Clinical Diagnosis

Spondylocostal dysostosis (SCDO) refers to a radiologic phenotype that includes multiple segmentation defects of the vertebrae (M-SDV) with abnormalities of the ribs, e.g., rib fusion, malalignment, and/or abnormal rib number (usually reduced). The radiologic phenotype is characterized in general by:

• Abnormal segmentation of virtually all vertebrae, with at least ten contiguous segments affected

• A mild degree of scoliosis, which is usually non-progressive

• Malalignment of at least some ribs with a variable number of intercostal rib fusions, and sometimes a reduction in rib number

• Overall, a general symmetry to the shape of the thorax (at least, no major asymmetry)

Four subtypes of AR SCDO are recognized, based on the underlying gene involved. The radiographic phenotype for each subtype can be somewhat distinctive.

• SCDO1: DLL3-associated SCDO. The features so far are remarkably consistent: the four diagnostic criteria are present plus an irregular pattern of ossification of the vertebral bodies on spinal radiographs prenatally and in early childhood. Each vertebral body has a round or ovoid shape with smooth boundaries and, when viewed as a whole, this appearance is termed the “pebble beach sign” [Turnpenny et al 2003] (Figure 1). As ossification proceeds after mid to late childhood, the pebble beach appearance gives way to multiple irregularly shaped vertebral bodies and hemivertebrae that may be difficult to distinguish individually on plain x-ray; vertebral architecture may be easier to discern on MRI. Two individuals have had slightly milder phenotypes as a result of relatively milder distortion of vertebral architecture (Figure 2).

• SCDO2: MESP2-associated SCDO. All vertebral segments show at least some disruption to form and shape. However, compared to SCDO1 the lumbar vertebrae are relatively mildly affected compared to those in the thoracic region (Figure 3A and Figure 3B). Thus far only one family with SCDO2 has been published [Whittock et al 2004b, Figure 3A]; Figure 3B depicts a similar, previously unpublished case.

• SCDO3: LFNG-associated SCDO. Severe. The shortening of the spine is more severe than that seen in SCDO1 and SCDO2 (Figure 4) because all vertebral bodies appear to show more severe segmentation defects. Rib anomalies are similar to those seen in SCDO1 and SCDO2.

• SCDO4: HES7-associated SCDO. The published case resembles STD (see Genetically Related Disorders); all vertebrae display abnormal segmentation (Figure 5).

Figure

Figure 1. Typical axial skeletal features in an infant with SCDO caused by mutations in DLL3 (type 1). All vertebrae are abnormal: the vertebral bodies are ovoid and vary in size and shape (“pebble beach” sign). Ribs show occasional fusion (more...)

Figure

Figure 2. Radiograph of a child with a mild form of SCDO1 caused by mutations in DLL3. All vertebrae show at least some relatively mild segmentation abnormality.

Figure

Figure 3. SCDO type 2 caused by mutations in MESP2. The generalized SDV show more angular features than in SCDO1.

Figure

Figure 4. MRI of the spine in SCDO3 caused by mutations in LFNG. All vertebrae have major segmentation abnormalities and the spine is markedly shortened.
Reproduced from Sparrow et al [2006] with permission from Elsevier

Figure

Figure 5. SCDO type 4 caused by mutations in HES7. Segmentation anomalies of all vertebrae are severe. The vertebral pedicles are relatively prominent (“tramline” sign) compared with those of SCDO1. These radiographic findings resemble (more...)

AR SCDO is usually isolated, i.e., restricted to the vertebral column and ribs. However, additional anomalies have been present in some cases, as described under the four individual subtypes.

Molecular Genetic Testing

Genes. To date, mutations in four different genes, DLL3, MESP2, LFNG, and HES7, account for AR SCDO caused by a single-gene defect.

Other loci. No other loci are known to be associated with the AR SCDO phenotype, although it is anticipated that more loci will be identified through ongoing research.

Clinical testing

• DLL3 sequence analysis. Sequence analysis of DLL3 exons 2-9 and conserved splice sites detects mutations in 80% to 90% of individuals with SCDO1 [Bulman et al 2000, Bonafé et al 2003, Turnpenny et al 2003].

• MESP2 sequence analysis. Mutation rate has not yet been established for sequence analysis of MESP2 exons and conserved splice sites.

