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Genetics in Medicine : Official Journal... Feb 2022This study aimed to describe the comorbidity pattern in 47,XXX syndrome.
PURPOSE
This study aimed to describe the comorbidity pattern in 47,XXX syndrome.
METHODS
This was a registry-based study of hospital diagnoses and prescribed medication in a nationwide cohort of females with 47,XXX (n = 103) and 46,XX/47,XXX (n = 57) in which they were compared with 16,000 age-matched general population female controls.
RESULTS
The overall occurrence of hospital diagnoses was significantly increased in females with 47,XXX when compared with controls (incidence rate ratio = 2.1, CI = 1.7-2.5), and when divided into 19 organ-specific groups, there was a significantly increased risk in the following 14 groups: infection, blood, endocrine and metabolism, mental, nervous system, eye, ear, respiratory, oral cavity and gastrointestinal, musculoskeletal, perinatal, congenital malformations, external factors, and "other." The risk of being prescribed any medication was not significantly increased in females with 47,XXX when compared with controls (hazard ratio = 1.2, CI = 0.9-1.4). However, when stratified according to medication groups, a significantly increased risk was detected in 4 of 13 groups. The overall occurrence of hospital diagnoses was also significantly increased when females with 46,XX/47,XXX were compared with controls (incidence risk ratio = 1.3, CI = 1.01-1.8), but generally, in comparison with controls, females with 46,XX/47,XXX were less severely affected than females with 47,XXX.
CONCLUSION
The 47,XXX syndrome is associated with an increased occurrence of a wide variety of diseases. Increased awareness of this may contribute to improve counseling and clinical assessment of these patients.
Topics: Chromosomes, Human, X; Comorbidity; Epidemiologic Studies; Female; Humans; Pregnancy; Sex Chromosome Aberrations; Sex Chromosome Disorders of Sex Development; Trisomy
PubMed: 34906506
DOI: 10.1016/j.gim.2021.10.012 -
Journal of Indian Association of... 2022The aim is to study the complications of neonatal thoracotomy and its preventive measures.
AIM
The aim is to study the complications of neonatal thoracotomy and its preventive measures.
METHODS
We retrospectively reviewed 53 neonates who underwent thoracotomy from January 2017 to December 2019 for a period of 3 years. Patient demographic data, primary disease for which they underwent thoracotomy, postoperative complications (immediate and delayed) during follow-up were documented.
RESULTS
During 3-year period, 53 neonates underwent thoracotomy for various surgical pathologies. The indications were esophageal atresia with tracheoesophageal fistula ( = 49), eventration of diaphragm ( = 3), congenital lobar emphysema of left upper lobe of lung ( = 1). Most of them were right posterolateral thoracotomies ( = 48, 90.56%) and left posterolateral thoracotomy was done in only 5 cases (9.43%). Associated anomalies were seen in 22 cases, such as cardiac ( = 19), renal ( = 4) and gastrointestinal ( = 5). Associated comorbidities seen in 14 cases; preterm ( = 4), low birth weight ( = 13), delayed presentation ( = 6). Early postoperative complications such as pneumonia (34%, n = 18) and wound infection (11.3%, n = 6) were noted. Delayed complications include musculoskeletal abnormalities ( = 19, 35.8%) and esthetic complications such as asymmetry of chest (5.6%).
CONCLUSION
Neonatal thoracotomy is associated with complications such as pneumonia, wound infections, and musculoskeletal abnormalities such as asymmetry of chest and scoliosis. These can be prevented by adequate postoperative pain relief, muscle-sparing thoracotomies, avoiding tight closures, and nerve injuries. Long-term follow-up is required because these complications may manifest later on also. Early detection and institution of physiotherapy may help.
PubMed: 35733596
DOI: 10.4103/jiaps.JIAPS_19_21 -
Orphanet Journal of Rare Diseases Jul 2023Noonan syndrome spectrum disorders (NSSDs) constitute a group within the Rasopathies, and are one of the largest groups of syndromes with impact on multi-organ...
