Spondylocostal Dysostosis Research Articles

Posterior Column Release and Lengthening with a Magnetic Growing Rod Construct in Severe Congenital Thoracic Fusion: A Report of 2 Cases.

We describe treatment of severe multilevel congenital thoracic fusion in a 3-year-old girl with Apert Syndrome by posterior element excision, posterior column osteotomies, and gradual distraction with magnetically controlled growing rods (MCGR) with 3-year follow-up. We also describe short-term follow-up with similar management in an 8-year-old patient with a congenitally fused thoracic spine from Jarcho-Levin syndrome. Posterior element resection and targeted posterior column osteotomies combined with gradual distraction with MCGR offers a promising treatment course for children with severe thoracic insufficiency syndrome derived from congenital fusions.

Casamassima-Morton-Nance Syndrome and Limb-Body Wall Defect: Presentation of the Second Case and Phenotypic Assessment.

Casamassima-Morton-Nance syndrome (CMNS) is a rare disorder characterized by spondylocostal dysostosis (SCD), anal atresia, and urogenital anomalies. We describe a fetus with CMNS associated with a limb-body wall defect (LBWD), the second such case in the literature. We compare the phenotypic differences with previously reported cases, including those with segmentation anomalies of the axial skeleton, body wall defects, or absent/abnormal genitalia, revealing the consistent presence of SCD in CMNS. However, as expected, a wide phenotypic spectrum emerges, providing useful observations for fetal/neonatal screening relevant to differential diagnoses. Advanced diagnostic methods using imaging and next-generation skeletal dysplasia multi-gene panels are advisable, as they enable timely, actionable, well-informed decisions for parental counseling, potential elective termination of pregnancy, and prenatal and/or postnatal care. Most reported cases do not mention the recurrence of these usually lethal anomalies.

Intestinal malrotation with levocardia and Spondylo-costal dysostosis: A case report

Background: Intestinal malrotation with midgut volvulus is usually present in the neonatal period but can present at any age, and can be associated with various congenital anomalies. These congenital defects increase the morbidity of the disease per se and require a multidisciplinary approach. Case Presentation: The index case was an eight-month-old child with intestinal malrotation, situs inversus, levo-cardia, single ventricle, and Spondylo-costal dysostosis. Here, we discuss its presentation, treatment, challenges during management, and review of pertinent literature. Conclusion: The association of intestinal malrotation with situs inversus, levocardia, and SCD requires further reporting as well as genetic studies to understand its embryo pathogenesis. The multidisciplinary team is essential for the ideal treatment of this type of complex case.

Anaesthetic management in neonate with rare finding of absent ribs as a part of Jacho Levin syndrome posted for thoracolumbar meningomyelocele repair: A case report

The congenital absence of ribs is a very rare finding. It can manifest as a standalone anomaly or as part of the syndrome. We came across a case in which the absence of ribs was associated with a neural tube defect. These findings were in favor of Jarcho Levin syndrome. Jarcho Levin syndrome, also known as spondylocostal dysostosis, is an uncommon genetic disorder with a global incidence of 1/40000 births. Very few case reports of it are in the Indian literature. It is characterized by vertebral malformations and the congenital absence of ribs, resulting in a crab-like appearance in the chest. It is linked to a wide range of non-skeletal abnormalities, including hydrocephalus, neural tube defects, tracheal anomalies, and abnormalities in the cardiac, renal, gastrointestinal, and urinary systems. The preoperative evaluation should be thoroughly done with a detailed systemic examination for the multisystem affliction of this syndrome. The anesthetic challenges in neonates with Jarcho Levin syndrome includes challenging airways due to defects in skeletal growth and hydrocephalus, proper positioning to avoid sac rupture, prone position ventilation, temperature control and fluid management. The prone position ventilation can be complicated by the absence of ribs and decreased respiratory reserve due to associated scoliosis and kyphosis. This case report highlights the anesthetic management of a three-day-old neonate with Jarcho Levin syndrome posted for thoracolumbar meningomyelocele repair.

Integrative analysis of Lunatic Fringe variants associated with spondylocostal dysostosis type-III.

