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Acta Ortopedica Mexicana 2020Joint hypermobility syndrome is an inherited disorder with autosomal dominant pattern; is characterized by joint hyperlaxity and musculoskeletal pains. Thermal... (Review)
Review
Joint hypermobility syndrome is an inherited disorder with autosomal dominant pattern; is characterized by joint hyperlaxity and musculoskeletal pains. Thermal hypermobility refers to the increase in active or passive movements of joints based on their normal ranges. Joint hypermobility syndrome also has gastrointestinal symptoms, sleep disorders, fibromyalgia, psychological disorders, migraine headache, ophthalmic, autonomic, among others. To diagnose hypermobility syndrome, Brighton's criteria are generally accepted and published in 1998. This criteria also known as benign joint hypermobility syndrome. The term benign is used to distinguish it from other more severe conditions such as Ehler-Danlos (classic or vascular type), Marfan syndrome, and imperfect osteogenesis. Treatment with physiotherapy and pharmacological means help improve patients' quality of life.
Topics: Ehlers-Danlos Syndrome; Humans; Joint Instability; Quality of Life; Range of Motion, Articular; Skin Abnormalities
PubMed: 34020527
DOI: No ID Found -
Current Rheumatology Reports Nov 2021Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations... (Review)
Review
PURPOSE OF REVIEW
Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5-10,000 (Chiu et al. Mayo Clin Proc. 89(1):34-42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476-85, 4).
RECENT FINDINGS
The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30-50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149-58, 147, Murdoch et al. N Engl J Med. 286(15):804-8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308-1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the "systemic features score" (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.
Topics: Cardiovascular Diseases; Humans; Marfan Syndrome; Quality of Life
PubMed: 34825999
DOI: 10.1007/s11926-021-01045-3 -
Nature Jun 2018CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results... (Clinical Trial)
Clinical Trial
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Topics: Adult; Animals; Child; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; HeLa Cells; Heart Failure; Humans; Lipoma; Male; Mice; Molecular Targeted Therapy; Musculoskeletal Abnormalities; Nevus; Phenotype; Scoliosis; Sirolimus; Syndrome; Thiazoles; Vascular Malformations; Vascular Neoplasms
PubMed: 29899452
DOI: 10.1038/s41586-018-0217-9 -
Human Mutation Apr 2010Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or... (Review)
Review
Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling.
Topics: Humans; Mutation; Transcription Factors; Waardenburg Syndrome
PubMed: 20127975
DOI: 10.1002/humu.21211 -
Birth Defects Research Nov 2019Using the National Birth Defects Prevention Network (NBDPN) annual data report, U.S. national prevalence estimates for major birth defects are developed based on birth...
BACKGROUND
Using the National Birth Defects Prevention Network (NBDPN) annual data report, U.S. national prevalence estimates for major birth defects are developed based on birth cohort 2010-2014.
METHODS
Data from 39 U.S. population-based birth defects surveillance programs (16 active case-finding, 10 passive case-finding with case confirmation, and 13 passive without case confirmation) were used to calculate pooled prevalence estimates for major defects by case-finding approach. Fourteen active case-finding programs including at least live birth and stillbirth pregnancy outcomes monitoring approximately one million births annually were used to develop national prevalence estimates, adjusted for maternal race/ethnicity (for all conditions examined) and maternal age (trisomies and gastroschisis). These calculations used a similar methodology to the previous estimates to examine changes over time.
RESULTS
The adjusted national birth prevalence estimates per 10,000 live births ranged from 0.62 for interrupted aortic arch to 16.87 for clubfoot, and 19.93 for the 12 critical congenital heart defects combined. While the birth prevalence of most birth defects studied remained relatively stable over 15 years, an increasing prevalence was observed for gastroschisis and Down syndrome. Additionally, the prevalence for atrioventricular septal defect, tetralogy of Fallot, omphalocele, and trisomy 18 increased in this period compared to the previous periods. Active case-finding programs generally had higher prevalence rates for most defects examined, most notably for anencephaly, anophthalmia/microphthalmia, trisomy 13, and trisomy 18.
CONCLUSION
National estimates of birth defects prevalence provide data for monitoring trends and understanding the impact of these conditions. Increasing prevalence rates observed for selected conditions warrant further examination.
Topics: Adult; Cardiovascular Abnormalities; Central Nervous System Diseases; Congenital Abnormalities; Eye Diseases; Female; Genetic Diseases, Inborn; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Middle Aged; Musculoskeletal Diseases; Population Surveillance; Pregnancy; Prevalence; Registries; United States; Young Adult
PubMed: 31580536
DOI: 10.1002/bdr2.1589 -
Italian Journal of Pediatrics Feb 2021Positional plagiocephaly (PP) is a cranial deformation frequent amongst children and consisting in a flattened and asymmetrical head shape. PP is associated with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Positional plagiocephaly (PP) is a cranial deformation frequent amongst children and consisting in a flattened and asymmetrical head shape. PP is associated with excessive time in supine and with congenital muscular torticollis (CMT). Few studies have evaluated the efficiency of a manual therapy approach in PP. The purpose of this parallel randomized controlled trial is to compare the effectiveness of adding a manual therapy approach to a caregiver education program focusing on active rotation range of motion (AROM) and neuromotor development in a PP pediatric sample.
