The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. The ... The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. The term 'spondylocostal dysostosis' is best applied to those phenotypes with generalized SDV and a broadly symmetric thoracic cage (summary by Gucev et al., 2010). - Genetic Heterogeneity Other forms of autosomal recessive SCDO include SCDO2 (608681), caused by mutation in the MESP2 gene (605195) on chromosome 15q26.1; SCDO3 (609813), caused by mutation in the LFNG gene (602576) on chromosome 7p22; and SCDO4 (613686), caused by mutation in the HES7 gene on chromosome 17p13.2. An autosomal dominant form of SCDO has also been described (SCDO5; 122600).
Lavy et al. (1966) observed 4 of 7 offspring of a third-cousin marriage who had characteristic vertebral anomalies including hemivertebrae and block vertebrae accompanied by deformity of the ribs. All affected children died of respiratory infection under 1 ... Lavy et al. (1966) observed 4 of 7 offspring of a third-cousin marriage who had characteristic vertebral anomalies including hemivertebrae and block vertebrae accompanied by deformity of the ribs. All affected children died of respiratory infection under 1 year of age. Moseley and Bonforte (1969) described the same disorder in 2 apparently unrelated children of nonconsanguineous Puerto Rican parents. Caffey (1967) described brother and sister with short neck and trunk in contrast to extremities of normal length. Both showed 'hemivertebrae at practically all levels in the spine.' The skeletons were otherwise normal. Norum (1969) observed 4 similar cases in 2 related sibships in an inbred community in eastern Kentucky. Fused ribs also occurred in affected persons. See 122600 for an autosomal dominant form of spondylocostal dysostosis. Eller and Morton (1970) described similar deformity of the chest and spine, with additional craniolacunia, rachischisis, and urinary tract anomalies, in the offspring of a woman who admitted to a single exposure to LSD about the time of conception. Cantu et al. (1971) described 5 cases in an inbred kindred. Castroviejo et al. (1973) reported spondylothoracic dysplasia in 3 Spanish sisters who showed the typically short thorax, short neck with limited mobility, winged scapulae, and scoliosis or kyphoscoliosis. Particularly noteworthy were the vertebral anomalies, including hemivertebrae and vertebral fusions affecting the whole vertebral column. Rib abnormalities in form and number were seen. One sister showed decreased mental function and another showed incompletely formed odontoid process. Bartsocas et al. (1974) described 3 affected sibs (2 of them identical twin sisters). Satar et al. (1992) described this disorder in identical twins whose parents were first cousins. Van Thienen and Van der Auwera (1994) described monozygotic twins discordant for this syndrome, either due to a postzygotic mutation or to a phenocopy. Jarcho and Levin (1938) are credited with first describing this syndrome, in a black brother and sister in Baltimore, but they mistakenly spoke of the condition as the same as the Klippel-Feil syndrome (118100). Perez-Comas and Garcia-Castro (1974) described 6 cases in Puerto Ricans, including 2 affected sibs. Their designation, occipito-facial-cervico-thoracic-abdomino-digital dysplasia, seems in the first place ridiculously long, but really unwarranted since all changes seem to be secondary or tertiary to the primary changes in the spine. Several authors refer to a typical 'crab-like' radiologic appearance of the thoracic skeleton. Conceivably the early lethal form represented by the cases of Jarcho and Levin (1938) and the cases with survival to a later age, e.g., the cases of Norum (1969) and Cantu et al. (1971) are produced by homozygosity for alleles at the same locus. Devos et al. (1978) described associated abnormalities of ureters and renal pelvis. Gassner and Grabs (1982) described 8 affected persons in 4 interrelated families. One also had Down syndrome and died at the age of 7 days. The others showed no decrease in life expectancy and no other malformations. Autosomal recessive inheritance was well documented. Young and Moore (1984) reported a case in a child of first-cousin parents. They claimed it to be the first report of the condition in the United Kingdom. Cassidy et al. (1984) reported observations on a Puerto Rican child living in Connecticut. Giacoia and Say (1991) found diastematomyelia, spina bifida, and open meningocele in an American Indian