S Zhu, Y Jiang, J Zhu, J Qiao

Abstract

Epidermolysis bullosa dystrophica, Bart type (EBD-B) is an extremely rare congenital disease. Here, we report a case of a male newborn from China who presented with aplasia cutis congenita, epidermolysis bullosa, and toenail dysplasia that we diagnosed as EBD-B. Exon sequencing and Sanger sequencing showed that the child had a COL7A1 gene mutation inherited from his mother, so the epidermolysis bullosa type was determined to be dominant dystrophic epidermolysis bullosa. The blister symptoms of this type are relatively mild. Therefore, we only used conservative treatment to prevent the infection in the region of aplasia cutis congenita. Two months later, aplasia cutis congenita was completely cured except for sporadic skin blisters, and the growth of the child was not affected.

Introduction

Epidermolysis bullosa dystrophica, Bart type (EBD-B) was first proposed and described by Bruce J. Bart in 1966.¹ Common characteristic manifestations are a triad: aplasia cutis congenita (ACC) that affect the lower limbs, epidermolysis bullosa (EB) regardless of type, and nail dysplasia. Due to very limited number of reported cases, its incidence, aetiology, and pathogenesis are not clear. Heredity, teratogens, amniotic membrane adhesion, and placental infarction are suspected to be related to EBD-B, but there is no direct evidence of causality. The diagnosis of EBD-B is mainly based on clinical symptoms, which can be observed at birth.² Therefore, early recognition of the disease by paediatricians has a great impact on the prognosis of children.

This study describes the case of a newborn with EBD-B that will increase the understanding of the disease amongst paediatricians.

Case Report

A 1-hour-old boy was admitted to the neonatal intensive care unit due to congenital absence of skin on his right lower limbs. The child was born vaginally at 39+2 weeks with a birth weight of 3800 g. Both head and chest circumferences were within the normal reference range. There was no asphyxia at birth, and Apgar scores were 9 points at 1 minute (skin colour was reduced by 1 point) and 10 points at 5 minutes. There was no exposure to radioactive substances or drug use during pregnancy, and all routine antepartum examination results of the baby were normal. There were no consanguineous marriages in this family within three generations. However, the mother had toe nail dysplasia, which was similar to the clinical phenotype of the child. In addition, the mother's skin was very fragile, where even minor trauma could cause skin damage or blisters. Her husband was healthy.

We carried out a careful physical examination of the child. The S-shaped skin defect had a clear boundary. It started at the lower part of the right thigh, descended along the anteromedial direction, and extended through the knee and ankle joint to the dorsum of the foot. Movement of the knee and ankle was not restricted. The basal surface of the skin defect was red, covered by a very thin transparent membrane, and the blood vessels below the membrane were clearly visible (Figure 1). The child was restless and cried upon touching the area. A blister was observed in the lesion area of the skin on the inside of the right foot. The blister wall was slightly tense with clear liquid inside. The rest of the skin on the body and the oral mucosa were normal. In addition, some of the child's toenails had dysplasia. Except for the above symptoms, no other positive symptoms were found during the physical examination.

Figure 1 The S-shaped skin defect with clear boundary located on the right lower limb.

After admission, his blood cell analysis, C-reactive protein, electrolytes, blood culture tests, and ultrasonic examination of the digestive and urinary systems were normal. Histopathology of the skin near the blister lesion with hematoxylin and eosin staining showed the presence of subepidermal blisters and no infiltration of inflammatory cells. Whole exon sequencing and Sanger sequencing revealed a heterozygous mutation in the COL7A1 gene inherited from the mother, c.6043G>C, p.Gly2015Arg.

We have adopted a conservative treatment for children. Mupirocin ointment was applied externally to the skin defect area and then covered with Vaseline gauze. Infection indicators were normal, so no systemic antibiotics were used in any way during hospitalisation. The child experienced scattered blisters on areas of normal skin since the age of 3 days, especially in places where rubbing occurs. These blisters have not been specially treated. After blood culture results returned negative, we discharged the patient and trained the parents on how to take care of the child. Through follow-up, it was known that the skin lesions on the right leg healed completely by the age of 2 months. No obvious pigmentation was found on the skin surface but millet-like changes could be felt. Although feeding and growth were good during the follow-up period, sporadic blisters, alternating between old and new, were still visible on the skin. The parents of the patient provided informed consent, and the study design was approved by the appropriate ethics review board.

