UNASSIGNED: Bullosa is a rare hereditary skin condition that causes blisters. Genes encoding structural proteins at or near the dermal-epidermal junction are mutated recessively or dominantly, and this is the primary cause of EB. Herein, two Chinese boys were diagnosed with the condition, each with a different variant in a gene that serves as a reference for EB genetic counseling. Skincare significantly impacted their prognosis and quality of life.
METHODS: Two Chinese boys, with phenotypically normal parents, have been diagnosed with distinct blister symptoms, one with Dominant Dystrophic Epidermolysis Bullosa and the other with a severe form of Epidermolysis Bullosa Simplex. The first patient had a G-to-A variant in the COL7A1 allele, at nucleotide position 6163 which was named \"G2055A\". The proband is heterozygous for Dystrophic Epidermolysis Bullosa due to a COL7A1 allele with a glycine substitution at the triple helix domain. A similar variant has been discovered in his mother, indicating its potential transmission to future generations. Another patient had severe Epidermolysis Bullosa Simplex with a rare c.377T > A  variant resulting in substitution of amino acid p.Leu126Arg (NM_000526.5 (c.377T > G, p.Leu126Arg) in the Keratin 14 gene. In prior literature, Keratin 14 has been associated with an excellent prognosis. However, our patient with this infrequent variant tragically died from sepsis at 21 days old. There has been a reported occurrence of the variant only once.
CONCLUSIONS: Our study reveals that Epidermolysis Bullosa patients with COL7A1 c.6163G > A and KRT14 c.377T>A variants have different clinical presentations, with dominant forms of Dystrophic EB having milder phenotypes than recessive ones. Thus, the better prognosis in the c.6163G > A patient. Furthermore, c.377T>A patient was more prone to infection than the patient with c.6163G>A gene variant. Genetic testing is crucial for identifying the specific variant responsible and improving treatment options.

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Dear Editor, Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by erosive mucosal lesions mainly on the oral and ocular mucosae (1). We report a case of oral and ocular anti-BP180-type MMP with variable IgG and IgA reactivities and underlying dementia. An 84-year-old Japanese man presented with a 4-year history of erosions in the oral cavity and on the conjunctivae, with progressive vision impairment. The medical history included benign prostatic hyperplasia, cataract, sinusitis, and dementia. Physical examination revealed erosions and white atrophic scars along the gingival mucosa and on the hard palate (Figure 1, a, b). Conjunctival inflammation and corneal scarring were also observed only on the left eye (Figure 1, c, d). No lesions were observed on the skin or on any other mucosae. A skin biopsy from the patient\'s oral mucosa showed lymphocytic infiltration in the superficial dermis without apparent subepithelial blister. Direct immunofluorescence showed linear depositions of IgG, IgA, and C3 at the epithelial basement membrane zone (Figure 1, e-g). Circulating IgG and IgA autoantibodies were not detected by indirect immunofluorescence of normal human skin, while circulating IgA, but not IgG, autoantibodies were bound to the epidermal side of 1M NaCl-split normal human skin at 1:10 serum dilution (Figure 1, h, i). Commercially available IgG enzyme-linked immunosorbent assays (ELISAs) of BP180 NC16a domain, BP230, and type VII collagen (MBL, Nagoya, Japan) showed negative results. IgG and IgA immunoblotting analyses of six different antigen sources, including BP180 C-terminal domain recombinant protein, were all negative. However, ELISA of full-length BP180 was slightly positive for IgG antibodies (index = 5.79; cut-off <4.64). Immunoblotting analysis of full-length BP180 was negative for both IgG and IgA antibodies (Figure 1, j, k). Immunoblotting analysis of hemidesmosome-rich fraction was negative for both IgG and IgA antibodies to integrin β4 (Figure 1, l). Based mainly on the clinical and immunological findings, we established a diagnosis of MMP with IgG and IgA autoantibodies, likely reactive with BP180. Because the patient refused systemic treatments, we prescribed a mouth rinse sodium gualenate hydrate and eyedrops of fluorometholone and purified sodium hyaluronate, which did not improve the oral and ocular mucosal symptoms during the 8 month follow-up period (Figure 1, m, n). Both IgG and IgA autoantibodies in anti-BP180-type MMP tend to react with the C-terminal domain of BP180 (2), and IgG autoantibodies in 39.7% of MMP patients reactive with the epidermal side of split skin were reported to be positive with BP180 C-terminal domain (3). The full-length BP180 ELISA shows excellent sensitivity for diagnosing BP180-type MMP (4). The different IgG and IgA reactivities among various methods used in the present study may be attributed either to different methodologies (i.e., immunoblotting or ELISA) or to the different substrates, since BP180-type MMP targets various regions of BP180, including the NC16a domain, the C-terminal domain, and the intracytoplasmic region (5). Precise diagnosis for MMP by various immunological methods is critical, because urgent and extensive treatments are necessary for the ocular and laryngeal lesions, which may result in loss of eyesight and airway obstruction, respectively. Acknowledgments: We express our gratitude to Ms. Mako Mine and Dr. Daisuke Hayashi, Department of Dermatology, Osaka City University Graduate School of Medicine in Osaka, Japan for the HD-rich fraction immunoblotting analysis, and Dr. Yoshiaki Hirako, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan for the preparation of the HD-rich fraction sample. This work was supported by JSPS KAKENHI Grant Number JP20k08684 and the Hirosaki University Research Support System.

