Curr Rheumatol Rep (2014) 16:442 DOI 10.1007/s11926-014-0442-7
ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Pachydermodactyly: A Review Tomáš Dallos & Bastian Oppl & László Kovács & Jochen Zwerina
Published online: 31 August 2014 # Springer Science+Business Media New York 2014
Abstract Synovitis is the characteristic feature of inflammatory joint disease. If synovitis is localized to interphalangeal joints, rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis are among the most common differential diagnoses. The absence of pain, tenderness, and limitation of function despite progressive swelling of proximal interphalangeal joints suggests an alternative diagnosis, for example pachydermodactyly (PDD). This is a benign disease, associated with asymptomatic, progressive swelling of periarticular soft tissue, which usually occurs in young males. PDD is probably the result of repetitive mechanical stimulation. One hundred and twenty-one cases have been reported in the literature. Some of these were initially misdiagnosed and treated for inflammatory arthritis. We provide a comprehensive review of the This article is part of the Topical Collection on Orphan Diseases T. Dallos (*) : L. Kovács Second Department of Pediatrics, Comenius University Medical School, Limbová 1, 83340 Bratislava, Slovakia e-mail: [email protected] T. Dallos e-mail: [email protected] L. Kovács e-mail: [email protected] B. Oppl : J. Zwerina Ludwig Boltzmann Institute for Osteology at the First Medical Department, Hanusch Hospital, Heinrich-Collin-Str. 30, 1140 Vienna, Austria B. Oppl e-mail: [email protected] J. Zwerina e-mail: [email protected] J. Zwerina Institut für Rheumatologie der Kurstadt Baden, Kurstadt Baden, Austria
literature on pachydermodactyly to promote awareness of this rare but important differential diagnosis of arthritis. Keywords Pachydermodactyly . Proximal interphalangeal joint . Painless swelling . Repetitive trauma . Obsessive-compulsive disorder
Introduction In rheumatology, the term swelling is used to describe the thickening of a joint. Edema of periarticular soft tissue, synovitis, and accumulation of synovial fluid are the characteristics of swollen joints in inflammatory joint disease, for example rheumatoid arthritis. In contrast, hard swelling caused by osteophyte formation is characteristic of the bony swelling of osteoarthritis. In juvenile idiopathic arthritis (JIA), tender joints with concurrent limited range of motion and swollen joints are regarded as indicating active disease. Thus joint swelling is an important sign of rheumatic joint disease in both children and adults, and usually leads to consultation of a rheumatologist. However, less prevalent causes of periarticular intumescence may imitate joint swelling and thus cause diagnostic confusion. Pachydermodactyly (pachy: thick, dermis: skin, dactylos: finger; PDD), a term coined by Verbov in 1975 [1], is the pathological progressive thickening of periarticular skin, most commonly affecting proximal interphalangeal (PIP) joints. Since its first description by Bazex in 1973 [2], relatively few cases have been published, reflecting either its low incidence or, more probably, a lack of recognition by clinicians. Consideration of a diagnosis of inflammatory joint disease (especially juvenile idiopathic arthritis) is common for patients with PDD [3–6], and sometimes even results in unnecessary treatment with immunosuppressive drugs [6, 7]. Herein, we review clinical data on published PDD cases to summarize the characteristics of this rare disease.
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in this age group (50 % occurrence, vs. 2 % in adolescents) [10, 11].
Epidemiology Since the original description of PDD, 80 reports of individuals and small series have been published, totaling 121 individual cases. Reports originate from all over the world, including Europe, the Americas, the Middle East, and SouthEast Asia. Although rising in number, possibly reflecting increasing awareness in the medical community, the number of reported cases is still low. This may not reflect the true prevalence of this condition; absence of subjective complaints and a self-limited course, with halting of progression in adolescence without permanent damage, most probably lead to unrecognized cases.
