- Email: [email protected]
Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A
Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A Samer Ghosn, MD,a Imad Uthman, MD,b Maurice Dahdah, MD,a Abdul Ghani Kibbi, MD,a and Nelly Rubeiz, MDa Beirut, Lebanon Background: Pachydermoperiostosis (PDP) is a rare hereditary disorder characterized by digital clubbing, periostosis, and pachydermia. Pachydermia results in leonine facies, a major cause of cosmetic and functional morbidity in these patients. Its treatment is usually surgical. So far, no medical treatment has been suggested to alleviate this morbidity. Objective: We sought to assess the role of botulinum toxin type A (BTX-A) in improving the cosmetic appearance of pachydermia in patients with PDP. Methods: Three patients with PDP were treated with BTX-A for their leonine facies. A total of 70 to 80 U were used to treat the upper third of the face. Photographs were taken at baseline and at 2 and 6 weeks after the injections. The patients were followed up periodically for at least 6 months. Wrinkle severity was assessed at relaxation using the 4-point facial wrinkle scale at baseline, week 6, and month 6. In addition, a subjective assessment of the improvement of the extent and depth of the facial rhytides/furrows over the upper third of the face was performed by the same investigator at week 6 and month 6. Results: Using the subjective assessment of the improvement of wrinkles, all 3 patients exhibited a fair to excellent response at week 6 that started manifesting 1 week after the BTX-A treatment. All patients demonstrated a residual effect 6 months after the treatment. One patient exhibited a mild exacerbation of his ptosis. Limitations: Major limitations were the small number of patients and the administration of BTX-A injections and assessment of their response by a single unblinded physician. Conclusion: BTX-A is a simple procedure that may be of value in temporarily improving the cosmetic appearance of pachydermia in patients with PDP. ( J Am Acad Dermatol 2010;63:1036-41.) Key words: botulinum toxin type A; leonine facies; pachydermia; pachydermoperiostosis; primary hypertropic osteoarthropathy.
P
achydermoperiostosis (PDP) was first described in 1868 and is also known as primary hypertrophic osteoarthropathy and TouraineSolente-Gole´ syndrome. It is a rare hereditary From the Department of Dermatologya and Department of Internal Medicine, Division of Rheumatology,b American University of Beirut Medical Center. Funding sources: None. Conflicts of interest: None declared. Accepted for publication August 12, 2009. Reprints not available from the authors. Correspondence to: Nelly Rubeiz, MD, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh St, Beirut, Lebanon. E-mail: [email protected]. Published online October 8, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.08.067
1036
Abbreviations used: BTX-A: FWS: PDP: PGE2:
botulinum toxin type A facial wrinkle scale pachydermoperiostosis prostaglandin E2
disorder characterized by digital clubbing, periostosis, and pachydermia. Other findings include polyarthritis, cutis verticis gyrata, seborrheic dermatitis, acne, bilateral blepharoptosis, and hyperhidrosis. PDP accounts for 5% of all cases of hypertrophic osteoarthropathy. In contrast to secondary hypertrophic osteoarthropathy, PDP is not associated with underlying cardiopulmonary disease and/or malignancy. Touraine et al described 3 forms of PDP: (1) a complete form with pachydermia and periostitis; (2) an incomplete form with evidence of
Ghosn et al 1037
J AM ACAD DERMATOL VOLUME 63, NUMBER 6
bone abnormalities but lacking pachydermia; and medications. They were given the diagnosis of the (3) a forme fruste with prominent pachydermia complete form of PDP described by Touraine et al.1 Patients 1 and 3 were brothers with a family history and minimal-to-absent skeletal changes. PDP is only of digital clubbing in their father. Patient 2 more common in African Americans and in male had consanguineous parents (first-degree relatives) individuals (male-to-female case ratio is approxibut no affected family members. mately 7:1). Although the progression of PDP To evaluate response to freshly reconstituted typically ceases after 10 years, patients may be left toxin, a single bottle of lyophwith significant morbidity ilized botulinum neurotoxin from severe kyphosis, CAPSULE SUMMARY type-A (Neuronox, Medytox restricted motion, and neuInc, Kak-rl, Ochang-myeon, rologic problems. In addiPachydermoperiostosis is a rare Cheongwongun, Chungtion, the thickened folded hereditary disorder characterized by cheongbuk-do, Korea) was skin of PDP (pachydermia) digital clubbing, periostosis, and reconstituted in 2.0 mL of preresults in coarse facial feapachydermia (thickening of the facial served sterile saline (5 U/0.1 tures and leonine facies, skin, scalp, or both). mL). We used 1-mL insulin leading to cosmetic and Pachydermia results in coarse facial syringes with removable 30functional morbidity.1 