Alternative titles; symbols
SNOMEDCT: 716700003; ORPHA: 158681;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Epidermolysis bullosa simplex 2E, with migratory circinate erythema | 609352 | Autosomal dominant | 3 | KRT5 | 148040 |
A number sign (#) is used with this entry because of evidence that epidermolysis bullosa simplex 2E with migratory circinate erythema (EBS2E) is caused by heterozygous mutation in the keratin-5 gene (KRT5; 148040) on chromosome 12q13.
Epidermolysis bullosa simplex 2E with migratory circinate erythema (EBS2E) is a skin disorder in which multiple vesicles are present from birth onward and acquire over time a typical migratory circinate pattern on an erythematous background. Postinflammatory hyperpigmentation develops gradually and may have a mottled pattern (summary by Has et al., 2020).
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Gu et al. (2003) described a form of epidermolysis bullosa simplex that was milder than the Dowling-Meara phenotype (131760) but involved an unusual migratory circinate erythema with multiple vesicles on the area affected by the erythema. The lesions, which appeared from birth primarily on the hands, feet, and legs but spared the nails, ocular epithelia, and mucosae, healed with brown pigmentation but no scarring. Electron microscopy findings were distinct from those seen in the Dowling-Meara type of EBS (see 131760), with no evidence of tonofilament clumping.
Kumagai et al. (2017) reported 4 patients from 2 unrelated Japanese families with mutation in the KRT5 gene who exhibited EBS with infantile-onset migratory circinate erythema but later developed mottled pigmentation. In family 1, a 3-year-old boy developed blisters after birth and displayed circinate edematous pruritic erythema from 2 years of age. The centers of the erythematous lesions healed with pigmentation. At age 3 years, the erythema disappeared spontaneously, but the mechanical stress-induced bulla formation and reticular hyperpigmentation over the entire body surface remained. His father, paternal grandmother, and paternal great-grandfather were similarly affected. A biopsy from the affected father showed intraepidermal bullae. In family 2, a 3-year-old girl had a history of blister formation starting 1 week after birth, with erythema of the neck, bilateral axillae, and lower legs developing at 1 month of age. At age 7 months, migrating circinate erythema appeared on her neck, bilateral axillae, and inguinal regions, with brown pigmentation over the central healed areas. No circinate erythema was apparent after 1 year of age, but hyperpigmentation with hypopigmented macules remained. Biopsy showed intraepidermal bullae and degeneration of basal cells with blister formation at the epidermal-dermal junction. There was no punctate palmoplantar keratoderma (PPK) in either family, which Kumagai et al. (2017) noted had been observed in patients with EBS with mottled pigmentation (EBS2F; 131960).
Lee et al. (2018) studied a Korean boy with EBS with migratory circinate erythema and mutation in the KRT5 gene. He was born with aplasia cutis and erosive patches on the extremities; biopsy revealed subepidermal separation and basal cell cytolysis. He had occasional blisters on trauma-prone areas without obvious scarring. At age 9 years, he developed circinate migrating erythema with vesicles in the area of the groin and axillae. Biopsy of the circinate margin revealed intraepidermal blistering with prominent inflammatory infiltrates and degeneration of basal cells. The authors stated that this was the first reported patient to experience onset of migratory circinate erythema later than infancy.
Yalici-Armagan et al. (2020) reported a 2.5-year-old Turkish boy with EBS with migratory circinate erythema and mutation in the KRT5 gene. He was born with small blisters on the hands and feet, and at 11 months of age developed centrifugally expanding circinate erythematous lesions on the trunk and limbs. Examination revealed erythematous to brownish pigmented patches on the neck, axillae, knees, and dorsum of hands, as well as pruritic circinate erythema with marginal fine scaling and small blisters on the dorsum of the feet and popliteal fossa. There was no mucosal or nail involvement, or PPK. Biopsy from an erythematous margin showed hyperkeratosis and parakeratosis, with subepidermal separation. Immunohistochemistry revealed collagen type IV (see 120130) and laminin (150320) positivity on the floor of the blister, confirming the diagnosis of EBS. The proband's mother had similar childhood blistering that later resolved.
