Dyschromatosis Universalis Research Articles

A Case Report on Dyschromatosis Universalis Hereditaria with Palmar Involvement

Dyschromatosis universalis hereditaria (DUH) is a rare genetic disorder characterized by hyper- and hypopigmented macules forming a reticulate pattern on the skin. This report presents an unusual case of a 14-year-old male patient with DUH involving the palms, a relatively uncommon manifestation of the condition. The patient presented with hyperpigmented lesions on the palms, which had developed over the previous eight years. Family history revealed similar pigmentary changes, suggesting a hereditary pattern. Clinical examination revealed no history of chemical or drug exposure, photosensitivity, or photophobia. Systemic evaluation was unremarkable, except for a low cortisol level of 1.12 mcg/dl (normal range: 6.2 to 19.4 mcg/dl) on the ACTH stimulation test. Skin biopsy from the left palm revealed diffuse hypermelanosis confined to the basal cell layer and occasionally extending to the lower third of the epidermis. Additionally, increased collagenization was observed in the deep dermis. Based on these findings, a diagnosis of DUH was established. The patient was initiated on long-term hydrocortisone therapy for cortisol hormone replacement. This case highlights the rare occurrence of palmar involvement in DUH and underscores the importance of thorough clinical evaluation and histopathological examination in establishing an accurate diagnosis. DUH is an uncommon genodermatosis, and reports of palmar involvement are scarce in the literature. This case contributes to the existing knowledge about the varied clinical presentations of DUH and emphasizes the need for increased awareness among clinicians

Dyschromatosis universalis hereditaria.

Reticulate pigmentary dyschromatoses primarily include dyschromatosis universalis hereditaria (DUH), dyschromatosis symmetrica hereditaria (DSH) (Reticulate acropigmentation of Dohi), and unilateral dermatomal pigmentary dermatosis, which differ in their patterns of distribution. The disease was initially described by Ichikawa and Hiraga in Germany in 1933. The prevalence of DUH is 0.3 per 100,000 with a female preponderance. The skin lesions usually appear in infancy or early childhood and cease to progress beyond adolescence. The subtypes DUH 1 and DUH 3 are found to have autosomal dominant inheritance, which is the most common inheritance pattern, while DUH 2 has an autosomal recessive pattern. The most common gene involved in DUH is ABCB6, while the other genes include SASH 1, PER 3, and KITLG (DUH type 2). DUH is characterized by multiple irregular hyperpigmented macules interspersed with hypopigmented macules in a mottled pattern over the trunk and extremities. The face is involved in 50% of individuals. Rarely, it can also involve hairs, nails, mucous membranes, palms, and soles. Other varied presentations include localized forms, localization of lesions to sun-exposed areas, large macules, uniform palmar hypopigmentation, diffuse hyperpigmentation with spotty depigmented macules, and unilateral involvement. DUH has been reported to be associated with various cutaneous and systemic diseases. The authors have observed cases of DUH associated with hepatocellular carcinoma, solitary keratoacanthoma, and dermoid cyst. The various diagnostic modalities include dermoscopy, histopathology, electron microscopy, and targeted gene sequencing. Though various treatment modalities like NBUVB and lasers have been tried, no treatment is promising.

Uncovering a new SASH1 mutation associated with dyschromatosis universalis hereditaria using whole-exome-sequencing: A case report.

Dyschromatosis universalis hereditaria (DUH) is an uncommon form of pigmented genodermatosis that is typically inherited autosomally and dominantly. In the previous study, the pathogenic genes of DUH have been identified in ATP-binding cassette subfamily B, member 6 and SASH1. However, the mutational screening of the causative gene remains incomplete and still lacks sufficient proof in the etiology. A 2-generation Chinese family clinically diagnosed with DUH were enrolled. They showed pigmented spots from their childhood and came to the hospital for medical advice and genetic analysis. We found a novel mutation c.1757T > C (p.I586T) of SASH1 in 3 affected family members by whole-exome sequencing. Genetic outcomes and clinical examinations confirmed the diagnosis of DUH in 3 family members with lentiginous syndrome. Using whole-exome sequencing and sanger sequencing technologies, we identified a novel mutation c.1757T > C (p.I586T) of SASH1 that co-segregated in 3 afflicted family members but not in the normal individuals. Significantly, c.1757T > C (p.I586T) is a novel mutation which had not been previously reported. The same codon position in SASH1 (c.1758C > G, p.I586M) has been reported in a Japanese man, and he showed identical phenotype compared to our study participants. Our study broadens the spectrum of DUH mutations and provides more genetic characteristics of DUH in understanding its etiology. Furthermore, we demonstrated the diagnostic accuracy of whole-exome sequencing for inherited skin diseases and provided new information for etiological study.

