CASE REPORT Pediatric Dermatology 1–4, 2013
Prurigo Pigmentosa after a Strict Ketogenic Diet Jason D. Michaels, M.D., M.S.,* Elika Hoss, B.S.,† David J. DiCaudo, M.D.,*,‡ and Harper Price, M.D.§ *Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, †College of Medicine University of Arizona at Phoenix, Phoenix, Arizona, ‡Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, §Department of Dermatology, Phoenix Children’s Hospital, Phoenix, Arizona
Abstract: Prurigo pigmentosa (PP) is a rare inflammatory dermatosis of unknown cause characterized by a predominantly truncal eruption of pruritic erythematous papules in a reticular pattern, resolving with hyperpigmentation. PP is twice as common in girls and women, and the mean age at onset is 25 years. Diagnosis of PP is challenging and is aided by characteristic histopathologic findings. We report a case of PP in a 17-year-old white boy. The eruption arose during strict adherence to a ketogenic diet.
A previously healthy 17-year-old white boy presented with a 2-week history of a mildly pruritic rash on the chest, upper back, and abdomen accompanied by acute onset of arthralgias and arthritis of the knees, elbows, wrists, and ankles. Before transferring to our institution, the boy was evaluated at an outside hospital and was believed to have dermatomyositis, which prompted treatment with a single 1.5-mg/kg dose of intravenous methylprednisolone. This treatment dramatically improved his joint condition within 72 hours, but his rash persisted. On clinical examination, countless poorly marginated, 3- to 4-mm scaly pink papules were present on the central middle and upper back and coalesced into a larger reticulated plaque (Fig. 1). Superficial erosions were observed throughout the larger plaque and at its periphery. Biopsy specimens were obtained from representative lesions of the upper back.
Histopathologic examination revealed intraepidermal vesicles underlying a basket-woven stratum corneum (Fig. 2). Neutrophils and eosinophils filled the vesicles and infiltrated the epidermis as single cells (Fig. 3). Apoptotic keratinocytes were scattered throughout the lower levels of the epidermis (Fig. 4). The dermis contained a superficial and deep infiltrate of neutrophils, eosinophils, and lymphocytes. Direct immunofluorescence was negative for autoimmune blistering disorders. Laboratory studies including complete blood cell count, comprehensive metabolic panel, immunofixation electrophoresis, erythrocyte sedimentation rate, and C-reactive protein, creatine kinase, lactate dehydrogenase, and aldolase levels completed during hospitalization were within reference limits. Serologic testing was negative for Epstein-Barr virus, cytomegalovirus, parvovirus B19, hepatitis B and C,
Address correspondence to David J. DiCaudo, M.D., Department of Dermatology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, or e-mail: [email protected]. DOI: 10.1111/pde.12275
© 2013 Wiley Periodicals, Inc.
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2 Pediatric Dermatology 2013
Figure 1. Ill-defined scaly, pink papules coalesced into a reticulated plaque on the upper back.
Figure 2. Intraepidermal (subcorneal) vesicles and perivascular dermal inflammation (hematoxylin and eosin, 1009).
Figure 4. Scattered necrotic keratinocytes (arrows) within the epidermis (hematoxylin and eosin, 4009).
mycoplasma pneumonia, anti-DNAse B, antistreptolysin O, Coccidioides spp., and syphilis through rapid plasma reagin. An autoimmune evaluation, including antinuclear antibody, C3, C4, antiproteinase-3 antibody, and antimyeloperoxidase antibody, revealed no abnormalities. The patient was monitored closely for several months, during which time his rash waxed and waned in severity. It was learned at a follow-up appointment that he had consumed a diet almost completely devoid of carbohydrates for the past year. He was referred to a dietitian, who instituted a balanced diet including carbohydrates. He concurrently started 2 months of treatment with doxycycline at a dose of 100 mg twice daily. Within a week his rash improved significantly (Fig. 5) and has not recurred during 15 months of follow-up, during which time he has maintained his carbohydrate-replete diet. The arthritis observed on presentation never recurred and ultimately was attributed to a viral origin, although no specific viral etiology was found. Taken together, the clinical, histopathologic, and laboratory examinations and his response to diet modification and tetracyclineclass antibiotic therapy support the diagnosis of prurigo pigmentosa (PP). DISCUSSION
Figure 3. Subcorneal vesicle with neutrophils eosinophils (hematoxylin and eosin, 2009).
and
More than 250 cases of PP have been reported since Nagashima et al (1) first described it in 1971, largely in the Japanese population (2–4). PP is observed at least twice as commonly in girls and women as in boys and men, and it typically presents at a mean age of 25 years, with no family history of the disease (2–5).
