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Journal of Clinical Medicine Apr 2024Achondroplasia is a rare genetic disease, yet the most common form of dwarfism, characterized by limb shortening and disproportionate short stature along with...
Achondroplasia is a rare genetic disease, yet the most common form of dwarfism, characterized by limb shortening and disproportionate short stature along with musculoskeletal changes, such as postural deviations. Although postural changes in the spine in children with achondroplasia have been well investigated, little is known about the association of achondroplasia with spinal movements/mobility. This preliminary study aims to explore the association of achondroplasia with spinal mobility in children with achondroplasia compared to age- and sex-matched healthy individuals. Spinal posture and mobility were assessed using a radiation-free back scan, the Idiag M360 (Idiag, Fehraltorf, Switzerland). Between-group differences were determined using a two-way analysis of variance. Children with achondroplasia had smaller thoracic lateral flexion [difference between groups (Δ) = 20.4°, 95% CI 0.1°-40.6°, = 0.04], lumbar flexion (Δ = 17.4°, 95% CI 5.5°-29.4°, = 0.006), lumbar extension (Δ = 14.2°, 95% CI 5.7°-22.8°, = 0.002) and lumbar lateral flexion (Δ = 19.6°, 95% CI 10.7°-28.4°, < 0.001) than age- and sex-matched healthy individuals, except for thoracic extension (Δ = 16.5°, 95% CI 4.4°-28.7°, = 0.009) which was greater in children with achondroplasia. No differences were observed in global spinal postures between the two groups. Spinal mobility appears to be more influenced by achondroplasia than global spinal postures in childhood. These results also highlight the importance of considering the musculoskeletal assessment of segmental spinal postures and rehabilitative interventions aimed at promoting spinal flexibility in children with achondroplasia.
PubMed: 38610900
DOI: 10.3390/jcm13072135 -
Proceedings (Baylor University. Medical... 2024Achondroplasia is the most common form of dwarfism, and cesarean delivery is often required in parturients with achondroplasia due to cephalopelvic disproportion. Given...
BACKGROUND
Achondroplasia is the most common form of dwarfism, and cesarean delivery is often required in parturients with achondroplasia due to cephalopelvic disproportion. Given the challenges for both regional and general anesthetic techniques, there is no consensus on the optimal anesthetic management for cesarean delivery in these patients.
METHOD
A search of our electronic medical records for all female patients who had a diagnosis of achondroplasia and had a delivery in our health system from January 1, 2001 through June 16, 2023 was performed. Institutional review board exemption was obtained.
RESULTS
We identified seven achondroplastic patients with 12 cesarean deliveries and described their anesthetic management during labor and delivery.
CONCLUSION
Despite the historical preference of general anesthesia in achondroplastic patients due to concerns of unpredictable spinal anatomy and unreliable local anesthetic spread, neuraxial anesthesia was successfully utilized in achondroplastic parturients and is a viable option in carefully selected patients. Reduction of intrathecal local anesthetic dose that minimizes the risk of high spinal and emergent intubation, as well as a titratable neuraxial technique, can be effective in this patient population.
PubMed: 38173994
DOI: 10.1080/08998280.2023.2261084 -
Pediatric Pulmonology Dec 2023An increasing number of children with diverse medical conditions are using long-term noninvasive ventilation (NIV). This study examined the impact of demographic,...
BACKGROUND AND OBJECTIVES
An increasing number of children with diverse medical conditions are using long-term noninvasive ventilation (NIV). This study examined the impact of demographic, clinical, and technology-related factors on long-term NIV adverse events in a large cohort of children using long-term NIV.
METHODS
This was a multicenter retrospective review of all children who initiated long-term NIV in the province of Alberta, Canada, from January 2005 to September 2014, and followed until December 2015. Inclusion criteria were children who had used NIV for 3 months or more and had at least one follow-up visit with the NIV programs.
