Two missense mutations in Dystonin lead to epidermolysis bullosa simplex complicated with lepromatous leprosy: a case report

Introduction

Background

Epidermolysis bullosa (EB) is a severe skin disease characterized by blisters, bullae, and erosion after minor trauma (1). Epidermolysis bullosa simplex (EBS) is one of the four main types of EB, typically caused by heterozygous mutations in KRT5 or KRT14, inherited in an autosomal dominant (AD) manner. Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), associated with recurrent erythema nodosum leprosum (ENL) symptoms (2). Diagnosis depends on clinical manifestations, histopathology, and acid-fast staining.

Rationale and knowledge gap

The co-occurrence of EBS and lepromatous leprosy (LL) in a single patient is exceptionally rare and provides an opportunity to explore interactions between a genetic skin disorder and an infectious disease. Although it is known that EBS can result from mutations in KRT5, KRT14, and Dystonin (DST) genes (3,4), how these mutations might influence susceptibility to infectious diseases like leprosy remains unclear, particularly in the role of DST mutations.

Objective

This case of EBS resulting from two missense mutations in DST, complicated by LL. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-167/rc).

Case presentation

A 32-year-old male presented with erythema and blisters on his limbs for over a year, and yellow nodules on the back of his hands with numbness for one year. He was previously diagnosed with bullous pemphigoid (BP) by biopsy. The pathological results are shown in Figure S1. After hospitalization, his condition improved with hormone treatment, but relapses occurred over the year. Physical examination revealed yellow nodules and blisters on his limbs, which, upon rupture, led to erosion (Figure 1A-1C). Small spherical papules appeared on his ears and lips (Figure 1D,1E). There was no pain in the limbs and joints. No family history of similar disease was reported.

Figure 1 Clinical image. (A-C) Yellow nodules and blisters were scattered on the limbs. (D,E) Small spherical papules could be seen on the ears and lips. Before the biopsy, the patient signed a document acknowledging the possibility of sharing this case report in the future and agreed to it by signing the form.

Histopathological findings included epidermal atrophy with numerous foam cells, macrophages, and interstitial lymphocytes in the dermis, regional degeneration, necrosis and neutrophils (Figure 2A). Special staining results revealed acid-fast staining 5+ (Figure 2B), alcian blue foci + (Figure 2C) leading to diagnosis of LL with ENL. At the suggestion of the doctor, the patient underwent whole exome sequencing, and the results showed that two missense mutations related to the phenotype of the patient were detected in the DST gene: c.5972A>G(p.Asn1991Ser) (Figure 2D) and c.5137A>G(p.Asn1713Asp) (Figure 2E). In silico analyses using PolyPhen-2, SIFT (sorting intolerant from tolerant), and Mutation Taster were conducted and showed the following: PolyPhen-2 predicted the p.Asn1991Ser variant to be “probably damaging” (score: 0.955) and the p.Asn1713Asp variant to be “possibly damaging” (score: 0.706). SIFT classified both variants as “deleterious”, with scores of 0.02 and 0.03, respectively. Mutation Taster predicted both variants as “disease-causing”. These results indicate that the identified variants are likely pathogenic, supported by their rarity in population databases (ExAC and gnomAD). The final diagnosis was EBS with LL and ENL. The patient’s close relatives had no similar medical history.

Figure 2 Histopathologic appearances. (A) H&E, the epidermis is atrophic; a large number of foam cells, macrophages, and a small number of interstitial lymphocytes diffuse in the dermis; regional degeneration and necrosis, neutrophils, and nuclear dust can be seen (×200). (B) Acid fast staining 5+ (×400). (C) Alcian blue foci + (×200) whole exome sequencing. Sequence chromatogram showing two heterozygous mutations in DST: (D) c.5972A>G(p.Asn1991Ser) and (E) c.5137A>G(p.Asn1713Asp). DST, Dystonin; H&E, hematoxylin and eosin.

The patient was transferred to a leprosy prevention center for further treatment.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Patient perspective

I first noticed the symptoms over a year ago when I developed red patches and blisters on my limbs. These were accompanied by yellow nodules on the back of my hands and numbness. When I went to the hospital, I was diagnosed with BP and started treatment. After the initial hospitalization, my condition improved, and I felt hopeful. However, over the past year, my condition kept recurring. The blisters and nodules would come back. I also started noticing small papules on my ears and lips. It was frustrating and disheartening to experience these repeated attacks without understanding why they kept happening. I had another extensive examination at the hospital, which revealed more details about my condition. The doctors found significant changes in my skin, including a large number of foam cells, macrophages, and lymphocytes. They performed special staining tests and diagnosed me with LL with ENL. After the doctor’s suggestion and going through whole exome sequencing, genetic testing showed that I had two mutations in the DST gene, leading to an eventual diagnosis of EBS complicated by LL and ENL. Despite the challenges, the medical team was supportive and thorough in explaining my condition and the necessary steps forward. I was transferred to a specialized leprosy prevention center, which gave me some relief knowing I would receive targeted treatment.

