|Year : 2022 | Volume
| Issue : 4 | Page : 251-252
Protein O-fucosyltransferase-1 mutation in familial Dowling-Degos Disease concomitant with atopic dermatitis
Ro-Wei Wu1, Hui-Ying Weng2, Wei-Ping Huang1, Yung-Feng Lin3, Yen-Ming Liu3, Shih-Feng Tsai3, Chung-Hsing Chang4
1 Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
2 Biomedical Industry PhD Program, National Yang-Ming University; Biomedical Industry PhD Program, National Yang Ming Chiao Tung University, Taipei, Taiwan
3 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
4 Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia Sinica, College of Medicine, Tzu Chi University; Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
|Date of Submission||04-Aug-2022|
|Date of Decision||18-Sep-2022|
|Date of Acceptance||20-Sep-2022|
|Date of Web Publication||20-Oct-2022|
Prof. Chung-Hsing Chang
No. 707, Sec. 3, Chung-Yang Road, Hualien 970
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Wu RW, Weng HY, Huang WP, Lin YF, Liu YM, Tsai SF, Chang CH. Protein O-fucosyltransferase-1 mutation in familial Dowling-Degos Disease concomitant with atopic dermatitis. Dermatol Sin 2022;40:251-2
|How to cite this URL:|
Wu RW, Weng HY, Huang WP, Lin YF, Liu YM, Tsai SF, Chang CH. Protein O-fucosyltransferase-1 mutation in familial Dowling-Degos Disease concomitant with atopic dermatitis. Dermatol Sin [serial online] 2022 [cited 2023 Feb 8];40:251-2. Available from: https://www.dermsinica.org/text.asp?2022/40/4/251/359341
Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticulate hyperpigmentation of the major flexures such as the neck, axillae, cubital fossa, and popliteal fossa. Causative genes of DDD include KRT5, protein O-fucosyltransferase-1 (POFUT1), POGLUT1, and PSENEN. Herein, we report three DDD patients with POFUT1 mutations (c. 879delT; p. Val294fs) in a Taiwanese family, which is a novel mutation variant never been reported yet. Notably, two of the affected family members co-occur with atopic dermatitis (AD).
The proband was a 22-year-old female with AD history since childhood. She had xerosis and erythematous plaques with lichenification on the major flexures, neck, and trunk [Figure 1]a, [Figure 1]b, [Figure 1]c, and a serum immunoglobulin E (IgE) level of 4992 U/mL. Notably, she had reticulate hyperpigmented macules on her neck [Figure 1]a, flexural sites of extremities [Figure 1]b overlapping with AD lesions since her 10 years old and later progressed to the trunk [Figure 1]c. A skin biopsy of the reticulate hyperpigmented lesion was performed. The pathology result revealed downward elongated, filiform rete ridges with basal hyperpigmentation [Figure 1]d. Based on clinical and pathological features, DDD is the most favored diagnosis. Further, her family history was surveyed and her mother and younger brother were thoroughly examined. The family pedigree is shown in [Figure 2]a.
|Figure 1: (a-c) DDD and AD phenotype of the proband: reticulate hyperpigmented macules over the face, neck, anterior chest, cubital fossa, arm, and abdomen; erythematous, lichenified plaques over the neck, cubital fossa, and abdomen. (d) Skin biopsy of reticulate hyperpigmented lesion: downward elongated, filiform rete ridges with basal hyperpigmentation (×100). AD: Atopic dermatitis; DDD: Dowling-Degos disease.|
Click here to view
|Figure 2: (a) Family pedigree and genetic analysis, showing frameshift mutation in POFUT1 (c. 879delT; p.Val294fs). (b) Proband's brother: reticulate hyperpigmented macules and erythematous eczema over the neck. (c) Proband's mother: Hypopigmented macules over the abdomen.|
Click here to view
Her younger brother (age, 17 years) also had AD since childhood and typical DDD presentation on the flexures and the neck [Figure 2]b. Her mother (age, 49 years) had multiple hypopigmented macules on the trunk [Figure 2]c and extremities. The mother did not have AD skin lesions at her visiting, but whether or not her AD history during childhood cannot be confirmed.
