   |
|
SHORT COMMUNICATION |
|
| Year : 2014 | Volume
: 59
| Issue : 5 | Page : 476-480 |
|
| The first report of krt5 mutation underlying acantholytic dowling-degos disease with mottled hypopigmentation in an Indian family |
|
|
Shyam Verma1, Sandra M Pasternack2, Arno Rutten3, Thomas Ruzicka4, Regina C Betz2, Sandra Hanneken5
1 Nirvana Skin Clinic, Vadodara, Gujarat, India
2 Institute of Human Genetics, University of Bonn, Bonn, Germany
3 Laboratory of Dermatohistopathology, Friedrichshafen, Germany
4 Department of Dermatology, Ludwig-Maximilian's University of Munich, Munich, Germany
5 Department of Dermatology, University of Düsseldorf, Medical Faculty, D-40225 Düsseldorf, Germany
| Date of Web Publication | 1-Sep-2014 |
Correspondence Address:
Sandra M Pasternack
Department of Dermatology University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf
Germany
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0019-5154.139884
|
|
 Abstract | | |
Galli Galli disease (GGD) is the name given to a rare form of acantholytic Dowling-Degos disease. (DDD), the latter itself being a rare condition. We believe we are describing for the first time in Indian dermatologic literature a case of GGD in a family where 25 persons have DDD and have been able to document a KRT5 mutation in four members of the family. Whereas reticulate pigmentation is a hallmark of DDD there are rare reports of mottled pigmentation with multiple asymptomatic hypopigmented macules scattered diffusely along with the pigmentation. All the cases described here show a mottled pigmentation comprising hypo and hyperpigmented asymptomatic macules. After the clinical diagnosis was made by one of the authors (SV) in India, the German authors repeated histological examination and successfully demonstrated a heterozygous nonsense mutation, c.C10T (p.Gln4X), in exon 1 of the KRT5 gene, from various centers in Munich, Bonn, Dusseldorf and Friedrichschafen in Germany.
Keywords: Acantholytic Dowling-Degos disease, Galli Galli disease, hypopigmentation, Indian skin, Keratin 5 mutation
How to cite this article:
Verma S, Pasternack SM, Rutten A, Ruzicka T, Betz RC, Hanneken S. The first report of krt5 mutation underlying acantholytic dowling-degos disease with mottled hypopigmentation in an Indian family. Indian J Dermatol 2014;59:476-80 |
How to cite this URL:
Verma S, Pasternack SM, Rutten A, Ruzicka T, Betz RC, Hanneken S. The first report of krt5 mutation underlying acantholytic dowling-degos disease with mottled hypopigmentation in an Indian family. Indian J Dermatol [serial online] 2014 [cited 2023 Nov 29];59:476-80. Available from: https://www.e-ijd.org/text.asp?2014/59/5/476/139884 |
What was known?
1. Only few reports on a distinctive clinical picture in Dowling-Degos disease with hypopigmented macules in Asian and African American patients exist.
2. In a Chinese family with Dowling-Degos disease with hypopigmented macules, the mutation c.C10T in the KRT5 gene had recently been identified.