Retyping and molecular pathology diagnosis of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic-like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH-like patients. More importantly, heterozygous distribution or mosaic-like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic-like melanin in the affected layers of hyper- and/or hypo-pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis.

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.

The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP of PER3 (PER3rs772027021 SNP) and a novel mutation in exon 14 of SASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carrying PER3rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3rs772027021 SNP and SASH1 T525R mutation. Increased melanin synthesis was induced by PER3rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3rs772027021 SNP synergistically led to increased melanin synthesis and enhanced proliferation of melanoma cells in vitro. We also phenotypically characterized a commercially available zebrafish mutant line harboring the PER3rs772027021 SNP to induce melanocyte proliferation in vivo. Our results are the first to reveal that this PER3 SNP may be pathogenic for a novel DUH subtype with mild hyperpigmented and/or hypopigmented phenotypes and that mutation of SASH1 and PER3 cooperatively promotes hyperpigmentation phenotypes. KEY MESSAGES: PER3rs772027021 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3rs772027021 SNP probably contributed the pathogenesis of DUH. SASH1T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3rs772027021 SNP.

Dyschromatosis Universalis Hereditaria: A Rare Case Report in Southern India

Dyschromatosis Universalis Hereditaria (DUH) is a rare genodermatosis characterised by hyper and hypo pigmented macules in reticulate pattern. The clinical manifestations includes occurrence of lesions at the trunk and extremities as the dominants sites. The lesions may spread to the face, hands and feet. Hair, teeth, nails, palms and soles may also be involved. Here, we present a case of 7 year old male patient with DUH with the involvement of whole body surface. The treatment pattern in this case includes cortisol hormone replacement therapy with the use of hydrocortisone tablets for a long period of time.

Siblings with Dyschromatosis Universalis Hereditaria a Rare Case Report

Dyschromatoses are a group of genodermatosis characterized by the presence of both hyperpigmented and hypopigmented macules of variable shapes and sizes. Here, we report siblings presented with asymptomatic progressive mottled pigmentation of reticulate pattern over the trunk and limbs since 6 years of their age without any systemic or other cutaneous illness. They were born to nonconsanguineous parents following an uneventful pregnancy. Their paternal grandfather had a similar appearance. Histological examination was consistent with dyschromatosis universalis hereditaria (DUH). Based on the clinical and histological findings, a diagnosis of DUH was made. We report this case of rare genodermatosis in siblings affected by the same disease.

Reticulate Acropigmentation of Dohi

Reticulate acropigmentation of Dohi is a rare genodermatosis inherited as an autosomal dominant trait. It is a localized form of dyschromatosis universalis hereditarian, characterized by the presence of hyperpigmented and hypopigmented macules with symmetrical, irregular size and shape forming a reticulate pattern over the dorsa of the hands and feet. Onset is normally in the first decade but occasionally be delayed. Biopsy is not diagnostic but helps to rule out its differentials. Dermoscopy is a new investigative tool which gives specific characteristic changes. We report two cases of acropigmentation of Dohi with classical dermatoscopic changes reported previously and some new features. No treatment is effective for this genodermatosis.

A rare association of dyschromatosis universalis hereditaria and bilateral corneal ulcer

Dyschromatosis universalis hereditaria (DUH) is a rare entity in the Indian subcontinent presenting with generalized pigmented macule all over the body. We report a case of a 13-year-old patient of DUH with bilateral gradual progressive diminution of vision and increasing white opacity for the past 5 years. The patient presented with a bilateral central corneal ulcer. The microbiological report of the corneal scraping sample was negative. The ulcer responded to topical gatifloxacin eye drop, and the epithelial defect healed with excessive brown pigmentation in both eyes. Whether this bilateral keratopathy and healing with pigmentation are a part of the spectrum of DUH or not needs to be evaluated further.

Sporadic Dyschromatosis Universalis Hereditaria: A Second Case Report From Iran

Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis mostly reported from Japan. It is usually characterized by widespread hyper/hypopigmented macules all over the body. Here, we report the case of a patient from Iran who presented with disseminated hyper and hypopigmented lesions over the trunk, neck, and extremities since the age of eight. To the best of our knowledge, to date, there has been only one reported case of DUH from Iran.

Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

BackgroundDyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH.MethodsSanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations.ResultsA novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6.ConclusionAlthough the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

Dyschromatosis Universalis Hereditaria

Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis usually inherited in autosomal dominant fashion characterized by multiple pinpoint to pea-sized hypo- and hyper-pigmented macules arranged in reticulate pattern that develops within the first few years of life. An 11 years old boy presented with multiple gradually progressive asymptomatic hypopigmented macules on hyperpigmented background on trunk, extremities and face since 2 years of age. Family history was absent. Punch biopsies revealed increased number of melanocytes in the epidermis with basal cell vacuolar alteration and pigmentary incontinence and perivascular infiltration by lymphocytes and melanophages in the dermis. We herein present a sporadic case of dyschromatosis universalis hereditaria.

