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Spondylocostal Dysostosis, Autosomal Recessive

Synonyms: Costovertebral Dysplasia, Spondylocostal Dysplasia

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

Author Information

Initial Posting: ; Last Update: December 21, 2017.

Summary

Clinical 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; 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 radiographic features. The subtype is defined by identification of biallelic pathogenic variants in one of the six genes known to cause autosomal recessive SCDO: DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2.

Management.

Treatment of manifestations: Respiratory support, including intensive care, is provided as needed for the small proportion of cases with acute respiratory distress and chronic respiratory failure. Inguinal hernia are treated as per routine. Surgical intervention may be necessary when scoliosis is significant; external bracing (e.g., 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.

SCDO caused by pathogenic variants in DLL3, MESP2, LFNG, HES7, and RIPPLY2 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. SCDO caused by biallelic TBX6 pathogenic variants is inherited in an autosomal recessive manner and the same genetic counseling principles apply. However, heterozygous TBX6 pathogenic variants have also been reported in individuals with autosomal dominant SCDO and some individuals with congenital scoliosis where the pattern of inheritance is uncertain. When autosomal recessive inheritance clearly applies, carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants 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.

Diagnosis

Suggestive Findings

Spondylocostal dysostosis (SCDO) should be suspected in individuals with the following radiographic features:

  • Multiple segmentation defects of the vertebrae (M-SDV). Abnormal segmentation of virtually all vertebrae, with at least ten contiguous segments affected; the strict diagnosis excludes most cases of congenital scoliosis in which segmentation anomalies affect very few vertebrae (or a single vertebra). The radiologic presentation is therefore crucial and most easily assessed from an anteroposterior radiograph of the whole spine.
  • A mild degree of scoliosis, which is usually non-progressive
  • Rib abnormalities. 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)
  • Absence (usually) of other congenital anomalies (e.g., renal and cardiac) (see Differential Diagnosis)

Six subtypes of autosomal recessive SCDO (AR SCDO) are recognized, based on the gene involved. AR SCDO is usually isolated (i.e., restricted to the vertebral column and ribs). However, additional anomalies have been present in some individuals, as described under the six individual subtypes.

  • SCDO1 (DLL3-associated SCDO). The features so far are remarkably consistent, comprising the main diagnostic criteria plus an irregular pattern of ossification of the vertebral bodies on spinal radiographs prenatally and in early childhood. In the fetus or young child each vertebral body has a round or ovoid shape with smooth boundaries; when viewed as a whole, this appearance has been referred to as the "pebble beach sign" [Turnpenny et al 2003] (see 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, though 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 (see 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 (see Figure 3A-3B). Thus far only one family with SCDO2 has been published [Whittock et al 2004b] (see Figure 3A). Figure 3B depicts an unpublished report of an affected individual with compound heterozygous pathogenic variants in MESP2.
  • SCDO3 (LFNG-associated SCDO). The shortening of the spine is more severe than that seen in SCDO1 and SCDO2 (see 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 individual [Sparrow et al 2008] resembles spondylothoracic dysostosis (STD) (see Figure 5; Genetically Related Disorders), while the second published individual [Sparrow et al 2010; see figures] resembles DLL3-associated SCDO; all vertebrae display abnormal segmentation.
  • SCDO5 (TBX6-associated SCDO) (OMIM 122600). A three-generation family of male-to-male transmission demonstrating SCDO and fulfilling the diagnostic criteria was reported [Gucev et al 2010, Sparrow et al 2013a] (see Figure 6). A heterozygous TBX6 pathogenic variant, disrupting the natural stop codon, segregated with the condition, and functional studies demonstrated approximately half the wild type transcriptional activation activity. Both published [Lefebvre et al 2017] and unpublished data [Turnpenny & Sloman, unpublished data] have identified biallelic TBX6 pathogenic variants and/or deletions in AR SCDO.
  • SCDO6 (RIPPLY2-associated SCDO). Two brothers born to nonconsanguineous parents had vertebral segmentation defects affecting the posterior elements of C1-C4, hemivertebrae and butterfly vertebrae of T2-T7 (see Figure 7). Marked cervical kyphosis at C2-C3 was associated with cord compression and mild thoracic scoliosis was present [McInerney-Leo et al 2015]. The radiologic pattern was distinct from other forms of SCDO.
Figure 1. . Typical axial skeletal features in an infant with SCDO caused by pathogenic variants in DLL3 (type 1).

