Spondylothoracic Dysostosis Research Articles

EP324: Biallelic variants in DLL1 as a novel cause of severe spondylocostal dysostosis

Spondylocostal dysostosis (SCDO), also referred to as spondylothoracic dysostosis, is a rare disorder characterized by multiple segmentation defects of the vertebrae, a short trunk and neck, and rib abnormalities, including malalignment with missing or fused ribs. Pathogenic variants in six genes (DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2) have been identified to cause SCDO, mostly through autosomal recessive inheritance, although TBX6 has been associated with dominant inheritance as well. All six genes encode key components of the Notch1 receptor signaling pathway, which is essential for normal somitogenesis during development.

COVID-19 in a case of Jarcho Levin syndrome

Jarcho-Levin syndrome (JLS) also called spondylothoracic dysostosis is a rare congenital disorder. It is characterized by short stature with multiple abnormalities in the rib cage and vertebrae. The vertebrocoastal anomalies make the thoracic cage incapable of accommodating the growing lung. This in turn leads to thoracic insufficiency, severe cardio-respiratory complications, and frequent chest infections. We present the case of a 1-year-old baby girl who presented with symptoms of acute respiratory tract infection and was diagnosed with The novel Coronavirus Dis¬ease-2019 (COVID-19) by a positive rapid antigen test. During workup, she was also diagnosed to be a case of JLS with help of a skeletal survey. The baby died shortly after.

Rare health conditions 24: Severe combined immunodeficiency (SCID), papilloedema, spondylothoracic dysostosis (STD)

The purpose of this series is to briefly highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000 and many HCAs and nurses will encounter some of these conditions, given the high number of these conditions. This 24th article will briefly explore three of these conditions.

Nöral tüp defekti bulunan spondilotorasik dizositoz tip Jarcho-Levin sendromu: Bir olgu sunumu

Jarcho-Levin syndrome is rare a congenital disorder characterized by numerical and structural costo-vertebral abnormalities. The subtypes of this syndrome are, spondylothoracic and spondylocostal dysostosis. Rib and vertebrae aberrations cause respiratory insufficiency and result in recurrent respiratory infections. Since it is a rare entity, a newborn diagnosed as spondylothoracic dysostosis with meningomyelocele, who had ventriculoperitoneal shunting due to severe hydrocephalus and could not be weaned from respiratory support due to chest deformity, is presented in this case report.

Jarcho-Levin syndrome with association of unilateral pulmonary hypoplasia and diastometamyelia: A case illustration.

Sir, Jarcho–Levin syndrome (JLS) is a rare distinctive form of short-trunk dwarfism with rib and vertebral anomalies. This is the first case of a newborn exhibiting an unusual combination of spondylothoracic and spndylocostal JLS with lung anomaly and diastematomyelia to be reported. A new born (1-day-old) male baby, born by Lower segment Caesarean section (indication was nonprogression of labor), birth weight 2.35 kg, first child of nonconsanguinous marriage, was referred to our tertiary care hospital with multiple anomalies and recurrent episodes of cough, cold, vomiting after feeds, and rapid breathing. On examination, the baby was afebrile, with tachycardia, and tachypnea (32 per min). Head circumference was 35 cm, short stature (length is 37 cm), short neck, anteverted nares and dysmorphic features (low-set ears, hypertelorism, high-arched palate, short upper segment). Distal penile hypospadias with chordee and penile torsion, bifid scrotum, hypertrophy of left hemiscrotum were also present. On further examination, abdomen was distended with visible bowel loops. Imperforate anus and anal pit was noted. Spinal examination showed scoliosis in thoracolumbar region with curvature to right along with sacral agenesis, left calcaneovalgus, and over-riding of feet. Chest radiography showed fusion and fanning of ribs [Figure 1a and b]. Milks scan [Figure 1c] was performed due to vomiting after feeds and images revealed no evidence of gastroesophageal reflux. Computed tomography of thorax showed hypoplastic left lung. MRI spine [Figure 2] showed severe kyphoscolotic deformity of dorsolumbar spine, agenesis of sacral segments, multiple vertebral segmentation and fusion anomalies in the dorsolumbar region. Bifid ribs were noted. Cervical cord was normal. There was a low-lying cord, split at D5 level by fibrous bar, which is known as diastometamyelia. 99m Tc DTPA (diethylene triamine penta acetic acid) renogram was performed to look for any associated renal anomalies and revealed bilateral normally functioning kidneys [Figure 1d]. Based on the constellation of symptoms and imaging findings, JLS was suspected and was advised DNA isolation.Figure 1: (a) Chest radiography showing short neck, fusion, and fanning of bilateral ribs. (b) radiography of spine showed scoliosis in thoracolumbar region with curvature to right along with sacral agenesis. (c) 99m Tc sulphur colloid gastroesophageal (GE) scintigraphy (otherwise known as milk scan) was performed to look for any GE reflux disease and was confirmed to be negative. (d) 99m Tc DTPA (diethylene triamine penta acetic acid) renogram showed normally functioning, PUJ (pelviureteric junction) nonobstructed bilateral kidneysFigure 2: Magnetic resonance imaging and computed tomography spine: Images revealed severe dorsolumbar kyphoscoliosis, sacral agenesis, multiple vertebral segmentation and fusion anomalies, and bifid ribs. Patient also showed diastometamyelia at D5 level (arrow)JLS is a rare distinctive form of short-trunk dwarfism with rib and vertebral anomalies. This is the first case of JLS revealing a rare combination of both subtypes of JLS with lung anomaly and diastematomyelia the other case published from India showed diastematomyelia and spondylocostal dysostosis.[1] Hernias, neural tube defects and anomalies of the anal opening, urinary tract, external genitalia, uterus and lower limbs may be associated.[2] Recently, airway abnormalities have been described in two patients with the JLS similar to our case.[3] Malformations of the spinal cord with a separation into two hemicords have been termed “diastematomyelia,” which has been rarely reported in the literature, which is present in our patient. JLS has been divided into two major subtypes, that is, spondylothoracic dysostosis (“fan-like” or crab-like” rib) and spondylocostal dysostosis (vertebral anomalies with marked rib anomalies such as absent ribs, abnormal orientation, irregularity of shape and size, bifurcation, broadening, fusion). They are more often short statured than patients with spondylothoracic dysostosis and have twice their survival rate and have no associated neural tube defects. Both these subtypes of JLS are inherited as autosomal recessive traits, and exhibit a high mortality rate.