The transmission pattern of EBS2E in the family reported by Nagao-Watanabe et al. (2004) was consistent with autosomal dominant inheritance from a parent with somatic and germline mosaicism.
In an affected Japanese girl and affected members of an unrelated Korean family, Gu et al. (2003) identified heterozygosity for a 1649delG mutation in the KRT5 gene (148040.0017). The mutation was assumed to have arisen de novo in the Japanese girl. When a younger sister with EBS was born and was found to have the same 1649delG mutation as her older sib, Nagao-Watanabe et al. (2004) reinvestigated the familial segregation of the mutation and identified heterozygosity for the deletion in the mother's DNA from hair bulb and buccal cell samples. Closer scrutiny of the mother's history revealed that she had migratory circinate pigmentation of the skin in childhood, and Nagao-Watanabe et al. (2004) concluded that this represented maternal somatic and germline mosaicism.
In patients from 2 unrelated Japanese families with EBS with migratory circinate erythema, Kumagai et al. (2017) identified heterozygosity for mutations in the KRT5 gene: in family 1, the proband and his affected father and paternal grandmother had a 4-bp deletion (148040.0026), and in family 2, the proband had a de novo occurrence of the previously reported c.1649delG mutation. All affected individuals displayed infantile-onset circinate erythema that spontaneously resolved, but then developed mottled pigmentation. The authors noted that both mutations resulted in deletion of C-terminal peptides of KRT5 in the V2 domain with the addition of frameshifted peptides with identical reading frames, and suggested that the shared frameshifted peptides contributed to the characteristic inflammatory phenotype by triggering immune reactions.
In a Korean boy with EBS who developed migratory circinate erythema at 9 years of age, Lee et al. (2018) identified heterozygosity for a de novo in-frame 12-bp deletion in the KRT5 gene (148040.0027). The mutation was not found in his unaffected parents or in public variant databases.
In a 2.5-year-old Turkish boy who had onset of EBS with migratory circinate erythema at 11 months of age, Yalici-Armagan et al. (2020) directly sequenced the KRT5 gene and identified heterozygosity for a 1-bp deletion (148040.0028), inherited from his affected mother. He was also heterozygous for a D197E substitution in KRT5, for which his unaffected father was homozygous; this variant was believed to be nonpathogenic.
Gu, L.-H., Kim, S.-C., Ichiki, Y., Park, J., Nagai, M., Kitajima, Y. A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema. J. Invest. Derm. 121: 482-485, 2003. [PubMed: 12925204] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12424.x]
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Kumagai, Y., Umegaki-Arao, N., Sasaki, T., Nakamura, Y., Takahashi, H., Ashida, A., Tsunemi, Y., Kawashima, M., Shimizu, A., Ishiko, A., Nakamura, K., Tsuchihashi, H., Amagai, M., Kubo, A. Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5. J. Europ. Acad. Derm. Venereol. 31: e241-e243, 2017. [PubMed: 27730678] [Full Text: https://doi.org/10.1111/jdv.14005]
Lee, S. E., Choi, J. Y., Kim, S.-E., Kim, S.-C. A novel deletion mutation in the 2B domain of KRT5 in epidermolysis bullosa simplex with childhood-onset migratory circinate erythema. Europ. J. Derm. 28: 123-125, 2018. [PubMed: 29180315] [Full Text: https://doi.org/10.1684/ejd.2017.3190]
Nagao-Watanabe, M., Fukao, T., Matsui, E., Kaneko, H., Inoue, R., Kawamoto, N., Kasahara, K., Nagai, M., Ichiki, Y., Kitajima, Y., Kondo, N. Identification of somatic and germline mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case. Clin. Genet. 66: 236-238, 2004. [PubMed: 15324323] [Full Text: https://doi.org/10.1111/j.1399-0004.2004.00292.x]
Yalici-Armagan, B., Kabacam, S., Taskiran, Z. E., Gokoz, O., Utine, G. E., Ersoy-Evans, S. A novel mutation of keratin 5 in epidermolysis bullosa simplex with migratory circinate erythema. Pediat. Derm. 37: 358-361, 2020. [PubMed: 31965605] [Full Text: https://doi.org/10.1111/pde.14087]