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Spondylocostal Dysostosis, Autosomal Recessive

Synonyms: Costovertebral Dysplasia, Spondylocostal Dysplasia. Includes: DLL3-Related Spondylocostal Dysostosis, Autosomal Recessive; HES7-Related Spondylocostal Dysostosis, Autosomal Recessive; LFNG-Related Spondylocostal Dysostosis, Autosomal Recessive; MESP2-Related Spondylocostal Dysostosis, Autosomal Recessive

, BSc, MB, ChB, FRCP, FRCPCH, FRCPath, , BSc, PhD, and .

Author Information
Peninsula Clinical Genetics Service and Honorary Senior Lecturer
Peninsula Medical School
Royal Devon & Exeter Healthcare NHS Trust
Exeter, United Kingdom
, BSc, PhD
Department of Molecular Genetics
Royal Devon & Exeter Healthcare NHS Trust
Exeter, United Kingdom

Initial Posting: ; Last Update: January 17, 2013.


Disease characteristics. Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) 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, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.

Diagnosis/testing. The diagnosis of SCDO is based on radiologic findings. Subtypes are defined by identification of two mutant alleles in any one of the four genes in which mutations are known to cause autosomal recessive (AR) SCDO: DLL3, MESP2, LFNG, and HES7.

Management. Treatment of manifestations: Respiratory support, including intensive care, is provided as needed for acute respiratory distress and chronic respiratory failure. Inguinal herniae are treated as per routine. Surgical intervention may be necessary when scoliosis is significant; external bracing, for example by use of an expandable prosthetic titanium rib, may be attempted but experience is limited.

Prevention of secondary complications: Expert management is indicated for chronic respiratory failure, which can result in pulmonary hypertension and cardiac failure.

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.

Genetic counseling. AR SCDO 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 in the family are known. In experienced hands, detailed fetal ultrasound scanning is sensitive enough to detect M-SDV as early as 13 weeks’ gestation.


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 [usually reduced] rib number). The radiologic phenotype is characterized in general by the following:

  • 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. There are similarities as well as some distinguishing features in the radiographic phenotype for each subtype.

  • SCDO1 (DLL3-associated SCDO). The features so far are remarkably consistent, comprising the four diagnostic criteria 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; 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-3B). Thus far only one family with SCDO2 has been published [Whittock et al 2004b, Figure 3A]. Figure 3B depicts an unpublished case in which the affected individual is heterozygous for different MESP2 mutations.
  • SCDO3 (LFNG-associated SCDO). 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 first published case [Sparrow et al 2008] resembles spondylothoracic dysostosis (STD) (Figure 5; Genetically Related Disorders), while the second published case [Sparrow et al 2010; see figures] resembles DLL3-associated SCDO; all vertebrae display abnormal segmentation.
Figure 1


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 2


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 3


Figure 3. SCDO2, caused by mutations in MESP2. The generalized SDV show more angular features than in SCDO1.

Figure 4


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 5


Figure 5. SCDO4, 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 those (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. DLL3, MESP2, LFNG, and HES7 are the genes in which mutations are known to cause AR SCDO. In an affected individual both alleles are mutated in any one of the involved genes.

Evidence for locus heterogeneity. 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

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

Gene 1
(Locus Name)
Proportion of SCDO Attributed to Mutations in This GeneTest MethodMutations Detected 2
~70%Sequence analysis 3Sequence variants 4
Deletion/duplication analysis 5Exonic or whole-gene deletions; none reported 6
~25% (including spondylothoracic dysostosis)Sequence analysisSequence variants 4
Deletion/duplication analysis 5Exonic or whole-gene deletions; none reported 6
~5%Sequence analysisSequence variants 4
Deletion/duplication analysis 5Exonic or whole-gene deletions; none reported 6
~1%Sequence analysisSequence variants 4

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Sequence analysis of DLL3 exons 2-9 and conserved splice sites detects mutations in ~70% of individuals with SCDO [Bulman et al 2000, Bonafé et al 2003, Turnpenny et al 2003].

