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Spondylothoracic Dysostosis

, MD, PhD
Hospital de la Concepción
San Germán, Puerto Rico
Ponce School of Medicine
Ponce, Puerto Rico

Initial Posting: .

Summary

Disease characteristics. Spondylothoracic dysostosis (STD) (known as Jarcho-Levin syndrome when it occurs in Puerto Ricans of Spanish descent) is characterized by a short and rigid neck, short thorax, protuberant abdomen, and inguinal and umbilical hernias. Abnormal vertebral segmentation and posterior rib fusion can result in significant thoracic restriction and respiratory insufficiency. Poor growth of the spine results in a short trunk and hence short stature. Scoliosis is not common, but when present can be severe.

Diagnosis/testing. Diagnosis relies on distinctive radiographic findings including abnormal segmentation of all vertebral segments, severe shortening of the spine, especially the thoracic spine, and rib fusions. MESP2 is the only gene known to be associated with spondylothoracic dysostosis.

Management. Treatment of manifestations: symptomatic treatment of respiratory distress in neonates, often with surfactant factor, CPAP (constant positive air pressure) for hypercapnea, and continuous drip (rather than bolus) feedings. Endotracheal intubation and mechanical ventilation should be avoided and, when necessary, ventilator pressures should be set as low as possible and discontinued as soon as possible. In older children, aggressive treatment of upper respiratory tract diseases, immunization against RSV, and therapy with bronchodilators as needed. Physical and occupational therapies may help support development progress. Surgical intervention as needed for scoliosis and inguinal hernias.

Surveillance: Growth, development, respiratory function, and spinal curvature should be monitored. Young males need to be monitored for the signs of inguinal hernias and their complications.

Genetic counseling. Spondylothoracic dysostosis (STD) is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family. Prenatal ultrasound examination can be performed early in the second trimester to identify multiple vertebral segmentation defects and rib fusions.

Diagnosis

Clinical Diagnosis

Spondylothoracic dysostosis (STD) (known as Jarcho-Levin syndrome when it occurs in Puerto Ricans of Spanish descent) is characterized by short and rigid neck, short thorax, protuberant abdomen, inguinal and umbilical hernias, urinary tract abnormalities, and disproportionate dwarfism.

The distinctive radiographic findings [Cornier et al 2004]:

  • Abnormal segmentation of all vertebral segments with characteristic “sickle cell shaped vertebrae”; severe shortening of the spine, especially the thoracic spine (see Figure 1)
  • Rib fusions typically occurring posteriorly at the costovertebral origins, where the spinal shortening is most severe. The ribs usually appear straight and neatly aligned without points of fusion along their length. On antero-posterior x-ray the ribs characteristically ‘fan out’ from their costovertebral origins in a ‘crab-like’ fashion.
  • A distinctive radiographic appearance called the ‘tramline sign’ that results from early radiographic prominence of the vertebral pedicles, in contrast to the vertebral bodies, which have no regular form or layout [Turnpenny et al 2007]
  • Overall, a general symmetry to the shape of the thorax
Figure 1

Figure

Figure 1. Severe shortening of the spine with fusion of the ribs posteriorly at the costovertebral junctions in an infant with STD resulting from mutations in MESP2. The ribs fan out in a “crab-like” manner. Many ribs show no intercostal (more...)

Molecular Genetic Testing

Gene. MESP2 is the only gene known to be associated with spondylothoracic dysostosis.

Clinical testing

Sequence analysis. Sequence analysis of MESP2 identified mutations in the majority of persons with STD of Puerto Rican and Spanish heritage. The three following mutations account for approximately 90% of cases [Cornier et al 2008].

  • A homozygous nonsense mutation that consists of a single-base pair substitution in the beta helix-loop-helix (bHLH) domain was responsible for approximately 80% of STD cases in the Puerto Rican population, suggesting a founder effect. The mutation, p.Gly103*, occurs in exon 1 and results in a non-functional protein.
  • Two other less frequent mutations:
    • p.Leu125Val, occurring in a conserved leucine residue in the bHLH domain
    • p.Glu230*, resulting in the replacement of a glutamic acid at position 230

Table 1. Summary of Molecular Genetic Testing Used in Spondylothoracic Dysostosis

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MESP2Sequence analysisSequence variants 290% 3

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Both mutant alleles identified

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • In individuals with STD in whom MESP2 mutations are not identified in the coding region, a partial gene deletion or a mutation(s) in the promoter or regulatory region may theoretically be causal.

