-
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 -
Journal of Bone and Mineral Research :... Jan 2005
Topics: Acro-Osteolysis; Bone Morphogenetic Proteins; Carrier Proteins; Foot Deformities, Acquired; Hand Deformities, Acquired; Humans; Mutation; Sequence Analysis, DNA
PubMed: 15619682
DOI: 10.1359/JBMR.041023 -
Seminars in Cell & Developmental Biology Jun 2012Mutations in Notch signaling pathway members cause developmental phenotypes that affect the liver, skeleton, heart, eye, face, kidney, and vasculature. Notch associated... (Review)
Review
Mutations in Notch signaling pathway members cause developmental phenotypes that affect the liver, skeleton, heart, eye, face, kidney, and vasculature. Notch associated disorders include the autosomal dominant, multi-system, Alagille syndrome caused by mutations in both a ligand (Jagged1 (JAG1)) and receptor (NOTCH2) and autosomal recessive spondylocostal dysostosis, caused by mutations in a ligand (Delta-like-3 (DLL3)), as well as several other members of the Notch signaling pathway. Mutations in NOTCH2 have also recently been connected to Hajdu-Cheney syndrome, a dominant disorder causing focal bone destruction, osteoporosis, craniofacial morphology and renal cysts. Mutations in the NOTCH1 receptor are associated with several types of cardiac disease and mutations in NOTCH3 cause the dominant adult onset disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a vascular disorder with onset in the 4th or 5th decades. Studies of these human disorders and their inheritance patterns and types of mutations reveal insights into the mechanisms of Notch signaling.
Topics: Abnormalities, Multiple; Alagille Syndrome; Animals; Calcium-Binding Proteins; Hajdu-Cheney Syndrome; Heart Defects, Congenital; Heart Diseases; Hernia, Diaphragmatic; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mutation; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction
PubMed: 22306179
DOI: 10.1016/j.semcdb.2012.01.010 -
Orphanet Journal of Rare Diseases Apr 2018Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of... (Review)
Review
BACKGROUND
Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2, which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment.
METHODS
We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6-39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals).
RESULTS
The mean lumbar spine bone mineral density (BMD) z-score before treatment was - 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age (p = 0.01). There was no evidence that acro-osteolysis was prevented.
CONCLUSIONS
Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation.
Topics: Adolescent; Adult; Bone Density; Child; Female; Hajdu-Cheney Syndrome; Humans; Lumbar Vertebrae; Male; Osteoporosis; Receptor, Notch2; Retrospective Studies; Young Adult
PubMed: 29618366
DOI: 10.1186/s13023-018-0795-5 -
International Journal of Molecular... Sep 2022Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the gene. NOTCH signaling has variations... (Review)
Review
Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient's quality of life. However, no effective treatment has been established for HCS to date. There are genetic variants of that have been reported in the ClinVar database of the U.S. National Institutes of Health. In total, 26 mutant variants were detected based on the American College of Medical Genetics and Genomics (ACMC). To date, there has been no comprehensive compilation of HCS mutations. In this review, we provide the most comprehensive list possible of HCS variants, nucleotide changes, amino acid definitions, and molecular consequences reported to date, following the ACMC guidelines.
Topics: Amino Acids; Genetic Research; Hajdu-Cheney Syndrome; Humans; Mutation; Nucleotides; Quality of Life
PubMed: 36232677
DOI: 10.3390/ijms231911374 -
Proceedings of the Royal Society of... Aug 1972
Topics: Adolescent; Barium Sulfate; Bone Diseases; Bone Resorption; Calcinosis; Fingers; Humans; Jejunum; Male; Protein-Losing Enteropathies; Radiography
PubMed: 5085964
DOI: No ID Found -
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 -
Journal of Cellular and Molecular... Jul 2022Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and...
Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and characterized by a prematurely aged appearance with lipoatrophy, skin lesions, thin hair and acro-osteolysis. Activating mutations in PDGFRB have been associated with other human diseases, including Kosaki overgrowth syndrome, infantile myofibromatosis, fusiform aneurysms, acute lymphoblastic leukaemia and myeloproliferative neoplasms associated with eosinophilia. The goal of the present study was to characterize the PDGFRB p.Val665Ala variant associated with Penttinen syndrome at the molecular level. This substitution is located in a conserved loop of the receptor tyrosine kinase domain. We observed that the mutant receptor was expressed at a lower level but showed constitutive activity. In the absence of ligand, the mutant activated STAT1 and elicited an interferon-like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase Cγ was weak or undetectable. It was devoid of oncogenic activity in two cell proliferation assays, contrasting with classical PDGF receptor oncogenic mutants. STAT1 activation was not sensitive to ruxolitinib and did not rely on interferon-JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild-type receptor. Importantly, this concentration remained in the therapeutic range. Dasatinib, nilotinib and ponatinib also inhibited the mutant receptor. In conclusion, the p.Val665Ala variant confers unique features to PDGF receptor β compared with other characterized gain-of-function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.
Topics: Acro-Osteolysis; Aged; Humans; Interferons; Limb Deformities, Congenital; Myofibromatosis; Progeria; Receptor, Platelet-Derived Growth Factor beta; STAT1 Transcription Factor
PubMed: 35689379
DOI: 10.1111/jcmm.17427 -
JAMA Dermatology Mar 2023Degos-like lesions are cutaneous manifestations of a small-vessel vasculopathy that appear as atrophic, porcelain-white papules with red, telangiectatic borders. No...
IMPORTANCE
Degos-like lesions are cutaneous manifestations of a small-vessel vasculopathy that appear as atrophic, porcelain-white papules with red, telangiectatic borders. No study has adequately examined Degos-like lesions in patients with systemic sclerosis (SSc).
OBJECTIVE
To characterize the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions in a large cohort of patients with SSc.
DESIGN, SETTINGS, AND PARTICIPANTS
This retrospective cohort study involved adult patients with SSc who were seen at Stanford Rheumatologic Dermatology Clinic between January 1, 1998, and December 31, 2018. Participants fulfilled the 2013 classification criteria for SSc. Data analysis was conducted from February 1 to June 1, 2019.
MAIN OUTCOMES AND MEASURES
Data on demographic characteristics; autoantibody status; clinical characteristics, including cutaneous and systemic manifestations of SSc; and presence of Degos-like lesions were collected.
RESULTS
The cohort comprised 506 patients with SSc (447 females [88.3%]; mean [SD] age at first non-Raynaud disease symptoms, 46.1 [15.2] years). Twenty-seven patients (5.3%) had Degos-like lesions, of whom 24 (89.0%) had lesions affecting the fingers. Patients with Degos-like lesions were more likely to have diffuse cutaneous SSc compared with patients without lesions (15 [55.6%] vs 181 [37.8%]; P = .04). Degos-like lesions were also associated with acro-osteolysis (10 [37.0%] vs 62 [12.9%]; P < .01), digital ulcers (15 [55.6%] vs 173 [36.1%]; P = .04), and calcinosis (15 [55.6%] vs 115 [24.0%]; P < .01). While Degos-like lesions were not associated with internal organ manifestations, such as scleroderma renal crisis, interstitial lung disease, or pulmonary arterial hypertension, there was P < .10 for the association with gastric antral vascular ectasia.
CONCLUSIONS AND RELEVANCE
Results of this study suggest an association of Degos-like lesions with diffuse cutaneous SSc and other cutaneous manifestations of vasculopathy, including acro-osteolysis, calcinosis, and digital ulcers. A prospective longitudinal study is warranted to examine the onset of Degos-like lesions and to elucidate whether these lesions play a role in SSc.
Topics: Adult; Female; Humans; Adolescent; Longitudinal Studies; Prospective Studies; Retrospective Studies; Scleroderma, Systemic; Acro-Osteolysis; Vascular Diseases; Calcinosis
PubMed: 36753129
DOI: 10.1001/jamadermatol.2022.6330