| Introduction | |  |
Acantholytic Dowling-Degos disease (DDD) [MIM 179850] (syn. Galli-Galli disease) is a rare genodermatosis which belongs to the spectrum of reticulate pigmentary disorders and is inherited in an autosomal-dominant manner. It classically presents with reticulate pigmentation, usually hyperpigmented macules in combination with hyperkeratotic papules mainly of the flexures; [1] Cases with disseminated monomorphous reddish-brown macules and papules have also been described. [2],[3] Recently, it has been shown that the most common mutation in the keratin 5 (KRT5) gene (c. 418dupA; p.Ile140AsnfsX39) is seen in Galli-Galli disease (GGD) as well as Dowling-Degos disease. Although the clinical picture of both forms is indistinguishable, [4] detection of acantholysis on histopathological evaluation in GGD patients is believed to be the differentiating criterion between GGD and DDD. [5] However, acantholysis can also be found in patients with DDD, supporting the hypothesis that GGD is a variant of DDD. [1]
There have been infrequent reports on a distinctive clinical picture in DDD presenting with hypopigmented macules in Asian and African American patients, either with merely hypopigmentation [6] or in combination with the aforementioned reticular pigmentation and erythematous erosive papules with the typical flexural focus. [7],[8] Guo et al. reported on a Chinese family with DDD exhibiting hypopigmented macules along with the well-known typical clinical and histopathological features of DDD and identified a novel heterozygous nonsense mutation, c.10C > T, in exon 1 of KRT5. [7] Wu and Lin presented three patients from one family with clinical and histological DDD along with hypopigmented macules; the histopathological evaluation in one of their patients in papules from the axillary region had features of Galli-Galli disease, however, they did not detect any mutation in KRT5. [8] However, recently, another gene was identified for DDD in two Chinese families, called POFUT1, encoding protein O-fucosyltransferase 1 (Li et al. Am J Hum Genet 2013). [9]
We herein describe a family from India with clinical and histopathological features of GGD who exhibit hypopigmentation along with the typical reticular hyperpigmentation and erosive skin colored as well as erythematous papules pronounced on the trunk and flexural areas. At least 25 family members are affected. We performed molecular genetic analyses in several affected family members and identified the heterozygous nonsense mutation c.C10T in the KRT5 gene.
| Patients and Methods | | |
Patients
All patients were seen and diagnosed as GGD/DDD by Dr. Shyam Verma in Vadodara, India.
The 57-year-old Indian female patient (patient 1) presented with extensive, confluent reticular hyperpigmentation in combination with erythematous macules and skin colored papules pronounced around the neck, decolleté, sternal and submammary region and-to a lesser extent-in the axillary region. Some areas on the trunk had multiple erosions [Figure 1]. Hyperpigmentation was also seen on the extremities and the face. Moreover, she had multiple hypopigmented macules between 3 and 10 mm size distributed symmetrically on her lower abdomen, legs and axillary region. She gave a history of exacerbation of the lesions and itching when exposed to summer heat of her native town and dramatic relief from this in winters and when she went to visit her daughter in United States. | Figure 1: Eroded hyperpigmented lesions of Galli Galli disease with accompanying hypopigmented macules in the index case
Click here to view |
The patient's 32-year-old son (patient 2) showed identical hyperpigmentation on the back of the hands, the face and the extremities; sparse hyperpigmented papules were found in the axillary region. In addition, sharply demarcated hypopigmented macules were symmetrically disseminated over chest, lower abdomen, back and groins [Figure 2] and [Figure 3]. The patient's 39-year-old daughter (patient 3) and her 19-year-old granddaughter (patient 4) displayed the same clinical findings as patient 2 [Figure 4]. In addition, patient 3 showed some eroded papules on the lower back and lower abdomen with aggravation and itching during heat and summer. Further history revealed that the skin changes had started in all patients as asymptomatic hyperpigmented and hypopigmented macules after about 15 years of age. Subsequently many of the hyperpigmented macular lesions became raised and keratotic after 45 years of age in patient 1, and after 34 years of age in patient 3 with erosions, burning and aggravation of symptoms occurring during hot and humid climate as well as by sweating. | Figure 2: Predominantly hypopigmented macules scattered diffusely on the trunk in son
Click here to view |
 | Figure 3: Hyperpigmented raised lesions in the axilla with hypopigmented
macules on chest and hyperpigmented macules visible on neck of son
Click here to view |
 | Figure 4: Multiple hypo and hyperpigmented macules diffusely scattered on extremities and trunk in daughter
Click here to view |
Dermatopathological findings
Dermatohistopathological evaluation of skin biopsies from a hyperpigmented macule from abdomen from patient 1 and a hyperpigmented and hypopigmented macule from patient 2 revealed classic antler like rete ridges, lentiginous hyperplasia in all cases and formation of discrete cleft consistent with GGD in one [Figure 5], [Figure 6], [Figure 7]. Moreover, there was in part a very pronounced pigment incontinency [Figure 6]. | Figure 6: Fusing rete ridges with deeply pigmented basal cell layer and
marked pigment incontinence
Click here to view |
Molecular genetic analyses
For the molecular genetic analyses, DNA was extracted from four affected individuals from peripheral blood leukocytes according to standard procedures. All coding exons of the KRT5 gene were amplified by PCR of an affected individual (patient 1). The PCR products were purified with the GFX TM PCR DNA Purification Kit (GE Healthcare) and directly sequenced using the BigDye ® Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems) on an ABI 3100 genetic analyzer (Applied Biosystems). All patients provided written informed consent, and the investigation was approved by the Ethics Committee of the Medical Faculty of the University of Dόsseldorf.