• LFNG sequence analysis. Mutation detection rate has not been established.

Research testing

• HES7 sequence analysis. Mutation detection rate has not been established. Such testing is available on a research basis only.

Table 1. Summary of Molecular Genetic Testing Used in Autosomal Recessive Spondylocostal Dysostosis

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Gene Symbol (Locus Name)	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
DLL3 (SCDO1)	Sequence analysis	Sequence variants 2	>80%	Clinical
MESP2 (SCDO2)	Sequence analysis	Sequence variants 2	~50% - ~70%	Clinical
LFNG (SCDO3)	Sequence analysis	Sequence variants 2	Unknown	Clinical
HES7 (SCDO4)	Sequence analysis	Sequence variants 2	Unknown	Research only 3

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Mutation detection frequency in individuals with SCDO radiologic phenotype defined in Clinical Diagnosis [unpublished data]

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

3. No laboratories offering clinical molecular genetic testing for this disease are listed in the GeneTests Laboratory Directory. However, clinical confirmation of mutations identified in research laboratories may be available for families in which the disease-causing mutations have been identified. For laboratories offering such testing, see .

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband. To determine if M-SDV meet the diagnostic criteria of SCDO, it is usually appropriate to:

• Perform a skeletal survey to look for evidence of other skeletal anomalies; a complete physical examination; and ultrasound imaging of the heart, abdomen, and renal tract to determine if radiographic and/or clinical findings are consistent with one of the disorders included in Differential Diagnosis;

• Obtain a family history with attention to the history of affected sibs and/or parental consanguinity.

Once the diagnosis of SCDO has been established in an individual, the following approach can be used to determine the specific gene involved:

Radiographic phenotype. Based on radiographic appearance of the vertebral column and ribs, distinctions might be made between SCDO1, SCDO2, and spondylothoracic dysostosis ([STD]; see Genetically Related Disorders) and SCDO3 (severe truncal shortening). SCDO4, based on limited experience of published cases, resembles STD. More experience is needed to determine whether clear genotype-phenotype correlations exist for SCDO3 and SCDO4.

Molecular genetic testing

• Sequencing of DLL3 is usually undertaken initially because this gene is most commonly implicated.
  
  If DLL3 sequence analysis is normal, consideration should be given to sequencing MESP2.

• If the radiographic phenotype is closer to that of STD (a “crab-like” appearance), it is appropriate to sequence MESP2 first, followed by DLL3 if no mutations are identified.

• If severe truncal shortening is observed on radiographs, LFNG is sequenced first.

• If the phenotype resembles that of SCDO1 and SCDO2, but no mutation was identified in DLL3 or MESP2, sequence analysis of HES7 should be undertaken in preference to LFNG.
  
  Note: Sequence analysis of HES7 is available on a research basis only. Clinical confirmation of mutations identified in a research laboratory may be available.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

DLL3, LFNG, HES7. No other known phenotypes are known to be associated with mutations in these genes.

MESP2. STD, despite similarities to AR SCDO, has distinctive phenotypic features that warrant this separate designation. To date, most individuals reported with STD have had nonsense mutations in exon 1 of MESP2, which 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] (Figure 6). STD occurs most frequently in Puerto Ricans of Spanish descent [Alberto Cornier, personal communication], presumably as a result of the MESP2 founder mutation, p.Glu103X; in this population the phenotype has been known as Jarcho-Levin syndrome [Jarcho & Levin 1938]. Note: The original patients reported by Jarcho and Levin were not Puerto Rican (see also Nomenclature).

Figure

Figure 6. An infant with STD caused by mutations in MESP2. STD is relatively common in Puerto Rican Indians because of a founder mutation. The spine is severely shortened with fusion of the ribs posteriorly at the costovertebral junctions. The ribs fan (more...)

The clinical aspects of STD have been studied in detail [Cornier et al 2004]. The differences in the radiologic findings in STD that distinguish it from SCDO are:

• More severe shortening of the spine (all vertebral segments affected), especially the thoracic spine, leading to impaired respiratory function in infancy

• 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]

Natural History

Spondylocostal dysostosis (SCDO), defined radiographically as M-SDV in combination with abnormalities of the ribs, is characterized clinically by:

• A short trunk in proportion to height

• Short neck

• Non-progressive mild scoliosis in most affected individuals; more significant scoliosis in a few affected individuals

The most important consideration in neonates diagnosed with SCDO is respiratory function, which may be compromised by reduced size of the thorax. In these infants, respiratory insufficiency may be the presenting clinical problem.

