- Email: [email protected]
Pseudoclubbing: Is It Different from Clubbing?
BONE
Pseudoclubbing: Is It Different from Clubbing? Mittermayer B. Santiago, MD,* Isabella Lima, MD,† Alina Coutinho Rodrigues Feitosa, MD,‡ Alessandra de Souza Braz, MD,§ and Luciana Gadelha A. Miranda, MD¶
Objectives: Contrary to digital clubbing, there is no clear definition for “pseudoclubbing” (PC). The aim of this study was to review the literature on this subject. Additionally, differences and similarities between clubbing and PC are shown. Methods: The PubMed database (1950-2006) was searched for the keyword “pseudoclubbing” and all published manuscripts and secondary references were examined. An additional search using the keywords “clubbing” and “hypertrophic osteoarthropathy”—and limited to those review types—was also undertaken and all relevant articles were examined. Results: Using the keyword “pseudoclubbing” in the PubMed database, we retrieved 10 articles that described 19 cases. Eleven of those cases were associated with renal failure/secondary hyperparathyroidism, 3 with subungual hemangioma, 2 with chromosomal deletion, 1 with sarcoidosis, 1 with primary hyperparathyroidism, and 1 with scleroderma. Of the 4 cases of PC seen in our institution, 3 associated with scleroderma and 1 associated with primary hyperparathyroidism are presented in this study. There is to be no convincing etiopathogenic mechanism for PC. The main features of PC were the asymmetric finger involvement observed in the large majority of the cases, but not in all, and acro-osteolysis, although this feature may also occur in “true” clubbing. Conclusions: Although some characteristics have been noted in differentiating PC from clubbing, sometimes these features are not present. © 2009 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 38:452-457 Keywords: pseudoclubbing, clubbing, hypertrophic osteoarthropathy, systemic sclerosis, hyperparathyroidism
A
variety of internal disorders, particularly congenital cyanotic heart diseases, pulmonary and intestinal illnesses, and several neoplasias, are associated with the development of hypertrophic osteoarthropathy (HOA), which is characterized by the presence of clubbing, periosteal reaction, and synovial effusion. A primary form of HOA, with hereditary predisposition, has also been described and is well known as pachydermoperiostosis. Sometimes, HOA is incomplete; that is, only the clubbing phenomenon is present and may represent distinct progression stages of the same disease.
*Coordinator of the Serviço de Reumatologia do Hospital Santa Izabel/Adjunct Professor at Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil. †Rheumatologist, Hospital Santa Izabel, Salvador, Bahia, Brazil. ‡Endocrinologist, Hospital Santa Izabel, Salvador, Bahia, Brazil. §Rheumatologist/Faculdade de Medicina Nova Esperança, Paraíba, Brazil. ¶Rheumatologist/Faculdade de Ciências Médicas da Paraíba, Paraíba, Brazil. The authors have no conflicts of interest to disclose. Address reprint requests to: Mittermayer B. Santiago, Serviço de Reumatologia do Hospital Santa Izabel, Praça Almeida Couto, 500, Nazaré, Salvador, Bahia, CEP 40.000-000. E-mail: [email protected].
452
The mechanism for the development of clubbing in HOA is not clear, although several hypotheses have been proposed. Previously, neurocirculatory reflex was suggested as the common denominator of the various conditions associated with clubbing (1). A more recent hypothesis suggested that a fibroblast growth factor, such as vascular endothelial growth factor, produced by large platelets (macrothrombocytes) and not fragmented by the pulmonary circulation, may be responsible for the fibroblast proliferation and collagen deposition leading to the development of the hypertrophic changes seen in HOA (2-4). Other potential factors are prostaglandins, transforming growth factor beta-1, and plasma endothelin (comprehensively reviewed in ref. 3). Classically, clubbing in HOA is an enlargement of distal phalanges, assuming the form of “drumstick,” with round nails and losing the normal nail-fold angle. It tends to be symmetrical and affects both hands and feet. The corresponding radiographic alteration in clubbing is an overgrowth of the distal tufts.
0049-0172/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2008.01.018
M.B. Santiago et al.
453
The term pseudoclubbing (PC) has been utilized to describe an atypical presentation of clubbing, generally with asymmetrical distribution in the fingers, and radiographically characterized by resorption of the terminal tufts (acro-osteolysis). It has previously been described in secondary hyperparathyroidism (5-7), thyroid carcinoma with primary hyperparathyroidism (8), sarcoidosis (9), subungual hemangioma (10), chromosome anomaly (11), and scleroderma (12). The aim of the present study was to describe 4 cases of pseudoclubbing and present a literature review on the subject, emphasizing the similarities and differences from “classical” clubbing.
In addition, we presented 4 cases of PC seen in our institution. Case 1
The PubMed database (1950-2006) was searched for the keyword “pseudoclubbing” and all published articles were examined along with all secondary references. An additional search using the keywords “clubbing” and “hypertrophic osteoarthropathy”—limited to those review types—was also undertaken and all relevant articles were examined. Four cases of PC were seen in our institution and are used for illustrative purposes in this article.
