Clubbing of the Nails
- Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD more...
Since Hippocrates first described digital clubbing in patients with empyema, digital clubbing has been associated with various underlying pulmonary, cardiovascular, neoplastic, infectious, hepatobiliary, mediastinal, endocrine, and gastrointestinal diseases. Finger clubbing also may occur, without evident underlying disease, as an idiopathic form or as a Mendelian dominant trait. Clubbing is a clinically descriptive term, referring to the bulbous uniform swelling of the soft tissue of the terminal phalanx of a digit with subsequent loss of the normal angle between the nail and the nail bed.
Digital clubbing is classified into primary (ie, idiopathic, hereditary) and secondary forms. Digital clubbing may be symmetric bilaterally, or it may be unilateral or involve a single digit. Anatomic considerations, such as the classic measurement of the Lovibond angle or the more recently derived index of nail curvature by Goyal et al , usually can be identified on simple physical examination and can be used to identify digital clubbing and to monitor this dynamic process objectively. Various imaging modalities have been used not only to evaluate clubbing but also to help identify possible clues to its development.
Clubbing is a feature of pachydermoperiostosis (PDP), a rare genodermatosis characterized by pachydermia, digital clubbing, periostosis, and an excess of affected males. Although usually an autosomal dominant model with incomplete penetrance and variable expression, both autosomal recessive and X-linked inheritance have been suggested in some PDP families.
Primary hypertrophic osteoarthropathy (PHO), a rare hereditary disorder with digital clubbing, subperiosteal new bone formation, and arthropathy, has been linked mutations in the 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) encoding gene HPGD, which causes PHO. A mutation was identified in a large Pakistani family with isolated congenital nail clubbing. In another study of homozygous mutations, an intragenic deletion that results in frameshift and a missense mutation was associated with a severe PHO phenotype. A heterozygous carrier of a stop mutation had isolated digital clubbing.
The specific pathophysiologic mechanism of digital clubbing remains unknown. Many theories have been proposed, yet none have received widespread acceptance as a comprehensive explanation for the phenomenon of digital clubbing. As stated best by Samuel West in 1897, "Clubbing is one of those phenomena with which we are all so familiar that we appear to know more about it than we really do."
Alterations in size and configuration of the clubbed digit result from changes in the nail bed, beginning with increased interstitial edema early in the process. As clubbing progresses, the volume of the terminal portion of the digit may increase because of an increase in the vascular connective tissue and change in quality of the vascular connective tissue, although some cases have been associated with spurs of bone on the terminal phalanx.
Although clubbing is a common physical finding in many underlying pathological processes, surprisingly, the mechanism of clubbing remains unclear. Different pathological processes may follow different pathways to a common end. Many studies have shown increased blood flow in the clubbed portion of the finger.
High-resolution magnetic resonance imaging uisng a contrast agent in 4 patients with finger clubbing and 4 healthy volunteers documented nail bed hypervascularization as linked with clubbed nails. Most researchers agree that this results from an increase in distal digital vasodilation, the cause of which is unknown. Also unknown is the exact mechanism by which increased blood flow results in changes in the vascular connective tissue under the nail bed.
Many researchers agree that the common factor in most types of clubbing is distal digital vasodilation, which results in increased blood flow to the distal portion of the digits. Whether the vasodilation results from a circulating or local vasodilator, neural mechanism, response to hypoxemia, genetic predisposition, or a combination of these or other mediators is not agreed on currently.
Evidence that favors the presence of a circulating vasodilator derives from the association of clubbing with cyanotic congenital heart disease. Many potential vasodilators, which usually are inactivated as blood passes through the lungs, bypass the inactivation process in patients with right-to-left shunts. Patients with tetralogy of Fallot with substantial shunting have a high incidence of clubbing. After surgical correction diminishes the shunt, the clubbing improves. Also previously observed is clubbing confined to the feet in patients with late untreated patent ductus arteriosus in whom blood from the pulmonary artery bypasses the lungs and is shunted into the descending aorta. In the absence of a shunt, the circulating vasodilator may be produced by the lung tissue, or, possibly, it passes through the pulmonary circulation without becoming inactivated. Proposed vasodilatory factors include ferritin, prostaglandins, bradykinin, adenine nucleotides, and 5-hydroxytryptamine.
