Introduction

Cronkhite–Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic hamartomatous gastrointestinal polyposis, hair loss, nail atrophy, hyperpigmentation, and diarrhea. While the etiology of CCS remains unclear, it has been reported that in CCS, hamartomatous polyps are infiltrated with IgG4 plasma cells; thus, CCS may have an autoimmune background [1]. Indeed, in the literature, CCS has been associated with some autoimmune diseases, including hypothyroidism [2, 3], systemic lupus erythematosus [4], Basedow’s disease [5], and type 1 diabetes [6]. Regarding complications of nephritis, there are only seven reports of nephritis accompanied by CCS, all of which have been proven to be membranous nephropathy (MN), but a functional link between CCS and MN has not been demonstrated. Herein, we report a case of MN with CCS. In this case, immunofluorescent staining of the renal biopsy specimen showed that IgG4 was predominantly stained in the IgG subclass.

Case report

A 57-year-old man with CCS was referred to our department because of urinary protein and occult blood. Three years prior to the presentation, he developed dysgeusia, frequent diarrhea, hair loss, nail plate atrophy, and skin pigmentation. The endoscopic examination showed multiple reddish gastrointestinal inflamed areas and adenomatous polyposis (Fig. 1A and B), and the histopathological examination of the polyp specimens revealed a severely edematous stroma, cystic dilated ducts, and mononuclear or neutrophil cell infiltration (Fig. 1E and F) without malignancy. These findings led to the diagnosis of CCS. Immunohistochemical analysis of IgG4 of colon polyp was negative. Prednisolone therapy (30 mg/day) was started to treat CCS; thereafter, the clinical symptoms gradually improved. However, when the prednisolone dose was gradually tapered, the hair loss and nail plate atrophy worsened and urinary protein and occult blood appeared. The patient had a history of pituitary adenoma, hypopituitarism, adrenal insufficiency, central hypothyroidism, symptomatic epilepsy, and atopic dermatitis. There was no family history of gastrointestinal and kidney diseases.

Fig. 1
figure 1

Findings of CCS. A Multiple reddish areas of gastrointestinal inflammation seen via esophagogastroduodenoscopy at the time of CCS diagnosis. B Multiple reddish adenomatous polyposis seen via colonoscopy at the time of CSS diagnosis. C Head image, showing hair loss, skin pigmentation, and vitiligo. D Hand image, showing nail plate atrophies (arrow). E, F Hematoxylin and Eosin stain images of colon polyp biopsy specimen, showing inflammatory cell infiltrations, including eosinophils. Scale bars: 100 μm (E) and 20 μm (F)

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On admission, he was on prednisolone (8 mg/day) for CCS, hydrocortisone (15 mg/day) for hypopituitarism, and levothyroxine sodium (25 μg/day) for central hypothyroidism. The patient’s body temperature was 36.6 °C, pulse rate was 84 per minute, and blood pressure was 123/80 mmHg. Pigmentation of the limbs and trunk, vitiligo on the head, and nail plate atrophy were observed (Fig. 1). Lower-leg edema was not observed. The laboratory data on admission are shown in Table 1. The urinalysis showed proteinuria (3 +) quantitated at 3.97 g/gCr and occult blood ( ±). The blood tests showed low levels of serum total protein (6.0 g/dL), serum albumin (3.2 g/dL), and a normal serum creatinine level (0.88 mg/dL). The chest and abdomen computed tomography (CT) revealed no abnormal findings. Esophagogastroduodenoscopy and colonoscopy revealed multiple polyposis of the stomach and large intestine, but the number of polyps was decreased in comparison to before the treatment with prednisolone. A renal biopsy was performed two days after admission. Light microscopy revealed glomerular capillary wall thickening in periodic acid-Schiff staining and subepithelial spikes in periodic acid silver–methenamine staining (Fig. 2). Focal lymphocytic infiltration around sclerotic glomerulus and mild interstitial fibrosis were observed. Immunofluorescence microscopy showed diffuse granular capillary wall staining of IgG, IgA, and IgM and light staining of C3 (Fig. 3). In the IgG subclass analysis, IgG4 was predominant (Fig. 4), while the Phospholipase A2 receptor (PLA2R) was negative. Transmission electron microscopy showed subepithelial electron-dense deposits (Fig. 2). Taken together, the patient was diagnosed with MN. The cause of secondary MN was not found, including malignant tumors, collagen disease, or infections, nor was it drug-related. The progression of hypoproteinemia and hypercholesterolemia was observed. Considering the nephrotic syndrome and the worsening condition of CCS, the dose of prednisolone was increased to 30 mg/day. Renin–angiotensin system inhibitor was not applied because he had no history of hypertension and the blood pressure was low during hospitalization. The clinical symptoms of hair loss and nail atrophy gradually improved after the increase in the prednisolone dose, and endoscopic analysis showed an improvement in the polypoid lesions without tumor. On the other hand, the nephrotic-range proteinuria persisted even three months after the steroid dose was increased. Therefore, we added cyclosporine for the patient’s steroid-resistant MN. However, severe proteinuria persisted for another five months; thus, we further added mizoribine to prednisolone and cyclosporine, which led to the decrease in proteinuria and the increase in the serum albumin concentration, which finally achieved incomplete remission type 1 (Fig. 5). Considering the quick response after mizoribine, we conclude that mizoribine was effective for steroid-resistant nephrotic syndrome in this case.