A 20-year-old woman complained of Raynaud’s phenomenon and heartburn of a few months duration. There was no history of skin stiffness or articular complaints. On examination, her joints were normal but there was asymmetric enlargement of the distal phalangeal ends of some fingers of both hands (Fig. 1A). The remainder of the physical examination was unremarkable. Such finger abnormalities had been observed since her childhood. An investigation showed antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) in HEp-2 positive 1/1280 with a centromere pattern. Endoscopy showed erosive esophagitis and stenosis of the gastroesophageal junction. Esophageal manometry demonstrated distal dysfunction. Lung radiography and high-resolution computed tomography were normal. Hand radiographs showed acro-osteolysis in distal phalanges of the corresponding fingers with PC (Fig. 1B). These findings indicated a diagnosis of systemic sclerosis (SSc) sine scleroderma based on LeRoy criteria (13) associated with PC.
RESULTS
Case 2
Entering the keyword “pseudoclubbing” in the PubMed database, we retrieved 10 articles that described 19 cases. Eleven of those cases were associated with renal failure/ secondary hyperparathyroidism, 3 with subungual hemangioma, 2 with chromosomal deletion, and 1 case of each of the following: sarcoidosis, primary hyperparathyroidism, and scleroderma. Of the 4 cases of PC seen in our institution, 3 associated with scleroderma and 1 associated with primary hyperparathyroidism are presented here (Table 1). Seventy review articles on “clubbing” and 175 on “hypertrophic osteoarthropathy” were identified but only a few were chosen for the purpose of this review.
A 61-year-old man was admitted for investigation of multiple previous bone pathological fractures, including bilateral femoral neck and clavicular fractures. At physical examination, he was afebrile and had normal blood pressure with no abnormalities of his cardiovascular or pulmonary systems. There was enlargement of the distal phalanx on his left index finger (PC) (Fig. 2A). Laboratory findings showed serum calcium 11.6 mg/dL(normal range, 8.6-10.0 mg/dL), phosphorus 2.1 mg/dL (normal range, 2.7-4.5 mg/dL), alkaline phosphatase 680 U/L (normal range, 25-100 U/L), urea 15 mg/dL e-creatinine, 0.3 mg/dL, parathyroid hormone (PTH) 986 pg/mL (normal range, 10-65 pg/mL). Bone scintigraphy (Tc99 sestamibi) revealed multiple areas of in-
METHODS
Table 1 Cases of Pseudoclubbing Published in the Literature and Their Clinical Associations Year
Origin
Age/Gender (Y)
Richards (8)
Author (reference)
1971
England
59/F
Lieberman and Krauthammer (9) Hoo et al. (11) Rault and Carpenter (7) Backman et al. (5) Wong and Milkes (6) Piraccini et al. (10) Lo Monaco et al. (12) Farzaneh-Far (15) Chow et al. (29)
1983
USA
25/M
1985 1989 1995 2001 2005 2006 2006 2007
Canada USA Iraq USA Italy Italy USA China
F, female; M, male.
2 cases, 10 and 15 years/2/F 7 cases from 23 to 57 years/4/M; 3/F 36/M 31/F 3 cases ⬍1 year old/2 M;1/F 67/F 36/M 50/M
Disease Associated Thyroid carcinoma and primary hyperparathyroidism Sarcoidosis Chromosomal deletion Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism Subungual hemangioma Scleroderma Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism
454
Pseudoclubbing, different from clubbing
Figure 1 (A) Asymmetric pseudoclubbing in a 20-year-old female with systemic sclerosis sine scleroderma. (B) Radiograph of the hands showing asymmetric acro-osteolysis in some digits corresponding clinically to the presence of pseudoclubbing. (Color version of figure is available online.)
creased uptake (femurs, tibia, humerus, clavicles, ribs, lumbar spine). Radiographic examination showed osteolytic lesions on long bones in addition to acro-osteolysis in the distal phalanx of the left index finger (Fig. 2B). A diagnosis of primary hyperparathyroidism was established and a parathyroidectomy was performed. A solitary adenoma was demonstrated on histology.
4th fingers, the remainder of the physical examination was normal. ANA by IIF was positive 1/5120 with a coarse speckled pattern. Anti-Sm, anti-RNP, anti-dsDNA, antiRo, and anti-La autoantibodies were negative. Echocardiogram, lung high-resolution computed tomography, and pulmonary tests were normal. She was diagnosed with limited scleroderma and, since that diagnosis, has been treated with vasodilators for Raynaud’s phenomenon.
Case 3 A 46-year-old woman presented with a history of pain in her fingertips and Raynaud’s phenomenon for 2 years. Except for sclerodactily and “pseudoclubbing” in her right 3rd and
Case 4 A 37-year-old woman had a 3-year history of skin stiffness and patchy hyperchromia associated with Raynaud’s phe-
M.B. Santiago et al.
