Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies.

Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The MYF5 gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in MYF5 were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in MYF5 have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous MYF5 frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four MYF5 variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.

Slipping rib syndrome.

Slipping rib syndrome (SRS) is a possibly lesser known but not rare condition associated with severe pain in the lower part of the thorax and/or upper abdomen. SRS is caused by an anatomical variant where typical costa 9 collides with costa 8 resulting in neuralgic pain. Surgery with reconstruction of the rib curvature has few recurrences. The diagnosis and treatment of SRS patients are presented, but our primary aim is to raise awareness about a painful and largely overlooked condition as a differential diagnosis in patients with unexplained chronic pain in the lower thorax.

Comprehensive analysis of donor-site chest deformities after autologous costal cartilage microtia reconstruction: A systematic review.

BACKGROUND: Autologous costal cartilage has gained widespread acceptance as an important material for ear reconstruction in patients with microtia. Despite its recognition as being "worth the trade-off," attention should be directed toward donor-site deformities. This systematic review focused on existing English literature related to microtia reconstruction and aimed to reveal the incidence of chest wall deformities and assess the effectiveness of the various proposed surgical techniques aimed at reducing donor-site morbidities. METHODS: A comprehensive search was conducted on Pubmed and OVID using the keywords "microtia," and "chest deformity" or "rib harvest." Articles were screened based on predefined inclusion and exclusion criteria. Data acquisition encompassed patient demographics, employed surgical techniques, methods for evaluating chest deformity, and incidence of associated complications. RESULTS: Among the 362 identified articles, 21 met the inclusion criteria. A total of 2600 cases involving 2433 patients with microtia were analyzed in this review. Perichondrium preservation during cartilage harvesting led to a significant reduction in chest deformities. However, the wide incidence range (0% to 50%) and the lack of specific assessment methods suggested potential underestimation. Computed tomography revealed reduced chest wall growth in the transverse and sagittal directions, resulting in decreased thoracic area. Innovative surgical techniques have shown promising results in reducing chest deformities. CONCLUSIONS: Although a quantitative analysis was not feasible, objective evidence of deformities was established through computed tomography scans. This analysis highlighted the need for dedicated studies with larger sample sizes to further advance our understanding of chest wall deformities in microtia reconstruction.

Slipping rib syndrome in childhood. A case series. / Síndrome de la costilla deslizante en la edad pediátrica. Serie de casos.

Among the causes of chest pain, slipping rib has a low prevalence, usually with a history of trauma, and its management is controversial. Slipping rib syndrome should be included in the differential diagnosis of causes of chest pain in children. When not associated with previous trauma and cartilage deformity, it is necessary to consider an alteration in rib development, regardless of the typical traumatic etiology in adults. Here we describe a series of pediatric patients with slipping rib seen at a referral hospital between 2001 and 2022. Nine patients aged 11 to 16 years were included. Only 2 had a history of trauma. All patients described a sudden onset of severe thoracic abdominal pain. The patients underwent open resection of the affected costal cartilages, with resolution of pain.

Entre las causas de dolor torácico, la costilla deslizante presenta baja prevalencia, antecedentes traumáticos y manejo controvertido. Este síndrome merece ser incluido en el diagnóstico diferencial de causas de dolor torácico en niños. Al no asociarse a traumatismos previos y la deformidad de cartílagos, nos induce a pensar en una alteración en el desarrollo costal, al margen de la etiología traumática típica en adultos. Se presenta una serie de pacientes pediátricos intervenidos por costilla deslizante en un centro de referencia entre 2001 y 2022. Se incluyeron nueve pacientes, con un rango de edades de 11 a 16 años. Solo dos casos describen traumatismo previo. Todos presentan un inicio súbito de dolor toracoabdominal intenso. Los pacientes fueron intervenidos mediante resección abierta de cartílagos costales afectos, con resolución del dolor.

