Correspondence Clinical Letter
Clinical Letter Flare-up of incontinentia pigmenti in association with Behçet disease
DOI: 10.1111/ddg.12452
Dear Editors, A 16-year-old girl, who was diagnosed as having incontinentia pigmenti (IP) during infancy, presented with diffuse hyperpigmented patches along the lines of Blaschko over most of her body below the neck. She had no associated ocular or neurological abnormalities, but dental X-ray revealed congenital absence of one lower lateral and two upper lateral incisors. At the age of 7, she suffered from recurrent genital ulcers, oral aphthosis, and facial pustules. Pathergy test was positive. Behçet disease was diagnosed. After systemic corticosteroids were administered, her condition improved and remained stable for years. She experienced occasional flares of oral aphthous ulcers, but no recurrence of genital ulcers developed. Her mother and older sister had been diagnosed with IP, and her mother also had Behçet disease. She recently presented with itching, stinging erythematous patches with vesiculobullous lesions on previous hyperpigmented patches over her left calf. Genital ulcers and oral aphthous ulcers recurred simultaneously. There were no other infectious symptoms and signs over the upper respiratory tract and genitourinary tract. Routine laboratory tests revealed mild leukocytosis and elevated erythrocyte sedimentation
rate (113 mm/hr.). Blood chemistry, urinalysis, and antinuclear antibodies were within normal limits. The erythematous lesions disappeared quickly and turned to hyperkeratotic verrucous papules and vesicles (Figure 1a, b) within one week. Virus cultures for varicella-zoster virus and herpes simplex virus of lesional skin and bacterial cultures of blood and urine were negative. Histological examination showed marked hyperkeratosis, acanthosis, papillomatosis, and focal dyskeratosis of the epidermis (Figure 2a). The dyskeratotic cells were arranged in a whorled configuration (Figure 2b). The skin lesions resolved in ten days. The oral aphthous ulcers and genital ulcers healed two weeks later. Recurrent inflammation of incontinentia pigmenti associated with flare-up of Behçet disease was diagnosed. Incontinentia pigmenti is an X-linked dominant multisystemic syndrome with cutaneous, neurologic, dental, and ophthalmologic manifestations. Classically, there are four stages of cutaneous lesions: vesicular, verrucous, hyperpigmented, and hypopigmented. In recent studies, mutation in the gene NEMO (nuclear factor κB [NF-κB] essential modulator), also known as “the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma”, on the X chromosome at Xq28, has been related to the development of incontinentia pigmenti [1, 2]. NF-κB may protect keratinocytes from tumor necrosis factor-α (TNF-α)-induced apoptosis [1, 2]. Epidermal cells with the mutant NEMO gene cannot activate NF-κB, so they will lose the ability to inhibit TNFα-induced apoptosis, giving rise to cutaneous lesions associated with IP [1, 2]. Most patients with IP remain stable after the initial inflammatory stage. However, some patients experienced episodes of late reactivation of the inflammatory cutaneous
Figure 1 Diffuse hyperpigmented patches along the lines of Blaschko with hyperkeratotic verrucous papules and vesicles over the patient’s left calf (arrow) (a). Close view shows hyperkeratotic verrucous papules and vesicles, corresponding to the verrucous stage of incontinentia pigmenti (b).
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© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
Correspondence Clinical Letter
Figure 2 Histopathology showed marked hyperkeratosis, acanthosis, papillomatosis, and focal dyskeratosis of the epidermis (hematoxylin and eosin; original magnification x 100) (a). The dyskeratotic cells were arranged in a whorled configuration (hematoxylin and eosin; original magnification x 400) (b).
