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Familial primary cryofibrinogenemia
Journal of the European Academy of Dermatology and Venereology 12 (1999) 47–50
Case report
Familial primary cryofibrinogenemia A.J. van Geest a ,*, R.J. van Dooren-Greebe a, M.P.M. Andriessen b, C.E.M. Blomjous c, I.H. Go a b
a Department of Dermatology, TweeSteden Hospital, Tilburg, the Netherlands Department of Dermatology, University Hospital Nijmegen, Nijmegen, the Netherlands c Department of Pathology, TweeSteden Hospital, Tilburg, the Netherlands
Abstract Background To our best knowledge this is the second case ever described of familial primary cryofibrinogenemia (CFG). Patients A 29-year-old Moroccan female and two of her three children suffered from painful purpura, slow healing small ulcerations and edema of both feet during the winter season. Laboratory investigations revealed the presence of cryofibrinogen in their blood plasma. All three patients were otherwise healthy and no associated disease could be demonstrated. Conclusions The diagnosis of CFG has to be considered in patients with livedo reticularis, edema, painful purpura and slow healing ulcera after cold exposure. Cryofibrinogen-precipitates in the blood plasma have to be determined. Because secondary CFG occurs much more frequently than the primary form, it is important to rule out associated diseases through extensive physical examination and laboratory investigations. This communication also stresses the importance of a thorough family history of patients with CFG. An autosomal dominant mode of inheritance is supposed. 1999 Elsevier Science B.V. All rights reserved. Keywords: Familial cryofibrinogenemia; Primary cryofibrinogenemia; Ulcerations; Cold exposure
1. Introduction
2. Case reports
Cryofibrinogenemia (CFG) is characterised by painful ulcerations, purpura, livedo reticularis and sometimes necrosis of the skin after cold exposition. These symptoms present predominantly on the feet and lower parts of the legs, but sometimes they occur also in the face. CFG was described for the first time by Korst and Kratochvil in 1955 [1]. We describe a familial form of CFG, which has to the best of our knowledge been reported only once in the literature [2].
2.1. Case 1
* Corresponding author. Tel.: +31-13-4655420; fax: +31-134630196.
0926-9959/99/$ - see front matter PII: S09 26-9959(98)001 11-1
A 29-year-old Moroccan female was referred to our department, because of painful, edematous feet with slow healing small ulcerations occurring exclusively in the winter season. These symptoms started when she moved to the Netherlands a few years ago, and relapse every year. Two of her three children (cases 2 and 3) suffer from identical complaints, whereas all other family members are free of symptoms. Our patient is a completely healthy woman and she does not take any medication. Physical examination showed edema of both feet with purpura which were
1999 Elsevier Science B.V. All rights reserved.
48
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
painful at palpation (Fig. 1). On the lower legs purpura were present. Total body examination revealed no abnormalities. Laboratory testing showed cryofibrinogen in the plasma; cryoglobulins were negative. Further blood investigations (Hb, WBC, differential count, blood platelets, ANF, creatinin, glucose, alk.phos, bilirubin, liver-transaminases, LDH, gamma GT, albumin, total protein, prothrombin-time, AP TT) showed no abnormalities. Fibrinogen showed to be 2.45 g/l (normally 1.7–4.1 g/l) and the ESR was 4 mm in the first hour. Histological examination of a biopsy specimen revealed intravascular plugging of homogeneous PASpositive material in the superficial dermis and a perivascular mononuclear inflammatory infiltrate (Fig. 2a,b). Because of pregnancy-wish no therapy was started. After the patient followed our advice to keep the extremities warm, her symptoms diminished. 2.2. Case 2 A 6-year-old male infant, son of the patient described in case 1 and brother of the patient described in case 3, has painful feet with purpura of the toes when exposed to cold. Symptoms started when he was 3 years old. Both his parents are Moroccan and they are not consanguine. He is otherwise healthy and does not take any medication. On physical examination painful purpura were present on both lateral parts of the feet. There were also dried-up bullae on the soles of his feet. No other abnormalities were found at physical examination. Cryofibrinogen in the plasma was positive, cryoglobulins were negative. Routine
Fig. 1. Purpura on the toes in case 1.
