Spondylocostal Dysostosis Research Articles

Butterfly vertebra with lumbar intervertebral disc herniation

A butterfly vertebra is a rare congenital anomaly that is usually asymptomatic. The authors, however, describe a novel case involving a butterfly vertebra overlapping with disc herniation that presented as radiculopathy. A butterfly vertebra is characterized by a symmetrical fusion defect resulting in a sagittal cleft vertebra. Only a few cases of butterfly vertebrae have been reported as incidental findings. This spinal anomaly may be associated with other congenital conditions such as Pfeiffer, Crouzon, Jarcho-Levin, and Alagille syndromes. Moreover, there is no previous report of a case associated with symptomatic disc herniation from the sagittal cleft. The authors excised the herniated disc fragment. They performed intraoperative discography after exposure of the corresponding intervertebral space via a conventional interlaminar approach. Histological examination of a tissue specimen showed scattered chondrocytes in the myxohyaline stroma, which indicated the nucleus pulposus.

The mouse notches up another success: understanding the causes of human vertebral malformation

The defining characteristic of all vertebrates is a spine composed of a regular sequence of vertebrae. In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1,000 live births and arise when the formation of vertebral precursors in the embryo is disrupted. These precursors (somites) form in a process (somitogenesis) in which each somite is progressively separated from an unsegmented precursor tissue. In the past decade the underlying genetic mechanisms driving this complex process have been dissected using animal models, revealing that it requires the coordinated action of at least 300 genes. Deletion of many of these genes in the mouse produces phenotypes with similar vertebral defects to those observed in human congenital abnormalities. This review highlights the role that such mouse models have played in the identification of the genetic causes of the malsegmentation syndrome spondylocostal dysostosis.

Spondylocostal dysostosis associated with type i split cord malformation and double nipple on one side: a case report

Jarcho Levin syndrome is a rare genetic disorder characterized by multipl vertebral and costal anomalies at birth. Jarcho Levin syndrome includes two phenotypic groups: spondylothoracic dysostosis and spondylocostal dysostosis. The prognosis of spondylothoracic dysostosis has worse than spondylocostal dysostosis, because of respiratory complications. Associated malformations include those of the congenital heart disease, urogenital malformation, skeletal anomalies and neural tube defects. We present a patient with spondylocostal dysostosis, who also had type I split cord malformation, tethered cord, scoliosis and double nipple on the right. Although the association of spondylocostal dysostosis and type I split cord malformation is very rare, double nipples on one side is no previously reported.

Jarcho-Levin syndrome with diastematomyelia : A case report and review of literature

Jarcho–Levin syndrome (JLS) is a type of segmental costovertebral malformation. It is a congenital disorder characterized by a variety of vertebral and costal anomalies. Only four cases of Jarcho–Levin syndrome with diastematomyelia have been reported in the literature. We report the fifth case of Jarcho–Levin syndrome with diastematomyelia and review the literature. A one-and-half-year-old male child born of full-term normal delivery was brought with complaints of progressively increasing weakness in lower limbs with inability to stand since 1 month. Radiological examination revealed irregular fusion of ribs, spina bifida, and diastematomyelia at L2–L3 vertebral level. The patient underwent L1 to L3 laminectomy. A large bony spur was identified and excised with microrongeurs. Spondylocostal dysplasia may be associated with diastematomyelia or other surgically correctable occult intraspinal anomalies which may be diagnosed in early asymptomatic stage by magnetic resonance image screening of spine.

Iniencephaly clausus: A case report with review of literature

Iniencephaly is a rare neural tube defect characterized by extreme retroflexion of the head with the absence of neck due to spinal deformities. The important features that help us to diagnose a case of iniencephaly are occipital bone deficit leading to enlarged foramen magnum, fusion of malformed cervical and thoracic vertebrae, and upward turned face with chin continuous with chest because of the absence of neck. The differential diagnoses include anencephaly with spinal retroflexion, Klippel–Fiel syndrome, nuchal tumors such as teratoma, goiter, and lymphangioma and Jarcho–Levin syndrome. Previously many case reports on radiological features of iniencephaly are published, but there are very few articles on necropsy findings and differential diagnosis. In the present case we have discussed in detail the necropsy findings of iniencephaly clausus with special reference to differential diagnosis.

