Classification and Etiologic Dissection of Vertebral Segmentation Anomalies


Syndromes/disorders

OMIM

Gene

Acrofacial dysostosisa

263750
 
Alagille syndrome

118450

JAG1, NOTCH2

Anhalta

601344
 
Atelosteogenesis III

108721

FLNB

Campomelic dysplasia

211970

SOX9

Casamassima-Morton-Nancea

271520
 
Caudal regressiona

182940
 
Cerebro-facio-thoracic dysplasiaa

213980
 
CHARGE syndrome

214800

CHD7

‘Chromosomal’
  
Currarino

176450

HLXB9

Atelosteogenesis, type II (de la Chapelle syndrome)

256050

SLC26A2

DiGeorge/deletion 22q11.2/velocardiofacial syndrome

188400
 
Dysspondylochondromatosisa
  
Femoral hypoplasia-unusual faciesa

134780
 
Fibrodysplasia ossificans progressiva

135100

ACVR1

Fryns-Moermana
  
Goldenhar/OAV Spectruma

164210
 
Holmes-Schimkea
  
Incontinentia pigmenti

308310

IKBKG

Kabuki syndrome

147920

MLL2

McKusick-Kaufman syndrome

236700

MKKS

KBG syndrome

148050

ANKRD11

Klippel-Feila

148900

GDF6, GDF3, MEOX1

PAX1 b

Larsen syndrome

150250

FLNB

Lower mesodermal agenesisa
  
Maternal diabetes mellitusa
  
MURCS associationa

601076
 
Multiple pterygium syndrome

265000

CHRNG

OEIS syndromea

258040
 
Phavera

261575
 
RAPADILINO syndrome (RECQL4-related disorders)

266280

RECQL4

Robinow (ROR2-related disorders)

180700

ROR2

Rolland-Desbuquoisa

224400
 
Rokitansky sequencea

277000

WNT4 b

Silverman-Handmaker type of dyssegmental dysplasia (DDSH)

224410

HSPG2

Simpson-Golabi-Behmel syndrome

312870

GPC3

Sirenomeliaa

182940
 
Spondylocarpotarsal synostosis

272460

FLNB

Thakker-Donnaia

227255
 
Torielloa
  
Uriostea
  
VATER/VACTERLa

192350
 
Verloove-Vanhoricka

215850
 
Wildervancka

314600
 
Zimmera

301090
 

aUnderlying cause not known

bPossible associations reported: PAX1 [6]; WNT4 [7]



Although CS is frequently associated with SDV this is not always so and CS may occur in the absence of segmentation anomalies, though abnormalities of vertebral formation may be present. In cases of this kind a diagnosis of one of the skeletal dysplasias should be considered, though a precise radiological diagnosis may require follow-up skeletal surveys as the child grows. A clinical genetics opinion with a view to genetic testing may be very helpful and examples include: congenital contractural arachnodactyly (aka Beals syndrome), which is autosomal dominant and due to mutations in FBN2; chondrodysplasia punctata, Conradi-Hünermann type (aka 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 sulphate transporter gene SLC26A2 (aka DTDST); and spondylometaphyseal dysplasia, Kozlowski type, which is autosomal dominant and due to mutations in TRPV4.



Spondylocostal Dysostosis, Somitogenesis, and the Notch Signaling Pathway


The main progress in understanding the genetic basis of SDV has come through the study of somitogenesis in animal models , mainly mouse but also chick. Animals with specific gene knockouts are generated and multiple gene expression assays undertaken to help elucidate the developmental pathways. Somitogenesis is the sequential process whereby paired blocks of paraxial mesoderm are patterned and laid down on either side of the midline from the presomitic mesoderm (PSM) to form somites, a process that takes place between days 20–32 of human embryonic development, proceeding in a rostro-caudal direction. In mouse, a pair of somites is formed every 1–3 h, whilst in humans the process is estimated to take 6–12 h based on cell culture models and analysis of staged anatomical collections [8, 9]. Somites ultimately give rise to four substructures—sclerotome , which forms the axial skeleton and ribs; dermotome, which forms the dermis; myotome, which forms the axial musculature and syndetome, which forms the tendons [10, 11]. Somitogenesis begins shortly after gastrulation and continues until the pre-programmed number of somite blocks is formed. In man 31 blocks of paired tissue are formed but the number is species-specific. The establishment of somite boundaries takes place as a result of very finely tuned molecular processes determined by activation and negative feedback interactions between components of the Notch, Wnt and FGF signaling pathways [12, 13] (Fig. 7.1). In the rostral third of the PSM formation of segmental boundaries is subject to levels of the factor FGF8, which is produced in the caudal region of the embryo [14] and which probably maintains cells in an immature state until levels fall below a threshold, allowing boundary formation. Somites already harbour specification toward their eventual vertebral identity, a process regulated by the Hox family of transcription factors [15], which also display oscillatory expression in the mouse during somitogenesis [16].