RESULTS
We identified 507 children who initiated NIV at a median age of 7.5 (interquartile range: 8.6) years and 93% of them reported at least one NIV-related adverse event during the initial follow-up visit. Skin injury (20%) and unintentional air leaks (19%) were reported more frequently at the initial visit. Gastrointestinal symptoms, midface hypoplasia, increased drooling, aspiration and pneumothorax were rarely reported (<5%). Younger age and underlying conditions such as Down syndrome, achondroplasia, and Duchenne muscular dystrophy were early predictors of unintentional air leak. Younger age also predicted child sleep disruption in the short term and ongoing parental sleep disruption. Obesity was a risk factor for persistent nasal symptoms. Mask type was not a significant predictor for NIV-related short- or long-term complications.
CONCLUSIONS
This study demonstrates that NIV-related complications are frequent. Appropriate mask-fitting and headgear adaptation, and a proactive approach to early detection may help to reduce adverse events.
Topics: Humans; Child; Noninvasive Ventilation; Continuous Positive Airway Pressure; Sleep; Retrospective Studies; Obesity
PubMed: 37701936
DOI: 10.1002/ppul.26689 -
The Journal of Craniofacial Surgery Sep 2023This study describes the craniofacial features of achondroplastic dwarfism in the paintings of Velázquez. In a PubMed search, using [Velázquez] and [dwarf], 13 titles...
This study describes the craniofacial features of achondroplastic dwarfism in the paintings of Velázquez. In a PubMed search, using [Velázquez] and [dwarf], 13 titles were found. In a Google Image search, [Velázquez] and [dwarf] retrieved 5 paintings. The craniofacial manifestations of the dwarfs depicted in the paintings were analyzed. Frontal bossing, antimongoloid slant, depressed nasal bridge (saddle nose), bulbous tip, malar hypoplasia, malocclusion, and chin asymmetry were observed. The presence of each manifestation was checked. In 5 paintings, portraits of 6 dwarfs having craniofacial deformities were found: Mariabárbola Asquin (left) in Las Meninas , Nicolasito Pertusato (right) in Las Meninas , Portrait of Sebastián de Morra, Portrait of Francisco Lezcano, The Jester Don Diego de Acedo, and Prince Balthasar Charles with a Dwarf. The most frequent craniofacial manifestation was malar hypoplasia (100%), followed by a bulbous tip (83.3%), saddle nose (66.7%), and frontal bossing (50%). Antimongoloid slant, malocclusion, and chin asymmetry were relatively rare (16.7% each). Through an analysis of 6 dwarfs in Velázquez's paintings, we can show that he realized and frequently expressed the craniofacial manifestations of achondroplasia: malar hypoplasia, bulbous tip, saddle nose, and frontal bossing. Despite the rarity of these presentations, he was also aware of antimongoloid slant, malocclusion, and chin asymmetry. Velázquez was a famous painter in the 17th century (i.e., during the Baroque period). Based on his excellent expression of the craniofacial manifestations of dwarfism, we can assume that he had a sound knowledge of anatomy, as well as malformations.
Topics: Male; Humans; Paintings; Medicine in the Arts; Achondroplasia; Bone and Bones; Dwarfism
PubMed: 37220719
DOI: 10.1097/SCS.0000000000009368 -
Journal of Functional Morphology and... Feb 2024Achondroplasia is a rare genetic skeletal condition characterized by disproportionate short stature. There is limited evidence on postural control in adults with...
BACKGROUND
Achondroplasia is a rare genetic skeletal condition characterized by disproportionate short stature. There is limited evidence on postural control in adults with achondroplasia and how lower limb lengthening (intervention) interacts with body dynamics. This study investigated sway variability during quiet standing in adults with achondroplasia with natural growth (N) and with lower limb lengthening (LL).
METHODS
Sixteen adults performed bilateral/unilateral standing tasks. Linear (total excursion, amplitude, and ellipse area) and nonlinear (sample entropy and correlation dimension) center of pressure sway metrics were analyzed in the anteroposterior/mediolateral directions. Relationships between posture metrics, strength, and physical activity were explored. Between-groups statistics were calculated.
