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BMC Medical Genomics Jun 2024Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft...
BACKGROUND
Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis.
CASE PRESENTATION
A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition).
CONCLUSION
This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.
Topics: Humans; Myositis Ossificans; Female; Hallux Valgus; Infant; Bone Morphogenetic Protein Receptors, Type I
PubMed: 38879467
DOI: 10.1186/s12920-024-01931-6 -
Head & Face Medicine Jun 2024Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can...
INTRODUCTION
Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can commonly be classified into four primary groups. In this retrospective analysis, specific orofacial characteristics are described and associated with each of the AI types based on a patient cohort from Witten/Herdecke University, Germany.
METHODS
Data from 19 patients (ten male and nine female, mean age 12.27 ± 4.06 years) with AI who presented at the Department of Orthodontics between July 2011 and December 2023 were analyzed. Baseline skeletal and dental conditions were assessed, including the presence of hypodontia, displacements, and taurodontism. AI was classified into classes I-IV based on phenotype. Treatment needs were evaluated according to the main findings following the German KIG classification, while the radiological enamel situation was determined using panoramic radiographs.
RESULTS
An approximately equal distribution between classes II and III was found and a slight inclination toward a dolichofacial configuration (ΔML-NSL: 5.07 ± 9.23°, ΔML-NL: 4.24 ± 8.04°). Regarding orthodontic findings, disturbance in tooth eruption as well as open bite were the most prevalent issues (both 36.8%, n = 7). The most common AI classes were type I and II, which show an almost even distribution about the skeletal classes in sagittal dimension, while dolichofacial configuration was found most frequently in vertical dimension.
CONCLUSION
Both clinical and radiological orthodontic findings in context with AI are subject to extensive distribution. It seems that no specific orofacial findings can be confirmed in association with AI with regard to the common simple classes I-IV. It may be more appropriate to differentiate the many subtypes according to their genetic aspects to identify possible associated orthodontic findings.
Topics: Humans; Amelogenesis Imperfecta; Male; Female; Retrospective Studies; Child; Adolescent; Germany; Radiography, Panoramic; Orthodontics, Corrective; Malocclusion
PubMed: 38877506
DOI: 10.1186/s13005-024-00436-y -
Molecular Genetics & Genomic Medicine Jun 2024Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes...
BACKGROUND
Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.
METHODS
Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.
RESULTS
The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.
CONCLUSION
This is the first report linking UXS1 to short-limbed short stature in humans.
Topics: Humans; Male; Dwarfism; Carboxy-Lyases; Alleles; Phenotype; Mutation; Adult; Pedigree
PubMed: 38860481
DOI: 10.1002/mgg3.2472 -
Molecular Genetics & Genomic Medicine Jun 2024The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause... (Review)
Review
Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review.
BACKGROUND
The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features.
CASE REPORT
A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization.
CONCLUSIONS
We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.
Topics: Humans; Female; Heterozygote; Adult; Pregnancy; Mutation; Prenatal Diagnosis; Limb Deformities, Congenital
PubMed: 38860479
DOI: 10.1002/mgg3.2477 -
JCI Insight Jun 2024The transcription factor SRY-related HMG box 9 (Sox9) is essential for chondrogenesis. Mutations in and around SOX9 cause campomelic dysplasia (CD) characterized by...
The transcription factor SRY-related HMG box 9 (Sox9) is essential for chondrogenesis. Mutations in and around SOX9 cause campomelic dysplasia (CD) characterized by skeletal malformations. Although the function of Sox9 in this context is well studied, the mechanisms that regulate Sox9 expression in chondrocytes remain to be elucidated. Here, we have used genome-wide profiling to identify 2 Sox9 enhancers located in a proximal breakpoint cluster responsible for CD. Enhancer activity of E308 (located 308 kb 5' upstream) and E160 (located 160 kb 5' upstream) correlated with Sox9 expression levels, and both enhancers showed a synergistic effect in vitro. While single deletions in mice had no apparent effect, simultaneous deletion of both E308 and E160 caused a dwarf phenotype, concomitant with a reduction of Sox9 expression in chondrocytes. Moreover, bone morphogenetic protein 2-dependent chondrocyte differentiation of limb bud mesenchymal cells was severely attenuated in E308/E160 deletion mice. Finally, we found that an open chromatin region upstream of the Sox9 gene was reorganized in the E308/E160 deletion mice to partially compensate for the loss of E308 and E160. In conclusion, our findings reveal a mechanism of Sox9 gene regulation in chondrocytes that might aid in our understanding of the pathophysiology of skeletal disorders.
Topics: SOX9 Transcription Factor; Animals; Chondrocytes; Mice; Campomelic Dysplasia; Chondrogenesis; Cell Differentiation; Enhancer Elements, Genetic; Chromatin; Gene Expression Regulation, Developmental; Mice, Knockout; Bone Morphogenetic Protein 2; Humans; Bone Development
PubMed: 38855864
DOI: 10.1172/jci.insight.175486 -
Gait & Posture Jun 2024Rare bone diseases (RBD) cause physical and sensory disability that affects quality of life. Mobility challenges are common for people with RBDs, and travelling to gait...
