None Orthokeratosis Hyperkeraotis Palms and soles
8 in 3 generations
None Orthokeratosis Hyperkeratosis Palms and soles
None
Blisters were observed on the soles at birth None Orthokeratosis Hyperkeratosis Sole
Electron microscopy: decreased melanin and melanosome within keratinocytes Other affected two siblings and a nephew Hyperkeratosis Palms and soles
Palms and soles
6 in 3 generations Hyperkeratosis Palms and soles
Site
Histopathology
3 months Decreased density of melanocytes Whole body F Present case 5
3 months
M Schieder et al.4 4
26
At birth Not done
3 months 2 M Megan et al.3 3
At birth
6 months 9 F
17
Both extremities
3 months Patchy hypomelanosis with normal density of melanocytes Both extremities
6 months
At birth
Patchy reduction in the melanin pigment in keratinocytes At birth 5 M Vignale et al.2 2
Both extremities
Both extremities
3-year old Slight decrease in melanin pigment in the basal cell layer Most of the body sparing the acral portions 18 M Cole1
Site Onset age
1
6 months
Onset age
Clinical manifestation Histopathology
Sex
Age
Cole Disease does not have characteristic histologic findings of diagnostic value, and little is known about its pathogenesis. Vignale et al.2 suggested that the disease may be a keratinocyte disorder causing disruption of melanosome transfer or dysregulation of epidermopoiesis. However, they reported decreased immunoreactivity of melan A in the hypopigmented patch; Cole showed decreased melanin in the basal cell layer of the hypopigmented macules.1,2 The present case also revealed decreased numbers of melanocytes, suggesting that the hypopigmented macules may result from a genetic abnormality related to melanoblast differentiation, migration and survival. When a patient presents with congenital hypopigmented macules showing a variegated pattern, several pigmentary abnormalities should be ruled out. The history, pattern, distribution and histological findings can help rule out other acquired or congenital causes of hypopigmentation. In addition, punctuate keratoderma is required to differentiate Cole Disease. Further investigations, including genetic studies, are needed to reveal the mechanisms of the disease’s cutaneous manifestations. J.M. Kim,1 H.H. Cho,1,2 H.C. Ko1,2,* 1
Authors
Clinical manifestation
2493
No.
Table 1 Reported cases of Cole disease
Hypopigmented patches
Keratotic papules
Affected family members
None
Other study
Letters to the Editor
JEADV 2015, 29, 2487–2499
Department of Dermatology, School of Medicine, Pusan National University, Busan, 2Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea *Correspondence: H.C. Ko. E-mail: [email protected]
References 1 Cole MA. Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermaol 1976; 112: 998–1000. 2 Vignale R, Yusin A, Panuncia A, Abulafia J, Reyno Z, Vaglio A. Cole disease: hypopigmentation with punctate keratosis of the palms and soles. Pediatr Dermatol 2002; 19: 302–306. 3 Moore MM, Orlow SJ, Kamino H, Wang N, Schaffer JV. Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma. Arch Dermatol 2009; 145: 495–497. 4 Schmieder A, Hausser I, Schneider SW, Goerdt SG, Peitsch WK. Palmopantar hyperkeratoses and hypopigmentation: a quiz. Acta Derm Venereol 2011; 91: 737–738. DOI: 10.1111/jdv.12599
The utility of ancillary tests in monitoring cutaneous melanoma patients to detect visceral metastasis Editor The utility of ancillary tests in monitoring cutaneous melanoma patients to detect visceral recurrences is considered
© 2014 European Academy of Dermatology and Venereology
2494
Figure 1 Specific survival from melanoma diagnosis for patients with visceral recurrence detected in asymptomatic patients by ancillary tests comparing with patients with visceral recurrence detected by tests ordered because of signs or symptoms (log-rank test: P = 0.348).