455
anti-RNP, anti-dsDNA antibodies were all negative. Hand radiographs showed acro-osteolysis (Fig. 3B). DISCUSSION The true frequency of PC is difficult to determine since the proper definition of PC is not well established in the literature. As demonstrated in Table 1, if 1 utilizes the PubMed database and takes into consideration only those cases strictly classified as “pseudoclubbing,” only a few cases of PC can be identified. However, this may be an underestimation as typical cases of PC have been reported as “central acro-osteolysis” (14). Similar to the clubbing seen in HOA, the mechanisms responsible for the appearance of PC are also not known. It has been suggested that the clinical feature of PC could simply be the result of soft-tissue collapse due to severe bone erosions of the terminal phalanges (15). However,
Figure 2 (A) Pseudoclubbing of the left index finger in a patient with primary hyperparathyroidism. (B) Radiograph of the left hand showing acro-osteolysis in the distal phalanx of the index finger and an osteolytic lesion in the third middle phalanx. (Color version of figure is available online.)
nomenon. She was previously misdiagnosed with systemic lupus erythematosus and treated with hydroxychloroquine 400 mg and prednisone 20 mg daily. Recently, she presented with ischemic necrosis of her right ring finger and was referred to our hospital. Physical examination revealed skin thickness characteristic of diffuse scleroderma. In addition to the signs of ischemia of the right ring finger, there was enlargement of the distal phalanges of her 1st, 2nd, and 3rd fingers bilaterally. In the 3rd fingers the Lovibond’s angle exceeded 180° (Fig. 3A). The ANA was positive by both enzymelinked immunosorbent assay and IIF (nuclear speckled pattern). Rheumatoid factor, anti-Ro, anti-La, anti-Sm,
Figure 3 (A) Detail of the distal phalanx of the 3rd left finger presenting pseudoclubbing. Note that the Lovibond’s angle exceeds 180°. (B) Radiograph of the hands showing acroosteolysis in the 1st, 2nd, and 3rd digits bilaterally. (Color version of figure is available online.)
456
the majority of patients with SSc and acro-osteolysis do not have PC. In our study, case 1 had clinical findings of SSc sine scleroderma based on LeRoy criteria, although this entity should be included in the spectrum of limited scleroderma (16). Case 3 also suggests a limited form of scleroderma. Thus, these 2 cases resembled that described previously (12), in which PC occurred in a patient with limited scleroderma and no lung involvement. Case 4 was a clear example of diffuse SSc. Although indurated skin suggesting scleroderma in association with clubbing as a paraneoplastic manifestation has been previously described (17), neoplasia was not identified in these patients. Of note, in these patients the PC was not present in all digits of the hands. This suggests that Raynaud’s phenomenon with chronic digital ischemia, which generally affects all digits in SSc, may not be the cause of PC. However, digital ulcerations—another manifestation related to Raynaud’s phenomenon—also do not involve all the fingers. Curiously, there is no association between the presence of digital ulcerations and PC. An additional argument against the ischemic theory for PC suggests that, despite the high frequency of Raynaud’s phenomenon in SSc, only a minority of patients develop such a complication. Our case 2 had primary hyperparathyroidism as did another previously described patient (8). However, most frequently, PC is described in association with the secondary form of the disease due to renal failure. Although vessel calcification has been observed in patients with renal osteodystrophy, vascular ischemia does not seem to be an explanation for the development of PC, since such calcification does not occur in all patients and, in those with PC, involvement of the fingers is frequently asymmetric. Also, excessive production of the PTH does not explain all the cases of PC since plasma PTH levels are within the normal range in SSc. Although acro-osteolysis has been attributed to trauma in a guitar player (18), the possibility of local trauma as the reason for PC seems to be less probable as there has been radiological healing of PC after parathyroidectomy in cases of hyperparathyroidism. Other causes for acroosteolysis such as polyvinyl chloride exposure (19) were not observed in our patients as well as in those listed in Table 1. Some authors have suggested that vascular endothelial growth factor, prostaglandins, transforming growth factor beta-1, and plasma endothelin may play a role in the development of clubbing/HOA. Further research should be done, including patients with PC, to explore the possibility that these factors have a role in the pathogenesis of this complication. There are some characteristics that could help to differentiate PC from “true” clubbing as seen in HOA: 1. In PC there is a preservation of the angle between the nail plate and the proximal nail-fold (Lovi-
Pseudoclubbing, different from clubbing
2.
3.
4.
5.
bond’s angle). Such an angle is usually less than 160°. In clubbing this angle exceeds 180°, while in PC it is less than 180° (10,20). However, relying on this clinical appearance is not seem to be prudent as was seen in our case 4. Clubbing and PC are associated with various clinical conditions. For instance, sarcoidosis occurs with PC (9) and clubbing (21), and “clubbing” has been described in secondary hyperparathyroidism (22). In general, finger involvement is asymmetrical in PC, in contrast to the clubbing of HOA. However, PC with a symmetrical pattern has been reported (15) and there have been a few reports of unilateral clubbing associated with arterial aneurysms, trauma, or vascular graft infection (23,24). The classical radiographic finding in PC is acro-osteolysis instead of an overgrowth of the phalangeal tufts seen in clubbing. However, acro-osteolysis has also been described in HOA, particularly in younger individuals (25-28). Also, acro-osteolysis may represent the later stages of an earlier hypertrophic process (28). In PC, there are no signs of periostitis or synovial effusion as observed in HOA.