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications involving DLL3, MESP2 or LFNG have been reported to cause autosomal recessive spondylocostal dysostosis.

Testing Strategy

To confirm/establish the diagnosis in a proband. To determine if multiple segmentation defects of the vertebrae (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; and
    • 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 could 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
    • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having SCDO is as follows:
      • Initial sequencing of DLL3, the gene most commonly implicated, is appropriate.

        If DLL3 sequence analysis does not identify the disease-causing mutations, 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 HES7, and then DLL3 if no mutations are identified.

        If no mutations are identified in these three genes, consideration can be given to testing LFNG.
      • If severe truncal shortening is observed on radiographs, LFNG may be 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.
    • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having SCOD is use of a multi-gene panel.

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

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.

Males with SCDO appear to be at increased risk for 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).

    Two affected sibs had features of fetal akinesia sequence and succumbed in early childhood [C McKeown, personal communication]; however, the family was multiply consanguineous 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 complication secondary to disorganization of the abnormally segmented cervical spine.
  • SCDO4 (HES7-associated SCDO). The first reported affected individual [Sparrow et al 2008] had a lumbosacral meningomyelocele, but it was uncertain whether this was a direct effect of the causative mutation or a coincidence. The authors are aware of another, unpublished case with a neural tube defect but the strength of the association is not yet fully established.
Figure 7


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

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 probably 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 between the SCDO2 and STD phenotypes.


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 confirm that reduced penetrance does not occur.


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. The historical aspects have been recently clarified [Berdon et al 2011]. STD, as described in Puerto Ricans of Spanish descent, is relatively frequent because of the MESP2 founder mutation, p.Glu103Ter (see Genetically Related Disorders).

Furthermore, the term ‘Jarcho-Levin syndrome’ is frequently confusingly 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 led to great confusion. Of note, these disorders are really dysostoses rather than dysplasias:

The wide range of 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 8


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 (more...)

Figure 9


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.


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 (in England, Wales, The Netherlands, and Switzerland) were compound heterozygotes [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 population in the UK would be approximately 1:350.

SCDO2 (MESP2-associated SCDO) was reported in one small consanguineous family [Whittock et al 2004b, Figure 3A]. A second family with the identical mutation was presented at the Sixth International Skeletal Dysplasia Society meeting, Martigny, Switzerland, in 2005 [Bonafé & Superti-Furga 2005]. An additional, unpublished, case is depicted in Figure 3B.

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

SCDO4 (HES7-associated SCDO) has been reported in two families from Southern Europe [Sparrow et al 2008, Sparrow et al 2010], one of which was consanguineous.

Differential Diagnosis

See Spondylocostal Dysostosis: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Rarely, spondylocostal dysostosis (SCDO) occurs in association with chromosomal abnormalities; however, apart from trisomy 8 mosaicism, no consistent genomic region has been involved and the significance of these associations is unknown.

Syndromic forms of multiple segmentation defects of the vertebrae (M-SDV) need to be considered if the diagnostic criteria for SCDO or STD are not met. Some of the M-SDV syndromes to consider are listed in Table 2.

Table 2. Some Syndromes that Include M-SDV (SCDO and STD excluded)