limited, and there are no universally accepted follow-up guidelines.1–6 However, in many hospitals patients are followed with expensive imaging tests.7 Our objective was to determine the effectiveness of imaging tests in detecting recurrences of melanoma. Patients with cutaneous melanoma diagnosed from 1995 to 2011 with a minimum of 2-year follow-up were included in the study. Invasive melanomas with less than 1 mm Breslow index were monitored every 4 months during the first 2 years and every 6 months for 5 years. LDH analyses and chest X-rays were performed on alternating visits every 6 months for 5 years. Melanomas more than 1 mm in Breslow index were monitored every 4 months the first 2 years and every 6 months for 5 years and then annually until 10 years. Blood tests with LDH were performed at each visit, and annual chest X-rays were done for the first 5 years. Abdominal ultrasound was performed every 6 months in stage IIb, IIc, or III patients for 5 years. Other imaging tests were performed only if the patient had signs or symptoms of melanoma recurrence. After 5 or 10 years all melanoma patients were referred to their local dermatologists for annual checks indefinitely. Ninety of 1090 patients developed metastasis to visceral organs (8.26%) (50 males and 40 females, mean age 58.20 years, SD 17.2). In 79/90 patients (87.8%), the presence of visceral recurrence was suggested by anamnesis or by physical examina-
JEADV 2015, 29, 2487–2499
Letters to the Editor
Figure 2 Specific survival from visceral recurrence for patients with visceral recurrence detected in asymptomatic patients by ancillary tests comparing with patients with visceral recurrence detected by tests ordered because of signs or symptoms (log-rank test: P = 0.182).
tion and subsequently confirmed by non-programmed imaging tests. The programmed imaging tests detected 11/90 visceral recurrences in asymptomatic patients (12.2%). Survival analyses with the Kaplan–Meier method did not detect significant differences in specific survival between the two groups of patients from diagnosis of melanoma (log-rank test, P = 0.348) neither from visceral recurrence detection (log-rank test, P = 0.182) (Figs 1,2). Clinicians have the feeling that the early detection of melanoma recurrences may improve survival and tend to order surveillance imaging studies for patients with stage I and II disease and the patients are usually followed with higher frequency that suggested by the current melanoma guidelines.7,8 However, this impression is not based on scientific evidences. In several studies, regular clinical examination offered higher diagnostic yield than imaging tests in melanoma surveillance.3,6 Moreover, survival analyses comparing patients with recurrences detected by clinical examination to patients with asymptomatic recurrences detected with imaging failed to detect significant differences.1,2,9 In the last 25 years, we have applied a relatively inexpensive follow-up procedure. As in previous studies, the detection of visceral recurrences in asymptomatic patients with image tests did not improve survival. Given the increasing incidence of melanoma, the appropriate use of surveillance imaging after melanoma treatment may have important financial implications that may not be justified
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
only for reassurance of patients. In addition, radiation exposure from radiographic images is associated with an increase in melanoma, soft tissue, urogenital, brain and haematologic malignancies.10 Our results confirm previous studies that suggest that imaging tests are of limited value in the follow-up of melanoma patients. Inexpensive and non-invasive scans may be positive for reassurance of patients, but expensive imaging tests with possible long-term side-effects are not necessary. J.R. Ferreres,1 J. Marcoval,1,* K. Fodge,1 M. Ochoa de ~als,3 A. Fabra3 Olza,2 A. Vin 1 Department of Dermatology, Bellvitge Hospital, IDIBELL, Barcelona University, 2Department of Medical Oncology, Hospital Duran i Reynals, Oncologia, 3Molecular Oncology Laboratory, IDIBELL, Institut Catala Barcelona University, Barcelona, Spain *Correspondence: J. Marcoval. E-mail: [email protected]