With regard to treatment, in PC, as occurs in HOA, the response is variable. Thus, in PC secondary to hyperparathyroidism, parathyroidectomy resulted in the correction of the abnormality clinically and radiographically in 1 case (29) and no improvement in another (8). Curiously, in the series of PC secondary to hyperparathyroidism described by Rault and Carpenter the treatment resulted in radiologic healing but no improvement of finger deformities (7). In PC secondary to sarcoidosis, improvement was noted after corticosteroid therapy in 1 case (9). In conclusion, although some characteristics seen in PC, such as asymmetric finger involvement and acro-osteolysis, may distinguish it from clubbing, differentiation is not always possible. ACKNOWLEDGMENT MS is currently receiving a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). REFERENCES 1. Gold AH, Bromberg BE, Herbstritt JG, Stein H. Digital clubbing: a unique case and a new hypothesis. J Hand Surg [Am] 1979;4(1):60-6. 2. Vazquez-Abad D, Martinez-Lavin M. Macrothrombocytes in the peripheral circulation of patients with cardiogenic hypertrophic osteoarthropathy. Clin Exp Rheumatol 1991;9(1):59-62. 3. Martinez-Lavin M. Exploring the cause of the most ancient clinical sign of medicine: finger clubbing. Semin Arthritis Rheum 2007;36(6):380-5. 4. Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987;2(8573):1434-5. 5. Backman U, Butler G, Fletchner P, McMullin J. A case study with
M.B. Santiago et al.
6. 7. 8. 9. 10.
11. 12. 13. 14. 15. 16.
delayed renal graft function as a consequence of severe secondary hyperparathyroidism. Artif Organs 1995;19(1):72-5. Wong E, Milkes D. Photo quiz. New-onset digital clubbing. Am Fam Physician 2001;64(1):141-2. Rault R, Carpenter B. Pseudoclubbing in chronic renal failure. Q J Med 1989;73(271):1063-9. Richards AJ. A case of thyroid carcinoma and primary hyperparathyroidism with pseudoclubbing. Br J Clin Pract 1971;25(1): 34-6. Lieberman J, Krauthammer M. Pseudoclubbing in a patient with sarcoidosis of the phalangeal bones. Arch Intern Med 1983;143(5): 1017-9. Piraccini BM, Antonucci A, Rech G, Iorizzo M, Neri I, Patrizi A, et al. Congenital pseudoclubbing of a fingernail caused by subungual hemangioma. J Am Acad Dermatol 2005;53(2 Suppl 1): S123-6. Hoo JJ, Lowry RB, Lin CC, Haslam RH. Recurrent de novo interstitial deletion of 16q in two mentally retarded sisters. Clin Genet 1985;27(4):420-5. Lo Monaco A, Govoni M, Trotta F. Digital clubbing or digital “pseudoclubbing” in systemic sclerosis. J Clin Rheumatol 2006; 12(2):97. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15(2):202-5. George EA, Suprakash S, Sarojini PA. Central acro-osteolysis. Indian J Dermatol Venereol Leprol 1993;59:264-5. Farzaneh-Far A. Images in clinical medicine. Pseudoclubbing. N Engl J Med 2006;354(15):e14. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000;43(2):444-51.
457 17. Gray RG, Gottlieb NL. Pseudoscleroderma in hypertrophic osteoarthropathy. JAMA 1981;246(18):2062-3. 18. Baran R, Tosti A. Occupational acroosteolysis in a guitar player. Acta Derm Venereol 1993;73(1):64-5. 19. Walker A. Occupational acro-osteolysis (two cases). Proc R Soc Med 1975;68(6):343-4. 20. Spicknall KE, Zirwas MJ, English JC III. Clubbing. An update on diagnosis, differential diagnosis, pathophysiology, and clinical relevance. J Am Acad Dermatol 2005;52(6):1020-8. 21. Yancey J, Luxford W, Sharma OP. Clubbing of the fingers in sarcoidosis. JAMA 1972;222(5):582. 22. Grekas D, Avdelidou A. Digital clubbing as an unusual complication associated with severe secondary hyperparathyroidism: report of two cases. Hemodial Int 2007;11(2):193-7. 23. Saunders PR, Hanna M. Unilateral clubbing of fingers associated with causalgia. BMJ 1988;297(6664):1635. 24. Stiles RG, Resnick D, Sartoris DJ, Savoia MC. Unilateral lower extremity hypertrophic osteoarthropathy associated with aortic graft infection. South Med J 1988;81(6):788-91. 25. Ansell BM. Hypertrophic osteoarthropathy in the paediatric age. Clin Exp Rheumatol 1992;10(Suppl 7):15-8. 26. Joseph B, Chacko V. Acro-osteolysis associated with hypertrophic pulmonary osteoarthropathy and pachydermoperiostosis. Radiology 1985;154(2):343-4. 27. Pineda C. Diagnostic imaging in hypertrophic osteoarthropathy. Clin Exp Rheumatol 1992;10(Suppl 7):27-33. 28. Pineda CJ, Guerra J Jr, Weisman MH, Resnick D, MartinezLavin M. The skeletal manifestations of clubbing: a study in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy. Semin Arthritis Rheum 1985;14(4):263-73. 29. Chow KM, Szeto CC, Li PK. Pseudoclubbing of fingers. Nephrology (Carlton) 2007;12(2):206.