Clinical and radiological distinction between spondylothoracic dysostosis (Lavy-Moseley syndrome) and spondylocostal dysostosis (Jarcho-Levin syndrome)

In 1938, Saul Jarcho and Paul Levin from Johns Hopkins Hospital reported cases of thoracic insufficiency due to vertebral and rib anomalies. Nearly 30 years later, in 1966, Norman Lavy and associates from Indiana University reported a similar syndrome in a family from Puerto Rico. Lavy's description was followed by a report by John E. Moseley from New York City, where the name spondylothoracic dysplasia (dysostosis) was first used. For more than half a century, there has been confusion regarding the distinction between these two phenotypically similar syndromes that cause thoracic insufficiency. Spondylocostal dysostosis (SCD), or Jarcho-Levin syndrome, causes mild to moderate respiratory insufficiency, is panethnic and has been linked to genes such as DLL3, which is known to be associated with the Notch pathway. In contrast, spondylothoracic dysostosis (STD), or Lavy-Moseley syndrome, results in more severe respiratory compromise, is largely linked to Puerto Rican cohorts and is thought to be associated to the MESP2 gene, also a Notch pathway gene. Long-term studies of Puerto Rican cohorts with STD contradicts the previously held belief that individuals affected with STD have markedly diminished life expectancy with as many as 25% surviving into later childhood and adult life.

Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis

Mutations in the DELTA-LIKE 3 (DLL3) gene cause the congenital abnormal vertebral segmentation syndrome, spondylocostal dysostosis (SCD). DLL3 is a divergent member of the DSL family of Notch ligands that does not activate signalling in adjacent cells, but instead inhibits signalling when expressed in the same cell as the Notch receptor. Targeted deletion of Dll3 in the mouse causes a developmental defect in somite segmentation, and consequently vertebral formation is severely disrupted, closely resembling human SCD. In contrast to the canonical Notch signalling pathway, very little is known about the mechanism of cis-inhibition by DSL ligands. Here, we report that Dll3 is not presented on the surface of presomitic mesoderm (PSM) cells in vivo, but instead interacts with Notch1 in the late endocytic compartment. This suggests for the first time a mechanism for Dll3-mediated cis-inhibition of Notch signalling, with Dll3 targeting newly synthesized Notch1 for lysosomal degradation prior to post-translational processing and cell surface presentation of the receptor. An inhibitory role for Dll3 in vivo is further supported by the juxtaposition of Dll3 protein and Notch1 signalling in the PSM. Defining a mechanism for cis-inhibition of Notch signalling by Dll3 not only contributes greatly to our understanding of this ligand's function during the formation of the vertebral column, but also provides a paradigm for understanding how other ligands of Notch cis-inhibit signalling.

Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG

The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV) and abnormality of the thoracic cage with mal-aligned ribs and often a reduction in rib number. The four known monogenic forms of SCD follow autosomal recessive inheritance, have generalized SDV, a broadly symmetrical thoracic cage, and result from mutations in Notch signaling pathway genes-DLL3, MESP2, LFNG, and HES7. Autosomal dominant (AD) SCD has been reported less often, is very variable, and molecular genetic mechanisms remain elusive. Here, we report a three-generation, non-consanguineous family with four affected individuals demonstrating multiple or generalized SDV. Scoliosis was present and the trunk shortened but the ribs were relatively mildly affected. There were no other significant organ abnormalities, no obvious dysmorphic features, neurodevelopment was normal, and all investigations, including mutation analysis of DLL3, MESP2, LFNG, and HES7, were normal. A non-pathogenic variant was detected in LFNG but it did not segregate with the phenotype. This Macedonian kindred adds to knowledge of AD SCD and to our knowledge is the first to be tested for the four Notch pathway genes known to be associated with SCD.

Etiology of Congenital Scoliosis

Congenital scoliosis may have an environmental or genetic etiology. Environmental etiologies have focused on maternal carbon monoxide exposure in mice early in gestation. Genetic studies have focused on skeletal patterning genes in the human and the mouse. Genetic mutations have been isolated in the related Jarcho-Levin syndrome.

