Effects of abnormal muscle forces on prenatal joint morphogenesis in mice

AbstractFetal movements are essential for normal development of the human skeleton. When fetal movements are reduced or restricted, infants are at higher risk of developmental dysplasia of the hip and arthrogryposis (multiple joint contractures). Joint shape abnormalities have been reported in mouse models with abnormal or absent musculature, but the effects on joint shape in such models have not been quantified or characterised in detail. In this study, embryonic mouse forelimbs and hindlimbs at a single developmental stage (Theiler Stage 23) with normal, reduced or absent muscle were imaged in 3D. Skeletal rudiments were virtually segmented and rigid image registration was used to reliably align rudiments with each other, enabling repeatable assessment and measurement of joint shape differences between normal, reduced-muscle and absent muscle groups. We demonstrate qualitatively and quantitatively that joint shapes are differentially affected by a lack of, or reduction in, skeletal muscle, with the elbow joint being the most affected of the major limb joints. Surprisingly, the effects of reduced muscle were often more pronounced than those of absent skeletal muscle, indicating a complex relationship between muscle mass and joint morphogenesis. These findings have relevance for human developmental disorders of the skeleton in which abnormal fetal movements are implicated, particularly developmental dysplasia of the hip and arthrogryposis.

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Prenatal murine skeletogenesis partially recovers from absent skeletal muscle as development progresses

10.1101/2022.01.01.473639 ◽

2022 ◽

Author(s):

Vivien Sotiriou ◽

Saima Ahmed ◽

Niamh Nowlan

Keyword(s):

Skeletal Muscle ◽

Mouse Model ◽

Developmental Stages ◽

Skeletal Development ◽

Normal Growth ◽

Developmental Dysplasia ◽

Muscle Contractions ◽

Joint Shape ◽

Dysplasia Of The Hip ◽

Over Time

Skeletal muscle contractions are critical for normal growth and morphogenesis of the skeleton, but it is unclear how the detrimental effects of absent muscle on the bones and joints change over time. Joint size, shape and cavitation, and rudiment length and mineralisation were assessed in multiple rudiments at two developmental stages (Theiler Stage (TS)24 and TS27) in the splotch-delayed 'muscleless limb' mouse model and littermate controls. As development progressed, the effects of absent muscle on all parameters except for cavitation become less severe. All major joints in muscleless limbs were qualitatively and quantitatively abnormal in shape at TS24, while, by TS27, most muscleless joint shapes were normal, or nearly normal. In contrast, any joints which were fused at TS24 did not cavitate by TS27. Therefore, recovery in joint shape over development occurred despite absent cavitation. Mineralisation showed the most pronounced changes between TS24 and TS27 in the muscleless limbs. At TS24, all muscleless rudiments studied had less mineralisation than the controls, while at TS27, muscleless limb rudiments had either the same or significantly more mineralisation than controls of the same age. We conclude that the effects of absent muscle on prenatal murine skeletogenesis are most pronounced in early skeletal development and reduce in severity prior to birth. Understanding how mammalian bones and joints continue to develop in an environment without muscle contractions, but with mechanical stimulation due to the movement of the mother, provides important insights into conditions affecting human babies such as developmental dysplasia of the hip and arthrogryposis.

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Prenatal Screening for Developmental Displacement of the Hip: The BUDDHA (Pre-Birth Ultrasound for Developmental Displacement of the Hip Assessment) Study

Diagnostics ◽

10.3390/diagnostics11050868 ◽

2021 ◽

Vol 11 (5) ◽

pp. 868

Author(s):

Elena Contro ◽

Laura Larcher ◽

Jacopo Lenzi ◽

Arianna Benfenati ◽

Giulia Massinissa Magini ◽

...

Keyword(s):

Normal Development ◽

Normal Values ◽

3D Ultrasound ◽

Tertiary Hospital ◽

Developmental Dysplasia ◽

Prenatal Ultrasound ◽

3D Volume ◽

Volume Acquisition ◽

The Buddha ◽

Dysplasia Of The Hip

Background: developmental dysplasia of the hip has an incidence of 3–5 out of 1000 children. Currently, only postnatal screening is available. Objective: to test the feasibility of a method based on Graf technique application at antenatal ultrasound in assessing the normal development of the hip in unselected term fetuses. Methods: a prospective cohort study in a single university tertiary hospital from January 2017 to January 2020. Single uncomplicated term pregnancies (37–40 weeks) attending our center for routine ultrasound were consecutively recruited for the purpose of the study. A 3D volume acquisition was launched on the coxofemoral joint of the fetus by a single expert operator, and offline analysis was then performed in the multiplanar mode by two operators (blinded to each other analysis) in order to measure the alpha and beta angles according to our modified Graf technique. Intra- and inter-observer variations were calculated. Reference charts for normal values of both angles were produced. Postnatal ultrasound was then performed to measure the Graf angles in newborns, confirming a normal development of the hip. Results: in the study period, 433 uncomplicated term pregnancies underwent 3D ultrasound for the assessment of the fetal hip. One case was subsequently excluded because of confirmed postnatal diagnosis of developmental dysplasia of the hip. The measurement of our modified Graf angles was feasible at prenatal ultrasound with a good reproducibility. The inter-rater and intra-rater reliability of both angles was substantial. Reference charts for normal values of both angles were produced. Conclusions: the evaluation of the coxofemoral joint in fetuses at term of gestation has never been attempted before. The Graf technique application, currently employed at postnatal ultrasound, may also be adapted to prenatal ultrasound with a substantial reproducibility. However, there was no evidence of a linear relationship between prenatal and postnatal alpha angles and beta angles. Further research is needed to establish if developmental dysplasia of the hip could be diagnosed antenatally.