lesions. In 2008, Hsiao et al. conducted a comprehensive literature review [3], which included 16 cases of reactivation of IP. Nine of the cases appeared to be related to a preceding infection or fever, one case was associated with estrogen therapy and one case with laser therapy. The remaining cases had no identifiable triggering factor. Bodak et al. proposed that the mutated cells persist in the epidermis for a long period of time [4]. After exposure to an event, such as an infection, proinflammatory cytokines, including TNF-α, reactivate NEMO mutant cells, which contribute to the development of recurrent inflammation of keratinocytes [4]. This also explains why most of the recurrences were observed in the previously affected areas [3]. Behçet disease is a chronic relapsing inflammatory disease characterized clinically by recurrent oral aphthous and genital ulcers, iridocyclitis/posterior uveitis, skin lesions, and other systemic manifestations. Genetic susceptibility, infectious agents, hormonal factors, and endothelial activation/injury have all been implicated in the etiology of Behçet disease [5]. One hypothesis is that this disease is caused by immunological abnormalities. In recent studies, some pro-inflammatory cytokines have been shown to be elevated in the sera of patients with Behçet disease, including IL-1, -8, -12, -17, -23, interferon-γ and TNF-α [5–7]. Only three cases of IP concurrent with Behçet disease have been reported in the literature [8–10]. However, no cases of recurrent inflammation in both IP and Behçet disease have been reported. To the best of our knowledge, this is the first reported case of reactivation of cutaneous inflammation of IP associated with flare-up of Behçet disease. Little is known about the pathogenesis of the association between recurrent IP and Behçet disease. We postulated that this
e pisode of concomitant flare up of genital and oral aphthous ulcers in Behçet disease may be associated with a marked elevation of proinflammatory cytokine levels, including TNF-α. This level might be have sufficient potency to induce apoptosis of residual NEMO mutant cells of the epidermis, leading to this first episode of recurrent inflammation of IP. Recent research has provided us with a better understanding of this interesting phenomenon, but the exact pathophysiology of this event needs to be further clarified. Conflicts of interest None.
Chao-Kuei Juan1, Jui-Lung Shen1, Chii-Shuenn Yang2, Kwei-Lan Liu1, Yi-Ju Chen1, 3 (1) Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan (2) Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan (3) Department of Dermatology, National Yang-Ming University, Taipei, Taiwan
Correspondence to Yi-Ju Chen, MD, PhD Department of Dermatology National Yang-Ming University Taichung Veterans General Hospital No. 1650, Sec. 4, Taiwan Boulevard Taichung 40705, Taiwan. E-mail: [email protected]
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
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Correspondence Clinical Letter
References 1
2
3
4
156
Fusco F, Bardaro T, Fimiani G et al. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappa B activation. Hum Mol Genet 2004; 13: 1763–73. Makris C, Godfrey VL, Krahn-Senftieben G et al. Female mice heterozygous for IKK gamma/ NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 2000; 5: 969–79. Hsiao HW, Chang CL, Chen HH et al. Recurrent inflammation of incontinentia pigmenti in a 30-year-old woman. Dermatol Sinica 2008; 26: 242–7. Bodak N, Hadj-Rabia S, Hamel-Teillac D et al. Late recurrence of inflammatory first-stage lesions in incontinentia pigmenti. Arch Dermatol 2003; 139: 201–4.