Lunatic Fringe (LFNG) is required for spinal development. Biallelic pathogenic variants cause spondylocostal dysostosis type-III (SCD3), a rare disease generally characterized by malformed, asymmetrical, and attenuated development of the vertebral column and ribs. However, a variety of SCD3 cases reported have presented with additional features such as auditory alterations and digit abnormalities. There has yet to be a single, comprehensive, functional evaluation of causative LFNG variants and such analyses could unveil molecular mechanisms for phenotypic variability in SCD3. Therefore, nine LFNG missense variants associated with SCD3, c.564C>A, c.583T>C, c.842C>A, c.467T>G, c.856C>T, c.601G>A, c.446C>T, c.521G>A, and c.766G>A, were assessed invitro for subcellular localization and protein processing. Glycosyltransferase activity was quantified for the first time in the c.583T>C, c.842C>A, and c.446C>T variants. Primarily, our results are the first to satisfy American College of Medical Genetics and Genomics PS3 criteria (functional evidence via well-established assay) for the pathogenicity of c.583T>C, c.842C>A, and c.446C>T, and replicate this evidence for the remaining six variants. Secondly, this work indicates that all variants that prevent Golgi localization also lead to impaired protein processing. It appears that the FRINGE domain is responsible for this phenomenon. Thirdly, our data suggests that variant proximity to the catalytic residue may influence whether LFNG is improperly trafficked and/or enzymatically dysfunctional. Finally, the phenotype of the axial skeleton, but not elsewhere, may be modulated in a variant-specific fashion. More reports are needed to continue testing this hypothesis. We anticipate our data will be used as a basis for discussion of genotype-phenotype correlations in SCD3.

Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review.

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

Jarcho Levin Syndrome with open neural tube defect: A case report

Background: Jarcho Levin syndrome is a rare genetic disorder characterized by spine abnormalities and the absence of ribs. It is associated with various congenital malformations and carries significant morbidity and mortality. The simultaneous presentation of this syndrome with neural tube defects is seldom encountered. Case Presentation: We report a case of a 2-day-old male who presented with a lesion on his back since birth. Clinical and radiological examinations revealed thoracolumbar meningomyelocele with the absence of upper ribs on the right side and a patent foramen ovale. Subsequently, the patient underwent surgery for meningomyelocele, while the rib anomalies were managed conservatively. Conclusion: Jarcho Levin syndrome is a rare disorder, and its association with meningomyelocele is extremely uncommon. It should be considered in the evaluation of a patient with a neural tube defect and respiratory distress.

Early prenatal diagnosis of spondylocostal dysostosis caused by a novel variant in MESP2.

Early prenatal diagnosis of spondylocostal dysostosis caused by a novel variant in MESP2.

Spondylocostal dysostosis: A rare case report

Spondylocostal dysostosis (SCD), also known as Jarcho Levin syndrome, is a rare congenital dysostosis characterized by multiple congenital vertebral and rib anomalies. The child usually presents with respiratory distress at birth with eventual development of short trunk dwarfism. Associated congenital anomalies are rare; however, they need evaluation. We report a 6-month-old Indian girl with SCD who presented with respiratory distress and an asymmetrical small thoracic cavity. The diagnosis was made with radiographs, computed tomography scans, and magnetic resonance imaging (MRI) showing multiple rib and vertebral segmentation anomalies. We would also highlight the importance of MRI in these patients and illustrate other associated brain and spine anomalies.

Anesthetic management of a parturient with spondylocostal dysostosis (Jarcho-Levin syndrome) for cesarean delivery