Notch and the Skeleton

Notch receptors are transmembrane receptors that regulate cell fate decisions. There are four Notch receptors in mammals. Upon binding to members of the Delta and Jagged family of transmembrane proteins, Notch is cleaved and the Notch intracellular domain (NICD) is released. NICD then translocates to the nucleus, where it associates with the CBF-1, Suppressor of Hairless, and Lag-2 (CSL) and Mastermind-Like (MAML) proteins. This complex activates the transcription of Notch target genes, such as Hairy Enhancer of Split (Hes) and Hes-related with YRPF motif (Hey). Notch signaling is critical for the regulation of mesenchymal stem cell differentiation. Misexpression of Notch in skeletal tissue indicates a role as an inhibitor of skeletal development and postnatal bone formation. Overexpression of Notch inhibits endochondral bone formation and osteoblastic differentiation, causing severe osteopenia. Conditional inactivation of Notch in the skeleton causes an increase in cancellous bone volume and enhanced osteoblastic differentiation. Notch ligands are expressed in the hematopoietic stem cell niche and are critical for the regulation of hematopoietic stem cell self-renewal. Dysregulation of Notch signaling is the underlying cause of diseases affecting the skeletal tissue, including Alagille syndrome, spondylocostal dysostosis, and possibly, osteosarcoma.

Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis

Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, with only individuals carrying both mutant alleles being affected by SCD. In vitro functional analysis revealed that one of the mutant HES7 proteins was unable to repress gene expression by DNA binding or protein heterodimerization.

Tomographic assessment of the spine in children with spondylocostal dysotosis syndrome

OBJECTIVE:The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome.METHOD:Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality.RESULTS:Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients.CONCLUSION:This article throws light on the most serious osseous manifestations of spondylocostal dysostosis syndrome.

Disostose espôndilo-costal associada a defeitos de fechamento do tubo neural

OBJETIVO: Salientar a relação dos defeitos de fechamento do tubo neural com a disostose espôndilo-costal (DEC) por meio da descrição de três pacientes. DESCRIÇÃO DOS CASOS: Paciente 1: menina branca, 22 meses, nascida com mielomeningocele lombar. Na avaliação, apresentava hipotonia, baixa estatura, dolicocefalia, fendas palpebrais oblíquas para cima, pregas epicânticas e tronco curto com tórax assimétrico. A avaliação radiográfica revelou hemivértebras múltiplas, vértebras em borboleta e fusão e ausência de algumas costelas. Paciente 2: menina branca, 22 meses, com moderado atraso do desenvolvimento neuropsicomotor, baixa estatura, olhos profundos, pregas epicânticas, pescoço e tronco curtos com assimetria do tórax, abdome protruso, hemangioma plano na altura da transição lombossacra e fosseta sacral profunda no dorso. A avaliação radiográfica identificou hemivértebras, fusão incompleta de vértebras e vértebras em borboleta, malformações de costelas e espinha bífida oculta em L5/S1. Paciente 3: menina branca, 9 dias de vida, com fendas palpebrais oblíquas para cima, ponte nasal alargada, orelhas baixo implantadas e rotadas posteriormente, tronco curto, tórax assimétrico e meningocele tóraco-lombar. A avaliação radiográfica evidenciou hemivértebras, malformação e ausência de algumas costelas e agenesia diafragmática à esquerda. A tomografia computadorizada de encéfalo mostrou estenose de aqueduto. COMENTÁRIOS: Vários defeitos de fechamento do tubo neural, de espinha bífida oculta a grandes mielomeningoceles, são observados em pacientes com DEC, indicando que tais pacientes devem ser cuidadosamente avaliados quanto à possível presença desses defeitos.

Prenatal Diagnosis of Jarcho-Levin Syndrome in Combination with Inguinoscrotal Hernia

Jarcho-Levin syndrome is characterized by short trunk dwarfism associated with rib and vertebral anomalies. The syndrome encompasses a group of disorders with phenotypic and inheritance variations. Here we report a prenatally diagnosed patient with spondylocostal dysostosis (SCD) with accompanying congenital inguinoscrotal hernia. A 28-year-old pregnant women, gravida 4, para 3, was referred to our clinic with a diagnosis of wedging of fetal thoracal vertebra and kyphoscoliosis at 28 weeks of gestation. Upon evaluation, fetal vertebral wedging and kyphoscoliosis were confirmed with the addition of thoracic circumference below 3rd percentile, short thorax length, and mild pyelectasis. During follow-up, in utero inguinoscrotal hernia developed. Prenatal diagnosis of SCD is important to provide appropriate genetic counseling and to have an adequate setting for the delivery of the fetus.