After obtaining written informed consent from each family member, we extracted DNA from whole blood samples for whole exome sequencing. We detected a frameshift mutation in POFUT1 (c. 879delT; p. Val294fs) in the proband, her brother, and her mother but not in her father [Figure 2]a. There were no other pathogenic mutations found in KRT5, POGLUT1, and PSENEN. The above finding confirmed the diagnosis of DDD in the three members who carry the same mutation, despite the differences in phenotypes.
POFUT1 encodes the POFUT1. POFUT1 adds O-fucose monosaccharides to the epidermal growth factor-like repeats of numerous cell surfaces or secreted proteins, including Notch receptors. POFUT1 mutation impairs this fucosylation function, thus disrupting Notch signaling. Li et al. demonstrated that zebrafish with knockdown of POFUT1 presented with an abnormal melanin distribution at 72 h postfertilization, replicating the clinical features of DDD.
The concomitance of DDD and hidradenitis suppurativa with a mutation in POFUT1 or PSENEN has been reported. A hypothesis for the concomitance is the involvement of impaired Notch signaling, as the Notch pathway regulates melanocyte homeostasis and differentiation in the hair follicles and interfollicular epithelium. Although DDD concomitant with AD has not been reported, we find interestingly that the DDD lesions and AD lesions in our cases had overlapping distributions over the major flexures. Studies have suggested that the Notch pathway plays an important role in the pathogenesis of AD. The Notch receptor protein was impaired in the skin lesions of AD. In Notch-deficient mice, the expression of thymic stromal lymphopoietin, interleukin (IL)-4, and IL-13 in the epidermis and IgE levels in the serum were increased and subsequently causing AD lesions.
Here, we hypothesize that frameshift mutation in POFUT1 (c. 879delT; p. Val294fs) causing DDD concomitant with AD in our cases may be due to the impaired Notch signaling pathway, leading to abnormal development of the skin and skin appendages with defective barrier function, innate immunity, and abnormal homeostasis of melanocytes within the epidermis. Skin flexures are rich in appendages such as hair follicles, eccrine, apocrine, and sebaceous glands, and therefore may be the main initiation sites of eczema in AD as well as pigmentary changes in DDD.
Several other skin diseases have been reported to co-occur with DDD, including psoriasis, Darier disease, and pemphigus vulgaris (PV). POFUT1 and CARD14 mutations were identified in a DDD concomitant with psoriasis patient. Darier disease and PV co-presenting with DDD are reported in the single case report, respectively., However, both cases are diagnosed based on clinical and pathological findings instead of genetic analysis. To sum up, further studies and more case reports are warranted to understand the intrinsic mechanisms of the concomitancy of DDD and all other skin diseases.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
Prof. Chung-Hsing Chang, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
| References|| |
Stephan C, Kurban M, Abbas O. Dowling-Degos disease: A review. Int J Dermatol 2021;60:944-50.
McMillan BJ, Zimmerman B, Egan ED, Lofgren M, Xu X, Hesser A, et al
. Structure of human POFUT1, its requirement in ligand-independent oncogenic notch signaling, and functional effects of Dowling-Degos mutations. Glycobiology 2017;27:777-86.
Li M, Cheng R, Liang J, Yan H, Zhang H, Yang L, et al
. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet 2013;92:895-903.
Pavlovsky M, Sarig O, Eskin-Schwartz M, Malchin N, Bochner R, Mohamad J, et al
. A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN. Br J Dermatol 2018;178:502-8.
Dumortier A, Durham AD, Di Piazza M, Vauclair S, Koch U, Ferrand G, et al
. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin. PLoS One 2010;5:e9258.
Liu Z, Zhu Z, Luo J, Yang B. A case report of Dowling-Degos disease caused by POFUT1 exon deletion with possible coexistent CARD14 mutation-related psoriasis. J Eur Acad Dermatol Venereol 2022;36:e643-5.
Balighi K, Dastgheib M, Ghannadan A, Qadikolaee PY, Hamzelou S. Co-occurrence of Dowling-Degos disease and pemphigus vulgaris. Int J Dermatol 2021;60:e311-3.
Strausburg M, Linos K, Staser K, Mousdicas N. Dowling-Degos disease co-presenting with darier disease. Clin Exp Dermatol 2016;41:410-2.
[Figure 1], [Figure 2]