5
Gül A. Behçet’s disease: an update on the pathogenesis. Clin Exp Rheumatol 2001; 19: S6–S12. 6 Hamzaoui K, Hamzaoui A, Guemira F et al. Cytokine profile in Behçet’s disease: relationship with disease activity. Scand J Rheumatol 2002; 31: 205–10. 7 Chi W, Zhu X, Yang P et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49: 3058–64. 8 Lin HK, Fu LS. Concurrence of incontinentia pigmenti and Behçet’s disease. J Chin Med Assoc 2010; 73: 275–8. 9 Endoh M, Yokozeki H, Maruyama R et al. Incontinentia pigmenti and Behçet’s disease: a case of impaired neutrophil chemotaxis. Dermatology 1996; 192: 285–7. 10 Menni S, Piccinno R, Biolchini A et al. Incontinentia pigmenti and Behçet’s syndrome: an unusual combination. Acta Derm Venereol 1986; 66: 351–4.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
Clinical Letter Flare-up of incontinentia pigmenti in association with Behçet disease
DOI: 10.1111/ddg.12452
Dear Editors, A 16-year-old girl, who was diagnosed as having incontinentia pigmenti (IP) during infancy, presented with diffuse hyperpigmented patches along the lines of Blaschko over most of her body below the neck. She had no associated ocular or neurological abnormalities, but dental X-ray revealed congenital absence of one lower lateral and two upper lateral incisors. At the age of 7, she suffered from recurrent genital ulcers, oral aphthosis, and facial pustules. Pathergy test was positive. Behçet disease was diagnosed. After systemic corticosteroids were administered, her condition improved and remained stable for years. She experienced occasional flares of oral aphthous ulcers, but no recurrence of genital ulcers developed. Her mother and older sister had been diagnosed with IP, and her mother also had Behçet disease. She recently presented with itching, stinging erythematous patches with vesiculobullous lesions on previous hyperpigmented patches over her left calf. Genital ulcers and oral aphthous ulcers recurred simultaneously. There were no other infectious symptoms and signs over the upper respiratory tract and genitourinary tract. Routine laboratory tests revealed mild leukocytosis and elevated erythrocyte sedimentation
rate (113 mm/hr.). Blood chemistry, urinalysis, and antinuclear antibodies were within normal limits. The erythematous lesions disappeared quickly and turned to hyperkeratotic verrucous papules and vesicles (Figure 1a, b) within one week. Virus cultures for varicella-zoster virus and herpes simplex virus of lesional skin and bacterial cultures of blood and urine were negative. Histological examination showed marked hyperkeratosis, acanthosis, papillomatosis, and focal dyskeratosis of the epidermis (Figure 2a). The dyskeratotic cells were arranged in a whorled configuration (Figure 2b). The skin lesions resolved in ten days. The oral aphthous ulcers and genital ulcers healed two weeks later. Recurrent inflammation of incontinentia pigmenti associated with flare-up of Behçet disease was diagnosed. Incontinentia pigmenti is an X-linked dominant multisystemic syndrome with cutaneous, neurologic, dental, and ophthalmologic manifestations. Classically, there are four stages of cutaneous lesions: vesicular, verrucous, hyperpigmented, and hypopigmented. In recent studies, mutation in the gene NEMO (nuclear factor κB [NF-κB] essential modulator), also known as “the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma”, on the X chromosome at Xq28, has been related to the development of incontinentia pigmenti [1, 2]. NF-κB may protect keratinocytes from tumor necrosis factor-α (TNF-α)-induced apoptosis [1, 2]. Epidermal cells with the mutant NEMO gene cannot activate NF-κB, so they will lose the ability to inhibit TNFα-induced apoptosis, giving rise to cutaneous lesions associated with IP [1, 2]. Most patients with IP remain stable after the initial inflammatory stage. However, some patients experienced episodes of late reactivation of the inflammatory cutaneous
Figure 1 Diffuse hyperpigmented patches along the lines of Blaschko with hyperkeratotic verrucous papules and vesicles over the patient’s left calf (arrow) (a). Close view shows hyperkeratotic verrucous papules and vesicles, corresponding to the verrucous stage of incontinentia pigmenti (b).
154
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
Correspondence Clinical Letter
Figure 2 Histopathology showed marked hyperkeratosis, acanthosis, papillomatosis, and focal dyskeratosis of the epidermis (hematoxylin and eosin; original magnification x 100) (a). The dyskeratotic cells were arranged in a whorled configuration (hematoxylin and eosin; original magnification x 400) (b).