RESULTS
The LL group exhibited amplified linear sway, indicating larger postural deviations, and reduced sample entropy and correlation dimension, indicative of more rigid and repeated corrections. The N group exhibited more unpredictable and adaptive movement corrections. Numerous correlations emerged between strength and posture measures, with relationships altered by intervention.
CONCLUSIONS
Adults with achondroplasia display distinct balance strategies influenced by intervention. The results indicate that LL is associated with altered variability and adaptability compared to natural development. Relationships with muscle strength spotlight a key role of muscle capacity in postural control modulation after growth alterations in this population.
PubMed: 38535419
DOI: 10.3390/jfmk9010039 -
BioRxiv : the Preprint Server For... Dec 2023Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that...
Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing new insights into the genetic intersection of complex traits and Mendelian disorders.
PubMed: 38106188
DOI: 10.1101/2023.12.07.570544 -
Journal of Neurosurgery. Pediatrics Nov 2023Pediatric achondroplasia is often associated with conditions requiring neurosurgical intervention, including CSF diversion and multilevel spinal decompression. However,...
OBJECTIVE
Pediatric achondroplasia is often associated with conditions requiring neurosurgical intervention, including CSF diversion and multilevel spinal decompression. However, there is a lack of clinical guidelines and reliable estimates of the benefits and risks of these interventions. This study aimed to summarize the literature on the neurosurgical management of pediatric achondroplasia patients in order to aid in determining optimal treatment and standardization of care.
METHODS
A systematic review of peer-reviewed studies with an objective diagnosis of achondroplasia, patient demographic information, and available data on neurosurgical interventions performed before 18 years of age for cervicomedullary compression, spinal stenosis, and hydrocephalus was performed. Study quality and risks of bias were assessed using standardized scores. Independent patient data on surgical indications, outcomes, reoperations, and complication risks were aggregated using means and percentages.
RESULTS
Of 204 records, 25 studies with 287 pediatric achondroplasia patients (mean age 25 ± 36 months) treated for cervicomedullary compression (n = 153), spinal stenosis (n = 100), and obstructive hydrocephalus (n = 34) were evaluated. Symptomatic cervicomedullary compression occurred early in life (mean age 31 ± 25 months), with apnea (48%), T2-weighted MRI cord signal (28%), myelopathy (27%), and delayed motor skills (15%) requiring foramen magnum decompression observed in 99% of patients, as well as cervical laminectomy in 65% of patients. Although 91% of treated patients had resolution of symptoms, 2% mortality, 9% reoperation, and 21% complication rates were reported. Spinal stenosis was treated in relatively older children (mean age 13 ± 3 years) with laminectomy (23%), as well as with instrumented fusion (73%) for neurogenic claudication (59%), back pain (15%), and sciatica (8%). Although 95% of patients had symptom resolution after surgery, 17% reported complications and 18% required reoperation. Of the hydrocephalus patients (mean age 56 ± 103 months), half were treated with endoscopic third ventriculostomy (ETV) and half had a shunt placed for progressive ventriculomegaly (66%), headaches (32%), and delayed cognitive development (4%). The shunted patients had a 3% mortality rate and an average of 1.5 shunt revisions per patient. None of the patients who underwent ETV as the primary procedure required a revision.
CONCLUSIONS
Neurosurgical intervention for pediatric achondroplasia conditions, including cervicomedullary compression, spinal stenosis, and hydrocephalus, is associated with high recovery rates and good outcomes. However, complications and reoperations are common. Further studies with follow-up into adulthood are needed to evaluate the long-term outcomes.
Topics: Child; Humans; Infant; Adolescent; Child, Preschool; Spinal Stenosis; Retrospective Studies; Laminectomy; Hydrocephalus; Achondroplasia
PubMed: 37728398
DOI: 10.3171/2023.6.PEDS23162 -
Anatomical Record (Hoboken, N.J. : 2007) Sep 2023Achondroplasia, the most common chondrodysplasia in humans, is caused by one of two gain of function mutations localized in the transmembrane domain of fibroblast growth...