Table 1 Laboratory data on admission
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Fig. 2
figure 2

Pathological findings of renal biopsy specimens. A Thickening of glomerular basement membrane with periodic acid-Schiff staining. B Subepithelial spike appearance with periodic acid-methenamine silver staining. C Subepithelial spike (red arrows) with periodic acid-methenamine silver staining. Scale bar: 10 μm. D Transmission electron microscopy images, showing subepithelial electron-dense deposits. Scale bar: 20 μm

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Fig. 3
figure 3

Immunofluorescence findings of renal biopsy specimens. Immunofluorescence staining of IgG (A), IgA (B), C3 (C) and C1q (D), showing diffuse granular capillary wall staining of IgA and IgA, and weekly of C3

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Fig. 4
figure 4

Immunofluorescence findings of renal biopsy specimens for IgG subclass. Immunofluorescence staining of subclass, IgG1 (A), IgG2 (B), IgG3 (C) and IgG4 (D), showing diffuse granular capillary wall staining (IgG4 > IgG1, IgG2, IgG3)

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Fig. 5
figure 5

Patient’s clinical course. PSL Prednisolone, UP Urinary protein, CR Creatinine

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Discussion

CCS was first described in 1955 as a rare non-hereditary disorder manifested by diffuse gastrointestinal polyposis with associated ectodermal changes, including hair loss, hyperpigmentation, and nail atrophy [7]. Only approximately 500 CCS cases have been reported worldwide [8]. Many of the reports are from Japan. Among them, in the largest cohort of 210 patients with CCS from Japan, the average age of diagnosis was 63.5 years, and the male to female ratio of cases was 1.8 to 1 [9]. The etiology of CCS remains unclear, likely owing to the rarity of CCS. Several factors have shown to be associated with CCS, such as genetic mutations [10, 11], stress [12], low-turnover cell differentiation [13, 14], Helicobacter pylori infection [15, 16], and allergic reactions [17, 18]. Some studies have suggested that CCS may have an autoimmune background. For example, it was reported that hamartomatous polyps in CCS are infiltrated with IgG4 positive plasma cells, and this finding was the first clue to the pathophysiology of CCS [1]. CCS has been reported to be associated with antinuclear antibodies [12, 17, 19, 20], and autoimmune diseases such as hypothyroidism [2, 3], systemic lupus erythematosus [4], Basedow’s disease [5], and type 1 diabetes [6]. Immunosuppression using corticosteroids or long-term azathioprine may eradicate or lessen the manifestations of CCS, which is consistent with an autoimmune mechanism [21].

MN is an autoimmune disease characterized by a thickening of glomerular capillary walls, which result from immune complexes along the subepithelial region of the glomerular basement membrane. MN has been classified as idiopathic or secondary MN, based on clinical and pathological clues. Different distribution patterns of glomerular IgG subclass deposits are observed in patients with glomerular disease, and a predominant glomerular deposition of IgG4 is characteristic of idiopathic MN in general [22, 23]. In 2009, PLA2R was identified as a target antigen in idiopathic MN, and the anti-PLA2R autoantibodies were mainly IgG4 in the predominant immunoglobulin subclass in glomerular deposits [24]. Approximately 70% of patients with idiopathic MN had autoantibodies to PLA2R in their serum [24], while the prevalence of anti-PLA2R antibodies in Japanese patients was about 50%, lower than that of European and other Asian countries[25, 26]. In addition, other proteins, such as thrombospondin type 1 domain–containing 7A (THSD7A), exotosin 1 (EXT1), exotosin 2 (EXT2), neural epidermal growth factor-like 1 protein (NELL1), semaphorin 3B (Sema3B), and protocadherin 7 (PCDH7), have been shown to be etiological antigens [27], although they are less frequent. Secondary MN occurs due to malignancy, autoimmune/collagen vascular disease, infection, or drug exposure, and the treatment for the underlying disorder is expected to lead to the resolution of MN [28].