A rare skeletal dysplasia in the etiology of severe scoliosis: Diaphanospondylodysostosis.

Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the BMPER gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel BMPER mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.

Instrumentation failure following pediatric spine deformity growth-sparing surgery using traditional growing rods or vertical expandable prosthetic titanium ribs.

BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.

Pudgy mouse rib deformities emanate from abnormal paravertebral longitudinal cartilage/bone accumulations.

The pudgy (pu/pu) mouse, caused by a recessive mutation in the Notch family Delta like-3 gene (Dll3), has severe rib, vertebral body and intervertebral disc abnormalities. Using whole-mount preparations and serial histologic sections we demonstrate: 1) localized paravertebral longitudinal cartilage/bone accumulations (PVLC/BAs) invariably associated with branched, fused and asymmetrically spaced ribs that emanate from it laterally; 2) abnormal rib formation immediately adjacent to abnormal vertebral body and intervertebral disc formation in asymmetric right/left fashion; and 3) patterns of rib deformation that differ in each mouse. Normal BALB/c embryo and age-matched non-affected pu/+ mice assessments allow for pu/pu comparisons. The Dll3 Notch family gene is involved in normal somitogenesis via the segmentation clock mechanism. Although pathogenesis of rib deformation is initially triggered by the Dll3 gene mutation, these findings of abnormal asymmetric costo-vertebral region structure imply that differing patterns cannot be attributed to this single gene mutation alone. All findings implicate a dual mechanism of malformation: the Dll3 gene mutation leading to subtle timing differences in traveling oscillation waves of the segmentation clock and further subsequent misdirection of tissue formation by altered chemical reaction-diffusion and epigenetic landscape responses. PVLC/BAs appear as primary supramolecular structures underlying severe rib malformation associated both with time-sensitive segmentation clock mutations and subsequent reactions.

Defects of the spliceosomal gene SNRPB affect osteo- and chondro-differentiation.

Although gene splicing occurs throughout the body, the phenotype of spliceosomal defects is largely limited to specific tissues. Cerebro-costo-mandibular syndrome (CCMS) is one such spliceosomal disease, which presents as congenital skeletal dysmorphism and is caused by mutations of SNRPB gene encoding Small Nuclear Ribonucleoprotein Polypeptides B/B' (SmB/B'). This study employed in vitro cell cultures to monitor osteo- and chondro-differentiation and examined the role of SmB/B' in the differentiation process. We found that low levels of SmB/B' by knockdown or mutations of SNRPB led to suppressed osteodifferentiation in Saos-2 osteoprogenitor-like cells, which was accompanied by affected splicing of Dlx5. On the other hand, low SmB/B' led to promoted chondrogenesis in HEPM mesenchymal stem cells. Consistent with other reports, osteogenesis was promoted by the Wnt/ß-catenin pathway activator and suppressed by Wnt and BMP blockers, whereas chondrogenesis was promoted by Wnt inhibitors. Suppressed osteogenic markers by SNRPB knockdown were partly rescued by Wnt/ß-catenin pathway activation. Reporter analysis revealed that suppression of SNRPB results in attenuated Wnt pathway and/or enhanced BMP pathway activities. SNRPB knockdown altered splicing of TCF7L2 which impacts Wnt/ß-catenin pathway activities. This work helps unravel the mechanism underlying CCMS whereby reduced expression of spliceosomal proteins causes skeletal phenotypes.

Consideration of the thoracic phenotype of cerebro-costo-mandibular syndrome.

