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11 pages, 2933 KiB

Open AccessArticle

Sustained Surface ICAM-1 Expression and Transient PDGF-B Production by Phorbol Myristate Acetate-Activated THP-1 Cells Harboring Blau Syndrome-Associated NOD2 Mutations

by Mizuho Nishiyama, Hong-jin Li, Ikuo Okafuji, Akihiko Fujisawa, Mizue Ehara, Naotomo Kambe, Fukumi Furukawa and Nobuo Kanazawa

Children 2021, 8(5), 335; https://doi.org/10.3390/children8050335 - 25 Apr 2021

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Abstract

Objectives: Blau syndrome is a distinct class of autoinflammatory syndrome presenting with early-onset systemic granulomatosis. Blau syndrome-causing NOD2 mutations located in the central nucleotide-oligomerization domain induce ligand-independent basal NF-κB activation in an in vitro reporter assay. However, the precise role of this signaling [...] Read more.

Objectives: Blau syndrome is a distinct class of autoinflammatory syndrome presenting with early-onset systemic granulomatosis. Blau syndrome-causing NOD2 mutations located in the central nucleotide-oligomerization domain induce ligand-independent basal NF-κB activation in an in vitro reporter assay. However, the precise role of this signaling on granuloma formation has not yet been clarified. Methods: Blau syndrome-causing NOD2 mutations were introduced into human monocytic THP-1 cells, and their morphological and molecular changes from parental cells were analyzed. Identified molecules with altered expression were examined in the patient’s lesional skin by immunostaining. Results: Although the production of proinflammatory cytokines was not altered without stimulation, mutant NOD2-expressing THP-1 cells attached persistently to the culture plate after stimulation with phorbol myristate acetate. Sustained surface ICAM-1 expression was observed in association with this phenomenon, but neither persistent ICAM-1 mRNA expression nor impaired ADAM17 mRNA expression was revealed. However, the transient induction of PDGF-B mRNA expression was specifically observed in stimulated THP-1 derivatives. In the granulomatous skin lesion of a Blau syndrome patient, ICAM-1 and PDGF-B were positively immunostained in NOD2-expressing giant cells. Conclusions: Sustained surface ICAM-1 expression and transient PDGF-B production by newly differentiating macrophages harboring mutant NOD2 might play a role in granuloma formation in Blau syndrome. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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Review

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17 pages, 2727 KiB

Open AccessEditor’s ChoiceReview

Current Insights into Atopic March

by Mitsuru Tsuge, Masanori Ikeda, Naomi Matsumoto, Takashi Yorifuji and Hirokazu Tsukahara

Children 2021, 8(11), 1067; https://doi.org/10.3390/children8111067 - 19 Nov 2021

Cited by 58 | Viewed by 19750

Abstract

The incidence of allergic diseases is increasing, and research on their epidemiology, pathophysiology, and the prevention of onset is urgently needed. The onset of allergic disease begins in infancy with atopic dermatitis and food allergy and develops into allergic asthma and allergic rhinitis [...] Read more.

The incidence of allergic diseases is increasing, and research on their epidemiology, pathophysiology, and the prevention of onset is urgently needed. The onset of allergic disease begins in infancy with atopic dermatitis and food allergy and develops into allergic asthma and allergic rhinitis in childhood; the process is defined as “atopic march”. Atopic march is caused by multiple immunological pathways, including allergen exposure, environmental pollutants, skin barrier dysfunction, type 2 inflammation, and oxidative stress, which promote the progression of atopic march. Using recent evidence, herein, we explain the involvement of allergic inflammatory conditions and oxidative stress in the process of atopic march, its epidemiology, and methods for prevention of onset. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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10 pages, 260 KiB

Open AccessReview

Elucidation of the Pathogenesis of Autoinflammatory Diseases Using iPS Cells

by Megumu K. Saito

Children 2021, 8(2), 94; https://doi.org/10.3390/children8020094 - 1 Feb 2021

Cited by 3 | Viewed by 2687

Abstract

Autoinflammatory diseases are a disease entity caused by the dysregulation of innate immune cells. Typical autoinflammatory diseases are monogenic disorders and often very rare. As a result, there is a relative lack of understanding of the pathogenesis, poor diagnosis and little available treatment. [...] Read more.