Acrofacial dysostosis 1263750
Alagille syndrome118450JAG1, NOTCH2
Anhalt 1601344
Atelosteogenesis III108721FLNB
Campomelic dysplasia211970SOX9
Casamassima-Morton-Nance 1271520
Caudal regression 1182940
Cerebro-facio-thoracic dysplasia 1213980
CHARGE syndrome214800CHD7
Atelosteogenesis, type II (de la Chapelle syndrome)256050SLC26A2
DiGeorge / deletion 22q11.2 / velocardiofacial syndrome188400
Dysspondylochondromatosis 1
Femoral hypoplasia-unusual facies 1134780
Fibrodysplasia ossificans progressiva 135100ACVR1
Fryns-Moerman 1
Goldenhar / OAV Spectrum 1164210
Holmes-Schimke 1
Incontinentia pigmenti308310IKBKG
Kabuki syndrome 1147920MLL2
McKusick-Kaufman syndrome236700MKKS
KBG syndrome 1148050ANKRD11
Klippel-Feil 1148900GDF6, PAX1 2
Larsen syndrome150250FLNB
Lower mesodermal agenesis 1
Maternal diabetes mellitus 1
MURCS association 1601076
Multiple pterygium syndrome265000CHRNG
OEIS syndrome 1258040
Phaver 1261575
RAPADILINO syndrome (RECQL4-related disorders)266280RECQL4
Robinow (ROR2-related disorders)180700ROR2
Rolland-Desbuquois 1224400
Rokitansky sequence 1277000WNT4 2
Silverman-Handmaker type of dyssegmental dysplasia (DDSH)224410HSPG2
Simpson-Golabi-Behmel syndrome312870GPC3
Sirenomelia 1182940
Spondylocarpotarsal synostosis272460FLNB
Thakker-Donnai 1227255
Toriello 1
Urioste 1
Verloove-Vanhorick 1 215850
Wildervanck 1314600
Zimmer 1301090

1. Underlying cause not known

2. Possible associations reported: PAX1 [McGaughran et al 2003]; WNT4 [Philibert et al 2008]

Casamassima-Morton-Nance syndrome was described by Casamassima et al [1981]. This syndrome combines SDV with urogenital anomalies. Consistency in the phenotype is lacking as Poor et al [1983] and Daïkha-Dahmane et al [1998] subsequently reported a different SDV phenotype in individuals designated with this syndrome. Inheritance appears to be autosomal recessive.

Klippel-Feil anomaly (KFA) refers to cervical vertebral fusion anomalies. The term KFA is used broadly for a number of phenotypes. KFA, used to describe different forms of cervical vertebral fusion or segmentation error, has also been subclassified [Feil 1919, Thomsen et al 1997, Clarke et al 1998].

Neural tube defects (NTDs) are also frequently associated with severe segmentation anomalies of the spine; however, current consensus is that such cases should not be designated as forms of SCDO.

Autosomal dominant spondylocostal dysostosis. Although rare, SCDO can follow autosomal dominant inheritance in a clear Mendelian pattern, although the extent of SDV is variable within affected families [Rimoin et al 1968, Kubryk & Borde 1981, Temple et al 1988, Lorenz & Rupprecht 1990].

One Macedonian family with AD SCDO was not found to have mutations in DLL3, MESP2, LFNG, or HES7 [Gucev et al 2010]. In two families reported by Sparrow et al [2012], both of which demonstrated quite variable (and in one case non-penetrant) spinal segmentation anomalies, one had a novel single nucleotide polymorphism (SNP) in MESP2 and the other a novel SNP in HES7.

Unknown cause. For most of the diverse SCDO phenotypes seen in clinical practice the underlying cause is not known. It is anticipated that eventually more genes in the integrated Notch-signaling and FGF- and Wnt-signaling pathways will be identified as causes of SCDO (see Molecular Genetic Pathogenesis).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


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 for other (e.g., renal and cardiac) anomalies
  • Evaluation of a male child for the presence of inguinal hernia
  • Medical genetics consultation

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 as needed if scoliosis is significant. External bracing, for example by use of an expandable prosthetic titanium rib [Ramirez et al 2010], 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.


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.

Evaluation of Relatives at Risk

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

Pregnancy Management

Virtually all individuals with SCDO have relative truncal shortening, and some have generalized short stature. For affected women pregnancy may give rise to exaggerated intra-abdominal pressure problems, though there is no published research on this issue. As the spine is distorted there are likely to be concerns with offering spinal and/or epidural anesthesia. However, spinal anesthesia has been successfully administered [Dolak & Tartt 2009].