Testing Strategy

To establish the diagnosis in a proband

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The vertebral and rib anomalies that characterize STD lead to significant thoracic restriction in approximately 60% of newborns resulting in some type of respiratory distress requiring medical intervention. Because of the extensive rib fusion in the entire posterior and sometimes lateral chest wall, the intercostal muscles are not able to expand the chest adequately. Although these infants have hypoplastic lung syndrome from the small size of the chest, no intrinsic lung abnormality has been described in STD. Because of respiratory compromise, infants with STD have a nearly 44% mortality rate by the end of infancy [Cornier et al 2004].

Over time the lungs expand, depressing the diaphragm and making the abdominal cavity more protuberant.

Differences in chest circumference diameter and spine length between those infants who survive and those who do not have been described suggesting that homozygotes for the p.Glu103* mutation exhibit a shorter spine and smaller chest circumference than heterozygotes and compound heterozygotes [Cornier et al 2008] (see Genotype-Phenotype Correlations).

The growth of the spine is closely related to chest and lung development, with the most rapid growth occurring from birth to age five years and then again in puberty [Dimeglio 1993, Dimeglio 2005]. Poor growth in the spine results in a short trunk and hence short stature. Average height in STD is 115.7 cm (range: from 44-155.96 cm) corresponding to 1.15 percentile for age.

Scoliosis is not common because the bilateral symmetric fusion of the ribs at the costovertebral junction results in little tethering effect in the spine and hence, minimal scoliosis. However, severe vertebral segmentation defects in which the tethering effect on the spine is unbalanced may lead to significant scoliosis. Those with STD who have the congenital anomaly known as a “bone bar” (i.e., a failure in bone segmentation) may develop scoliosis. When present, early-onset scoliosis results in limited potential for spine and chest growth and can lead to severe spinal deformity with associated poor quality of life and thoracic insufficiency [Ramirez et al 2009].

Approximately 20% of persons with STD develop spine rotation anomalies in which the spine is rotated in its axis with minimal to mild scoliosis [Cornier et al 2004].

A short, rigid, non-functional neck secondary to malformation of the cervical spine is present in all individuals with STD. Neck length ranges from 1.0 cm in the newborn to 4.7 in the adult.

Approximately 90% of individuals with STD develop inguinal hernias; up to 75% are bilateral. These hernias result from increased pressure in the abdominal cavity as a result of excessive use of the diaphragm during breathing.

Approximately 15% have umbilical hernias as well.

No neurologic abnormalities have been documented. Muscle tone, muscle strength, and tendon reflexes are normal. Neurocognitive development is generally normal, although some children may have mild delays in milestones such as sitting, crawling, and walking, which are likely secondary to the lack of neck motion and the disproportionate length of the extremities compared to the spine. Adults with STD have achieved professional goals, including doctoral and postdoctoral degrees.

Other. Clinical features of STD include prominent occiput in newborns that becomes flat with time, giving a brachycephalic appearance to the head. Posterior hairline insertion is low. Inner canthal, interpupillary and outer canthal distances are normal. The nasal bridge is prominent in 33%. The philtrum is normal in length and shape and the palate is high in 75% [Cornier et al 2004].

Heart anomalies are uncommon. Atrial septal defect (ASD), the most common congenital heart anomaly, is present in fewer than 5% of individuals with STD [Cornier et al 2004]. ASDs usually close by age ten years.

Other congenital anomalies include:

  • Talipes equinovarus (in 1.2%)
  • Double urinary collecting system (1%)
  • Cleft soft palate (<1%)
  • Unilateral glenoid agenesis (0.5%)

Liver and spleen are of normal size.

Genotype-Phenotype Correlations

Data of genotype-phenotype correlation in STD is preliminary but may provide insight to develop a medical plan.

