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Clinical and Experimental Dermatology Jan 2024
Topics: Humans; Acro-Osteolysis; Osteolysis
PubMed: 37889144
DOI: 10.1093/ced/llad360 -
Development (Cambridge, England) May 2017Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands... (Review)
Review
Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.
Topics: Abnormalities, Multiple; Alagille Syndrome; Animals; Developmental Biology; Ectodermal Dysplasia; Genetic Diseases, Inborn; Hajdu-Cheney Syndrome; Hernia, Diaphragmatic; Humans; Limb Deformities, Congenital; Meningocele; Receptors, Notch; Scalp Dermatoses
PubMed: 28512196
DOI: 10.1242/dev.148007 -
Rheumatology (Oxford, England) Oct 2021
Topics: Female; Finger Phalanges; Humans; Middle Aged; Osteolysis; Radiography; Scleroderma, Systemic
PubMed: 33493313
DOI: 10.1093/rheumatology/keab031 -
Clinical Rheumatology Mar 2021The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM)...
The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.
Topics: Acro-Osteolysis; Hand; Humans; Longitudinal Studies; Patient Reported Outcome Measures; Scleroderma, Systemic
PubMed: 33094395
DOI: 10.1007/s10067-020-05467-9 -
Journal of the Endocrine Society Aug 2022Pyknodysostosis is an uncommon inherited disorder associated with consanguinity, often presenting with sclerotic bone disease, short stature, dysmorphic features, and...
CONTEXT
Pyknodysostosis is an uncommon inherited disorder associated with consanguinity, often presenting with sclerotic bone disease, short stature, dysmorphic features, and recurrent fragility fractures at an early age.
CASE
A 34-year-old woman was evaluated for the cause of recurrent fragility fractures. She was born of a third-degree consanguineous marriage and had a twin brother who was of short stature. The index patient had a height of 141 cm, dysmorphic features including frontoparietal bossing, blue sclera with short stubby fingers and toes. Radiological evaluation revealed diffuse osteosclerosis with acro-osteolysis exclusively in the toes, apart from mid-facial hypoplasia, lack of pneumatization of the paranasal sinuses, dental abnormalities, and scoliosis. Dual-energy x-ray absorptiometry revealed increased bone mineral density. Based on the clinical features, the patient was tested for cathepsin gene variants using next-generation sequencing and was found to be positive for a novel homozygous c.224T>C, p.Met75Thr likely pathogenic missense variant.
DISCUSSION
This patient presented at a later age than expected with recurrent fragility fractures and the diagnosis was not suspected till adulthood, owing to the subtle clinical features. Confirmation with genetic testing helped in establishing the diagnosis.
CONCLUSION
Pyknodysostosis, although uncommon, is one of the differential diagnoses for diffuse osteosclerosis presenting with recurrent fragility fractures. Next-generation sequencing in an appropriate setting may confirm the diagnosis.
PubMed: 35854980
DOI: 10.1210/jendso/bvac102 -
Der Radiologe May 2021Progressive systemic scleroderma (PSS) and mixed connective tissue disease (MCTD) represent vasculitic autoimmune diseases from the group of collagenoses with... (Review)
Review
BACKGROUND
Progressive systemic scleroderma (PSS) and mixed connective tissue disease (MCTD) represent vasculitic autoimmune diseases from the group of collagenoses with manifestations in various organ systems such as the skin, the internal organs and the joints.
OBJECTIVE
To present the atypical arthritis patterns of the hands in PSS and MCTD that differ from those in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in the context of clinical and serologic findings and in consideration of the classification of PSS and MCTD.
MATERIALS AND METHODS
Narrative review based on the current literature on the subject from the radiological and rheumatological point of view.
RESULTS
In PSS, combinations of acral soft tissue atrophy, nonreactive acro-osteolysis, and interstitial calcifications can be visualized by projection radiography, which in the final stage can lead to a scleroderma claw hand. Digital pharmacoangiography of the hands can be used to reliably diagnose manifest vascular occlusions of the digital arteries. MCTD is characterized by various overlapping symptoms of at least two systemic autoimmune diseases and most frequently presents in the hand with symmetrical involvement of the PIP (proximal interphalangeal), MCP (metacarpophalangeal) and wrist joints with the manifestation of so-called "puffy fingers".
CONCLUSIONS
The presented morphological atypical arthritis patterns of the hands in PSS and MCTD differ considerably from the typical patterns in the hands in RA and PsA. MRI is useful to diagnose early stages and pharmacoangiography can be used to differentiate between temporary and manifest digital vascular occlusions.
Topics: Arthritis, Rheumatoid; Collagen Diseases; Hand; Humans; Mixed Connective Tissue Disease; Radiography
PubMed: 33792744
DOI: 10.1007/s00117-021-00842-2 -
BMC Musculoskeletal Disorders Sep 2023Multicentric osteolysis nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder characterized by marked progressive bone loss and joint destruction...
BACKGROUND
Multicentric osteolysis nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder characterized by marked progressive bone loss and joint destruction resulting in skeletal deformities. MONA is caused by MMP2 deficiency. Here we report clinical and molecular analyses of four patients in two families from Pakistan and Finland.
METHODS
Clinical analyses including radiography were completed and blood samples were collected. The extracted DNA was subjected to whole-exome analysis or target gene sequencing. Segregation analyses were performed in the nuclear pedigree. Pathogenicity prediction scores for the selected variants and conservation analyses of affected amino acids were observed.