Achondroplasia, the most common chondrodysplasia in humans, is caused by one of two gain of function mutations localized in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leading to constitutive activation of FGFR3 and subsequent growth plate cartilage and bone defects. Phenotypic features of achondroplasia include macrocephaly with frontal bossing, midface hypoplasia, disproportionate shortening of the extremities, brachydactyly with trident configuration of the hand, and bowed legs. The condition is defined primarily on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3 mouse model of achondroplasia, we investigated the developing chondrocranium and Meckel's cartilage (MC) at embryonic days (E)14.5 and E16.5. Sparse hand annotations of chondrocranial and MC cartilages visualized in phosphotungstic acid enhanced three-dimensional (3D) micro-computed tomography (microCT) images were used to train our automatic deep learning-based 3D segmentation model and produce 3D isosurfaces of the chondrocranium and MC. Using 3D coordinates of landmarks measured on the 3D isosurfaces, we quantified differences in the chondrocranium and MC of Fgfr3 mice relative to those of their unaffected littermates. Statistically significant differences in morphology and growth of the chondrocranium and MC were found, indicating direct effects of this Fgfr3 mutation on embryonic cranial and pharyngeal cartilages, which in turn can secondarily affect cranial dermal bone development. Our results support the suggestion that early therapeutic intervention during cartilage formation may lessen the effects of this condition.
PubMed: 37747411
DOI: 10.1002/ar.25327 -
Journal of Pediatric Orthopedics Apr 2024Individuals with achondroplasia are prone to symptomatic spinal stenosis requiring surgery. Revision rates are thought to be high; however, the precise causes and rates...
BACKGROUND
Individuals with achondroplasia are prone to symptomatic spinal stenosis requiring surgery. Revision rates are thought to be high; however, the precise causes and rates of reoperation are unknown. The primary aim of this study is to investigate the causes of reoperation after initial surgical intervention in individuals with achondroplasia and spinal stenosis. In addition, we report on surgical techniques aimed at reducing the risks of these reoperations.
METHODS
A retrospective review was conducted over an 8-year period of all patients with achondroplasia at a single institution that serves as a large referral center for patients with skeletal dysplasias. Patients with achondroplasia who underwent spinal surgery for stenosis were identified and the need for revision surgery was studied. Data collected included demographic, surgical, and revision details. Fisher exact test was used to determine if an association existed between construct type and the need for revisions.
RESULTS
Thirty-three of the 130 (22%) patients with achondroplasia required spinal stenosis surgery. Twenty-four individuals who met the criteria were selected for analysis. The initial spine surgery was at an average age of 18.7 years (SD: 10.1 y). Nine patients (38%) required revision surgeries, and 3 required multiple revisions. Five of 9 (56%) of the revisions had primary surgery at an outside institution. Revision surgeries were due to caudal pseudarthrosis (the distal instrumented segment) (8), proximal junctional kyphosis (PJK) (7), and new neurological symptoms (7). There was a significant association found between construct type and the need for revision (P=0.0111). The pairwise comparison found that short fusions were significantly associated with the need for revision compared with the interbody group (P=0.0180). PJK was associated with short fusions when compared with the long fusion group (P=0.0294) and the interbody group (P=0.0300). Caudal pseudarthrosis was associated with short fusions when compared with the interbody group (P=0.0015). Multivariate logistic regression found long fusion with an interbody was predictive of and protective against the need for revision surgery (P=0.0246). To date, none of the initial cases that had long fusions with caudal interbody required a revision for distal pseudarthrosis.
CONCLUSIONS
In patients with achondroplasia, the rate of surgery for spinal stenosis is 22% and the risk of revision is 38% and is primarily due to pseudarthrosis, PJK, and recurrent neurological symptoms. Surgeons should consider discussing spinal surgery as part of the patient's life plan and should consider wide decompression of the stenotic levels and long fusion with the use of an interbody cage at the caudal level in all patients to reduce risks of revision.
LEVEL OF EVIDENCE
Level IV-Retrospective case series.
PubMed: 38595075
DOI: 10.1097/BPO.0000000000002687 -
JBMR Plus Dec 2023The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is...
The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold ( < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower ( < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
PubMed: 38130766
DOI: 10.1002/jbm4.10816