Infants with STD (caused by MESP2 mutations), who are at the highest risk of respiratory insufficiency, have a nearly 50% mortality rate by the end of infancy [Cornier et al 2004].

Survival into childhood and beyond is partly related to the availability of medical expertise and technology to support respiratory function.

By age two years lung growth may improve sufficiently to support relatively normal growth and development. However, even then life-threatening complications, especially pulmonary hypertension in children with severely restricted lung capacity from birth, can occur.

Males with SCDO appear to have an increased risk of inguinal hernia.

Neurologic complications appear to be rare.

Findings by Specific AR SCDO Subtype

SCDO1: DLL3-associated SCDO. Generally, mild, non-progressive scoliosis occurs and the need for surgical intervention to stabilize the spine is rare. However, more significant scoliosis has been observed in some cases (Figure 7).

Figure

Figure 7. SCDO1 caused by mutations in DLL3, demonstrating unusually severe scoliosis

One individual had abdominal situs inversus; however, it is not known whether this was a consequence of the DLL3 genotype.

Two sibs had features of fetal akinesia sequence and succumbed in early childhood [C McKeown, personal communication]; however, the family was multiply inbred and it is considered likely that fetal akinesia was a separate AR condition segregating in the family.

SCDO3: LFNG-associated SCDO. The one known affected individual had a distal arthrogryposis, but it was uncertain whether this was a direct effect of the causative mutation or a secondary complication.

SCDO4: HES7-associated SCDO. The one reported affected individual had a lumbosacral meningomyelocele, but it was uncertain whether this was a direct effect of the causative mutation or a coincidence.

Genotype-Phenotype Correlations

The radiologic phenotype of SCDO1 appears to be very consistent (Figure 1). However, two individuals homozygous for DLL3 missense mutations in the region encoding the EGF domain with slightly milder phenotypes have been seen (Figure 2). Some evidence [unpublished data] suggests that these missense mutations would allow the EGF domains to adopt the correct fold in the DLL3 protein but perhaps be thermodynamically less stable than the wild-type protein. However, some of the missense mutations identified in affected individuals cause a phenotype that is indistinguishable from that caused by DLL3 protein-truncating mutations. This likely results from the different effects conferred upon protein folding compared to those missense mutations associated with the slightly milder phenotype.

The 4-bp duplication, c.500_503dup, occurs after the bHLH domain and causes a frameshift resulting in a premature stop codon within the second, and final, MESP2 exon [Whittock et al 2004b]. Transcripts with this mutation would not be subject to nonsense-mediated decay. These individuals are predicted to have a truncated protein containing an intact bHLH domain, which may retain some function. In contrast, the nonsense mutations identified in STD (see Genetically Related Disorders) are located within the first 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 and STD phenotypes.

Penetrance

According to current knowledge, penetrance is 100% for the mutations implicated in AR SCDO types 1-4. However, further experience is required in order to be sure that reduced penetrance does not occur.

Nomenclature

Jarcho & Levin [1938] originally reported two “colored” sibs with a form of SCDO that most closely resembles SCDO2, but in the literature the term “Jarcho-Levin syndrome” has tended to be more closely associated with STD than any form of SCDO. STD, as described in Puerto Ricans of Spanish descent, is relatively frequent because of the MESP2 founder mutation, p.Glu103X (see Genetically Related Disorders).

Furthermore, the term “Jarcho-Levin syndrome” is frequently incorrectly used for all radiologic phenotypes that include segmentation defects of the vertebrae (SDV) and abnormal rib alignment, including reports of phenotypes that are neither similar to the description of Jarcho and Levin nor consistent with STD [Poor et al 1983, Karnes et al 1991, Simpson et al 1995, Aurora et al 1996, Eliyahu et al 1997, Rastogi et al 2002].

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 really dysostoses rather than dysplasias. The term:

• Costovertebral dysplasia [Norum & McKusick 1969, Cantú et al 1971, David & Glass 1983] is used less often today.