Demographics Young males are predominantly affected. Only 25 affected females have been reported [4, 8, 9], resulting in a male-tofemale ratio of 3.9:1 (Table 1). In most cases, periarticular thickening starts in puberty at a median age of 14 years (range: 5–74 years), progresses insidiously over a period of several years, and stabilizes in adolescence. Most patients consult a physician after a lengthy delay of 3.6±3.8 years, at the median age of 18 years. Hence, occurrence in young adults may be the result of long-standing disease since puberty that has not been medically assessed. Only four cases of PDD in the elderly have been reported. They had a similar presentation to the adolescent age group, although the otherwise rare involvement of distal interphalangeal joints was present in two cases
Table 1 Characteristics of pachydermodactyly with number of analyzed cases for each feature Demographic data (n=121) Patients (n) Male/female (n, (%)) Disease characteristics (n=64) Age at onset (median, (range))a Duration at presentation (median, (range)) Clinical findings (n=80) Subjective complaints (n, (%)) Swelling and/or intumescence (n, (%)) Tenderness (n, (%)) Limited range of motion (n, (%)) Itching (n, (%)) Etiology (n=121) Mechanical cause identified (n, (%)) Psychological and/or psychiatric disease (n, (%)) Positive family history (n, (%)) a
Age at onset and not age at presentation
121 96 (79)/25 (21) 14 (5–74)years 2.5 (0.25–15)years 4 (5) 80 (100) 0 (0) 2 (2.5) 2 (2.5) 53 (44) 18 (15) 7 (5)
Etiology PDD frequently occurs in otherwise healthy individuals. The etiology is not fully understood; however, several precipitating factors acting in a possibly genetically predisposed individual seem to have an effect. Excessive mechanical stimulation of periarticular skin of proximal interphalangeal (PIP) joints is believed to be the most important factor, and activities leading to such stimulation could be identified for 43 % of affected individuals. Restriction of the intumescence to the lateral (radial and ulnar) aspects of the PIP joints of patients provides supporting evidence of the causative effect of repetitive rubbing, stretching, interlacing, and cracking of fingers. Extension of changes to the dorsal aspect of the PIP joints and the extensor surface of MCP joints, or even the skin between the bases of the 1st and 2nd digits, may reflect an unusual mode of microtraumatization. Patients with obsessive-compulsive disorders may present with such repetitive behaviors. We found a total of 18 individuals with Asperger syndrome [12], attention-deficit and hyperactivity disorder [4, 13], mental retardation [14], and tic and obsessive-compulsive disorders including Tourette syndrome [15]. Some authors regard PDD as an important indicator of a psychiatric disorder. The fingers of psychically healthy individuals may be exposed to increased mechanical irritation resulting from their profession (poultry workers, farmers, and computer workers) [6, 16–18], or from sporting (climbing, weight lifting, basketball, football, and martial arts) [19, 20] and musical (playing guitar and flute) [1] activities. Increased use of computer keyboards could be identified in three cases, and may be a novel mechanism to be considered particularly for adolescent boys [6, 21, 22]. Having progressed to an extent where periarticular tissue of digits is in contact with that of adjacent joints, permanent irritation may contribute to perpetuation of hypertrophy. Hormonal factors may have an effect, as suggested by the predominance of male subjects and symptoms starting at the onset of puberty. Androgens have been revealed to promote fibroblast proliferation and collagen synthesis in vitro [23, 24] and thus may explain, at least in part, the histological findings. Growth hormone and thyroid dysfunction have been speculated to have a function in the development of PDD. PDD may not develop in all male adolescents who experience repetitive mechanical irritation of periarticular soft tissue, and thus genetic predisposition may be essential. In at least five cases, PDD was associated with tuberous sclerosis, a disease characterized by cell proliferation leading to the development of central nervous system, heart, kidney, and skin tumors resulting from mutations in tumor-suppressor genes involved
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in the mTOR signaling pathway [25]. Interestingly, PDD had been present since birth and was localized to one digit of each hand only in some cases [26, 27]. PDD has also been associated with Ehlers-Danlos syndrome, a collagen-synthesis disorder [28]. Some authors have suggested that PDD may be a mild form of pachydermoperiostosis. In one case, an increased scintigraphic signal in the digit most affected by PDD was attributed to periostosis [29]; however, the involvement of bony structures has not been observed in any other case. These associations, and the co-occurrence with plantar pachydermy in one case [14], suggest that unidentified genetic aberrations, especially those leading to increased fibroblast proliferation and aberrant collagen synthesis, may be responsible for the development of hyperkeratotic skin at sites of increased mechanical irritation. Although four families with PDD occurrence in parent–child and sibling pairs have been reported [8, 30, 31], in most cases family members are not affected.
Clinical Presentation The leading clinical sign of PDD is insidious, progressive, painless swelling of proximal interphalangeal (PIP) joints, with 2nd to 4th PIP joints being most frequently affected (Fig. 1). The findings were asymmetrical in one third of patients for whom degree of symmetry of involvement was described, ranging from different numbers and patterns of affected joints and varying degrees of intumescence between two hands to unilateral involvement [21] and single-joint involvement (localized form) [26]. This provides supporting evidence for the effect of mechanical factors. Nonetheless, from the current literature, no conclusion of a possible correlation with hand dexterity can be drawn. Rarely, involvement of the thumbs and toes has been reported [32–35]. Distal interphalangeal joints were affected in only two elderly patients [10, 11] and three juvenile patients [30, 36]. The distribution of affected PIP joints in 75 cases of PDD is shown in Fig. 2. PDD is usually reported to be restricted to the medial and lateral aspects of the PIP joints. However, involvement of both lateral and dorsal aspects of PIP joints was noted in 41 of 62 cases for whom detailed information about localization of the changes was provided. The resulting shape of the swelling is fusiform or even saccular. Extension to the palm and dorsum of the hand, including metacarpophalangeal areas (transgradient form), has been reported [15, 37]. The affected skin is thick and firm, sometimes described as a freely movable tumor. It may have signs of hyperkeratosis, lichenification, and hyperpigmentation, and usually does not cause any pruritus or pain. Irritated, reddened, and pruritic skin was present in two cases of poultry workers believed to suffer from diffuse PDD of the entire hands [16], for whom antigenic stimulation of microtraumatized skin is likely to have been an additional factor.
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No warmth, erythema, tenderness on palpation, or effusion, and most importantly no limitation of function, are seen even in long-standing disease. Full range of motion, despite longterm progression of swelling, and absence of pain are the most striking findings (Fig. 1c). Only one case of a deforming course of PDD with non-erosive subluxation of the interphalangeal joint has been reported [38], and is not the typical pattern of involvement.
