Case report
Type 2 segmental Hailey–Hailey disease with systematized bilateral arrangement Arti Nanda1, MD, DNBE, Fatima Khawaja1, MD, Humoud Al-Sabah1, MD, and Rudolf Happle2, MD
1 As’ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait, and 2Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany
Correspondence Arti Nanda, MD, DNBE PO Box 6759 Salmiya 22078 Kuwait E-mail: [email protected]
Conflicts of interest: None.
476
Hailey–Hailey disease (HHD) is an autosomal dominant disorder characterized by recurrent vesicles and erosions predominantly of intertriginous areas. Lesions usually appear after puberty and continue throughout life. Histopathologically, acantholysis with epidermal clefting is noted. Widespread partial loss of intercellular bridges between the keratinocytes gives the epidermis an appearance resembling that of a dilapidated brick wall.1 Hailey–Hailey disease is caused by mutations in the calcium-dependent adenosine triphosphatase ATP2C1 gene encoding an adenosine triphosphate-powered Ca2+ pump.2 Rarely, a segmental arrangement of the disorder may occur.3–8 Both type 1 and type 2 segmental presentations of HHD, reflecting mosaicism, have been reported.3–10 Type 1 segmental HHD reflects heterozygosity for a de novo post-zygotic mutation that occurs at an early stage of embryogenesis and leads to a segmental disease. Outside the segmental area, the skin is both clinically and genetically normal. By contrast, type 2 segmental manifestations reflect a post-zygotic mutation that occurs in a heterozygous embryo at an early developmental stage, resulting in loss of heterozygosity and giving rise to a segmental area that is either homozygous or hemizygous for the underlying mutation.9,10 Clinically, patients with HHD will have pronounced segmental lesions superimposed on the ordinary non-segmental pheInternational Journal of Dermatology 2014, 53, 476–478
notype. The concept has been proved at the molecular level.8 In earlier reports of segmental HHD, a unilateral distribution of one or more segmental lesions was observed.3–7 In this report, we describe a patient with type 2 segmental HHD in the form of systematized bilateral lesions that are superimposed on a classical, non-segmental involvement. Case report A 60-year-old Kuwaiti man presented in November 2006 with a history of recurrent papulovesicular, pustular eruptions and erosions on the trunk, neck, and extremities of >40 years in duration. The lesions had first emerged in the axillary regions but soon progressed to affect other areas and demonstrated a band-shaped distribution on the trunk. Throughout the history, the lesions had continued to recur and had worsened on exposure to hot and humid conditions and to friction. The subject’s son and a maternal uncle (deceased) were reported to have the same disorder in a non-segmental form, predominantly affecting the flexures, with a relapsing course. On examination, the subject was found to have multiple erosions and crusted lesions intermingled with scattered papulovesicular lesions in a band-shaped distribution along Blaschko’s lines on the trunk (Fig. 1a) and extremities. Non-segmenª 2013 The International Society of Dermatology
Nanda et al.
Hailey–Hailey disease with systematized bilateral arrangement
(a)
Case report
(b)
Figure 1 (a and b) Linear lesions of Hailey–Hailey disease (HHD) arranged along Blaschko’s lines on the trunk.