Figure 1.

Typical axial skeletal features in an infant with SCDO caused by pathogenic variants 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 distal to the (more...)

Figure 2. . Radiograph of a child with a mild form of SCDO1, caused by pathogenic variants in DLL3.

Figure 2.

Radiograph of a child with a mild form of SCDO1, caused by pathogenic variants in DLL3. All vertebrae show at least some relatively mild segmentation abnormality.

Figure 3. . SCDO2, caused by pathogenic variants in MESP2.

Figure 3.

SCDO2, caused by pathogenic variants in MESP2. The generalized SDV show more angular features than in SCDO1.

Figure 4. . MRI of the spine in SCDO3, caused by pathogenic variants in LFNG.

Figure 4.

MRI of the spine in SCDO3, caused by pathogenic variants 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. . SCDO4, caused by pathogenic variants in HES7.

Figure 5.

SCDO4, caused by pathogenic variants 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 of spondylothoracic (more...)

Figure 6.

Figure 6.

SCDO phenotypes: x-ray and MRI images showing vertebral and rib malformations and dextrocardia A & C. Individuals with SDV and dextrocardia

Figure 7.

Figure 7.

Clinical images of affected individuals A-C. 3D-CT of male age 15 months with SDV, showing failure of formation of the posterior elements of C1 to C4 with descent of the occipital bone, resulting in canal stenosis and cord compression

Establishing the Diagnosis

The diagnosis of AR SCDO is established in a proband with the above radiographic features and identification of biallelic pathogenic variants in one of the genes listed in Table 1 on molecular genetic testing.

Molecular testing approaches can include use of a multigene panel, serial single-gene testing (in certain circumstances), and more comprehensive genomic testing:

  • A multigene panel that includes DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2, and other genes of interest (see Differential Diagnosis), may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Serial single-gene testing. Prioritized genetic testing may be pursued as single-gene testing based on clinical features:
    • LFNG: severe truncal shortening observed on radiographs
    • MESP2: radiographic phenotype closer to that of STD (a "crab-like" appearance)
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Recessive Spondylocostal Dysostosis

Gene 1
(AR SCDO subtype)
Proportion of AR SCDO Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
DLL3
(SCDO1)
~60% 595%2 individuals 6
MESP2
(SCDO2)
~20% 7100%See footnote 8
LFNG
(SCDO3)
<2%100%See footnote 8
HES7
(SCDO4)
<5% 9100%See footnote 8
TBX6
(SCDO5)
~10% 10100%See footnote 11
RIPPLY2
(SCDO6)
<2%100%See footnote 8
Unknown≤5%NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

One individual with a deletion of exons 2-4 (detected by an in-house-designed MLPA kit) and one individual with a whole-gene deletion (detected by array CGH and confirmed by in-house-designed MLPA) [Author, personal communication]

7.

Includes individuals with spondylothoracic dysostosis; three known families with SCDO2 caused by MESP2 pathogenic variants [Whittock et al 2004b; Authors, unpublished data]

8.

No deletions or duplications involving MESP2, LFNG, HES7, or RIPPLY2 have been identified in individuals with AR SCDO [Author, personal communication].

9.

Three reported families and an additional 3.4% of unreported cases [P Turnpenny, personal communication]

10.

Six families with TBX6-related AR SCDO have been reported [Lefebvre et al 2017; P Turnpenny, personal communication].

11.

TBX6 deletions have been reported in individuals with sporadic congenital scoliosis and müllerian aplasia [Sandbacka et al 2013, Wu et al 2015] (see Genetically Related Disorders).

Clinical Characteristics

Clinical Description

Skeletal. Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV), which is usually generalized throughout the spine in these monogenic disorders, 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

Respiratory. 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. 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.

Inguinal hernia. Males with SCDO appear to be at increased risk for inguinal hernia.

Neurologic complications appear to be rare.

Phenotype Correlations by Gene

DLL3 (SCDO1). Scoliosis is generally mild and non-progressive, and the need for surgical intervention to stabilize the spine is rare. However, more significant scoliosis has been observed in some individuals (see Figure 8).