A305840_1_En_7_Fig1_HTML.gif


Fig. 7.1
The putative relationships between the Notch, Wnt and FGF pathways in somitogenesis. (Adapted from Gibb et al. [13] ©Elsevier)

The Wnt signalling pathway also displays oscillatory expression in a different temporal phase from Notch pathway genes, and plays a key role in the segmentation clock [1719]. The mediators of the determination front and the segmentation clock (Notch, FGF, Wnt) are required for forming the somite boundary and specify rostro-caudal patterning of presumptive somites, for which Mesp2 is crucial [20]. Mesp2 is expressed caudal to the somite which is forming and this domain is set where Notch signalling is active, FGF signalling is absent, and the transcription factor Tbx6 is expressed. Precise periodicity in the establishment of somite blocks is mediated by several so-called ‘cycling’, or ‘oscillatory’, genes, two of which, LFNG and HES7, are implicated in human SCD.

Somites themselves, having formed, are subsequently partitioned into rostral and caudal compartments, with vertebrae formed from the caudal compartment of one somite and the adjacent rostral compartment of the next, a phenomenon that is known as ‘resegmentation’ [2124]. An understanding of the molecular biology of somitogenesis in animal models, in combination with finding patients and families with specific forms, or patterns, of segmentation anomalies, has led to the most definitive progress in understanding the causes of rare mendelian forms of SDV. Ongoing research is identifying more cycling genes and pathways involved in the regulation of somitogenesis .


Varied Use of Clinical Terminology



Spondylocostal Dysostosis


In clinical practice the use of terms for vertebral segmentation abnormalities has been inconsistent and confusing . ‘Spondylocostal dysostosis’ (SCD) continues to be applied to a wide variety of radiological phenotypes where abnormal segmentation is evident together with rib involvement. For this review I use our preferred definition as given in Table 7.2. This restricts use of the term to generalised SDV , which defines the mendelian forms of SCD thus far identified, as summarised in Table 7.3. This is usually a short trunk, short stature condition with multiple/generalised SDV accompanied by rib fusions and/or mal-alignment. A mild, non-progressive kyphoscoliosis is present, usually without additional organ abnormalities. Five Notch signalling pathway genes are now linked to this group, four demonstrating autosomal recessive (AR) inheritance and one autosomal dominant (AD), as described below.


Table 7.2
Proposed definitions for the terms spondylocostal dysostosis (SCD) and spondylothoracic dysostosis (STD) (ICVAS)


































Features

Spondylocostal Dysostosis (SCD)

Spondylothoracic Dysostosis (STD)

General

No major asymmetry to chest shape

Chest shape symmetrical, with ribs fanning out in a ‘crab-like’ appearance

Mild, non-progressive scoliosis

Mild, non-progressive scoliosis, or no scoliosis

Multiple SDV (MSDV) ≥ 10 contiguous segments

Generalised SDV (GSDV)

Absence of a bar

Regularly aligned ribs, fused posteriorly at the costovertebral origins, but no points of intercostal fusion

Mal-aligned ribs with intercostal points of fusion
 

Specific, descriptive

‘Pebble beach’ appearance of vertebrae in early childhood radiographs (Fig. 7.3)

‘Tramline’ appearance of prominent vertebral pedicles in early childhood radiographs, not seen in SCD (Fig. 7.6)

‘Sickle cell’ appearance of vertebrae on transverse imaging [49]



Table 7.3
Genes causing generalised SDV, i.e. ‘spondylocostal dysostosis’ according to the definition proposed in Table 7.2







































