Spondylocostal Dysostosis, Autosomal Recessive

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 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.

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