0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Sibling Cases of Hailey-Hailey Disease Showing Atypical Clinical Features and Unique Disease Course FREE

Shigeruko Iijima, MD1; Takahiro Hamada, MD2; Mirei Kanzaki, MD1; Chika Ohata, MD2; Takashi Hashimoto, MD2
[+] Author Affiliations
1Department of Dermatology, Mito Saiseikai General Hospital, Mito, Ibaraki, Japan
2Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Kurume, Fukuoka, Japan
JAMA Dermatol. 2014;150(1):97-99. doi:10.1001/jamadermatol.2013.5666.
Text Size: A A A
Published online

Hailey-Hailey disease (HHD), a well-characterized autosomal dominant hereditary disease, is caused by mutation in ATP2C1 gene and clinically shows characteristic erosive lesions predominantly on the intertriginous areas.13 We herein report sibling cases of HHD with novel mutations in the ATP2C1 gene that showed unique and atypical clinical phenotypes mimicking seborrheic dermatitis, pemphigus vulgaris, or pemphigus foliaceus as well as considerable alterations during the disease course.

REPORT OF CASES

Case 1

A 61-year-old Japanese man with intractable pulmonary arterial hypertension, pulmonary fibrosis, and emphysema was receiving oxygen supply from a nasal tube at the time of presentation. Physical examination revealed seborrheic dermatitis–like diffuse scaly erythemas on the face and anterior neck, where the nasal tube of the oxygen supply contacted the skin (Figure 1A). In addition, extensive erosive erythemas with severe pain were seen on the abdomen, and a few pemphigus vulgaris—like flaccid bullae were also observed (Figure 1B). No skin lesions were seen in any intertriginous areas, including axillae and groin. No mucosal membranes were involved. Detailed medical history indicated that, beginning at age 19 years, the patient had occasional mild eczematous lesions on the axillae, groin, popliteal fossa, and head.

Place holder to copy figure label and caption
Figure 1.
Clinical and Histopathologic Features of Case 1 and Case 2 at the First Visit

A and B, Skin lesions on the neck (A) and abdomen (B) in case 1. Clinical features on the neck in case 2 (C). D and E, Histopathologic features (hematoxylin-eosin) from the abdomen in case 1 (D, original magnification ×100) and the neck in case 2 (E, original magnification ×200)

Graphic Jump Location
Case 2

A 57-year-old younger sister of patient 1 reported that, beginning at age 20 years, she had developed dermatitis-like skin lesions on the genital region during menstrual periods. Subsequently, itchy erosive lesions appeared on the axillae and groin, which worsened in the summer every year. The skin lesions on the axillae and groin gradually decreased, while skin lesions on the face, neck, and chest continued to develop.

Physical examination revealed erythemas with small erosions scattered on the forehead, neck, chest, and upper back (Figure 1C) but not on the intertriginous areas, except for minimum lesions on the left axilla. There were no apparent vesicles or bullae.

COMMENT

Histopathologic analysis of the seborrheic dermatitis–like lesion and pemphigus vulgaris–like lesion in case 1 and pemphigus foliaceus–like lesion in case 2 revealed acantholysis without any dyskeratotic keratinocytes in the lower epidermis (Figure 1D and E). Indirect immunofluorescence studies showed IgG antibodies to epithelia of monkey esophagus and rat bladder in case 1 (Figure 2A and B), but no conclusive pattern was seen in case 2. Genetic study revealed a novel splice-site mutation in the ATP2C1 gene in both cases (Figure 2C).

Place holder to copy figure label and caption
Figure 2.
The Results of Immunologic and Genetic Studies for Case 1

A and B, The results of IgG indirect immunofluorescence studies of monkey esophagus (A) and rat bladder (B) (original magnification ×200 for both). C, The results of ATP2C1 gene analysis of genomic DNA for case 1 (top) and healthy control individual (bottom), showing a heterozygous G>C transition at first residue in intron 11 only in the patient (down-pointing arrow).

Graphic Jump Location

The 2 cases were diagnosed as HHD by identification of a novel mutation in the ATP2C1 gene. However, while both patients showed more typical HHD features when they were younger, as they aged into their 60s, they manifested atypical clinical features and unique disease courses. Intriguingly, the clinical features in the 2 cases were significantly different from each other, in spite of the presence of the same genomic mutation. Taking the changes in clinical features during the disease courses of the 2 cases together, we speculate that some environmental conditions, in addition to the genetic defect, may affect the development of skin lesions of HHD.