Jarcho Levin syndrome was first described by Saul Jarcho and Paul Levin in 1938. The syndrome is characterized by multiple skeletal deformities due to axial skeletal developmental defects during the embryologic stage. Generalized vertebral defects include fused, missing, or deformed vertebrae, and these are seen throughout the cervical, thoracic, and lumbar spine. The patients have short stature and kyphoscoliosis. In pregnancy, these skeletal defects may have pronounced effects on the parturient and the baby, so special considerations are needed by the obstetricians as well as the obstetric anesthesiologists. This case report highlights the challenges our anesthesiology team faces while providing patient care and points out the different anesthetic management approaches that can be used in cesarean delivery for parturients with spondylocostal dysostosis.
 Key words: Jarcho-Levin Syndrome; Anesthesia; Congenital; Hereditary; Abnormalities; Growth Disorders; Physical Appearance
 Citation: Ibrahim MA, Almetwalli RR. Anesthetic management of a parturient with spondylocostal dysostosis (Jarcho-Levin syndrome) for cesarean delivery. Anaesth. pain intensive care 2023;27(6):780−782; DOI: 10.35975/apic.v27i6.2353
 Received: September 02, 2023; Reviewed: October 25, 2023; Accepted: November 01, 2023

Functional Characterization of Novel Lunatic Fringe Variants in Spondylocostal Dysostosis Type-III with Scoliosis

Scoliosis affects over four million Americans, with most cases having an idiopathic cause. Pathogenic variants in the LUNATIC FRINGE (LFNG) gene can cause spondylocostal dysostosis type-III (SCD3), which is a rare skeletal dysplasia characterized by the absence, fusion, or partial development of vertebrae and ribs. Acute restrictive lung disease and scoliosis may also be present in some cases. The variability in symptoms suggests that there may be other underlying pathological mechanisms that are yet to be discovered. We conducted an analysis of two novel LFNG variants, c.766G>A (p.G256S) and c.521G>A (p.R174H), that were observed in a patient with SCD3 phenotype and scoliosis. Characterizing these variants can help us better understand the relationship between genotype and phenotype. We assessed both variants for impaired glycosyltransferase activity, subcellular mislocalization, and aberrant pre-proprotein processing. Our results indicate that the p.G256S variant is enzymatically nonfunctional, while the p.R174H variant is functionally less effective. Both variants were correctly localized and processed. Our findings suggest that the hypomorphic variant (p.R174H) may have partially improved the patient’s stature, as evidenced by a lower arm span-to-height ratio, increased height, and more vertebrae. However, this variant did not appear to have any effect on the severity of vertebral malformations, including scoliosis. Further research is necessary to determine the extent to which variations in LFNG activity affect the presentation of SCD3.

Jarcho–Levin Syndrome

Background: Jarcho–Levin syndrome (JLS) is a rare, congenital skeletal disorder involving the spine and the ribs, resulting in varying degrees of thoracic insufficiency, presenting at birth. We report such a case in a tribal population in India. Clinical Description: A newborn baby was referred on the 2nd day of life with respiratory distress and abnormal thoracic anatomy. Radiographs of the chest showed anomalies of the spine and ribs and decreased lung volume, the features being consistent with JLS (spondylocostal dysostosis). Management: The baby was provided respiratory support initially with continuous positive airway pressure and then shifted to oxygen by nasal prongs by 7 days of life. Ultrasound cranium and abdomen did not reveal any other associated anomalies and routine blood investigations were within normal limits. Respiratory distress settled and the baby was finally discharged successfully on the 12th day, on breastfeeds. Conclusion: Respiratory distress in a newborn, soon after birth, may be due to thoracic insufficiency. The case creates awareness among pediatricians and neonatologists regarding this rare disorder which can be identified by specific vertebral and rib abnormalities. Survival depends on the severity of the bony abnormality and compromise in lung volume.

Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3.

Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the "segmentation clock" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings.

Identification of a Novel Nonsense Variant in the DLL3 Gene Underlying Spondylocostal Dysostosis in a Consanguineous Pakistani Family