| Results and Discussion | | |
By sequencing analysis, we identified a heterozygous nonsense mutation, c.C10T (p.Gln4X), in exon 1 of the KRT5 gene in the index patient (patient 1). Further analyses revealed the same mutation in the son, the daughter and the granddaughter of the index patient (patients 2-4). Additional family members were unfortunately not available for molecular genetic studies.
The heterozygous nonsense mutation c.10C > T in KRT5 identified in this study was recently described in a Chinese family with DDD with hypopigmented macules adjacent to the classic lesions showing histological features of DDD. [7] Wu and Lin published a family with reticular hyperpigmentation and hypopigmented macules with DDD with some biopsies showing features on histopathology in accordance with GGD, however, a mutation in KRT5 could not be detected. [8]
Upon review of the international dermatologic literature our study seems to be the first mutation report on GGD in patients from India; moreover, the mutation c. 10C > T has so far not been described in the literature for GGD (acantholytic DDD). The detection of this mutation not only in DDD [7] but also in GGD patients gives further confirmation for our hypothesis that GGD is a variant of DDD. [1] In addition, so far there have not been any reports on GGD with hypopigmentation where detection of a mutation in the KRT5 gene has been possible. Further studies have to show if there is a phenotypical correlation between the mutation c.10C > T of KRT5 and GGD resp. DDD with hypopigmentation in Asian patients. On the basis of the present literature, together with the mutation c.10C > T in GGD, five different mutations in KRT5 underlying either GGG or DDD have been described so far, mostly in patients of European origin. [7],[10],[11],[12]
The understanding of the mechanisms leading to reticulate hyper- and/or hypopigmentation in DDD and GGD is rudimentary at the present time. A single subtype of the hereditary bullous disorder, epidermolysis bullosa simplex (EBS) with hyper- and hypopigmentation, EBS with mottled pigmentation, has been described. Mutations in KRT5 are the underlying cause of EBS with mottled pigmentation. [13] In analogy and terms of a correct terminology, we propose that patients with GGD or DDD clinically displaying hyper and hypopigmentation have to be classified as GGD resp. DDD with mottled pigmentation. Going by existing literature and from the author's personal communications, the latter with mottled pigmentation seems to be a fairly commonly occurring phenotype in the Asian population whereas in publications on Caucasian patients the patients mainly exhibit the reticular phenotype.