Pseudoclubbing: Is It Different from Clubbing? Mittermayer B. Santiago, MD,* Isabella Lima, MD,† Alina Coutinho Rodrigues Feitosa, MD,‡ Alessandra de Souza Braz, MD,§ and Luciana Gadelha A. Miranda, MD¶
Objectives: Contrary to digital clubbing, there is no clear definition for “pseudoclubbing” (PC). The aim of this study was to review the literature on this subject. Additionally, differences and similarities between clubbing and PC are shown. Methods: The PubMed database (1950-2006) was searched for the keyword “pseudoclubbing” and all published manuscripts and secondary references were examined. An additional search using the keywords “clubbing” and “hypertrophic osteoarthropathy”—and limited to those review types—was also undertaken and all relevant articles were examined. Results: Using the keyword “pseudoclubbing” in the PubMed database, we retrieved 10 articles that described 19 cases. Eleven of those cases were associated with renal failure/secondary hyperparathyroidism, 3 with subungual hemangioma, 2 with chromosomal deletion, 1 with sarcoidosis, 1 with primary hyperparathyroidism, and 1 with scleroderma. Of the 4 cases of PC seen in our institution, 3 associated with scleroderma and 1 associated with primary hyperparathyroidism are presented in this study. There is to be no convincing etiopathogenic mechanism for PC. The main features of PC were the asymmetric finger involvement observed in the large majority of the cases, but not in all, and acro-osteolysis, although this feature may also occur in “true” clubbing. Conclusions: Although some characteristics have been noted in differentiating PC from clubbing, sometimes these features are not present. © 2009 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 38:452-457 Keywords: pseudoclubbing, clubbing, hypertrophic osteoarthropathy, systemic sclerosis, hyperparathyroidism
A
variety of internal disorders, particularly congenital cyanotic heart diseases, pulmonary and intestinal illnesses, and several neoplasias, are associated with the development of hypertrophic osteoarthropathy (HOA), which is characterized by the presence of clubbing, periosteal reaction, and synovial effusion. A primary form of HOA, with hereditary predisposition, has also been described and is well known as pachydermoperiostosis. Sometimes, HOA is incomplete; that is, only the clubbing phenomenon is present and may represent distinct progression stages of the same disease.
*Coordinator of the Serviço de Reumatologia do Hospital Santa Izabel/Adjunct Professor at Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil. †Rheumatologist, Hospital Santa Izabel, Salvador, Bahia, Brazil. ‡Endocrinologist, Hospital Santa Izabel, Salvador, Bahia, Brazil. §Rheumatologist/Faculdade de Medicina Nova Esperança, Paraíba, Brazil. ¶Rheumatologist/Faculdade de Ciências Médicas da Paraíba, Paraíba, Brazil. The authors have no conflicts of interest to disclose. Address reprint requests to: Mittermayer B. Santiago, Serviço de Reumatologia do Hospital Santa Izabel, Praça Almeida Couto, 500, Nazaré, Salvador, Bahia, CEP 40.000-000. E-mail: [email protected].
452
The mechanism for the development of clubbing in HOA is not clear, although several hypotheses have been proposed. Previously, neurocirculatory reflex was suggested as the common denominator of the various conditions associated with clubbing (1). A more recent hypothesis suggested that a fibroblast growth factor, such as vascular endothelial growth factor, produced by large platelets (macrothrombocytes) and not fragmented by the pulmonary circulation, may be responsible for the fibroblast proliferation and collagen deposition leading to the development of the hypertrophic changes seen in HOA (2-4). Other potential factors are prostaglandins, transforming growth factor beta-1, and plasma endothelin (comprehensively reviewed in ref. 3). Classically, clubbing in HOA is an enlargement of distal phalanges, assuming the form of “drumstick,” with round nails and losing the normal nail-fold angle. It tends to be symmetrical and affects both hands and feet. The corresponding radiographic alteration in clubbing is an overgrowth of the distal tufts.
0049-0172/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2008.01.018
M.B. Santiago et al.
453
The term pseudoclubbing (PC) has been utilized to describe an atypical presentation of clubbing, generally with asymmetrical distribution in the fingers, and radiographically characterized by resorption of the terminal tufts (acro-osteolysis). It has previously been described in secondary hyperparathyroidism (5-7), thyroid carcinoma with primary hyperparathyroidism (8), sarcoidosis (9), subungual hemangioma (10), chromosome anomaly (11), and scleroderma (12). The aim of the present study was to describe 4 cases of pseudoclubbing and present a literature review on the subject, emphasizing the similarities and differences from “classical” clubbing.
In addition, we presented 4 cases of PC seen in our institution. Case 1
The PubMed database (1950-2006) was searched for the keyword “pseudoclubbing” and all published articles were examined along with all secondary references. An additional search using the keywords “clubbing” and “hypertrophic osteoarthropathy”—limited to those review types—was also undertaken and all relevant articles were examined. Four cases of PC were seen in our institution and are used for illustrative purposes in this article.