tal lesions were noted in the large body folds, including on the axillae, neck (Figs. 1a and 2), and groin. Skin biopsies obtained from lesions on the trunk and neck showed similar histopathologic changes. The epidermis showed widespread acantholysis affecting more than half of the spinous layer in an incomplete fashion, resulting in partially tethered keratinocytes, and a visual impression reminiscent of a dilapidated brick wall. The dermis showed the presence of perivascular and interstitial lymphocytic infiltrates with few intermingled eosinophils (Fig. 3a,b). Both direct and indirect immunofluorescence as well as desmoglein 1 and 3 enzyme-linked immunosorbent assay (ELISA) were negative. Various other investigations, including complete blood counts, serum biochemistry, urinalysis, chest x-ray, and blood glucose-6 phosphate dehydrogenase
Figure 2 Non-segmental lesions of Hailey–Hailey disease on
the neck ª 2013 The International Society of Dermatology
(G-6PD), produced normal results. A diagnosis of type 2 segmental HHD was made, and the patient was started on dapsone (2 mg/kg/d). He showed a dramatic response in which most of the skin lesions healed. Since then, the patient has been maintained on dapsone (1–2 mg/kg/d) along with topical antibiotics and tacrolimus 0.1% ointment. His response has been satisfactory. Discussion A case of early-onset, pronounced, linear HHD was reported in 1985 as ‘‘relapsing linear acantholytic dermatosis’’.3 It was later reclassified as type 2 segmental HHD,5 and this diagnosis was subsequently confirmed at the molecular level.8 Duschet et al.4 described another case of ‘‘relapsing linear acantholytic dermatosis’’ that may likewise represent an example of type 2 segmental HHD. Type 1 segmental HHD has also rarely been reported.6 Our patient represents a typical example of type 2 segmental manifestation with linear lesions superimposed on nonsegmental HHD. Although molecular testing was not performed in this case, the diagnosis was corroborated by classic clinical and histopathologic findings and was further supported by a positive family history of HHD. In the differential diagnosis, verrucous epidermal nevus was considered clinically, and Darier’s disease was considered on histology. Epidermal nevus can be distinguished clinically by the presence of vesicular, pustular lesions and erosions and histologically by the presence of acantholysis. Darier’s disease can be differentiated clinically by the presence of recurrent vesiculopustular eruption, a positive family history, and response to dapsone treatment, and histologically by the absence of prominent dyskeratosis. International Journal of Dermatology 2014, 53, 476–478
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Case report
Hailey–Hailey disease with systematized bilateral arrangement
(a)
Nanda et al.
(b)
Figure 3 (a) Histopathology shows widespread intraepidermal acantholysis affecting more than half of the spinous layer in an
incomplete fashion, resulting in an appearance reminiscent of a dilapidated brick wall. (Hematoxylin and eosin stain; original magnification ·10.) (b) Suprabasal lacunae with widespread acantholysis. In the dermis a perivascular and interstitial lymphocytic infiltrate with a few intermingled eosinophils is present. (H&E stain; ·40)
Earlier reported cases of both type 1 and 2 segmental HHD showed a unilateral distribution. As a general rule, in patients with type 2 segmental HHD, the segmental lesions appear in infancy or early childhood, prior to the onset of classical HHD, and tend to be more pronounced. In our patient, both the segmental and classical lesions of HHD were observed to appear at the same time. This patient represents a rare case of type 2 segmental HHD demonstrating, unusually, a systematized bilateral distribution of superimposed linear lesions. Acknowledgment We acknowledge with thanks Professor Jag Bhawan, Head of the Section of Dermatopathology, Boston University School of Medicine, Boston, MA, USA, for reviewing the histopathology of this case. References 1 Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992; 126: 275–282. 2 Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nat Genet 2000; 24: 61–65. 3 Vakilzadeh F, Kolde G. Relapsing linear acantholytic dermatosis. Br J Dermatol 1985; 112: 349–355.
International Journal of Dermatology 2014, 53, 476–478
4 Duschet P, Happle R, Schwarz T, Gschnait F. Relapsing linear acantholytic dermatosis. J Am Acad Dermatol 1995; 33: 920–922. 5 König A, Hörster S, Vakilzadeh F, Happle R. Type 2 segmental manifestation of Hailey–Hailey disease: poor therapeutic response to dermabrasion is due to severe involvement of adnexal structures. Eur J Dermatol 2000; 10: 265–268. 6 Hwang LY, Lee JB, Richard G, et al. Type 1 segmental manifestation of Hailey–Hailey disease. J Am Acad Dermatol 2003; 49: 712–714. 7 Arora S, Arora G, Ranjan P. Relapsing linear acantholytic dermatosis in a four-year-old boy. Indian J Dermatol Venereol Leprol 2005; 71: 351–353. 8 Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey–Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004; 114: 1467–1474. 9 Happle R. Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. Am J Med Genet 1996; 66: 241–242. 10 Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol 1997; 133: 1505–1509.