  • Those homozygous for the p.Glu103* mutation seem to have a more severe phenotype than compound heterozygotes, including serious respiratory complications such as respiratory failure.
  • The p.Glu103* and p.Glu230* mutations are located within the first exon of MESP2 and the resulting mutant mRNA transcripts are predicted to be susceptible to nonsense-mediated decay. Therefore, individuals homozygous or compound heterozygous for these mutations are likely to have reduced or absent MESP2 protein. Data suggest that being heterozygous or compound heterozygous for the p.Glu103* mutation produces a milder phenotype in terms of the thoracic measurements; however, only a small number of individuals have been evaluated for this finding and, therefore, the differences may not be statistically significant [Cornier et al 2008]. Results from pulmonary function tests of individuals heterozygous for p.Glu103* should show a less restrictive pattern than in those who are homozygous.

Nomenclature

Spondylothoracic dysostosis (STD) has been well characterized as an autosomal recessive disorder with high prevalence in the Puerto Rican population. The name “Jarcho-Levin syndrome” has been used to describe a variety of clinical phenotypes consisting of short-trunk dwarfism associated with rib and vertebral anomalies. This admixture of phenotypes under the name Jarcho-Levin syndrome has lead to some confusion re phenotype, prognosis, and mortality.

Many names have been used in the past to describe the Jarcho-Levin phenotype of short trunk dwarfism characterized by multiple segmentation defects of the vertebral bodies and ribs, including spondylocostal dysplasia [Rimoin et al 1968], spondylocostal dysostosis [Franceschini et al 1974, Casamassima et al 1981, Ayme & Preus 1986, Floor et al 1989], spondylothoracic dysplasia [Moseley & Bonforte 1969, Pochaczevsky et al 1971, Solomon et al 1978, Herold et al 1988], and costovertebral dysplasia [Cantu et al 1971].

Use of the terms costovertebral/spondylocostal/spondylothoracic dysostosis/dysplasia for segmentation abnormalities of the spine and ribs has lead to great confusion. Of note, these disorders are dysostoses rather than dysplasias. (The term dysostosis refers to intrinsic pathology related to the embryologic mesoderm that forms the vertebrae.) Recent publications have provided more insight into the clinical and molecular diagnosis, prognosis, and management of individuals with these phenotypes [Turnpenny et al 2007]. Based on these findings, two groups of distinct phenotypes have been determined: spondylothoracic dysostosis (STD) and spondylocostal dysostosis (SCD).

Prevalence

The prevalence of STD has been estimated at one in 12,000 live births in the Puerto Rican population. No exact prevalence data exist for the rest of the world; worldwide prevalence is thought to be one in 200,000 live births.

MESP2 is the gene responsible for STD in more than 90% of persons with STD in Puerto Rico. The percent of STD caused by mutations in MESP2 may vary by ethnic background.

First- or second-degree consanguinity has been observed in families with STD. However, lack of consanguinity has been documented in approximately 30% of the families, suggesting potential positive-selection pressure or heterozygote advantage.

Differential Diagnosis

Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae in combination with abnormalities of the ribs, is characterized clinically by a short trunk in proportion to height, short neck, and non-progressive mild scoliosis in most affected individuals. Respiratory function in neonates may be compromised by reduced size of the thorax; however, by age two years lung growth may improve sufficiently to support relatively normal growth and development. Subtypes are defined by identification of two mutant alleles in any one of the four genes known to be associated with autosomal recessive SCDO: DLL3, MESP2, LFNG, and HES7.

Differences in the radiologic findings in STD distinguish it from SCDO:

  • More severe shortening of the spine, leading to impaired respiratory function in infancy
  • Rib fusions that typically occur posteriorly at the costovertebral origins
  • The ‘tramline sign’ radiographic finding [Turnpenny et al 2007] with a more symmetric pattern in STD than in SCDO.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spondylothoracic dysostosis (STD), the following evaluations are recommended:

  • Evaluation by a pediatric pulmonologist when possible for assessment of respiratory function, especially if tachypnea and/or feeding difficulties suggest the possibility of respiratory insufficiency
  • Evaluation of the child for the presence of inguinal hernia(s)

Treatment of Manifestations

Management varies by age.