Among the patients with CCS, seven cases in combination with MN have been reported (Table 2) [3, 6, 19, 29,30,31,32], three cases of which were associated with malignancies, while others were not. MN is one of the important causes of paraneoplastic glomerulonephritis. The prevalence of gastric or colon cancer among the patients with CCS is approximately 10–20%, significantly higher than the prevalence among the general Japanese population [9, 33]; thus, it is necessary to conduct a search assuming that CCS patients with MN may have malignant tumors. In several cases, including the present case, cancer was not found by the esophagogastroduodenoscopy, colonoscopy, and capsule enteroscopy, suggesting that the development of MN in patients with CCS is not always related to malignancy [29]. Regarding the onset of CCS and MN, there are both cases in which CCS first developed and MN first developed (Table 2). In several cases, including the present case, the onset of MN was accompanied by worsening of CCS during steroid tapering; thus it is likely that the onset of MN is secondary to CCS. On the other hand, there were cases in which the onset of MN was not accompanied by worsening of CCS, though it may be due to the effects with introduced steroid or immunosuppressant.

Table 2 Reported cases of CCS Associated with MN
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While it is unknown whether MN and CCS are related, the combination rate with MN seems to be high, considering of the rarity of CCS. In addition, no other cases of the combination with nephritis, except for MN, have been reported so far, suggesting a possible association between CCS and MN. Importantly, we first indicated that IgG4 was predominantly stained in renal biopsy specimens of CCS patients, using immunofluorescent analysis. It was reported that CCS hamartomatous polyps are infiltrated with IgG4 plasma cells [1]; thus, CCS and its associated MN may have a common autoimmune mechanism related to IgG4. Nevertheless, in our present case, immunohistochemical analysis of IgG4 of small intestine was negative. Further exploration of association between MN and CCS is required.

Current CCS treatment mainly uses steroids, and other reported treatments include 5-aminosalicylate acid, histamine H2 receptor antagonists, anti-tumor necrosis factor α agents, and immunomodulators [9]. 80–91% of patients with CCS respond to corticosteroids; however, relapse is commonly observed under steroid tapering, and it was reported that azathioprine or cyclosporine may be a therapeutic option for the treatment of CCS [9, 21, 34]. The treatment for MN in patients with CCS has not been established. According to the previous literature, treatment for MN in patients with CCS included prednisolone [19], cyclosporine [29]. In one case, cyclosporine was not effective for patients with steroid-resistant MN, and rituximab was effective [3]. Rituximab is an anti-CD20 chimeric antibody that depletes B cells via complement-mediated and antibody-dependent cell cytotoxicity [35]; thus, the effectiveness of rituximab supports the hypothesis that the mechanism of MN in patients with CCS is associated with B cells. In the present case, proteinuria decreased by adding mizoribine to prednisolone and cyclosporine. Mizoribine is an imidazole nucleoside and an immunosuppressive agent, which inhibits DNA synthesis in the S phase of the cell cycle and both humoral and cellular immunity by selectively inhibiting lymphocyte proliferation [36]. Furthermore, mizoribine suppresses antibody production and proliferation of B cells by acting directly on B cells [37]. Therefore, the effect of mizoribine on B cells may be effective for MN in patients with CCS. Although further prospective studies are needed to confirm its effectiveness, our case suggests that mizoribine may be an option for patients with steroid-resistant MN.

CCS patients have chronic diarrhea and protein-losing enteropathy at a high rate, and the mean serum albumin level is reported to be low (2.96 ± 0.74 g/dL at the time of diagnosis) [9]. Indeed, more than 88% of CCS patients were reported to develop hypoalbuminemia [38]. Therefore, it is possible to overlook proteinuria without a urinalysis, even if CCS patients exhibit hypoalbuminemia due to nephritic syndrome.

In conclusion, there may be an association between MN and CCS. Mizoribine may be an effective option for CCS patients with steroid-resistant MN. Proteinuria might be overlooked, considering the hypoproteinemia due to chronic diarrhea and protein-losing enteropathy that frequently complicate CCS. Therefore, we would like to highlight the importance of follow-up urinalysis in patients with CCS for the early detection of MN, which may occur concurrently.