Medifeatures and, later on, leonine facies cal care of PDP is palliative gauge needles. BTX-A was inleading to cosmetic and functional and includes nonsteroijected into relaxed muscles morbidity. dal anti-inflammatory drugs, while the patients were in a corticosteroids, pamidrositting position. The adminisThe treatment of pachydermia is usually nate, tamoxifen citrate, and tered doses and the injection centered on improving the cosmetic risedronate sodium to allevisites were as follows. The proappearance through plastic surgery. ate the painful polyarthritis/ cerus muscle was injected Botulinum toxin type A injection is a osteoarthropathy.2,3 Surgical with a single 10-U injection. simple procedure that may be of value in care includes vagotomy to The corrugator muscles were improving the cosmetic appearance of improve the associated articinjected in 2 spots: medially at pachydermia in patients with ular pain and swelling, and the site of their attachment to pachydermoperiostosis. surgical correction of digital bone (7.5 U each) and laterclubbing. The management ally at their skin insertion sites of pachydermia is surgical and includes bilateral (2.5 U each). The tail of the eyebrow was also treated blepharoplasties, tarsal wedge resections, excision with a single 5-U injection on each side. Injecting the of skin furrows, and facial rhytidectomy.4-7 We brow symmetrically at the medial and lateral edges herein report the successful management of leonine and concomitantly releasing the procerus muscle were facies in 3 patients with PDP with botulinum toxin performed to produce elevation at the medial and type A (BTX-A) injections. lateral ends of the brow and relieve the existing brow ptosis. An average of 7 intradermal injections (5 U each) along the deep furrows of the forehead was METHODS performed (Fig 1). Areas of nodulocystic acne were Three young male patients with PDP were reavoided. A total of 70 to 80 U were used for each ferred for management of ‘‘wrinkled facies’’ that patient. The patients were followed up for 6 months. began manifesting insidiously around puberty. Photographs were taken at the time of the injections Physical examination of the upper aesthetic unit of and at 2 and 6 weeks after the injections. One investhe face demonstrated thickened skin with folded tigator (S. G.) assessed wrinkle severity at relaxation horizontal frontal and vertical glabellar furrows not using the 4-point facial wrinkle scale (FWS)8 (0 = none, amenable to correction by manual distension of the 1 = mild, 2 = moderate, and 3 = severe) at baseline, skin, a picture consistent with leonine facies. When week 6, and month 6. In view of the lack of a sensitive asked to frown, the contribution of the forehead assessment tool that detects mild improvement of muscles to these wrinkles was found to be scarce. In wrinkling in patients with leonine facies, a subjective addition, all 3 patients had severe nodulocystic acne, assessment of the improvement of the extent and oily skin, prominent nasolabial folds, digital clubdepth of the facial rhytides/furrows over the upper bing, palmoplantar hyperhidrosis, eyelid ptosis, and third of the face was also performed by the same periostitis (documented by radiographs and bone treating physician. The following grading system of scans). All had normal serum thyrotropin and growth improvement was used: none or poor ( # 25%), hormone levels, had negative reactive plasma reafair (26%-50%), good (51%-75%), and excellent gent and/or VDRL testing results, and were on no d
d
d
d
1038 Ghosn et al
J AM ACAD DERMATOL DECEMBER 2010
Fig 1. Injection sites and amount of botulinum toxin type A used in patient 1: blue, 2.5 U; green, 5 U; orange, 7.5 U; red, 10 U.
(76%-100%). At each assessment, a patient was classified as having improved if their FWS score was less than at baseline, or if they experienced at least fair improvement as per subjective assessment. The study was approved by the institutional review board committee at our medical center. The patients signed a consent form and a photography release form before the treatment visit.
RESULTS All patients tolerated the procedure extremely well and did not experience any adverse events from the injections. At week 6, only patient 1 (with severe leonine facies) had improvement of wrinkling detected by the FWS. When using the subjective assessment, all 3 patients were reported as responders at week 6 with excellent, good, and fair improvement, respectively. Patients reported that the improvement started within the first week of treatment and culminated between weeks 4 and 6. This was documented by photographs taken at week 2. At month 6, a poor to good improvement was still detected in all patients. Two patients reported improvement of their ptosis whereas only one (patient
3) experienced an exacerbation that became manifest after the first week (Figs 2 and 3; Table I). All 3 patients were very satisfied with the results and reported a marked improvement in their quality of life.