A study of 58 patients with HHD in the United Kingdom2 indicated that predilection sites were the flexure areas, including the groin, axilla, perineum, inframammary region, umbilicus, and retroauricular region, in descending order, as well as neck/nape, shoulders, chest, arms, and back.2 The abdomen was not involved in any cases. Only a few cases showed lesions on the popliteal fossae, head, and face, which were frequently associated with eczematous changes but rarely showed bullae or pustules.

Two clinically unique and atypical HHD cases have been reported,4,5 although genetic study was not performed in either case. One case showed seborrheic dermatitis–like lesions on the scalp as well as other typical HHD lesions,4 while the other case showed generalized vesiculobullous lesions with occasional pustules.5 To our knowledge, our patients represent the first sibling cases with seborrheic dermatitis–like, pemphigus vulgaris–like, or pemphigus foliaceus–like atypical clinical and histopathologic features of HHD diagnosed by genetic analysis.

ARTICLE INFORMATION

Corresponding Author: Takashi Hashimoto, MD, Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan (hashimot@med.kurume-u.ac.jp).

Published Online: December 18, 2013. doi:10.1001/jamadermatol.2013.5666.

Conflicts of Interest Disclosures: None reported.

Funding/Support: This study was supported by Grants-in-Aid for Scientific Research Nos. 20390308, 20591331, 21659271, 23591634, 23791298, 23791299, 23791300, 23791301, 24659534, 24591672, 24591640, 24791185, and 22590543 and by Supported Program for the Strategic Research Foundation at Private Universities 2011-2015 from the Ministry of Education, Culture, Sports, Science and Technology; and by Research on Measures for Intractable Diseases Project matching fund subsidies “H23-028 (K. Iwatsuki)” and “H24-038 (T. Hamada)” from the Ministry of Health, Labor and Welfare. The study was also supported by grants from the Kaibara Morikazu Medical Science Promotion Foundation, Ishibashi Foundation, Kanae Foundation for the Promotion of Medical Science, Takeda Science Foundation, Chuo Mitsui Trust and Banking Company, Limited, and Nakatomi Foundation.

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

REFERENCES

Hamada  T, Tsuruta  D, Fukuda  S,  et al.  How do keratinizing disorders and blistering disorders overlap? Exp Dermatol. 2013;22(2):83-87.
PubMed   |  Link to Article
Burge  SM.  Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126(3):275-282.
PubMed   |  Link to Article
Hu  Z, Bonifas  JM, Beech  J,  et al.  Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1):61-65.
PubMed   |  Link to Article
Marren  P, Burge  S.  Seborrhoeic dermatitis of the scalp: a manifestation of Hailey-Hailey disease in a predisposed individual? Br J Dermatol. 1992;126(3):294-296.
PubMed   |  Link to Article
Hunt  MJ, Salisbury  EL, Painter  DM, Lee  S.  Vesiculobullous Hailey-Hailey disease: successful treatment with oral retinoids. Australas J Dermatol. 1996;37(4):196-198.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Clinical and Histopathologic Features of Case 1 and Case 2 at the First Visit

A and B, Skin lesions on the neck (A) and abdomen (B) in case 1. Clinical features on the neck in case 2 (C). D and E, Histopathologic features (hematoxylin-eosin) from the abdomen in case 1 (D, original magnification ×100) and the neck in case 2 (E, original magnification ×200)

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
The Results of Immunologic and Genetic Studies for Case 1

A and B, The results of IgG indirect immunofluorescence studies of monkey esophagus (A) and rat bladder (B) (original magnification ×200 for both). C, The results of ATP2C1 gene analysis of genomic DNA for case 1 (top) and healthy control individual (bottom), showing a heterozygous G>C transition at first residue in intron 11 only in the patient (down-pointing arrow).

Graphic Jump Location

Tables

References

Hamada  T, Tsuruta  D, Fukuda  S,  et al.  How do keratinizing disorders and blistering disorders overlap? Exp Dermatol. 2013;22(2):83-87.
PubMed   |  Link to Article
Burge  SM.  Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126(3):275-282.
PubMed   |  Link to Article
Hu  Z, Bonifas  JM, Beech  J,  et al.  Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1):61-65.
PubMed   |  Link to Article
Marren  P, Burge  S.  Seborrhoeic dermatitis of the scalp: a manifestation of Hailey-Hailey disease in a predisposed individual? Br J Dermatol. 1992;126(3):294-296.
PubMed   |  Link to Article
Hunt  MJ, Salisbury  EL, Painter  DM, Lee  S.  Vesiculobullous Hailey-Hailey disease: successful treatment with oral retinoids. Australas J Dermatol. 1996;37(4):196-198.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

561 Views
0 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
×