lesions. In 2008, Hsiao et al. conducted a comprehensive literature review [3], which included 16 cases of reactivation of IP. Nine of the cases appeared to be related to a preceding infection or fever, one case was associated with estrogen therapy and one case with laser therapy. The remaining cases had no identifiable triggering factor. Bodak et al. proposed that the mutated cells persist in the epidermis for a long period of time [4]. After exposure to an event, such as an infection, proinflammatory cytokines, including TNF-α, reactivate NEMO mutant cells, which contribute to the development of recurrent inflammation of keratinocytes [4]. This also explains why most of the recurrences were observed in the previously affected areas [3]. Behçet disease is a chronic relapsing inflammatory disease characterized clinically by recurrent oral aphthous and genital ulcers, iridocyclitis/posterior uveitis, skin lesions, and other systemic manifestations. Genetic susceptibility, infectious agents, hormonal factors, and endothelial activation/injury have all been implicated in the etiology of Behçet disease [5]. One hypothesis is that this disease is caused by immunological abnormalities. In recent studies, some pro-inflammatory cytokines have been shown to be elevated in the sera of patients with Behçet disease, including IL-1, -8, -12, -17, -23, interferon-γ and TNF-α [5–7]. Only three cases of IP concurrent with Behçet disease have been reported in the literature [8–10]. However, no cases of recurrent inflammation in both IP and Behçet disease have been reported. To the best of our knowledge, this is the first reported case of reactivation of cutaneous inflammation of IP associated with flare-up of Behçet disease. Little is known about the pathogenesis of the association between recurrent IP and Behçet disease. We postulated that this
e pisode of concomitant flare up of genital and oral aphthous ulcers in Behçet disease may be associated with a marked elevation of proinflammatory cytokine levels, including TNF-α. This level might be have sufficient potency to induce apoptosis of residual NEMO mutant cells of the epidermis, leading to this first episode of recurrent inflammation of IP. Recent research has provided us with a better understanding of this interesting phenomenon, but the exact pathophysiology of this event needs to be further clarified. Conflicts of interest None.
Chao-Kuei Juan1, Jui-Lung Shen1, Chii-Shuenn Yang2, Kwei-Lan Liu1, Yi-Ju Chen1, 3 (1) Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan (2) Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan (3) Department of Dermatology, National Yang-Ming University, Taipei, Taiwan
Correspondence to Yi-Ju Chen, MD, PhD Department of Dermatology National Yang-Ming University Taichung Veterans General Hospital No. 1650, Sec. 4, Taiwan Boulevard Taichung 40705, Taiwan. E-mail: [email protected]
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
155
Correspondence Clinical Letter
References 1
2
3
4
156
Fusco F, Bardaro T, Fimiani G et al. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappa B activation. Hum Mol Genet 2004; 13: 1763–73. Makris C, Godfrey VL, Krahn-Senftieben G et al. Female mice heterozygous for IKK gamma/ NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 2000; 5: 969–79. Hsiao HW, Chang CL, Chen HH et al. Recurrent inflammation of incontinentia pigmenti in a 30-year-old woman. Dermatol Sinica 2008; 26: 242–7. Bodak N, Hadj-Rabia S, Hamel-Teillac D et al. Late recurrence of inflammatory first-stage lesions in incontinentia pigmenti. Arch Dermatol 2003; 139: 201–4.
5
Gül A. Behçet’s disease: an update on the pathogenesis. Clin Exp Rheumatol 2001; 19: S6–S12. 6 Hamzaoui K, Hamzaoui A, Guemira F et al. Cytokine profile in Behçet’s disease: relationship with disease activity. Scand J Rheumatol 2002; 31: 205–10. 7 Chi W, Zhu X, Yang P et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49: 3058–64. 8 Lin HK, Fu LS. Concurrence of incontinentia pigmenti and Behçet’s disease. J Chin Med Assoc 2010; 73: 275–8. 9 Endoh M, Yokozeki H, Maruyama R et al. Incontinentia pigmenti and Behçet’s disease: a case of impaired neutrophil chemotaxis. Dermatology 1996; 192: 285–7. 10 Menni S, Piccinno R, Biolchini A et al. Incontinentia pigmenti and Behçet’s syndrome: an unusual combination. Acta Derm Venereol 1986; 66: 351–4.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