Figure 8.

Figure 8.

SCDO1, caused by pathogenic variants in DLL3, demonstrating unusually severe scoliosis

MESP2 (SCDO2). The ribs tend to be straight and more regularly aligned than in the other forms of SCDO (i.e., demonstrating fewer points of fusion). This pattern is also seen in the more severe form of MESP2-related spondylothoracic dysostosis (STD).

LFNG (SCDO3). The one known affected individual had a distal arthrogryposis, but it was uncertain whether this was a direct effect of the pathogenic variant or a complication secondary to disorganization of the abnormally segmented cervical spine.

HES7 (SCDO4). 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 pathogenic variant or a coincidence. The authors are aware of another, unpublished individual with a neural tube defect but the strength of the association is not yet fully established. A large consanguineous Middle Eastern kindred with SCDO4 demonstrated cosegregation of dextrocardia [Sparrow et al 2013a]; whether this was directly due to the pathogenic variant or a separate genetic cause has not been established.

TBX6 (SCDO5). In the three-generation affected family following autosomal dominant inheritance (all male) reported by Sparrow et al [2013b] the widespread vertebral malformations consisted of a mixture of hemivertebrae and blocks of fused segments. There was relative sparing of rib involvement. Mild scoliosis was centered on the mid-thoracic region. No other anomalies were identified in this family and neurodevelopment was normal. Published [Lefebvre et al 2017] and unpublished data [Turnpenny & Sloman, unpublished data] indicate that an autosomal recessive form of SCDO caused by biallelic TBX6 pathogenic variants gives rise to multiple vertebral segmentation defects following a pattern that is essentially generalized and may cause mild scoliosis. A designation of SCDO5 is therefore justified.

RIPPLY2 (SCDO6). The two brothers reported by McInerney-Leo et al [2015] had vertebral segmentation defects affecting the posterior elements of C1-C4, hemivertebrae and butterfly vertebrae of T2-T7. Marked cervical kyphosis was present at C2-C3 and associated with cord compression; mild thoracic scoliosis was also present. The radiologic pattern in this entity was distinct from other forms of SCDO because it was limited to particular regions and not generalized. However, the phenotypic range may change if more individuals are reported.

Genotype-Phenotype Correlations

DLL3. The radiographic features of SCDO1 appear to be very consistent (see Figure 1). However, two individuals homozygous for DLL3 pathogenic missense variants in the region encoding the EGF domain had slightly milder phenotypes (see Figure 2). Some evidence [Authors, unpublished data] suggests that these pathogenic missense variants 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 pathogenic missense variants identified in affected individuals cause a phenotype that is indistinguishable from that caused by DLL3 pathogenic truncating variants. This probably results from the different effects conferred upon protein folding compared to those pathogenic missense variants associated with the slightly milder phenotype.

MESP2. 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 pathogenic variant 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 pathogenic nonsense variants identified in spondylothoracic dysostosis (STD) (see Genetically Related Disorders) are located within the first exon, and the resulting mutated mRNA transcripts are predicted to be susceptible to nonsense-mediated decay. Therefore, persons homozygous or compound heterozygous for these pathogenic nonsense variants 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.

Penetrance

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

Nomenclature

Jarcho & Levin [1938] originally reported sibs with a form of syndromic SCDO that most closely resembles SCDO2, but in the literature the term "Jarcho-Levin syndrome" (JLS) has tended to be more closely associated with STD than any form of SCDO. The historical aspects have been clarified [Berdon et al 2011]. STD, as described in Puerto Ricans of Spanish descent, is relatively frequent in that population group because of the MESP2 founder variant p.Glu103Ter (see Genetically Related Disorders).

Furthermore, the term "Jarcho-Levin syndrome" is very often 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 case 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 segmentation defects of the vertebrae (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 (see Figure 9). 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 (see Figure 10).
Figure 9.

Figure 9.

ICVAS clinical classification algorithm SDV = segmentation defect(s) of the vertebrae

Figure 10. . ICVAS research classification algorithm: a more detailed, systematic analysis of radiographic anatomic features.

Figure 10.