Neonatal period

  • It is extremely important to identify babies with STD prenatally to alert an expert health care team that includes physicians specializing in obstetrics, anesthesiology, neonatology, pediatrics, and medical genetics as well as nurses, dieticians, and genetic counselors.
  • Surfactant factor should be provided immediately after birth using standard protocols for neonates with respiratory distress. Approximately 65% of infants have some type of respiratory problem in the neonatal period that may range from mild distress requiring indirect oxygen supplementation to frank uncompensated respiratory acidosis requiring mechanical ventilation.
  • Elevated CO2 levels (hypercapnea) may be present. Babies with STD seem to tolerate hypercapnea relatively well. CO2 levels as high as 60 to 70 mmHg have improved with CPAP (constant positive air pressure), thus avoiding intubation. Follow-up of these children for more than ten years has shown no neurologic or developmental impairment.
  • If mechanical ventilation is unavoidable, ventilator pressures should be set as low as possible to avoid hypoxia and to correct respiratory acidosis. The ventilatory problem is not caused by poor alveolar gas exchange but rather by insufficient mechanical expansion of the thorax and in some cases, secondary lung hypoplasia. Mechanical ventilation should be discontinued as soon as possible.
  • Constant cardio-respiratory monitoring should be provided.
  • If possible, bolus feedings (which expand the stomach and interfere with use of the diaphragm) should be avoided because respiration in affected infants depends solely on the diaphragm muscle, since the accessory intercostal muscles are impaired by extensive rib fusion. Slow nasogastric feedings with 20 calories per ounce baby formula should be considered at a rate of approximately 0.75-1 oz/hour for 16-20 hours with a rest period of four to six hours. For babies weighing between 2.72 and 3.18 kg at birth this regimen provides 125-147 kcal/day, which should be sufficient in the newborn period. More concentrated formulas may be used to optimize caloric intake as needed.
  • Infectious diseases need to be treated aggressively.

Infancy and early childhood

  • Upper respiratory tract diseases need to be treated aggressively, including antibiotic therapy as needed.
  • From birth until age three to five, children with STD should be immunized against the RSV (respiratory syncytial virus) year round – not only in the RSV season.
  • Respiratory therapy with bronchodilators may be considered in the management of upper respiratory tract infections with or without bronchoconstriction (wheezing).
  • Mechanical ventilation should be avoided unless absolutely necessary. Infants and children seem to tolerate increased levels of CO2 without significant clinical complications. Close and constant cardiorespiratory monitoring is warranted.
  • Physical and occupational therapies may help support developmental progress.

Late childhood and adulthood

  • Respiratory tract infections need aggressive medical management.
  • Orthopedic follow up should include monitoring for scoliosis, spine malrotation, and bone bars. These may need to be addressed surgically if the malformation is asymmetrical.
  • Preliminary data suggest that adults with STD develop osteoporosis in their early 40s. It is not clear if this finding is secondary to an endocrine abnormality or to lack of strenuous physical activity throughout life.

Other

  • In the majority of individuals treatment is conservative because the vertebral and rib malformations cause progressive difficulties.
  • Respiratory support, including intensive care as needed, is used to treat acute respiratory distress and chronic respiratory failure.
  • Routine surgical procedures to correct the hernias are well tolerated from respiratory and surgical perspectives, even when corrected as early as age eight months. There is no associated surgical mortality.
  • Surgical intervention may be necessary when scoliosis is significant. External bracing may be attempted but experience is limited.

Prevention of Secondary Complications

The most significant secondary complication is chronic respiratory failure as a result of reduced lung capacity, which can result in pulmonary hypertension and cardiac failure. Expert management of these complications is indicated.

Surveillance

Growth, development, respiratory function, and spinal curvature should be monitored.