Classification A classification proposed by Bardazzi et al. [8], on the basis of a heterogeneous set of characteristics including localization, familial occurrence, and association with tuberous sclerosis, recognizes five types of PDD: 1. classic (affecting more than one PIP joint and related to repeated microtrauma); 2. localized (affecting a single joint); 3. transgredient (extending to the dorsum of the hand, and also affecting the metacarpophalangeal areas); 4. familial (with more family members affected); and 5. associated with tuberous sclerosis. The clinical and prognostic significance of this classification has not been evaluated.
Laboratory Examinations and Imaging Laboratory tests were completely normal for all reported cases, without elevated inflammatory markers, thyroid dysfunction, acromegaly, hematological disorders, or autoantibodies including rheumatoid factor (RF), anti-CCP, or ANA antibodies. On x-rays soft-tissue swelling can be found, but no periarticular osteoporosis, periostosis, erosions, cysts, or osteophytes. MRI does not identify joint effusion, synovitis, or tendinitis; only non-enhancing soft-tissue swelling without hypervascularization is seen [22]. Sonography may be equally effective at revealing soft-tissue hypertrophy without increased signal in power-Doppler mapping and in the absence of joint disease; however, this diagnostic modality was largely underused in published reports (n=5). There is usually no increase in osteoblast or osteolyte activity in the phalanges on bone scans.
Histology PDD is a benign digital fibromatosis resulting from the deposition of structurally abnormal collagen in the periarticular dermis [39]. For 79 reported histology results the epidermis was
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Fig. 1 Pachydermodactyly of the 2nd to 4th PIP joints of the left hand in a 16-year-old boy (a), with most prominent findings on the 2nd and 3rd PIP joints (b). Full flexion in affected joints and mild hyperkeratosis on the lateral aspect of the 2nd PIP joint (c). Progression of soft-tissue swelling, with no pathology in bony structures, in the same patient at first presentation (d) and after two years of follow-up (e). MRI of the hand confirming periarticular-PIP-joint soft-tissue swelling without synovitis (f). (Patient originally described in reference [6]; adapted with permission)
hyperplastic (48 %), with thickening of the stratum corneum (hyperkeratosis) and stratum spinosum (acanthosis) in 67 % and 48 % of cases, respectively. In the hypodermis, proliferating fibroblasts and increased deposition of collagen were reported in 35 % and 76 % of cases, respectively, the latter being the most prevalent histological feature and thus justifying use of the term fibromatosis for PDD. Type I collagen is reduced, immature type III collagen has been revealed to predominate, and the otherwise unusual type V collagen has also been identified in PDD [39]. The latter two types of collagen fiber are thin, uniform, loosely packed, and haphazardly arranged (13 %) in the dermis, and extend into the subcutis. Deposition of mucin
between collagen fibers (39 %), although not consistently reported and identified, may be increased. A discrete mononuclear infiltration has been described in only three cases. Vascular proliferation and eccrine gland entrapment by collagen have been reported occasionally [38]. According to some authors, these changes are characteristic of PDD and of pseudo-knuckle pads, both related to chronic skin irritation. It may therefore be difficult to strictly separate these two conditions, which may be part of a wider range of mechanically-induced “pachydermy” disorders. Similarly, PDD types 1, 2, and 3, according to the above classification, may simply reflect variants whose localization is determined by the mechanism of skin irritation.
Differential Diagnosis
Fig. 2 Distribution of affected 1st interphalangeal (IP1) and proximal interphalangeal (PIP) joints in 75 subjects with pachydermodactyly
Because of its swelling-like appearance and localization around usually more than one PIP joints, PDD may imitate arthropathy. This will inevitably lead to the consideration of inflammatory joint diseases, especially juvenile idiopathic arthritis, as reported in 12 published cases. However, a painless course without morning stiffness and without reduced joint function excludes these conditions. Pachydermoperiostosis is idiopathic or hereditary and presents as digital clubbing, with periostosis of tubular bones of
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the limbs and accompanying scleroderma-like thickening “pachydermy” of the dermis [40]. Secondary forms of pachydermoperiostosis caused by chronic cardiac, pulmonary, hepatic, gastrointestinal, and malignant diseases are better known as hypertrophic osteoarthropathy. Because bones of the digits are affected by the process, the digits assume a tubular shape and prominent periostosis is seen on x-rays. Hence radiographs are an important tool to exclude underlying bone and joint disease. Unlike pachydermodactyly, pachydermoperiostosis is symptomatic and causes pain [41]. Characteristically, periostosis involves the epiphysis in the hereditary, but not in the secondary, form. Periostosis can also be a feature of thyroid acropachy (EMO syndrome) [42]. Other skin callosities of the hand