Autoimmune response to cutaneous basement membrane components superimposed on a genetic skin fragility disease, hereditary epidermolysis bullosa (EB), has been described, but its effects on disease course remain unclear. We report a 69-year-old individual with congenital skin fragility and acral trauma-induced blistering that had suddenly worsened with the onset of severe itch and diffuse spontaneous inflammatory blisters. Next-generation sequencing identified compound heterozygous null and missense COL7A1 mutations, allowing the diagnosis of recessive dystrophic EB. However, the patient\'s clinical history prompted us to investigate whether he might have developed a pathological autoimmune response against basement membrane components. Tissue-bound and circulating IgG antibodies to the major bullous pemphigoid (BP) antigen, BP180, were detected in the patient\'s skin and serum, respectively, consistent with a diagnosis of BP. Corticosteroid therapy was initiated resulting in remission of BP manifestations. EB patients presenting rapid disease worsening should be investigated for the development of a concomitant autoimmune blistering disease.

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Collagen VII is the main constituent of the anchoring fibrils, important adhesive structures that attach the epidermis to the dermal extracellular matrix. Two disorders are caused by dysfunction of collagen VII, both characterized by skin and mucosa fragility, epidermolysis bullosa acquisita (EBA) and dystrophic epidermolysis bullosa (DEB). EBA and DEB share high clinical similarities with significant difference in patients\' age of onset and pathogenesis. Our patients presented with severe and recalcitrant mechanobullous EBA with characteristic DIF, IIF and ELISA diagnostics. But in both women recessive COL7A1 variants were also found, in a monoallelic state. Collagen VII from EBA keratinocytes of our cases was significantly more vulnerable to proteolytic degradation than control keratinocytes, hinting that the heterozygous pathogenic variants were sufficient to destabilize the molecule in vitro. Thus, even if the amount and functionality of mutant and normal type VII collagen polypeptides is sufficient to assure dermal-epidermal adhesion in healthy individuals, the functionally-impaired proteins are probably more prone to development of autoantibodies against them. Our work suggests that testing for COL7A1 genetic variants should be considered in patients with EBA, which either have a patient history hinting towards underlying dystrophic epidermolysis bullosa or pose therapeutic challenges.

