3 The Genetics of Congenital Scoliosis and Abnormal Vertebral Segmentation

Before the modern molecular era, genetic analyses were often undertaken as epidemiologic studies, leading to the detailed assembly of empiric data that would allow analysis of possible inheritance patterns and recurrence risks for the purpose of genetic counseling. In the field of infantile idiopathic scoliosis, Wynne-Davies examined 134 infants and their first-degree relatives and found that approximately 3% of parents and 3% of siblings had the same, or a similar, deformity. ¹ Congenital heart disease was present in 2.5% (the general population incidence is ~6 per 1,000 live births) and mental retardation in 13%, suggesting that a significant proportion of children had a syndromic form of congenital scoliosis (CS). Erol et al studied 81 patients with different forms of CS and segmentation defects of the vertebrae (SDV); of 39 patients prospectively recruited into study, 15 (38%) were found to have multiple-organ/syndromic associations, many of which fit into the oculo-auriculo-vertebral (OAV) (or Goldenhar) spectrum. ² Purkiss et al studied 237 patients with CS and identified 49 patients who had two or more family members with either congenital or idiopathic scoliosis, suggesting a much higher recurrence rate of 20.7%. ³ There was also a history of idiopathic scoliosis in 17.3% of the families. Maisenbacher et al reported that 10% of patients with CS reported having first-degree relatives with idiopathic scoliosis. ⁴ These risk data are diverse, and there is a need for more studies with clearer phenotypic stratification.

Table 3.1 lists rare syndromes that may include CS and/or SDV, along with the genetic basis, if known. Most are very rare, and those most commonly encountered in clinical practice are OAV/Goldenhar spectrum, VATER or VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb) association, MURCS (müllerian duct, renal aplasia, cervicothoracic somite dysplasia) association, and maternal diabetes syndrome. The pathogenesis of these broad clinical groups is poorly understood. Any case series presenting to the spinal surgeon, pediatrician, or geneticist will demonstrate enormous radiologic and structural heterogeneity, and a syndromic or genetic diagnosis will be at best vague (including the OAV/VACTERL/MURCS associations because the cause[s] of these groups is unknown) and at worst completely elusive. Table 3.1 is a reminder that young (and not so young) patients presenting with CS/SDV should be examined and investigated very thoroughly for additional anomalies and a syndrome diagnosis considered. Referral to a clinical geneticist should therefore be part of the patient care pathway.

Although CS is frequently associated with SDV, this is not always so, and it may occur in severe forms of some syndromes in which segmentation anomalies are absent, although abnormalities of vertebral formation may be present. A presentation of this kind should prompt consideration of a diagnosis of one of the skeletal dysplasias, although a precise radiologic diagnosis may require follow-up skeletal surveys as the child grows and generalized bone growth evolves. A clinical genetics opinion with a view to genetic testing may be very helpful, and examples include the following: congenital contractural arachnodactyly (Beals syndrome), which is autosomal dominant and due to mutations in FBN2; chondrodysplasia punctata, Conradi–Hünermann type (Happle syndrome), which is X-linked and due to mutations in the EBP gene; diastrophic dysplasia, which is autosomal recessive and due to mutations in the sulfate transporter gene SLC26A2 (also known as DTDST); and spondylometaphyseal dysplasia, Kozlowski type, which is autosomal dominant and due to mutations in TRPV4.

3.2 Terminology

At this point, it is necessary to explain the use of terms, which in clinical practice is very inconsistent and confusing. The term spondylocostal dysostosis (SCD) has been, and continues to be, applied to a wide variety of radiologic phenotypes in which abnormal segmentation is evident, together with rib involvement. For the purposes of this review, however, the definition given in Table 3.2 is used. A number of attempts have been made to classify SDV. The scheme proposed by Mortier et al combines phenotype and inheritance pattern (Table 3.3). ²² The scheme proposed by Takikawa et al allows a very broad definition of SCD (Table 3.4), ²³ but both these schemes identify Jarcho–Levin syndrome ²⁴ with a crablike chest, which on more detailed scrutiny is misapplied. The surgical approach to classification of McMaster and Singh distinguishes between formation and segmentation errors (Table 3.5). ²⁵ Like the scheme of McMaster and Singh, the classification scheme for vertebral abnormalities of Aburakawa et al, ^{23 ,​ 26} which includes vertebral morphology (Table 3.6), does not attempt to identify phenotypic patterns of malformation based on assessment of the spine as a whole. Vertebral fusion or segmentation errors involving the cervical region, Klippel–Feil anomaly, has been subclassified (Table 3.7), ^{27 ,​ 28} and Clarke et al (Table 3.8) proposed a further, detailed classification combining modes of inheritance. ²⁹ The use of a limited number of terms in these classification schemes fails to reflect the great diversity of radiologic SDV phenotypes seen in clinical practice, and the schemes do not incorporate knowledge from molecular genetics. Furthermore, the diversity of SDV is not captured within the classification of osteochondrodysplasias. ^{30 ,​ 31} A new scheme for classification and reporting from the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) is described later.

Table 3.2 Proposed definitions for the terms spondylocostal dysostosis and spondylothoracic dysostosis ⁷²

Features	Spondylocostal dysostosis	Spondylothoracic dysostosis
General	No major asymmetry to chest shape Mild, nonprogressive scoliosis Multiple SDV (M-SDV; >10 contiguous segments) Absence of a bar Malaligned ribs with intercostal points of fusion	Chest shape symmetric, with ribs fanning out in a “crablike” appearance Mild, nonprogressive scoliosis or no scoliosis Generalized SDV (G-SDV) Regularly aligned ribs, fused posteriorly at the costovertebral origins, but no points of intercostal fusion
Specific, descriptive	“Pebble beach” appearance of the vertebrae in early childhood radiographs (Fig. 3.1)	“Tramline” appearance of prominent vertebral pedicles in early childhood radiographs, not seen in SCD (Fig. 3.2) “Sickle cell” appearance of vertebrae on transverse imaging 40
Abbreviations: SCD, spondylocostal dysostosis; SDV, segmentation defects of the vertebrae.

