Skeletal Malformations Research Articles

THU456 Beyond Guidelines: Treatment Of Concurrent Osteogenesis Imperfecta And Metastatic Bone Disease

Abstract Disclosure: M. Kanin: None. M. Lechner: None. Introduction: Osteogenesis imperfecta (OI) is a rare inherited skeletal dysplasia characterized by bone fragility and skeletal malformation predisposing patients to multiple, recurrent fractures. Treatment of OI is challenging and requires a multidisciplinary approach with emphasis on physical therapy and exercise in addition to medications. There is limited guidance on treatment in adults given truncated life expectancy. Furthermore, guidance on the treatment of OI in the setting of cancer bone metastases is lacking. We present the unique case of a woman with OI and new fracture in the setting of bone-metastatic endometrial cancer. Clinical Case: A 70 year old woman with Type I OI and endometrial adenocarcinoma initially presented to clinic with left hip and groin pain. Prior OI therapy included at least 10 years of bisphosphonate therapy and 3 years of intranasal calcitonin in her fifties. CT imaging revealed a lytic lesion in the L inferior pubic ramus with an associated pathologic fracture. She was treated with denosumab 120mg s.c. every 3 months for six total doses and palliative radiation to the pubic ramus. She developed osteonecrosis of the jaw and further treatment was terminated. She represented 2 years later with right hip pain and was found to have cancer involvement of her right iliac bone. Labs showed creatinine of 0.48 mg/dL, Calcium 9.8 mg/dl, bone specific alkaline phosphatase 17.9ug/L (7.0-22.4 ug/L), n-telopeptide 18.6 nM BCE (6.2-19.0 nM BCE), and vitamin D-25 48ng/ml. DEXA scan showed T scores at the AP spine of -3.2, LFN of -2.1, and RFN of -2.5. Our patient had a high functional status, minimal pain and acceptable quality of life. Given the presence of active bone metastases, we favored treatment with zolendronic acid 4mg i.v. monthly given her high fracture risk, combined with continued cancer therapy targeted to bone metastases. Clinical Lesson: To our knowledge, there are no guidelines or case reports for optimal treatment of patients with concurrent OI and bone metastases. While bisphosphonates are typically a first line treatment for OI, osteoporosis and metastatic bone disease, the duration and dosing of bisphosphonates varies for each condition. For example, zolendronic acid 4mg i.v. monthly is recommended for cancer patients with metastatic bone disease, while a dose of 5mg i.v. yearly is used for osteoporosis, depending on the severity. Additionally, no clear consensus exists for how often or how long bisphosphonates may be given in adults with OI and treatment durations vary markedly. Other agents that may be considered include denosumab, with indications across bone metastases, osteoporosis, and OI, though this was not available to our patient given her prior complication. Data for newer agents PTH analogs and romosuzumab are lacking. We present this case to highlight the need for an individualized treatment approach in these patients. Presentation: Thursday, June 15, 2023

Chromosome Microarray Analysis and Exome Sequencing: Implementation in Prenatal Diagnosis of Fetuses with Digestive System Malformations.

(1) Purpose: Retrospective back-to-back comparisons were performed to evaluate the accuracy, effectiveness, and incremental yield of chromosome microarray analysis (CMA) and exome sequencing (ES) analysis in fetuses with digestive system malformations (DSMs). (2) Methods: In total, 595 women with fetal DSMs who underwent prenatal diagnosis were enrolled. We analyzed the diagnostic yields of CMA and ES and evaluated pregnancy outcomes. Copy number variants (CNVs) were classified according to the American College of Medical Genetics and Genomics guidelines. (3) Results: Pathogenic CNVs were detected in 11/517 (2.12%) fetuses, and variants of unknown significance (VUS) were identified in 69 (13.35%) fetuses using CMA. ES detected 29 pathogenic/likely pathogenic variants in 23/143 (16.08%) fetuses and 26/143 (18.2%) VUS. In those with other ultrasound abnormalities, the detection rate of multiple system structural malformations was 41.2%, followed by skeletal (33.3%), cardiovascular (25.4%), and central nervous system (18.6%) malformations. Of the 391 surviving children, 40 (10.2%) exhibited varying degrees of mental retardation. (4) Conclusion: A correlation exists between DSMs and chromosomal abnormalities. When combined with other systemic abnormalities, the incidence of chromosomal abnormalities increases significantly. Patients with congenital DSM are at risk of developing neurodevelopmental disorders. Combined CMA and ES detection of fetal DSM has good clinical application potential.

Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence.

Pontocerebellar hypoplasia type 8(PCH8) is a rare neurodegenerative disorder, reportedly caused by pathogenic variants of the CHMP1A in autosomal recessive inheritance, and CHMP1A variants have also been implicated in other diseases, and yet none of the prenatal fetal features were reported in PCH8. In this study, we investigated the phenotype and genotype in a human subject with global developmental delay, including clinical data from the prenatal stage through early childhood. Prenatally, the mother had polyhydramnios, and the bilateral ventricles of the fetus were slightly widened. Postnatally, the infant was observed to have severely delayed psychomotor development and was incapable of visual tracking before 2 years old and could not fix on small objects. The young child had hypotonia, increased knee tendon reflex, as well as skeletal malformations, and dental crowding; she also had severe and recurrent pulmonary infections. Magnetic resonance imaging of the brain revealed a severe reduction of the cerebellum (vermis and hemispheres) and a thin corpus callosum. Through whole exome sequencing and whole genomics sequencing, we identified two novel compound heterozygous variations in CHMP1A [c.53 T > C(p.Leu18Pro)(NM_002768.5) and exon 1 deletion region (NC_000016.10:g.89656392_89674382del)]. cDNA analysis showed that the exon1 deletion region led to the impaired expression, and functional verification with zebrafish embryos using base edition indicated variant c.53 T > C (p.Leu18Pro), causing dysplasia of the cerebellum and pons. These results provide further evidence that CHMP1A variants in a recessive inheritance pattern contribute to the clinical characteristics of PCH8 and further expand our knowledge of the phenotype and genotype spectrum of PCH8.

Schimke immuno-osseous dysplasia in a boy with generalized edema; a case report

Schimke immuno-osseous dysplasia (SIOD) is a rare disease diagnosed by skeletal malformations, steroid-resistant nephrotic syndrome (SRNs), and T-cell immunodeficiency. Proteinuria with focal segmental glomerulosclerosis (FSGS) is the most common renal pathologic finding in SIOD. In this case report, we present an 8-year-old boy with generalized edema, kyphosis, and nephrotic syndrome who was eventually diagnosed with SIOD.

Genetic and phenotypic spectrum of non-21-hydroxylase-deficiency primary adrenal insufficiency in childhood: data from 111 Chinese patients

BackgroundPrimary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition.MethodsTo describe the genetic composition and presentations...

Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.

Developmental Toxicity Study of DL-4-Hydroxy-4-Phenylhexanamide (DL-HEPB) in Rats.

Antiepileptic drugs affect embryonic development when administered during pregnancy, generating severe alterations, such as as cleft lip, spina bifida, heart abnormalities, or neuronal alterations. The compound DL-4-hydroxy-4-phenylhexanamide (DL-HEPB), a phenyl alcohol amide structurally different from known anticonvulsants, has shown good anticonvulsant effects in previous studies. However, its effects on intrauterine development are unknown. So, the purpose of this study was to determine the potential of DL-HEPB to produce alterations in conceptus. Pregnant Wistar rats were orally exposed to 0, 50, 100, and 200 mg/kg of DL-HEPB during organogenesis, and their food consumption and weight gain were measured. On gestation day 21, pregnant females were euthanized to analyze the fetuses for external, visceral, and skeletal malformations. A significant decrease in food consumption and body weight was observed in mothers, without any other manifestation of toxicity. In fetuses, no external malformations, visceral, or skeletal abnormalities, were observed under the dose of 100 mg/kg, while the dose of 200 mg/kg caused malformations in low frequency in brain and kidneys. In view of the results obtained, DL-HEPB could be a good starting point for the design of new highly effective anticonvulsant agents, with much lower developmental toxicity than that shown by commercial anticonvulsants.

