Dowling-Degos Disease Research Articles

Proposing GLMN, encoding glomulin, as a novel gene for Dowling-Degos disease.

Dowling-Degos disease (DDD) is a rare hyperpigmentation disorder with autosomal-dominant inheritance. To date, work by our group and others has identified a total of four DDD sub-phenotypes, which arise secondary to variants in KRT5, POFUT1, POGLUT1, and PSENEN. We postulate that GLMN is a novel fifth gene for DDD that contributes to a hitherto unrecognized DDD sub-phenotype.

Dowling-Degos disease: a classic presentation of a rare disease

Dowling-Degos disease: a classic presentation of a rare disease

Cancer and hidradenitis suppurativa

Patients with hidradenitis suppurativa (HS) have an increased risk of developing cancer. This includes not only hematologic malignancies and solid tumors but also cutaneous squamous cell carcinoma (SCC) originating within the HS lesions. The development of SCC is most commonly associated with Caucasian men who smoke and have severe gluteal or perianal lesions of more than 25 years. Other factors that have occasionally been associated with HS-related SCC include treatment with a tumor necrosis factor-alpha inhibitor (such as infliximab and adalimumab), genodermatoses (such as keratitis-ichthyosis-deafness syndrome and Dowling-Degos disease), and paraneoplastic syndromes (such as hypercalcemia, hypercalcemia-leukocytosis, and paraneoplastic neuropathy). The tumor may demonstrate the presence of human papillomavirus; even after treatment, patients have a poor prognosis because cancer metastasis, recurrence, or both commonly occur. The potential role of human papillomavirus vaccination for cancer prevention and early treatment of SCC with targeted therapy (with an epidermal growth factor inhibitor such as cetuximab) and/or checkpoint inhibitor immunotherapy (such as cemiplimab and pembrolizumab) remains to be determined. Rarely, HS lesions have mimicked cutaneous metastases in patients with visceral malignancy by demonstrating an increased uptake of fluorine-18 fluorodeoxyglucose on positron emission tomography and/or computed tomography scans. Primary cancers (such as cutaneous SCC and mucinous adenocarcinoma) and breast cancer skin metastases can masquerade as HS lesions. When a lesion is located at a current or earlier site of HS that is new or rapidly growing and/or does not respond to HS-directed therapy, prompt evaluation to establish or exclude the diagnosis of cancer should be considered.

Reticulate acropigmentation of Kitamura and Dowling-Degos disease overlap: a rare case report

Reticulate acropigmentation of Kitamura (RAK) and Dowling-Degos disease (DDD) belong to the rare heterogeneous group of reticulate pigmentary disorders. They are inherited as an autosomal dominant trait with variable penetrance and are characterized by the presence of hyperpigmented macules coalescing in a reticular fashion. We hereby describe a 29-year-old male patient having hyperpigmented macules on the neck, axillae, dorsum of the hands and feet, along with palmar pitting. A clinicopathological overlap of both these entities (RAK and DDD) was seen in this patient, which is a rare occurrence, indicating that they are two different phenotypic presentations of a single disease.

Dowling-Degos Disease with Reticulate Acropigmentation of Kitamura: Two Facets of a Single Disease Complex

Dowling-Degos Disease with Reticulate Acropigmentation of Kitamura: Two Facets of a Single Disease Complex

Galli Galli Disease: A Challenging Diagnosis in a Bahraini Female Patient

Dowling-Degos Disease (DDD) is an inherited cutaneous disease which presents with classic and atypical cutaneous findings, including macules of hyperpigmentation and hypopigmentation in the flexural creases. A variant, termed Galli-Galli Disease (GGD), presents similarly, with the distinguishing feature of acantholysis on histology. Reports of GGD in the literature are rare, due to the infrequency of the diagnosis. This may contribute to a lack of available information and delayed diagnosis, which can result in a frustrating clinical course for patients. We present a female patient who presented with complaints of a burning sensation and painful rash for the last three years on a background of hypopigmented and hyperpigmented macules on the trunk, upper extremities and flexural creases. Comprehensive dermatopathological evaluation and clinical correlates led to the diagnosis of GGD.