RESULTS
The phenotype in the four affected individuals was consistent with multicentric osteolysis or MONA, as the patients had multiple affected joints, osteolysis of hands and feet, immobility of knee joint and progressive bone loss. Long-term follow up of the patients revealed the progression of the disease. We found a novel MMP2 c.1336 + 2T > G homozygous splice donor variant segregating with the phenotype in the Pakistani family while a MMP2 missense variant c.1188 C > A, p.(Ser396Arg) was homozygous in both Finnish patients. In-silico analysis predicted that the splicing variant may eventually introduce a premature stop codon in MMP2. Molecular modeling for the p.(Ser396Arg) variant suggested that the change may disturb MMP2 collagen-binding region.
CONCLUSION
Our findings expand the genetic spectrum of Multicentric osteolysis nodulosis and arthropathy. We also suggest that the age of onset of this disorder may vary from childhood up to late adolescence and that a significant degree of intrafamilial variability may be present.
Topics: Adolescent; Humans; Child; Hajdu-Cheney Syndrome; Matrix Metalloproteinase 2; Joint Diseases; Osteolysis
PubMed: 37710205
DOI: 10.1186/s12891-023-06856-2 -
American Journal of Medical Genetics.... Jan 2023Hajdu-Cheney syndrome is an ultra-rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct...
Hajdu-Cheney syndrome is an ultra-rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct facial appearance, skull deformity, joint laxity, osteoporosis, and short stature. Associated abnormalities are congenital heart disease, congenital defects of the kidney, and neurological problems. Here, we present the first reported case of an African child with a variant in NOTCH2 gene and features of Hajdu-Cheney syndrome in whom we detected a congenital heart defect that has not been previously reported in association with the syndrome. To appropriately characterize this disease and document correct proportion of cardiovascular malformation associations, echocardiography is recommended for all cases of Hajdu Cheney syndrome.
Topics: Child; Humans; Hajdu-Cheney Syndrome; Receptor, Notch2; Osteoporosis; Heterozygote; Cardiovascular Abnormalities
PubMed: 36301051
DOI: 10.1002/ajmg.a.63013 -
Dermatology Online Journal Aug 2022Werner syndrome (WS) is an autosomal recessive syndrome characterized by genomic instability that affects multiple body systems. The characteristic features of the...
Werner syndrome (WS) is an autosomal recessive syndrome characterized by genomic instability that affects multiple body systems. The characteristic features of the disease include growth retardation, short stature, alopecia, scleroderma, atrophic skin with ulcerations, infertility, cataracts, premature arteriolosclerosis, diabetes, osteoporosis, and increased risk of malignancies. Werner syndrome protein (WRN) protein deficiency in this disease causes changes in gene expression, similar to those observed in normal aging. As the median age of death in WS is the fourth or fifth decade of life, early diagnosis leads to a better screening opportunity for malignancies. Herein, we present a 28-year-old woman who presented with growth arrest, dyspigmentation, and acroosteolysis and was later diagnosed with Werner syndrome.
Topics: Female; Humans; Adult; Werner Syndrome; Acro-Osteolysis; Osteoporosis; Diabetes Mellitus; Aging
PubMed: 36259858
DOI: 10.5070/D328458520 -
JMIR Dermatology Sep 2023Environmental vinyl chloride (VC) exposure may result in serious acute and chronic dermatological conditions. Because existing literature largely focuses on exposures in... (Review)
Review
BACKGROUND
Environmental vinyl chloride (VC) exposure may result in serious acute and chronic dermatological conditions. Because existing literature largely focuses on exposures in occupational settings, a gap persists in our understanding of the medical consequences of large-scale chemical spills.
OBJECTIVE
This study aims to examine the potential dermatological manifestations of VC exposure in the context of industrial spills and other environmental disasters and to highlight the public health and justice implications of such releases.
METHODS
In this narrative review, relevant evidence-based, peer-reviewed scientific sources, gray literature, and media reports were identified via searches of search PubMed and Google using predetermined keyword search terms related to VC, VC spills and releases, train derailment, cutaneous disease, public health, and vulnerable and marginalized populations.
RESULTS
Contact dermatitis and frostbite may arise acutely, highlighting the importance of swift decontamination. Long-term manifestations from chronic VC exposure due to persistence in environmental reservoirs include Raynaud disease, sclerodermatous skin changes, acro-osteolysis, and cutaneous malignancies. The clinical severity of cutaneous manifestations is influenced by individual susceptibility as well as duration, intensity, and route of exposure. Additionally, chemical releases of VC more frequently impact Communities of Color and those of lower socioeconomic status, resulting in greater rates of exposure-related disease.
CONCLUSIONS
With environmental release events of hazardous chemicals becoming increasingly common and because the skin has increased contact with environmental toxins relative to other organs, an urgent need exists for a greater understanding of the overall short- and long-term health impacts of large-scale, toxic exposures, underscoring the need for ongoing clinical vigilance. Dermatologists and public health officials should also aim to better understand the ways in which the disproportionate impacts of hazardous chemical exposures on lower-income and minority populations may exacerbate existing health disparities. Herein, we describe the health implications of toxic releases with particular consideration paid to marginalized and vulnerable populations. In addition to legal and regulatory frameworks, we advocate for improved public health measures, to not only mitigate the risk of environmental catastrophes in the future, but also ensure timely and effective responses to them.
PubMed: 37676716
DOI: 10.2196/48998