and fingers that may look like PDD include knuckle pads and pseudo-knuckle pads. Because of the similar histological presentation, PDD is believed to be a variant of knuckle pads by some authors. Knuckle pads, also known as Garrod’s pads, are asymptomatic, skin-colored, circumscribed hard areas of epidermal hyperplasia located on the extensor surfaces of fingers and hand joints (MCP and PIP). Their etiology is not known; however, they may have an autosomal dominant pattern of inheritance or be sporadic, with no connection to mechanical injury. Unlike PDD they occur equally in both genders from the 5th decade, and they have a different histological appearance [43]. Pseudo-knuckle pads are the result of chewing, sucking, or otherwise manipulating the skin of the hands and are therefore also referred to as chewing pads in children. They are usually on the dorsum of the knuckles (MCP joints), rather than the radial and ulnar aspect of PIP joints, and the skin may be erythematous and rough. Other rare conditions affecting the PIP joint area may have to be considered in the differential diagnosis of PDD; these are listed in Table 2. Among these, Thiemann’s disease, a genetically determined osteochondrosis of multiple epiphyses of the phalanges, results in progressive, sometimes painful, swelling of PIP joints in adolescents [44]. Importantly, it leads to limited range of motion, with fixed flexion deformities and characteristic radiographic changes (beak-shaped broadening, flattening, and fragmentation of epiphysis in short phalanges). The swelling is typically bony in nature. Similarly, progressive, mildly painful swelling of phalanges in adolescence may be caused by multiple cystoid osteitis Jüngling, in which multiple large pseudo-cysts without sclerosis form to produce a thickened appearance of the digits [45]. Progressive pseudorheumatoid epiphyseal dysplasia resulting from WISP3 gene mutations causes progressive, painless swelling of IP joints of the hands, without signs of inflammation. All epiphyses are affected, and anterior wedging and platyspondyly of vertebral bodies is characteristic [46]. Infantile digital fibromatosis forms domeshaped polypoid nodules over IP joint surfaces, and fibroblasts have characteristic paranuclear eosinophilic cytoplasmic inclusions [47]. Association of PDD with tuberous sclerosis
Page 5 of 7, 442 Table 2 Differential diagnosis of pachydermodactyly Rheumatic disease
Bone disease
Skin disease
Endocrine disease Tumors
Genetic causes
Juvenile idiopathic arthritis Rheumatoid arthritis Rheumatoid nodules Secondary pachydermoperiostosis Osteitis multiplex cystoides Jüngling Tuberculous dactylitis (spina ventosa) Knuckle (Garrod’s) pads Pseudo-knuckle (chewing) pads Foreign body granuloma Collagenous plaques of the hands Infantile or juvenile digital fibromatosis Progressive nodular fibrosis of the skin Acropachydermodactyly of psoriasis Connective tissue nevi Thyroid acropachy Acromegaly Fibromas Sarcomas Paraneoplastic acropachydermodactyly Tuberous sclerosis Primary pachydermoperiostosis (Touraine-Solente-Golé syndrome) Thiemann’s disease
warrants a search for other skin manifestations (angiofibromas, periungual fibromas, hypomelanotic macules, and Shagreen patches) of this neurocutaneous syndrome. In summary, the clinical presentation of PDD is characteristic, making it easy to exclude inflammatory rheumatic disorders. Laboratory examinations and x-rays may be helpful in delineating it from conditions affecting bones of the phalanges. Histology, although pathognomonic and reported in 63 % of analyzed cases, may not be necessary in clinical practice.
Treatment There is no universally accepted treatment for PDD. Cessation of mechanical stimulation may be sufficient for regression [48, 49], but may only lead to stabilization. Protective gloves or bandages have been recommended to prevent mechanical stimulation [50]. Taking pharmacological control of any underlying psychiatric condition may facilitate reduction of repetitive microtraumatization and thus promote regression of findings within a few months [51]. Treatment by surgical resection of fibrous tissue [52] and by intralesional triamcinolone injections [53] has been reported in at least two and eight cases, respectively, with some effect. Although some authors deny the effectiveness of topical corticosteroids, others report significant regression of periarticular tissue thickness. The risk of poorer wound healing in the proximity of PIP joints in conjunction with the tissue atrophy or tendon damage possible with corticosteroid injections has to be weighed against the usually benign course, the good effect
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of the elimination of mechanical stimulation, and the risk of recurrence after most therapeutic approaches if repetitive trauma continues. Some patients may wish to correct the cosmetic appearance of their digits, and others may prefer to avoid invasive procedures given the benign nature of PDD.
Prognosis PDD is a benign skin disorder. Only in two cases has mild limitation of range of motion been reported, and a single case was connected to progressive non-erosive subluxation with flexion deformity in the PIP joints [38]. Findings may stabilize after a few years of progression, and have been observed to regress or remain stable for up to 15 years [53].