Galli-Galli Disease: A Comprehensive Literature Review.

Galli-Galli disease (GGD) is a rare genodermatosis that exhibits autosomal dominant inheritance with variable penetrance. GGD typically manifests with erythematous macules, papules, and reticulate hyperpigmentation in flexural areas. A distinct atypical variant exists, which features brown macules predominantly on the trunk, lower limbs, and extremities, with a notable absence of the hallmark reticulated hyperpigmentation in flexural areas. This review includes a detailed literature search and examines cases since GGD's first description in 1982. It aims to synthesize the current knowledge on GGD, covering its etiology, clinical presentation, histopathology, diagnosis, and treatment. A significant aspect of this review is the exploration of the genetic, histopathological, and clinical parallels between GGD and Dowling-Degos disease (DDD), which is another rare autosomal dominant genodermatosis, particularly focusing on their shared mutations in the KRT5 and POGLUT1 genes. This supports the hypothesis that GGD and DDD may be different phenotypic expressions of the same pathological condition, although they have traditionally been recognized as separate entities, with suprabasal acantholysis being a distinctive feature of GGD. Lastly, this review discusses the existing treatment approaches, underscoring the absence of established guidelines and the limited effectiveness of various treatments.

Co-existent Dowling–Degos disease, reticulate acropigmentation of Kitamura, and acropigmentation of Dohi in two generations: An overlap or concept of a single disease?

Reticulate pigmentary disorders (RPDs) are a group of rare autosomal dominant dermatoses with a distinctive clinical net-like pattern with specific arrangements and distributions in each entity. A forty-year-old female presented with asymptomatic, light and dark, macular lesions existing for over fifteen years with perioral scars and palmer pits and her twenty-year-old daughter beginning to develop similar lesions four years earlier. Cutaneous and histopathological examinations suggested a diagnosis of Dowling–Degos disease co-existent with reticulate acropigmentation of Kitamura in the mother and Dowling–Degos disease co-existent with acropigmentation of Dohi in the daughter. The co-existence of three infrequently encountered dermatoses with an irregular disease presentation within the family suggested the possibility of differing entities in the reticulate pigmentary group of disorders belonging to the diverse spectrums of the same disease. Key words: Reticulate pigmentary disorders, Dowling–Degos disease, Reticulate acropigmentation of Kitamura, Reticulate acropigmentation of Dohi

Descriptive assay of the clinico-morphological characteristics of dermatoses presenting with reticulate pigmentation

Background: Reticulate pigmentation is characterized by freckle-like lesions configured to form a net-like or chicken-wire configuration with varying degrees of pigmentation. It intermingles with similar terms such as mottled pigmentation and dyschromia and poses difficulty in classification. Both genetic and acquired dermatoses may present with reticulate patterns yet may vary in morphology as well as the age of onset and presentation. Materials and methods: This was a hospital-based, descriptive, observational study conducted on thirty-two patients over a period of fifteen months at the dermatology OPD. Patients presented with reticulate pigmentary dermatoses were enrolled in the study after giving written informed consent. A detailed history and clinical examination were performed, and findings were recorded on a standard predesigned proforma. The data was analyzed with appropriate statistical tests. Results: In our study, a total of thirty-two patients with reticulate pigmentary dermatoses were enrolled, fourteen males and eighteen females, yielding a male-to-female ratio of 1:1.28. The most common age group affected was 41–50 years (28.12%). The onset of lesions was in young to middle adulthood (56.25%), followed by childhood and teenage years (34.37%). The most common disorder found was erythema ab igne (15.62%), while livedoid vasculopathy, Dowling–Degos disease, and confluent reticulate papillomatosis each constituted 9.37% of cases. Conclusion: This study assisted to incorporate the spectrum of RPD and to assess its frequency, morphological patterns, and prognosis. Owing to the paucity of research studies on RPD, the present study will be helpful in exploring future treatment modalities, thereby decreasing the enigma and concerns associated with RPD. Key words: Reticulate pigmentary dermatoses, Net-like lesions, Dyschromia

A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa.

Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.

Altered Notch signalling in Dowling-Degos disease: a transcriptomic insight into disease pathogenesis.

Dowling-Degos disease (DDD) is a rare autosomal-dominant hyperpigmentation disorder caused by mutations in KRT5, POFUT1, POGLUT1 and PSENEN. Our results suggest that dysfunctional Notch signalling in melanocytes plays a key role in DDD pathogenesis, and that altered biogenesis and intracellular trafficking of melanosomes, receptor tyrosine kinase signalling and oestrogen signalling receptor-mediated signalling may represent downstream molecular mechanisms through which decreased Notch signalling leads to hyperpigmentation in DDD. Furthermore, a common downstream pathomechanism for both POGLUT1 and PSENEN mutation carriers can be assumed.

Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

P02 Galli Galli disease: a rare variant of the genodermatosis Dowling–Degos disease

Abstract A 35-year-old woman presented with a 4-year history of a persistent pruritic rash affecting her upper and lower limbs, concerning to the patient for cosmetic reasons. She denied any precipitating factors and reported no improvement with the use of topical clobetasol propionate. Notably, her mother had a similar rash, which had also developed in her 30s and continued to progress over time. Physical examination revealed a bilateral symmetrical papular eruption with superficial scale affecting extensor surfaces of her upper and lower limbs. The patient’s mother was also reviewed and had similar clinical findings, although a more generalized distribution was noted. Skin biopsy from the right thigh of the daughter showed acantholysis in the stratum spinosum with dyskeratotic cells. Biopsy from the left thigh of the patient’s mother showed elongation of rete ridges with foci of increased basal pigmentation and intraepidermal acantholysis. The presence of acantholysis and elongation of rete ridges with basal pigmentation histologically confirmed the diagnosis of the Galli–Galli variant of Dowling–Degos disease (DDD). The genetic basis for DDD involves a heterozygous loss of expression mutation affecting KRT5. Other implicated mutations include POGLUT1, POFUT1 and PSENEN, which are important in melanosome transfer, and the differentiation of melanocytes and keratinocytes. Galli–Galli disease remains a therapeutic challenge. Reported treatments trialled include topical retinoids, oral corticosteroids, and narrowband ultraviolet, although the outcomes have been disappointing. Successful treatment with erbium : yttrium aluminium garnet laser has been reported. Owing to the progressive nature of this condition, patient counselling regarding treatment expectations is important.

Inherited Reticulate Pigmentary Disorders.

Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli-Franceschetti-Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.

In silico modelling of the function of disease-related CAZymes.

In silico modelling of proteins comprises a diversity of computational tools aimed to obtain structural, electronic, and/or dynamic information about these biomolecules, capturing mechanistic details that are challenging to experimental approaches, such as elusive enzyme-substrate complexes, short-lived intermediates, and reaction transition states (TS). The present article gives the reader insight on the use of in silico modelling techniques to understand complex catalytic reaction mechanisms of carbohydrate-active enzymes (CAZymes), along with the underlying theory and concepts that are important in this field. We start by introducing the significance of carbohydrates in nature and the enzymes that process them, CAZymes, highlighting the conformational flexibility of their carbohydrate substrates. Three commonly used in silico methods (classical molecular dynamics (MD), hybrid quantum mechanics/molecular mechanics (QM/MM), and enhanced sampling techniques) are described for nonexpert readers. Finally, we provide three examples of the application of these methods to unravel the catalytic mechanisms of three disease-related CAZymes: β-galactocerebrosidase (GALC), responsible for Krabbe disease; α-mannoside β-1,6-N-acetylglucosaminyltransferase V (MGAT5), involved in cancer; and O-fucosyltransferase 1 (POFUT1), involved in several human diseases such as leukemia and the Dowling-Degos disease.

KRT5 mutation regulate melanin metabolism through notch signalling pathway between keratinocytes and melanocytes.