Michaels et al: Prurigo Pigmentosa after Ketogenic Diet
Figure 5. Significant resolution of the reticulated plaque on the upper back with minimal postinflammatory hyperpigmentation, observed 2 months after diet modification and institution of doxycycline monotherapy.
Prurigo pigmentosa is a pruritic dermatosis characterized by recurrent erythematous papules distributed on the back, chest, and neck and converging into a reticular pattern. Vesicular variants have been reported and in most cases the eruption resolves with mottled hyperpigmentation (2,3,6). Although the etiologic factors of PP are unclear, it has been associated with several exogenous factors, including physical trauma, friction from clothing, and acupuncture (7). The long-term relapsing nature of PP has led to conjecture of a viral pathogenesis, but association with herpes simplex virus 1, herpes simplex virus 2, and human herpesvirus 6 has been disproven (8). Of particular interest in our case, PP has been associated with metabolic derangements, including those observed in ketosis (diet-induced or diabetes mellitus–associated ketosis), anorexia nervosa, and rapid weight loss (9–12). As in previous reports, upon diet modification, our patient had rapid resolution of his PP without subsequent recurrence (12). Our patient had evidence of reference blood glucose levels. Ketone levels were not obtained during his examination. The histopathologic characteristics of PP are distinctive and have been described as rapidly evolving through three phases (2). The initial phase shows a superficial, perivascular infiltration of neutrophils, followed by neutrophil collections in the papillary dermis and epidermis. The second phase shows neutrophilic spongiosis, microabscesses, and ballooning degeneration of keratinocytes. The third and final phase shows a lichenoid infiltrate composed of eosinophils and lymphocytes and basal layer
3
vacuolization. Later lesions show parakeratosis and melanophages scattered throughout the papillary dermis. The inflammation of PP is believed to be largely attributable to neutrophilic infiltrate—a notion that the histopathologic findings and the disease response to dapsone and tetracycline-class antibiotics bolster. Minocycline and dapsone inhibit neutrophil chemotaxis, downregulate matrix metalloprotease activity, decrease proinflammatory cytokine production (e.g., tumor necrosis factor-a, interleukin-1b), and inhibit neutrophil myeloperoxidase, leading to impairment of the respiratory burst. Doxycycline has recently replaced minocycline because it has fewer adverse effects and offers similar therapeutic benefit (8,13). Additional treatments with reported benefit include macrolides, potassium iodide, and isotretinoin (8). Antihistamines and corticosteroids have consistently proved ineffective in the treatment of PP (8). Despite the characteristic clinical and histopathologic presentation, the diagnosis of PP can be difficult because of the lack of experience with these findings of Western physicians with this disease; only six cases of PP have been described in the United States (14–16). Our case illustrates the prudence of a careful review of dietary habits and nascent diabetes in the examination of a recurrent reticulated, pruritic rash of the trunk. The association between PP and ketosis has been reported extensively, with most cases improve upon correction of the metabolic derangement (3,9–12). The mechanism for the role of ketosis in PP remains elusive. In conclusion, our patient was a 17-year-old boy diagnosed with PP that was temporally associated with strict adherence to a ketogenic diet and improved markedly with diet modification and doxycycline therapy. REFERENCES 1. Nagashima M, Ohshiro A, Shimizu N. [A peculiar dermatosis with gross reticular pigmentation] [in Japanese]. Jpn J Dermatol 1971;81:78–91. 2. Boer A, Misago N, Wolter M et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol 2003;25:117–129. 3. Teraki Y, Teraki E, Kawashima M et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol 1996;34:509–511. 4. Oh YJ, Lee MH. Prurigo pigmentosa: a clinicopathologic study of 16 cases. J Eur Acad Dermatol Venereol 2012;26:1149–1153. 5. Shin JW, Lee SY, Lee JS et al. Prurigo pigmentosa in Korea: clinicopathological study. Int J Dermatol 2012;51:152–157.