Discussion

The histopathological results found in this newborn were consistent with those of EB, and combined with toenail dysplasia and a congenital skin defect of the right leg, EBD-B was definitively diagnosed. There are individual differences within the three typical clinical manifestations of EBD-B. For example, ACC can be unilateral, bilateral, and even involve the upper limbs and trunk.^2-4 Hypoplasia of the nail may manifest as a deformity or deletion.² The performance of the blister can also be different, with the liquid in the blister being colorless, light yellow, or dark red.^3,5 It is worth noting that nail abnormalities and ACC can be found at birth, but blisters may occur several days later, which may affect the diagnosis time of the disease.³ Fortunately, the blisters of children diagnosed with EBD-B reported so far all have appeared within 7 days. Therefore, EBD-B can be diagnosed within 1 week of birth.

Most children with EBD-B have a good prognosis. The skin defect usually completely recovers within 2-3 months, with few resulting in pigmentation, but the scabbed surface often has millet-like changes.^6,7 Therefore, paediatricians should choose conservative treatment when dealing with children with EBD-B in the neonatal period. Prevention of infection and reduction of skin friction are the main treatment measures for this disease.^7,8 At present, there is no final conclusion on whether to use antibiotics or how to use them. It often depends on the experience of the paediatrician. Since there was no inflammatory manifestation in the skin defect area of this patient, and the infection indicators in the blood were normal, we only used external antibiotics to prevent infection and achieved good results. However, not all children with EBD-B will progress in the same good direction. Two deaths have been reported.^4,9 Both cases were of premature infants with ear malformations, and the skin defects involved four limbs and the face. Considering that the immune function has not yet developed well in premature infants, and multiple areas of skin loss is a high-risk factor for infection, it is not surprising that one infant died of severe neonatal sepsis.⁹ Therefore, paediatricians should pay more attention to EBD-B in premature infants with multiple skin defects.

Recurrent episodes of blisters are the main factor that affects the quality of life in children with EBD-B. Heredity is the key factor in determining the clinical manifestation of EB. In general, the symptoms of autosomal recessive EB are generally systemic and severe, while those of autosomal dominant EB are usually mild with a relatively limited lesion site.¹⁰ Our patient had a mutation in the COL7A1 gene that was inherited from the mother. Combined with their clinical symptoms, it can be inferred that the EB of the patient was autosomal dominant inheritance. Type Ⅶ collagen α-chain 1 encoded by COL7A1 gene is the main component of anchor fibril under the dense layer of epidermal basement membrane. COL7A1 gene mutations are the direct cause of epidermolysis bullosa dystrophica, among which missense mutations are the most common.¹⁰ In this case, the mutation of the COL7A1 gene led to the replacement of glycine at site 2015 to arginine, resulting in changes of the triple helix domain of α chain in type VII collagen. To our knowledge, the mutation of this site has not yet been reported. Due to dominant inheritance, the patient did not develop severe generalised blisters during follow-up. This information also provides us with great help in judging the prognosis. Recently, mutations in the KRT5 gene and PLEC gene, which can lead to EB simplex, have been reported in children with EBD-B.⁸ If a child has EB of this type, blisters can gradually lighten or disappear with age. Therefore, we believe that gene detection is necessary in children with EBD-B. The test results can not only clarify the type of EB to help predict the prognosis, but can also provide genetic counselling for families.

To sum up, most children with EBD-B have a good prognosis after conservative treatment, but we need to be alert to premature infants with multiple skin defects. Gene detection is very helpful for the diagnosis of EB type and the prognosis of the disease. Paediatricians should consider using this during the early routine examination.

Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgements

We are thankful to the family for their collaboration. We also thank Youqing Shen and Jing Zhang for their assistance during the writing period. This study was supported by the Jiangsu Province Maternal and Child Health Research Project (F201941) and Suqian Science and Technology Plan Project (Z2019154 and S201912).

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