Dowling-Degos disease (DDD) is an autosomal dominant hereditary skin disease characterized by acquired reticular hyperpigmentation in flexural sites, and one of its causative genes is KRT5 gene. But the effect of KRT5, expressed only in keratinocytes, on melanocytes is unclear. Other pathogenic genes of DDD include POFUT1, POGLUT1 and PSENEN genes, which is involved in posttranslational modification of Notch receptor. In this study, we aim to determine the ablation of keratinocyte KRT5 affect melanogenesis in melanocyte through Notch signalling pathway. Here we found that KRT5 downregulation decreased the expression of the Notch ligand in keratinocytes and Notch1 intracellular domain in melanocytes, by establishing two cell models of ablation of KRT5 in keratinocytes based on CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA. Treatment of melanocytes with Notch inhibitors had same effects with ablation of KRT5 on increase of TYR and decrease of Fascin1. Activation of Notch signalling reverses the effect of ablation of KRT5 on melanogenesis. Immunohistochemistry of DDD lesions with KRT5 gene mutation confirmed changes in the expression of relevant molecules in Notch signalling. Our research elucidates molecular mechanism of KRT5-Notch signalling pathway in the regulation of melanocytes by keratinocytes, and preliminary reveal the mechanism of DDD pigment abnormality caused by KRT5 mutation. These findings identify potential therapeutic targets of the Notch signalling pathway for the treatment of skin pigment disorders.

A case of delayed diagnosis of Dowling Degos disease

Dowling–Degos disease (DDD) is a rare genodermatosis characterized by acquired reticular hyperpigmentation of flexural sites, comedo-like lesions, and pitted facial scars. The classic disease is inherited by the autosomal dominant pattern. Herein, we present here the case of a fifty-year-old female diagnosed with Dowling–Degos disease.

Follicular Becker's Nevus: A Relatively New Variant.

A 50-year-old man presented with multiple asymptomatic, follicular, hyperpigmented macules of diameter 2–3 mm covering an area of 7 cm × 5 cm over the left side of the upper chest since adolescence [Figure 1]. There was no hypertrichosis, acneiform eruptions, skeletal deformity, or any other system involvement. No follicular pits, keratotic follicular papules, comedo-like papules, or any other features suggestive of follicular Dowling-Degos disease or sometimes associated reticulate hyperpigmentation as seen in Dowling-Degos disease, were present in our patient. None of the family members had similar lesions. A punch biopsy from one of the macules revealed the epidermis showing mild papillomatosis, acanthosis, and prominent basal cell melanization. interconnected and broad rete ridges were visible at places and the dermis was essentially normal [Figure 2]. A diagnosis of follicular Becker’s nevus was made based on clinical features confirmed by histopathology.Figure 1: Multiple discrete, follicular, hyperpigmented macules of diameter 2–3 mm covering an area of 7 cm × 5 cm over the left side of the upper chestFigure 2: The epidermis showing mild papillomatosis, acanthosis, and prominent basal cell melanization. The dermis was essentially normal (H and E, 100X) Inset: Fontana Masson stain highlighting the basal pigmentationFollicular Becker’s nevus is a relatively newer variant. It has been described only recently in a case series of four patients with a short duration of mean 1.93 years.[1] The authors had speculated that with time, the follicular lesions might evolve into the classical lesions of Becker’s nevus.[1] Our patient had these lesions for about 35 years and the lesions remained exclusively follicular. This case of a rare variant of Becker’s nevus with a long history highlights the fact that this morphology is a distinct entity with no evolution into the classical form of Becker’s nevus. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Dermoscopy of classic Dowling–Degos disease with review of literature

Dermoscopy of classic Dowling–Degos disease with review of literature

An acantholytic variant of dowling degos disease

Galli- Galli disease is a rare acantholytic variant of Dowling- Degos disease, with few cases reported in the literature till date. We here, describe an interesting case of Galli- Galli disease with prominent histopathological findings. Future studies and genotype-phenotype correlations may elucidate why acantholysis is observed in some patients, but not in others.