Summary PDD is a dermatological condition, frequently associated with repetitive mechanical stimulation, which may have to be considered in the differential diagnosis of rheumatic joint disease. Because of its asymptomatic course and good prognosis, it may be rarely recognized and is underrepresented in medical literature. Progressive, asymptomatic swelling of PIP joints without loss of joint function, especially in young male subjects, should lead to the inclusion of PDD in the differential diagnosis of PIP joint swelling. Correct recognition of PDD prevents unnecessary referrals and tests, undue anxiety for patients or their parents, and, most importantly, inappropriate treatment [39]. Acknowledgments We thank Wolfgang Baum (University of ErlangenNuremberg) for excellent support with the literature search. Compliance with ethics guidelines Conflict of interest Tomáš Dallos, Bastian Oppl, László Kovács, and Jochen Zwerina declare that they have no conflict of interest. Human and animal rights and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Pachydermodactyly: A Review Tomáš Dallos & Bastian Oppl & László Kovács & Jochen Zwerina
Published online: 31 August 2014 # Springer Science+Business Media New York 2014
Abstract Synovitis is the characteristic feature of inflammatory joint disease. If synovitis is localized to interphalangeal joints, rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis are among the most common differential diagnoses. The absence of pain, tenderness, and limitation of function despite progressive swelling of proximal interphalangeal joints suggests an alternative diagnosis, for example pachydermodactyly (PDD). This is a benign disease, associated with asymptomatic, progressive swelling of periarticular soft tissue, which usually occurs in young males. PDD is probably the result of repetitive mechanical stimulation. One hundred and twenty-one cases have been reported in the literature. Some of these were initially misdiagnosed and treated for inflammatory arthritis. We provide a comprehensive review of the This article is part of the Topical Collection on Orphan Diseases T. Dallos (*) : L. Kovács Second Department of Pediatrics, Comenius University Medical School, Limbová 1, 83340 Bratislava, Slovakia e-mail: [email protected] T. Dallos e-mail: [email protected] L. Kovács e-mail: [email protected] B. Oppl : J. Zwerina Ludwig Boltzmann Institute for Osteology at the First Medical Department, Hanusch Hospital, Heinrich-Collin-Str. 30, 1140 Vienna, Austria B. Oppl e-mail: [email protected] J. Zwerina e-mail: [email protected] J. Zwerina Institut für Rheumatologie der Kurstadt Baden, Kurstadt Baden, Austria
literature on pachydermodactyly to promote awareness of this rare but important differential diagnosis of arthritis. Keywords Pachydermodactyly . Proximal interphalangeal joint . Painless swelling . Repetitive trauma . Obsessive-compulsive disorder
Introduction In rheumatology, the term swelling is used to describe the thickening of a joint. Edema of periarticular soft tissue, synovitis, and accumulation of synovial fluid are the characteristics of swollen joints in inflammatory joint disease, for example rheumatoid arthritis. In contrast, hard swelling caused by osteophyte formation is characteristic of the bony swelling of osteoarthritis. In juvenile idiopathic arthritis (JIA), tender joints with concurrent limited range of motion and swollen joints are regarded as indicating active disease. Thus joint swelling is an important sign of rheumatic joint disease in both children and adults, and usually leads to consultation of a rheumatologist. However, less prevalent causes of periarticular intumescence may imitate joint swelling and thus cause diagnostic confusion. Pachydermodactyly (pachy: thick, dermis: skin, dactylos: finger; PDD), a term coined by Verbov in 1975 [1], is the pathological progressive thickening of periarticular skin, most commonly affecting proximal interphalangeal (PIP) joints. Since its first description by Bazex in 1973 [2], relatively few cases have been published, reflecting either its low incidence or, more probably, a lack of recognition by clinicians. Consideration of a diagnosis of inflammatory joint disease (especially juvenile idiopathic arthritis) is common for patients with PDD [3–6], and sometimes even results in unnecessary treatment with immunosuppressive drugs [6, 7]. Herein, we review clinical data on published PDD cases to summarize the characteristics of this rare disease.
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in this age group (50 % occurrence, vs. 2 % in adolescents) [10, 11].
Epidemiology Since the original description of PDD, 80 reports of individuals and small series have been published, totaling 121 individual cases. Reports originate from all over the world, including Europe, the Americas, the Middle East, and SouthEast Asia. Although rising in number, possibly reflecting increasing awareness in the medical community, the number of reported cases is still low. This may not reflect the true prevalence of this condition; absence of subjective complaints and a self-limited course, with halting of progression in adolescence without permanent damage, most probably lead to unrecognized cases.