infant with the features of the Jarcho-Levin syndrome. Turnpenny et al. (1991) indicated the wide variability in 7 affected members of an inbred Israeli-Arab family. Romeo et al. (1991) reported 2 affected brothers and 2 affected sisters related to each other as first cousins once removed. Karnes et al. (1991) reported 4 new cases. They supported the classification of Solomon et al. (1978) into 2 subtypes: spondylocostal dysostosis and spondylothoracic dysostosis. McCall et al. (1994) described the case of a Puerto Rican child with unusually long survival to age 11 years. Aurora et al. (1996) reported a newborn with characteristic features of Jarcho-Levin syndrome in addition to complex congenital heart disease (situs solitus, double outlet right ventricle, atrial septal defect) and hypospadias. Mortier et al. (1996) analyzed 26 new patients with multiple vertebral segmentation defects and reviewed 115 previously reported cases. They recognized 3 distinct entities based on radiographic and clinical findings: Jarcho-Levin syndrome, a lethal autosomal recessive form, characterized by a symmetric crab-chest; spondylocostal dysostosis (122600), a benign autosomal dominant condition; and spondylothoracic dysostosis, which shows considerable clinical and radiographic overlap with spondylocostal dysostosis and has an autosomal recessive mode of inheritance. The authors noted that intrafamilial variability is striking (Cantu et al., 1971; Franceschini et al., 1974; Trindade and de Nobrega, 1977; Turnpenny et al., 1991); affected individuals either die in infancy of respiratory failure or survive into adulthood with minimal symptoms. Associated anomalies are not common and are only observed in lethal cases. Mortier et al. (1996) stated that sporadic cases of vertebral segmentation defects are difficult to classify as to etiology, genetic versus nongenetic, and concluded that they probably represent a heterogeneous group. Associated anomalies are more common in this group than in the familial types and may involve both mesodermally and ectodermally derived structures. Mortier et al. (1996) also concluded that the body segment in which the nonvertebral malformations occur corresponds to the site of the vertebral segmentation defects. Bannykh et al. (2003) reported 2 affected Caucasian sibs and provided a review of the Jarcho-Levin syndrome and related disorders.
Turnpenny et al. (1999) performed genomewide scanning by homozygosity mapping in a large consanguineous Arab-Israeli family in which there were 6 definite cases of autosomal recessive spondylocostal dysostosis. Significant linkage was found to 19q13, with a lod score ... Turnpenny et al. (1999) performed genomewide scanning by homozygosity mapping in a large consanguineous Arab-Israeli family in which there were 6 definite cases of autosomal recessive spondylocostal dysostosis. Significant linkage was found to 19q13, with a lod score of 6.9. This was confirmed in a second Pakistani family with 3 affected members, with a lod score of 2.4. The combined haplotype data identified a critical region between D19S570 and D19S908, an interval of 8.5 cM on 19q13.1-q13.3. Using homology of synteny and linkage data suggesting that the SCDO1 locus is on chromosome 19q13.1-q13.3 and that a mouse region containing the Notch ligand delta-like-3 gene is mutated in the x-ray-induced mouse mutant 'pudgy,' causing a variety of vertebral costal defects similar to the SCDO1 phenotype, Bulman et al. (2000) cloned and sequenced human DLL3 to evaluate it as a candidate gene for SCDO1. They identified mutations in 3 autosomal recessive SCDO1 families. Two of the mutations (602768.0001 and 602768.0002) predicted truncations within conserved extracellular domains; the third (602768.0003) was a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor repeat, which revealed an important functional role for this domain. These were the first mutations in a human delta homolog, thus highlighting the critical role of the Notch signaling pathway and its components in patterning the mammalian axial skeleton. Turnpenny et al. (2003) sequenced the DLL3 gene in a series of spondylocostal dysostosis patients from 14 families and identified 12 mutations, 2 of which occurred twice. The patients represented diverse ethnic backgrounds and 6 came from traditionally consanguineous communities. In all affected individuals, the radiologic phenotype was abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which Turnpenny et al. (2003) suggested