Table 3.3 Previously proposed classification of segmentation defects of the vertebrae according to Mortier et al ²²

Nomenclature	Definition
Jarcho–Levin syndrome	Autosomal recessive Symmetric crablike chest Lethal
Spondylothoracic dysostosis	Autosomal recessive Intrafamilial variability, severe/lethal Associated anomalies uncommon
Spondylocostal dysostosis	Autosomal dominant Benign
Heterogeneous group	Sporadic Associated anomalies common

Table 3.4 Previously proposed classification / definition of segmentation defects of the vertebrae according to Takikawa et al ²³

Nomenclature	Definition
Jarcho–Levin syndrome	Symmetric crablike chest
Spondylocostal dysostosis	More than two vertebral anomalies associated with rib anomalies (fusion and/or absence)

Table 3.5 Classification (surgical/anatomical) of vertebral segmentation abnormalities causing congenital kyphosis/kyphoscoliosis according to McMaster and Singh ²⁵

Type	Anatomical deformity	Anomalies
I	Anterior failure of vertebral body formation	Posterolateral quadrant vertebrae Single vertebra Two adjacent vertebrae Posterior hemivertebrae Single vertebra Two adjacent vertebrae Butterfly (sagittal cleft) vertebrae Anterior or anterolateral wedged vertebrae Single vertebra Two adjacent vertebrae
II	Anterior failure of vertebral body segmentation	Anterior unsegmented bar Anterolateral unsegmented bar
III	Mixed	Anterolateral unsegmented bar Contralateral posterolateral quadrant vertebrae
IV	Unclassifiable

Table 3.6 Classification of vertebral segmentation abnormalities ^{23 ,​ 26} (modified North American classification)

Failure of formation
Type I
A. Double pedicle
B. Semisegmented
C. Incarcerated
Type II
D. Not incarcerated, no lateral shift
E. Not incarcerated, plus lateral shift
Type III
F. Multiple
Type IV
G. Wedge
H. Butterfly
Failure of segmentation
I. Unilateral bar
J. Complete block
K. Wedge (plus narrow disk)
Mixed
L. Unilateral bar plus hemivertebra
M. Unclassifiable
Note: Hemivertebrae are seen in types B through F and in type L.

Table 3.7 Classification of Klippel–Feil anomaly, referring to segmentation defects or fusion of the cervical vertebrae, according to Feil and Thomsen ^{27 ,​ 28}

Type	Site	Anomaly
I	Cervical and upper thoracic vertebrae	Massive fusion with synostosis
II	Cervical vertebrae	One or two interspaces only, hemivertebrae, occipito-atlantoid fusion
III	Cervical and lower thoracic or lumbar vertebrae	Fusion

Table 3.8 Classification of Klippel–Feil anomaly according to Clarke et al ²⁹ (adapted from original publication)

Class	Vertebral fusions	Inheritance	Possible anomalies
KF1	Only class with C1 fusions C1 fusion not dominant Variable expression of other fusions	Recessive	Very short neck; heart, urogenital, craniofacial, hearing, limb, digital, ocular defects Variable expression
KF2	C2-C3 fusion dominant C2-C3 most rostral fusion Cervical, thoracic, and lumbar fusion variable within a family	Dominant	Craniofacial, hearing, otolaryngeal, skeletal, and limb defects Variable expression
KF3	Isolated cervical fusions Variable position Any cervical fusion except C1	Recessive or reduced penetrance	Craniofacial, facial dysmorphology Variable expression
KF4	Fusion of cervical vertebrae, data limited	Possibly X-linked Predominantly females affected	Hearing and ocular anomalies: abducens palsy with retraction bulbi, also called Wildervanck syndrome

According to the definition used here, SCD is a condition characterized by a short trunk and short stature due to multiple or generalized SDV (M-SDV or G-SDV), usually accompanied by rib fusions and/or malalignment. A mild, nonprogressive kyphoscoliosis is present, usually without additional organ abnormalities. Five Notch signaling pathway genes are now linked to this group, four demonstrating autosomal recessive inheritance and one autosomal dominant inheritance. These are now described in more detail, and Table 3.9 summarizes the conditions and their genes.

Table 3.9 Genes causing generalized segmentation defects of the vertebrae (i.e., “spondylocostal dysostosis”) according to the definition proposed in Table 3.2

Gene symbol	Chromosomal locus	Protein name
DLL3	19q13.1	Delta-like protein 3
MESP2	15q26.1	Mesoderm posterior protein 2
LFNG	7p22	Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe
HES7	17p13.2	Transcription factor HES-7
TBX6	16p11.2	DNA-binding protein T-BOX-6

In clinical practice, patients with abnormal vertebral segmentation, usually with only regional or very limited involvement of the spine, are much more commonly seen than patients with the rare monogenic forms, which perhaps affect 1 in 1,000 newborns. They are likely to occur sporadically, demonstrate more asymmetry, and be associated with other organ malformations.

Related posts:

2 Development of the Spine 1 Frontier of the Impossible 4 Respiratory Implications of Abnormal Development of the Spine 18 Surgical Treatment and Outcomes 22 Nonoperative Treatment of Syndromic Scoliosis 12 Dual Growing Rod Treatment

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