SCD

Gene symbol

Chromosomal locus

Protein name

SCD type 1

DLL3

19q13

Delta-like protein 3

SCD type 2 and STD

MESP2

15q26.1

Mesoderm posterior protein 2

SCD type 3

LFNG

7p22

Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe

SCD type 4

HES7

17p13.2

Transcription factor HES-7

SCD type 5

TBX6

16p11.2

T-box6 protein

A number of attempts have been made to classify SDV. The scheme proposed by Mortier et al. [25] combines phenotype and inheritance pattern (Table 7.4). The scheme proposed by Takikawa et al. [26] allows a very broad definition of SCD (Table 7.5), and both these schemes identify Jarcho-Levin Syndrome (JLS) with a ‘crab-like’ chest. McMaster and Singh’s [27] surgical approach to classification (1999) distinguishes between formation and segmentation errors (Table 7.6). As with McMaster’s scheme, Aburakawa’s [28] classification scheme for vertebral abnormalities (1996), which includes vertebral morphology (Table 7.7) , does not attempt to identify phenotypic patterns of malformation based on assessment of the spine as a whole. The use of a limited number of terms in these classification schemes neither reflects the great diversity of radiological SDV phenotypes seen in clinical practice nor incorporates knowledge from molecular genetics . Furthermore, the diversity of SDV is not captured within the classification of osteochondrodysplasias [29, 30]. A new scheme for classification and reporting from the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) is described later .


Table 7.4
Classification of SDV according to Mortier et al. [25]
































Nomenclature

Definition

Jarcho-Levin syndrome

Autosomal recessive

Symmetrical crab-like 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 7.5
Classification/definition of SDV according to Takikawa et al. [26]
















Nomenclature

Definition

Jarcho-Levin syndrome

Symmetrical crab-like chest

Spondylocostal dysostosis

≥ 2 vertebral anomalies associated with rib anomalies (fusion and/or absence)



Table 7.6
Classification (surgical/anatomical) of vertebral segmentation abnormalities causing congenital kyphosis/kyphoscoliosis, according to McMaster and Singh [27]
















































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 7.7
Aburakawa Classification of vertebral segmentation abnormalities [26, 28] (modified North American classification). Note that hemivertebrae are seen in Types B to F, and L













































Failure of formation

Type I

A. Double pedicle

B. Semi segmented

C. Incarcerated

Type II

D. Non incarcerated, no lateral shift

E. Non 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 disc)

Mixed

L. Unilateral bar plus hemivertebra

M. Unclassifiable


Klippel-Feil Syndrome


The term Klippel-Feil anomaly or syndromes (KFS) has a more specific application, even though the phenotypes within the general category are diverse. KFS refers to vertebral fusion or segmentation errors involving the cervical region and has been the subject of several classifications (Table 7.8) [31, 32]. Clarke et al. [33] (Table 7.9) proposed a further, detailed classification combining modes of inheritance. To these clinical classifications must now be added a classification based on the recently discovered gene associations with rare forms of KFS [3436] (Table 7.10). The Pax1 gene has been shown to be active during sclerotome formation and differentiation and mutations were identified in the mouse undulated, suggesting that sclerotome condensation is a Pax1-dependent process [37]. Two studies on patient cohorts with KFS were subsequently undertaken [6, 38] but despite some gene variants being identified in a small number the same variants were either detected in an asymptomatic parent or did not occur in a conserved region of the gene. Overall, the role of PAX1 in KFS remains to be elucidated .


Table 7.8
Classification of Klippel-Feil anomaly, referring to segmentation defects or fusion of the cervical vertebrae, according to Feil [31] and Thomsen et al. [32]
























Type

Site

Anomaly

I

Cervical and upper thoracic

Massive fusion with synostosis

II

Cervical

One or two interspaces only, hemivertebrae, occipito-atlantoid fusion

III

Cervical and lower thoracic or lumbar

Fusion



Table 7.9
Classification of Klippel-Feil anomaly according to Clarke et al. [33]. (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

C2-3 fusion dominant

C2-3 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

Possible X-linked

Predominantly females

Hearing and ocular anomalies—abducens palsy with retraction bulbi

aka Wildervanck syndrome



Table 7.10
Genes associated with Klippelp-Feil syndrome (KFS) [3436]

































KFS

Gene symbol

Chromosomal locus

Encodes

Inheritance

KFS1

GDF6

[aka cartilage-derived morphogenetic protein 2 (CDMP2)]

8q22.1

A member of the bone morphogenetic protein family

AD

KFS2

MEOX1

17q21.31

Homeodomain-containing protein

AR

KFS3

GDF3

12p13.1

A member of the bone morphogenetic protein family

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Sep 18, 2016 | Posted by in ORTHOPEDIC | Comments Off on Classification and Etiologic Dissection of Vertebral Segmentation Anomalies
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