Autoinflammatory diseases are a disease entity caused by the dysregulation of innate immune cells. Typical autoinflammatory diseases are monogenic disorders and often very rare. As a result, there is a relative lack of understanding of the pathogenesis, poor diagnosis and little available treatment. Induced pluripotent stem (iPS) cells are a new technology being applied to in vitro disease modeling. These models are especially useful for the analysis of rare and intractable diseases including autoinflammatory diseases. In this review, I will provide a general overview of iPS cell models for autoinflammatory diseases and a brief description of the results obtained from individual reports. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

11 pages, 632 KiB

Open AccessReview

Primary Immunodeficiency Disease Mimicking Pediatric Bechet’s Disease

by Mayuka Shiraki, Saori Kadowaki, Tomonori Kadowaki, Norio Kawamoto and Hidenori Ohnishi

Children 2021, 8(2), 75; https://doi.org/10.3390/children8020075 - 22 Jan 2021

Cited by 6 | Viewed by 4192

Abstract

Behcet’s disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the [...] Read more.

Behcet’s disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the well-studied HLA-B51, were mainly identified by genome-wide association studies. A heterozygous mutation in TNFAIP3, which leads to A20 haploinsufficiency, was found to cause an early-onset autoinflammatory disease resembling BD in 2016. Several monogenic diseases associated with primary immunodeficiency disease and trisomy 8 have recently been reported to display BD-like phenotypes. Among the genes causing these diseases, TNFAIP3, NEMO, RELA, NFKB1 and TNFRSF1A are involved in the NF-κB (nuclear factor κ light-chain enhancer of activated B cells) signaling pathway, indicating that this pathway plays an important role in the pathogenesis of BD. Because appropriate treatment may vary depending on the disease, analyzing the genetic background of patients with such diseases is expected to help elucidate the etiology of pediatric BD and assist with its treatment. Here, we summarize recently emerging knowledge about genetic predisposition to BD. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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8 pages, 7700 KiB

Open AccessEditor’s ChoiceCase Report

Dupilumab Improves Pruritus in Netherton Syndrome: A Case Study

by Yutaka Inaba, Nobuo Kanazawa, Kyoko Muraoka, Azusa Yariyama, Ami Kawaguchi, Kayo Kunimoto, Chikako Kaminaka, Yuki Yamamoto, Kaoru Tsujioka, Akira Yoshida, Teruki Yanagi and Masatoshi Jinnin

Children 2022, 9(3), 310; https://doi.org/10.3390/children9030310 - 24 Feb 2022

Cited by 15 | Viewed by 5910

Abstract

The patient was a 26-year-old male. He had red and scaling skin of the entire body since birth, as well as an elevated level of serum IgE. Genetic testing revealed a mutation in the SPINK5 gene, which had confirmed the diagnosis with Netherton [...] Read more.

The patient was a 26-year-old male. He had red and scaling skin of the entire body since birth, as well as an elevated level of serum IgE. Genetic testing revealed a mutation in the SPINK5 gene, which had confirmed the diagnosis with Netherton syndrome. He has had significant pruritis since birth, and subsequently had symptoms of sleeping disorders and concentration difficulty throughout the day. Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. Dupilumab has been administered for one year without any adverse events or recurrence of symptoms. Although studies have previously described cases who used dupilumab for Netherton syndrome, reported effects have been limited or transient. Additional studies are needed to confirm the effect of dupilumab for Netherton syndrome, which currently lack any effective treatment strategies. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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6 pages, 447 KiB

Open AccessCase Report

Lamotrigine Induced DRESS Syndrome in a Child: A Case Report and Literature Review

by Chien-Heng Lin, Sheng-Shing Lin, Syuan-Yu Hong, Chieh-Ho Chen and I-Ching Chou

Children 2021, 8(11), 1063; https://doi.org/10.3390/children8111063 - 19 Nov 2021

Cited by 5 | Viewed by 6145

Abstract

Lamotrigine is an important anticonvulsant drug. Its use, however, has been limited by the risk of potentially life-threatening dermatological reactions, such as a drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we report the case of a 7-year-6-month-old girl with a history [...] Read more.