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 for (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-related SCDO) is the most commonly encountered monogenic form of AR SCDO in clinical practice. Seventy-five percent of individuals (Exeter Laboratory experience) have been the offspring of consanguineous unions, mostly of Middle Eastern or Pakistani origin, and occasionally of Europeans and elsewhere. A small number of individuals from northern Europe (England, Wales, The Netherlands, and Switzerland) have been shown to be 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-related SCDO) was reported in one small consanguineous family [Whittock et al 2004b] (see Figure 3A). A second family with the identical homozygous pathogenic variant was presented at the Sixth International Skeletal Dysplasia Society meeting, Martigny, Switzerland, in 2005 [Bonafé & Superti-Furga 2005]. An additional, unpublished individual is depicted in Figure 3B.

SCDO3 (LFNG-related SCDO) has been reported in only one family [Sparrow et al 2006] and is therefore very rare. There is an anecdotal report of one other individual.

SCDO4 (HES7-related SCDO) has been reported in two families from southern Europe [Sparrow et al 2008, Sparrow et al 2010], one of which was consanguineous, and in a large Middle Eastern kindred [Sparrow et al 2013a].

SCDO5 (TBX6-related SCDO) (OMIM 122600) has been reported in one family demonstrating autosomal dominant inheritance [Sparrow et al 2013b] and a small number of individuals demonstrating AR inheritance [Lefebvre et al 2017]. However, TBX6 is an important gene in congenital scoliosis where the segmentation anomalies are more limited. [Wu et al 2015, Takeda et al 2017]. These reports suggest that TBX6 pathogenic variants are identified in approximately 10% of individuals with congenital scoliosis.

SCDO6 (RIPPLY2-associated SCDO) has been reported in one nonconsanguineous family and is therefore presumed on current evidence to be very rare.

Differential Diagnosis

Rarely, spondylocostal dysostosis (SCDO) occurs in association with chromosome 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 spondylothoracic dysostosis (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)

Syndromes/DisordersOMIMGene(s)
Alagille syndrome118450JAG1, NOTCH2
Atelosteogenesis type II (de la Chapelle dysplasia)256050SLC26A2
Atelosteogenesis type III108721FLNB
Campomelic dysplasia114290SOX9
Casamassima-Morton-Nance syndrome 1271520
Caudal dysgenesis syndrome600145VANGL1
Cerebro-facio-thoracic dysplasia213980TMCO1
CHARGE syndrome214800CHD7
Chromosome abnormality
Cleft-limb-heart malformation syndrome 1215850
Currarino syndrome176450MNX1
22q11.2 deletion syndrome (DiGeorge syndrome / velocardiofacial syndrome)188400, 192430
Dyssegmental dysplasia, Rolland-Desbuquois type 1224400
Dyssegmental dysplasia, Silverman-Handmaker type224410HSPG2
Facial dysmorphism with multiple malformations 1227255
Femoral hypoplasia-unusual facies syndrome 1134780
Fibrodysplasia ossificans progressiva135100ACVR1
Goldenhar syndrome / Oculo-auriculo-vertebral spectrum 1164210MYT1 2
Incontinentia pigmenti308300IKBKG
Kabuki syndrome147920KMT2D, KDM6A
McKusick-Kaufman syndrome236700MKKS
KBG syndrome148050ANKRD11
Klippel-Feil syndrome118100GDF6, GDF3, MEOX1 2
Larsen syndrome150250FLNB
Lower mesodermal agenesis 1
Maternal diabetes mellitus 1
Mayer-Rokitansky-Kuster-Hauser syndrome277000TBX6, WNT4 2, WNT9B 3
MURCS association601076TBX6
Multiple pterygium syndrome, Escobar variant265000CHRNG
OEIS complex 1258040
Phaver syndrome 1261575
Postaxial acrofacial dysostosis263750DHODH
RAPADILINO syndrome (RECQL4-related disorders)266280RECQL4
Robinow syndrome – autosomal dominant, WNT5A-related180700WNT5A
Robinow syndrome – autosomal recessive, ROR2 -related268310ROR2
Simpson-Golabi-Behmel syndrome type 1312870GPC3, GPC4
Spinal dysplasia, Anhalt type 1601344
Spondylocarpotarsal synostosis syndrome272460FLNB
Limb deficiency-vertebral hypersegmentation-absent thymus 1, 4
VATER/VACTERL 1192350
Verheij syndrome615583PUF60
Wildervanck syndrome 1314600
1.