References 1 Shumate CR, Urist MM, Maddox WA. Melanoma recurrence surveillance. Patient or physician based? Ann Surg 1995; 221: 566–569. 2 Hofmann U, Szedlak M, Rittgen W et al. Primary staging and follow-up in melanoma patients–monocenter evaluation of methods, costs and patient survival. Br J Cancer 2002; 87: 151–157. 3 Garbe C, Paul A, Kohler-Spath H et al. Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003; 21: 520–529. 4 Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with localised primary cutaneous melanoma. Lancet Oncol 2005; 6: 608–621. 5 Meyers MO, Yeh JJ, Frank J et al. Method of detection of initial recurrence of stage II/III cutaneous melanoma: analysis of the utility of followup staging. Ann Surg Oncol 2009; 16: 941–947. 6 Romano E, Scordo M, Dusza SW et al. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 2010; 28: 3042–3047. 7 Rychetnik L, McCaffery K, Morton R, Irwig L. Psychosocial aspects of post-treatment follow-up for stage I/II melanoma: a systematic review of the literature. Psychooncology 2013; 22: 721–736. 8 Holterhues C, van de Poll-Franse LV, de Vries E, Neumann HA, Nijsten TE. Melanoma patients receive more follow-up care than current guideline recommendations: a study of 546 patients from the general Dutch population. J Eur Acad Dermatol Venereol 2012; 26: 1389–1395. 9 Rueth NM, Xing Y, Chiang YJ et al. Is surveillance imaging effective for detecting surgically treatable recurrences in patients with melanoma? A comparative analysis of stage-specific surveillance strategies Ann Surg 2014; 259: 1215–1222. 10 Mathews JD, Forsythe AV, Brady Z et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 346: f2360. DOI: 10.1111/jdv.12602
JEADV 2015, 29, 2487–2499
2495
The ATP2C1 gene in Hailey– Hailey disease patients: one novel deletion and one novel splicing mutation Editor Hailey–Hailey disease (HHD, MIM 16960), otherwise known as familial benign chronic pemphigus, is a rare autosomal dominant genodermatosis characterized by recurrent pruritic vesicles, painful erosions and scaly erythematous plaques at the sites of friction and flexures.1 The disorder usually occurs in the third or fourth decade, mechanical trauma, heat, perspiration, infection and exposure in ultraviolet B often exacerbate the skin lesions.2 The typical histological features are prominent suprabasal keratinocyte acantholysis and clefts with mild dyskeratosis.3,4 Mutations in the ATP2C1 gene have been identified as the molecular basis of HHD. The gene encodes for the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1), which plays an important role in controlling the Ca2+ concentrations in the cytoplasm and Golgi apparatus of human keratinocytes.4–6 In this report, we performed mutation analysis of ATP2C1 in two typical Chinese families with HHD and identified two novel mutations. Two three-generation Han Chinese pedigree from Chongqing consisted of seven affected and nineteen unaffected individuals, which showed an autosomal dominant inheritance pattern. The proband in the pedigree A, a 43-year-old male, exhibited recurrent blisters, erythematous plaques and painful erosions in his axillae, groin, and crissum at the age of 28 years. The proband in the pedigree B was a 54-year-old female who presented with a 31-year history of pruritic vesicles, shallow ulcerations and erosions involving the axillae, groin and perineum (Fig. 1). Both individuals stated that their skin lesions were exacerbated in summer. All affected members of the pedigree showed clinic manifestations similar to that of the probands. Biopsy results confirmed the diagnosis of HHD in the two probands. Written informed consent was given by each participant, and the study protocol was approved by the Ethical Review Committee of the Hospital. Blood samples were collected from the family and from 200 unrelated healthy controls. Genomic DNA was extracted according to standard techniques. DNA encoding all exons of ATP2C1 was amplified by touchdown polymerase chain reaction (PCR).The PCR products were purified and then sequenced in an ABI 3730 genetic analyzer. Direct sequencing revealed a deletion of a single guanine nucleotide (134delG) in codon 45 in exon 2 of ATP2C1 (Fig. 2) in the proband of family A. A heterozygous G-to-C transversion at the splice acceptor site of intron 19 (c.1891-1G>C) (Fig. 2)