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

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 autosomal dominant inheritance, although the extent of SDV is variable [Temple et al 1988, Gucev et al 2010, Sparrow et al 2012]. In one such family [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.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 for fetal loss. However, molecular genetic testing of an at-risk pregnancy is still considered the gold standard for accurate prenatal diagnosis.

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


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
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

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. Spondylocostal Dysostosis, Autosomal Recessive: Genes and Databases

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 Spondylocostal Dysostosis, Autosomal Recessive (View All in OMIM)

602768DELTA-LIKE 3; DLL3

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.


Normal allelic variants. DLL3 consists of eight coding exons. Exon numbering for DLL3 follows that of the alternately spliced mouse Dll3 ortholog, so the human published transcript begins with exon 2.

Table 3. Selected DLL3 Normal Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.1547G>Tp. Arg516Leu

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.

Pathogenic allelic variants. To date nearly 40 mutations have been identified throughout DLL3, including frameshift, nonsense, and splicing mutations and insertions; 24 have been published [Turnpenny et al 2007]. Approximately three-quarters of the mutations predict protein-truncating variants, although it is possible that this class of mutations initiates nonsense-mediated decay of the transcript, and they are therefore null alleles (produce no protein).

Normal gene product. The human DLL3 transcript encodes a protein of 618 amino acids (NP_058637.1) and consists of a delta-serrate-lag2 region (DSL), six epidermal growth factor-like domains (EGF), and a transmembrane domain (TM). In animal models Dll3 shows spatially restricted patterns of expression during somite formation and is believed to have a key role in the cell-signaling processes giving rise to somite boundary formation [Dunwoodie et al 2002, Kusumi et al 2004], which proceeds in a rostro-caudal direction with a precise temporal periodicity driven by an internal oscillator, or molecular “segmentation clock,” as reported by McGrew & Pourquié [1998] and Pourquié [1999].

Abnormal gene product. The mutations identified to date in DLL3 are predicted to result in truncated proteins (or no protein, as a result of nonsense-mediated decay), lack of functional domains, misfolding of the protein, or aberrant splicing [Bulman et al 2000, Bonafé et al 2003, Turnpenny et al 2003]. The milder cases were homozygous for missense mutations located in the EGF domain of the DLL3 reading frame. There is some theoretical evidence (unpublished data) 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 protein-truncating mutations. This is likely the result of the different effects conferred upon protein folding compared to those missense mutations associated with the slightly milder phenotype.


Normal allelic variants. MESP2 has two exons spanning ~2 kb. Sequence analysis identified a variable-length polymorphism beginning at nucleotide 535 containing a series of 12-bp repeat units [Whittock et al 2004b]. 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 (see Table 4).

Pathogenic allelic variants. A 4-bp duplication in exon 1, c.500_503dup, results in a premature stop codon in the second and final exon of the gene [Whittock et al 2004b]. The mutations identified in a compound heterozygous individual, c.271A>G and c.385A>T, are believed to be pathogenic. To date, all reported cases of STD are attributable mutations in exon 1 of MESP2, including p.Glu103Ter, p.Leu125Val, p.Glu230Ter, and p.Gly81Ter. The nonsense mutations are predicted to result in nonsense-mediated decay [Cornier et al 2008]. In addition, other mutations identified in the STD phenotype include p.Glu230Ter, p.Leu125Val, and p.Gly81Ter [Cornier et al 2008].

In individuals of Puerto Rican descent who meet the diagnostic criteria for STD, at least one MESP2 pathogenic allele is always p.Glu103Ter. Some affected individuals in this population are homozygous for this mutation.

Table 4. Selected MESP2 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Normalc.535-46 GGGCAGGGGCAA(2_4) 1p.178-181GlyGlnGlyGln178(2_4) 1NM_001039958​.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.