Anaesthetic management of a patient with Jarcho-Levin syndrome.

Anaesthetic management of a patient with Jarcho-Levin syndrome.

Mechanisms in Endocrinology: Notch signaling in skeletal health and disease

Notch receptors are single-pass transmembrane proteins that determine cell fate. Upon Notch ligand interactions, proteolytic cleavages release the Notch intracellular domain, which translocates to the nucleus to regulate the transcription of target genes, including Hairy enhancer of split (Hes) and Hes related to YRPW motif (Hey). Notch is critical for skeletal development and activity of skeletal cells, and dysregulation of Notch signaling is associated with human diseases affecting the skeleton. Inherited or sporadic mutations in components of the Notch signaling pathway are associated with spondylocostal dysostosis, spondylothoracic dysostosis and recessive brachydactyly, diseases characterized by skeletal patterning defects. Inactivating mutations of the Notch ligand JAG1 or of NOTCH2 are associated with Alagille syndrome, and activating mutations in NOTCH2 are associated with Hajdu-Cheney syndrome (HCS). Individuals affected by HCS exhibit osteolysis in distal phalanges and osteoporosis. NOTCH is activated in selected tumors, such as osteosarcoma, and in breast cancer cells that form osteolytic bone metastases. In conclusion, Notch regulates skeletal development and bone remodeling, and gain- or loss-of-function mutations of Notch signaling result in important skeletal diseases.

Spatiotemporal disorder in the axial skeleton development of the Mesp2-null mouse: A model of spondylocostal dysostosis and spondylothoracic dysostosis

Spondylocostal dysostosis (SCDO) is a genetic disorder characterized by severe malformation of the axial skeleton. Mesp2 encodes a basic helix–loop–helix type transcription factor that is required for somite formation. Its human homologue, Mesp2, is a gene affected in patients with SCDO and a related vertebral disorder, spondylothoracic dysostosis (STDO). This work investigated how the loss of Mesp2 affects axial skeleton development and causes the clinical features of SCDO and STDO. We first confirmed, by three-dimensional computed tomography scanning, that Mesp2-null mice exhibited mineralized tissue patterning resembling the radiological features of SCDO and STDO. Histological observations and in situ hybridization probing for extracellular matrix molecules demonstrated that the developing vertebral bodies in Mesp2-null mice were extensively fused with rare insertions of intervertebral tissue. Unexpectedly, the intervertebral tissues were mostly fused longitudinally in the vertebral column, instead of exhibiting extended formation, as was expected based on the caudalized properties of Mesp2-null somite derivatives. Furthermore, the differentiation of vertebral body chondrocytes in Mesp2-null mice was spatially disordered and largely delayed, with an increased cell proliferation rate. The quantitative three-dimensional immunofluorescence image analyses of phospho-Smad2 and -Smad1/5/8 revealed that these chondrogenic phenotypes were associated with spatially disordered inputs of TGF-β and BMP signaling in the Mesp2-null chondrocytes, and also demonstrated an amorphous arrangement of cells with distinct properties. Furthermore, a significant delay in ossification in Mesp2-null vertebrae was observed by peripheral quantitative computed tomography. The current observations of the spatiotemporal disorder of vertebral organogenesis in the Mesp2-null mice provide further insight into the pathogenesis of SCDO and STDO, and the physiological development of the axial skeleton.