DISCUSSION PDP is believed to be inherited in an autosomal dominant pattern with variable penetrance; however, autosomal recessive forms have been reported. It has been recently mapped to band 4q33-q34 on chromosome 4. Mutations in HPGD encoding 15-hydroxyprostaglandin dehydrogenase, the key enzyme of prostaglandin degradation, have been identified. Individuals with homozygous mutations have chronically elevated prostaglandin E2 (PGE2) levels. The various clinical manifestations of PDP fit well with the pleiotropic range of physiologic actions of PGE2 in different tissues. Excess PGE2 may account for the periostosis, acro-osteolysis, clubbing, and patent ductus arteriosus.9 The exact effects of PGE2 on the skin are not completely understood. Experimentally, PGE2 has been shown to cause vasodilation through two separate and equally
J AM ACAD DERMATOL
Ghosn et al 1039
VOLUME 63, NUMBER 6
Fig 2. Preoperative view of frontal and glabellar wrinkles in patient 1 (A). Same patient at 2 (B) and 6 (C) weeks after treatment with botulinum toxin type A.
Fig 3. Preoperative view of frontal and glabellar wrinkles in patient 2 (A). Same patient at 2 (B) and 6 (C) weeks after treatment with botulinum toxin type A. Note that seemingly exacerbated eyelid ptosis (C) is caused by blepharitis secondary to isotretinoin therapy for nodulocystic acne treatment (initiated 1 month before photograph was taken).
important mechanisms: the first involves presynaptic inhibition of sympathetic vasoconstrictor tone, whereas the second is presumably a direct action on the vascular smooth muscle or endothelium.10 Recently, human sebocytes were demonstrated to express PGE2 receptors EP2 and EP4. Although the sebaceous gland is a steroidogenic organ similar to the gonads and adrenal cortex, the expression of these receptors was not found to affect testosterone production.11 So far, there is no evidence that excessive skeletal muscle contraction occurs in patients with PDP and that such excessive skeletal muscle contraction, if it exists, is mediated by PGE2. Using the subjective assessment of the improvement of wrinkles, all 3 patients exhibited a fair to excellent response at week 6 that started manifesting 1 week after the BTX-A treatment. Except for patient 1, this improvement could not be substantiated using the FWS. This may be because this scoring tool is not able to detect mild improvement in wrinkling in patients with leonine facies.
In a short span of time, the body of scientific articles for the medical indications of BTX-A in dermatology has expanded considerably. BTX-A has been shown to be useful in the management of hyperhidrosis,12 eccrine hydrocystomas,13 inverse psoriasis,14 and recently, epidermolysis bullosa15 and hypertrophic scars.16 The current study suggests that BTX-A may also play a role in the management of pachydermia in PDP. The exact mechanism of action is unknown. BTX-A blocks the cholinergic nerve terminals and inhibits release of acetylcholine acting at the neuromuscular junction. In addition, BTX-A has been shown to block the autonomic cholinergic junctions of the postganglionic sympathetic fibers to the sweat glands. In the current study, BTX-A mechanism of action remains unknown. The primary cause of the deep horizontal and vertical wrinkles in PDP is generally believed to be secondary to thickened skin (mostly dermis), and not to the repetitious use of the frontalis and corrugator muscles. This is supported by the small contribution of frowning to the baseline
1040 Ghosn et al
J AM ACAD DERMATOL
3 3 3 2 3 3 3 3 3 M/24 M/19 M/22 Patient 1 Patient 2 Patient 3
FWS, Facial wrinkle scale; M, male.