1. Indicates that the sequence is polymorphic in the population and can vary from two to four repeats

Normal gene product. MESP2 is predicted to produce a 397-amino acid protein that functions as a bHLH transcription factor, which is a downstream target of the Notch-signaling pathway. This protein has 58.1% identity with mouse MesP2. The human MESP2 amino terminus contains a bHLH region encompassing 51 amino acids divided into an 11-residue basic domain, a 13-residue helix I domain, an 11-residue loop domain, and a 16-residue helix II domain. In murine somitogenesis MesP2 has a key role in establishing rostro-caudal polarity, and defining the segment boundary, by participating in distinct Notch-signaling pathways [Takahashi et al 2003, Morimoto et al 2005].

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] (see Genotype-Phenotype Correlations).


Normal allelic variants. This is an eight-exon gene. Alternatively spliced transcript variants encoding different isoforms have been described; however, they have not all been fully characterized.

Pathogenic allelic variants. A homozygous missense mutation in a highly conserved phenylalanine close to the active site of the enzyme has been reported in exon 3 [Sparrow et al 2006]. See Table 5.

Table 5. Selected LFNG Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences

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. The gene is predicted to encode a 379-amino acid transcript NP_001035257.1, a glycosyltransferase that modifies the Notch family of cell-surface receptors. LFNG is a fucose-specific beta-1,3-N-acetylglucosaminyltransferase that adds N-acetylglucosamine (GlcNAc) residues to O-fucose on the EGF-like repeats of Notch receptors [Brückner et al 2000, Moloney et al 2000]. LFNG localizes to the Golgi, where the modification of Notch receptors is believed to occur [Haines & Irvine 2003]. Studies have shown that Lfng gene expression is severely disregulated in Dll3-null mice, suggesting that Lfng expression depends on Dll3 function [Dunwoodie et al 2002, Kusumi et al 2004].

Abnormal gene product. The phenylalanine residue affected by the mutation identified in SCDO3 is conserved in all known fringe proteins, from Drosophila melanogaster to humans [Correia et al 2003]. The resultant mutant LFNG protein does not localize correctly within the cell and has been shown by functional analysis to be unable to modulate Notch signaling and is enzymatically inactive [Sparrow et al 2006].


Normal allelic variants. This is a four-exon gene.

Pathogenic allelic variants. Homozygosity for a missense mutation, c.73C>T in exon 2, was found in the proband and its pathogenicity was again supported by functional studies [Sparrow et al 2008]. See Table 6.

Table 6. Selected HES7 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.73C>T p.Arg25TrpNM_032580​.2

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. The deduced human protein encodes a protein predicted to contain 225 amino acids that belongs to the bHLH superfamily of DNA-binding transcription factors. HES (and HEY, encoded by HEY1 and HEY2) proteins belong to the bHLH superfamily of more than 125 DNA-binding transcription factors. The ‘b’ (basic) portion of the domain is required for DNA-binding to E-box sequences, and the HLH portion for homo- and heterodimerization between different members of the superfamily. HES (and HEY) have an additional conserved domain carboxy-terminal to bHLH (Orange domain) and a carboxy-terminal tetrapeptide (WRPW in HES). HES proteins also have a conserved proline residue in the basic domain that changes DNA-binding-site specificity to N-box sequences (5’-CACNAG-3’). HES (and HEY) genes are direct targets of Notch signaling and act on their own promoters to repress transcription. Because of their short half-life autorepression is relieved, allowing a new wave of transcription and translation every 90-120 minutes (in mouse). Human and mouse HES7 are identical in the bHLH domain and share approximately 90% amino acid identity.

Abnormal gene product. The c.73C>T mutation affects the DNA-binding domain of the HES7 protein. Functional studies showed that the abnormal product was not able to repress gene expression by DNA binding or protein heterodimerization.


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

Published Guidelines/Consensus Statements

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.

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.