© 2014 European Academy of Dermatology and Venereology
8 in 3 generations
None Orthokeratosis Hyperkeratosis Palms and soles
None
Blisters were observed on the soles at birth None Orthokeratosis Hyperkeratosis Sole
Electron microscopy: decreased melanin and melanosome within keratinocytes Other affected two siblings and a nephew Hyperkeratosis Palms and soles
Palms and soles
6 in 3 generations Hyperkeratosis Palms and soles
Site
Histopathology
3 months Decreased density of melanocytes Whole body F Present case 5
3 months
M Schieder et al.4 4
26
At birth Not done
3 months 2 M Megan et al.3 3
At birth
6 months 9 F
17
Both extremities
3 months Patchy hypomelanosis with normal density of melanocytes Both extremities
6 months
At birth
Patchy reduction in the melanin pigment in keratinocytes At birth 5 M Vignale et al.2 2
Both extremities
Both extremities
3-year old Slight decrease in melanin pigment in the basal cell layer Most of the body sparing the acral portions 18 M Cole1
Site Onset age
1
6 months
Onset age
Clinical manifestation Histopathology
Sex
Age
Cole Disease does not have characteristic histologic findings of diagnostic value, and little is known about its pathogenesis. Vignale et al.2 suggested that the disease may be a keratinocyte disorder causing disruption of melanosome transfer or dysregulation of epidermopoiesis. However, they reported decreased immunoreactivity of melan A in the hypopigmented patch; Cole showed decreased melanin in the basal cell layer of the hypopigmented macules.1,2 The present case also revealed decreased numbers of melanocytes, suggesting that the hypopigmented macules may result from a genetic abnormality related to melanoblast differentiation, migration and survival. When a patient presents with congenital hypopigmented macules showing a variegated pattern, several pigmentary abnormalities should be ruled out. The history, pattern, distribution and histological findings can help rule out other acquired or congenital causes of hypopigmentation. In addition, punctuate keratoderma is required to differentiate Cole Disease. Further investigations, including genetic studies, are needed to reveal the mechanisms of the disease’s cutaneous manifestations. J.M. Kim,1 H.H. Cho,1,2 H.C. Ko1,2,* 1
Authors
Clinical manifestation
2493
No.
Table 1 Reported cases of Cole disease
Hypopigmented patches
Keratotic papules
Affected family members
None
Other study
Letters to the Editor
JEADV 2015, 29, 2487–2499
Department of Dermatology, School of Medicine, Pusan National University, Busan, 2Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea *Correspondence: H.C. Ko. E-mail: [email protected]
References 1 Cole MA. Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermaol 1976; 112: 998–1000. 2 Vignale R, Yusin A, Panuncia A, Abulafia J, Reyno Z, Vaglio A. Cole disease: hypopigmentation with punctate keratosis of the palms and soles. Pediatr Dermatol 2002; 19: 302–306. 3 Moore MM, Orlow SJ, Kamino H, Wang N, Schaffer JV. Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma. Arch Dermatol 2009; 145: 495–497. 4 Schmieder A, Hausser I, Schneider SW, Goerdt SG, Peitsch WK. Palmopantar hyperkeratoses and hypopigmentation: a quiz. Acta Derm Venereol 2011; 91: 737–738. DOI: 10.1111/jdv.12599
The utility of ancillary tests in monitoring cutaneous melanoma patients to detect visceral metastasis Editor The utility of ancillary tests in monitoring cutaneous melanoma patients to detect visceral recurrences is considered
© 2014 European Academy of Dermatology and Venereology
2494
Figure 1 Specific survival from melanoma diagnosis for patients with visceral recurrence detected in asymptomatic patients by ancillary tests comparing with patients with visceral recurrence detected by tests ordered because of signs or symptoms (log-rank test: P = 0.348).