Underlying cause not known

2.

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

3.
4.

Casamassima-Morton-Nance syndrome (OMIM 271520) 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 are also frequently associated with severe segmentation anomalies of the spine; however, current consensus is that this should not be designated as a form of SCDO.

Autosomal dominant spondylocostal dysostosis (OMIM 122600). One family with AD SCDO due to a heterozygous TBX6 pathogenic variant has been reported, (see Prevalence). Additional families with AD SCDO without an identified gene have also been reported; in these families the extent of SDV is very variable [Rimoin et al 1968, Kubryk & Borde 1981, Temple et al 1988, Lorenz & Rupprecht 1990].

Unknown cause. SDV are estimated to occur on 0.5-1.0 per 1,000 live births but in clinical practice the radiologic phenotypes and syndromic associations are extremely diverse. For most individuals the underlying cause is not known but with an increasing number of genes being identified (Table 2) careful consideration should be given to phenotypic characterization and decision making with respect to genetic testing. 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).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In the majority of individuals treatment is conservative because the vertebral and rib malformations do not cause progressive difficulties:

  • Respiratory support, including intensive care as needed, to treat acute respiratory distress and chronic respiratory failure
  • Routine treatment of inguinal hernia
  • Surgical intervention as needed if scoliosis is significant. External bracing – for example, by use of an expandable prosthetic titanium rib [Ramirez et al 2010, Pons-Odena et al 2017] – may be attempted, as well as growing rods and other devices as appropriate.

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.

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 intraabdominal 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 in the US and www.ClinicalTrialsRegister.eu in Europe 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

Spondylocostal dysostosis caused by pathogenic variants in DLL3, MESP2, LFNG, HES7, or RIPPLY2 is inherited in an autosomal recessive manner. Pathogenic variants in TBX6 give rise to both autosomal recessive and, rarely, autosomal dominant SCDO according to current data [Sparrow et al 2013b].

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive spondylocostal dysostosis (AR SCDO) are obligate heterozygotes (carriers) for a DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at 50% risk of being a carrier of a DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 pathogenic variants in the family.

Approximately 75% of individuals with AR SCDO are from consanguineous families, usually from communities in which cousin partnerships are common. Molecular genetic carrier testing of individuals from high-risk families, in which one or more individuals has been diagnosed with SCDO, may be helpful in identifying at-risk couples.

Related Genetic Counseling Issues

Pseudodominant inheritance. Although rare, there have been reports of SCDO appearing to be inherited in an autosomal dominant manner, although the extent of segmentation defects of the vertebrae (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 (i.e., an autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern) 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the SCDO-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Fetal ultrasound examination. In experienced hands, detailed fetal ultrasound scanning is sensitive enough to detect multiple segmentation defects of the vertebrae (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.

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

Resources

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

  • International Consortium for Vertebral Anomalies and Scoliosis Registry
    c/o Kenro Kusumi, PhD
    Email: kenro.kusumi@asu.edu
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu
  • 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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spondylocostal Dysostosis, Autosomal Recessive (View All in OMIM)

122600SPONDYLOCOSTAL DYSOSTOSIS 5; SCDO5
277300SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE; SCDO1
602427T-BOX 6; TBX6
602576LUNATIC FRINGE; LFNG
602768DELTA-LIKE 3; DLL3
605195MESODERM POSTERIOR BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR 2; MESP2
608059HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 7; HES7
608681SPONDYLOCOSTAL DYSOSTOSIS 2, AUTOSOMAL RECESSIVE; SCDO2
609813SPONDYLOCOSTAL DYSOSTOSIS 3, AUTOSOMAL RECESSIVE; SCDO3
609891RIPPLY TRANSCRIPTIONAL REPRESSOR 2; RIPPLY2
613686SPONDYLOCOSTAL DYSOSTOSIS 4, AUTOSOMAL RECESSIVE; SCDO4
616566SPONDYLOCOSTAL DYSOSTOSIS 6, AUTOSOMAL RECESSIVE; SCDO6

