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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 -
Science (New York, N.Y.) Jan 2023Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related...
Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.
Topics: Animals; Mice; Arthrogryposis; Contracture; Mechanotransduction, Cellular; Mutation; Sensory Receptor Cells; Ion Channels
PubMed: 36634173
DOI: 10.1126/science.add3598 -
American Journal of Human Genetics Jun 2021Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome...
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
Topics: Abnormalities, Multiple; Adenosine Triphosphatases; Case-Control Studies; Cohort Studies; Craniofacial Abnormalities; DNA Methylation; Epigenesis, Genetic; Female; Genetic Predisposition to Disease; Growth Disorders; Heart Septal Defects, Ventricular; Humans; Infant, Newborn; Male; Mutation; Neurodevelopmental Disorders; Phenotype
PubMed: 33909990
DOI: 10.1016/j.ajhg.2021.04.008 -
Frontiers in Endocrinology 2022Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the...
CONTEXT
Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy.
OBJECTIVE
This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response.
PATIENTS AND METHODS
One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including , and . The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized.
RESULTS
Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include , , , , and in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years.
CONCLUSIONS
A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required.
Topics: Cohort Studies; Collagen; Dwarfism; Human Growth Hormone; Humans; Musculoskeletal Abnormalities; Mutation; Recombinant Proteins
PubMed: 35250876
DOI: 10.3389/fendo.2022.820001 -
European Journal of Physical and... Jun 2023Flatfoot is a musculoskeletal problem associated with dysfunctional active and passive supporting structures of the normal foot curvature. Strengthening of the intrinsic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Flatfoot is a musculoskeletal problem associated with dysfunctional active and passive supporting structures of the normal foot curvature. Strengthening of the intrinsic foot muscles or using shoe orthosis are recommend treatment approaches. However, investigating the effect of combining both approaches is still warranted.
AIM
To examine the effect of applying short foot exercises (SFE) combined with shoe insole versus shoe insole alone on foot pressure measures, pain, function and navicular drop in individuals with symptomatic flexible flatfoot.
DESIGN
Prospective, active control, parallel-group, assessor-blinded, randomized controlled trial and intention-to-treat analysis.
SETTING
Outpatient physical therapy clinic of a university teaching hospital.
POPULATION
Forty participants with symptomatic flexible flatfoot.
METHODS
A six-week treatment protocol of SFE (three sets of 10 repetitions a day) in addition to shoe insole (eight hours a day) (experimental group, N.=20) or shoe insole only (eight hours a day) (control group, N.=20). Clinic visits were made at baseline and every two weeks for monitoring and follow-up. The static and dynamic foot area, force and pressure measures, pain, lower extremity function, and navicular drop were assessed at baseline and postintervention.
RESULTS
Forty participants joined the study and 37 (92.5%) completed the six-week intervention period. Foot pressure, pain and function showed a significant interaction (P=0.02 - <0.001) and time (P<0.001) effects with a non-significant group effect in favor of the experimental group. Post-hoc analysis revealed that the experimental group had lesser pain (P=0.002) and better function (P=0.03) than the control group at six weeks. Navicular drop decreased equally in both groups.
CONCLUSIONS
Implementation of shoe insole and SFE for six weeks improved pain and function and altered foot pressure distribution greater than shoe insole alone in patients with symptomatic flatfoot.
CLINICAL REHABILITATION IMPACT
Wearing shoe insole is an easy, but passive, treatment approach for a flatfoot problem. This study provided evidence regarding the added benefit of SFE. It is recommended that rehabilitation practitioners implement a comprehensive treatment protocol including both shoe insole and SFE for at least six weeks to achieve better results for their flatfoot patients.
Topics: Humans; Flatfoot; Prospective Studies; Foot Orthoses; Foot; Pain
PubMed: 36988565
DOI: 10.23736/S1973-9087.23.07846-2 -
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 -
Italian Journal of Pediatrics Jun 2021Positional plagiocephaly frequently affects healthy babies. It is hypothesized that manual therapy tailored to pediatrics is more effective in improving plagiocephalic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Positional plagiocephaly frequently affects healthy babies. It is hypothesized that manual therapy tailored to pediatrics is more effective in improving plagiocephalic cranial asymmetry than just repositioning and sensory and motor stimulation.
METHODS
Thirty-four neurologically healthy subjects aged less than 28 weeks old with a difference of at least 5 mm between cranial diagonal diameters were randomly distributed into 2 groups. For 10 weeks, the pediatric integrative manual therapy (PIMT) group received manual therapy plus a caregiver education program, while the controls received the same education program exclusively. Cranial shape was evaluated using anthropometry; cranial index (CI) and cranial vault asymmetry index (CVAI) were calculated. Parental perception of change was assessed using a visual analogue scale (- 10 cm to + 10 cm).
