Arising Concerns of Atypical Manifestations in Patients with Hand, Foot, and Mouth Disease

Abstract

Hand, foot, and mouth disease (HFMD) is a mild exanthematous, febrile disease, but it also remains a threat to global public health. HFMD is characterized by a brief febrile illness in children and with a typical skin rash of the hand and foot, with or without mouth ulcers. However, the morphology and distribution of vesicles, as well as accompanying symptoms, are varied among atypical HFMD. An upsurge in atypical presentations of HFMD caused by Coxsackievirus A6 (CVA6), including Gianotti-Crosti-like eruptions, eczema coxsackium, petechial/purpuric eruption, and vesiculobullous exanthema, can be difficult to diagnose clinically as it may mimic other severe skin diseases, such as eczema herpeticum, varicella, disseminated zoster, and erythema multiforme major. The recognition of the distinguishing features of atypical HFMD is vital for an accurate and timely diagnosis, as is initiating appropriate laboratory evaluation and supportive care. Clinicians must identify the wide range of cutaneous and mucosal alterations caused by atypical HFMD. A systemic, high-quality overview of atypical HFMD is needed for advances in better strategies for clinical diagnosis and treatment. Hence, this review is aimed at summarizing the available data on clinical investigations and differential diagnostics to provide a scientific guide for the timely diagnosis of HFMD for preventing serious complications.

Keywords: CVA6; HFMD; atypical manifestations; differential diagnosis; genetic evolution.

Figure 1

(A) Multiple individual, flat-topped, erythematous papules on the external surface of the lower limbs. (B) Well-defined and non-squamous papules on the right thigh. (C) Multiple monomorphic, flat-topped, erythematous papules on the external surface of the upper limb. (D) Monomorphic erythematous papules on the face, with sparing of the trunk. Reprinted/adapted with permission from Ref. [13]. 2019, Leung et al.

Figure 2

(A) Multiple erythematous papules and blisters with crusts on the extremities. Reprinted/adapted with permission from Ref. [23].2021, Su et al. (B) Elongated papulovesicles over palm and palmar aspect of fingers. (C) Erythematous papulovesicles over soles. (D) Crusted papules, vesicles and surrounding erythema and maceration in the groins, abdominal folds, and scrotum. Subfigures (B–D) were reprinted/adapted with permission from Ref. [21]. 2016, Ganguly et al.

Figure 3

(A) A boy experienced prominent skin eruptions and vesicles on his buttocks. Reprinted/adapted with permission from Ref. [28]. 2011, Wei et al. (B–E) Erythematous purpura of adult patients and scattered blisters on the palms and scrotum. Reprinted/adapted with permission from Ref. [29]. 2016, Laga et al.

Figure 4

(A) Bullae were formed on a sole, accompanied by mild pruritus and prickling sensations. Reprinted/adapted with permission from Ref. [35]. 2013, Huang et al. (B–D) Bullous lesions on the extremities (knees and/or elbows) in patients with atypical HFMD. Reprinted/adapted with permission from Ref. [36]. 2020, Justino et al.

Figure 5

Geographical distribution of atypical HFMD. Data are visualized with the help of online website services (https://www.chiplot.online/map_plot.html, accessed on 3 January 2023).

Figure 6

Evolutionary characteristics of CVA6 causing atypical HFMD available from GenBank were conducted applying MEGA 7 and Simplot 3.5.1 software. (A) The Bootscan analysis of MH371303.1/Italy/2017 based on the CDS region. The reference strains are represented in the legend. (B) Phylogenetic analyses of CVA6 based on a part of VP1 sequence (276 bp). The bootstrap test was performed with 1000 replications. All the strains are labelled using the following format: accession number/country of origin/year of isolation. The prototype strain of EVA71 marked with red circles indicates the outgroups. The prototype strain of CVA6 is marked as red triangles. The blue squares mark the representative strains causing atypical HFMD.