The parents/care providers of young children need to be alert for the signs of inguinal hernias and their potential complications.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spondylothoracic dysostosis (STD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with spondylothoracic dysostosis are obligate heterozygotes (carriers) for a disease-causing mutation in MESP2.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

The pregnancies of fetuses with STD are remarkably uneventful. In Puerto Rico more than 80% of STD is not diagnosed prenatally despite use of prenatal ultrasound examination. In the author’s experience, the majority of STD diagnosed prenatally is in at-risk siblings or in those with a family history of STD.

Ultrasound examination. Early in the second trimester of pregnancy the multiple segmentation and formation vertebral defects can be easily identified by ultrasound examination [Tolmie et al 1987].

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Consortium for Vertebral Anomalies and Scoliosis Registry
    c/o Dr. Kenro Kusumi
    Arizona State University
    PO Box 874501
    Tempe AZ 85287
    Phone: 480-727-8993
    Email: kenro.kusumi@asu.edu
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Spondylothoracic Dysostosis: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MESP215q26​.1Mesoderm posterior protein 2MESP2 homepage - Mendelian genesMESP2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Spondylothoracic Dysostosis (View All in OMIM)

605195MESODERM POSTERIOR 2; MESP2

Molecular Genetic Pathogenesis

Role of MESP2 in somitogenesis. In the mouse embryo, segmentation is first observed in the presomitic mesoderm (PSM) as a striped expression of Mesp2 [Saga et al 1997]. At a defined PSM level, cells respond to a periodic signal from the segmentation clock by activating the genes of the Mesp2 family in a segment-wide domain [Morimoto et al 2005]. These stripes of Mesp2 expression provide the blueprint on which the embryonic segments, the somites, will form. Hence, disrupting this process results in severe anomalies of the regular arrangement of vertebrae as is observed in patients with congenital scoliosis. Subsequently, genes of the Mesp2 family play a critical role in positioning the future somite boundary and in defining the anterior-posterior polarity of the forming somite [Morimoto et al 2005]. This rostrocaudal subdivision of the somite is critical for the formation of vertebrae. Studies by the author “...suggest that MESP2 mutations also disrupt somitogenesis in humans, resulting in STD and SCD.” [Cornier et al 2008].

Normal allelic variants. MESP2 has two exons spanning approximately 2 kb. Sequence analysis identified a variable-length polymorphism beginning at nucleotide 535 containing a series of 12-bp repeat units [Whittock et al 2004]. The smallest GlyGln region detected contains two type A units (GGG CAG GGG CAA, encoding the amino acids GlyGlnGlyGln), followed by two type B units (GGA CAG GGG CAA, encoding GlyGlnGlyGln) and one type C unit (GGG CAG GGG CGC, encoding GlyGlnGlyArg). The polymorphism comprises a variation in the number of type A units, with two, three, or four being present (Table 2).

Two MESP2 variants, c.197C>G and c.658T>C were identified in two parental carriers and were believed to be normal allelic variants, as these variants were not transmitted to their affected offspring.

Pathologic allelic variants. To date all reported cases of STD have been caused by mutations in exon 1 of MESP2, including p.Glu103*, p.Leu125Val, p.Glu230*, and p.Gly81*. Most of these are nonsense mutations that are predicted to result in nonsense-mediated decay; however, several affected individuals are heterozygous for a nonsense mutation and a missense mutation [Cornier et al 2008]. Other exon 1 mutations identified in the STD phenotype include p.Glu230*, and p.Leu125Val [Cornier et al 2008].

A homozygous nonsense mutation in MESP2 was identified as the most frequent cause of STD in the Puerto Rican population. This change consisted of a single base-pair substitution mutation (c.307G>T) in the beta helix-loop-helix (bHLH) domain of MESP2. The mutation resulted in the replacement of a glutamic acid codon (GAG) at position 103 with a stop codon (TAG) and the creation of a novel SpeI restriction enzyme site. The mutation (p.Glu103*) occurs in exon 1 in the middle of the bHLH domain and is predicted to encode a non-functional protein.

Other molecular changes identified include compound heterozygosity for a p.Glu103* mutation and a p.Leu125Val missense MESP2 mutation [Cornier et al 2008].