Three‐dimensional computed tomography of fetal spondylothoracic dysostosis at 23 weeks' gestation

Prenatal DiagnosisVolume 32, Issue 6 p. 604-606 Research Letter Three-dimensional computed tomography of fetal spondylothoracic dysostosis at 23 weeks' gestation Michelle Ranes, Michelle Ranes Department of Obstetrics and Gynecology, Winnie Palmer Hospital, Orlando Regional Healthcare, Orlando, FL, USASearch for more papers by this authorS. J. Carlan, Corresponding Author S. J. Carlan [email protected] Department of Obstetrics and Gynecology, Winnie Palmer Hospital, Orlando Regional Healthcare, Orlando, FL, USASteve J. Carlan. E-mail: [email protected]Search for more papers by this authorJose Perez, Jose Perez Department of Pediatrics, Division of Neonatology, Orlando, FL, USASearch for more papers by this authorSuzanna Attia, Suzanna Attia Department of Pediatrics, Orlando Regional Healthcare, Orlando, FL, USASearch for more papers by this author Michelle Ranes, Michelle Ranes Department of Obstetrics and Gynecology, Winnie Palmer Hospital, Orlando Regional Healthcare, Orlando, FL, USASearch for more papers by this authorS. J. Carlan, Corresponding Author S. J. Carlan [email protected] Department of Obstetrics and Gynecology, Winnie Palmer Hospital, Orlando Regional Healthcare, Orlando, FL, USASteve J. Carlan. E-mail: [email protected]Search for more papers by this authorJose Perez, Jose Perez Department of Pediatrics, Division of Neonatology, Orlando, FL, USASearch for more papers by this authorSuzanna Attia, Suzanna Attia Department of Pediatrics, Orlando Regional Healthcare, Orlando, FL, USASearch for more papers by this author First published: 04 May 2012 https://doi.org/10.1002/pd.3874Citations: 2 Funding sources: None Conflict of interest: None declared Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume32, Issue6June 2012Pages 604-606 RelatedInformation

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

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

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.

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.

Jarcho-Levin Syndrome Presenting with Diaphragmatic Hernia

Jarcho-Levin syndrome (spondylothoracic or spondylocostal dysostosis) is an eponym that is used to define individuals with a short neck, short trunk, and short stature and multiple vertebral anomalies. The prognosis is directly related to respiratory complications. Reported findings associated with Jarcho-Levin syndrome include congenital heart defects, abdominal wall malformations, genitourinary malformations, upper limb anomalies, and neural tube defects. We report on a 6-day-old girl who presented with an incomplete form of Jarcho-Levin syndrome with late-presenting congenital diaphragmatic hernia and congenital heart disease.

Mutations in the MESP2 Gene Cause Spondylothoracic Dysostosis/Jarcho-Levin Syndrome

Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a "crab-like" configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the mesoderm posterior 2 homolog (MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS.

Abstract

Spondylocostal dysostoses are a group of rare inherited disease with a heterogeneous disorder of vertebral segmentation defects and rib anomalies, which lead to respiratory problems predicting the clinical outcome. Spiral CT with three-dimensional (3D) imaging provides exact measurement of the bony rib cage. We report a case of an infant with spondylothoracic dysostosis, a phenotype of spondylocostal dysostoses, and 3D spiral CT findings of his rib cage since it may contribute to the surgical planning.

Spondylocostal dysostosis: thirteen new cases treated by conservative and surgical means.