Literature Cited

  1. Aburakawa K, Harada M, Otake S. Clinical evaluations of the treatment of congenital scoliosis. Orthop Surg & Trauma. 1996;39:55–62.
  2. Aurora P, Wallis CE, Winter RM. The Jarcho-Levin syndrome (spondylocostal dysplasia) and complex congenital heart disease: a case report. Clin Dysmorphol. 1996;5:165–9. [PubMed: 8723567]
  3. Berdon WE, Lampl BS, Cornier AS, Ramirez N, Turnpenny PD, Vitale MG, Seimon LP, Cowles RA. Clinical and radiological distinction between spondylothoracic dysostosis (Lavy-Moseley syndrome) and spondylocostal dysostosis (Jarcho-Levin syndrome). Pediatr Radiol. 2011;41:384–8. [PubMed: 21174082]
  4. Bonafé L, Giunta C, Gassner M, Steinmann B, Superti-Furga A. A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village. Clin Genet. 2003;64:28–35. [PubMed: 12791036]
  5. Bonafé L, Superti-Furga A. Sixth International Skeletal Dysplasia Society meeting. Martigny, Switzerland; 2005.
  6. Brückner K, Perez L, Clausen H, Cohen S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature. 2000;406:411–5. [PubMed: 10935637]
  7. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000;24:438–41. [PubMed: 10742114]
  8. Cantú JM, Urrusti J, Rosales G, Rojas A. Evidence for autosomal recessive inheritance of costovertebral dysplasia. Clin Genet. 1971;2:149–54. [PubMed: 5111758]
  9. Casamassima AC, Morton CC, Nance WE, Kodroff M, Caldwell R, Kelly T, Wolf B. Spondylocostal dysostosis associated with anal and urogenital anomalies in a Mennonite sibship. Am J Med Genet. 1981;8:117–27. [PubMed: 7246601]
  10. Clarke RA, Catalan G, Diwan AD, Kearsley JH. Heterogeneity in Klippel-Feil syndrome: a new classification. Pediatr Radiol. 1998;28:967–74. [PubMed: 9880643]
  11. Cornier AS, Ramírez N, Arroyo S, Acevedo J, García L, Carlo S, Korf B. Phenotype characterization and natural history of spondylothoracic dysplasia syndrome: a series of 27 new cases. Am J Med Genet A. 2004;128A:120–6. [PubMed: 15214000]
  12. Cornier AS, Staehling-Hampton K, Delventhal KM, Saga Y, Caubet JF, Sasaki N, Ellard S, Young E, Ramirez N, Carlo SE, Torres J, Emans JB, Turnpenny PD, Pourquié O. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome. Am J Hum Genet. 2008;82:1334–41. [PMC free article: PMC2427230] [PubMed: 18485326]
  13. Correia T, Papayannopoulos V, Panin V, Woronoff P, Jiang J, Vogt TF, Irvine KD. Molecular genetic analysis of the glycosyltransferase Fringe in Drosophila. Proc Natl Acad Sci U S A. 2003;100:6404–9. [PMC free article: PMC164459] [PubMed: 12743367]
  14. Daïkha-Dahmane F, Huten Y, Morvan J, Szpiro-Tapia S, Nessmann C, Eydoux P. Fetus with Casamassima-Morton-Nance syndrome and an inherited (6;9) balanced translocation. Am J Med Genet. 1998;80:514–7. [PubMed: 9880219]
  15. David TJ, Glass A. Hereditary costovertebral dysplasia with malignant cerebral tumour. J Med Genet. 1983;20:441–4. [PMC free article: PMC1049177] [PubMed: 6655670]
  16. Dequéant ML, Glynn E, Gaudenz K, Wahl M, Chen J, Mushegian A, Pourquié O. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science. 2006;314:1595–8. [PubMed: 17095659]
  17. Dequéant ML, Pourquié O. Segmental patterning of the vertebrate embryonic axis. Nat Rev Genet. 2008;9:370–82. [PubMed: 18414404]
  18. Dolak JA, Tartt S. Spinal anesthesia for Cesarean delivery in a parturient with spondylocostal dysostosis. Can J Anaesth. 2009;56:172–3. [PubMed: 19247767]
  19. Dunwoodie SL, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RS. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development. 2002;129:1795–806. [PubMed: 11923214]