Fig. 2. (a) Occlusion of two small vessels in the papillary dermis by microthrombi (centre right). (b) The fully developed lesion with a moderately dense and patchy mononuclear infiltrate.
laboratory testing (see case 1) revealed no abnormalities. 2.3. Case 3 A 3-year-old female infant, daughter of the patient
Fig. 3. Purpura on the feet in case 3.
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
described in case 1 and sister of the patient described in case 2 suffers from purpura with edema on both feet at winter time (Fig. 3). These symptoms were present during the past 2 years. Walking is painful and sometimes hardly possible. She is otherwise completely healthy. Cryofibrinogen in the plasma was positive; cryoglobulins were negative. Routine laboratory investigations (see case 1) were unremarkable.
3. Discussion To our knowledge a familial form of CFG has been reported only once previously [2]. With reference to this publication McKusick describes familial primary CFG as an autosomal dominant phenotype [3]. Also in the three cases described in the present communication, this disease appears to have an autosomal dominant mode of inheritance. Primary or essential CFG is a rare disorder. CFG is in most cases associated to an underlying disease, like malignancies, infections, familial Mediterranean fever and tromboembolic diseases. Usually CFG is a disorder of adults, it is a rare disorder in childhood. Occasionally it has been described in children [2,4– 6], in which it is usually a transient, benign process related to a respiratory or gastro-intestinal infection [4–6]. Enhanced levels of cryofibrinogen can also be a result of an acute phase reaction, like a sedimentation-rate. CFG is diagnosed by demonstrating cryofibrinogen in the blood plasma, not in the serum. Cryofibrinogen is a cryoprotein, like cryoglobulins. Cryofibrinogen exists of fibrinogen complexes which form insoluble precipitates when exposed to cold (at 4°C) [7]. The histological hallmarks are occlusion of small dermal vessels by fibrin and platelet thrombi, resulting in a perivascular mononuclear infiltrate. In contrast to cryoglobulinemia, a true leucocytoclastic vasculitis is absent. Apart from prevention of cold exposure, treatment of primary CFG with various drugs has been reported. Good results have been published with stanozolol, an androgenous steroid with fibrinolytic capacities [8,9]. Other possibilities for treatment of primary CFG have been described with varying results, including streptokinase/varidase [10,11], snake-poison [12], plasma-
49
pheresis [11] and immunosuppression by prednisone and azathioprine [13]. The patients described in this communication did not receive any drug treatment. In case 1 no medication was given because of the patient’s pregnancywish and the possibility of teratogenicity of the treatment modalities described above. The boy and girl (cases 2 and 3) were not treated with any medication because of their age and because little is known about the actions and possible side-effects of the reported treatment modalities in children. In both children symptoms were markedly reduced by the advice to keep the extremities warm. In the present communication we described a family with primary CFG. The supposed mode of inheritance is autosomal dominant. To our knowledge a familial form of primary CFG was reported only once previously in the literature [2,3]. The diagnosis of CFG has to be considered in patients with livedo reticularis, edema, painful purpura and slow healing ulcera after cold exposure. Apart from cryoglobulins in the serum, cryofibrinogen-precipitates in the blood plasma have to be determined. Because secondary CFG occurs much more frequently than the primary form, it is important to rule out associated diseases through extensive physical examination and laboratory investigations. This communication also stresses the importance of a thorough family history of patients with CFG.