ª 2013 The International Society of Dermatology
Type 2 segmental Hailey–Hailey disease with systematized bilateral arrangement Arti Nanda1, MD, DNBE, Fatima Khawaja1, MD, Humoud Al-Sabah1, MD, and Rudolf Happle2, MD
1 As’ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait, and 2Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany
Correspondence Arti Nanda, MD, DNBE PO Box 6759 Salmiya 22078 Kuwait E-mail: [email protected]
Conflicts of interest: None.
476
Hailey–Hailey disease (HHD) is an autosomal dominant disorder characterized by recurrent vesicles and erosions predominantly of intertriginous areas. Lesions usually appear after puberty and continue throughout life. Histopathologically, acantholysis with epidermal clefting is noted. Widespread partial loss of intercellular bridges between the keratinocytes gives the epidermis an appearance resembling that of a dilapidated brick wall.1 Hailey–Hailey disease is caused by mutations in the calcium-dependent adenosine triphosphatase ATP2C1 gene encoding an adenosine triphosphate-powered Ca2+ pump.2 Rarely, a segmental arrangement of the disorder may occur.3–8 Both type 1 and type 2 segmental presentations of HHD, reflecting mosaicism, have been reported.3–10 Type 1 segmental HHD reflects heterozygosity for a de novo post-zygotic mutation that occurs at an early stage of embryogenesis and leads to a segmental disease. Outside the segmental area, the skin is both clinically and genetically normal. By contrast, type 2 segmental manifestations reflect a post-zygotic mutation that occurs in a heterozygous embryo at an early developmental stage, resulting in loss of heterozygosity and giving rise to a segmental area that is either homozygous or hemizygous for the underlying mutation.9,10 Clinically, patients with HHD will have pronounced segmental lesions superimposed on the ordinary non-segmental pheInternational Journal of Dermatology 2014, 53, 476–478
notype. The concept has been proved at the molecular level.8 In earlier reports of segmental HHD, a unilateral distribution of one or more segmental lesions was observed.3–7 In this report, we describe a patient with type 2 segmental HHD in the form of systematized bilateral lesions that are superimposed on a classical, non-segmental involvement. Case report A 60-year-old Kuwaiti man presented in November 2006 with a history of recurrent papulovesicular, pustular eruptions and erosions on the trunk, neck, and extremities of >40 years in duration. The lesions had first emerged in the axillary regions but soon progressed to affect other areas and demonstrated a band-shaped distribution on the trunk. Throughout the history, the lesions had continued to recur and had worsened on exposure to hot and humid conditions and to friction. The subject’s son and a maternal uncle (deceased) were reported to have the same disorder in a non-segmental form, predominantly affecting the flexures, with a relapsing course. On examination, the subject was found to have multiple erosions and crusted lesions intermingled with scattered papulovesicular lesions in a band-shaped distribution along Blaschko’s lines on the trunk (Fig. 1a) and extremities. Non-segmenª 2013 The International Society of Dermatology
Nanda et al.
Hailey–Hailey disease with systematized bilateral arrangement
(a)
Case report
(b)
Figure 1 (a and b) Linear lesions of Hailey–Hailey disease (HHD) arranged along Blaschko’s lines on the trunk.
