|Year : 2007 | Volume
| Issue : 4 | Page : 178-181
Epidermolysis bullosa dystrophica with renal failure due to secondary amyloidosis
F Mutlubas1, S Mir1, C Kabasakal1, O Yavascan1, B Sarsik2
1 Department of Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey
2 Department of Patology, Ege University Faculty of Medicine, Izmir, Turkey
Ege Universitesi Tip Fakultesi, Cocuk Sagligi ve Hastaliklari AnabilimDali, Bornova - 35100, Izmir
Source of Support: None, Conflict of Interest: None
Epidermolysis bullosa dystrophica is a rare hereditary disorder with multiple bullous lesions, erosions and repeated infections. Although skin lesions can be treated with dermatologic care, the patient can also be complicated by life-threatening clinics such as nephropathy, systemic amyloidosis and skin cancers by years. A 16-year-old male who had been followed-up since birth with epidermolysis bullosa dystrophica referred to the nephrology department for nephrotic proteinuria and deep anemia. He went on renal biopsy that demonstrated AA amyloidosis. Although effective colchicine treatment was given, end stage renal disease developed after 6 months that resulted in the death of the patient. Epidermolysis bullosa causes a chronic inflammatory process that progresses with time and can be fatal. Colchicine treatment must be given before the onset of amyloidosis.
Keywords: Colchicine, end-stage renal disease, epidermolysis bullosa dystrophica, secondary amyloidosis
|How to cite this article:|
Mutlubas F, Mir S, Kabasakal C, Yavascan O, Sarsik B. Epidermolysis bullosa dystrophica with renal failure due to secondary amyloidosis. Indian J Nephrol 2007;17:178-81
|How to cite this URL:|
Mutlubas F, Mir S, Kabasakal C, Yavascan O, Sarsik B. Epidermolysis bullosa dystrophica with renal failure due to secondary amyloidosis. Indian J Nephrol [serial online] 2007 [cited 2020 Oct 23];17:178-81. Available from: https://www.indianjnephrol.org/text.asp?2007/17/4/178/39175
| Introduction|| |
Epidermolysis bullosa dystrophica (EDB) is a type of genodermatosis resulting from mutations in COL7A1, the gene encoding type VII collagen. This causes a perturbation in the anchoring fibrils lying between the epidermis and dermis. Recessive type of epidermolysis bullosa dystrophica (RDEB) presents with clinical findings of blisters by birth; scars can be observed in infancy. , Some typical features such as the flexion contractures of the limbs, microstomia, ankyloglossia and mitten deformity of the hands are age-related. Mucous membrane involvements cause gastrointestinal problems. Nail, hair, cornea and external ear may also be affected. In addition to these phenotypic changes, skin carcinomas, infections and renal involvement may occur as complications on the follow-up. 
We report a case with severe phenotypic findings of RDEB associated with AA type of amyloidosis that led to terminal renal failure.
| Case Report|| |
The patient was a 16-year-old male born of a consanguineous marriage who had a history of recurrent blisters and erosions on his whole body and oral mucosa since birth. There were patchy areas of cicatricial alopecia on the scalp and deformed blisters and erosions on the back [Figure - 1] and distal portions of the extremities. Mitten-hand deformity was observed on the hands [Figure - 2]. He was hospitalized for the contracture operation of the knees that existed for 6 years. He had severe dysarthria due to the impaired tongue mobility and dental anomalies. Ocular examinations were normal. His parents were second-degree relatives and no any relatives with blistering disorders were described.
Before the contracture operation, proteinuria was detected (+++) with dipstick and confirmed with 24-h collected urine (38 g/day) in nephrotic ranges. Thus, he was referred to nephrology department. Following were the laboratory findings: hemoglobin: 8.6 g/dl, hematocrit: 26.1%, white blood cell count: 12.000/mm≥, platelet count: 865,000/mm≥ and erythrocyte sedimentation rate (ESR): 116 mm/h (<20 mm/h). Total protein [3.8 g/dL; (normal ranges: 5.5-7.5g/dL)] and albumin [1.4 g/dl (normal ranges: 3-4.5g/dL)] levels significantly decreased,while the renal and liver functions were normal. In urine analysis, the following data were obtained: pH: 5.5, osmolarity: 324 mOsm/l, protein (+++).Quantitation revealed nephrotic range proteinuria (24 g/day). Anemia was due to chronic disease since the serum iron level was low with increased levels of ferritin (582ng/ml). As the other acute phase reactants (ESR, ferritin, CRP and thrombocytosis, serum amyloid A protein (SAA) level [>180 mg/dL (normal range: <10 mg/dL)] also increased. The urine electrophoresis showed pure albuminuria. Increased parenchymal echogenicity (grade 2) of both the kidneys was detected in the ultrasonography, and Tc-99m DMSA (scintigraphy) uptake was diminished in both the kidneys. Renal biopsy showed amorphous homogeneous eosinophilic deposits in the glomeruli on hematoxylin-eosin staining. These structures were positive with Congo red and amyloid AA staining [Figure - 3]. Therefore, the patient was prescribed colchicine (1.5 mg/day). There was little improvement in the symptomatology and he continued to have massive proteinuria, hypoproteinemia and worsening anemia; He required several infusions of human albumin . Over time, serum creatinine levels began to increase, while the renal clearance decreased. After 3 months, he attained terminal renal failure with a serum creatinine level of 5.9 mg/dl (normal ranges: 0.6-1 mg/dl). Although hemodialysis was insisted on as a treatment, it was refused by the parents and the patient died.