Spondylocostal Dysostosis Associated with Methylmalonic Aciduria

Spondylocostal dysostosis (SCD) is a genetic disorder characterized by vertebral segmentation and formation defects associated with changes of the ribs. Autosomal dominant and recessive modes of inheritance have been reported. Methylmalonic aciduria (MMA) is an inborn error of propionate or cobalamin metabolism. It is an autosomal recessive disorder and one of the most frequent forms of branched-chain organic acidurias. Here we report on a case of a Brazilian boy with both diseases. As we know, it is the first case in the literature with the occurrence of both SCD and MMA--the first a skeletal disease and the latter an inborn error of metabolism.

Reporte de cuatro casos de pacientes con síndrome de Jarcho-Levin en el departamento de Antioquia, Colombia

Four cases of Jarcho-Levin's syndrome in the province of Antioquia, Colombia Jarcho-Levin's syndrome is a skeletal dysplasia with changes in the morphogenesis and costal vertebrae segmentation. It is manifested by hemivertebrae, fused vertebral bodies, absent vertebrae or fused ribs. This entity has also been called spondylo-costal or spondylo-thoracic dysplasia-dysostosis. This paper presents four cases evaluated at the Hospital University San Vicente de Paúl, Medellín, Colombia. Three had family origins in southwestern Antioquia and one in Medellin, indicating the possibility of a predisposing genetic allele with elevated frequency in this population. The clinical and radiological manifestations were described, a well as the most notable complications, such as restrictive lung disease with permanent oxygen requirement (all 4 patients) and portal hypertension etiology (1 patient). The latter has not been reported previously as a manifestation of this syndrome.

Spinal anesthesia for Cesarean delivery in a parturient with spondylocostal dysostosis

To the Editor, Spondylocostal dysostosis (SCD) is a form of shorttrunked dwarfism resulting from a defect in somitogenesis. Both general (GA) and neuraxial anesthesia (NA) may present anesthetic challenges in these patients. A 40-yr-old multiparous woman (G6P3), 140 cm 59 kg, with SCD was examined in anticipation of a planned repeat Cesarean delivery (CD). She had one prior vaginal delivery and two CDs. All previous surgeries were performed under GA. Due to intraoperative awareness with a prior CD, she requested use of NA. The patient’s physical examination revealed a short trunk with disproportionately long extremities and the presence of scoliosis. Her airway examination revealed a restricted neck extension, a 3.5 cm thyromental distance, and a normal mouth opening with a Mallampati II classification. No evidence of cardiopulmonary dysfunction was noted and laboratory studies were unremarkable. A spinal magnetic resonance imaging showed multiple vertebral abnormalities along with cervical spinal stenosis and a C3–C4 disc herniation (Fig. 1). Termination of the thecal sac occurred at the level of the L5 vertebral body, with the conus medullaris ending near the L2–L3 interspace. The operating room (OR) was prepared with an assortment of difficult airway tools, in the event that tracheal intubation became necessary due to either failed or total spinal anesthesia. After aspiration prophylaxis with metoclopramide 10 mg po and sodium citrate/citric acid (30 ml po), the patient was taken to the OR and placed in the sitting position. Spinal anesthesia was achieved with some difficulty using 0.75% spinal bupivacaine 6 mg, fentanyl 10 lg, and preservative-free morphine 100 lg, by means of a 27-G Quinke needle at the L2–L3 interspace. The patient was then placed supine with left lateral uterine displacement, and a bilateral T3 level to pinprick was attained. A male infant was delivered by CD with Apgar scores of 8 and 9 (at one and five minutes, respectively). After approximately two hours of recovery time, the patient was discharged to the postpartum unit in stable condition. The patient consented to publication of this report and the related images. Spondylocostal dysostosis can be either a recessive or a dominant trait, and is characterized by multiple vertebrocostal anomalies without severe thoracic impairment. Costal anomalies include broadening, bifurcation, and fusion; whereas the vertebral defects include block-, wedge-, butterfly-, and hemi-vertebrae. These malformations may lead to progressive scoliosis. Other anomalies associated with SCD include facial dysmorphism, oropharyngeal abnormalities, torticolis, and patent foramen ovale. Despite the suggestion that, in the face of short-stature, catheter-based techniques are superior to single-shot techniques, we chose to use the latter. We thought a flexible spinal needle might be easier to manipulate through the patient’s disordered vertebral anatomy. It was unclear if an uninterrupted epidural space was present; therefore, the success of an epidural block was uncertain. Finally, since treating a spinal headache with a blood patch would likely be very difficult, continuous spinal anesthesia would be a poor choice. It is our practice to adjust the dosage of local anesthetic (LA) in a single-shot spinal, based on the height of the J. A. Dolak, MD, PhD (&) Emory Crawford Long Hospital, Atlanta, USA e-mail: jdolak@emory.edu