the term 'pebble beach sign.' This appeared to be a very consistent phenotype-genotype correlation. Turnpenny et al. (2003) suggested the designation SCD type 1 for the autosomal recessive form caused by mutation in the DLL3 gene. Day and Fryer (2003) reported 2 pregnancies in 1 family in which diaphragmatic hernia and preaxial polydactyly accompanied spondylothoracic dysplasia. The first pregnancy was monozygous male twins and the second was a female sib. The pregnancies were terminated. The authors suggested that spondylothoracic dysplasia and spondylocostal dysostosis may be allelic. In a family with spondylocostal dysostosis, previously reported by Floor et al. (1989) and believed to represent autosomal dominant inheritance, Whittock et al. (2004) performed haplotype analysis which suggested pseudodominant transmission with segregation of 2 distinct disease alleles. Direct sequencing of the DLL3 gene revealed that the affected father was homozygous and all 4 sibs were heterozygous for a 1440delG mutation (602768.0007), whereas the unaffected mother and 2 affected sibs were heterozygous for a G504D substitution (602768.0008), thus confirming autosomal recessive inheritance in all affected members of the family.
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. ...
DiagnosisClinical 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 thoraxFigureFigure 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 testingSequence 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 View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMESP2Sequence analysisSequence variants 290% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Both mutant alleles identifiedInterpretation 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 Perform a skeletal survey to confirm the radiographic findings of STD. Obtain a family history with attention to the history of affected sibs and/or parental consanguinity and Puerto Rican or Spanish ancestry.Perform molecular genetic testing of MESP2.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.Genetically Related (Allelic) DisordersThe other phenotype in which mutations in MESP2 are observed is spondylocostal dysostosis type 2 (SCDO2) (see Spondylocostal Dysostosis, Autosomal Recessive). In SCDO2 virtually all vertebral segments show at least some disruption to form and shape; the lumbar vertebrae are relatively mildly affected compared to those in the thoracic region. Thus far only one small consanguineous family has been found with this milder form of spondylocostal dysostosis [Whittock et al 2004]. See Genotype-Phenotype Correlations.
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]. ...
Natural HistoryThe 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.
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....
Differential DiagnosisSpondylocostal 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 infancyRib fusions that typically occur posteriorly at the costovertebral originsThe ‘tramline sign’ radiographic finding [Turnpenny et al 2007] with a more symmetric pattern in STD than in SCDO.
To establish the extent of disease in an individual diagnosed with spondylothoracic dysostosis (STD), the following evaluations are recommended:...
ManagementEvaluations 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 ManifestationsManagement varies by age.Neonatal periodIt 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 childhoodUpper 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 adulthoodRespiratory 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.OtherIn 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 ComplicationsThe 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.SurveillanceGrowth, 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMESP215q26.1Mesoderm posterior protein 2MESP2 homepage - Mendelian genesMESP2Data 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) View in own window 605195MESODERM POSTERIOR 2; MESP2Molecular Genetic PathogenesisRole 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 View in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences Normalc.197C>Gp.Ala66GlyNM_001039958.1 NP_001035047.1c.658T>Cp.Ser220ProBC111413.1 AAI11414.1c.535-46 GGGCAGGGGCAA(2_4)p.178-181GlyGlnGlyGln178(2_4)NM_001039958.1 NP_001035047.1Pathologicc.241G>Tp.Gly81*c.307G>Tp.Glu103*c.373C>Gp.Leu125Valc.688G>Tp.Glu230*BC111413.1 AAI11414.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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].