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4-year follow-up of ultrasound-based diagnosis and non-surgical treatment of developmental dysplasia of the hip in mongolia: a prospective cohort study

Ultraschall in der Medizin - European Journal of Ultrasound ◽

10.1055/s-0036-1587724 ◽

2016 ◽

Vol 37 (S 01) ◽

Cited By ~ 1

Author(s):

T Baumann ◽

B Munkhuu ◽

B Chuluunbaatar ◽

R Schmid ◽

S Essig

Keyword(s):

Cohort Study ◽

Surgical Treatment ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Developmental Dysplasia ◽

Dysplasia Of The Hip ◽

Non Surgical Treatment

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Faculty Opinions recommendation of Avascular necrosis following closed reduction for treatment of developmental dysplasia of the hip: a systematic review.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.729524230.793540307 ◽

2017 ◽

Author(s):

Edilson Forlin

Keyword(s):

Systematic Review ◽

Avascular Necrosis ◽

Closed Reduction ◽

Developmental Dysplasia ◽

Dysplasia Of The Hip

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Screening of Developmental Dysplasia of the Hip in Neonates with Breech Presentation

مجلة دراسات الطفولة ◽

10.21608/jsc.2015.60708 ◽

2015 ◽

Vol 18 (10.2015) ◽

pp. 0-0

Keyword(s):

Breech Presentation ◽

Developmental Dysplasia ◽

Dysplasia Of The Hip

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Prediction of the requirement of open reduction for developmental dysplasia of the hip

Journal of International Medical Research ◽

10.1177/0300060517717357 ◽

2017 ◽

Vol 46 (1) ◽

pp. 54-61 ◽

Cited By ~ 8

Author(s):

Nabil Alassaf

Keyword(s):

Open Reduction ◽

Area Under The Curve ◽

Internal Validity ◽

Developmental Dysplasia ◽

Estimation Model ◽

Cross Sectional ◽

Noninvasive Treatment ◽

Dysplasia Of The Hip ◽

Logistic Regression Equation ◽

Objective Tool

Objective Closed reduction (CR) is a noninvasive treatment for developmental dysplasia of the hip (DDH), and this treatment is confirmed intraoperatively. This study aimed to develop a preoperative estimation model of the probability of requiring open reduction (OR) for DDH. Methods The study design was cross-sectional by screening all patients younger than 2 years who had attempted CR between October 2012 and July 2016 by a single surgeon. Potential diagnostic determinants were sex, age, side, bilaterality, International Hip Dysplasia Institute (IHDI) grade, and acetabular index (AI). An intraoperative arthrogram was the reference standard. A logistic regression equation was built from a reduced model. Bootstrapping was performed for internal validity. Results A total of 164 hips in 104 patients who met the inclusion criteria were analysed. The prevalence of CR was 72.2%. Independent factors for OR were older age, higher IHDI grade, and lower AI. The probability of OR = 1/[1 + exp − (−2.753 + 0.112 × age (months) + 1.965 × IHDI grade III (0 or 1) + 3.515 × IHDI grade IV (0 or 1) − 0.058 × AI (degrees)]. The area under the curve was 0.79. Conclusion This equation is an objective tool that can be used to estimate the requirement for OR.

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Accuracy of New Deep Learning Model-Based Segmentation and Key-Point Multi-Detection Method for Ultrasonographic Developmental Dysplasia of the Hip (DDH) Screening

Diagnostics ◽

10.3390/diagnostics11071174 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1174

Author(s):

Si-Wook Lee ◽

Hee-Uk Ye ◽

Kyung-Jae Lee ◽

Woo-Young Jang ◽

Jong-Ha Lee ◽

...

Keyword(s):

Deep Learning ◽

Intraclass Correlation ◽

Alpha Angle ◽

Learning Model ◽

Developmental Dysplasia ◽

Human Observer ◽

Intraobserver Variability ◽

Cad System ◽

Deep Learning Model ◽

Dysplasia Of The Hip

Hip joint ultrasonographic (US) imaging is the golden standard for developmental dysplasia of the hip (DDH) screening. However, the effectiveness of this technique is subject to interoperator and intraobserver variability. Thus, a multi-detection deep learning artificial intelligence (AI)-based computer-aided diagnosis (CAD) system was developed and evaluated. The deep learning model used a two-stage training process to segment the four key anatomical structures and extract their respective key points. In addition, the check angle of the ilium body balancing level was set to evaluate the system’s cognitive ability. Hence, only images with visible key anatomical points and a check angle within ±5° were used in the analysis. Of the original 921 images, 320 (34.7%) were deemed appropriate for screening by both the system and human observer. Moderate agreement (80.9%) was seen in the check angles of the appropriate group (Cohen’s κ = 0.525). Similarly, there was excellent agreement in the intraclass correlation coefficient (ICC) value between the measurers of the alpha angle (ICC = 0.764) and a good agreement in beta angle (ICC = 0.743). The developed system performed similarly to experienced medical experts; thus, it could further aid the effectiveness and speed of DDH diagnosis.

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