BACKGROUND
Noonan syndrome spectrum disorders (NSSDs) constitute a group within the Rasopathies, and are one of the largest groups of syndromes with impact on multi-organ involvement known. The extreme variability of the clinical phenotype is, among others, due to the numerous different genes that are involved, and the differences in clinical presentation over the life span. We have studied the needs of patients and their relatives aiming to develop, evaluate and choose focus in research, medical care and policy to better meet their perspectives.
METHODS
Using the participatory and interactive Dialogue method, 80 patients and relatives mentioned 53 different problems or needs (topics) that were categorized into eight themes. These themes and the topics within each theme, were subsequently prioritized by putting them in order of importance methodologically.
RESULTS
The four highest prioritized themes were: (1) Physical problems (non-musculoskeletal related); (2) Social, emotional and behavioral problems; (3) Cognitive functioning and information processing; and (4) Problems related to the musculoskeletal system. Nineteen out of the 53 topics were physical problems. According to the total group of respondents, the top 3 prioritized topics within theme 1 were coagulation problems, heart problems, and feeding problems. Also data stratified by age groups, phenotype (NS and other NSSDs) and gender showed some remarkable results. For instance, feeding problems were prioritized as the most important topic of the highest prioritized theme, according to patients aged 0-12 years. Also feeding problems show a significant difference in its prioritization according to female patients (2) compared to male patients (7). On the other hand, heart problems were not mentioned in the top three prioritized topics in the youngest age groups, although heart problems are generally considered most important for patients with NSSD.
CONCLUSIONS
With our results we underline the importance of methodologically inventorying the needs of NSSD patients, not only at the group level, but to also focus on specific needs according to e.g. age, phenotype and gender. For instance, it is remarkable that both the current Clinical Guidelines and the Noonan Syndrome diagnostic criteria give little to no attention to feeding problems, though our results indicate that, to the youngest patients, these problems have top priority. A similar situation appears to apply to the clinical management of e.g. coagulation, neuropsychological and musculoskeletal problems (like physiotherapy or occupational therapy) and to a need for (educational) tools to support patients at school or at work. Our study may help to shape targeted (clinical) management, research and policy inside and outside medical (research) institutes and shed light on the complex phenotypes of NSSDs, the families' and patients' perspectives on the everyday consequences of the many different problems, as well as their needs.
Topics: Humans; Male; Female; Noonan Syndrome; Cognition; Phenotype
PubMed: 37480127
DOI: 10.1186/s13023-023-02818-y -
Human Mutation Jul 2022Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome... (Review)
Review
Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.
Topics: Brachydactyly; Fibrillin-1; Fibrillin-2; Humans; Marfan Syndrome; Musculoskeletal Abnormalities; Phenotype
PubMed: 35419902
DOI: 10.1002/humu.24383 -
American Journal of Physical Medicine &... Oct 2021Individuals living with cerebral palsy or spina bifida are at heightened risk for a number of chronic health conditions, such as secondary comorbidities, that may... (Comparative Study)
Comparative Study
BACKGROUND
Individuals living with cerebral palsy or spina bifida are at heightened risk for a number of chronic health conditions, such as secondary comorbidities, that may develop or be influenced by the disability, the presence of impairment, and/or the process of aging. However, very little is known about the prevalence and/or risk of developing secondary comorbidities among individuals living with cerebral palsy or spina bifida throughout adulthood. The objective of this study was to compare the prevalence of psychological, cardiometabolic, and musculoskeletal morbidity and multimorbidity among adults with and without cerebral palsy or spina bifida.
METHODS
Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code for cerebral palsy or spina bifida (n = 29,841). Adults without cerebral palsy or spina bifida were also included (n = 5,384,849). Prevalence estimates of common psychological, cardiometabolic, and musculoskeletal morbidity and multimorbidity (≥2 conditions) were compared.