Prospective assessment of a cohort of patients affected by spondylocostal dysostosis. To report on the results of conservative and operative management of spondylocostal dysostosis and, based on this, to propose an assessment and treatment protocol for the condition. Spondylocostal dysostosis and spondylothoracic dysostosis are subtypes of Jarcho-Levin syndrome, a hereditary condition manifested by vertebral body and related rib malformations. Mortality prevails in spondylothoracic dysostosis because of more severe respiratory compromise. Details of prenatal and postnatal diagnosis, history, and management of 13 patients with spondylocostal dysostosis are presented. All patients were treated postnatally with repeated chest physiotherapy. Two patients refractory to conservative treatment underwent surgical intervention: the first had a chest wall reconstruction via a latissimus dorsi flap, the second a posterior spinal instrumented fusion for progressive scoliosis. Prenatal ultrasound in 4 of 13 cases showed full details of vertebral and rib anomalies. Thoracic and lumbar hemivertebrae were most common, leading to congenital scoliosis in 10 of 13 cases. A number of extraskeletal abnormalities were also identified. At an average follow-up of 4.5 years, the survival rate was 100% with a remarkable decrease of the rate of respiratory complications. Surgical treatment in selected cases led to satisfactory results. Prenatal diagnosis of spondylocostal dysostosis allows exclusion of spondylothoracic dysostosis and aids genetic counseling in quantifying the risk to siblings. Postnatally, prompt management of these patients with physiotherapy leads to prolonged survival. Surgical intervention may then be indicated to stabilize chest wall or spine deformities, with promising results.

Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review.

We report two consecutive Caucasian male siblings of nonconsanguineous parents autopsied at 22 and 13 weeks gestational age both with prenatal diagnosis of Jarcho-Levin syndrome (JLS). Segmentation anomalies of the vertebrae and ribs encompass a spectrum of syndromes with or without associated anomalies of other developmental fields, and include spondylothoracic dysostosis (STD), JLS, Casamassima-Morton-Nance (CMN) syndrome, and spondylocostal dysostosis (SCD), among others. In both these new JLS cases the autopsies confirmed that there were severe developmental alterations in the thoracic and vertebral skeleton (including "crab-like" thorax), accompanied in the older fetus by renal defects. Because vertebral development is controlled by a limited number of master genes including Pax1 and Pax9, we analyzed protein expression from these genes in these two cases compared to age-matched controls. Immunochemical analysis showed a significant reduction in levels of Pax1 and Pax9 protein expression in chondrocytes of the vertebral column. Implications for the etiology and pathogenesis of JLS and related disorders are discussed.

Rib defects in patterns of multiple malformations: a retrospective review and phenotypic analysis of 47 cases.

Rib anomalies may occur in isolation, as well as in association with abnormalities of vertebral segmentation and multi-system malformations. Specific entities include the VACTERL and MURCS associations, spondylocostal dysostosis, and spondylothoracic dysostosis. The relative significance of rib anomalies in other lesser known syndromes and associations remains unclear. To document the diagnoses and related defects in patients with rib anomalies as part of broader pattern of anomalies, we retrospectively identified 47 cases from a hospital population, and evaluated specific costal findings and associated birth defects. In our study, fusion was the most common pattern of rib anomaly (72%), followed by bifid (28%) and hypoplastic ribs (26%). Unrecognized patterns of multiple congenital anomalies (MCA) and VACTERL association were the commonest specific diagnoses with a frequency of 30 and 28%, respectively. An associated vertebral defect was found in 72% of the patients. Of those with no vertebral anomaly, the combinations of "rib and cardiac defects alone" and "rib and renal defects alone" were seen in one-third of the patients (4/13). Both the occurrence and type of rib anomaly were helpful in defining certain syndromes and enhanced the likelihood of identifying related malformations.

Multiple vertebral segmentation defects: Analysis of 26 new patients and review of the literature

To further delineate and classify those forms of short trunk dwarfism characterized by multiple vertebral segmentation defects, we analyzed 26 new patients and reviewed 115 described in the literature. Three distinct entities were recognized based on radiographic and clinical findings. Jarcho-Levin syndrome is the lethal autosomal recessive form, characterized by a symmetric crab-like chest. Spondylocostal dysostosis is the benign autosomal dominant condition. Spondylothoracic dysostosis shows considerable clinical and radiographic overlap with spondylocostal dysostosis. Malformations observed in association with multiple vertebral segmentation defects are more common in the sporadic patients. Analysis of the 26 new individuals revealed that the body segment in which these nonvertebral malformations occur corresponds to the site of the vertebral segmentation defects.

Congenital heart disease in spondylothoracic dysostosis: two familial cases.

Two familial cases of spondylothoracic dysostosis are reported. Both cases had severe congenital heart disease in addition to the skeletal malformations which are characteristic of the condition.