A Prospective Survey of Skin Manifestations in Children With Inborn Errors of Immunity From a National Registry Over 17 Years

Waleed Al-Herz 1 2, Mohammad Zainal 3, Arti Nanda 4

Affiliations

30 September 2021

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doi: 10.3389/fimmu.2021.751469

Abstract

Background and objectives: Reports on skin manifestations in inborn errors of immunity (IEI) are based on retrospective analysis, small series, or isolated case reports. The present prospective study aimed to determine the spectrum of skin manifestations in children with IEI and their relevance to specific molecular defects.

Materials and methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of 2004-2020.

Results: A total of 313 pediatric cases of IEI, 71% diagnosed at molecular level, were registered with a cumulative follow-up period of 29,734 months. Skin manifestations were seen in 40.3% of the patients, and they were among the presenting manifestations in 33%. Patients with skin manifestations were older at both onset and diagnosis ages of IEI symptoms, but this was statistically significant for the latter only. The diagnosis delay was significantly longer in patients with skin manifestations. There was a statistically significant association between having skin manifestations and IEI category, being more common in patients with complement deficiencies, combined immunodeficiencies, and diseases of immune dysregulation. There was no statistically significant association between having skin manifestations and both gender and survival. Skin infections were the most frequent manifestations followed by eczema and autoimmune associations. Among IEI with more than 10 cases, skin lesions were a consistent finding in dedicator of cytokinesis 8 (DOCK8) deficiency, hyper IgE syndrome, ataxia-telangiectasia, and recombination activation gene (RAG)1 deficiency.

Conclusions: Skin manifestations are common in IEI patients, and they had significant diagnosis delay and referral to specialists. Improvement of awareness about IEI is needed among pediatricians and dermatologists.

Keywords: autoimmunity; cutaneous infections; eczematoid rashes; immunodeficiency; inborn errors of immunity; non-infectious cutaneous granulomas; skin manifestations.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1 (A) Perinasal ecthyma gangrenosum in a patient with DCLRE1C deficiency. (B, C) Multiple recalcitrant warts in a patient with common variable immunodeficiency (CVID). (D) Generalized molluscum contagiosum in a patient with dedicator of cytokinesis 8 (DOCK8) deficiency. (E) Severe eczematous rashes in a patient with signal transducer and activator of transcription 3 (STAT3) deficiency. (F) Erythroderma in a patient with Omenn syndrome due to recombination activation gene 1 (RAG1) deficiency

Figure 1 (A) Perinasal ecthyma gangrenosum in a patient with DCLRE1C deficiency. (B, C) Multiple recalcitrant warts in a patient with common variable immunodeficiency (CVID). (D) Generalized molluscum contagiosum in a patient with dedicator of cytokinesis 8 (DOCK8) deficiency. (E) Severe eczematous rashes in a patient with signal transducer and activator of transcription 3 (STAT3) deficiency. (F) Erythroderma in a patient with Omenn syndrome due to recombination activation gene 1 (RAG1) deficiency

Figure 2 (A) Alopecia areata in a patient with nuclear factor kappa B subunit 2 (NFKB2) deficiency. (B–D) Erythematous scaly plaques and palmoplantar keratoderma in a patient with Papillon–Lefèvre syndrome. (E–G) Tumid lupus erythematosus lesions on the face, skin histopathology showing features of lupus erythematosus, and direct immunofluorescence with granular deposition of IgM at the basement membrane zone in a patient with activation-induced cytidine deaminase (AID) deficiency.

Figure 2 (A) Alopecia areata in a patient with nuclear factor kappa B subunit 2 (NFKB2) deficiency. (B–D) Erythematous scaly plaques and palmoplantar keratoderma in a patient with Papillon–Lefèvre syndrome. (E–G) Tumid lupus erythematosus lesions on the face, skin histopathology showing features of lupus erythematosus, and direct immunofluorescence with granular deposition of IgM at the basement membrane zone in a patient with activation-induced cytidine deaminase (AID) deficiency.

Figure 3 Kaplan–Meier survival plot of the chance of survival among children with inborn errors of immunity (IEI) with respect to having skin manifestations. The probabilities that patients with no skin manifestations survived 2, 6, and 14 years after diagnosis were 77%, 74%, and 72%. At the same time, they were 82%, 74%, and 42% among patients with skin manifestations.

Figure 3 Kaplan–Meier survival plot of the chance of survival among children with inborn errors of immunity (IEI) with respect to having skin manifestations. The probabilities that patients with no skin manifestations survived 2, 6, and 14 years after diagnosis were 77%, 74%, and 72%. At the same time, they were 82%, 74%, and 42% among patients with skin manifestations.

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