RESULTS
CVAI presented a greater decrease in PIMT group: 3.72 ± 1.40% compared with 0.34 ± 1.72% in the control group (p = 0.000). CI did not present significant differences between groups. Manual therapy led to a more positive parental perception of cranial changes (manual therapy: 6.66 ± 2.07 cm; control: 4.25 ± 2.31 cm; p = 0.004).
CONCLUSION
Manual therapy plus a caregiver education program improved CVAI and led to parental satisfaction more effectively than solely a caregiver education program.
TRIAL REGISTRATION
Trial registration number: NCT03659032 ; registration date: September 1, 2018. Retrospectively registered.
Topics: Cephalometry; Female; Humans; Infant; Infant, Newborn; Male; Musculoskeletal Manipulations; Plagiocephaly, Nonsynostotic
PubMed: 34090515
DOI: 10.1186/s13052-021-01079-4 -
JAMA Network Open Aug 2022Universal ultrasonographic screening for developmental dysplasia of the hip (DDH) has gained increasing popularity despite the lack of benefit in terms of reducing the... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Universal ultrasonographic screening for developmental dysplasia of the hip (DDH) has gained increasing popularity despite the lack of benefit in terms of reducing the rates of late-detected cases (age ≥12 weeks) in randomized clinical trials.
OBJECTIVE
To report the reported incidence of DDH in the English scientific literature and compare rates of late-detected cases in settings with different DDH screening strategies.
DATA SOURCES
PubMed, Scopus, and Web of Science databases were searched on November 25 and 27, 2021. No time filters were used in the search.
STUDY SELECTION
All observational studies reporting the incidence of early-detected or late-detected (age ≥12 weeks) DDH were included. Non-English reports were excluded if the abstract did not include enough information to be included for analysis.
DATA EXTRACTION AND SYNTHESIS
The number of newborns screened and the detection rates were extracted. Meta-analysis calculated the pooled incidence of DDH per 1000 newborns with 95% CIs using a random- or fixed-effects model. This study is reported according to the PRISMA and MOOSE guidelines.
MAIN OUTCOMES AND MEASURES
The main outcome measures were early detection, early treatment, late detection, and operative treatment incidences.
RESULTS
A total of 1899 studies were identified, 203 full texts were assessed, and 76 studies with 16 901 079 infants were included in final analyses. The early detection rate was 8.4 (95% CI, 4.8-14.8) infants with DDH per 1000 newborns with clinical screening, 4.4 (95% CI, 2.4-8.0) infants with DDH per 1000 newborns with selective ultrasonographic screening, and 23.0 (95% CI, 15.7-33.4) infants with DDH per 1000 newborns with universal ultrasonographic screening. Rates for nonoperative treatment were 5.5 (95% CI, 2.1-14) treatments per 1000 newborns with clinical screening, 3.1 (95% CI, 2.0-4.8) treatments per 1000 newborns with selective ultrasonographic screening, and 9.8 (95% CI, 6.7-14.4) treatments per 1000 newborns with universal ultrasonographic screening. The incidence of late-detected DDH was 0.5 (95% CI, 0.2-1.5) infants with DDH per 1000 newborns with clinical screening, 0.6 (95% CI, 0.3-1.3) infants with DDH per 1000 newborns with selective ultrasonographic screening, and 0.2 (95% CI, 0.0-0.8) infants with DDH per 1000 newborns with universal ultrasonographic screening. The corresponding incidences of operative treatment were 0.2 (95% CI, 0.0-0.9) operations per 1000 newborns with clinical screening, 0.5 (95% CI, 0.4-0.7) operations per 1000 newborns with selective ultrasonographic screening, and 0.4 (95% CI, 0.2-0.7) operations per 1000 newborns with universal ultrasonographic screening.
CONCLUSIONS AND RELEVANCE
This meta-analysis found that early detection rates and nonoperative treatments were higher with universal screening. The late detection and operative treatment rates with universal screening were similar to those among selectively and clinically screened newborns. Based on these results, universal screening may cause initial overtreatment without reducing the rates of late detection and operative treatment.
Topics: Developmental Dysplasia of the Hip; Hip Dislocation, Congenital; Humans; Incidence; Infant; Infant, Newborn; Neonatal Screening; Ultrasonography
PubMed: 35980635
DOI: 10.1001/jamanetworkopen.2022.27638