Abstract
Skin lesions in X-linked Alport syndrome (XLAS) are rarely observed. Bullous pemphigoid (BP) is caused by autoantibodies against BP180, also called α1 (XVII) chain, in the basement membrane zone (BMZ). A 48-year-old man with XLAS developed tense blisters. A skin biopsy showed a cleft between the basal cell layer and dermis, with the infiltration of neutrophils and eosinophils. α1 (XVII) staining was positive on the epidermal side of α2/5 (IV) staining. Oral prednisolone improved his symptoms gradually. Abundant tense blisters on the palms and soles might suggest an important role of the α5 (IV) chain in the integrity of BMZ.
Keywords: basement membrane zone, bullous pemphigoid, COL4A5, X-linked Alport syndrome
Introduction
X-linked Alport syndrome (XLAS) is an inherited disorder caused by mutations in the COL4A5 gene, which encodes α5 chain of type IV collagen (1). XLAS is characterized by progressive nephropathy with structural abnormalities of the glomerular basement membranes, which leads to end-stage kidney disease (ESKD), sensorineural hearing loss, or ocular abnormalities (2). Although aortic abnormalities and diffuse leiomyomatosis of the esophagus and tracheobronchial tree were observed in a small number of XLAS cases (3,4), skin lesions were rarely observed, while the α5 (IV) chain existed in the epidermal basement membranes (5).
Bullous pemphigoid (BP) is an autoimmune bullous dermatosis caused by autoantibodies against two hemidesmosomal proteins (BP180 and BP230) in the basement membrane zone (BMZ) (6). The alternative name of BP180 is COL17A1, which encodes α1 chain of type XVII collagen. Several clinical factors (e.g., old age), medications (e.g., dipeptidyl peptidase-4 inhibitors), and physical factors (e.g., insect bite, irradiation, and ultraviolet exposure) have been reported to be associated with the development of BP (7). Even though comorbidities, such as hematological malignancies, neurological disorders, and acquired reactive perforating collagenosis are reportedly associated with the onset of BP (7,8), there have been no reports on the association between BP and XLAS.
We herein report a patient undergoing hemodialysis (HD) due to XLAS who developed BP.
Case Report
The patient was a 48-year-old Japanese man in whom microhematuria had been pointed out at 2 years old. A kidney biopsy at nine years old had shown mild mesangial hypercellularity with negative results on an immunofluorescence study. A second kidney biopsy showed minor glomerular abnormalities with negative results in an immunofluorescence study under light microscopy, as well as no apparent abnormality in the glomerular basement membranes under electron microscopy. He developed sensorineural hearing loss at 22 years old. The hearing loss and kidney dysfunction with microhematuria and proteinuria progressed further at 32 years old, and he eventually started to receive HD at 35 years old. Later, he was diagnosed with XLAS after a genetic analysis identified COL4A5 c.404 G＞A (p.G135D) (Fig. 1a).
Figure 1.
(a) A genetic analysis identified COL4A5 c.404 G>A (p.G135D). (b) Many tense blisters and erosions were observed on the right sole. (c) The results of a skin biopsy showed a cleft between the basal cell layer and the dermis (left panel, bar=500 μm), and a high-magnification view of the open black rectangle showed infiltration of neutrophils and eosinophils just below the cleft (right panel, bar=50 μm). (d) An immunofluorescence study showed strong staining of complement 3 and weak staining of immunoglobulin G (IgG) along the basal cell layer, while there was no staining of IgA or IgM along the basal cell layer. Bars=50 μm.
The patient had hypertension and a history of hepatitis B infection. His family history showed microhematuria in his mother and sister. His medications included precipitated calcium carbonate (3,000 mg/day), lanthanum carbonate hydrate (1,500 mg/day), and ferric citrate hydrate (750 mg/day) for hyperphosphatemia; sodium polystyrene sulfonate (15 g/day) for hyperkalemia; suvorexant (15 mg/day) for insomnia; nalfurafine hydrochloride (2.5 μg/day) and rupatadine fumarate (10 mg/day) for pruritus; and vonoprazan fumarate (10 mg/day) for gastric ulcer.
