Panniculitis revealing qualitative alpha 1 antitrypsine deficiency (MS variant)

ARTICLE

Alpha 1-antitrypsin (alpha1 AT) deficiency is one of the most common hereditary disorders of Caucasians and Europeans. We report the case of a 16-year-old girl who presented with panniculitis on her abdomen for 2 months. alpha1-antitrypsin level was found to be normal but M1S phenotype of alpha1-antitrypsin was determined by isoelectric focusing in polyacrylamide gel. Panniculitis is rarely reported and seems to occur principally with low levels of alpha1 AT, but normal levels of alpha1 AT in the serum have previously been reported as in our case, suggesting that other triggering agents like trauma and infections must be present.

Case report

A 16-year-old girl was in good health until June 1997 when she presented with painful swelling and red nodular lesions with an ecchymotic area on the abdomen that became coalescent, broke down, and drained sterile serosanguineous fluid. When she came to consult us in September 1997, physical examination revealed cicatricial indurated plaques with central hyperpigmentation. The rest of the clinical examination was normal and there was no clinical familial history. In September 1997, results of the following studies were negative or unremarkable: erythrocyte sedimentation rate, hemoglobin, platelet count, white blood cell count, electrolytes, coagulation survey, liver tests, amylase, lipase, serum protein electrophoresis, cryoglobulins, antinuclear antibody, urinalysis, chest radiography. An elliptic incisional cutaneous biopsy specimen from one of these 2-month-old lesions showed mild inflammatory cell infiltrate and fibrosis in the dermis. There was significant inflammatory infiltrate made of plasmocytes, lymphocytes, and sparse spumous macrophages extended into the septa and isolated adipocyte lobules. Residual fibrosis of the septa was noted and there was no evidence of vasculitis. There was no liquefactive necrosis of the dermis nor adipocyte necrosis (Fig. 1, 2). Because of the suspicion of alpha1-antitrypsin deficiency panniculitis, an alpha1-antitrypsin level was measured out and found to be normal at 1,21 g/l (1,05-2,15 g/l). M1S phenotype of alpha1-antitrypsin was determined by isoelectric focusing in polyacrylamide gels at a pH between 3 and 5. Cutaneous lesions spontaneously disappeared in one month with fibrous scarring. alpha1-antitrypsin level was normal for her father, mother, brother and sister but M2S phenotype was found in her father (her mother was M1M1). Other etiology like factitious dermatitis or lupus panniculitis has been evoked but there were no clinical or biological arguments. Moreover, correlation between panniculitis and alpha1 AT is not established and normal levels of alpha1 AT have already been reported, as in our case, suggesting that other triggering agents like trauma must be present when alpha1 AT efficiency is decreased.