Demographics Young males are predominantly affected. Only 25 affected females have been reported [4, 8, 9], resulting in a male-tofemale ratio of 3.9:1 (Table 1). In most cases, periarticular thickening starts in puberty at a median age of 14 years (range: 5–74 years), progresses insidiously over a period of several years, and stabilizes in adolescence. Most patients consult a physician after a lengthy delay of 3.6±3.8 years, at the median age of 18 years. Hence, occurrence in young adults may be the result of long-standing disease since puberty that has not been medically assessed. Only four cases of PDD in the elderly have been reported. They had a similar presentation to the adolescent age group, although the otherwise rare involvement of distal interphalangeal joints was present in two cases
Table 1 Characteristics of pachydermodactyly with number of analyzed cases for each feature Demographic data (n=121) Patients (n) Male/female (n, (%)) Disease characteristics (n=64) Age at onset (median, (range))a Duration at presentation (median, (range)) Clinical findings (n=80) Subjective complaints (n, (%)) Swelling and/or intumescence (n, (%)) Tenderness (n, (%)) Limited range of motion (n, (%)) Itching (n, (%)) Etiology (n=121) Mechanical cause identified (n, (%)) Psychological and/or psychiatric disease (n, (%)) Positive family history (n, (%)) a
Age at onset and not age at presentation
121 96 (79)/25 (21) 14 (5–74)years 2.5 (0.25–15)years 4 (5) 80 (100) 0 (0) 2 (2.5) 2 (2.5) 53 (44) 18 (15) 7 (5)
Etiology PDD frequently occurs in otherwise healthy individuals. The etiology is not fully understood; however, several precipitating factors acting in a possibly genetically predisposed individual seem to have an effect. Excessive mechanical stimulation of periarticular skin of proximal interphalangeal (PIP) joints is believed to be the most important factor, and activities leading to such stimulation could be identified for 43 % of affected individuals. Restriction of the intumescence to the lateral (radial and ulnar) aspects of the PIP joints of patients provides supporting evidence of the causative effect of repetitive rubbing, stretching, interlacing, and cracking of fingers. Extension of changes to the dorsal aspect of the PIP joints and the extensor surface of MCP joints, or even the skin between the bases of the 1st and 2nd digits, may reflect an unusual mode of microtraumatization. Patients with obsessive-compulsive disorders may present with such repetitive behaviors. We found a total of 18 individuals with Asperger syndrome [12], attention-deficit and hyperactivity disorder [4, 13], mental retardation [14], and tic and obsessive-compulsive disorders including Tourette syndrome [15]. Some authors regard PDD as an important indicator of a psychiatric disorder. The fingers of psychically healthy individuals may be exposed to increased mechanical irritation resulting from their profession (poultry workers, farmers, and computer workers) [6, 16–18], or from sporting (climbing, weight lifting, basketball, football, and martial arts) [19, 20] and musical (playing guitar and flute) [1] activities. Increased use of computer keyboards could be identified in three cases, and may be a novel mechanism to be considered particularly for adolescent boys [6, 21, 22]. Having progressed to an extent where periarticular tissue of digits is in contact with that of adjacent joints, permanent irritation may contribute to perpetuation of hypertrophy. Hormonal factors may have an effect, as suggested by the predominance of male subjects and symptoms starting at the onset of puberty. Androgens have been revealed to promote fibroblast proliferation and collagen synthesis in vitro [23, 24] and thus may explain, at least in part, the histological findings. Growth hormone and thyroid dysfunction have been speculated to have a function in the development of PDD. PDD may not develop in all male adolescents who experience repetitive mechanical irritation of periarticular soft tissue, and thus genetic predisposition may be essential. In at least five cases, PDD was associated with tuberous sclerosis, a disease characterized by cell proliferation leading to the development of central nervous system, heart, kidney, and skin tumors resulting from mutations in tumor-suppressor genes involved
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in the mTOR signaling pathway [25]. Interestingly, PDD had been present since birth and was localized to one digit of each hand only in some cases [26, 27]. PDD has also been associated with Ehlers-Danlos syndrome, a collagen-synthesis disorder [28]. Some authors have suggested that PDD may be a mild form of pachydermoperiostosis. In one case, an increased scintigraphic signal in the digit most affected by PDD was attributed to periostosis [29]; however, the involvement of bony structures has not been observed in any other case. These associations, and the co-occurrence with plantar pachydermy in one case [14], suggest that unidentified genetic aberrations, especially those leading to increased fibroblast proliferation and aberrant collagen synthesis, may be responsible for the development of hyperkeratotic skin at sites of increased mechanical irritation. Although four families with PDD occurrence in parent–child and sibling pairs have been reported [8, 30, 31], in most cases family members are not affected.
Clinical Presentation The leading clinical sign of PDD is insidious, progressive, painless swelling of proximal interphalangeal (PIP) joints, with 2nd to 4th PIP joints being most frequently affected (Fig. 1). The findings were asymmetrical in one third of patients for whom degree of symmetry of involvement was described, ranging from different numbers and patterns of affected joints and varying degrees of intumescence between two hands to unilateral involvement [21] and single-joint involvement (localized form) [26]. This provides supporting evidence for the effect of mechanical factors. Nonetheless, from the current literature, no conclusion of a possible correlation with hand dexterity can be drawn. Rarely, involvement of the thumbs and toes has been reported [32–35]. Distal interphalangeal joints were affected in only two elderly patients [10, 11] and three juvenile patients [30, 36]. The distribution of affected PIP joints in 75 cases of PDD is shown in Fig. 2. PDD is usually reported to be restricted to the medial and lateral aspects of the PIP joints. However, involvement of both lateral and dorsal aspects of PIP joints was noted in 41 of 62 cases for whom detailed information about localization of the changes was provided. The resulting shape of the swelling is fusiform or even saccular. Extension to the palm and dorsum of the hand, including metacarpophalangeal areas (transgradient form), has been reported [15, 37]. The affected skin is thick and firm, sometimes described as a freely movable tumor. It may have signs of hyperkeratosis, lichenification, and hyperpigmentation, and usually does not cause any pruritus or pain. Irritated, reddened, and pruritic skin was present in two cases of poultry workers believed to suffer from diffuse PDD of the entire hands [16], for whom antigenic stimulation of microtraumatized skin is likely to have been an additional factor.
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No warmth, erythema, tenderness on palpation, or effusion, and most importantly no limitation of function, are seen even in long-standing disease. Full range of motion, despite longterm progression of swelling, and absence of pain are the most striking findings (Fig. 1c). Only one case of a deforming course of PDD with non-erosive subluxation of the interphalangeal joint has been reported [38], and is not the typical pattern of involvement.