The patient had started to feel a general itching sensation four months before admission. Rash appeared approximately 40 days before admission, and oral prednisolone (5 mg/day) was initiated. Although the rash on his trunk temporarily improved, painful tense blisters appeared on his lower legs 10 days before admission. He visited the dermatology department of Mie University Hospital and received a skin biopsy from the dorsum of the right foot, and his oral prednisolone dose was increased to 10 mg/day 6 days before admission. His symptoms worsened further, so his oral prednisolone dose was increased to 20 mg/day 3 days before admission.
At admission, his height was 168 cm, and his body weight was 58 kg. A physical examination showed tattoos on his chest, back and right ankle. Many tense blisters with erosion were observed on the extremities and trunk of his body, being particularly abundant on the palms and soles (Fig. 1b). While there were small blisters with erosion around the patient's lips, there were no mucosal lesions on the oropharynx, hypopharynx, or larynx.
The laboratory data are shown in Table. Leukocytosis with eosinophilia, C-reactive protein elevation, and immunoglobulin E (IgE) elevation were observed. The anti-BP180 and anti-BP230 antibody titers were high at 1,470 and 67.7 U/mL, respectively. The results of the skin biopsy showed a cleft between the basal cell layer and the dermis, and infiltration of neutrophils and eosinophils was observed just below the cleft (Fig. 1c). An immunofluorescence study showed strong staining of complement 3 (C3) and weak staining of IgG along the basal cell layer (Fig. 1d). Triple staining with rabbit anti-α1 (XVII) and rat anti-α2/5 (IV) antibodies was positive for α1 (XVII) on the epidermal side of α2/5 (IV) staining (arrows, Fig. 2). α5 (IV) showed a mosaic pattern, while α2 (IV) showed a linear pattern, which was compatible with a previous report (arrowheads, Fig. 2) (9).
Table.
Laboratory Data.
| Complete blood count | |
| White blood cells (/µl, 3,300-8,600) | 17,150 |
| Eosinophils (%, 0.0-8.5) | 24.5 |
| Red blood cells (×104/µl, 435-555) | 401 |
| Hemoglobin (g/dL, 13.7-16.8) | 12.6 |
| Platelets (×104/µl, 15.8-34.8) | 32.1 |
| Coagulation | |
| Activated partial thromboplastin time (s, <37) | 27.5 |
| Prothrombin time-international normalized ratio (0.88-1.08) | 0.97 |
| D-dimer (µg/mL, <1.00) | 6.84 |
| Blood chemistry | |
| Glucose (mg/dL, 73-109) | 110 |
| Hemoglobin A1c (%, 4.9-6.0) | 5.2 |
| Total protein (g/dL, 6.6-8.1) | 6 |
| Albumin (g/dL, 4.1-5.1) | 3.5 |
| Blood urea nitrogen (mg/dL, 8-20) | 41.3 |
| Creatinine (mg/dL, 0.65-1.07) | 8.68 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 6.1 |
| Uric acid (mg/dL, 3.7-7.8) | 6.2 |
| Sodium (mEq/L, 138-145) | 139 |
| Potassium (mEq/L, 3.6-4.8) | 5 |
| Chloride (mEq/L, 101-108) | 98 |
| Calcium (mg/dL, 8.8-10.1) | 8.7 |
| Aspartate transaminase (U/L, 13-30) | 33 |
| Alanine transaminase (U/L, 10-42) | 24 |
| Lactate dehydrogenase (U/L, 124-222) | 274 |
| Alkaline phosphatase (U/L, 38-113) | 205 |
| γ-glutamyl transpeptidase (U/L, 13-64) | 20 |
| Creatine kinase (U/L, 59-248) | 637 |
| C-reactive protein (mg/dL, 0-0.14) | 3.17 |
| Immunoglobulin G (mg/dL, 861-1,747) | 854 |
| Immunoglobulin A (mg/dL, 93-393) | 104 |
| Immunoglobulin M (mg/dL, 33-183) | 30 |
| Immunoglobulin E (U/mL, 0-170) | 1,516 |
| Serology | |
| Antinuclear antibody (<1:40) | <1:40 |
| Anti-bullous pemphigoid 180 antibody (U/mL, <9.0) | 1,470 |
| Anti-bullous pemphigoid 230 antibody (U/mL, <9.0) | 67.7 |
| Hepatitis B virus antigen (U/mL, <0.05) | <0.01 |
| Hepatitis B surface antibody (mU/mL, <10) | >1,000 |
| Hepatitis B core antibody (S/CO, <1.00) | 2.66 |
| Hepatitis B virus DNA (LogU/mL, <1.3) | <1.3 |
| Hepatitis C virus antibody (S/CO, <1.00) | 0.06 |
| Human immunodeficiency virus antibody (S/CO, <1.00) | 0.06 |
Figure 2.