Discussion

key findings

EB is a serious single-gene skin disorder characterized by blisters, bullae, and erosion following minor trauma. EBS is primarily associated with KRT5 or KRT14 mutations inherited in an AD pattern, though rare cases arise from non-keratin mutations such as DST encode the epithelial subtype of dystonic inherited by autosomal recessive (AR) pattern (5).

Leprosy is a chronic infectious disease caused by M. leprae. The main way of infection is to contact healthy people with infectious leprosy patients. Type II leprosy reaction, also known as ENL, is mainly characterized by recurrent clusters of erythema nodosum, which may occur before, during, or even after treatment and can become the main symptom of some patients to see a doctor for the first time (6). The diagnosis of leprosy mainly depends on clinical manifestations, histopathology, and acid-fast staining tests of M. leprae. A case of EBS resulting from two missense mutations in DST complexed with LL was reported here.

In this study, our patient was initially diagnosed with BP but was later found to be concurrently infected with leprosy. Due to the possibility of leprosy causing bullous lesions, he was initially misdiagnosed with BP in the Traditional Chinese Medicine Department. Following hormone treatment, his condition improved, but he was subsequently correctly diagnosed with leprosy. The presence of DST mutations likely contributed to his susceptibility to leprosy.

This case underscores the importance of conducting thorough differential diagnoses in cases of bullous diseases. It highlights the need for comprehensive examinations including antibody detection, pathological examination, and potentially genetic testing to ensure accurate diagnosis and appropriate management.

Previous literature has reported only a limited number of cases of EBS caused by DST gene mutations, with various DST variants identified. p.Gln1124X, P.Arg1249X, P.Gln1269X, P.Gln2187X, P.Tyr2366X, P.Leu2477Serfs*13, P.Glu873del and P.H269R (7). The two variants in our case have never been reported before. In this case, we detected two missense mutations in DST: c.5972A>G(p.Asn1991Ser) and c.5137A>G(p.Asn1713Asp). Both variants were predicted to be damaging by in silico analyses and are rare in population databases. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the two loci are very low-frequency loci in recessive genetic diseases, which may constitute a compound heterozygous mutation causing pathogenicity. DST encodes the BPAG1 protein, which includes three subtypes, among which the skin subtype is BPAG1-e. BPAG1e is a hemidesmosome protein, that plays an important role in the keratinocyte adhesion, cell diffusion and migration (8). DST gene mutations lead to BPAG1-e deficiency and eventually cause disease.

Our patient after hospitalization was given a diagnosis of BP by biopsy. He was given glucocorticoid 40 mg/d. In the past year, the patient was treated with glucocorticoid ointment to control the disease progression. Long-term external use of glucocorticoids can cause a decline in skin immune function. Due to the erosion of the skin itself, the author speculates that the patient was infected with M. leprae during this period, but the specific pathogenesis remains to be verified. After identifying the DST gene mutations linked to EBS, the patient was transferred to the local leprosy prevention center for further treatment. This ensured access to specialized expertise, advanced therapeutic options, and support for managing the multifaceted aspects of leprosy and its complications.

Strengths and limitations

Strengths include identifying two novel DST mutations and providing valuable insights into the coexistence of EBS and leprosy. Limitations of our study include a lack of long-term follow-up data on EBS and leprosy treatment outcomes.

Comparison with similar research

Previous study have identified various DST mutations causing EBS and emphasized the role of BPAG1-e in maintaining skin integrity. However, cases complicated by leprosy remain rare. This report adds unique genetic data and underscores the need for careful management to prevent secondary infections in EBS patients.

Explanations of findings

These findings highlight the complexity of the case, involving both a genetic disorder (EBS) and an infectious disease (LL with ENL), and underscore the importance of comprehensive diagnostic approaches, including histopathology and genetic testing.

Implications and actions needed

This case reminds us of that long-term glucocorticoids or immunosuppressants use in bullous skin disease can increase infectious risks due to skin fragility. Therefore, careful glucocorticoid use and wound care are essential. We believe it is important to report this study because it can add to the existing literature and highlight the role and importance of not ignoring the cases of EBS complicated with leprosy.

Conclusions

This case of EBS caused by DST gene mutations expands the phenotypic variability associated with DST and emphasizes the importance of careful glucocorticoid use and wound care in bullous skin disease management.

Acknowledgments

We thank Dr. Jiefeng Li and Dr. Ruzeng Xue from the Department of Dermatology for their contribution to the diagnosis of this case.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-167/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-167/prf

Funding: The study was supported by Natural Science Foundation of Guangdong Province of China (grant Nos. 2021A1515011218 and 2020A1515010281).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-167/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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