Classification A classification proposed by Bardazzi et al. [8], on the basis of a heterogeneous set of characteristics including localization, familial occurrence, and association with tuberous sclerosis, recognizes five types of PDD: 1. classic (affecting more than one PIP joint and related to repeated microtrauma); 2. localized (affecting a single joint); 3. transgredient (extending to the dorsum of the hand, and also affecting the metacarpophalangeal areas); 4. familial (with more family members affected); and 5. associated with tuberous sclerosis. The clinical and prognostic significance of this classification has not been evaluated.
Laboratory Examinations and Imaging Laboratory tests were completely normal for all reported cases, without elevated inflammatory markers, thyroid dysfunction, acromegaly, hematological disorders, or autoantibodies including rheumatoid factor (RF), anti-CCP, or ANA antibodies. On x-rays soft-tissue swelling can be found, but no periarticular osteoporosis, periostosis, erosions, cysts, or osteophytes. MRI does not identify joint effusion, synovitis, or tendinitis; only non-enhancing soft-tissue swelling without hypervascularization is seen [22]. Sonography may be equally effective at revealing soft-tissue hypertrophy without increased signal in power-Doppler mapping and in the absence of joint disease; however, this diagnostic modality was largely underused in published reports (n=5). There is usually no increase in osteoblast or osteolyte activity in the phalanges on bone scans.
Histology PDD is a benign digital fibromatosis resulting from the deposition of structurally abnormal collagen in the periarticular dermis [39]. For 79 reported histology results the epidermis was
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Fig. 1 Pachydermodactyly of the 2nd to 4th PIP joints of the left hand in a 16-year-old boy (a), with most prominent findings on the 2nd and 3rd PIP joints (b). Full flexion in affected joints and mild hyperkeratosis on the lateral aspect of the 2nd PIP joint (c). Progression of soft-tissue swelling, with no pathology in bony structures, in the same patient at first presentation (d) and after two years of follow-up (e). MRI of the hand confirming periarticular-PIP-joint soft-tissue swelling without synovitis (f). (Patient originally described in reference [6]; adapted with permission)
hyperplastic (48 %), with thickening of the stratum corneum (hyperkeratosis) and stratum spinosum (acanthosis) in 67 % and 48 % of cases, respectively. In the hypodermis, proliferating fibroblasts and increased deposition of collagen were reported in 35 % and 76 % of cases, respectively, the latter being the most prevalent histological feature and thus justifying use of the term fibromatosis for PDD. Type I collagen is reduced, immature type III collagen has been revealed to predominate, and the otherwise unusual type V collagen has also been identified in PDD [39]. The latter two types of collagen fiber are thin, uniform, loosely packed, and haphazardly arranged (13 %) in the dermis, and extend into the subcutis. Deposition of mucin
between collagen fibers (39 %), although not consistently reported and identified, may be increased. A discrete mononuclear infiltration has been described in only three cases. Vascular proliferation and eccrine gland entrapment by collagen have been reported occasionally [38]. According to some authors, these changes are characteristic of PDD and of pseudo-knuckle pads, both related to chronic skin irritation. It may therefore be difficult to strictly separate these two conditions, which may be part of a wider range of mechanically-induced “pachydermy” disorders. Similarly, PDD types 1, 2, and 3, according to the above classification, may simply reflect variants whose localization is determined by the mechanism of skin irritation.
Differential Diagnosis
Fig. 2 Distribution of affected 1st interphalangeal (IP1) and proximal interphalangeal (PIP) joints in 75 subjects with pachydermodactyly
Because of its swelling-like appearance and localization around usually more than one PIP joints, PDD may imitate arthropathy. This will inevitably lead to the consideration of inflammatory joint diseases, especially juvenile idiopathic arthritis, as reported in 12 published cases. However, a painless course without morning stiffness and without reduced joint function excludes these conditions. Pachydermoperiostosis is idiopathic or hereditary and presents as digital clubbing, with periostosis of tubular bones of
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the limbs and accompanying scleroderma-like thickening “pachydermy” of the dermis [40]. Secondary forms of pachydermoperiostosis caused by chronic cardiac, pulmonary, hepatic, gastrointestinal, and malignant diseases are better known as hypertrophic osteoarthropathy. Because bones of the digits are affected by the process, the digits assume a tubular shape and prominent periostosis is seen on x-rays. Hence radiographs are an important tool to exclude underlying bone and joint disease. Unlike pachydermodactyly, pachydermoperiostosis is symptomatic and causes pain [41]. Characteristically, periostosis involves the epiphysis in the hereditary, but not in the secondary, form. Periostosis can also be a feature of thyroid acropachy (EMO syndrome) [42]. Other skin callosities of the hand and fingers that may look like PDD include knuckle pads and pseudo-knuckle pads. Because of the similar histological presentation, PDD is believed to be a variant of knuckle pads by some authors. Knuckle pads, also known as Garrod’s pads, are asymptomatic, skin-colored, circumscribed hard areas of epidermal hyperplasia located on the extensor surfaces of fingers and hand joints (MCP and PIP). Their etiology is not known; however, they may have an autosomal dominant pattern of inheritance or be sporadic, with no connection to mechanical injury. Unlike