A 20-year-old woman complained of Raynaud’s phenomenon and heartburn of a few months duration. There was no history of skin stiffness or articular complaints. On examination, her joints were normal but there was asymmetric enlargement of the distal phalangeal ends of some fingers of both hands (Fig. 1A). The remainder of the physical examination was unremarkable. Such finger abnormalities had been observed since her childhood. An investigation showed antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) in HEp-2 positive 1/1280 with a centromere pattern. Endoscopy showed erosive esophagitis and stenosis of the gastroesophageal junction. Esophageal manometry demonstrated distal dysfunction. Lung radiography and high-resolution computed tomography were normal. Hand radiographs showed acro-osteolysis in distal phalanges of the corresponding fingers with PC (Fig. 1B). These findings indicated a diagnosis of systemic sclerosis (SSc) sine scleroderma based on LeRoy criteria (13) associated with PC.
RESULTS
Case 2
Entering the keyword “pseudoclubbing” in the PubMed database, we retrieved 10 articles that described 19 cases. Eleven of those cases were associated with renal failure/ secondary hyperparathyroidism, 3 with subungual hemangioma, 2 with chromosomal deletion, and 1 case of each of the following: sarcoidosis, primary hyperparathyroidism, and scleroderma. Of the 4 cases of PC seen in our institution, 3 associated with scleroderma and 1 associated with primary hyperparathyroidism are presented here (Table 1). Seventy review articles on “clubbing” and 175 on “hypertrophic osteoarthropathy” were identified but only a few were chosen for the purpose of this review.
A 61-year-old man was admitted for investigation of multiple previous bone pathological fractures, including bilateral femoral neck and clavicular fractures. At physical examination, he was afebrile and had normal blood pressure with no abnormalities of his cardiovascular or pulmonary systems. There was enlargement of the distal phalanx on his left index finger (PC) (Fig. 2A). Laboratory findings showed serum calcium 11.6 mg/dL(normal range, 8.6-10.0 mg/dL), phosphorus 2.1 mg/dL (normal range, 2.7-4.5 mg/dL), alkaline phosphatase 680 U/L (normal range, 25-100 U/L), urea 15 mg/dL e-creatinine, 0.3 mg/dL, parathyroid hormone (PTH) 986 pg/mL (normal range, 10-65 pg/mL). Bone scintigraphy (Tc99 sestamibi) revealed multiple areas of in-
METHODS
Table 1 Cases of Pseudoclubbing Published in the Literature and Their Clinical Associations Year
Origin
Age/Gender (Y)
Richards (8)
Author (reference)
1971
England
59/F
Lieberman and Krauthammer (9) Hoo et al. (11) Rault and Carpenter (7) Backman et al. (5) Wong and Milkes (6) Piraccini et al. (10) Lo Monaco et al. (12) Farzaneh-Far (15) Chow et al. (29)
1983
USA
25/M
1985 1989 1995 2001 2005 2006 2006 2007
Canada USA Iraq USA Italy Italy USA China
F, female; M, male.
2 cases, 10 and 15 years/2/F 7 cases from 23 to 57 years/4/M; 3/F 36/M 31/F 3 cases ⬍1 year old/2 M;1/F 67/F 36/M 50/M
Disease Associated Thyroid carcinoma and primary hyperparathyroidism Sarcoidosis Chromosomal deletion Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism Subungual hemangioma Scleroderma Renal failure/hyperparathyroidism Renal failure/hyperparathyroidism
454
Pseudoclubbing, different from clubbing
Figure 1 (A) Asymmetric pseudoclubbing in a 20-year-old female with systemic sclerosis sine scleroderma. (B) Radiograph of the hands showing asymmetric acro-osteolysis in some digits corresponding clinically to the presence of pseudoclubbing. (Color version of figure is available online.)
creased uptake (femurs, tibia, humerus, clavicles, ribs, lumbar spine). Radiographic examination showed osteolytic lesions on long bones in addition to acro-osteolysis in the distal phalanx of the left index finger (Fig. 2B). A diagnosis of primary hyperparathyroidism was established and a parathyroidectomy was performed. A solitary adenoma was demonstrated on histology.
4th fingers, the remainder of the physical examination was normal. ANA by IIF was positive 1/5120 with a coarse speckled pattern. Anti-Sm, anti-RNP, anti-dsDNA, antiRo, and anti-La autoantibodies were negative. Echocardiogram, lung high-resolution computed tomography, and pulmonary tests were normal. She was diagnosed with limited scleroderma and, since that diagnosis, has been treated with vasodilators for Raynaud’s phenomenon.
Case 3 A 46-year-old woman presented with a history of pain in her fingertips and Raynaud’s phenomenon for 2 years. Except for sclerodactily and “pseudoclubbing” in her right 3rd and
Case 4 A 37-year-old woman had a 3-year history of skin stiffness and patchy hyperchromia associated with Raynaud’s phe-
M.B. Santiago et al.