Keratin 5 constitutes an integral part of the basal cell layer of keratinocytes and thus dominant mutations in KRT5 may play a significant role, besides cell adhesion, in uptake and distribution of melanosomes in keratinocytes. [10] Functional analyses showing that keratins are involved in this process support this hypothesis. [10],[14]
It could be assumed that post-inflammatory hypopigmentation in patients with Fitzpatrick type IV, V or VI leads to the phenotype of GGD or DDD with mottled pigmentation. However, in our patients hypopigmentation occurred without preceding cutaneous inflammation. In addition, postinflammatory pigmentary changes usually regress over time if melanocytes are not destroyed. [15] Permanent hypopigmentation in contrast can be due to the absence or diminution of melanocytes or aberrations in the complex process of melanin synthesis, transport and release to keratinocytes; underlying causes comprise severe cutaneous inflammation [15] or diverse genetic disorders. [16] Future studies have to contribute to the understanding of hyper- and hypopigmentation in reticulate pigment disorders like GGD and DDD in general, as well as with special regard to patients with skin type IV, V and VI, appreciating and further elucidating the notion of a possibly genetically determined 'individual chromatic tendency'. [17]
The idea that hypopigmentation can also be an expression of subclinical acantholysis was suggested in 1995 by Rowley et al. They studied hypopigmented lesions in two patients with dark skin diagnosed with the acantholytic dermatoses, Darier's and Grover's disease and detected acantholytic histopathological features, leading to the hypothesis that the associated leucoderma in those cases became apparent on surrounding dark skin. [18] Also, in our patients reported here, acantholysis was found in hypopigmented lesions. This is what makes it an interesting hypothesis which could possibly be applied to our cases. Moreover, the mechanisms leading to acantholysis in GGD have to be explored further, especially the question whether acantholysis in DDD is indeed rare or is a disregarded or underobserved histopathological feature. [1],[3],[12]
In conclusion, the analyses of our family from India further contribute to the broad and probably origin-related diverging spectrum of clinical symptoms and molecular genetic findings which is expanding steadily in GGD and DDD. The correlation of hypopigmented macules with these genetically determined reticulate pigment disorders is uncommonly reported in literature and is worth studying further, especially with respect to patients with skin type IV, V and VI. A serious consideration needs to be given to the fact that hypopigmented lesions in the Dowling-Degos disease-spectrum may be underreported, a fact emerging from personal communications with several esteemed colleagues from India who have seen coexistence of hypo- and hyperpigmented macules in this disease spectrum. This study also reiterates published observations and discussions suggesting that reticulate pigmentary disorders like DDD, GGD, acropigmentation of Kitamura, acropigmentation of Dohi and Haber's syndrome may have many overlaps clinically. [19],[20] Further studies will throw more light on whether there are true overlaps between these diseases or whether these entities are placed variably in a continuum under the broad rubric of reticulate pigmentary disorders. Mottled hypopigmentation in addition to the classic signs and symptoms of DDD and GGD may be well recognized over a period of time to be a distinct phenotype in individuals who have dark skin.
| Acknowledgments | | |
The authors thank all patients for their participation in the study. R.C.B. is recipient of a Heisenberg Professorship from the German Research Foundation (DFG).
| References | | |
| 1. | Hanneken S, Rütten A, Pasternack SM, Eigelshoven S, El Shabrawi-Caelen L, Wenzel J, et al. Systematic mutation screening of KRT5 supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos disease. Br J Dermatol 2010;163:197-200. 
|
| 2. | Hanneken S, Rütten A, Eigelshoven S, Braun-Falco M, Pasternack SM, Ruzicka T, et al. Galli-Galli disease: Clinical and histopathological investigation using a case series of 18 patients. Hautarzt 2011;62:842-51.
|
| 3. | El Shabrawi-Caelen L, Rütten A, Kerl H. The expanding spectrum of Galli-Galli disease. J Am Acad Dermatol 2007;56 Suppl 5:S86-91.
|
| 4. | Müller CS, Pföhler C, Tilgen W. Changing a concept-controversy on the confusing spectrum of the reticulate pigmented disorders of the skin. J Cutan Pathol 2009;36:44-8.
|
| 5. | Braun-Falco M, Volgger W, Borelli S, Ring J, Disch R. Galli-Galli disease: An unrecognized entity or an acantholytic variant of Dowling-Degos disease? J Am Acad Dermatol 2001;45:760-3.
|
| 6. | Pickup TL, Mutasim DF. Dowling-Degos disease presenting as hypopigmented macules. J Am Acad Dermatol 2011;64:1224-5.