Molecular Genetic Pathogenesis

The six genes known to be associated with the six subtypes 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 of Notch1 that inhibits signaling;
  • MESP2 is a member of the basic helix-loop-helix (bHLH) family of transcriptional regulatory proteins; MESP2 is a direct target of Notch1 receptor signaling;
  • LFNG is a glycosyltransferase that post-translationally modifies the Notch family of cell-surface receptors; LFNG is a direct target of Notch1 receptor signaling; LFNG is also a cycling gene expressed in the presomitic mesoderm;
  • HES7 is a bHLH-Orange domain transcriptional repressor protein; HES7 is a direct target of Notch1 receptor signaling; HES7 is also a cycling gene expressed in the presomitic mesoderm;
  • TBX6 is a T-box transcription factor; TBX6 activates DLL1 gene expression, which is an activating ligand of the Notch1 receptor; it also activates MESP2 gene expression;
  • RIPPLY2 is a negative regulator of TBX6; RIPPLY2 is a direct transcriptional target of MESP2 and of TBX6.

DLL3

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date 30 pathogenic variants have been identified throughout DLL3, including frameshift, nonsense, missense, splicing site variants and partial- and whole-gene deletions; 24 have been published [Turnpenny et al 2007]. Approximately three fourths of the pathogenic variants predict protein-truncating variants, although it is possible that this class of pathogenic variants 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 rostrocaudal 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 pathogenic variants 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]. Individuals with milder features were homozygous for pathogenic missense variants located in the EGF domain of the DLL3 reading frame. There is some theoretic evidence [Authors, unpublished data] that these pathogenic missense variants 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 pathogenic missense variants identified in affected individuals cause a phenotype that is indistinguishable from that caused by protein-truncating variants. This is likely the result of the different effects conferred upon protein folding compared to those pathogenic missense variants associated with the slightly milder phenotype.

MESP2

Gene structure. MESP2 has two exons spanning approximately 2 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Sequence analysis identified a variable-length polymorphism beginning at c.535 containing a series of 12-bp repeat units coding glycine and glutamine [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 3).

Pathogenic 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 pathogenic variants identified in a compound heterozygous individual, c.271A>G and c.385A>T, are believed to be pathogenic. Other pathogenic variants, including a nonsense variant in exon 1, have been identified in individuals with spondylothoracic dysostosis (STD) [Cornier et al 2008]. See Table 3.

Table 3.

MESP2 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.535_46[2_4] 1p.Gly178_Gln181[2_4] 1NM_001039958​.1
NP_001035047​.1
Pathogenicc.271A>Gp.Lys91Glu
c.385A>Tp.Ile129Phe
c.500_503dupp.Gly169ProfsTer199

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.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 encodes a 397-amino acid bHLH transcription factor, which is a downstream target of the Notch-signaling pathway. The 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 rostrocaudal polarity, and defining the segment boundary, by participating in distinct Notch-signaling pathways [Takahashi et al 2003, Morimoto et al 2005].

Abnormal gene product. 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).

LFNG

Gene structure. This is an eight-exon gene. Alternatively spliced transcript variants encoding different isoforms have been described; however, they have not all been fully characterized. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A homozygous pathogenic missense variant 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 4.

Table 4.

LFNG Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.564C>Ap.Phe188LeuNM_001040167​.1
NP_001035257​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. LFNG encodes 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 dysregulated 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 pathogenic variant identified in SCDO3 is conserved in all known fringe proteins, from Drosophila melanogaster to humans [Correia et al 2003]. The resultant mutated LFNG protein does not localize correctly within the cell, is unable to modulate Notch signaling, and is enzymatically inactive [Sparrow et al 2006].

HES7

Gene structure. This is a four-exon gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Homozygosity for a pathogenic missense variant, 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 5.

Table 5.

HES7 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.73C>Tp.Arg25TrpNM_032580​.2
NP_115969​.2

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. HES7 encodes a 225-amino acid protein that belongs to the bHLH superfamily of DNA-binding transcription factors. HES proteins (and HEY, encoded by HEY1 and HEY2) belong to the bHLH superfamily of more than 125 DNA-binding transcription factors. HES superfamily proteins are characterized by the following:

  • "b" (basic) domain for DNA-binding to E-box sequences
  • HLH portion for homo- and heterodimerization between members of the superfamily
  • Conserved domain carboxy-terminal to bHLH
  • Carboxy-terminal tetrapeptide (WRPW in HES)
  • Conserved proline residue in the basic domain that changes DNA-binding-site specificity to N-box sequences

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).