A third mutation, p.Glu230* (c.688G>T) results in the replacement of glutamic acid at position 230 with a premature termination codon. Heterozygous carriers of all of these mutations were unaffected.

The data suggest that multiple mutations in MESP2, including compound heterozygosity, can be associated with STD phenotypes. Heterozygosity for the MESP2 p.Glu103* mutation – apparently without harboring an MESP2 mutation – has also been described. This finding suggests that there may be another gene(s) responsible for the STD phenotype (genetic heterogeneity).

Table 2. Selected MESP2 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Normalc.197C>Gp.Ala66GlyNM_001039958​.1
NP_001035047​.1
c.658T>Cp.Ser220ProBC111413​.1
AAI11414​.1
c.535-46 GGGCAGGGGCAA(2_4)p.178-181GlyGlnGlyGln178(2_4)NM_001039958​.1
NP_001035047​.1
Pathologicc.241G>Tp.Gly81*
c.307G>Tp.Glu103*
c.373C>Gp.Leu125Val
c.688G>Tp.Glu230*BC111413​.1
AAI11414​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. See Spondylocostal Dysostosis, Autosomal Recessive (Molecular Genetics, MESP2, Normal gene product).

Abnormal gene product. The nonsense mutations identified in STD are located within the first MESP2 exon, and the resulting mutant mRNA transcripts are predicted to be susceptible to nonsense-mediated decay. Therefore, persons homozygous or compound heterozygous for these nonsense mutations are likely to have reduced or absent levels of MESP2 protein which may account for the difference in severity of the SCDO2 (see Spondylocostal Dysostosis, Autosomal Recessive) and STD phenotypes. The mutations p.Glu230* and p.Leu125Val are predicted to alter MESP2 function. The p.Glu230* mutation is predicted to truncate the protein in the C-terminal domain. The p.Leu125Val mutation occurs in a conserved leucine residue in the basic helix-loop-helix bHLH domain and is predicted to be deleterious by the Sorting Intolerant From Tolerant (SIFT) prediction program [Ng & Henikoff 2001].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  15. Ramirez N, Flynn JM, Serrano JA, Carlo S, Cornier AS. The Vertical Expandable Prosthetic Titanium Rib in the treatment of spinal deformity due to progressive early onset scoliosis. J Pediatr Orthop B. 2009;18:197–203. [PubMed: 19390461]
  16. Rimoin DL, Fletcher BD, McKusick VA. Spondylocostal dysplasia. A dominantly inherited form of short-trunked dwarfism. Am J Med. 1968;45:948–53. [PubMed: 5722643]
  17. Saga Y, Hata N, Koseki H, Taketo MM. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 1997;11:1827–39. [PubMed: 9242490]
  18. Solomon L, Jimenez RB, Reiner L. Spondylothoracic dysostosis: report of two cases and review of the literature. Arch Pathol Lab Med. 1978;102:201–5. [PubMed: 350188]
  19. Tolmie JL, Whittle MJ, McNay MB, Gibson AA, Connor JM. Second trimester prenatal diagnosis of the Jarcho-Levin syndrome. Prenat Diagn. 1987;7:129–34. [PubMed: 3554211]
  20. Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, Pourquie O, Kusumi K, Dunwoodie S. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn. 2007;236:1456–74. [PubMed: 17497699]
  21. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL, Turnpenny PD. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet. 2004;74:1249–54. [PMC free article: PMC1182088] [PubMed: 15122512]

Suggested Reading

  1. Acevedo JR. 2009
  2. Jarcho S, Levin P. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp. 1938;62:216–26.
  3. McCall CP, Hudgins L, Cloutier M, Greenstein RM, Cassidy SB. Jarcho-Levin syndrome: unusual survival in a classical case. Am J Med Genet. 1994;49:328–32. [PubMed: 8209895]
  4. Schulman M, Gonzalez MT, Bye MR. Airway abnormalities in Jarcho-Levin syndrome: a report of two cases. J Med Genet. 1993;30:875–6. [PMC free article: PMC1016574] [PubMed: 8230167]

Chapter Notes

Revision History

  • 5 August 2010 (me) Review posted live
  • 18 December 2009 (ac) Original submission
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