  20. Eliyahu S, Weiner E, Lahav D, Shalev E. Early sonographic diagnosis of Jarcho-Levin syndrome: a prospective screening program in one family. Ultrasound Obstet Gynecol. 1997;9:314–8. [PubMed: 9201874]
  21. Feil A. L'absence et la diminution des vertèbres cervicales (étude clinique et pathologique); le syndrome de réduction numérique cervicale. Paris, France: Librairie Littéraire et Médicale; 1919.
  22. Floor E, De Jong RO, Fryns JP, Smulders C, Vles JS. Spondylocostal dysostosis: an example of autosomal dominant transmission in a large family. Clin Genet. 1989;36:236–41. [PubMed: 2805381]
  23. Gucev ZS, Tasic V, Pop-Jordanova N, Sparrow DB, Dunwoodie SL, Ellard S, Young E, Turnpenny PD. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet A. 2010;152A:1378–82. [PubMed: 20503311]
  24. Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol. 2003;4:786–97. [PubMed: 14570055]
  25. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp. 1938;62:216–26.
  26. Karnes PS, Day D, Berry SA, Pierpont ME. Jarcho-Levin syndrome: four new cases and classification of subtypes. Am J Med Genet. 1991;40:264–70. [PubMed: 1951427]
  27. Kubryk N, Borde M. La dysostose spondylocostale. Pédiatrie. 1981;17:137–46.
  28. Kusumi K, Mimoto MS, Covello KL, Beddington RS, Krumlauf R, Dunwoodie SL. Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis. 2004;39:115–21. [PubMed: 15170697]
  29. Lorenz P, Rupprecht E. Spondylocostal dysostosis: dominant type. Am J Med Genet. 1990;35:219–21. [PubMed: 2309760]
  30. McGaughran JM, Oates A, Donnai D, Read AP, Tassabehji M. Mutations in PAX1 may be associated with Klippel-Feil syndrome. Eur J Hum Genet. 2003;11:468–74. [PubMed: 12774041]
  31. McGrew MJ, Pourquié O. Somitogenesis: segmenting a vertebrate. Curr Opin Genet Dev. 1998;8:487–93. [PubMed: 9729727]
  32. McMaster MJ, Singh H. Natural history of congenital kyphosis and kyphoscoliosis. A study of one hundred and twelve patients. J Bone Joint Surg Am. 1999;81:1367–83. [PubMed: 10535587]
  33. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF. Fringe is a glycosyltransferase that modifies Notch. Nature. 2000;406:369–75. [PubMed: 10935626]
  34. Morimoto M, Takahashi Y, Endo M, Saga Y. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature. 2005;435:354–9. [PubMed: 15902259]
  35. Mortier GR, Lachman RS, Bocian M, Rimoin DL. Multiple vertebral segmentation defects: analysis of 26 new patients and review of the literature. Am J Med Genet. 1996;61:310–9. [PubMed: 8834041]
  36. Moseley JE, Bonforte RJ. Spondylothoracic dysplasia--a syndrome of congenital anomalies. Am J Roentgenol Radium Ther Nucl Med. 1969;106:166–9. [PubMed: 5769299]
  37. Norum RA, McKusick VA. Costovertebral anomalies with apparent recessive inheritance. Birth Defects OAS. 1969;18:326–9.
  38. Offiah A, Alman B, Cornier AS, Giampietro PF, Tassy O, Wade A, Turnpenny PD. ICVAS (International Consortium for Vertebral Anomalies and Scoliosis). Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. Am J Med Genet A. 2010;152A:1357–71. [PubMed: 20503308]
  39. Philibert P, Biason-Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, Schoenle E, Sultan C. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab. 2008;93:895–900. [PubMed: 18182450]
  40. Poor MA, Alberti O, Griscom NT, Driscoll SG, Holmes LB. Nonskeletal malformations in one of three siblings with Jarcho-Levin syndrome of vertebral anomalies. J Pediatr. 1983;103:270–2. [PubMed: 6875723]
  41. Pourquié O. Notch around the clock. Curr Opin Genet Dev. 1999;9:559–65. [PubMed: 10508694]