limited, and there are no universally accepted follow-up guidelines.1–6 However, in many hospitals patients are followed with expensive imaging tests.7 Our objective was to determine the effectiveness of imaging tests in detecting recurrences of melanoma. Patients with cutaneous melanoma diagnosed from 1995 to 2011 with a minimum of 2-year follow-up were included in the study. Invasive melanomas with less than 1 mm Breslow index were monitored every 4 months during the first 2 years and every 6 months for 5 years. LDH analyses and chest X-rays were performed on alternating visits every 6 months for 5 years. Melanomas more than 1 mm in Breslow index were monitored every 4 months the first 2 years and every 6 months for 5 years and then annually until 10 years. Blood tests with LDH were performed at each visit, and annual chest X-rays were done for the first 5 years. Abdominal ultrasound was performed every 6 months in stage IIb, IIc, or III patients for 5 years. Other imaging tests were performed only if the patient had signs or symptoms of melanoma recurrence. After 5 or 10 years all melanoma patients were referred to their local dermatologists for annual checks indefinitely. Ninety of 1090 patients developed metastasis to visceral organs (8.26%) (50 males and 40 females, mean age 58.20 years, SD 17.2). In 79/90 patients (87.8%), the presence of visceral recurrence was suggested by anamnesis or by physical examina-
JEADV 2015, 29, 2487–2499
Letters to the Editor
Figure 2 Specific survival from visceral recurrence for patients with visceral recurrence detected in asymptomatic patients by ancillary tests comparing with patients with visceral recurrence detected by tests ordered because of signs or symptoms (log-rank test: P = 0.182).
tion and subsequently confirmed by non-programmed imaging tests. The programmed imaging tests detected 11/90 visceral recurrences in asymptomatic patients (12.2%). Survival analyses with the Kaplan–Meier method did not detect significant differences in specific survival between the two groups of patients from diagnosis of melanoma (log-rank test, P = 0.348) neither from visceral recurrence detection (log-rank test, P = 0.182) (Figs 1,2). Clinicians have the feeling that the early detection of melanoma recurrences may improve survival and tend to order surveillance imaging studies for patients with stage I and II disease and the patients are usually followed with higher frequency that suggested by the current melanoma guidelines.7,8 However, this impression is not based on scientific evidences. In several studies, regular clinical examination offered higher diagnostic yield than imaging tests in melanoma surveillance.3,6 Moreover, survival analyses comparing patients with recurrences detected by clinical examination to patients with asymptomatic recurrences detected with imaging failed to detect significant differences.1,2,9 In the last 25 years, we have applied a relatively inexpensive follow-up procedure. As in previous studies, the detection of visceral recurrences in asymptomatic patients with image tests did not improve survival. Given the increasing incidence of melanoma, the appropriate use of surveillance imaging after melanoma treatment may have important financial implications that may not be justified
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
only for reassurance of patients. In addition, radiation exposure from radiographic images is associated with an increase in melanoma, soft tissue, urogenital, brain and haematologic malignancies.10 Our results confirm previous studies that suggest that imaging tests are of limited value in the follow-up of melanoma patients. Inexpensive and non-invasive scans may be positive for reassurance of patients, but expensive imaging tests with possible long-term side-effects are not necessary. J.R. Ferreres,1 J. Marcoval,1,* K. Fodge,1 M. Ochoa de ~als,3 A. Fabra3 Olza,2 A. Vin 1 Department of Dermatology, Bellvitge Hospital, IDIBELL, Barcelona University, 2Department of Medical Oncology, Hospital Duran i Reynals, Oncologia, 3Molecular Oncology Laboratory, IDIBELL, Institut Catala Barcelona University, Barcelona, Spain *Correspondence: J. Marcoval. E-mail: [email protected]