References [1] Korst DR, Kratochvil CH. ‘Cryofibrinogen’ formation in case of lung neoplasm associated with thromboflebitis migrans. Blood 1955;10:945–953. [2] Lolin Y, Razis PA, O’Gorman P. et al. Transient nephrotic syndrome after anaesthesia resulting from a familial cryofibrinogen precipitating at 35°C. J Med Genet 1989;26:631– 636. [3] McKusick VA. In: McKusick VA, editor. Mendelian inheritance in man. A catalog of human genes and genetic disorders, eleventh ed. Baltimore, MD: John Hopkins University Press 1994:379–380. [4] Robinson MG, Troiano G, Cohen H, Foadi M. Acute transient cryofibrinogenemia in infants. J Pediatr 1966;69:35–39. [5] Ireland TA, Werner DA, Rietschel RL. et al. Cutaneous lesions in cryofibrinogenemia. J Pediatr 1984;105;67–69. [6] Furioli J, Bourdon, C, Le Loc’h H. Infection a` Mycoplasma pneumoniae. Re´ve´lation chez un enfant de 3 ans par un phe´nome`ne de Raynaud. Arch Fr Pediatr 1985;42:313–314.
50
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
[7] Smith SB, Arkin C. Cryofibrinogenemia: incidence, clinical correlations, and a review of the literature. Am J Clin Pathol 1972;58:524–530. [8] Falanga V, Kirsner RS, Eaglestein WH. et al. Stanozolol in treatment of leg ulcers due to cryofibrinogaenemia. Lancet 1991;338:347–348. [9] Kirsner RS, Eaglestein WH, Katz MH. et al. Stanozolol causes rapid pain relief and healing of cutaneous ulcers caused by cryofibrinogenemia. J Am Acad Dermatol 1993;28:71–74. [10] Rachmilewitz EA, Sacks MI, Zlotnick A. Essential cryofibri-
nogenemia, clinical, pathological and immunological studies. Isr J Med 1970;6:32–34. [11] Copeman PWM. Cryofibrinogenaemia and skin ulcers: treatment with plasmapheresis. Br J Dermatol 1979;17:57–58. [12] Bru¨ning H, Christophers E. Kryofibrinogena¨mie-erfolgreiche Therapie durch Fibrinogenverminderung. Hautarzt 1991; 42:227–232. [13] Beightler E, Diven DG, Sanchez RL, Solomon AR. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 1991;24:324–325.
Case report
Familial primary cryofibrinogenemia A.J. van Geest a ,*, R.J. van Dooren-Greebe a, M.P.M. Andriessen b, C.E.M. Blomjous c, I.H. Go a b
a Department of Dermatology, TweeSteden Hospital, Tilburg, the Netherlands Department of Dermatology, University Hospital Nijmegen, Nijmegen, the Netherlands c Department of Pathology, TweeSteden Hospital, Tilburg, the Netherlands
Abstract Background To our best knowledge this is the second case ever described of familial primary cryofibrinogenemia (CFG). Patients A 29-year-old Moroccan female and two of her three children suffered from painful purpura, slow healing small ulcerations and edema of both feet during the winter season. Laboratory investigations revealed the presence of cryofibrinogen in their blood plasma. All three patients were otherwise healthy and no associated disease could be demonstrated. Conclusions The diagnosis of CFG has to be considered in patients with livedo reticularis, edema, painful purpura and slow healing ulcera after cold exposure. Cryofibrinogen-precipitates in the blood plasma have to be determined. Because secondary CFG occurs much more frequently than the primary form, it is important to rule out associated diseases through extensive physical examination and laboratory investigations. This communication also stresses the importance of a thorough family history of patients with CFG. An autosomal dominant mode of inheritance is supposed. 1999 Elsevier Science B.V. All rights reserved. Keywords: Familial cryofibrinogenemia; Primary cryofibrinogenemia; Ulcerations; Cold exposure
1. Introduction
2. Case reports
Cryofibrinogenemia (CFG) is characterised by painful ulcerations, purpura, livedo reticularis and sometimes necrosis of the skin after cold exposition. These symptoms present predominantly on the feet and lower parts of the legs, but sometimes they occur also in the face. CFG was described for the first time by Korst and Kratochvil in 1955 [1]. We describe a familial form of CFG, which has to the best of our knowledge been reported only once in the literature [2].