Side effects
None None Exacerbation of ptosis Excellent Good Fair
Good Fair Poor
state of furrowing. Therefore, the injection of BTX-A should theoretically not improve significantly the cosmetic appearance in these patients. Recently, BTX-A has been used successfully in the management of hypertrophic scars. The suggested mechanism of action is through correction of the imbalance in cellular dynamics of the fibroblast cell cycle caused by the overabundance of cellular proliferation and the lack of cellular apoptosis.16 It is tempting to speculate that this mechanism also contributes to the significant cosmetic response to BTX-A in our patients. It does not explain, however, the prompt cosmetic improvement seen in the first 2 weeks. The authors hypothesize that inhibition of skeletal muscle contraction is the most likely explanation to account for this early improvement. The failure of frowning to contribute significantly to the furrowing may reflect a baseline excessive contraction of the involved facial muscles. Whether this excessive skeletal muscle contraction is PGE2-mediated and whether BTX-A inhibits or antagonizes PGE2 effect in the skin remain to be determined. This article presents only 3 cases of BTX-Ae treated pachydermia, but the results look promising even after one single treatment. It remains to be seen if repeated BTX-A treatments would further enhance the cosmetic outcomes that were achieved after the first treatment. Although the type of BTX-A used in this study, Neuronox (Medytox Inc), is not available in the United States, the results could be extrapolated to Botox (Allergan, Inc, Irvine, CA) based on a study that showed both formulations produced equivalent dose responses in a murine model, and based on our personal experience with both products.17 Other limitations to our study include a single unblinded physician (S. G.) who administered the injections and assessed their effect. Larger studies may be needed to further consolidate these results.
Severe Moderate Moderate
Subjective assessment of improvement at mo 6 Subjective assessment of improvement at wk 6 Subjective assessment of extent of leonine facies at baseline FWS at mo 6 FWS at wk 6 FWS at baseline Sex/age, y
Table I. Summary of patients’ characteristics, facial wrinkle scale (at baseline, week 6, and month 6), subjective assessment of their response (6 weeks and 6 months after botulinum toxin type A treatment), and side effects of procedure
DECEMBER 2010
REFERENCES 1. Castori M, Sinibaldi L, Mingarelli R, Lachman RS, Rimoin DL, Dallapiccola B. Pachydermoperiostosis: an update. Clin Genet 2005;68:477-86. 2. Bhansali A, Singh R, Sriraam M, Bhadada S. Pachydermoperiostitis and bisphosphonates. J Assoc Physicians India 2006; 54:340. 3. Okten A, Mungan I, Kalyoncu M, Orbak Z. Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia. Clin Rheumatol 2007;26:8-11. 4. George L, Sachithanandam K, Gupta A, Pulimood S. Frontal rhytidectomy as surgical treatment for pachydermoperiostosis: a case report. J Dermatolog Treat 2008;19:61-3. 5. Monteiro E, Carvalho P, Silva A, Ferraro A. Frontal rhytidectomy: a new approach to improve deep wrinkles in a case of pachydermoperiostosis. Plast Reconstr Surg 2003;112: 1189-91.
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6. Seyhan T, Ozerdem OR, Aliagaoglu C. Severe complete pachydermoperiostosis (Touraine-Solente-Gole syndrome). Dermatol Surg 2005;31:1465-7. 7. Bruner S, Frerichs O, Raute-Kreinsen U, Fansa H. Correction of finger clubbing in primary hypertrophic osteoarthropathy (Touraine-Solente-Gole syndrome) [German]. Handchir Mikrochir Plast Chir 2007;39:135-8. 8. Carruthers A, Carruthers J, Cohen J. A prospective, doubleblind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dermatol Surg 2003;29:461-7. 9. Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, et al. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 2008;40:789-93. 10. Ballard HJ, Achike FI. Mechanism of action of prostaglandin E2 in the dog skeletal muscle circulation. Chin Med J (Engl) 1998; 111:945-50. 11. Chen W, Tsai SJ, Wang CA, Tsai JC, Zouboulis CC. Human sebocytes express prostaglandin E2 receptors EP2 and EP4 but
12.
13.
14.
15.
16.
17.
treatment with prostaglandin E2 does not affect testosterone production. Br J Dermatol 2009;161:674-7. Moffat CE, Hayes WG, Nyamekye IK. Durability of botulinum toxin treatment for axillary hyperhidrosis. Eur J Vasc Endovasc Surg 2009;38:188-91. Ebrahimi A, Radmanesh M. Botulinum toxin type-A (BT-A) for the treatment of multiple eccrine hydrocystomas. J Dermatolog Treat 2010;21:80-2. Zanchi M, Favot F, Bizzarini M, Piai M, Donini M, Sedona P. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 2008;22:431-6. Abitbol RJ, Zhou LH. Treatment of epidermolysis bullosa simplex, Weber-Cockayne type, with botulinum toxin type A. Arch Dermatol 2009;145:13-5. Xiao Z, Zhang F, Cui Z. Treatment of hypertrophic scars with intralesional botulinum toxin type A injections: a preliminary report. Aesthetic Plast Surg 2009;33:409-12. Stone AV, Ma J, Whitlock PW, Koman LA, Smith TL, Smith BP, et al. Effects of Botox and Neuronox on muscle force generation in mice. J Orthop Res 2007;25:1658-64.