Lamotrigine is an important anticonvulsant drug. Its use, however, has been limited by the risk of potentially life-threatening dermatological reactions, such as a drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we report the case of a 7-year-6-month-old girl with a history of epilepsy who developed a skin rash with dyspnoea after 2 weeks of lamotrigine treatment, with DRESS ultimately being diagnosed. After discontinuation of the offending drug and the initiation of systemic glucocorticosteroids, the DRESS symptoms were relieved and the patient was discharged in a stable condition. Anticonvulsant drugs such as lamotrigine are among the factors that induce DRESS in children. When a patient displays skin rash and systemic organ involvement following the initiation of an anticonvulsant drug, DRESS should not be overlooked as a diagnosis, and immunosuppressant drugs should be considered as an option for treating DRESS patients. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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5 pages, 1099 KiB

Open AccessCase Report

Epidermal Nevus Syndrome Associated with Dwarfism and Atopic Dermatitis

by Yuki Mizutani, Miki Nagai, Hitoshi Iwata, Kunihiro Matsunami and Mariko Seishima

Children 2021, 8(8), 697; https://doi.org/10.3390/children8080697 - 12 Aug 2021

Cited by 1 | Viewed by 2428

Abstract

Epidermal nevus syndrome (ENS) is a congenital disorder characterized by widespread linear epidermal lesions consisting of epidermal nevus and extracutaneous involvements, especially of the central nervous system and skeletal system. Garcia–Hafner–Happle syndrome, also known as fibroblast growth factor receptor 3 (FGFR3)-ENS, is characterized [...] Read more.

Epidermal nevus syndrome (ENS) is a congenital disorder characterized by widespread linear epidermal lesions consisting of epidermal nevus and extracutaneous involvements, especially of the central nervous system and skeletal system. Garcia–Hafner–Happle syndrome, also known as fibroblast growth factor receptor 3 (FGFR3)-ENS, is characterized by a systematized keratinocytic EN of soft and velvety type with neurological abnormalities such as seizures, intellectual impairment, and cortical atrophy. We present a case of a 9-year-old Japanese boy afflicted with Garcia–Hafner–Happle syndrome associated with dwarfism and atopic dermatitis. We show the results of physical examination, DNA analysis, and imaging studies and discuss the mutation underlying the child’s disorder. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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4 pages, 923 KiB

Open AccessCase Report

NOD2 Mutation-Associated Case with Blau Syndrome Triggered by BCG Vaccination

by Akiko Arakawa, Naotomo Kambe, Ryuta Nishikomori, Akiyo Tanabe, Masamichi Ueda, Chikako Nishigori, Yoshiki Miyachi and Nobuo Kanazawa

Children 2021, 8(2), 117; https://doi.org/10.3390/children8020117 - 6 Feb 2021

Cited by 7 | Viewed by 3099

Abstract

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional [...] Read more.

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional mutation in NOD2 was detected by a genetic analysis, and he was diagnosed as sporadic Blau syndrome. Since NOD2 acts as a sensor for the BCG component, it is possible that BCG vaccination may trigger granuloma formation in Blau syndrome patients with such genetic background. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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6 pages, 1960 KiB

Open AccessCase Report

A Case of Eosinophilic Pustular Folliculitis since Birth

by Satoshi Yoshida, Kazuki Yatsuzuka, Kenji Chigyo, Yuta Kuroo, Koji Takemoto and Koji Sayama

Children 2021, 8(1), 30; https://doi.org/10.3390/children8010030 - 7 Jan 2021

Cited by 2 | Viewed by 7329

Abstract

A newborn male infant presented with multiple pustules and erosions with erythema involving his scalp and forehead at birth. One week after birth, new pustules continued to appear, forming crusted, ring-shaped plaques with pigmentation. Tests for possible pathogens were negative. Tzanck smear and [...] Read more.

A newborn male infant presented with multiple pustules and erosions with erythema involving his scalp and forehead at birth. One week after birth, new pustules continued to appear, forming crusted, ring-shaped plaques with pigmentation. Tests for possible pathogens were negative. Tzanck smear and skin biopsy revealed pustules beneath the stratum corneum at sites corresponding to hair follicles, which contained eosinophils and neutrophils. Taken together, a diagnosis of eosinophilic pustular folliculitis (EPF) was made. The pustules on the head disappeared rapidly with topical corticosteroid treatment, although new eruptions were still observed on the trunk about one month after birth. To our knowledge, only two cases of EPF since birth have been reported to date. Here, we also discuss the differential diagnosis of noninfectious pustular diseases at birth, including erythema toxicum neonatorum and transient neonatal pustular melanosis. These diseases, and EPF, may present with very similar clinical symptoms at birth, and the Tzanck test or biopsy may be required for differential diagnosis. Full article

(This article belongs to the Special Issue Current Research on Pediatric Allergy and Immunodeficiency)

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