Cutis laxa acquisita: is there any association with Borrelia burgdorferi?

ARTICLE

The cutis laxa is a rare group of disorders in which the involved areas of the skin hang in loose, pendulous folds. Cutis laxa may be inherited or acquired [1]. Both of these types show similar clinical changes and exhibit the same histopathological changes, independent of the clinical variant [2]. The acquired type is less common than the inherited form [3]. There is no family history in the acquired form and the onset is later in age than in inherited forms [4]. Generalized acquired form is very rare and is generally preceded by an inflammatory skin reaction [5]. Although it has been described in association with various inflammatory skin disorders, up to now, it has not been reported in association with lyme disease. In recent years, the relationship between various scleroatrophic dermatoses and lyme disease has been investigated. Here we report the first case of a generalized form of acquired cutis laxa which has positive serology and positive polymerase chain reaction (PCR) result for lyme borreliosis.

Case report

A 44-year-old man presented with a complaint of excessively loose skin. He had noticed the first skin changes four years previously and described them as urticaria-like lesions 1-2 cm in diameter. Over the next three years, these lesions were replaced by loose, wrinkled skin. The patient's personal history includes a successfully treated peptic ulcus, occasional palpitation attacks and a progressive feeling of fatigue and loss of appetite over the last two years. He had no recollection of a tick bite. There was no family history of any skin disease and there was no consanguinity of the parents.

Physical examination showed lax and wrinkled skin all over the patient's body. The decrease in elasticity was mostly pronounced on the cheeks (Fig. 1), around the neck, axilla (Fig. 2) and inguinal skin. In these areas the skin was in large folds and showed minimal elasticity. A few urticarial lesions about 1 cm were also noted in the sternal region and upper back.

Urinalysis, complete blood cell count, serum analysis for glucose, blood urea nitrogen, creatinine, uric acid, copper, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatinine phosphokinase, alkalen phosphatase, bilirubin, cholesterol, triglicerydes, total protein and albumin values were normal. Erythrocyte sedimentation rate was 32 mm/hr. Anti HIV antibody, VDRL, antinuclear antibodies, rheumatoid factor, C-reactive protein were found negative. A skin biopsy from the axillar wrinkled skin showed a normal epidermis and dermis except for elastic fibers. Along with a decrease in number, a disarranged and fragmented appearence of the elastic fibers was also noted with the help of elastic tissue stains (Verhoeff's stain). A skin biopsy from one of the urticarial lesions showed a mild perivascular lymphohistiocytic infiltration and decrease of elastic fibers in the dermis along with minimal epidermal atrophy and direct immunofluorescence showed globular IgM deposition at the basement membrane zone and perivascular, granular IgG, C3 and fibrinogen deposition. Lyme borreliosis serology results were as follows; IgM negative with Indirect Immunofluorescence Assay (IFA) (Lyme-spot IF Bio Mérieux), Enzyme Immun Assay (EIA) (Virotech) and Virion Elisa Classic. IgG positive with IFA (1:160 dilution), strongly positive with EIA (absorbance/cut-off value as 3.445/0.407) and positive (25 U/ml) with Virion Elisa Classic (positive result: > 6 U/ml). Hepatitis serology was positive for anti HAV IgG, anti HBc IgG, anti Hbs and anti Hbe antibodies. Alphafetoprotein, carcinoembriyogenic antigen, CA 125, CA 19-9 levels were normal. Chest X ray, electrocardiogram, abdominal ultrasound, upper gastrointestinal endoscopy and rectoscopy were evaluated as normal. Echocardiography showed mitral valve prolapse and cystoscopy showed bladder diverticula. The PCR technique was used selectively to amplify Borrelia burgdorferi (Bb) specific gene from the skin biopsy material which was taken from one of the urticarial lesions of our patient (Fig. 3).

DNA isolation

DNA extraction from biopsy specimen was performed with standard protocols using proteinase K digestion and phenol/chloroform/isoamylalcohol extraction. After ethanol precipitation, DNA was suspended in 0.2xTE and 7 µl of that used as a template of reaction.

PRIMERS: Bb European strain flagellin gene specific two primer sets designed by Melchers et al. [6] were used for PCR. The sequences for the first set primers were, sense: 5' GAT AAA AAC GAA GAT AAT CG, antisense: 5' ACT AGG ATC TGT GGA TAT TC and amplified a 356 bp DNA fragment of the Bb European strain. The second set primers which produce a 126 bp product were used for nested reaction. The sequences of the nested inner primers were, sense: 5' CCA ACT TTA TCA AAT TCT GC, antisense: 5' AGG ATC TAT TCC AAA ATC (Genemed Synthesis, Inc. USA).

PCR amplification and detection of PCR products

Bb specific target sequences were amplified in a 30 µl reaction mixture containing 10XPCR buffer (Promega), 1.5 mM MgCl₂, 200 µm each of deoxyribose triphosphates, 20 pmol each primer and 1.25 U Taq DNA Polymerase (Promega). In the first step 356 bp fragment was amplified in a programmable heating block (PTC-100^™, MJ Research, USA). After initial denaturation at 95° C for 7 min, 35 cycles of PCR were performed 1 min at 94° C, 1 min at 37° C and 1 min at 60° C. Subsequently, 0.5 µl of this product was used as a template in the second PCR with nested primers in the same PCR mixture. Amplification of 126 bp fragment was performed under following conditions: 35 cycles of 1 min at 94° C, 45 second at 50° C, 1 min at 72° C and 7 min at 72° C for final extension. For each PCR reaction Bb European strain flagellin gene specific DNA obtained from Bb amplimer inserted InvitroGen TA-vector (pCR©2.1) (a generous gift of Willem JG Melchers, University Hospital Nijmegen, Nijmegen, Netherland) was used as a positive control and distilled water as a negative control. PCR products were analyzed by ethidium bromide-staining of agarose gel electophoresis and visualized by UV light.