• Spondylothoracic dysostosis/dysplasia (STD), first used by Moseley & Bonforte [1969], is recognized as being distinct from SCDO (see Differential Diagnosis).

The diverse radiologic phenotypes with M-SDV within SCDO has highlighted the need to rationalize nomenclature for these diverse and poorly understood disorders.

• Schemes to classify SDV and SDCO include that proposed by Mortier et al [1996], which combines phenotype and inheritance pattern, and that proposed by Takikawa et al [2006], which proposes a very broad definition of SCDO.

• McMaster’s surgical approach to classification distinguishes between formation errors and segmentation errors [McMaster & Singh 1999].

• The International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) proposed two algorithms:

  • The Clinical Algorithm, used for routine reporting of SDV, identifies seven broad categories (Figure 8). For the purposes of clinical reporting, additional comments can describe SDV findings in more detail. The new classification incorporates appropriate existing terminology, such as the classification of spinal abnormalities of Aburakawa et al [1996]. Within undefined SDV groups, new specific entities may emerge with time.

  • The Research Algorithm, used for more detailed documentation of SDV, employs ontology applicable to humans and animal models (Figure 9).

Figure

Figure 8. ICVAS Clinical Classification Algorithm
SDV = segmentation defect(s) of the vertebrae
M = multiple
S = single
R = regional
G = generalized
U = undefined
All forms of SDV can be placed (more...)

Figure

Figure 9. ICVAS Research Classification Algorithm. A more detailed, systematic analysis of radiographic anatomic features. Documentation of phenotypes in a systematic ontology facilitates direct interspecies comparison and stratification of patient cohorts (more...)

Note: In the classification system proposed by the ICVAS, SCDO is the preferred term for generalized segmentation defects of the vertebrae (G-SDV) with rib involvement [Turnpenny et al 2007, Offiah et al 2010].

The clinical delineation and classification of SCDO phenotypes are expected to evolve as more genetic causes of abnormal vertebral segmentation are identified.

Prevalence

SCDO1: DLL3-associated SCDO is the most commonly encountered monogenic form of AR SCDO in clinical practice. Seventy-five percent of cases have been the offspring of consanguineous unions, mostly of Middle Eastern or Pakistani origin, and occasionally of Europeans from England, The Netherlands, and Switzerland. Four Europeans were compound heterozygotes, two in England and Wales one in The Netherlands, and one in Switzerland [Bonafé et al 2003, Whittock et al 2004a]. Assuming a period of time during which approximately one million births occurred, the carrier frequency in the European UK population would be approximately 1:350.

SCDO2: MESP2-associated SCDO has been reported in only one small consanguineous family thus far [Whittock et al 2004b]. A second family with the identical mutation was presented at the 6^th International Skeletal Dysplasia Society meeting, Martigny, Switzerland, in 2005 [Bonafé & Superti-Furga 2005].

SCDO3: LFNG-associated SCDO has been reported in only one family [Sparrow et al 2006].

SCDO4: HES7-associated SCDO has been reported in one consanguineous family from southern Europe [Sparrow et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with autosomal recessive spondylocostal dysostosis (AR SCDO), the following are recommended:

• Assessment of respiratory function, especially if tachypnea and/or feeding difficulties suggest the possibility of respiratory insufficiency

• Evaluation of a male child for the presence of inguinal hernia

Treatment of Manifestations

In the majority of individuals treatment is conservative because the vertebral and rib malformations cause progressive difficulties.

• Respiratory support, including intensive care as needed, to treat acute respiratory distress and chronic respiratory failure

• Routine treatment of inguinal herniae

• 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 caused by reduced lung capacity, which can result in pulmonary hypertension and cardiac failure. Expert management of these clinical problems is indicated.

Surveillance

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

The parents/care providers of young males need to be alert for the signs of inguinal hernia and its potential complications.

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Autosomal recessive spondylocostal dysostosis (AR SCDO) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry 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 AR SCDO are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

Approximately 75% of cases of AR SCDO have occurred in consanguineous families, usually from communities in which cousin partnerships are the norm. Molecular genetic testing of individuals from these high-risk areas may be helpful in identifying at-risk couples.