| Discussion|| |
Epidermolysis bullosa dystrophica (EDB) is a genodermatosis resulting from mutations in COL7A1, the gene encoding type VII collagen. The site of the mutation determines the clinical phenotype. It is inherited either in autosomal dominant (DDEB) or recessive mode (RDEB). The recessive mode also presents differ clinic phenotypes as Hallopeau-Siemens subtype (HS-RDEB) or non-HS-RDEB form. ,
This case was determined as DEB with skin biopsy [Figure - 4] and clinical features. Either HS-RDEB or junctional EB (JEB) forms were thought to be the probable diagnosis because the pathologic specimen had not been documented by electron microscopy. Clinical findings due to the skin lesions (the main typical clinical features of HS-RDEB) include blisters from birth, extensive dystrophic scarring on the acral surfaces such as mitten-hand deformity, flexion contractures of the limbs, mucosal involvement that resulted in dysphagia, dystrophic nails and scalp alopecia. All these were present in our patient and the renal failure seemed to be temporally related to HS-RDEB. Junctional EB can cause acute renal failure due to obstructive uropathy or due to sepsis developing after severe skin lesions in the early period of life. , There were no other individuals related with blister disorders but he was born of a consanguineous marriage. Horn et al . also described nine individuals with HS-RDEB group who had had unaffected parents. 
RDEB is a well-known disease with gastrointestinal, dental, scleral, eye and ear complications in the follow-up.  Skin cancer, systemic infection, cardiomyopathy and nephropathy are rare; however, with RDEB, life-threatening complications develop over time. ,,,,,,,,,
Nephropathy is a serious complication of the major types of EB. Kidneys may be injured either by obstruction due to strictures or by glomerular diseases. In a national registry, obstructive uropathy was reported to be related with JEB, but it was not found to be a cause of death.  Glomerulary diseases can occur by either secondary amyloidosis or glomerulonephritis. There are RDEB cases with local or systemic amyloidosis in the literature. ,,,,, The other reported conditions include IgA glomerulonephritis and poststreptococcal glomerulonephritis, probably due to recurring superinfections of bullous skin lesions and mesangioproliferative glomerulonephritis due to prolonged sepsis. ,, Renal amyloidosis is the best described glomerulopathy; it develops with increasing disease duration and is the major cause of ESRD. Despite the severity of skin disease, death from renal failure has been described in 0.52% and 1.48% in JEB and RDEB, respectively.  In this national registry, the cumulative risk of death from renal failure was high in RDEB by 25-30 years. Amyloidosis can cause severe nephrotic syndrome. Thus, intravascular hypovolemia needs repetitive human albumin solutions, as in this case.
Although the mechanisms of how amyloid nephropathy develops in RDEB patients are currently unknown, it can be thought to be associated with chronic inflammatory process as in the other chronic diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever More Details and Castleman's disease.  It was also speculated that the nephropathy is the result of repeated infections with the sustained activation of a major acute phase response.  The elevated levels of SAA derivatives form insoluble aggregates in multiple organs resulting in AA type of amyloidosis. ,
There is no specific therapy for DEB. Phenytoin, minocycline cyclosporin and vitamin E have been used for the skin lesions.  However, these therapies were not helpful and have been abandoned. Kaneko et al . discussed the effects of colchicine on four RDEB patients with renal amyloidosis. Two patients remained stable, while the other two patients developed ESRD after 3-years.  Although these studies are experimental  or small numbered,  further studies must be planned to answer the use of colchicine for the amyloid prophylaxis and the treatment in RDEB patients. Daily colchicine is the mainstay of the therapy of familial Mediterranean fever, resulting in complete remission or reduction in the attacks. In an appropriate dosage, it prevents amyloidosis and also helps in arresting renal amyloidosis.  Colchicine treatment was clearly shown to ameliorate the course of FMF and to prevent the development of amyloidosis.  Although RDEB is known to develop due to hereditary collagen disorder, inflammatory process secondary to recurrent skin infections play an important role in the survey of the disease. Therefore, colchicine treatment, which may improve the survey of RDEB patients, must be used before tissue amyloid deposition occurs . However, prescribing prophylactic colchicine for RDEB patients is not supported in large studies. In addition, we have to point out with this case report that colchicine treatment that was given after amyloidosis had already developed and hence was unable to stop the progression to ESRD.
Patients with ESRD could be treated with dialysis. Two patients had been reported to have long-term hemodialysis and peritoneal dialysis in the literature.  The role of renal transplantation for ESRD due to secondary amyloidosis in EB has not been reported yet.
In conclusion, RDEB is a serious skin disorder with multiple phenotypic and late-onset complications. Renal and systemic amyloidosis are the well-known ones. Chronic inflammation may lead to this complication. Therefore, these patients should be examined by immunology and nephrology departments on a routine basis. The patients should be periodically screened by urinalysis and serum SAA levels. Colchicine treatment must be given early, before the development of amyloidosis.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]