Discussion

alpha1-antitrypsin (alpha1 AT) deficiency is one of the most common hereditary disorders in Caucasians of European descent. The two parental alpha1 AT genes are codominantly expressed. alpha1 AT, a 52-kD spheroid glycoprotein, is essentially synthetized by hepatocytes and its level is increased in trauma and pregnancy [1, 2]. The stimuli that upregulate its synthesis are not known but, in vitro, interleukin 6 increases alpha1 AT mRNA levels [3]. alpha1 AT is the principal serum protease inhibitor whose targets are serine proteases. Principal serine proteases inhibited by alpha1 AT are trypsin, alpha chymotrypsin and neutrophil elastase. alpha1 AT inhibits neutrophil elastase with great avidity, this serine protease destroys elastin and all other major connective tissue matrix components [4]. The alpha1 AT locus is pleiomorphic and 75 alleles have been identified. There are four normal alleles (M1 (Ala²¹³), M1 (Val²¹³), M2 and M3) and numerous pathological mutations that can be classified by the mechanisms by which they cause alpha1 AT deficiency. Thus, gene deletion corresponds to the Null_{isola di procida} allele, mRNA degradation corresponds to the Null_bellingham and null_granite falls alleles, intracellular protein accumulation corresponds to the Z, M_malton and Null_{hong kong} alleles, intracellular protein degradation corresponds to the S, P_lowell and W_bethesda alleles and incompetent function of the mature secreted protein as an inhibitor of neutrophil elastase corresponds to the M_{mineral springs} allele. The Z allele is the most common pathological one with a frequency of 1-2% in Caucasians. Each mutation has been characterized. The Z mutation is a single-base substitution in exon V of the normal M1 (Ala²¹³) allele inducing a Glu³⁴² –> Lys substitution in the molecule that causes an accumulation of alpha1 AT molecules in the Rough Endoplasmic Reticulum (RER) of hepatocytes [1, 5]. There is also evidence that the Z molecules do not function normally as an inhibitor of neutrophil elastase [6]. Laboratory detection of alpha1 AT deficiency can use a simple measurement of the serum alpha1 AT level (e.g.: radial immunodiffusion). Identification of the phenotype is conventionally done by isoelectric focusing in polyacrylamide gel at a pH between 3,5 and 5 [1]. Detection of variants with site-specific monoclonal antibodies (Glu³⁴²) and a rapid in vitro screening for alpha1 AT inhibitor activity are also possible [7, 8]. alpha1 AT genotyping is most frequently determined using the polymerase chain reaction (PCR) [1]. The major clinical importance of alpha1 AT deficiency relates to its association with emphysema and liver disease [1, 2]. The risk for emphysema is directly related to the alpha1 AT serum level with the threshold level of 11 µM separating the "at risk" and "not at risk" group regardless of the phenotype [1, 9]. Cigarette smoking clearly increases the development of emphysema [10]. For liver disease, only two homozygous mutations, Z and M malton, have been clearly incriminated corresponding to mutations causing the accumulation of alpha1 AT in hepatocytes. This abnormality can induce cholestasis with hepatitis that can progresss to cirrhosis [1, 2, 11]. The role of other cofactors such as alcohol consumption and hepatitis B or C virus infection has been suggested [12]. Other clinical diseases are associated with alpha1 AT deficiency like pancreatic disease, corneal ulceration, intracranial aneurysm and fibromuscular dysplasia [13, 15]. Concerning cutaneous involvement, panniculitis is rarely reported associated with this enzyme defect [16]. The term panniculitis is only partially correct since Hendrick in 1988 and Geller in 1994 studied early cutaneous lesions [17, 18]. The primary histological lesion has been described as neutrophils infiltrating between collagen bundles throughout the reticular dermis followed by a dissolution of the dermal collagen that may progress to liquefactive necrosis. Transepidermal elimination can occur and because of an anatomic bridge between the reticular dermis and fibrous septa of the subcuti, the necrosis secondarily involves septa and then adipocytes lobules. Neutrophils and macrophages are less prominent as the necrosis increases and fibrous scar formation persists. These cutaneous lesions occur principally for the ZZ or MZ phenotype but MS phenotype has been reported, as in our case [20]. Low levels of alpha1 AT are often reported for panniculitis but the number of cases is insufficient to establish a correlation and normal levels of alpha1 AT in the serum have already been reported, as in our case [19]. This last point suggests the study of alpha1 AT phenotype even if the plasma level is normal, when cutaneous lesions are suspected to be related to alpha1 AT defect. The rarity of cutaneous lesions in relation to the alpha1 AT deficiency frequency suggests that other triggering agents like trauma and infections must be present: these factors could initiate an inflammatory cascade resulting in tissue damage when alpha1 AT efficiency is decreased [16-19]. Concerning the treatment, corticosteroid, colchicine, dapsone and cyclophosphamide have been described as efficient [16, 17]. Anti-collagenase properties of doxycycline have been used with success in some cases [20]. alpha1 AT purified from plasma is used in perfusion or by aerosol for emphysema but it can be used in perfusion for severe cutaneous involvment [21-23]. Finally, several strategies of gene therapy have been considered to safely place the normal gene in cells to produce sufficient quantities of enzyme to protect the lower respiratory tract. Therapy for liver disease other than transplantation is more complex since accumulation of alpha1 AT in the RER is responsible for hepatocyte lesions [1, 11].

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