Results

A specific 126 bp amplification product was detected in our patient by nested PCR. In contrast, no specific amplification was seen in the negative control (distilled water) (Fig. 3). The specific amplification was observed from DNA obtained by Bb amplimer inserted in vitro Gen TA-vector (pCR©2.1).

The patient was treated with oral tetracycline, 500 mg four times a day for four weeks. The erythematopapular lesions dissappeared in a few days but reappeared three months later.

Discussion

Cutis laxa acquisita has been described in association with some inflammatory skin disorders (erythema multiforme, erythema perstans, urticaria, eczema, SWEET syndrome and vesicular eruptions) [3, 5, 7, 8], various drugs (penicillin, penicillamine, isoniazid) [4, 9] and some systemic disorders (systemic lupus erythematosus, nephrotic syndrome due to membranoproliferative glomerulonephritis and sarcoidosis) [3, 5, 10]. Besides this, it has been described with multiple myeloma and cutaneous lymphoplasmocytoid lymphoma [11, 12].

In the light of these data, the acquired form of cutis laxa may be classed as idiopathic and secondary to drugs, inflammation, neoplasia and some systemic disorders. Our patient, a middle aged man with the late onset disease, no family history of any skin disease, no medication prior to this dermatological complaint, no systemic disorders or neoplasia, is accepted as an example of generalized cutis laxa acquisita secondary to inflammation due to chronic infectious disease.

The acquired elastolytic disorders include; cutis laxa acquisita, middermal elastolysis (MDE), anetoderma, elastoderma, acrodermatitis chronica atrophicans (ACA), granulomatous slack skin and pseudoxanthoma elasticum. Some of these elastolytic disorders such as anetoderma, mid dermal elastolysis and cutis laxa acquisita appear to be the parts of the same spectrum with the clinical manifestation depending on the extent and depth of the elastolytic process. Although the underlying mechanism of these elastolytic disorders still remains a puzzle, it is known that inflammatory cells, which contain elastases or elastase-like proteases, may contribute to the destruction of elastic fibers [13]. It has been reported that in the skin lesions of anetoderma, besides the focal loss of normal elastic fibers, there is a perivascular inflammatory infiltrate consisting of lymphocytes, plasma cells and histiocytes [14, 15]. The phagocytosis of elastic fibers by macrophages has also been proposed, however it has been considered that phagocytosis might be a secondary phenomenon due to abnormal elastin production [16]. The recent data indicate that anetoderma appears to be a part of a wide spectrum of autoimmune disorders in which the elastic fibers evidently are one of the many target tissues [17-20]. Some cases of primary anetoderma have direct immunofluorescent findings [19, 21]. In addition, the occurrence of anetoderma with ACA suggested a possible infectious cause (a spirochetal infection) in some cases [19, 22]. Also, secondary anetoderma in syphilis developing at the sites of nonlesional skin has been reported [1]. Recently, anetoderma has been reported with lyme disease [23].

The pathogenesis of MDE is also unknown. Elastic fiber phagocytosis is essential in the disappearance of the middermal elastic tissue [24]. However, the triggering factors for phagocytosis have remained unclear. The destruction of elastic fibers results from preceding inflammation [25] or actinic damage [26, 27]. Also, autoimmune mechanisms have been proposed [28, 29]. Ultrastructural findings and the evidence of photodistribution suggest that ultraviolet damage might be the inciting or contributing factor [30, 31]. Snider et al., have speculated that MDE might be an idiosyncratic reaction to ultraviolet radiation [27]. Lyme serology studies have been performed in some patients. While Trueb et al. reported negative lyme serology, Kirsner et al. reported false-positive lyme serology and they suggested that MDE might be an immune mediated disorder [28].

In cutis laxa acquisita, various hypotheses such as altered copper metabolism, excess elastase, immune-mediated mechanisms and elastolysis due to inflammatory cells have been proposed [3, 5, 7]. It has also been reported in association with syphilis [1]. In postinflammatory elastolysis and cutis laxa (PECL) which has some clinical features intermediate between anetoderma and cutis laxa, preceding urticarial erythematous lesions were thought to be due to arthropod bites [1, 5].

It is interesting to find positive lyme serology and positive PCR result for Bb in our patient although there were no symptoms of lyme disease and no history of arthropod bite. VDRL, rheumatoid factor and antinuclear antibodies were investigated to avoid false positive results. As it is known that lyme borreliosis, a zoonotic disease caused by the spirochete Bb, has a variable clinical picture and course. In the recent years various scleroatrophic skin diseases including lichen sclerosus et atrophicus, localized and generalized scleroderma, porphyria cutanea tarda with sclerodermic alteration, progressive facial hemiatrophy of Parry-Romberg, idiopathic atrophoderma of Pasini-Pierini have been reported as possible late manifestations of lyme disease [32]. Certainly the association of cutis laxa and Bb may be coincidental in our patient. However considering the pathomechanisms of the elastolytic disorders (e.g. the elastolysis due to inflammatory cells or immune mediated mechanisms) a possible association can not be excluded.

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