455
anti-RNP, anti-dsDNA antibodies were all negative. Hand radiographs showed acro-osteolysis (Fig. 3B). DISCUSSION The true frequency of PC is difficult to determine since the proper definition of PC is not well established in the literature. As demonstrated in Table 1, if 1 utilizes the PubMed database and takes into consideration only those cases strictly classified as “pseudoclubbing,” only a few cases of PC can be identified. However, this may be an underestimation as typical cases of PC have been reported as “central acro-osteolysis” (14). Similar to the clubbing seen in HOA, the mechanisms responsible for the appearance of PC are also not known. It has been suggested that the clinical feature of PC could simply be the result of soft-tissue collapse due to severe bone erosions of the terminal phalanges (15). However,
Figure 2 (A) Pseudoclubbing of the left index finger in a patient with primary hyperparathyroidism. (B) Radiograph of the left hand showing acro-osteolysis in the distal phalanx of the index finger and an osteolytic lesion in the third middle phalanx. (Color version of figure is available online.)
nomenon. She was previously misdiagnosed with systemic lupus erythematosus and treated with hydroxychloroquine 400 mg and prednisone 20 mg daily. Recently, she presented with ischemic necrosis of her right ring finger and was referred to our hospital. Physical examination revealed skin thickness characteristic of diffuse scleroderma. In addition to the signs of ischemia of the right ring finger, there was enlargement of the distal phalanges of her 1st, 2nd, and 3rd fingers bilaterally. In the 3rd fingers the Lovibond’s angle exceeded 180° (Fig. 3A). The ANA was positive by both enzymelinked immunosorbent assay and IIF (nuclear speckled pattern). Rheumatoid factor, anti-Ro, anti-La, anti-Sm,
Figure 3 (A) Detail of the distal phalanx of the 3rd left finger presenting pseudoclubbing. Note that the Lovibond’s angle exceeds 180°. (B) Radiograph of the hands showing acroosteolysis in the 1st, 2nd, and 3rd digits bilaterally. (Color version of figure is available online.)
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the majority of patients with SSc and acro-osteolysis do not have PC. In our study, case 1 had clinical findings of SSc sine scleroderma based on LeRoy criteria, although this entity should be included in the spectrum of limited scleroderma (16). Case 3 also suggests a limited form of scleroderma. Thus, these 2 cases resembled that described previously (12), in which PC occurred in a patient with limited scleroderma and no lung involvement. Case 4 was a clear example of diffuse SSc. Although indurated skin suggesting scleroderma in association with clubbing as a paraneoplastic manifestation has been previously described (17), neoplasia was not identified in these patients. Of note, in these patients the PC was not present in all digits of the hands. This suggests that Raynaud’s phenomenon with chronic digital ischemia, which generally affects all digits in SSc, may not be the cause of PC. However, digital ulcerations—another manifestation related to Raynaud’s phenomenon—also do not involve all the fingers. Curiously, there is no association between the presence of digital ulcerations and PC. An additional argument against the ischemic theory for PC suggests that, despite the high frequency of Raynaud’s phenomenon in SSc, only a minority of patients develop such a complication. Our case 2 had primary hyperparathyroidism as did another previously described patient (8). However, most frequently, PC is described in association with the secondary form of the disease due to renal failure. Although vessel calcification has been observed in patients with renal osteodystrophy, vascular ischemia does not seem to be an explanation for the development of PC, since such calcification does not occur in all patients and, in those with PC, involvement of the fingers is frequently asymmetric. Also, excessive production of the PTH does not explain all the cases of PC since plasma PTH levels are within the normal range in SSc. Although acro-osteolysis has been attributed to trauma in a guitar player (18), the possibility of local trauma as the reason for PC seems to be less probable as there has been radiological healing of PC after parathyroidectomy in cases of hyperparathyroidism. Other causes for acroosteolysis such as polyvinyl chloride exposure (19) were not observed in our patients as well as in those listed in Table 1. Some authors have suggested that vascular endothelial growth factor, prostaglandins, transforming growth factor beta-1, and plasma endothelin may play a role in the development of clubbing/HOA. Further research should be done, including patients with PC, to explore the possibility that these factors have a role in the pathogenesis of this complication. There are some characteristics that could help to differentiate PC from “true” clubbing as seen in HOA: 1. In PC there is a preservation of the angle between the nail plate and the proximal nail-fold (Lovi-
Pseudoclubbing, different from clubbing
2.
3.
4.
5.
bond’s angle). Such an angle is usually less than 160°. In clubbing this angle exceeds 180°, while in PC it is less than 180° (10,20). However, relying on this clinical appearance is not seem to be prudent as was seen in our case 4. Clubbing and PC are associated with various clinical conditions. For instance, sarcoidosis occurs with PC (9) and clubbing (21), and “clubbing” has been described in secondary hyperparathyroidism (22). In general, finger involvement is asymmetrical in PC, in contrast to the clubbing of HOA. However, PC with a symmetrical pattern has been reported (15) and there have been a few reports of unilateral clubbing associated with arterial aneurysms, trauma, or vascular graft infection (23,24). The classical radiographic finding in PC is acro-osteolysis instead of an overgrowth of the phalangeal tufts seen in clubbing. However, acro-osteolysis has also been described in HOA, particularly in younger individuals (25-28). Also, acro-osteolysis may represent the later stages of an earlier hypertrophic process (28). In PC, there are no signs of periostitis or synovial effusion as observed in HOA.