Abnormal gene product. The c.73C>T pathogenic variant 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.

TBX6

Gene structure. TBX6 is an eight-exon gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Heterozygosity for an extension variant, c.1311A>T (p.Ter437CysextTer81), was found in the proband and two other affected individuals in the family and its pathogenicity was supported by functional studies [Sparrow et al 2013b]. See Table 6.

Table 6.

TBX6 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1311A>Tp.Ter437CysextTer81NM_004608​.3
NP_004599​.2

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TBX6 encodes a 436-amino acid protein that belongs to the T-box superfamily of DNA-binding transcription factors [Ghosh et al 2017]. The T-box is necessary and sufficient for sequence-specific DNA binding and all members bind to the DNA consensus sequence TCACACCT. During somite formation, Tbx6 activates the Dll1 (ligand of the Notch1 receptor) and Mesp2 promoters (target of Notch1 signalling) [Hofmann et al 2004].

In mouse, Tbx6 is required for specification of paraxial mesoderm; this is absent and replaced by neural-tube-like structures in Tbx6 homozygous null embryos [Chapman & Papaioannou 1998]. Embryos heterozygous null for Tbx6 have vertebral defects with incomplete penetrance [Sparrow et al 2013b].

Abnormal gene product. The c.1311A>T extension variant, p.Ter437CysextTer81, results in loss of the translation stop codon and the addition of 81 amino acids. TBX6 p.Ter437CysextTer81 has reduced transcriptional activating activity compared with the wild type TBX6 [Sparrow et al 2013b]. The additional 81 amino acids added to the C-terminal may affect the ability of TBX6 to interact with other proteins that are critical in vertebral formation, such as MESP2 and RIPPLY2 [Hitachi et al 2008; Kawamura et al 2008].

RIPPLY2

Gene structure. RIPPLY2 is a four-exon gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Compound heterozygous variants were identified in the proband: a maternal nonsense variant, c.238A>T (p.Arg80Ter) and a paternal c.240-4T>G, which lies in the highly conserved splice site consensus sequence 5′ to the terminal exon [McInerney-Leo et al 2015]. Functional studies support pathogenicity of c.238A>T (p.Arg80Ter). The pathogenicity of c.240-4T>G has not been tested.

Table 7.

RIPPLY2 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.238A>T
c.240-4T>G
p.Arg80TerNM​_001009994
NP_001009994​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RIPPLY2 encodes a 128 amino acid protein. RIPPLY proteins contain:

  • A tetrapeptide WRPW motif required for interaction with the transcriptional repressor Groucho;
  • A carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression.

RIPPLY proteins are negative regulators of T-box proteins (including TBX6), converting them from transcriptional activators to repressors [Kawamura et al 2008]. RIPPLY proteins simultaneously bind to the DNA binding domain of T-box proteins (via their Ripply homology domain), and to Groucho/TLE transcriptional corepressor proteins (via the highly conserved tetrapeptide WRPW motif in their amino terminal region) [Kawamura et al 2005].

Abnormal gene product. The p.Arg80Ter pathogenic variant results in loss of protein function [McInerney-Leo et al 2015].

References

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.

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 determine which individuals are most suitable for genetic testing.

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Chapter Notes

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), Neil Whittock, and recently Melissa Sloman, 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 individuals with segmentation defects of the vertebrae (SDV), 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.

Author History

Sally Dunwoodie, PhD (2017-present)
Melissa Sloman, BSc (2017-present)
Peter D Turnpenny, BSc, MB, ChB, FRCP, FRCPCH, FRCPath (2009-present)
Elizabeth Young, PhD; Royal Devon & Exeter NHS Foundation Trust (2009-2017)

Revision History

  • 21 December 2017 (sw) Comprehensive update posted live
  • 17 January 2013 (me) Comprehensive update posted live
  • 14 October 2010 (cd) Revision: sequence analysis and prenatal testing available clinically for pathogenic variants in HES7
  • 25 August 2009 (et) Review posted live
  • 6 February 2009 (pdt) Original submission
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