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Ichthyosiform Rashes and Joint Pain in a Boy

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A school-aged boy experienced generalized erythematous rashes for 4 years. Skin examination showed ichthyosiform brownish plaques on his lower extremities and multiple erythematous confluent papules and plaques on his trunk and face (Figure, A and B). Topical steroid and pimecrolimus were administered, but their effects were limited. In addition, painful distal and proximal interphalangeal joints were noted for 2 years, and the patient could not clench his fists. Uveitis in both eyes was also diagnosed by an ophthalmologist. Microscopic examination of his hair showed no trichorrhexis invaginata or trichorrhexis nodosa. A skin biopsy specimen was obtained and submitted for further histopathologic analysis (Figure, C and D).

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D. Blau syndrome

A skin biopsy from the ichthyosiform rash on the right arm showed small noncaseating granulomas, multinucleated giant cells, and neutrophil infiltration in the dermis and subcutis. Acid-fast staining, Gomori methenamine-silver staining, and modified Ziehl-Neelsen staining all showed an absence of microorganisms, and sarcoidosis was confirmed. Whole-exome sequencing revealed a heterozygous missense variation (Arg334Trp) in NOD2 that has previously been detected in Blau syndrome.1 Accordingly, the diagnosis of Blau syndrome was confirmed.

Blau syndrome is an autosomal dominant inflammatory disease characterized by a triad of granulomatous dermatitis, uveitis, and systemic polyarthritis. Variations in NOD2/CARD15 on chromosome 16q12 have been identified in patients with Blau syndrome. NOD2/CARD15 is primarily expressed in monocytes, a cell type capable of differentiation into multinucleated giant cells and epithelioid cells.2 It has been hypothesized that NOD2/CARD15 variation is associated with increased NF-kB activation, macrophage death, and granulomatous inflammation.2

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Article Information

Corresponding Author: Chun-Bing Chen, MD, Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, No. 5, Fusing St, Taoyuan, 333 Taiwan (chunbing.chen@gmail.com).

Published Online: September 8, 2021. doi:10.1001/jamadermatol.2021.3498

Conflicts of Interest: None reported.

Additional Contributions: We thank the patient’s father for granting permission to publish this information. We also thank Wen-Hung Chung, Yu-Chuan Teng, and Chuang-Wei Wang, Whole-Genome Research Core Laboratory of Human Diseases at CGMH (Keelung, Taiwan) and Genomic Medicine Core Laboratory at CGMH (Linkou, Taiwan), for their genetic analytic support. These individuals did not receive compensation for their contributions.

References
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Matsuda  T , Kambe  N , Ueki  Y ,  et al; Primary Immunodeficiency and Autoinflammatory Diseases Database Project Members in the Japanese Society for Immunodeficiency and Autoinflammatory Diseases.  Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.   Ann Rheum Dis. 2020;79(11):1492-1499. doi:10.1136/annrheumdis-2020-217320PubMedGoogle ScholarCrossref
2.
Caruso  R , Warner  N , Inohara  N , Núñez  G .  NOD1 and NOD2: signaling, host defense, and inflammatory disease.   Immunity. 2014;41(6):898-908. doi:10.1016/j.immuni.2014.12.010PubMedGoogle ScholarCrossref
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Poline  J , Fogel  O , Pajot  C ,  et al; French Society for Rheumatology and Inflammatory Diseases and the Research Group of Pediatric Dermatology French Society.  Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.   J Eur Acad Dermatol Venereol. 2020;34(2):340-348. doi:10.1111/jdv.15963PubMedGoogle ScholarCrossref
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Brown  SJ , Relton  CL , Liao  H ,  et al.  Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children.   Br J Dermatol. 2009;161(4):884-889. doi:10.1111/j.1365-2133.2009.09339.xPubMedGoogle ScholarCrossref
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Steuer  AB , Cohen  DE .  Treatment of Netherton syndrome with dupilumab.   JAMA Dermatol. 2020;156(3):350-351. doi:10.1001/jamadermatol.2019.4608PubMedGoogle ScholarCrossref
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Takeichi  T , Sugiura  K , Nomura  T ,  et al.  Pityriasis rubra pilaris type V as an autoinflammatory disease by CARD14 mutations.   JAMA Dermatol. 2017;153(1):66-70. doi:10.1001/jamadermatol.2016.3601PubMedGoogle ScholarCrossref
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