Cerebro-costo-mandibular syndrome (CCMS) is a congenital condition with skeletal and orofacial abnormalities that often results in respiratory distress in neonates. The three main phenotypes in the thorax are posterior rib gaps, abnormal costovertebral articulation and absent ribs. Although the condition can be lethal, accurate diagnosis, and subsequent management help improve the survival rate. Mutations in the causative gene SNRPB have been identified, however, the mechanism whereby the skeletal phenotypes affect respiratory function is not well-studied due to the multiple skeletal phenotypes, lack of anatomy-based studies into the condition and rarity of CCMS cases. This review aims to clarify the extent to which the three main skeletal phenotypes in the thorax contribute to respiratory distress in neonates with CCMS. Despite the posterior rib gaps being unique to this condition and visually striking on radiographic images, anatomical consideration, and meta-analyses suggested that they might not be the significant factor in causing respiratory distress in neonates. Rather, the increase in chest wall compliance due to the rib gaps and the decrease in compliance at the costovertebral complex was considered to result in an equilibrium, minimizing the impact of these abnormalities. The absence of floating ribs is likely insignificant as seen in the general population; however, a further absence of ribs or vestigial rib formation is associated with respiratory distress and increased lethality. Based on these, we propose to evaluate the number of absent or vestigial ribs as a priority indicator to develop a personalized treatment plan based on the phenotypes exhibited.

Evaluation of congenital rib anomalies with multi-detector computed tomography in the Turkish population.

BACKGROUND: This study aimed to evaluate the congenital anomalies of ribs in the Turkish population using multi-detector computed tomography (CT) and to reveal the prevalence and distribution of these anomalies according to sexes and body sides. MATERIALS AND METHODS: This study included 1120 individuals (592 male, 528 female) over 18 who presented to our hospital with a suspicion of COVID-19 and who had thoracic CT. Anomalies such as a bifid rib, cervical rib, fused rib, Srb anomaly, foramen rib, hypoplastic rib, absent rib, supernumerary rib, pectus carinatum, and pectus excavatum, which were previously defined in the literature, were examined. Descriptive statistics were performed with the distribution of anomalies. Comparisons were made between the sexes and body sides. RESULTS: A prevalence of 18.57% rib variation was observed. Females had 1.3 times more variation than males. Although there was a significant difference in the distribution of anomalies by sex (p = 0.000), there was no difference in terms of body side of anomaly (p > 0.05). The most common anomaly was the hypoplastic rib, followed by the absence of a rib. While the incidence of the hypoplastic rib was similar in females and males, 79.07% of the absent ribs was seen in females (p < 0.05). The study also includes a rare case of bilateral first rib foramen. At the same time, this study includes a rare case of rib spurs extending from the left 11th rib to the 11th intercostal space. CONCLUSIONS: This study demonstrates detailed information about congenital rib anomalies in the Turkish population, which may vary between people. Knowing these anomalies is essential for anatomy, radiology, anthropology, and forensic sciences.

Pediatric Ribs at Chest Radiography: Normal Variants and Abnormalities.

Normal variants and abnormalities of the ribs are frequently encountered on chest radiographs. Accurate identification of normal variants is crucial to avoid unnecessary investigations. A meticulous evaluation of rib abnormalities can provide valuable insights into the patient's symptoms, and even when no osseous condition is suspected, rib abnormalities may offer critical clues to underlying conditions. Rib abnormalities are associated with various conditions, including benign tumors, malignant tumors, infectious and inflammatory conditions, vascular abnormalities, metabolic disorders, nonaccidental injuries, malformation syndromes, and bone dysplasias. Abnormalities of the ribs are classified into three groups based on their radiographic patterns: focal, multifocal, and diffuse changes. Focal lesions are further subdivided into nonaggressive lesions, aggressive lesions, and infectious and inflammatory disorders. Radiologists should be aware of individual disorders of the pediatric ribs, including their imaging findings, relevant clinical information, and underlying pathogenesis. Differential diagnoses are addressed as appropriate. Since chest radiographs can suffice for diagnosis in certain cases, the authors emphasize a pattern recognition approach to radiographic interpretation. However, additional cross-sectional imaging may be necessary for focal lesions such as tumors or inflammatory conditions. Awareness of disease-specific imaging findings helps ascertain the nature of the lesion and directs appropriate management. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Mutations of PTCH1 gene in two pedigrees with bifid rib-basal cell nevus-jaw cyst syndrome. / 肋骨分叉-基底细胞痣-é¢Œéª¨å›Šè‚¿ç»¼åˆå¾ä¸¤å®¶ç³»åŸºå› åºåˆ—å˜å¼‚åˆ†æž.

