventually closed-angle glaucoma that needed trabeculectomy. Anticipation and a lookout for current therapy for granulomatous uveitis are necessary as various dosages of topical corticosteroids, nonsteroidal anti-inflammatory drugs, and immunosuppressive agents such as cyclosporin A were proven to be ineffective.[7]

Expanded manifestations have been reported in about one-third of the BS patients.[8] R334Q/W mutations, recurrent fever, generalized lymphadenopathy, splenomegaly, hepatomegaly, and/or hepatitis have been described in many patients.[4],[5] The presence of large vessels and Takayasu's arteritis have been reported in two patients with BS carrying p.R334W and p.G464W mutations, respectively.[9] Our patient, however, did not show any of the above-mentioned symptoms, while among three other Chinese families, only one was reported to have recurrent fever.[8]

NOD2 is a large gene consisting of 12 exons. A full mutation screening of NOD2 would be laborious and costly. Our report further affirms the ubiquitousness of BS and the recurrence of NOD2 mutation. However, the rarity of BS has made it challenging to fully characterize the disease and the lack of awareness often results in misdiagnosis and late diagnosis. With this finding, it could possibly shorten the time needed to provide patients with the right clinical and molecular diagnosis. Mutation screening could be streamlined to first identify the p.R334Q/W before proceeding on to screen other exons in NOD2.

BS reports from SEA are still very limited. Findings from this report will add on to the current knowledge about BS and the mutations associated with it. The international registry initiative will help socialize the awareness of this disease and drive studies toward understanding the complex pathogenic mechanism behind granulomatous inflammation to achieve a complete model of the disease pathogenesis that leads to more targeted treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We would like to acknowledge the Funding support from NMRC/CG/011/2013

This study was financially supported by Research Laboratory of Molecular Dermatology, National Skin Centre, Singapore NMRC/CG/011/2013 (under Theme of Genetics).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689-93.  Back to cited text no. 1
Jabs DA, Houk JL, Bias WB, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 1985;78:801-4.  Back to cited text no. 2
Caso F, Costa L, Rigante D, Vitale A, Cimaz R, Lucherini OM, et al. Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early-onset sarcoidosis. Autoimmun Rev 2014;13:1220-9.  Back to cited text no. 3
Aróstegui JI, Arnal C, Merino R, Modesto C, Antonia Carballo M, Moreno P, et al. NOD2 gene-associated pediatric granulomatous arthritis: Clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum 2007;56:3805-13.  Back to cited text no. 4
Rosé CD, Pans S, Casteels I, Anton J, Bader-Meunier B, Brissaud P, et al. Blau syndrome: Cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford) 2015;54:1008-16.  Back to cited text no. 5
Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H, et al. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol 2010;27:69-73.  Back to cited text no. 6
Xiang H, Zhang T, Chen M, Zhou X, Li Z, Yan N, et al. NOD2/CARD15 gene mutation identified in a Chinese family with Blau syndrome. Mol Vis 2012;18:617-23.  Back to cited text no. 7
Wu D, Shen M. Two chinese pedigrees of Blau syndrome with thirteen affected members. Clin Rheumatol 2018;37:265-70.  Back to cited text no. 8
Khubchandani RP, Hasija R, Touitou I, Khemani C, Wouters CH, Rose CD, et al. Blau arteritis resembling Takayasu disease with a novel NOD2 mutation. J Rheumatol 2012;39:1888-92.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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