2.1. Case 1
* Corresponding author. Tel.: +31-13-4655420; fax: +31-134630196.
0926-9959/99/$ - see front matter PII: S09 26-9959(98)001 11-1
A 29-year-old Moroccan female was referred to our department, because of painful, edematous feet with slow healing small ulcerations occurring exclusively in the winter season. These symptoms started when she moved to the Netherlands a few years ago, and relapse every year. Two of her three children (cases 2 and 3) suffer from identical complaints, whereas all other family members are free of symptoms. Our patient is a completely healthy woman and she does not take any medication. Physical examination showed edema of both feet with purpura which were
1999 Elsevier Science B.V. All rights reserved.
48
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
painful at palpation (Fig. 1). On the lower legs purpura were present. Total body examination revealed no abnormalities. Laboratory testing showed cryofibrinogen in the plasma; cryoglobulins were negative. Further blood investigations (Hb, WBC, differential count, blood platelets, ANF, creatinin, glucose, alk.phos, bilirubin, liver-transaminases, LDH, gamma GT, albumin, total protein, prothrombin-time, AP TT) showed no abnormalities. Fibrinogen showed to be 2.45 g/l (normally 1.7–4.1 g/l) and the ESR was 4 mm in the first hour. Histological examination of a biopsy specimen revealed intravascular plugging of homogeneous PASpositive material in the superficial dermis and a perivascular mononuclear inflammatory infiltrate (Fig. 2a,b). Because of pregnancy-wish no therapy was started. After the patient followed our advice to keep the extremities warm, her symptoms diminished. 2.2. Case 2 A 6-year-old male infant, son of the patient described in case 1 and brother of the patient described in case 3, has painful feet with purpura of the toes when exposed to cold. Symptoms started when he was 3 years old. Both his parents are Moroccan and they are not consanguine. He is otherwise healthy and does not take any medication. On physical examination painful purpura were present on both lateral parts of the feet. There were also dried-up bullae on the soles of his feet. No other abnormalities were found at physical examination. Cryofibrinogen in the plasma was positive, cryoglobulins were negative. Routine
Fig. 1. Purpura on the toes in case 1.
Fig. 2. (a) Occlusion of two small vessels in the papillary dermis by microthrombi (centre right). (b) The fully developed lesion with a moderately dense and patchy mononuclear infiltrate.
laboratory testing (see case 1) revealed no abnormalities. 2.3. Case 3 A 3-year-old female infant, daughter of the patient
Fig. 3. Purpura on the feet in case 3.
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
described in case 1 and sister of the patient described in case 2 suffers from purpura with edema on both feet at winter time (Fig. 3). These symptoms were present during the past 2 years. Walking is painful and sometimes hardly possible. She is otherwise completely healthy. Cryofibrinogen in the plasma was positive; cryoglobulins were negative. Routine laboratory investigations (see case 1) were unremarkable.