Triple staining with rabbit anti-α1 (XVII) and rat anti-α2/5 (IV) antibodies showed α1 (XVII) staining was positive on the epidermal side of the α2/5 (IV)-stained section (arrows). α5 (IV) showed a mosaic pattern, while α2 (IV) showed a linear pattern (arrowheads). Bars=100 μm.
The BP disease area index (BPDAI) on admission was 122, and oral prednisolone was increased to 55 mg/day (Fig. 3). His symptoms, BPDAI, and anti-BP180 antibody titer gradually improved. The BPDAI decreased to 13 on the 28th day of admission, and his prednisolone dose was decreased to 30 mg/day. He was discharged from the hospital on the 35th day of admission. His prednisolone dose was gradually tapered to 12.5 mg/day, and his anti-BP180 antibody titer recovered to 7 U/mL at 1 year and 3 months after admission.
Figure 3.
The clinical course. BPDAI: bullous pemphigoid disease area index
Discussion
We encountered a patient with HD due to XLAS who developed BP. The skin lesions in ESKD patients are diverse; therefore, it was necessary to carefully differentiate the diagnosis when we observed bullous dermatosis (10). Although there are limited data on the incidence of BP in ESKD patients, one single-center 10-year study showed that the incidence of BP in peritoneal dialysis patients was 3/478.3 person-years (7). As a rare autoimmune dermopathy, IgA-related diseases, such as linear IgA dermatosis and dermatitis herpetiformis, have been reported in ESKD patients, being characterized by subepidermal vesicles with IgA deposition in the dermal papillae and BMZ (10).
Immunofluorescence antigen mapping (IFM) on skin biopsy samples can provide overall information to help clarify the layer of skin where separation has occurred or the abundance of a certain type of protein using monoclonal antibodies against proteins of the dermal-epidermal junction zone (11). IFM revealed that keratin intermediate filaments inserted into hemidesmosomes, including BP230, which interacted with the transmembrane proteins, including collagen XVII (BP180), and then bound to collagen IV through laminin-332 (11). Indeed, α1 (XVII) staining in the present case was observed on the epidermal side of the α2/5 (IV) staining. Therefore, the abundant tense blisters on the palms and soles in the present case may suggest an important role of the α5 (IV) chain in the integrity of the BMZ, although the precise mechanisms are unclear, and further studies will be needed to draw any definitive conclusions.
Two studies have reported that autoantibodies to α5 (IV) led to the formation of subepidermal blisters. One case involved specific IgG autoantibodies to an 185-kDa polypeptide of the noncollagenous 1 (NC1) domain in the α5 (IV) chain, which led to the development of subepidermal bullous eruptions with IgG and C3 deposits along the dermal-epidermal junction of the skin (12). The other case involved autoantibodies against the 185- to 190-kDa antigen of the α5 and α6 chains, which led to the development of subepidermal blisters with linear IgA and C3 deposits along the dermal-epidermal junction (13). In addition, antibodies against native human type IV collagen were rarely detected, except in systemic lupus erythematosus (SLE), whereas antibodies against denatured human type IV collagen were detected in cases of rheumatoid arthritis, scleroderma, and SLE (14). Although we considered the possibility of the presence of autoantibodies against α5 (IV) in the present case, the presence of autoantibodies against α5 (IV) was not examined, and its involvement remained unclear.
In conclusion, we experienced a rare case of an XLAS patient who developed severe blisters due to BP.
The patient's consent was obtained for genetic screening. The genetic analyses were approved by the Institutional Review Board of Mie University Graduate School of Medicine (reference number H2019-113). Written informed consent was obtained from the patient for the publication of this case report.
Author's disclosure of potential Conflicts of Interest (COI).
Kaoru Dohi: Honoraria, Otsuka Pharmaceutical, Novartis Pharma, Daiichi Sankyo, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, and AstraZeneca; Research funding, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Novartis Pharma, Otsuka Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Kowa, and Abbott Medical Japan.
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