A neural mechanism has been proposed with particular consideration of the vagal system. An increased incidence of digital clubbing has been associated with the pathology and disease of vagally innervated organs. Furthermore, regression of clubbing after vagotomy has been reported. Although some factor related to the vagal system is a possible contributor to the development of clubbing, especially clubbing occurring with hypertrophic osteoarthropathy, the hypothesis of a neural mechanism has decreased in popularity because of the lack of evidence of clubbing in neurologic disorders and the presence of clubbing in diseases of organs not innervated by the vagal system.
Hypoxia has been proposed as an alternative explanation for clubbing in cyanotic heart disease and pulmonary diseases. An increase in hypoxia may activate local vasodilators, consequently increasing blood flow to the distal portion of the digits; however, in most cases, hypoxia is absent in the presence of clubbing, and many diseases with noted hypoxia are not associated with clubbing.
Genetic inheritance and predisposition also may play a role in digital clubbing. Hereditary clubbing is observed in 2 forms, including idiopathic hereditary clubbing and clubbing associated with pachydermoperiostosis. The 2 forms are believed to be separate entities. Both demonstrate autosomal dominant inheritance with incomplete penetrance.
More recently, platelet-derived growth factor released from fragments of platelet clumps or megakaryocytes has been proposed as the mechanism by which digital clubbing occurs. The fragments are large enough to lodge in the vascular beds of the fingertips, and, subsequently, they release platelet-derived growth factor. This factor has been shown to have general growth-promoting activity and causes increased capillary permeability and connective tissue hypertrophy.
Idiopathic or primary clubbing is rare, while the occurrence of secondary clubbing depends on the underlying disease.
Primary digital clubbing has been reported to occur in 89% of patients diagnosed with pachydermoperiostosis. This syndrome most often occurs in young males.
Of patients with idiopathic pulmonary fibrosis, 65% have clinical digital clubbing. In these patients, an increased occurrence has been shown in patients with higher grades of smooth muscle proliferation in the lungs.
Clubbing has been reported in 29% of patients with lung cancer and is observed more commonly in patients with non–small cell lung carcinoma (35%) than in patients with small cell lung carcinoma (4%).
Digital clubbing was reported in 38% of patients with Crohn disease, 15% of patients with ulcerative colitis, and 8% of patients with proctitis. Clubbing was observed in up to one third of Ugandan patients with pulmonary tuberculosis. It was not associated with stage of HIV infection, extensive disease, or hypoalbuminemia.
Racial predilection of secondary clubbing depends on the racial prevalence of the underlying disease.
Sex predilection of secondary clubbing of the fingers depends on the prevalence of the underlying disease.
Since clubbing of the fingers is a clinical finding, it is not an independent cause of mortality; however, mortality associated with underlying pathology in patients with secondary clubbing widely varies.
Morbidity is minimal and typically is associated with the cosmetic appearance of clubbed digits.
Treatment of the underlying pathological condition may decrease the clubbing or, potentially, reverse it if performed early enough. Once substantial chronic tissue changes, including increased collagen deposition, have occurred, reversal is unlikely. Prognosis of the underlying disease should be determined on an individual basis.
Goyal S, Griffiths AD, Omarouayache S, Mohammedi R. An improved method of studying fingernail morphometry: application to the early detection of fingernail clubbing. J Am Acad Dermatol. 1998 Oct. 39(4 Pt 1):640-2. [Medline].
Castori M, Sinibaldi L, Mingarelli R, Lachman RS, Rimoin DL, Dallapiccola B. Pachydermoperiostosis: an update. Clin Genet. 2005 Dec. 68(6):477-86. [Medline].
Seifert W, Kühnisch J, Tüysüz B, Specker C, Brouwers A, Horn D. Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing. Hum Mutat. 2012 Feb 13. [Medline].
Tariq M, Azeem Z, Ali G, Chishti MS, Ahmad W. Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet. 2009 Jan. 46(1):14-20. [Medline].
Nakamura J, Halliday NA, Fukuba E, Radjenovic A, Tanner SF, Emery P, et al. The Microanatomic Basis of Finger Clubbing -- A High-resolution Magnetic Resonance Imaging Study. J Rheumatol. 2014 Mar. 41(3):523-7. [Medline].
Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet. 1987 Dec 19. 2(8573):1434-5. [Medline].
Ddungu H, Johnson JL, Smieja M, Mayanja-Kizza H. Digital clubbing in tuberculosis--relationship to HIV infection, extent of disease and hypoalbuminemia. BMC Infect Dis. 2006 Mar 10. 6:45. [Medline].
Saigal R, Kansal A, Mittal M, Singh Y, Ram H. Pachydermoperiostosis with myelofibrosis and empty sella. J Assoc Physicians India. 2010 Apr. 58:253-5. [Medline].
Ozdemir B, Senturk T, Kaderli AA, et al. Postoperative regression of clubbing at an unexpected rate in a patient with aortic and mitral valve replacement due to infective endocarditis. Ir J Med Sci. 2008 Oct 9. [Medline].
Moralidis E, Gerasimou G, Theodoridou A, Hilidis I, Mylonaki E, Gotzamani-Psarrakou A. Hypertrophic osteoarthropathy manifested with isolated calcaneal periostitis in bone scintigraphy. Ann Nucl Med. 2010 Feb 2. [Medline].
Pinto-Almeida T, Caetano M, Alves R, Selores M. Cutaneous lesions and finger clubbing uncovering hypocomplementemic urticarial vasculitis and hepatitis C with mixed cryoglobulinemia. An Bras Dermatol. 2013 Nov-Dec. 88(6):973-6. [Medline]. [Full Text].
Pallarés-Sanmartín A, Leiro-Fernández V, Cebreiro TL, Botana-Rial M, Fernández-Villar A. Validity and reliability of the Schamroth sign for the diagnosis of clubbing. JAMA. 2010 Jul 14. 304(2):159-61. [Medline].
Hugosson C, Bahabri S, Rifai A, al-Dalaan A. Hypertrophic osteoarthropathy caused by lipoid pneumonia. Pediatr Radiol. 1995. 25(6):482-3. [Medline].
Shneerson JM. Digital clubbing and hypertrophic osteoarthropathy: The underlying mechanisms. Br J Dis Chest. 1981 Apr. 75(2):113-31. [Medline].
Fawcett RS, Linford S, Stulberg DL. Nail abnormalities: clues to systemic disease. Am Fam Physician. 2004 Mar 15. 69(6):1417-24. [Medline].
Sridhar KS, Lobo CF, Altman RD. Digital clubbing and lung cancer. Chest. 1998 Dec. 114(6):1535-7. [Medline].
Grathwohl KW, Thompson JW, Riordan KK, Roth BJ, Dillard TA. Digital clubbing associated with polymyositis and interstitial lung disease. Chest. 1995 Dec. 108(6):1751-2. [Medline].
Kanematsu T, Kitaichi M, Nishimura K, Nagai S, Izumi T. Clubbing of the fingers and smooth-muscle proliferation in fibrotic changes in the lung in patients with idiopathic pulmonary fibrosis. Chest. 1994 Feb. 105(2):339-42. [Medline].
West SG, Gilbreath RE, Lawless OJ. Painful clubbing and sarcoidosis. JAMA. 1981 Sep 18. 246(12):1338-9. [Medline].
Loredo JS, Fedullo PF, Piovella F, Moser KM. Digital clubbing associated with pulmonary artery sarcoma. Chest. 1996 Jun. 109(6):1651-3. [Medline].
Smahi M, Lakranbi M, Choumi I, Elbiaz M, Amara B, Benjelloun MC. [Nail clubbing and lung hydatid cysts]. Rev Mal Respir. 2010. 27(1):99-101. [Medline].
Pineda CJ, Guerra J Jr, Weisman MH, Resnick D, Martinez-Lavin M. The skeletal manifestations of clubbing: a study in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy. Semin Arthritis Rheum. 1985 May. 14(4):263-73. [Medline].
Younis I, Sarwar S, Butt Z, Tanveer S, Qaadir A, Jadoon NA. Clinical characteristics, predictors, and survival among patients with hepatopulmonary syndrome. Ann Hepatol. 2015 May-Jun. 14 (3):354-60. [Medline].
Kitis G, Thompson H, Allan RN. Finger clubbing in inflammatory bowel disease: its prevalence and pathogenesis. Br Med J. 1979 Oct 6. 2(6194):825-8. [Medline].