P
achydermoperiostosis (PDP) was first described in 1868 and is also known as primary hypertrophic osteoarthropathy and TouraineSolente-Gole´ syndrome. It is a rare hereditary From the Department of Dermatologya and Department of Internal Medicine, Division of Rheumatology,b American University of Beirut Medical Center. Funding sources: None. Conflicts of interest: None declared. Accepted for publication August 12, 2009. Reprints not available from the authors. Correspondence to: Nelly Rubeiz, MD, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh St, Beirut, Lebanon. E-mail: [email protected]. Published online October 8, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.08.067
1036
Abbreviations used: BTX-A: FWS: PDP: PGE2:
botulinum toxin type A facial wrinkle scale pachydermoperiostosis prostaglandin E2
disorder characterized by digital clubbing, periostosis, and pachydermia. Other findings include polyarthritis, cutis verticis gyrata, seborrheic dermatitis, acne, bilateral blepharoptosis, and hyperhidrosis. PDP accounts for 5% of all cases of hypertrophic osteoarthropathy. In contrast to secondary hypertrophic osteoarthropathy, PDP is not associated with underlying cardiopulmonary disease and/or malignancy. Touraine et al described 3 forms of PDP: (1) a complete form with pachydermia and periostitis; (2) an incomplete form with evidence of
Ghosn et al 1037
J AM ACAD DERMATOL VOLUME 63, NUMBER 6
bone abnormalities but lacking pachydermia; and medications. They were given the diagnosis of the (3) a forme fruste with prominent pachydermia complete form of PDP described by Touraine et al.1 Patients 1 and 3 were brothers with a family history and minimal-to-absent skeletal changes. PDP is only of digital clubbing in their father. Patient 2 more common in African Americans and in male had consanguineous parents (first-degree relatives) individuals (male-to-female case ratio is approxibut no affected family members. mately 7:1). Although the progression of PDP To evaluate response to freshly reconstituted typically ceases after 10 years, patients may be left toxin, a single bottle of lyophwith significant morbidity ilized botulinum neurotoxin from severe kyphosis, CAPSULE SUMMARY type-A (Neuronox, Medytox restricted motion, and neuInc, Kak-rl, Ochang-myeon, rologic problems. In addiPachydermoperiostosis is a rare Cheongwongun, Chungtion, the thickened folded hereditary disorder characterized by cheongbuk-do, Korea) was skin of PDP (pachydermia) digital clubbing, periostosis, and reconstituted in 2.0 mL of preresults in coarse facial feapachydermia (thickening of the facial served sterile saline (5 U/0.1 tures and leonine facies, skin, scalp, or both). mL). We used 1-mL insulin leading to cosmetic and Pachydermia results in coarse facial syringes with removable 30functional morbidity.1 Medifeatures and, later on, leonine facies cal care of PDP is palliative gauge needles. BTX-A was inleading to cosmetic and functional and includes nonsteroijected into relaxed muscles morbidity. dal anti-inflammatory drugs, while the patients were in a corticosteroids, pamidrositting position. The adminisThe treatment of pachydermia is usually nate, tamoxifen citrate, and tered doses and the injection centered on improving the cosmetic risedronate sodium to allevisites were as follows. The proappearance through plastic surgery. ate the painful polyarthritis/ cerus muscle was injected Botulinum toxin type A injection is a osteoarthropathy.2,3 Surgical with a single 10-U injection. simple procedure that may be of value in care includes vagotomy to The corrugator muscles were improving the cosmetic appearance of improve the associated articinjected in 2 spots: medially at pachydermia in patients with ular pain and swelling, and the site of their attachment to pachydermoperiostosis. surgical correction of digital bone (7.5 U each) and laterclubbing. The management ally at their skin insertion sites of pachydermia is surgical and includes bilateral (2.5 U each). The tail of the eyebrow was also treated blepharoplasties, tarsal wedge resections, excision with a single 5-U injection on each side. Injecting the of skin furrows, and facial rhytidectomy.4-7 We brow symmetrically at the medial and lateral edges herein report the successful management of leonine and concomitantly releasing the procerus muscle were facies in 3 patients with PDP with botulinum toxin performed to produce elevation at the medial and