3. Discussion To our knowledge a familial form of CFG has been reported only once previously [2]. With reference to this publication McKusick describes familial primary CFG as an autosomal dominant phenotype [3]. Also in the three cases described in the present communication, this disease appears to have an autosomal dominant mode of inheritance. Primary or essential CFG is a rare disorder. CFG is in most cases associated to an underlying disease, like malignancies, infections, familial Mediterranean fever and tromboembolic diseases. Usually CFG is a disorder of adults, it is a rare disorder in childhood. Occasionally it has been described in children [2,4– 6], in which it is usually a transient, benign process related to a respiratory or gastro-intestinal infection [4–6]. Enhanced levels of cryofibrinogen can also be a result of an acute phase reaction, like a sedimentation-rate. CFG is diagnosed by demonstrating cryofibrinogen in the blood plasma, not in the serum. Cryofibrinogen is a cryoprotein, like cryoglobulins. Cryofibrinogen exists of fibrinogen complexes which form insoluble precipitates when exposed to cold (at 4°C) [7]. The histological hallmarks are occlusion of small dermal vessels by fibrin and platelet thrombi, resulting in a perivascular mononuclear infiltrate. In contrast to cryoglobulinemia, a true leucocytoclastic vasculitis is absent. Apart from prevention of cold exposure, treatment of primary CFG with various drugs has been reported. Good results have been published with stanozolol, an androgenous steroid with fibrinolytic capacities [8,9]. Other possibilities for treatment of primary CFG have been described with varying results, including streptokinase/varidase [10,11], snake-poison [12], plasma-
49
pheresis [11] and immunosuppression by prednisone and azathioprine [13]. The patients described in this communication did not receive any drug treatment. In case 1 no medication was given because of the patient’s pregnancywish and the possibility of teratogenicity of the treatment modalities described above. The boy and girl (cases 2 and 3) were not treated with any medication because of their age and because little is known about the actions and possible side-effects of the reported treatment modalities in children. In both children symptoms were markedly reduced by the advice to keep the extremities warm. In the present communication we described a family with primary CFG. The supposed mode of inheritance is autosomal dominant. To our knowledge a familial form of primary CFG was reported only once previously in the literature [2,3]. The diagnosis of CFG has to be considered in patients with livedo reticularis, edema, painful purpura and slow healing ulcera after cold exposure. Apart from cryoglobulins in the serum, cryofibrinogen-precipitates in the blood plasma have to be determined. Because secondary CFG occurs much more frequently than the primary form, it is important to rule out associated diseases through extensive physical examination and laboratory investigations. This communication also stresses the importance of a thorough family history of patients with CFG.
References [1] Korst DR, Kratochvil CH. ‘Cryofibrinogen’ formation in case of lung neoplasm associated with thromboflebitis migrans. Blood 1955;10:945–953. [2] Lolin Y, Razis PA, O’Gorman P. et al. Transient nephrotic syndrome after anaesthesia resulting from a familial cryofibrinogen precipitating at 35°C. J Med Genet 1989;26:631– 636. [3] McKusick VA. In: McKusick VA, editor. Mendelian inheritance in man. A catalog of human genes and genetic disorders, eleventh ed. Baltimore, MD: John Hopkins University Press 1994:379–380. [4] Robinson MG, Troiano G, Cohen H, Foadi M. Acute transient cryofibrinogenemia in infants. J Pediatr 1966;69:35–39. [5] Ireland TA, Werner DA, Rietschel RL. et al. Cutaneous lesions in cryofibrinogenemia. J Pediatr 1984;105;67–69. [6] Furioli J, Bourdon, C, Le Loc’h H. Infection a` Mycoplasma pneumoniae. Re´ve´lation chez un enfant de 3 ans par un phe´nome`ne de Raynaud. Arch Fr Pediatr 1985;42:313–314.
50
A.J. van Geest et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 47–50
[7] Smith SB, Arkin C. Cryofibrinogenemia: incidence, clinical correlations, and a review of the literature. Am J Clin Pathol 1972;58:524–530. [8] Falanga V, Kirsner RS, Eaglestein WH. et al. Stanozolol in treatment of leg ulcers due to cryofibrinogaenemia. Lancet 1991;338:347–348. [9] Kirsner RS, Eaglestein WH, Katz MH. et al. Stanozolol causes rapid pain relief and healing of cutaneous ulcers caused by cryofibrinogenemia. J Am Acad Dermatol 1993;28:71–74. [10] Rachmilewitz EA, Sacks MI, Zlotnick A. Essential cryofibri-
nogenemia, clinical, pathological and immunological studies. Isr J Med 1970;6:32–34. [11] Copeman PWM. Cryofibrinogenaemia and skin ulcers: treatment with plasmapheresis. Br J Dermatol 1979;17:57–58. [12] Bru¨ning H, Christophers E. Kryofibrinogena¨mie-erfolgreiche Therapie durch Fibrinogenverminderung. Hautarzt 1991; 42:227–232. [13] Beightler E, Diven DG, Sanchez RL, Solomon AR. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 1991;24:324–325.