  42. Ramirez N, Flynn JM, Emans JB, Betz R, Smith JT, Price N, St Hilaire T, Joshi AP, Campbell RM. Vertical expandable prosthetic titanium rib as treatment of thoracic insufficiency syndrome in spondylocostal dysplasia. J Pediatr Orthop. 2010;30:521–6. [PubMed: 20733413]
  43. Rastogi D, Rosenzweig EB, Koumbourlis A. Pulmonary hypertension in Jarcho-Levin syndrome. Am J Med Genet. 2002;107:250–2. [PubMed: 11807909]
  44. 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]
  45. Simpson JM, Cook A, Fagg NL, MacLachlan NA, Sharland GK. Congenital heart disease in spondylothoracic dysostosis: two familial cases. J Med Genet. 1995;32:633–5. [PMC free article: PMC1051639] [PubMed: 7473656]
  46. Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet. 2006;78:28–37. [PMC free article: PMC1380221] [PubMed: 16385447]
  47. Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O'Reilly VC, Saga Y, Zackai EH, Dormans JP, Alman BA, McGregor L, Kageyama R, Kusumi K, Dunwoodie SL. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149:295–306. [PubMed: 22484060]
  48. Sparrow DB, Guillén-Navarro E, Fatkin D, Dunwoodie SL. Mutation of hairy-and-enhancer-of-split-7 in humans causes spondylocostal dysostosis. Hum Mol Genet. 2008;17:3761–6. [PubMed: 18775957]
  49. Sparrow DB, Sillence D, Wouters MA, Turnpenny PD, Dunwoodie SL. Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. Eur J Hum Genet. 2010;18:674–9. [PMC free article: PMC2987349] [PubMed: 20087400]
  50. Takahashi Y, Inoue T, Gossler A, Saga Y. Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites. Development. 2003;130:4259–68. [PubMed: 12900443]
  51. Takikawa K, Haga N, Maruyama T, Nakatomi A, Kondoh T, Makita Y, Hata A, Kawabata H, Ikegawa S. Spine and rib abnormalities and stature in spondylocostal dysostosis. Spine. 2006;31:E192–7. [PubMed: 16582839]
  52. Temple IK, Thomas TG, Baraitser M. Congenital spinal deformity in a three generation family. J Med Genet. 1988;25:831–4. [PMC free article: PMC1051611] [PubMed: 3236365]
  53. Thomsen MN, Schneider U, Weber M, Johannisson R, Niethard FU. Scoliosis and congenital anomalies associated with Klippel-Feil syndrome types I-III. Spine. 1997;22:396–401. [PubMed: 9055366]
  54. Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, Pourquié O, Kusumi K, Dunwoodie S. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn. 2007;236:1456–74. [PubMed: 17497699]
  55. Turnpenny PD, Whittock N, Duncan J, Dunwoodie S, Kusumi K, Ellard S. Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. J Med Genet. 2003;40:333–9. [PMC free article: PMC1735475] [PubMed: 12746394]
  56. Whittock NV, Ellard S, Duncan J, de Die-Smulders CE, Vles JS, Turnpenny PD. Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations. Clin Genet. 2004a;66:67–72. [PubMed: 15200511]
  57. 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. 2004b;74:1249–54. [PMC free article: PMC1182088] [PubMed: 15122512]

Suggested Reading

  1. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20:905–16. [PubMed: 21147753]
  2. Ghebranious N, Blank RD, Raggio CL, Staubli J, McPherson E, Ivacic L, Rasmussen K, Jacobsen FS, Faciszewski T, Burmester JK, Pauli RM, 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]
  3. 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 A. 2008;146A:1117–27. [PMC free article: PMC2834558] [PubMed: 18386809]
  4. 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]

Chapter Notes


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

  • 17 January 2013 (me) Comprehensive update posted live
  • 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
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