-
Journal of Clinical Rheumatology :... Jan 2022Multicentric reticulohistiocytosis (MRH) is a rare multisystem disorder, primarily affecting the skin and joints. As severe joint damage is a possible symptom, early...
Multicentric reticulohistiocytosis (MRH) is a rare multisystem disorder, primarily affecting the skin and joints. As severe joint damage is a possible symptom, early diagnosis and therapeutic intervention are required. Cutaneous lesions present with characteristic features such as discrete reddish nodules, especially on acral locations. Additionally, the face, scalp, trunk and extremities are also affected. Xanthomatous plaques are also seen on the face. The cutaneous manifestations of MRH are various, which therefore should be differentiated from several diseases. In particular, MRH has been reported to assume clinical appearances resembling Gottron papules, periungual erythema, V-neck erythema, shawl sign, and poikiloderma associated with dermatomyositis. Histopathologic features show proliferation of multinucleated giant cells with abundant eosinophilic granular ground glass-like cytoplasm in the dermis. Multicentric reticulohistiocytosis is occasionally paraneoplastic and is associated with internal malignancies. The appropriate therapies are still challenging, and oral prednisolone, immunosuppressants, and recent biologics are used. In this article, cutaneous lesions, histopathology, and pathogenesis of MRH are mainly discussed from a dermatological perspective. It is important, not only for dermatologists but also for rheumatologists and orthopedists, to be able to distinguish between the various types of skin lesions brought on by MRH. Cutaneous signs are important diagnostic clues and assessment tools for therapeutic efficacy.
Topics: Arthritis; Dermatomyositis; Erythema; Histiocytosis, Non-Langerhans-Cell; Humans; Skin
PubMed: 33337805
DOI: 10.1097/RHU.0000000000001679 -
The Journal of Investigative Dermatology Apr 2021Aging results from intrinsic changes (chronologic) and damage from external exposures (extrinsic) on the human body. The skin is ideal to visually differentiate their... (Review)
Review
Aging results from intrinsic changes (chronologic) and damage from external exposures (extrinsic) on the human body. The skin is ideal to visually differentiate their unique features. Inherited diseases of DNA repair, such as xeroderma pigmentosum (XP), provide an excellent model for human aging due to the accelerated accumulation of DNA damage. Poikiloderma, atypical lentigines, and skin cancers, the primary cutaneous features of XP, occur in the general population but at a much older age. Patients with XP also exhibit ocular changes secondary to premature photoaging, including ocular surface tumors and pterygium. Internal manifestations of premature aging, including peripheral neuropathy, progressive sensorineural hearing loss, and neurodegeneration, are reported in 25% of patients with XP. Internal malignancies, such as lung cancer, CNS tumors, and leukemia and/or lymphoma, occur at a younger age in patients with XP, as do thyroid nodules. Premature ovarian failure is overrepresented among females with XP, occurring 20 years earlier than in the general population. Taken together, these clinical findings highlight the importance of DNA repair in maintaining genomic integrity. XP is a unique model of human premature aging, which is revealing new insights into aging mechanisms.
Topics: Aging; Aging, Premature; DNA Damage; DNA Repair; Humans; Mucous Membrane; Skin; Xeroderma Pigmentosum
PubMed: 33436302
DOI: 10.1016/j.jid.2020.11.012 -
Genetics in Medicine : Official Journal... Jul 2023Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature...
PURPOSE
Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).
METHODS
Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.
RESULTS
All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate.
CONCLUSION
CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.
Topics: Humans; Rothmund-Thomson Syndrome; Cellular Senescence; DNA Damage; Hydroxyurea; Fibroblasts; Mutation; Adaptor Proteins, Signal Transducing
PubMed: 37013901
DOI: 10.1016/j.gim.2023.100836 -
International Journal of Dermatology Jan 2022Dermoscopy has traditionally been used for the diagnosis of neoplasms and more recently in the evaluation of inflammatory conditions. Recent observational studies have... (Review)
Review
Dermoscopy has traditionally been used for the diagnosis of neoplasms and more recently in the evaluation of inflammatory conditions. Recent observational studies have suggested a role for dermoscopy in identifying and differentiating acquired pigmentary disorders. This comprehensive review will summarize the growing literature on the use of dermoscopy for pigmentary disorders. A literature review was performed on PubMed dating from inception to October 2020. The following pigmentary disorders were included in this study: melasma, solar lentigines, poikiloderma of Civatte, exogenous ochronosis, lichen planus pigmentosus, erythromelanosis follicularis faciei et colli, pigmented contact dermatitis, Riehl's melanosis, postinflammatory hyperpigmentation, erythema dyschromicum perstans, ashy dermatosis, confluent and reticulated papillomatosis, acanthosis nigricans, pityriasis versicolor, tinea versicolor, idiopathic guttate hypomelanosis, and vitiligo. Search terms used included each pigmentary disorder along with the terms "dermoscopy" or "dermatoscopy." Relevant case reports and case series were included. Many pigmentary disorders have unique and distinguishable features on dermoscopy. Given that these disorders can be clinically challenging for clinicians and emotionally distressing for patients, dermoscopy provides an additional, useful tool in the evaluation and assessment process.