BACKGROUND
Rare bone diseases (RBD) cause physical and sensory disability that affects quality of life. Mobility challenges are common for people with RBDs, and travelling to gait analysis labs can be very complex. Smartphone sensors could provide remote monitoring.
RESEARCH QUESTION
This study aimed to search for and identify variables that can be used to discriminate between people with RBD and healthy people by using built-in smartphone sensors in a real-world setting.
METHODS
In total, 18 participants (healthy: n=9; RBD: n=9), controlled by age and sex, were included in this cross-sectional study. A freely available App (Phyphox) was used to gather data from built-in smartphone sensors (accelerometer & gyroscope) at 60 Hz during a 15-min walk on a level surface without turns or stops. Temporal gait parameters like cadence, mean stride time and, coefficient variance (CoVSt) and nonlinear analyses, as the largest Lyapunov exponent (LLE) & sample entropy (SE) in the three accelerometer axes were used to distinguish between the groups and describe gait patterns.
RESULTS
The LLE (p=0.04) and the SE of the z-axis (p=0.01), which are correlated with balance control during walking and regularity of the gait, are sufficiently sensitive to distinguish between RBD and controls.
SIGNIFICANCE
The use of smartphone sensors to monitor gait in people with RBD allows for the identification of subtle changes in gait patterns, which can be used to inform assessment and management strategies in larger cohorts.
PubMed: 38850844
DOI: 10.1016/j.gaitpost.2024.05.033 -
Heliyon Jun 2024Fibroblast growth factors and their receptors (FGFR) have major roles in both human growth and oncogenesis. In adults, therapeutic FGFR inhibitors have been successful...
Fibroblast growth factors and their receptors (FGFR) have major roles in both human growth and oncogenesis. In adults, therapeutic FGFR inhibitors have been successful against tumors that carry somatic FGFR mutations. In pediatric patients, trials testing these anti-tumor FGFR inhibitor therapeutics are underway, with several recent reports suggesting modest positive responses. Herein, we report an unforeseen outcome in a pre-pubescent child with an FGFR1-mutated glioma who was successfully treated with FDA-approved erdafitinib, a pan-FGFR inhibitor approved for treatment of Bladder tumors. While on treatment with erdafitinib, the patient experienced rapid skeletal and long bone overgrowth resulting in kyphoscoliosis, reminiscent of patients with congenital loss-of-function mutations. We utilized normal dermal fibroblast cells established from the patient as a surrogate model to demonstrate that insulin-like growth factor 1 (IGF-1), a factor important for developmental growth of bones and tissues, can activate the PI3K/AKT pathway in erdafitinib-treated cells but not the MAPK/ERK pathway. The IGF-I-activated PI3K/AKT signaling rescued normal fibroblasts from the cytotoxic effects of erdafitinib by promoting cell survival. We, therefore, postulate that IGF-I-activated P13K/AKT signaling likely continues to promote bone elongation in the growing child, but not in adults, treated with therapeutic pan-FGFR inhibitors. Importantly, since activated MAPK signaling counters bone elongation, we further postulate that prolonged blockage of the MAPK pathway with pan-FGFR inhibitors, together with actions of growth-promoting factors including IGF-1, could explain the abnormal skeletal and axial growth suffered by our pre-pubertal patient during systemic therapeutic use of pan-FGFR inhibitors. Further studies to find more targeted, and/or appropriate dosing, of pan-FGFR inhibitor therapeutics for children are essential to avoid unexpected off-target effects as was observed in our young patient.
PubMed: 38841436
DOI: 10.1016/j.heliyon.2024.e30887 -
SA Journal of Radiology 2024Fibrous dysplasia (FD) is a rare, non-inherited, congenital bone disorder which may be monostotic or polyostotic. The polyostotic form may rarely present in syndromic...
UNLABELLED
Fibrous dysplasia (FD) is a rare, non-inherited, congenital bone disorder which may be monostotic or polyostotic. The polyostotic form may rarely present in syndromic forms when associated with extra-skeletal manifestations. Mazabraud syndrome is a rare syndrome consisting of polyostotic FD presenting with intramuscular myxomas. McCune-Albright syndrome is recognised by polyostotic FD, precocious puberty and 'café au lait' spots. This report describes an adult patient with Mazabraud syndrome and a child with McCune-Albright syndrome.
CONTRIBUTION
Radiographic findings are typical with bowing deformities, sclerotic, lucent or mixed lesions and bony expansion, often with endosteal scalloping. MRI is often non-contributory and may actually mimic a more aggressive process. Early detection and correct diagnosis allow for early preventative treatment and rehabilitation to prevent devastating neurological sequelae and disability.
PubMed: 38840825
DOI: 10.4102/sajr.v28i1.2877 -
ELife Jun 2024Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human gene have been linked to Seckel...
Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.
Topics: Animals; Osteoclasts; Osteogenesis; Mice, Knockout; Mice; Nuclear Proteins; Centrosome; Osteoblasts
PubMed: 38836552
DOI: 10.7554/eLife.93457 -
Journal of Biomedical Research May 2024Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common...
Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.
PubMed: 38832540
DOI: 10.7555/JBR.37.20230301