PDD they occur equally in both genders from the 5th decade, and they have a different histological appearance [43]. Pseudo-knuckle pads are the result of chewing, sucking, or otherwise manipulating the skin of the hands and are therefore also referred to as chewing pads in children. They are usually on the dorsum of the knuckles (MCP joints), rather than the radial and ulnar aspect of PIP joints, and the skin may be erythematous and rough. Other rare conditions affecting the PIP joint area may have to be considered in the differential diagnosis of PDD; these are listed in Table 2. Among these, Thiemann’s disease, a genetically determined osteochondrosis of multiple epiphyses of the phalanges, results in progressive, sometimes painful, swelling of PIP joints in adolescents [44]. Importantly, it leads to limited range of motion, with fixed flexion deformities and characteristic radiographic changes (beak-shaped broadening, flattening, and fragmentation of epiphysis in short phalanges). The swelling is typically bony in nature. Similarly, progressive, mildly painful swelling of phalanges in adolescence may be caused by multiple cystoid osteitis Jüngling, in which multiple large pseudo-cysts without sclerosis form to produce a thickened appearance of the digits [45]. Progressive pseudorheumatoid epiphyseal dysplasia resulting from WISP3 gene mutations causes progressive, painless swelling of IP joints of the hands, without signs of inflammation. All epiphyses are affected, and anterior wedging and platyspondyly of vertebral bodies is characteristic [46]. Infantile digital fibromatosis forms domeshaped polypoid nodules over IP joint surfaces, and fibroblasts have characteristic paranuclear eosinophilic cytoplasmic inclusions [47]. Association of PDD with tuberous sclerosis
Page 5 of 7, 442 Table 2 Differential diagnosis of pachydermodactyly Rheumatic disease
Bone disease
Skin disease
Endocrine disease Tumors
Genetic causes
Juvenile idiopathic arthritis Rheumatoid arthritis Rheumatoid nodules Secondary pachydermoperiostosis Osteitis multiplex cystoides Jüngling Tuberculous dactylitis (spina ventosa) Knuckle (Garrod’s) pads Pseudo-knuckle (chewing) pads Foreign body granuloma Collagenous plaques of the hands Infantile or juvenile digital fibromatosis Progressive nodular fibrosis of the skin Acropachydermodactyly of psoriasis Connective tissue nevi Thyroid acropachy Acromegaly Fibromas Sarcomas Paraneoplastic acropachydermodactyly Tuberous sclerosis Primary pachydermoperiostosis (Touraine-Solente-Golé syndrome) Thiemann’s disease
warrants a search for other skin manifestations (angiofibromas, periungual fibromas, hypomelanotic macules, and Shagreen patches) of this neurocutaneous syndrome. In summary, the clinical presentation of PDD is characteristic, making it easy to exclude inflammatory rheumatic disorders. Laboratory examinations and x-rays may be helpful in delineating it from conditions affecting bones of the phalanges. Histology, although pathognomonic and reported in 63 % of analyzed cases, may not be necessary in clinical practice.
Treatment There is no universally accepted treatment for PDD. Cessation of mechanical stimulation may be sufficient for regression [48, 49], but may only lead to stabilization. Protective gloves or bandages have been recommended to prevent mechanical stimulation [50]. Taking pharmacological control of any underlying psychiatric condition may facilitate reduction of repetitive microtraumatization and thus promote regression of findings within a few months [51]. Treatment by surgical resection of fibrous tissue [52] and by intralesional triamcinolone injections [53] has been reported in at least two and eight cases, respectively, with some effect. Although some authors deny the effectiveness of topical corticosteroids, others report significant regression of periarticular tissue thickness. The risk of poorer wound healing in the proximity of PIP joints in conjunction with the tissue atrophy or tendon damage possible with corticosteroid injections has to be weighed against the usually benign course, the good effect
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of the elimination of mechanical stimulation, and the risk of recurrence after most therapeutic approaches if repetitive trauma continues. Some patients may wish to correct the cosmetic appearance of their digits, and others may prefer to avoid invasive procedures given the benign nature of PDD.
Prognosis PDD is a benign skin disorder. Only in two cases has mild limitation of range of motion been reported, and a single case was connected to progressive non-erosive subluxation with flexion deformity in the PIP joints [38]. Findings may stabilize after a few years of progression, and have been observed to regress or remain stable for up to 15 years [53].
Summary PDD is a dermatological condition, frequently associated with repetitive mechanical stimulation, which may have to be considered in the differential diagnosis of rheumatic joint disease. Because of its asymptomatic course and good prognosis, it may be rarely recognized and is underrepresented in medical literature. Progressive, asymptomatic swelling of PIP joints without loss of joint function, especially in young male subjects, should lead to the inclusion of PDD in the differential diagnosis of PIP joint swelling. Correct recognition of PDD prevents unnecessary referrals and tests, undue anxiety for patients or their parents, and, most importantly, inappropriate treatment [39]. Acknowledgments We thank Wolfgang Baum (University of ErlangenNuremberg) for excellent support with the literature search. Compliance with ethics guidelines Conflict of interest Tomáš Dallos, Bastian Oppl, László Kovács, and Jochen Zwerina declare that they have no conflict of interest. Human and animal rights and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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