Study on the relationship between feelings of psychological control, sense of benefit, and burden on caregivers for children with congenital skeletal malformations

Negative life events can lead to positive psychological changes despite the adverse effects. This study aims to investigate positive psychology in caregivers of children with congenital bone deformities. The research analyzes caregivers’ burden, psychological control, and benefit. The results showed: The average burden on caregivers for children with congenital skeletal malformations was 36.46 (mild-to-moderate), the individual burden score was around 21.13, and the responsibility burden score was around 8.55. The burden of care was negatively associated with the sense of benefit, suggesting that higher levels of psychological control were associated with lower caregiver burden. The sense of benefit partially mediated between psychological control and the caregiver burden.

Vitamin D Deficiency in Obese Children Is Associated with Some Metabolic Syndrome Components, but Not with Metabolic Syndrome Itself.

Vitamin D deficiency in children is a common nutritional issue in many populations worldwide, associated not only with skeletal malformations but, as recent studies suggest, also with the development of obesity and metabolic syndrome. The aim of this observational study was to assess the nutritional status of vitamin D in a group of Polish children with obesity and different grades of metabolic syndrome, with a consequent analysis of the correlation between vitamin D levels and the components of metabolic syndrome. For that purpose, the group of 78 participants (mean age: 14.18 ± 2.67 years) was recruited and further grouped in relation to vitamin D status into two groups of children with and without vitamin D deficiency. The biochemical parameters associated with obesity as well as anthropometric measures were assessed and analysed in search of significant differences between the groups. In the current group of children with obesity and vitamin D deficiency, HDL (45.00 ± 9.29) and adiponectin (7.21 ± 1.64) were found to be significantly lower than in their peers without vitamin D deficiency, whereas W/HtR (0.60 ± 0.04) and TG (171.31 ± 80.75) levels proved to be significantly higher. Body composition analysis using bioelectrical impedance returned no significant findings. The above findings suggest that vitamin D deficiency may influence lipid and glucose metabolism in children, leading to the development of abnormalities characteristic of the metabolic syndrome. A W/HtR parameter was shown to be a sensitive marker of abdominal obesity, which might provide an important means of assessing the correlation between vitamin D and this type of obesity. Independently, vitamin D deficiency may also influence the endocrinological function of adipose tissue, leading to lower concentrations of adiponectin. These in turn presented a linear correlation with the high results of the OGTT in the second hour of the test, hinting at its potential role in the pathophysiology of insulin resistance.

Microdeletion 3q13.31 and Agenesis of the Corpus Callosum in a Patient with Intellectual Disability and Autism Spectrum Disorder: A Case Report

Total agenesis of the corpus callosum (ACC) is a rare condition characterized by the absence of corpus callosum formation during fetal development. It can occur in isolation or be associated with congenital syndromes, including the emerging microdeletion syndrome 3q13.31. This syndrome, caused by a deletion in the long arm of chromosome 3, presents with developmental delay, growth abnormalities, craniofacial dysmorphology, skeletal malformations, genital anomalies, and agenesis of the corpus callosum. The case of a 7½-year-old boy with microdeletion 3q13.31 is described, highlighting common clinical manifestations observed in this syndrome. The patient exhibited delayed psychomotor development, language delay, autism spectrum disorder, intellectual disability, facial dysmorphology, and agenesis of the corpus callosum. Comparison with existing literature showed similarities in features such as delayed development, language delays, intellectual disability, and brain anomalies. The 3q13.31 microdeletion syndrome encompasses a wide range of clinical phenotypes, and the identification of responsible genes contributes to understanding the condition, although treatment remains challenging.

Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease.

Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis. Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in ABCB11, ATP8B1, ABCB4 or JAG1 demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families. WES revealed biallelic variation in 3 ciliopathy genes (PKHD1, TMEM67 and IFT172) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in PPOX in one adult index subject, and homozygosity for an unreported splice-site variation in F11R in one child. Whereas phenotypes of the index patients with mutated PKHD1, TMEM67, and PPOX corresponded with those elsewhere reported, how F11R variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in IFT172, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for IFT172 rs780205001 c.167A>C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant IFT172 NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants IFT172 rs776310391 c.157T>A p.(Phe53Ile) and rs746462745 c.164C>G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations. Our findings suggest association of IFT172 variants with non-syndromic cholestatic liver disease.

OECD 414 supplementary prenatal developmental toxicity study of sodium molybdate dihydrate in the rat and benchmark dose evaluation

In a continuing investigation of the potential for reproductive and developmental toxicity of molybdenum (Mo), consequent to the previous published OECD studies [1,2] and as directed by the European Chemicals Agency [3], a supplemental rat GLP-compliant Prenatal Developmental Toxicity (PNDT) study was conducted to investigate higher dose levels of sodium molybdate dihydrate (SMD) in an identical study design (OECD 414)[4] to Murray et al. 2014a [1], at dietary concentrations calculated to provide target Mo levels of 80 and 120 mg/kg bw/day (the maximum-tolerated dose). There was no effect on post-implantation loss, litter size, sex ratio or the incidence of external, visceral or skeletal fetal malformations or variations. Fetal weight was reduced proportionate to maternal dose. Minimal differences observed in the ossification status of some extremities of fetuses from females receiving 120 mg Mo/kg bw/day were confirmed as transient by skeletal examination of PND 21 pups from a further group of females receiving the same dose regime. There was no evidence of copper depletion in serum, placenta or liver. A benchmark dose evaluation using continuous and dichotomous approaches by combining the fetal body weight data from this study and the previous study determined that the BMD05 ranged from 47 to 57 mg Mo/kg bw/day, depending on the modelling approach and the BMDL05 estimates ranged from 37 to 47 mg Mo/kg bw/day. These levels are considered a more statistically robust point of departure for risk assessment for reproductive effects than the established NOAEL of 40 mg Mo/kg bw/day.

First Record of Spinal Deformity in the South American Silver Croaker Plagioscion squamosissimus (Eupercaria: Sciaenidae) in the Xingu River, Brazil

Observations of skeletal malformations in fish in the wild are poorly documented and need to be investigated. Here we report the occurrence of body shortening in specimens of Plagioscion squamosissimus collected in the Volta Grande do Xingu, middle Xingu River region (Pará, Brazil), during a 12-month monitoring program (2021–2022). We observed morphological anomalies in nine individuals, of which two underwent radiographic analysis, recording the fusion and compression of vertebrae in different portions of the spine. The average percentage decrease in body length resulting from the deformity was 23.8%. This is the first record of malformation in this species.

Osteopetrosis: A rare disease with unusual presentation as non-neutropenic typhlitis

Osteopetrosis is a rare inherited disorder characterized by the inability to reabsorb and remodel bone due to osteoclast dysfunction. There is a resultant increased bone mass and density with skeletal malformation and bone marrow failure, which may be fatal. There is extramedullary hematopoiesis, which causes hepatosplenomegaly and anemia. In our case, the presentation of typhlitis in osteopetrosis proved to be life-threatening, and hence, the early diagnosis of osteopetrosis will help to improve the management and quality of life of the patient.