[PUBMED] |
| 7. | Guo L, Luo X, Zhao A, Huang H, Wei Z, Chen L, et al. A novel heterozygous nonsense mutation of keratin 5 in a Chinese family with Dowling-Degos disease. J Eur Acad Dermatol Venereol 2011;26:908-10.
|
| 8. | Wu YH, Lin YC. Generalized Dowling-Degos disease. J Am Acad Dermatol 2007;57:327-34.
|
| 9. | 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.
|
| 10. | Betz RC, Planko L, Eigelshoven S, Hanneken S, Pasternack SM, Bussow H, et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 2006;78:510-9.
|
| 11. | Liao H, Zhao Y, Baty DU, McGrath JA, Mellerio JE, McLean WH. A heterozygous frameshift mutation in the V1 domain of keratin 5 in a family with Dowling-Degos disease. J Invest Dermatol 2007;127:298-300.
|
| 12. | Sprecher E, Indelman M, Khamaysi Z, Lugassy J, Petronius D, Bergman R. Galli-Galli disease is an acantholytic variant of Dowling-Degos disease. Br J Dermatol 2007;156:572-4.
|
| 13. | Uttam J, Hutton E, Coulombe PA, Anton-Lamprecht I, Yu QC, Gedde-Dahl T Jr, et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci USA 1996;93:9079-84.
|
| 14. | Planko L, Böhse K, Höhfeld J, Betz RC, Hanneken S, Eigelshoven S, et al. Identification of a keratin-associated protein with a putative role in vesicle transport. Eur J Cell Biol 2007;86:827-39.
|
| 15. | Vachiramon V, Thadanipon K. Postinflammatory hypopigmentation. Clin Exp Dermatol 2011;36:708-14.
|
| 16. | Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: Lessons learned from the biology of melanocytes. Exp Dermatol 2009;18:741-9.
|
| 17. | Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg 1997;16:36-43.
|
| 18. | Rowley MJ, Nesbitt LT Jr, Carrington PR, Espinoza CG. Hypopigmented macules in acantholytic disorders. Int J Dermatol 1995;34:390-2.
|
| 19. | Müller CS, Tremezaygues L, Pföhler C, Vogt T. The spectrum of reticulate pigment disorders of the skin revisited. Eur J Dermatol 2012;22:596-604.
|
| 20. | Tang JC, Escandon J, Shiman M, Berman B. Presentation of reticulate acropigmentation of kitamura and Dowling-Degos disease overlap. J Clin Aesthet Dermatol 2012;5:41-3.
[PUBMED] |
What is new?
1. We have successfully detected the heterozygous mutation c.C10T
in KRT5 in an Indian family with acantholytic Dowling.Degos
disease (syn. Galli.Galli disease) with mottled pigmentation.
2. We are highlighting the presence of mottled pigmentation in the
reticulate pigmentary disorders of Dowling.Degos disease and Galli
Galli disease in patients with Fitzpatrick skin type IV and V. Such
reports are rather rare in literature. It is also possible that there is under
reporting of mottled pigmentation in this skin type with DDD/GGD.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] |
|
| This article has been cited by | | 1 |
An acantholytic variant of dowling degos disease |
|
| Sheena Kapoor, Vidya Kharkar, Dipali Rathod | | IP Indian Journal of Clinical and Experimental Dermatology. 2022; 8(4): 266 | | [Pubmed] | [DOI] | | | 2 |
Generalized Dyschromia and Erythematous Papules in a 66 Year-Old Man: Answer |
|
| Ali G. Al-Haseni, Jonathan D. Ho, Mayra Maymone, Jag Bhawan, Neelam A. Vashi | | The American Journal of Dermatopathology. 2019; 41(1): 70 | | [Pubmed] | [DOI] | |
|
|
|
|
|
|
|
|
|
|
|
| Article Access Statistics | | | Viewed | 6723 | | | Printed | 164 | | | Emailed | 1 | | | PDF Downloaded | 94 | | | Comments | [Add] | | | Cited by others | 2 | | |
|
|