References 1 Shumate CR, Urist MM, Maddox WA. Melanoma recurrence surveillance. Patient or physician based? Ann Surg 1995; 221: 566–569. 2 Hofmann U, Szedlak M, Rittgen W et al. Primary staging and follow-up in melanoma patients–monocenter evaluation of methods, costs and patient survival. Br J Cancer 2002; 87: 151–157. 3 Garbe C, Paul A, Kohler-Spath H et al. Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003; 21: 520–529. 4 Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with localised primary cutaneous melanoma. Lancet Oncol 2005; 6: 608–621. 5 Meyers MO, Yeh JJ, Frank J et al. Method of detection of initial recurrence of stage II/III cutaneous melanoma: analysis of the utility of followup staging. Ann Surg Oncol 2009; 16: 941–947. 6 Romano E, Scordo M, Dusza SW et al. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 2010; 28: 3042–3047. 7 Rychetnik L, McCaffery K, Morton R, Irwig L. Psychosocial aspects of post-treatment follow-up for stage I/II melanoma: a systematic review of the literature. Psychooncology 2013; 22: 721–736. 8 Holterhues C, van de Poll-Franse LV, de Vries E, Neumann HA, Nijsten TE. Melanoma patients receive more follow-up care than current guideline recommendations: a study of 546 patients from the general Dutch population. J Eur Acad Dermatol Venereol 2012; 26: 1389–1395. 9 Rueth NM, Xing Y, Chiang YJ et al. Is surveillance imaging effective for detecting surgically treatable recurrences in patients with melanoma? A comparative analysis of stage-specific surveillance strategies Ann Surg 2014; 259: 1215–1222. 10 Mathews JD, Forsythe AV, Brady Z et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 346: f2360. DOI: 10.1111/jdv.12602
JEADV 2015, 29, 2487–2499
2495
The ATP2C1 gene in Hailey– Hailey disease patients: one novel deletion and one novel splicing mutation Editor Hailey–Hailey disease (HHD, MIM 16960), otherwise known as familial benign chronic pemphigus, is a rare autosomal dominant genodermatosis characterized by recurrent pruritic vesicles, painful erosions and scaly erythematous plaques at the sites of friction and flexures.1 The disorder usually occurs in the third or fourth decade, mechanical trauma, heat, perspiration, infection and exposure in ultraviolet B often exacerbate the skin lesions.2 The typical histological features are prominent suprabasal keratinocyte acantholysis and clefts with mild dyskeratosis.3,4 Mutations in the ATP2C1 gene have been identified as the molecular basis of HHD. The gene encodes for the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1), which plays an important role in controlling the Ca2+ concentrations in the cytoplasm and Golgi apparatus of human keratinocytes.4–6 In this report, we performed mutation analysis of ATP2C1 in two typical Chinese families with HHD and identified two novel mutations. Two three-generation Han Chinese pedigree from Chongqing consisted of seven affected and nineteen unaffected individuals, which showed an autosomal dominant inheritance pattern. The proband in the pedigree A, a 43-year-old male, exhibited recurrent blisters, erythematous plaques and painful erosions in his axillae, groin, and crissum at the age of 28 years. The proband in the pedigree B was a 54-year-old female who presented with a 31-year history of pruritic vesicles, shallow ulcerations and erosions involving the axillae, groin and perineum (Fig. 1). Both individuals stated that their skin lesions were exacerbated in summer. All affected members of the pedigree showed clinic manifestations similar to that of the probands. Biopsy results confirmed the diagnosis of HHD in the two probands. Written informed consent was given by each participant, and the study protocol was approved by the Ethical Review Committee of the Hospital. Blood samples were collected from the family and from 200 unrelated healthy controls. Genomic DNA was extracted according to standard techniques. DNA encoding all exons of ATP2C1 was amplified by touchdown polymerase chain reaction (PCR).The PCR products were purified and then sequenced in an ABI 3730 genetic analyzer. Direct sequencing revealed a deletion of a single guanine nucleotide (134delG) in codon 45 in exon 2 of ATP2C1 (Fig. 2) in the proband of family A. A heterozygous G-to-C transversion at the splice acceptor site of intron 19 (c.1891-1G>C) (Fig. 2)
© 2014 European Academy of Dermatology and Venereology