Topics: Dermoscopy; Erythema; Humans; Hyperpigmentation; Lichen Planus; Melanosis
PubMed: 34235719
DOI: 10.1111/ijd.15741 -
Science (New York, N.Y.) Mar 2023Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA...
Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA maturation, the molecular mechanism underlying PN remains undetermined, as pre-mRNA splicing is unaffected in patients. We generated human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1 and show that this mutation impairs human hematopoiesis. Dysregulated microRNA (miRNA) levels in USB1 mutants during blood development contribute to hematopoietic failure, because of a failure to remove 3'-end adenylated tails added by PAPD5/7. Modulation of miRNA 3'-end adenylation through genetic or chemical inhibition of PAPD5/7 rescues hematopoiesis in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.
Topics: Humans; Hematopoiesis; Human Embryonic Stem Cells; MicroRNAs; Neutropenia; Phosphoric Diester Hydrolases; Mutation
PubMed: 36862787
DOI: 10.1126/science.abj8379 -
Journal of Medical Genetics Nov 2023Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I,...
Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in and juvenile cataracts, and type II, with biallelic variants in , increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in , with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of -related syndromes.
PubMed: 37055165
DOI: 10.1136/jmg-2022-109119 -
Pediatrics International : Official... Jan 2022Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile...
BACKGROUND
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated.
METHODS
In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan.
RESULTS
In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey.
CONCLUSIONS
Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated.
Topics: Humans; Japan; Mutation; Quality of Life; Rothmund-Thomson Syndrome; Surveys and Questionnaires
PubMed: 35616152
DOI: 10.1111/ped.15120 -
Indian Journal of Ophthalmology Jul 2022We aimed describe the chronic ocular sequelae of Kindler syndrome. All cases of Kindler syndrome with ocular involvement that presented to a tertiary eye care center...
We aimed describe the chronic ocular sequelae of Kindler syndrome. All cases of Kindler syndrome with ocular involvement that presented to a tertiary eye care center were included. Three cases of Kindler syndrome with ocular changes were reviewed. Case 1 (10 years, female) had recurrent epithelial breakdown with severe dry eye and corneal opacity secondary to keratitis. Case 2 (28 years, male) had symblepharon , ocular surface keratinization , and severe dry eye. Case 3 (16 years , female ) had partial limbal stem cell deficiency with dry eye. All cases were treated with topical lubricants, short course of low-potency steroids and immuno-modulators. Attention must be paid to the eye in addition to the oro-an-genital mucosa to avoid longterm ocular sequelae.
Topics: Adult; Blister; Child; Disease Progression; Epidermolysis Bullosa; Eye; Eye Diseases; Face; Female; Humans; Male; Periodontal Diseases; Photosensitivity Disorders
PubMed: 35791162
DOI: 10.4103/ijo.IJO_791_22 -
The Journal of Biological Chemistry Sep 2023The levels of non-coding RNAs (ncRNAs) are regulated by transcription, RNA processing, and RNA degradation pathways. One mechanism for the degradation of ncRNAs involves... (Review)
Review
The levels of non-coding RNAs (ncRNAs) are regulated by transcription, RNA processing, and RNA degradation pathways. One mechanism for the degradation of ncRNAs involves the addition of oligo(A) tails by non-canonical poly(A) polymerases, which then recruit processive sequence-independent 3' to 5' exonucleases for RNA degradation. This pathway of decay is also regulated by three 3' to 5' exoribonucleases, USB1, PARN, and TOE1, which remove oligo(A) tails and thereby can protect ncRNAs from decay in a manner analogous to the deubiquitination of proteins. Loss-of-function mutations in these genes lead to premature degradation of some ncRNAs and lead to specific human diseases such as Poikiloderma with Neutropenia (PN) for USB1, Dyskeratosis Congenita (DC) for PARN and Pontocerebellar Hypoplasia type 7 (PCH7) for TOE1. Herein, we review the biochemical properties of USB1, PARN, and TOE1, how they modulate ncRNA levels, and their roles in human diseases.
Topics: Humans; Dyskeratosis Congenita; Exoribonucleases; Neutropenia; RNA Stability; RNA, Untranslated; Loss of Function Mutation
PubMed: 37544646
DOI: 10.1016/j.jbc.2023.105139