Introduction: Spondylocostal dysostosis (SCD) is characterized by multiple vertebral abnormalities associated with abnormalities of the ribs. Five genes causative for the disease have been identified. These include DLL3 (OMIM *602768), MESP2 (OMIM #608681), LFNG (OMIM #609813), TBX6 (OMIM *602427), and HES7 (OMIM *608059). Methods: In the current study, we investigated a Pakistani consanguineous family segregating spondylocostal dysotosis. Whole-exome sequencing (WES) followed by Sanger sequencing was performed using DNA of affected and unaffected individuals to identify pathogenic variant(s). The identified variant was interpreted using ACMG classification. Literature review was performed to summarize currently known mutated alleles of DLL3 and the underlying clinical phenotypes. Results: Clinical examination using anthropometric measurements and radiographs diagnosed the patients to be afflicted with SCD. Pedigree analysis of the affected family showed an autosomal recessive inheritance pattern of the disease. WES followed by Sanger sequencing identified a novel homozygous nonsense variant (DLL3(NM_016941.4): c.535G>T; p.Glu179Ter) in the DLL3 gene located on chromosome 19q13.2. Conclusion: The study will be helpful in carrier testing and genetic counseling to prevent segregation of the disease to the next generations within this family. It also provides knowledge for clinicians and researchers in search of a better understanding of SCD anomalies.

Hemangioma–Benign Tumor in Childhood

Background: Hemangiomas are vascular tumors, i.e. neoplasms of the vascular network. These are the most common neoplasms in the age of infancy. They can be infantile and congenital. Objective: Present the case of a 7.5-year-old girl suffering from a benign vascular tumor–hemangiomatosis of the skin and liver, which is part of the autosomal recessive syndrome SDC (Spondylocostal dysostosis). Case presentation: This case shows that hemangiomas can be accompanied by other diseases as part of congenital syndromes or metabolopathies that are often genetically inherited. In the present case, it is an autosomal recessive form of SCD syndrome or spondylocostal dysostosis. Conclusion: It is important to consider SCD, i.e., spondylocostal dysostosis, as a rare autosomal recessive disease that can occur as part of hemangiomatosis. Recent studies from 2020 and 2013 have shown the efficacy of topical timolol as well as atenolol which can replace oral propranolol as the first-line agent in the treatment of hemangiomas. In randomized clinical trial (2020), when compared with propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of infants with problematic infantile hemangiomas.

Spondylocostal dysostosis 1 – case report and literature review

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Drachal E, Zapolnik P, Dembiński Ł, Zgurski M, Pyrkosz A. Spondylocostal dysostosis 1 – case report and literature review. Pediatria Polska - Polish Journal of Paediatrics. 2023. doi:10.5114/polp.2023.126112. APA Drachal, E., Zapolnik, P., Dembiński, Ł., Zgurski, M., & Pyrkosz, A. (2023). Spondylocostal dysostosis 1 – case report and literature review. Pediatria Polska - Polish Journal of Paediatrics. https://doi.org/10.5114/polp.2023.126112 Chicago Drachal, Elżbieta, Paweł Zapolnik, Łukasz Dembiński, Michał Zgurski, and Antoni Pyrkosz. 2023. "Spondylocostal dysostosis 1 – case report and literature review". Pediatria Polska - Polish Journal of Paediatrics. doi:10.5114/polp.2023.126112. Harvard Drachal, E., Zapolnik, P., Dembiński, Ł., Zgurski, M., and Pyrkosz, A. (2023). Spondylocostal dysostosis 1 – case report and literature review. Pediatria Polska - Polish Journal of Paediatrics. https://doi.org/10.5114/polp.2023.126112 MLA Drachal, Elżbieta et al. "Spondylocostal dysostosis 1 – case report and literature review." Pediatria Polska - Polish Journal of Paediatrics, 2023. doi:10.5114/polp.2023.126112. Vancouver Drachal E, Zapolnik P, Dembiński Ł, Zgurski M, Pyrkosz A. Spondylocostal dysostosis 1 – case report and literature review. Pediatria Polska - Polish Journal of Paediatrics. 2023. doi:10.5114/polp.2023.126112.

Clinical genetics of spondylocostal dysostosis: A mini review.

Spondylocostal dysostosis is a genetic defect associated with severe rib and vertebrae malformations. In recent years, extensive clinical and molecular diagnosis advancements enabled us to identify disease-causing variants in different genes for such severe conditions. The identification of novel candidate genes enabled us to understand the developmental biology and molecular and cellular mechanisms involved in the etiology of these rare diseases. Here, we discuss the clinical and molecular targets associated with spondylocostal dysostosis, including clinical evaluation, genes, and pathways involved. This review might help us understand the basics of such a severe disorder, which might help in proper clinical characterization and help in future therapeutic strategies.