Absence of maternal-fetal adverse effects of Alternanthera littoralis P. Beauv. following treatment during pregnancy in mice

ABSTRACT Alternanthera littoralis P. Beauv is a plant native to Brazil that exhibits various beneficial activities including antioxidant, antibacterial, antifungal, antiprotozoal, anti-hyperalgesic, and anti-inflammatory properties. The aim of this study was to assess the impact of the ethanol extract of Alternanthera littoralis (EEAl) on reproductive outcomes, embryofetal development, and DNA integrity of pregnant female mice. Pregnant Swiss female mice were randomly assigned to three experimental groups (n = 10): controls were administered either 1% Tween 80 (vehicle), EEAl 100 mg/kg or EEAl 1000 mg/kg. Treatment was administered through gavage during the gestational period until day 18. On gestational days 16, 17, and 18, a peripheral blood sample from the tail vein was obtained for DNA integrity analysis (micronucleus test). After the last collection, animals were euthanized by cervical dislocation. Maternal organs and fetuses were collected, weighed, and subsequently analyzed. Reproductive outcome parameters were assessed by measurement of number of implants, live fetuses, and resorptions. Embryonic development was determined by adequacy of weight for gestational age as well as determination of external, visceral, and skeletal malformations. Data demonstrated that EEAl did not produce maternal toxicity at either dose associated with no marked alterations in any of the reproductive outcome parameters including implantation sites, live/dead fetuses ratio, fetal viability, post-implantation losses, resorptions, and resorption rate. However, EEAl 1000 group reduced embryofetal development by lowering placental weight. In addition, there was an increase in the frequency of external and skeletal malformations in the EEAl 1000 group, which could not be attributed to extract exposure as these values were within control levels. Based upon our findings, evidence indicates that the EEAl at the concentrations employed in our study may be considered safe for use during pregnancy and extracts of this plant show potential for development of phytomedicines to be used in pregnancy.

Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes.

Pelger-Huët anomaly (PHA) in humans is an autosomal dominant hematological phenotype without major clinical consequences. PHA involves a characteristic hyposegmentation of granulocytes (HG). Human PHA is caused by heterozygous loss of function variants in the LBR gene encoding lamin receptor B. Bi-allelic variants and complete deficiency of LBR cause the much more severe Greenberg skeletal dysplasia which is lethal in utero and characterized by massive skeletal malformation and gross fetal hydrops. HG phenotypes have also been described in domestic animals and homology to human PHA has been claimed in the literature. We studied a litter of Australian Shepherd Dogs with four stillborn puppies in which both parents had an HG phenotype. Linkage analysis excluded LBR as responsible gene for the stillborn puppies. We then investigated the HG phenotype in Australian Shepherd Dogs independently of the prenatal lethality. Genome-wide association mapped the HG locus to chromosome 27 and established an autosomal recessive mode of inheritance. Whole genome sequencing identified a splice site variant in LMBR1L, c.191+1G>A, as most likely causal variant for the HG phenotype. The mutant allele abrogates the expression of the longer X2 isoform but does not affect transcripts encoding the shorter X1 isoform of the LMBR1L protein. The homozygous mutant LMBR1L genotype associated with HG is common in Australian Shepherd Dogs and was found in 39 of 300 genotyped dogs (13%). Our results point to a previously unsuspected function of LMBR1L in the myeloid lineage of leukocytes.