With regard to treatment, in PC, as occurs in HOA, the response is variable. Thus, in PC secondary to hyperparathyroidism, parathyroidectomy resulted in the correction of the abnormality clinically and radiographically in 1 case (29) and no improvement in another (8). Curiously, in the series of PC secondary to hyperparathyroidism described by Rault and Carpenter the treatment resulted in radiologic healing but no improvement of finger deformities (7). In PC secondary to sarcoidosis, improvement was noted after corticosteroid therapy in 1 case (9). In conclusion, although some characteristics seen in PC, such as asymmetric finger involvement and acro-osteolysis, may distinguish it from clubbing, differentiation is not always possible. ACKNOWLEDGMENT MS is currently receiving a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). REFERENCES 1. Gold AH, Bromberg BE, Herbstritt JG, Stein H. Digital clubbing: a unique case and a new hypothesis. J Hand Surg [Am] 1979;4(1):60-6. 2. Vazquez-Abad D, Martinez-Lavin M. Macrothrombocytes in the peripheral circulation of patients with cardiogenic hypertrophic osteoarthropathy. Clin Exp Rheumatol 1991;9(1):59-62. 3. Martinez-Lavin M. Exploring the cause of the most ancient clinical sign of medicine: finger clubbing. Semin Arthritis Rheum 2007;36(6):380-5. 4. Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987;2(8573):1434-5. 5. Backman U, Butler G, Fletchner P, McMullin J. A case study with
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delayed renal graft function as a consequence of severe secondary hyperparathyroidism. Artif Organs 1995;19(1):72-5. Wong E, Milkes D. Photo quiz. New-onset digital clubbing. Am Fam Physician 2001;64(1):141-2. Rault R, Carpenter B. Pseudoclubbing in chronic renal failure. Q J Med 1989;73(271):1063-9. Richards AJ. A case of thyroid carcinoma and primary hyperparathyroidism with pseudoclubbing. Br J Clin Pract 1971;25(1): 34-6. Lieberman J, Krauthammer M. Pseudoclubbing in a patient with sarcoidosis of the phalangeal bones. Arch Intern Med 1983;143(5): 1017-9. Piraccini BM, Antonucci A, Rech G, Iorizzo M, Neri I, Patrizi A, et al. Congenital pseudoclubbing of a fingernail caused by subungual hemangioma. J Am Acad Dermatol 2005;53(2 Suppl 1): S123-6. Hoo JJ, Lowry RB, Lin CC, Haslam RH. Recurrent de novo interstitial deletion of 16q in two mentally retarded sisters. Clin Genet 1985;27(4):420-5. Lo Monaco A, Govoni M, Trotta F. Digital clubbing or digital “pseudoclubbing” in systemic sclerosis. J Clin Rheumatol 2006; 12(2):97. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15(2):202-5. George EA, Suprakash S, Sarojini PA. Central acro-osteolysis. Indian J Dermatol Venereol Leprol 1993;59:264-5. Farzaneh-Far A. Images in clinical medicine. Pseudoclubbing. N Engl J Med 2006;354(15):e14. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000;43(2):444-51.
457 17. Gray RG, Gottlieb NL. Pseudoscleroderma in hypertrophic osteoarthropathy. JAMA 1981;246(18):2062-3. 18. Baran R, Tosti A. Occupational acroosteolysis in a guitar player. Acta Derm Venereol 1993;73(1):64-5. 19. Walker A. Occupational acro-osteolysis (two cases). Proc R Soc Med 1975;68(6):343-4. 20. Spicknall KE, Zirwas MJ, English JC III. Clubbing. An update on diagnosis, differential diagnosis, pathophysiology, and clinical relevance. J Am Acad Dermatol 2005;52(6):1020-8. 21. Yancey J, Luxford W, Sharma OP. Clubbing of the fingers in sarcoidosis. JAMA 1972;222(5):582. 22. Grekas D, Avdelidou A. Digital clubbing as an unusual complication associated with severe secondary hyperparathyroidism: report of two cases. Hemodial Int 2007;11(2):193-7. 23. Saunders PR, Hanna M. Unilateral clubbing of fingers associated with causalgia. BMJ 1988;297(6664):1635. 24. Stiles RG, Resnick D, Sartoris DJ, Savoia MC. Unilateral lower extremity hypertrophic osteoarthropathy associated with aortic graft infection. South Med J 1988;81(6):788-91. 25. Ansell BM. Hypertrophic osteoarthropathy in the paediatric age. Clin Exp Rheumatol 1992;10(Suppl 7):15-8. 26. Joseph B, Chacko V. Acro-osteolysis associated with hypertrophic pulmonary osteoarthropathy and pachydermoperiostosis. Radiology 1985;154(2):343-4. 27. Pineda C. Diagnostic imaging in hypertrophic osteoarthropathy. Clin Exp Rheumatol 1992;10(Suppl 7):27-33. 28. Pineda CJ, Guerra J Jr, Weisman MH, Resnick D, MartinezLavin M. The skeletal manifestations of clubbing: a study in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy. Semin Arthritis Rheum 1985;14(4):263-73. 29. Chow KM, Szeto CC, Li PK. Pseudoclubbing of fingers. Nephrology (Carlton) 2007;12(2):206.