4 Pediatric Dermatology 2013
6. Kim SK, Kang HY, Lee ES. Bullous prurigo pigmentosa. Int J Dermatol 2007;46:888–890. 7. Cota C, Donati P, Amantea A. Prurigo pigmentosa associated with an atopic diathesis in a 13-year-old girl. Pediatr Dermatol 2007;24:277–279. 8. Lu PH, Hui RC, Yang LC et al. Prurigo pigmentosa: a clinicopathological study and analysis of associated factors. Int J Dermatol 2011;50:36–43. 9. Kobayashi T, Kawada A, Hiruma M et al. Prurigo pigmentosa, ketonemia and diabetes mellitus. Dermatology 1996;192:78–80. 10. Nakada T, Sueki H, Iijima M. Prurigo pigmentosa (Nagashima) associated with anorexia nervosa. Clin Exp Dermatol 1998;23:25–27. 11. Murao K, Urano Y, Uchida N et al. Prurigo pigmentosa associated with ketosis. Br J Dermatol 1996;134:379–381.
12. Ohnishi T, Kisa H, Ogata E et al. Prurigo pigmentosa associated with diabetic ketoacidosis. Acta Derm Venereol 2000;80:447–448. 13. Mok YJ, Lim KS, Tey HL. Doxycycline: an emerging therapy for prurigo pigmentosa. J Eur Acad Dermatol Venereol 2012;26:526–527. 14. Whang T, Kirkorian AY, Krishtul A et al. Prurigo pigmentosa: report of two cases in the United States and review of the literature. Dermatol Online J 2011; 17:2. 15. Joyce AP, Horn TD, Anhalt GJ. Prurigo pigmentosa: report of a case and review of the literature. Arch Dermatol 1989;125:1551–1554. 16. Yanguas I, Goday JJ, Gonzalez-Guemes M et al. Prurigo pigmentosa in a white woman. J Am Acad Dermatol 1996;35(3 Pt 1):473–475.
Prurigo Pigmentosa after a Strict Ketogenic Diet Jason D. Michaels, M.D., M.S.,* Elika Hoss, B.S.,† David J. DiCaudo, M.D.,*,‡ and Harper Price, M.D.§ *Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, †College of Medicine University of Arizona at Phoenix, Phoenix, Arizona, ‡Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, §Department of Dermatology, Phoenix Children’s Hospital, Phoenix, Arizona
Abstract: Prurigo pigmentosa (PP) is a rare inflammatory dermatosis of unknown cause characterized by a predominantly truncal eruption of pruritic erythematous papules in a reticular pattern, resolving with hyperpigmentation. PP is twice as common in girls and women, and the mean age at onset is 25 years. Diagnosis of PP is challenging and is aided by characteristic histopathologic findings. We report a case of PP in a 17-year-old white boy. The eruption arose during strict adherence to a ketogenic diet.
A previously healthy 17-year-old white boy presented with a 2-week history of a mildly pruritic rash on the chest, upper back, and abdomen accompanied by acute onset of arthralgias and arthritis of the knees, elbows, wrists, and ankles. Before transferring to our institution, the boy was evaluated at an outside hospital and was believed to have dermatomyositis, which prompted treatment with a single 1.5-mg/kg dose of intravenous methylprednisolone. This treatment dramatically improved his joint condition within 72 hours, but his rash persisted. On clinical examination, countless poorly marginated, 3- to 4-mm scaly pink papules were present on the central middle and upper back and coalesced into a larger reticulated plaque (Fig. 1). Superficial erosions were observed throughout the larger plaque and at its periphery. Biopsy specimens were obtained from representative lesions of the upper back.