DNA Variation in Spinal Pathologies: Genetics Running Down the Spine

Commentary Nearly 400 types of skeletal malformations, including those that involve the spine, have been characterized by molecular and cellular analyses1. Identification of genetic components that control the integrity of intervertebral discs—and that predispose to spinal degeneration in aging patients when mutated—represents a challenging goal. Spinal conditions that occur later in life may emerge from faulty musculoskeletal tissue repair after accidental injury and the influences of comorbidities. The collective stochastic and often undocumented events in the life of a patient can easily complicate attempts at defining genetic predispositions. To manage the statistical noise that comes from random mutations within the human population (“nature”) and the randomness of life’s events (“nurture”), it is necessary to examine massive genetic data sets with many thousands of patients. Technological advances that allow cost-effective DNA sequencing have made it feasible to compare large patient populations matched on the basis of specific codes for medical conditions. Consequently, several studies have made impressive attempts at defining genetic variations linked to a range of surgically relevant musculoskeletal complications, including degenerative rotator cuff disease2, arthroplasty3, adhesive capsulitis of the shoulder4, and end-stage knee osteoarthritis5. The current paper by Bovonratwet et al. at the Hospital for Special Surgery in New York provides the latest installment in a growing set of orthopaedic studies in this journal that investigate the relationship between genetic variations and the risk of surgery for spinal conditions. Similar to prior published efforts by Yanik et al.2, Brüggemann et al.3, and Kulm et al.4,5, the study by Bovonratwet et al. leverages the power of the UK Biobank, which has genetic data for about 400,000 patients, of whom a total of about 20,000 (∼5%) had 1 of 4 spinal conditions (i.e., lumbar spondylolisthesis, spinal stenosis, degenerative disc disease, and pseudarthrosis after spinal fusion). Results from this large data set (“training population”) were then tested using the FinnGen database (“test population”) for validation. The analysis yielded multiple different genetic variants across 7 chromosomes. On average, the authors discovered 2 distinct loci per spinal condition. These findings are consistent with the genetic complexities of spinal conditions and suggest that the diseases are polygenic, as expected. Several nucleotide variants associated with 4 common spinal conditions were located in loci encoding anonymous genes that have not been experimentally explored. Degenerative disc disease was associated with a locus containing 2 genes that affect chondrogenesis: CHST3 (for carbohydrate sulfotransferase 3) promotes sulfation of chondroitin, and SMAD3 is the inducible target of chondrogenic transforming growth factor (TGF)-β signaling. Remarkably, 1 chromosomal region significantly associated with both lumbar spondylolisthesis and spinal stenosis contained overlapping sets of genes (i.e., GFPT1 and NFU1) that encode proteins involved in cell metabolism. These genes represent attractive targets for studies on genetic causality for these 2 spinal conditions. While it is tempting to speculate about potential mechanistic implications, the genetic biomarkers for spinal conditions mapped to large regions containing several genes. Whether these genes are even expressed in cell types and tissues relevant to homeostasis and repair of spinal tissues remains to be determined. Lack of similarity among studies indicates that endogenous tissue-specific repair processes may be predominant in the genetic landscape. One major strength of this study is the control for demographics and comorbidities. Yet, even with access to nearly 400,000 people who form a fairly homogeneous study cohort (i.e., White elderly people in Britain), this population size is not nearly large enough to identify the many genes that undoubtedly contribute to spinal conditions. The observation that only a few genetic variants were replicated in the Finnish cohort may further reflect the polygenicity of disease factors and genetic differences of Finnish patients. In closing, just as our emotions can run up or down our spine depending on whether we are in a positive or negative mood, genetic variation appears to affect spinal diseases. Some DNA mutations may literally be running down our spine, by destroying either disc integrity or our capacity for repair after injury. The positive news is that recognition of genetic predispositions may enhance consideration of behavioral modifications or guide surgical decisions. The paper by Bovonratwet et al. will inspire future studies, while bringing us 1 step closer to that goal.

Orofacial findings and orthodontic treatment conditions in patients with down syndrome – a retrospective investigation