Врожденный лордоз и лордосколиоз: состояние проблемы (обзор литературы)

the dorsal part of the vertebrae and normal growth of the ventral part. The most common nosological variant of the defect is lordoscoliotic deformity of the thoracic spine, which often occurs due to syndromic defects (spondylocostal dysostosis) and systemic diseases of the musculoskeletal system (arthrogryposis). Along with the vertebral syndrome, the pathological complex in congenital lordosis of the thoracic or thoracolumbar spine includes thoracic insufficiency syndrome, which in the overwhelming cases leads to the development of respiratory failure caused by bronchial obstruction. The purpose of the study is to summarize information and analyze literature data on a rare pathology of the spine, which is clinically manifested by the formation of thoracic lordosis due to congenital anomaly in the development of the vertebrae. Materials and methods An analysis of the literature on the diagnosis and treatment of congenital lordosis and lordoscoliosis in children was carried out. The depth of the search was more than 100 years. Inclusion criteria: presence of lordotic deformity of the thoracic, cervicothoracic or thoracolumbar spine. Results and discussion Respiratory failure in this group of patients develops due to reduction in the anteroposterior size of the chest (an increase in the chest penetration index), a decrease in the height of the thoracic spine, changes in the mechanics of rib movements, bronchial obstruction, worsening ventilation and perfusion on the convex side of the deformity. The leading component of disability and impairment of the quality of life of patients is respiratory failure syndrome. A decrease in lung function, primarily due to reduction in VC, is directly proportional to the magnitude of the deformation of the spine and chest. Surgical correction of spinal and chest deformity is the main component of treatment for this group of patients. Surgical treatment consists in the mandatory multilevel mobilization of all three columns of the spine (preferably combined access) and bilateral resection of the ribs to reduce chest rigidity. Postoperative respiratory support is critical in respiratory failure. Conclusion Congenital spinal deformities in the form of thoracic lordosis and lordoscoliosis are extremely rare. The key aspects of treatment are the fight against respiratory failure and the selective choice of surgical technologies for deformity correction with a trend towards simultaneity of interventions. The literature review confirmed the insufficient knowledge on the issues of this pathology.

TBX6 as a cause of a combined skeletal-kidney dysplasia syndrome.

TBX6 encodes transcription-factor box 6, a transcription factor critical to paraxial mesoderm segmentation and somitogenesis during embryonic development. TBX6 haploinsufficiency is believed to drive the skeletal and kidney phenotypes associated with the 16p11.2 deletion syndrome. Heterozygous and biallelic variants in TBX6 are associated with vertebral and rib malformations (TBX6-associated congenital scoliosis) and spondylocostal dysostosis, and heterozygous TBX6 variants are associated with increased risk of genitourinary tract malformations. Combined skeletal and kidney phenotypes in individuals harboring heterozygous or biallelic TBX6 variants are rare. Here, we present seven individuals with vertebral and rib malformations and structural kidney differences associated with heterozygous TBX6 gene deletion in trans with a hypomorphic TBX6 allele or biallelic TBX6 variants. Our case series highlights the association between TBX6 and both skeletal and kidney disease.

Spondylocostal dysplasia: a rare cause of respiratory distress in term neonates

Jarcho-Levin syndrome (JLS) also known as spondylocostal dysplasia is a rare congenital dysplastic disorder involving ribs and vertebrae. It as an autosomal recessive form of inheritance however dominant forms have also been reported. Multiple genes have been postulated to be causative, however exact genetic basis is not known. Infants usually present at birth with respiratory distress and have varying degree of thoracic and vertebral anomalies. We present a case of term male infant with a clinical diagnosis of JLS. The infant presented at birth with distress with no significant antenatal risk factors. On examination he was found to have a short neck, short trunk, accessory nipple with asymmetrical chest wall. X-ray suggested absent ribs (2-8) on left side with hemivertebrae (T3-T8). The baby was managed conservatively and is being followed up with neonatologists, orthopaedicians and pediatric surgeons.