RESULTS
Adults living with cerebral palsy or spina bifida had a higher prevalence of all psychological disorders and psychological multimorbidity (14.6% vs. 5.4%), all cardiometabolic disorders and cardiometabolic multimorbidity (22.4% vs. 15.0%), and all musculoskeletal disorders and musculoskeletal multimorbidity (12.2% vs. 5.4%), as compared with adults without cerebral palsy or spina bifida, and differences were to a clinically meaningful extent.
CONCLUSIONS
Adults with cerebral palsy or spina bifida have a significantly higher prevalence of common psychological, cardiometabolic, and musculoskeletal morbidity and multimorbidity, as compared with adults without cerebral palsy or spina bifida. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of disease onset/progression in these higher risk populations.
TO CLAIM CME CREDITS
Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME.
CME OBJECTIVES
Upon completion of this article, the reader should be able to: (1) List the main categories of morbidity that present with higher risk in adults with cerebral palsy and spina bifida; (2) Discuss the potential impact of multimorbidity on 'early aging' in adults living with cerebral palsy and spina bifida; and (3) Describe challenges that adults with cerebral palsy and spina bifida have in obtaining appropriate health care to address prevention and treatment of multimorbidity.
LEVEL
Advanced.
ACCREDITATION
The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Cerebral Palsy; Cross-Sectional Studies; Female; Humans; Male; Mental Disorders; Middle Aged; Multimorbidity; Musculoskeletal Diseases; Prevalence; Retrospective Studies; Spinal Dysraphism; Young Adult
PubMed: 34001837
DOI: 10.1097/PHM.0000000000001787 -
Topics in Spinal Cord Injury... 2022Individuals living with cerebral palsy (CP) or spina bifida (SB) are at heightened risk for chronic health conditions that may develop or be influenced by the impairment...
BACKGROUND
Individuals living with cerebral palsy (CP) or spina bifida (SB) are at heightened risk for chronic health conditions that may develop or be influenced by the impairment and/or the process of aging.
OBJECTIVES
The objective of this study was to compare the incidence of and adjusted hazards for musculoskeletal (MSK) morbidities among adults living with and without CP or SB.
METHODS
A retrospective, longitudinal cohort study was conducted among adults living with ( = 15,302) CP or SB and without ( = 1,935,480) CP or SB. Incidence estimates of common MSK morbidities were compared at 4 years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident MSK morbidities. The analyses were performed in 2019 to 2020.
RESULTS
Adults living with CP or SB had a higher 4-year incidence of MSK morbidity (55.3% vs. 39.0%) as compared to adults without CP or SB, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with CP or SB had a greater hazard for all MSK disorders; this ranged from hazard ratio (HR) 1.40 (95% CI, 1.33 to 1.48) for myalgia to HR 3.23 (95% CI, 3.09 to 3.38) for sarcopenia and weakness.
CONCLUSION
Adults with CP or SB have a significantly higher incidence of and risk for common MSK morbidities as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of MSK disease onset/progression in these higher risk populations.
Topics: Adult; Cerebral Palsy; Humans; Longitudinal Studies; Morbidity; Retrospective Studies; Spinal Cord Injuries; Spinal Dysraphism
PubMed: 36017121
DOI: 10.46292/sci21-00078 -
ELife May 2023Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and...
BACKGROUND
Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed.
METHODS
As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth.
RESULTS
We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic p.H1047R variant and fibroblasts.
CONCLUSIONS
Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component.
FUNDING
Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.
Topics: Humans; Mice; Animals; Endothelial Cells; Vascular Endothelial Growth Factor A; Signal Transduction; Protein Kinase Inhibitors; Class I Phosphatidylinositol 3-Kinases; Vascular Malformations
PubMed: 37199488
DOI: 10.7554/eLife.82543 -
Nature Communications Jan 2024WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the...
WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
Topics: Animals; Humans; Male; Brain; Ciliopathies; Cognition; WD40 Repeats; Zebrafish; Genes, X-Linked
PubMed: 38191484
DOI: 10.1038/s41467-023-44611-2 -
Indian Journal of Ophthalmology Jun 2023Collagen vascular disorders (CVDs), also known as connective tissue diseases (CTDs), are a heterogeneous group of entities that affect the connective tissues and are... (Review)
Review
Collagen vascular disorders (CVDs), also known as connective tissue diseases (CTDs), are a heterogeneous group of entities that affect the connective tissues and are capable of causing end-organ damage to multiple systems, primarily cardiopulmonary and musculoskeletal. However, the occurrence and severity are highly variable among patients. Ocular involvement occurs in a significant number of these disorders and may precede the onset of other extraocular features, thereby serving as an important marker in the diagnosis of these diseases. A timely and accurate diagnosis enables the management of complications. CTDs are primarily immune-mediated inflammatory diseases; however, classifications have encompassed heritable disorders affecting collagen-containing structures and disorders of vascular development. A review of literature published until 25 January 2022 and collected from various databases using the relevant keywords was conducted. All publications (original articles, review articles, as well as case reports) describing the ocular features in CTDs were studied in detail. The objective of this review is to recognize the common ophthalmic presentations of various autoimmune and heritable CTDs, distinguish them from overlapping diseases, elaborate on the prognosis and management of these varied eye presentations, and deliberate on their impact on other ophthalmic surgeries.
Topics: Humans; Connective Tissue Diseases; Connective Tissue; Skin Abnormalities; Autoimmune Diseases; Collagen
PubMed: 37322648
DOI: 10.4103/ijo.IJO_286_22 -
Orphanet Journal of Rare Diseases Mar 2022Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a...
BACKGROUND
Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present study was to assess the overall burden of musculoskeletal disease in patients with Marfan syndrome.
MATERIALS AND METHODS
A registry-based, nationwide epidemiological study of patients with a Ghent II verified Marfan syndrome diagnosis from 1977 to 2014. Each patient was matched on age, and sex with up to 100 controls from the background population.
RESULTS
We identified 407 patients with Marfan syndrome and 40,700 controls and compared their musculoskeletal diagnoses and surgical treatments using Cox proportional hazards ratio (HR). The risk of a registration of a musculoskeletal diagnosis in patients with Marfan syndrome was significantly increased compared to controls (HR: 1.94 (1.69-2.24). One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9). Scoliosis was more common in women with Marfan syndrome compared to men (HR: 4.30 (1.73-1.08)). One out of 11 were registered with a pectus deformity HR: 40.8 (28.1-59.3), and one out of six with a deformity of the foot. Primarily pes planus (HR: 26.0 (15.2-44.3). The proportion of patients with Marfan syndrome (94/407) that underwent musculoskeletal surgery was also significantly higher (HR: 1.76 (1.43-2.16)). The major areas of surgery were the spine, pectups correction, and surgery of the foot/ankle. Ten patients with Marfan syndrome had elective orthopedic surgery without being recognized and diagnosed with Marfan syndrome until later in life. None of these had scoliosis, pectus deformity or a foot deformity. Among patients with an aortic dissection, the age at dissection was 34.3 years in those with at least one major musculoskeletal abnormality. In patients without a major abnormality the age at dissection was 45.1 years (p < 0.01).
CONCLUSIONS
The extent of musculoskeletal disease is quite significant in Marfan syndrome, and many will need corrective surgery during their life span. Surgeons should be aware of undiagnosed patients with Marfan syndrome when treating patients with a Marfan syndrome like-phenotype.
Topics: Female; Humans; Marfan Syndrome; Proportional Hazards Models; Registries; Scoliosis
PubMed: 35248143
DOI: 10.1186/s13023-022-02272-2