Two male patients with bifid rib-basal cell nevus-jaw cyst syndrome (BCNS) were admitted to Department of Stomatology, the First Affiliated Hospital of Bengbu Medical College due to radiological findings of multiple low density shadows in the jaw. Clinical and imaging findings showed thoracic malformation, calcification of the tentorium cerebellum and falx cerebrum as well as widening of the orbital distance. Whole exon high-throughput sequencing was performed in two patients and their family members. The heterozygous mutations of c.C2541C>A(p.Y847X) and c.C1501C>T(p.Q501X) in PTCH1 gene were detected in both patients. Diagnosis of BCNS was confirmed. The heterozygous mutations of PTCH1 gene locus were also found in the mothers of the two probands. Proband 1 showed clinical manifestations of low intelligence, and heterozygous mutations of c.C2141T(p.P714L) and c.G3343A(p.V1115I) were detected in FANCD2 gene. Proband 2 had normal intelligence and no FANCD2 mutation. The fenestration decompression and curettage of jaw cyst were performed in both patients. Regular follow-up showed good bone growth at the original lesion, and no recurrence has been observed so far.

Effects of spinal deformities on lung development in children: a review.

Scoliosis before the age of 5 years is referred to as early-onset scoliosis (EOS). While causes may vary, EOS can potentially affect respiratory function and lung development as children grow. Moreover, scoliosis can lead to thoracic insufficiency syndrome when aggravated or left untreated. Therefore, spinal thoracic deformities often require intervention in early childhood, and solving these problems requires new methods that include the means for both deformity correction and growth maintenance. Therapeutic strategies for preserving the growing spine and thorax include growth rods, vertically expandable titanium artificial ribs, MAGEC rods, braces and casts. The goals of any growth-promoting surgical strategy are to alter the natural history of cardiorespiratory development, limit the progression of underlying spondylarthrosis deformities and minimize negative changes in spondylothorax biomechanics due to the instrumental action of the implant. This review further elucidates EOS in terms of its aetiology, pathogenesis, pathology and treatment.

A porcine model of early-onset scoliosis combined with thoracic insufficiency syndrome: Construction and transcriptome analysis.

BACKGROUND: Early-onset scoliosis (EOS) is a scoliosis deformity caused by various reasons before the age of 10 years and is often combined with thoracic insufficiency syndrome (TIS) causing patients with difficulty in securing lung growth in the thoracic cage. Currently, there is a shortage of effective large animal models for evaluating EOS + TIS in therapeutic studies. Consequently, we propose to construct a porcine EOS + TIS model and evaluate its transcriptome changes by RNA sequencing. METHODS: Piglets were constructed using unilateral posterior spine-tethering and ipsilateral rib-tethering in the EOS + TIS model, and X-ray and computed tomography (CT) were performed to assess growth changes in the spine, thoracic cage and lungs. The H&E and Masson staining was performed for pathological analysis of lung tissue. After RNA sequencing of lung tissues, data were analyzed for differential expression of mRNA, functional enrichment analysis (GO, KEGG and GSEA) and protein-protein interaction (PPI) network construction, and differential expression of hub gene was verified by RT-qPCR. RESULTS: In the model group, growth (body weight and length) of piglets was significantly delayed; fusion of ribs occurred and cobb angle changes in the coronal and sagittal planes were significantly enlarged; total lung volume (TLV) was significantly reduced, especially at the T7-T10 level. Pathological analysis revealed that, in the model lung tissue, the alveolar wall of was poorly perfused, the alveolar space was enlarged, the number and size of alveoli were significantly reduced, and it was accompanied by collagen fiber deposition. Moreover, a total of 432 differentially expressed mRNAs (DE-mRNAs) were identified in model lung tissues, which contained 262 down-regulated and 170 up-regulated DE-mRNAs, and they were mainly involved in the regulation of immunity, inflammation, cell cycle and extracellular matrix. A PPI network containing 71 nodes and 158 edges was constructed based on all DE-mRNAs, and JUN, CCL2, EGR1, ATF3, BTG2, DUSP1 and THBS1 etc. were hub gene. CONCLUSIONS: Overall, we constructed a porcine model that was capable of replicating the common clinical features of EOS + TIS such as rib fusion, asymmetric thoracic cage, increased cobb angle, decreased TLV, and pulmonary hypoplasia. Also, we revealed transcriptomic changes in the EOS + TIS model that may cause pulmonary hypoplasia.