Barraud-Klenovsek MM, Lübbe J, Burg G. Primary digital clubbing associated with palmoplantar keratoderma. Dermatology. 1997. 194(3):302-5. [Medline].
Mullins GM, Lenhard RE Jr. Digital clubbing in Hodgkin's disease. Johns Hopkins Med J. 1971 Mar. 128(3):153-7. [Medline].
Dispenzieri A, Gertz MA. Treatment options for POEMS syndrome. Expert Opin Pharmacother. 2005 Jun. 6(6):945-53. [Medline].
Miest RY, Comfere NI, Dispenzieri A, Lohse CM, El-Azhary RA. Cutaneous manifestations in patients with POEMS syndrome. Int J Dermatol. 2013 Apr 4. [Medline].
Grekas D, Avdelidou A. Digital clubbing as an unusual complication associated with severe secondary hyperparathyroidism: report of two cases. Hemodial Int. 2007 Apr. 11(2):193-7. [Medline].
Helvaci MR, Gokce C, Davran R, Acipayam C, Akkucuk S, Ugur M. Tonsilectomy in sickle cell diseases. Int J Clin Exp Med. 2015. 8 (3):4586-90. [Medline].
Schuller A, Cottin V, Hot A, Cordier JF. Finger clubbing and altered carbon monoxide transfer capacity in cannabis smokers. Eur Respir J. 2008 Feb. 31(2):473-4. [Medline].
El Bakkal A, Idrissi R, Meziane M, Mikou O, Sekal M, Belghiti H, et al. [Tripe palms and a hypertrophic osteoarthropathy syndrome revealing a neuroendocrine carcinoma of the lung]. Ann Dermatol Venereol. 2011 Oct. 138(10):668-72. [Medline].
Thompson MA, Warner NB, Hwu WJ. Hypertrophic osteoarthropathy associated with metastatic melanoma. Melanoma Res. 2005 Dec. 15(6):559-61. [Medline].
Lommatzsch M, Julius P, Lück W, Bier A, Virchow JC. [Hypertrophic Pulmonary Osteoarthropathy as a Cue for NSCLC: Four Cases in the Light of the Current Literature]. Pneumologie. 2012 Feb. 66(2):67-73. [Medline].
Tajbakhsh R, Dehghan M, Azarhoosh R, Haghighi AN, Sadani S, Zadeh SS, et al. Mucocutaneous manifestations and nail changes in patients with end-stage renal disease on hemodialysis. Saudi J Kidney Dis Transpl. 2013 Jan. 24(1):36-40. [Medline].
Salem A, Al Mokadem S, Attwa E, Abd El Raoof S, Ebrahim HM, Faheem KT. Nail changes in chronic renal failure patients under haemodialysis. J Eur Acad Dermatol Venereol. 2008 Nov. 22(11):1326-31. [Medline].
Rush PJ, Giorshev C, Shore A, Levinson H. The use of thermography in clubbing. Respir Med. 1992 May. 86(3):257-9. [Medline].
Ward RW, Chin R Jr, Keyes JW Jr, Haponik EF. Digital clubbing. Demonstration with positron emission tomography. Chest. 1995 Apr. 107(4):1172-3. [Medline].
Roy HS, Wang Z, Ran H, Song W, Zheng Y. Diagnosis of digital clubbing by high-frequency ultrasound imaging. Int J Dermatol. 2013 Jan. 52(1):1-5. [Medline].
Adams B, Amin T, Leone V, Wood M, Kraft JK. Primary hypertrophic osteoarthropathy: ultrasound and MRI findings. Pediatr Radiol. 2016 May. 46 (5):727-30. [Medline].
Li ZT, Wang D, Wang S. Successful treatment of pachydermoperiostosis with etoricoxib in a patient with a homozygous splice-site mutation in the SLCO2A1 gene. Br J Dermatol. 2016 Feb 15. [Medline].
Kumar U, Bhatt SP, Misra A. Unusual associations of pachydermoperiostosis: a case report. Indian J Med Sci. 2008 Feb. 62(2):65-8. [Medline].
Saghafi M, Azarian A, Nohesara N. Primary hypertrophic osteoarthropathy with myelofibrosis. Rheumatol Int. 2008 Apr. 28(6):597-600. [Medline].