tal lesions were noted in the large body folds, including on the axillae, neck (Figs. 1a and 2), and groin. Skin biopsies obtained from lesions on the trunk and neck showed similar histopathologic changes. The epidermis showed widespread acantholysis affecting more than half of the spinous layer in an incomplete fashion, resulting in partially tethered keratinocytes, and a visual impression reminiscent of a dilapidated brick wall. The dermis showed the presence of perivascular and interstitial lymphocytic infiltrates with few intermingled eosinophils (Fig. 3a,b). Both direct and indirect immunofluorescence as well as desmoglein 1 and 3 enzyme-linked immunosorbent assay (ELISA) were negative. Various other investigations, including complete blood counts, serum biochemistry, urinalysis, chest x-ray, and blood glucose-6 phosphate dehydrogenase
Figure 2 Non-segmental lesions of Hailey–Hailey disease on
the neck ª 2013 The International Society of Dermatology
(G-6PD), produced normal results. A diagnosis of type 2 segmental HHD was made, and the patient was started on dapsone (2 mg/kg/d). He showed a dramatic response in which most of the skin lesions healed. Since then, the patient has been maintained on dapsone (1–2 mg/kg/d) along with topical antibiotics and tacrolimus 0.1% ointment. His response has been satisfactory. Discussion A case of early-onset, pronounced, linear HHD was reported in 1985 as ‘‘relapsing linear acantholytic dermatosis’’.3 It was later reclassified as type 2 segmental HHD,5 and this diagnosis was subsequently confirmed at the molecular level.8 Duschet et al.4 described another case of ‘‘relapsing linear acantholytic dermatosis’’ that may likewise represent an example of type 2 segmental HHD. Type 1 segmental HHD has also rarely been reported.6 Our patient represents a typical example of type 2 segmental manifestation with linear lesions superimposed on nonsegmental HHD. Although molecular testing was not performed in this case, the diagnosis was corroborated by classic clinical and histopathologic findings and was further supported by a positive family history of HHD. In the differential diagnosis, verrucous epidermal nevus was considered clinically, and Darier’s disease was considered on histology. Epidermal nevus can be distinguished clinically by the presence of vesicular, pustular lesions and erosions and histologically by the presence of acantholysis. Darier’s disease can be differentiated clinically by the presence of recurrent vesiculopustular eruption, a positive family history, and response to dapsone treatment, and histologically by the absence of prominent dyskeratosis. International Journal of Dermatology 2014, 53, 476–478
477
478
Case report
Hailey–Hailey disease with systematized bilateral arrangement
(a)
Nanda et al.
(b)
Figure 3 (a) Histopathology shows widespread intraepidermal acantholysis affecting more than half of the spinous layer in an
incomplete fashion, resulting in an appearance reminiscent of a dilapidated brick wall. (Hematoxylin and eosin stain; original magnification ·10.) (b) Suprabasal lacunae with widespread acantholysis. In the dermis a perivascular and interstitial lymphocytic infiltrate with a few intermingled eosinophils is present. (H&E stain; ·40)
Earlier reported cases of both type 1 and 2 segmental HHD showed a unilateral distribution. As a general rule, in patients with type 2 segmental HHD, the segmental lesions appear in infancy or early childhood, prior to the onset of classical HHD, and tend to be more pronounced. In our patient, both the segmental and classical lesions of HHD were observed to appear at the same time. This patient represents a rare case of type 2 segmental HHD demonstrating, unusually, a systematized bilateral distribution of superimposed linear lesions. Acknowledgment We acknowledge with thanks Professor Jag Bhawan, Head of the Section of Dermatopathology, Boston University School of Medicine, Boston, MA, USA, for reviewing the histopathology of this case. References 1 Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992; 126: 275–282. 2 Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nat Genet 2000; 24: 61–65. 3 Vakilzadeh F, Kolde G. Relapsing linear acantholytic dermatosis. Br J Dermatol 1985; 112: 349–355.
International Journal of Dermatology 2014, 53, 476–478
4 Duschet P, Happle R, Schwarz T, Gschnait F. Relapsing linear acantholytic dermatosis. J Am Acad Dermatol 1995; 33: 920–922. 5 König A, Hörster S, Vakilzadeh F, Happle R. Type 2 segmental manifestation of Hailey–Hailey disease: poor therapeutic response to dermabrasion is due to severe involvement of adnexal structures. Eur J Dermatol 2000; 10: 265–268. 6 Hwang LY, Lee JB, Richard G, et al. Type 1 segmental manifestation of Hailey–Hailey disease. J Am Acad Dermatol 2003; 49: 712–714. 7 Arora S, Arora G, Ranjan P. Relapsing linear acantholytic dermatosis in a four-year-old boy. Indian J Dermatol Venereol Leprol 2005; 71: 351–353. 8 Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey–Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004; 114: 1467–1474. 9 Happle R. Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. Am J Med Genet 1996; 66: 241–242. 10 Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol 1997; 133: 1505–1509.
ª 2013 The International Society of Dermatology