De novo cavernous angiomas associated with developmental venous anomaly: a mini-series and literature review.

BACKGROUND: Despite being previously considered as congenital lesions, recent studies agree to classify cerebral cavernous malformations (CCM) as acquired forms with clear correlations with other pathological affections of the central nervous system (CNS). In addition, a special subgroup, notably known as de novo CCMs (dnCCM), are associated in a significant number of cases with developmental venous anomalies (DVAs) and, in other cases, with Radiotherapy treatments. METHODS: A mini-series of 4 patients with clinical history characterized by developing dnCCM is reported. In three patients, the dnCCM was associated with the presence of an isolated DVA. In one case, no DVA was detected, but the patient underwent brain radiotherapy. In three cases, the dnCCM was clinically symptomatic, and the patients were submitted to a surgical procedure for lesion removal. In one case, the dnCCM was detected during MRI follow-up. RESULTS: Adding a review of the literature, we describe 47 patients who presented dnCCMs. The most common presentation is a sporadic CCM with a DVA, and the onset presentation was bleeding in 4 out of 47 cases (8.5%). Bleeding of dnCCM was observed in 9 out of 47 cases (19%), and the choice treatment was surgical in 24 out of 47 cases (51%). CONCLUSIONS: We present our series with a review of the recent literature and discuss the "de novo" cavernous malformation pathogenesis. A throughout review of recent literature is reported to clarify the predisposing factors that may lead to dnCCM development in patients carrying specific genetic and molecular features. Considering the high risk of bleeding, strict follow-up and aggressive treatment should be evaluated in dnCCM management.

Mutations of PTCH1 gene in two pedigrees with bifid rib-basal cell nevus-jaw cyst syndrome / 浙江大学学报·医学版

Two male patients with bifid rib-basal cell nevus-jaw cyst syndrome (BCNS) were admitted to Department of Stomatology, the First Affiliated Hospital of Bengbu Medical College due to radiological findings of multiple low density shadows in the jaw. Clinical and imaging findings showed thoracic malformation, calcification of the tentorium cerebellum and falx cerebrum as well as widening of the orbital distance. Whole exon high-throughput sequencing was performed in two patients and their family members. The heterozygous mutations of c.C2541C>A(p.Y847X) and c.C1501C>T(p.Q501X) in PTCH1 gene were detected in both patients. Diagnosis of BCNS was confirmed. The heterozygous mutations of PTCH1 gene locus were also found in the mothers of the two probands. Proband 1 showed clinical manifestations of low intelligence, and heterozygous mutations of c.C2141T(p.P714L) and c.G3343A(p.V1115I) were detected in FANCD2 gene. Proband 2 had normal intelligence and no FANCD2 mutation. The fenestration decompression and curettage of jaw cyst were performed in both patients. Regular follow-up showed good bone growth at the original lesion, and no recurrence has been observed so far.

Snrpb is required in murine neural crest cells for proper splicing and craniofacial morphogenesis.

Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.