Histopathologic examination revealed intraepidermal vesicles underlying a basket-woven stratum corneum (Fig. 2). Neutrophils and eosinophils filled the vesicles and infiltrated the epidermis as single cells (Fig. 3). Apoptotic keratinocytes were scattered throughout the lower levels of the epidermis (Fig. 4). The dermis contained a superficial and deep infiltrate of neutrophils, eosinophils, and lymphocytes. Direct immunofluorescence was negative for autoimmune blistering disorders. Laboratory studies including complete blood cell count, comprehensive metabolic panel, immunofixation electrophoresis, erythrocyte sedimentation rate, and C-reactive protein, creatine kinase, lactate dehydrogenase, and aldolase levels completed during hospitalization were within reference limits. Serologic testing was negative for Epstein-Barr virus, cytomegalovirus, parvovirus B19, hepatitis B and C,
Address correspondence to David J. DiCaudo, M.D., Department of Dermatology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, or e-mail: [email protected]. DOI: 10.1111/pde.12275
© 2013 Wiley Periodicals, Inc.
1
2 Pediatric Dermatology 2013
Figure 1. Ill-defined scaly, pink papules coalesced into a reticulated plaque on the upper back.
Figure 2. Intraepidermal (subcorneal) vesicles and perivascular dermal inflammation (hematoxylin and eosin, 1009).
Figure 4. Scattered necrotic keratinocytes (arrows) within the epidermis (hematoxylin and eosin, 4009).
mycoplasma pneumonia, anti-DNAse B, antistreptolysin O, Coccidioides spp., and syphilis through rapid plasma reagin. An autoimmune evaluation, including antinuclear antibody, C3, C4, antiproteinase-3 antibody, and antimyeloperoxidase antibody, revealed no abnormalities. The patient was monitored closely for several months, during which time his rash waxed and waned in severity. It was learned at a follow-up appointment that he had consumed a diet almost completely devoid of carbohydrates for the past year. He was referred to a dietitian, who instituted a balanced diet including carbohydrates. He concurrently started 2 months of treatment with doxycycline at a dose of 100 mg twice daily. Within a week his rash improved significantly (Fig. 5) and has not recurred during 15 months of follow-up, during which time he has maintained his carbohydrate-replete diet. The arthritis observed on presentation never recurred and ultimately was attributed to a viral origin, although no specific viral etiology was found. Taken together, the clinical, histopathologic, and laboratory examinations and his response to diet modification and tetracyclineclass antibiotic therapy support the diagnosis of prurigo pigmentosa (PP). DISCUSSION
Figure 3. Subcorneal vesicle with neutrophils eosinophils (hematoxylin and eosin, 2009).
and
More than 250 cases of PP have been reported since Nagashima et al (1) first described it in 1971, largely in the Japanese population (2–4). PP is observed at least twice as commonly in girls and women as in boys and men, and it typically presents at a mean age of 25 years, with no family history of the disease (2–5).
Michaels et al: Prurigo Pigmentosa after Ketogenic Diet
Figure 5. Significant resolution of the reticulated plaque on the upper back with minimal postinflammatory hyperpigmentation, observed 2 months after diet modification and institution of doxycycline monotherapy.
Prurigo pigmentosa is a pruritic dermatosis characterized by recurrent erythematous papules distributed on the back, chest, and neck and converging into a reticular pattern. Vesicular variants have been reported and in most cases the eruption resolves with mottled hyperpigmentation (2,3,6). Although the etiologic factors of PP are unclear, it has been associated with several exogenous factors, including physical trauma, friction from clothing, and acupuncture (7). The long-term relapsing nature of PP has led to conjecture of a viral pathogenesis, but association with herpes simplex virus 1, herpes simplex virus 2, and human herpesvirus 6 has been disproven (8). Of particular interest in our case, PP has been associated with metabolic derangements, including those observed in ketosis (diet-induced or diabetes mellitus–associated ketosis), anorexia nervosa, and rapid weight loss (9–12). As in previous reports, upon diet modification, our patient had rapid resolution of his PP without subsequent recurrence (12). Our patient had evidence of reference blood glucose levels. Ketone levels were not obtained during his examination. The histopathologic characteristics of PP are distinctive and have been described as rapidly evolving through three phases (2). The initial phase shows a superficial, perivascular infiltration of neutrophils, followed by neutrophil collections in the papillary dermis and epidermis. The second phase shows neutrophilic spongiosis, microabscesses, and ballooning degeneration of keratinocytes. The third and final phase shows a lichenoid infiltrate composed of eosinophils and lymphocytes and basal layer