type A (BTX-A) injections. lateral ends of the brow and relieve the existing brow ptosis. An average of 7 intradermal injections (5 U each) along the deep furrows of the forehead was METHODS performed (Fig 1). Areas of nodulocystic acne were Three young male patients with PDP were reavoided. A total of 70 to 80 U were used for each ferred for management of ‘‘wrinkled facies’’ that patient. The patients were followed up for 6 months. began manifesting insidiously around puberty. Photographs were taken at the time of the injections Physical examination of the upper aesthetic unit of and at 2 and 6 weeks after the injections. One investhe face demonstrated thickened skin with folded tigator (S. G.) assessed wrinkle severity at relaxation horizontal frontal and vertical glabellar furrows not using the 4-point facial wrinkle scale (FWS)8 (0 = none, amenable to correction by manual distension of the 1 = mild, 2 = moderate, and 3 = severe) at baseline, skin, a picture consistent with leonine facies. When week 6, and month 6. In view of the lack of a sensitive asked to frown, the contribution of the forehead assessment tool that detects mild improvement of muscles to these wrinkles was found to be scarce. In wrinkling in patients with leonine facies, a subjective addition, all 3 patients had severe nodulocystic acne, assessment of the improvement of the extent and oily skin, prominent nasolabial folds, digital clubdepth of the facial rhytides/furrows over the upper bing, palmoplantar hyperhidrosis, eyelid ptosis, and third of the face was also performed by the same periostitis (documented by radiographs and bone treating physician. The following grading system of scans). All had normal serum thyrotropin and growth improvement was used: none or poor ( # 25%), hormone levels, had negative reactive plasma reafair (26%-50%), good (51%-75%), and excellent gent and/or VDRL testing results, and were on no d
d
d
d
1038 Ghosn et al
J AM ACAD DERMATOL DECEMBER 2010
Fig 1. Injection sites and amount of botulinum toxin type A used in patient 1: blue, 2.5 U; green, 5 U; orange, 7.5 U; red, 10 U.
(76%-100%). At each assessment, a patient was classified as having improved if their FWS score was less than at baseline, or if they experienced at least fair improvement as per subjective assessment. The study was approved by the institutional review board committee at our medical center. The patients signed a consent form and a photography release form before the treatment visit.
RESULTS All patients tolerated the procedure extremely well and did not experience any adverse events from the injections. At week 6, only patient 1 (with severe leonine facies) had improvement of wrinkling detected by the FWS. When using the subjective assessment, all 3 patients were reported as responders at week 6 with excellent, good, and fair improvement, respectively. Patients reported that the improvement started within the first week of treatment and culminated between weeks 4 and 6. This was documented by photographs taken at week 2. At month 6, a poor to good improvement was still detected in all patients. Two patients reported improvement of their ptosis whereas only one (patient
3) experienced an exacerbation that became manifest after the first week (Figs 2 and 3; Table I). All 3 patients were very satisfied with the results and reported a marked improvement in their quality of life.
DISCUSSION PDP is believed to be inherited in an autosomal dominant pattern with variable penetrance; however, autosomal recessive forms have been reported. It has been recently mapped to band 4q33-q34 on chromosome 4. Mutations in HPGD encoding 15-hydroxyprostaglandin dehydrogenase, the key enzyme of prostaglandin degradation, have been identified. Individuals with homozygous mutations have chronically elevated prostaglandin E2 (PGE2) levels. The various clinical manifestations of PDP fit well with the pleiotropic range of physiologic actions of PGE2 in different tissues. Excess PGE2 may account for the periostosis, acro-osteolysis, clubbing, and patent ductus arteriosus.9 The exact effects of PGE2 on the skin are not completely understood. Experimentally, PGE2 has been shown to cause vasodilation through two separate and equally
J AM ACAD DERMATOL
Ghosn et al 1039
VOLUME 63, NUMBER 6
Fig 2. Preoperative view of frontal and glabellar wrinkles in patient 1 (A). Same patient at 2 (B) and 6 (C) weeks after treatment with botulinum toxin type A.