Identification of a Novel Mutation in SASH1 Gene in a Chinese Family With Dyschromatosis Universalis Hereditaria and Genotype-Phenotype Correlation Analysis.

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by mottled hyperpigmented and hypopigmented macules. SASH1 and ABCB6 have been identified as the causative genes for this disorder. We performed whole exome sequencing on a Chinese family with DUH and genotype-phenotype correlation analysis in DUH and lentiginous phenotype patients. A novel heterozygous missense mutation p.Q518P in SASH1 gene was detected in this family. A majority of patients with SASH1 mutations presented as a distinct clinical phenotype clearly different from that in patients with ABCB6 mutations. Our findings further enrich the reservoir of SASH1 mutations in DUH. The clinical phenotypic difference between SASH1 and ABCB6 variants is suggestive of a close phenotype-genotype link in DUH.

Mutated SASH1 promotes Mitf expression inaheterozygous mutated SASH1 knock‑in mouse model.

The SAM and SH3 domain-containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia-associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf-positive epithelial cells was also detected. An increased expression of Mitf- and Mitf-positive cells was also demonstrated in the epithelial tissues of Y551D-SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1-mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1-Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.

SASH1 promotes melanin synthesis and migration via suppression of TGF-β1 secretion in melanocytes resulting in pathologic hyperpigmentation.

Dyschromatosis universalis hereditaria (DUH) is an autosomal dominant pigmentary genodermatosis characterized by the presence of patches of hyperpigmentation and hypopigmented macules distributed over the body, with most cases reported in Asia. DUH is a heterogeneous disease and a small portion of patients carry the ABCB6 variant. In the present study, exome sequencing of four generations of a Chinese family with DUH identified a c.1761C>G (p.Ser587Arg) mutation in exon 15 of SAM and SH3 domain containing 1 (SASH1) that was found to co-segregate in some family members. Immunohistological analysis of biopsy specimens showed that SASH1 was diffusely distributed in all layers of the epidermis, suggesting increased transepithelial migration of melanocytes (MCs). The point mutation c.1761C>G of SASH1 was successfully induced in immortalized human melanocyte (PIG1) cells, which resulted in the downregulation of SASH1 expression. Bioinformatics analysis showed that mutated SASH1 downregulated thrombospondin 1 (THBS1) expression and inactivated transforming growth factor beta 1 (TGF-β1) signaling. TGF-β1 expression by PIG1cells was found to negatively regulate SASH1 protein expression. Transwell migration and wound-healing assays showed an increase in the migration and invasion capabilities of the cells carrying the mutation. Further, SASH1 mutations induced downregulation of melanin content. The study results suggest cross-talking between SASH1-TGF-β1 signaling, demonstrating the proposed MC migration modulation models and affecting melanin trafficking in the epithelium.

Dyschromatosis Universalis Hereditaria with Hypospadias: A Rare Association.

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis, which presents as hyper- and hypopigmented macules all over the body. Although a benign condition, rarely DUH is associated with abnormalities of dermal connective tissue, nerve, and systemic conditions. We report a case of DUH associated hypospadias and complicated with hydronephrosis that has not been described earlier.

Sporadic Case of dyschromatosis universalis hereditaria showing moderate response to narrow-band ultraviolet-B

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis where the affected manifests mottled pigmentation with intermingled hyper- and hypo-pigmented macules. On most occasions, the lesions begin on limbs and then extend to trunk. Most of the cases reported in literature are from Japan. It is rarer in Indians. In this report, we describe a 12-year-old male child with DUH, who showed response to narrow-band ultraviolet-B therapy.

Atypical presentation of dyschromatosis universalis hereditaria with a novel ABCB6 mutation

Atypical presentation of dyschromatosis universalis hereditaria with a novel <i>ABCB6</i> mutation

ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation

Genetically inheritable pigmentation defects provide a unique opportunity to reveal the function of proteins contributing to melanogenesis. Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis associated with mutations in the ABCB6 gene. Here we use optical and electron microscopy imaging combined with biochemical tools to investigate the localization and function of ABCB6 in pigment cells. We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1. Depletion of ABCB6 by siRNA impaired PMEL amyloidogenesis in early melanosomes and induced aberrant accumulation of multilamellar aggregates in pigmented melanosomes. PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation. In line with the impairment of PMEL matrix formation in the absence of ABCB6, morphological analysis of the retinal pigment epithelium of ABCB6 knockout mice revealed a significant decrease of melanosome numbers. Our study extends the localization of ABCB6 to melanosomes, suggesting a potential link between the function of ABCB6 and the etiology of DUH to amyloid formation in pigment cells.