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.

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). 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. All vertebrae show at least some relatively mild segmentation abnormality.

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. 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. 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.

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

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 biallelic pathogenic variants in one of the genes listed in Table 1 identified 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 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.

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.

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:

• "Costovertebral dysplasia" [Norum & McKusick 1969, Cantú et al 1971, David & Glass 1983] is used less often today.
• "Spondylothoracic dysostosis/dysplasia," first used by Moseley & Bonforte [1969], is recognized as being distinct from SCDO (see Differential Diagnosis).

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.

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. 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.

Genetically Related (Allelic) Disorders

DLL3, LFNG, HES7. No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in these genes.

MESP2. Spondylothoracic dysostosis (STD), despite similarities to AR SCDO, has distinctive phenotypic features that warrant this separate designation. Infants with STD are at the highest risk for respiratory insufficiency and have a nearly 50% mortality rate by the end of infancy [Cornier et al 2004]. To date, most individuals reported with STD have had pathogenic nonsense variants in exon 1 of MESP2, which are predicted to result in nonsense-mediated decay; however, several affected individuals are heterozygous for a pathogenic nonsense variant and a pathogenic missense variant [Cornier et al 2008] (see Figure 11). STD occurs most frequently in Puerto Ricans of Spanish descent [Alberto Cornier, personal communication], presumably as a result of the MESP2 founder variant, p.Glu103Ter; in this population the phenotype has sometimes been known as Jarcho-Levin syndrome [Jarcho & Levin 1938] but the most appropriate eponymous designation is Lavy-Moseley syndrome [Berdon et al 2011]. Note: The original individuals reported by Jarcho and Levin were not Puerto Rican and the radiologic phenotype was distinct from that seen in MESP2-associated STD [Berdon et al 2011] (see also Nomenclature).

Figure 11.

An infant with spondylothoracic dysostosis (STD), caused by pathogenic variants in MESP2. STD is relatively common in Puerto Rican Indians because of a founder variant. The spine is severely shortened with fusion of the ribs posteriorly at the costovertebral (more...)

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

• More severe shortening of the spine (all vertebral segments affected), especially the thoracic spine, leading to impaired respiratory function in infancy
• Rib fusions typically occurring posteriorly at the costovertebral origins, where the spinal shortening is most severe. The ribs usually appear straight and neatly aligned without points of fusion along their length. On antero-posterior x-ray the ribs characteristically "fan out" from their costovertebral origins in a "crab-like" fashion.
• A distinctive radiographic appearance called the "tramline sign" that results from early radiographic prominence of the vertebral pedicles, in contrast to the vertebral bodies which have no regular form or layout [Turnpenny et al 2007]

TBX6. Information on a range of phenotypes associated with TBX6 pathogenic variants is emerging. This gene has been clearly associated with AD SCDO [Sparrow et al 2013b, Lefebvre et al 2017], and with variable segmentation anomalies, most commonly affecting the lower thoracic or upper lumbar regions and usually presenting as congenital scoliosis. This may be due to deletion of the gene on one allele and a high-risk haplotype of polymorphisms on the other allele [Wu et al 2015, Takeda et al 2017]. At the severe end of the spectrum a distinct, lethal form of spondylothoracic dysostosis occurs with müllerian duct anomalies [P Turnpenny, unpublished data]. TBX6 is also implicated in individuals with müllerian aplasia / MURCS association / Mayer-Rokitansky-Küster-Hauser syndrome [Sandbacka et al 2013].

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 EU Clinical Trials Register 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.

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 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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 testing 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.

Molecular 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.

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

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.

Literature Cited

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