METHODS
Thirty-four children with PP and less than 28 week-old were randomly distributed into two groups. AROM and neuromotor development with Alberta Infant Motor Scale (AIMS) were measured. The evaluation was performed by an examiner, blinded to the randomization of the subjects. A pediatric integrative manual therapy (PIMT) group received 10-sessions involving manual therapy and a caregiver education program. Manual therapy was addressed to the upper cervical spine to mobilize the occiput, atlas and axis. The caregiver educational program consisted in exercises to reduce the positional preference and to stimulate motor development. The control group received the caregiver education program exclusively. To compare intervention effectiveness across the groups, improvement indexes of AROM and AIMS were calculated using the difference of the final measurement values minus the baseline measurement values. If the distribution was normal, the improvement indexes were compared using the Student t-test for independent samples; if not, the Mann-Whitney U test was used. The effect size of the interventions was calculated using Cohen's d.
RESULTS
All randomized subjects were analysed. After the intervention, the PIMT group showed a significantly higher increase in rotation (29.68 ± 18.41°) than the control group (6.13 ± 17.69°) (p = 0.001). Both groups improved the neuromotor development but no statistically significant differences were found. No harm was reported during the study.
CONCLUSION
The PIMT intervention program was more effective in increasing AROM than using only a caregiver education program. The study has been retrospectively registered at clinicaltrials.gov, with identification number NCT03659032 . Registration date: September 1, 2018.
Topics: Female; Follow-Up Studies; Head Movements; Humans; Infant; Infant, Newborn; Male; Musculoskeletal Manipulations; Neck; Plagiocephaly, Nonsynostotic; Prospective Studies; Supine Position
PubMed: 33632268
DOI: 10.1186/s13052-021-00995-9 -
American Journal of Obstetrics and... Mar 2021Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity....
BACKGROUND
Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative.
OBJECTIVE
The study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis.
STUDY DESIGN
We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.
RESULTS
Overall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score-matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04-1.54); it was 1.33 (95% confidence interval, 1.08-1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60-1.50) for a daily dose of <400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified.
CONCLUSION
Our findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.
Topics: Abnormalities, Drug-Induced; Adult; COVID-19; Female; Humans; Hydroxychloroquine; Pregnancy; Pregnancy Complications; SARS-CoV-2
PubMed: 32961123
DOI: 10.1016/j.ajog.2020.09.007 -
Nature Communications Nov 2021Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of...
Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.
Topics: Animals; Bone Development; Bone Remodeling; Cell Differentiation; Homeodomain Proteins; Homeostasis; MSX1 Transcription Factor; Mesenchymal Stem Cells; Mice; Musculoskeletal Abnormalities; Osteoblasts; Osteogenesis; STAT3 Transcription Factor; Signal Transduction; Transcription, Genetic
PubMed: 34824272
DOI: 10.1038/s41467-021-27273-w -
The Cochrane Database of Systematic... Nov 2016There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available.
OBJECTIVES
To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child.
SEARCH METHODS
We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference abstracts (2010-2015) without language restriction.
SELECTION CRITERIA
We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy.
DATA COLLECTION AND ANALYSIS
Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta-analysis was not possible, we reviewed included studies narratively.
MAIN RESULTS
We included 50 studies, with 31 contributing to meta-analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random-effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro-facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose-response association for the other AEDs remained less clear.
AUTHORS' CONCLUSIONS
Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.
Topics: Abnormalities, Drug-Induced; Anticonvulsants; Cardiovascular Abnormalities; Craniofacial Abnormalities; Epilepsy; Female; Humans; Infant, Newborn; Musculoskeletal Abnormalities; Neural Tube Defects; Pregnancy; Pregnancy Complications
PubMed: 27819746
DOI: 10.1002/14651858.CD010224.pub2 -
Genetics in Medicine : Official Journal... Feb 2020Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated...
PURPOSE
Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.
METHODS
We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.
RESULTS
The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.
CONCLUSION
The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Chromatin Assembly and Disassembly; Developmental Disabilities; Female; Genetic Association Studies; Genotype; Hearing Loss; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Megalencephaly; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Musculoskeletal Abnormalities; Mutation, Missense; Neurodevelopmental Disorders; Phenotype; Syndrome; Transcription Factors
PubMed: 31388190
DOI: 10.1038/s41436-019-0612-0