3
vacuolization. Later lesions show parakeratosis and melanophages scattered throughout the papillary dermis. The inflammation of PP is believed to be largely attributable to neutrophilic infiltrate—a notion that the histopathologic findings and the disease response to dapsone and tetracycline-class antibiotics bolster. Minocycline and dapsone inhibit neutrophil chemotaxis, downregulate matrix metalloprotease activity, decrease proinflammatory cytokine production (e.g., tumor necrosis factor-a, interleukin-1b), and inhibit neutrophil myeloperoxidase, leading to impairment of the respiratory burst. Doxycycline has recently replaced minocycline because it has fewer adverse effects and offers similar therapeutic benefit (8,13). Additional treatments with reported benefit include macrolides, potassium iodide, and isotretinoin (8). Antihistamines and corticosteroids have consistently proved ineffective in the treatment of PP (8). Despite the characteristic clinical and histopathologic presentation, the diagnosis of PP can be difficult because of the lack of experience with these findings of Western physicians with this disease; only six cases of PP have been described in the United States (14–16). Our case illustrates the prudence of a careful review of dietary habits and nascent diabetes in the examination of a recurrent reticulated, pruritic rash of the trunk. The association between PP and ketosis has been reported extensively, with most cases improve upon correction of the metabolic derangement (3,9–12). The mechanism for the role of ketosis in PP remains elusive. In conclusion, our patient was a 17-year-old boy diagnosed with PP that was temporally associated with strict adherence to a ketogenic diet and improved markedly with diet modification and doxycycline therapy. REFERENCES 1. Nagashima M, Ohshiro A, Shimizu N. [A peculiar dermatosis with gross reticular pigmentation] [in Japanese]. Jpn J Dermatol 1971;81:78–91. 2. Boer A, Misago N, Wolter M et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol 2003;25:117–129. 3. Teraki Y, Teraki E, Kawashima M et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol 1996;34:509–511. 4. Oh YJ, Lee MH. Prurigo pigmentosa: a clinicopathologic study of 16 cases. J Eur Acad Dermatol Venereol 2012;26:1149–1153. 5. Shin JW, Lee SY, Lee JS et al. Prurigo pigmentosa in Korea: clinicopathological study. Int J Dermatol 2012;51:152–157.
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6. Kim SK, Kang HY, Lee ES. Bullous prurigo pigmentosa. Int J Dermatol 2007;46:888–890. 7. Cota C, Donati P, Amantea A. Prurigo pigmentosa associated with an atopic diathesis in a 13-year-old girl. Pediatr Dermatol 2007;24:277–279. 8. Lu PH, Hui RC, Yang LC et al. Prurigo pigmentosa: a clinicopathological study and analysis of associated factors. Int J Dermatol 2011;50:36–43. 9. Kobayashi T, Kawada A, Hiruma M et al. Prurigo pigmentosa, ketonemia and diabetes mellitus. Dermatology 1996;192:78–80. 10. Nakada T, Sueki H, Iijima M. Prurigo pigmentosa (Nagashima) associated with anorexia nervosa. Clin Exp Dermatol 1998;23:25–27. 11. Murao K, Urano Y, Uchida N et al. Prurigo pigmentosa associated with ketosis. Br J Dermatol 1996;134:379–381.
12. Ohnishi T, Kisa H, Ogata E et al. Prurigo pigmentosa associated with diabetic ketoacidosis. Acta Derm Venereol 2000;80:447–448. 13. Mok YJ, Lim KS, Tey HL. Doxycycline: an emerging therapy for prurigo pigmentosa. J Eur Acad Dermatol Venereol 2012;26:526–527. 14. Whang T, Kirkorian AY, Krishtul A et al. Prurigo pigmentosa: report of two cases in the United States and review of the literature. Dermatol Online J 2011; 17:2. 15. Joyce AP, Horn TD, Anhalt GJ. Prurigo pigmentosa: report of a case and review of the literature. Arch Dermatol 1989;125:1551–1554. 16. Yanguas I, Goday JJ, Gonzalez-Guemes M et al. Prurigo pigmentosa in a white woman. J Am Acad Dermatol 1996;35(3 Pt 1):473–475.