Related Genetic Counseling Issues

Pseudodominant inheritance. Although rare, there have been reports of SCDO following AD inheritance, although the extent of SDV is variable. In one such family, however [Floor et al 1989], the inheritance pattern was shown to be an example of pseudodominant inheritance of SCDO1 in a highly consanguineous family [Whittock et al 2004a].

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for DLL3-, MESP2-, and LFNG-related AR SCDO 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.

No laboratories offering molecular genetic testing for prenatal diagnosis of HES7-related AR SCDO are listed in the GeneTests Laboratory Directory.

However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

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

Fetal ultrasound examination. In experienced hands, detailed fetal ultrasound scanning is sensitive enough to detect M-SDV as early as 13 weeks gestation, especially when the malformation is anticipated and looked for specifically. If detected as early as this, ultrasound has the important benefit over molecular genetic testing of being a noninvasive mode of investigation, thus eliminating the risk of fetal loss.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The four genes known to be associated with the four forms of autosomal recessive spondylocostal dysostosis (AR SCDO) encode proteins that are key components of the Notch-signaling pathway which, together with FGF and Wnt signaling, is one of the developmental pathways essential to normal somitogenesis [Dequéant et al 2006, Dequéant & Pourquié 2008]. The protein encoded by:

• DLL3 is a ligand for Notch signaling.

• MESP2 is a member of the basic helix-loop-helix (bHLH) family of transcriptional regulatory proteins.

• LFNG is a glycosyltransferase that post-translationally modifies the Notch family of cell-surface receptors; LFNG is a cycling gene expressed in the presomitic mesoderm.

• HES7 is a member of the bHLH superfamily, encoding a bHLH-Orange domain transcriptional repressor protein; HES7 is also a cycling gene expressed in the presomitic mesoderm.

Published Guidelines/Consensus Statements

1. As previously indicated, it is normal for a review of the spinal x-ray(s) to be undertaken prior to genetic testing being performed. See www.rdehospital.nhs.uk.
2. The ICVAS classification system for congenital scoliosis and segmentation defects of the vertebrae has been published [Turnpenny et al 2007, Offiah et al 2010] and includes an algorithm which helps clinicians discern those cases that are most suitable for genetic testing.

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Suggested Reading

1. Ghebranious N, Blank R, Raggio C, Staubli J, McPherson E, Ivacic L, Rasmussen K, Jacobsen F, Faciszewski T, Burmester J, Pauli R, Boachie-Adjei O, Glurich I, Giampietro PF. A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations. J Bone Miner Res. 2008;23:1576–83. [PubMed: 18466071]
2. Kulkarni S, Nagarajan P, Wall J, Donovan DJ, Donell RL, Ligon AH, Venkatachalam S, Quade BJ. Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. Am J Med Genet Part A. 2008;146A:1117–27. [PMC free article: PMC2834558] [PubMed: 18386809]
3. Tassabehji M, Fang ZM, Hilton EN, McGaughran J, Zhao Z, de Bock CE, Howard E, Malass M, Donnai D, Diwan A, Manson FD, Murrell D, Clarke RA. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008;29:1017–27. [PubMed: 18425797]

Author Notes

www.peninsula-clinical-genetics.org

Acknowledgments

Research on SCDO in Exeter has been funded by Action Medical Research, British Scoliosis Research Foundation, and the Skeletal Dysplasia Group, to whom the authors are indebted. In the Exeter Molecular Genetics laboratory the work was undertaken by Mike Bulman, June Duncan (deceased), and Neil Whittock, all under the supervision of Professor Sian Ellard. The work greatly benefited from collaboration with Kenro Kusumi, Sally Dunwoodie, and, more recently, Olivier Pourquié, Philip Giampietro, Alberto Cornier, Amaka Offiah, and Ben Alman, through the ICVAS consortium. Many clinicians have sent images of SDV cases, but for this review particular thanks are due to Dr. Oivind Braaten, Oslo, Norway, and Drs. Karin van Spaendonck-Zwarts and Mirjam M. de Jong, Groningen, The Netherlands.

Revision History

• 14 October 2010 (cd) Revision: sequence analysis and prenatal testing available clinically for mutations in HES7

• 25 August 2009 (et) Review posted live

• 6 February 2009 (pdt) Original submission