IntroductionThe most common chromosomal anomaly is Down syndrome/Trisomy 21, which can be associated with varying degrees of intellectual disability and physical malformation. Specific orofacial characteristics regarding orthodontic treatment options and features are described on the basis of a patient collective from the Witten/Herdecke University, Germany.MethodsData of 20 patients (14 boys and 6 girls, mean age: 11.69 ± 3.94 years) who underwent orthodontic treatment between July 2011 and May 2022 were analyzed. Baseline skeletal and dental conditions were assessed, as well as the presence of hypodontia, displacements, and treatment-related root resorptions. The treatment need was evaluated based on the main findings according to the German KIG classification. In addition, treatment success was determined in relation to patient compliance.ResultsThe patient group was characterized predominantly by a class III relationship (ΔANB: −2.07 ± 3.90°; ΔWITS: −3.91 ± 4.33 mm) and a brachyfacial cranial configuration (ΔML-NL: −4.38 ± 7.05°, ΔArGoMe: − 8.45 ± 10.06°). The transversal discrepancy of the dental arch width from maxilla to mandible was −0.91 ± 3.44 mm anteriorly and −4.4 ± 4.12 mm posteriorly. Considering the orthodontic indication groups, the most frequent initial finding and treatment indication represented hypodontia (85%), followed by frontal (75%) and unilateral lateral (35%) crossbite. In 55% of the cases, the teeth had a regular shape, but in 35% a generalized and in 15% an isolated hypoplasia. Only 25% of the patients could be treated with a fixed multiband appliance due to sufficient cooperation. In each of these patients, varying degrees of root resorptions were detected during treatment, and 45% of all treatments had to be terminated prematurely due to a lack of cooperation by patients or parents.ConclusionThe extent of dental and skeletal malformations and the high rate of findings requiring treatment in patients with Down syndrome represent a significant indication for orthodontic therapy, which can be well illustrated by the KIG classification. However, this is in contrast to the eventually increased risk of root resorption, with significantly reduced patient cooperation. A compromised treatment outcome and process must be expected. Consequently, the orthodontic treatment must be simple and realistic to achieve fast and therapeutically satisfactory treatment result.

The ethanolic extract of Salvia lachnostachys Benth is not maternotoxic, does not alter reproductive performance, but has teratogenic potential

Salvia lachnostachys Benth is native to Brazil and has anti-inflammatory, anti-arthritic, cytotoxic, antitumor, and antihyperalgesic activities. The population, including pregnant women, consume this plant to treat pain, inflammation, flu, spasms, insomnia, and depression, mainly. There are no safety reports on the use of this plant during pregnancy. The present study aimed to evaluate the effects of S. lachnostachys ethanolic extract (EESl) on reproductive performance, embryofetal development, and DNA integrity of pregnant female mice. Pregnant females were randomly divided into three experimental groups (n = 10): The Control group was treated with a vehicle, and treatment groups were administered with EESl at 100 and 1000 mg/kg, respectively. Treatment occurred by gavage throughout the gestational period until day 18. Afterward, reproductive performance, embryofetal development, and DNA integrity parameters were evaluated. The results indicated that EESl did not alter any reproductive performance parameters. However, it changed embryofetal outcome through reduced placental weight (EESl 100 mg/kg), decreased fetal weight (EESl 100 and 1000 mg/kg), and increased frequency of small for gestational age fetuses (EESl 1000 mg/kg). In addition, EES1 increased the frequency of external, visceral, and skeletal malformations. Because of the above, it is considered that EESl is not maternotoxic, does not alter reproductive performance, but does alter embryofetal development. Its use in the gestational period is not indicated due to its teratogenic potential.

Nanoscale Whole-Body Expansion Microscopy Revealed the Early Skeletal Developmental Malformation Induced by Silver Nanoparticles

The widely used silver nanoparticles (AgNPs) can cause damage to skeletal development in aquatic organisms, which has a significant impact on their survival and reproduction. We hypothesized that the biological toxicity of AgNPs itself may be the culprit for early skeletal developmental malformation. In this study, we achieved the first nanoscale visualization of the notochord and skeletal muscle anatomy affected by exposure to AgNPs through a novel whole-body expansion microscopy technique (whole-ExM). This technique allows the whole zebrafish to be expanded equally in three dimensions by ∼4.5 times, enabling nanoscale resolution imaging without complex and expensive equipment. Our results suggested that AgNPs caused curvature deformation of the notochord as well as reduced and loosely arranged skeletal muscle. In addition, we demonstrated that the main source of Ag+ was the dissolution of AgNPs in vivo. Compared with that of the released Ag+, the developmental toxicity caused by AgNPs themselves was non-negligible. This work achieved cellular-level visualization of living animals and overcame the limitations of previous macroscopic or microscopic consideration of the toxicity of AgNPs. The study provided a new perspective for assessing the toxicity of nanomaterials by using whole-ExM to achieve ultraclear nanoscale imaging of biological organs.