A CASE OF JARCHO-LEVIN SYNDROME ASSOCIATED WITH BILATERAL CYSTIC RENAL DISEASE AND WILMS TUMOR: MR Imaging Findings

Jarcho-Levin syndrome (JLS) is a congenital disorder characterized by a variety of vertebral and costal anomalies that result in thoracic deformity. Hitherto, a plethora of associated anomalies have been described in several reports. In this report, the authors describe a case of JLS who has Wilms tumor and bilateral cystic renal disease. To the authors’ knowledge, there is only a single case of JLS who presented with multiple renal cortical cysts, but none with an associated Wilms tumor in the literature. Additional anomalies seen in the present case that are related with this syndrome are also discussed.

Mortality and Life-Threatening Events After Vertical Expandable Prosthetic Titanium Rib Surgery in Children With Hypoplastic Chest Wall Deformity

Severe complex hypoplastic chest wall and spine deformity with thoracic insufficiency syndrome may be associated with premature death secondary to multisystem involvement. The vertical expandable prosthetic titanium rib (VEPTR) reconstructs the chest wall to address the thoracic insufficiency seen in this patient population. The purpose of this study is to report the mortality and life-threatening adverse events in a cohort of subjects with severe hypoplastic chest wall deformity, specifically with Jeune syndrome and Jarcho-Levin syndrome, after treatment with the VEPTR device. A cohort of 43 patients with either Jeune syndrome or Jarcho-Levin syndrome was extracted from a multicenter Investigational Device Exemption study of 214 patients who had surgery with the VEPTR device. Of the 43 patients, 19 had Jeune syndrome and 24 had Jarcho-Levin syndrome. Fatal and life-threatening adverse events were analyzed, including an assessment of time postsurgery, etiology, and the relationship of the adverse event to the surgical procedure. Four (9%) of the 43 patients died during the follow-up period. All 4 (100%) of these patients had Jeune syndrome. After the initial surgery, 2 died within 6 months, and the remaining 2 within 1 year. Causes of death included respiratory complications in 2, renal failure in 1, and liver failure in 1. An additional 4 (9%) of the 43 patients had life-threatening adverse events. Two (50%) patients were diagnosed with Jeune syndrome and the remaining 2 (50%) with Jarcho-Levin syndrome. Two of the 4 life-threatening events were related to the surgery perioperatively: necrotizing enterocolitis and acute respiratory distress syndrome. The other two events included cardiac arrest secondary to central line placement and Demerol overdose. Surgeons should be aware of the potential for fatality and life-threatening events that occur in patients with hypoplastic chest wall and spine deformity undergoing surgical treatment. The majority of these events occur within 1 year of surgery. Therapeutic study, Level IV (case series, no comparison group).

Mutation of the fucose-specific β1,3 N-acetylglucosaminyltransferase LFNG results in abnormal formation of the spine

Notch signaling is an evolutionarily conserved mechanism that determines cell fate in a variety of contexts during development. This is achieved through different modes of action that are context dependent. One mode involves boundary formation between two groups of cells. With this mode of action, Notch signaling is central to vertebrate evolution as it drives the segmentation of paraxial mesoderm in the formation of somites, which are the precursors of the vertebra. In this case, boundary formation facilitates a mesenchymal to epithelial transition, leading to the creation of a somite. In addition, the boundary establishes a signaling center that patterns the somite, a feature that directly impacts on vertebral column formation. Studies in Xenopus, zebrafish, chicken and mouse have established the importance of Notch signaling in somitogenesis, and indeed in mouse how perturbations in somitogenesis affect vertebral column formation. Spondylocostal dysostosis is a congenital disorder characterized by formation of abnormal vertebrae. Here, mutation in Notch pathway genes demonstrates that Notch signaling is also required for normal somite formation and vertebral column development in humans; of particular interest here is mutation of the LUNATIC FRINGE (LFNG) gene, which causes SCD type 3. LUNATIC FRINGE encodes for a fucose-specific β1,3-N-acetylglucosaminyltransferase, which modifies Notch receptors and alters Notch signaling activity. This review will focus on Notch glycolsylation, and the role of LUNATIC FRINGE in somite formation and vertebral column development in mice and humans.