A male infant was born by spontaneous delivery on February 7, 2020, with a gestational age of 40 weeks and a birth weight of 4.1 kg. After birth, the infant presented with appearance of skin loss on the bilateral lower limbs, feet, left wrist, face, and lips. Large areas of skin defects, erosion, and exudation were noted on the extensor side of the bilateral lower limbs and feet, and some skin loss with a small amount of exudation was observed on the left wrist, face, and lips, which was accompanied by dorsal hyperextension of the right foot and oral mucosal ulceration (Figure 1). Because the parents refused invasive examinations (skin biopsy, i.e., transmission electron microscopy and immunofluorescence examination (1)) and the child was hospitalized in a period during which the strictest prevention and control measures for novel coronavirus pneumonia were enacted, the hospital canceled the invasive examinations; therefore, skin biopsy was not performed. The infant\'s parents were healthy and nonconsanguineous. They reported that neither of them had skin defects at birth. They also denied nail dystrophy or complete absence of the nail and a history of recurrent oral herpes or ulcers, and no other family members had such symptoms. The mother had multiple scheduled prenatal examinations during the pregnancy, and the sick infant delivered via natural birth was her first child. She did not have a history of previous miscarriage and underwent a thyroid function test and ultrasound B-mode examinations, which did not show obvious abnormalities. Ultrasound B-mode examination in the second trimester suggested bilateral renal sinus separation and excessive dorsiflexion of both feet of the fetus. A nuchal translucency (NT) scan, a noninvasive prenatal DNA test, and an oral glucose tolerance test (OGTT) showed no significant abnormalities. Ultrasound B-mode findings indicated that the infant had congenital dysplasia, suggesting that he may have a genetic disease. In a subsequent genetic test, compound heterozygous variations of c.C2005T (the nucleotide at position 2005 in the coding region was mutated from C to T) and c.G7922A (the nucleotide at position 7922 in the coding region was mutated from G to A) were detected in the child\'s collagen type VII alpha 1 chain (COL7A1) gene, and the mutations were from the child\'s parents\' genes (Table 1). The COL7A1 gene is a well-established causative gene for autosomal recessive dystrophic epidermolysis bullosa. Based on these results, COL7A1 gene mutations may have been the cause of the disease in the child; thus, the child was definitively diagnosed with autosomal recessive dystrophic epidermolysis bullosa. CASE REPORT After admission, the child received aggressive nutritional support. For treatment, cefmetazole was given for anti-infection, aseptic dressings were applied on the body surface with skin defects, iodophor disinfection was carried out, recombinant human epidermal growth factor gel and chlortetracycline eye ointment were applied externally, petrolatum was used to cover the skin defects, sterile gauze was used to wrap the lesions, and the dressings were changed daily or every other day. The wounds were kept dry, prolonged compression was avoided, and secondary bacterial infection was actively prevented and treated symptomatically as necessary. At discharge, the child\'s vital signs were stable, some epidermal defects were visible on the extensor side of the bilateral lower limbs, feet, and left wrist as well as on the face and lips with reduced exudation, and fresh epidermal coverage was observed (Figure 2). DISCUSSION Congenital epidermolysis bullosa must be differentiated from other diseases such as staphylococcal scalded skin syndrome (SSSS), neonatal impetigo, congenital bullous ichthyosiform erythroderma, congenital syphilis, and neonatal herpes simplex. Among these diseases, SSSS is a severe acute generalized exfoliative pustulosis that occurs in neonates and is characterized by the development of flaccid scalded bullae and large areas of skin exfoliation due to generalized erythema throughout the body (2). SSSS mostly occurs with sudden onset 1-5 weeks after birth. Initially, erythema occurs around the mouth or eyelids and then rapidly spreads to the trunk and proximal extremities or even to the entire body, which usually heals after 7-14 days. SSSS is a blistering and desquamative skin disease caused by the exfoliative toxins of staphylococcus aureus. It is a toxin-mediated condition (3), so the blisters and erosions are usually sterile. In this case, the child had three consecutive negative common bacterial culture test results during hospitalization, enabling exclusion of SSSS. Neonatal impetigo, congenital bullous ichthyosiform erythroderma, congenital syphilis, and neonatal herpes simplex all have associated specific pathogenic infections or are accompanied by other typical clinical manifestations, but in this case the child had no obvious infection manifestations except for specific skin lesions, allowing exclusion of the above diseases. Autosomal recessive dystrophic epidermolysis bullosa was first reported in 1966 by Bart et al. (4) and was confirmed to be caused by mutations in COL7A1 by Chrlstiano et al. in 1996 (5,6). The disease takes the form of dystrophic epidermolysis bullosa (7), and patients have congenital local skin defects, mucocutaneous blisters, and nail abnormalities (8). This disease is mostly sporadic, but familial predisposition has also been reported. In this case, the defective skin had begun to heal without complications at discharge. Based on our experience, nutritional support and infection prevention should be prioritized. The child was isolated from other patients during hospitalization, his blankets and clothes were autoclaved, and strict aseptic practices were carried out (9). Dressings were changed as needed by a designated person, and secretions were managed in a timely manner. The wounds were protected, and the child was carefully monitored and supported to improve his immunity and protect the function of his organs. This case once again demonstrates the crucial importance of prenatal diagnosis, genetic counseling, and genetic testing, which are effective measures to prevent the birth of children with genetic diseases, and early intervention can minimize the pain of the family.