Fig 3. Preoperative view of frontal and glabellar wrinkles in patient 2 (A). Same patient at 2 (B) and 6 (C) weeks after treatment with botulinum toxin type A. Note that seemingly exacerbated eyelid ptosis (C) is caused by blepharitis secondary to isotretinoin therapy for nodulocystic acne treatment (initiated 1 month before photograph was taken).
important mechanisms: the first involves presynaptic inhibition of sympathetic vasoconstrictor tone, whereas the second is presumably a direct action on the vascular smooth muscle or endothelium.10 Recently, human sebocytes were demonstrated to express PGE2 receptors EP2 and EP4. Although the sebaceous gland is a steroidogenic organ similar to the gonads and adrenal cortex, the expression of these receptors was not found to affect testosterone production.11 So far, there is no evidence that excessive skeletal muscle contraction occurs in patients with PDP and that such excessive skeletal muscle contraction, if it exists, is mediated by PGE2. Using the subjective assessment of the improvement of wrinkles, all 3 patients exhibited a fair to excellent response at week 6 that started manifesting 1 week after the BTX-A treatment. Except for patient 1, this improvement could not be substantiated using the FWS. This may be because this scoring tool is not able to detect mild improvement in wrinkling in patients with leonine facies.
In a short span of time, the body of scientific articles for the medical indications of BTX-A in dermatology has expanded considerably. BTX-A has been shown to be useful in the management of hyperhidrosis,12 eccrine hydrocystomas,13 inverse psoriasis,14 and recently, epidermolysis bullosa15 and hypertrophic scars.16 The current study suggests that BTX-A may also play a role in the management of pachydermia in PDP. The exact mechanism of action is unknown. BTX-A blocks the cholinergic nerve terminals and inhibits release of acetylcholine acting at the neuromuscular junction. In addition, BTX-A has been shown to block the autonomic cholinergic junctions of the postganglionic sympathetic fibers to the sweat glands. In the current study, BTX-A mechanism of action remains unknown. The primary cause of the deep horizontal and vertical wrinkles in PDP is generally believed to be secondary to thickened skin (mostly dermis), and not to the repetitious use of the frontalis and corrugator muscles. This is supported by the small contribution of frowning to the baseline
1040 Ghosn et al
J AM ACAD DERMATOL
3 3 3 2 3 3 3 3 3 M/24 M/19 M/22 Patient 1 Patient 2 Patient 3
FWS, Facial wrinkle scale; M, male.
Side effects
None None Exacerbation of ptosis Excellent Good Fair
Good Fair Poor
state of furrowing. Therefore, the injection of BTX-A should theoretically not improve significantly the cosmetic appearance in these patients. Recently, BTX-A has been used successfully in the management of hypertrophic scars. The suggested mechanism of action is through correction of the imbalance in cellular dynamics of the fibroblast cell cycle caused by the overabundance of cellular proliferation and the lack of cellular apoptosis.16 It is tempting to speculate that this mechanism also contributes to the significant cosmetic response to BTX-A in our patients. It does not explain, however, the prompt cosmetic improvement seen in the first 2 weeks. The authors hypothesize that inhibition of skeletal muscle contraction is the most likely explanation to account for this early improvement. The failure of frowning to contribute significantly to the furrowing may reflect a baseline excessive contraction of the involved facial muscles. Whether this excessive skeletal muscle contraction is PGE2-mediated and whether BTX-A inhibits or antagonizes PGE2 effect in the skin remain to be determined. This article presents only 3 cases of BTX-Ae treated pachydermia, but the results look promising even after one single treatment. It remains to be seen if repeated BTX-A treatments would further enhance the cosmetic outcomes that were achieved after the first treatment. Although the type of BTX-A used in this study, Neuronox (Medytox Inc), is not available in the United States, the results could be extrapolated to Botox (Allergan, Inc, Irvine, CA) based on a study that showed both formulations produced equivalent dose responses in a murine model, and based on our personal experience with both products.17 Other limitations to our study include a single unblinded physician (S. G.) who administered the injections and assessed their effect. Larger studies may be needed to further consolidate these results.
Severe Moderate Moderate
Subjective assessment of improvement at mo 6 Subjective assessment of improvement at wk 6 Subjective assessment of extent of leonine facies at baseline FWS at mo 6 FWS at wk 6 FWS at baseline Sex/age, y
Table I. Summary of patients’ characteristics, facial wrinkle scale (at baseline, week 6, and month 6), subjective assessment of their response (6 weeks and 6 months after botulinum toxin type A treatment), and side effects of procedure
DECEMBER 2010
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