Table 1 Genes associated with pathogenesis of some VMs syndromes [40, 155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181, 224]. C–cervical, Th–thoracic, L–lumbar, SD–skeletal deformities, N/A–not applicable, ND–not determined, VBs–vertebral bodies, VMs–vertebral malformations

ACVR1

102576

Fibrodysplasia ossificans progressiva

C VMs

SD (short thumbs, fifth finger clinodactyly, short broad femoral necks), deafness, mild mental retardation

AFF4

604417

CHOPS syndrome

C VMs (ND)

Cardiac defects (VSD, patent ductus arteriosus), intellectual disability, chronic lung disease, obesity, brachydactyly, horseshoe kidney, dysmorphic facial features, tracheomalacia, subglottic and tracheal stenosis, cryptorchidism, hearing loss

ARSL

300180

Chondrodysplasia punctata, X-linked recessive

Platyspondyly

Craniofacial anomalies, brachycephaly, foot syndactyly, limbs abnormalities

COL11A1

120280

Fibrochondrogenesis 1, Marshall syndrome, Stickler syndrome, type II

Platyspondyly

Flat midface with a small nose and anteverted nares, shortening of limb segments

COL2A1

120140

Kniest dysplasia

Platyspondyly

Coronal clefts, slight shortening of the ribs, dumbbell-shaped femurs

DDRGK1

616177

Spondyloepimetaphyseal dysplasia, Shohat type

Platyspondyly, hypoplasia of L vertebrae, square vertebrae

SD (long bone changes, short neck, L lordosis, limb shortening), hyperlaxity of joints

EBP

300205

Chondrodysplasia punctata, X-linked dominant

Hemivertebrae

SD (asymmetric rhizomelia, epiphyseal stippling),cataracts

FN1

135600

Spondylometaphyseal dysplasia, corner fracture type

Asymmetric vertebral pedicles, hypoplasia of Th12, ovoid VBs, irregular vertebrae

SD (thoracolumbar scoliosis, metaphyseal dysplasia, short stature)

GDF11

603936

Vertebral hypersegmentation and orofacial anomalies

C, Th, L vertebrae hypersegmentation

SD (rib abnormalities, hypermobile joints, winged scapulae), orofacial anomalies, ear anomalies

GPC3

300037

Simpson-Golabi-Behmel syndrome, type 1

Th hemivertebrae

Sprengel’s deformity

GPC4

300168

Keipert syndrome

VMs (ND)

Ribs, sternum, pelvis abnormalities

HSPG2

142461

Dyssegmental dysplasia, Silverman-Handmaker type

Anisospondyly

Neonatal short-limbed dwarfism

INPPL1

600829

Opsismodysplasia

Platyspondyly

SD (short hands/feet, short long bones, bony under mineralization, short and square metacarpals and phalanges, L kyphosis, narrow chest, small and cupped pubic bones), Eye defects (hypertelorism, proptosis/shallow orbits)

JAG1

601920

Alagille syndrome 1

Butterfly vertebra,

Decrease in interpediculate distance in the lumbar spine

Eye defects (posterior embryotoxon and retinal pigmentary changes), heart defects (pulmonic valvular stenosis, peripheral arterial stenosis), nervous system abnormalities, facial dysmorphism (broad forehead, pointed mandible and bulbous tip of the nose and in the fingers, varying degrees of foreshortening)

KIAA0586

610178

Short-rib thoracic dysplasia 14 with polydactyly

Th6 butterfly vertebra

SD (small chest with short ribs, bilateral hand post-axial polydactyly, short limbs), cleft palate, lower gingiva clefts, vision defects (papillary coloboma and atrophy of the choroid-retinal inferopapillary)

KIAA1217

617367

N/A

C, Th fusion, hemivertebrae, wedged-shape vertebrae

SD (Sprengel deformity), cardiac defects (ASD, VSD, dextrocardia, myocarditis), central nervous system abnormalities (hydrocephalus, macrocephaly, tethered cord, cerebellar tonsillar prolapse into spinal canal, basilar invagination)

LBR

600024

Rhizomelic skeletal dysplasia with Pelger-Huet anomaly

Platyspondyly and ovoid VBs

SD (short limbs, shortened ribs)

NADSYN1

608285

Vertebral, cardiac, renal, and limb defects syndrome 3

Butterfly vertebra, hemivertebra, L, Th wedge-shaped vertebra

Rib abnormalities, heart defects (mitral insufficiency, bicuspid aortic valve, mitral valve prolapse), renal aplasia, diastematomyelia, tethered cords, hepatic polycysts

NOTCH2

600275

Hajdu-Cheney Syndrome

Increased anterior height of the L VBs with reduced intervertebral distances

SD (wormian bones, serpentine fibulae, bathrocephaly, irregular tooth positioning, abnormal curvature of the C spine), polycystic kidneys, ventricular septal defect, facial dysmorphism (a thin upper lip, downturned mouth, wide nasal tip, long and flat philtrum, dysplastic and posteriorly rotated ears, and short neck), hearing loss, hypothyroidism

NSDHL

300275

CHILD syndrome

VMs (ND)

Absence of several facial muscles, shortening of right leg, VSD

PDE4D

600129

Acrodysostosis 2, with or without hormone resistance

L stenosis (absence of normal interpedicular widening in the lumbar vertebrae)

SD (short stature, small hands, midface hypoplasia), developmental disability

POGZ

614787

White-Sutton syndrome

Hypoplasia of the C VBs

Short stature, microcephaly, non-ocular visual impairment, failure to thrive, diaphragmatic hernia, a duplicated renal collecting system

SLC26A2

606718

Achondrogenesis Ib Atelosteogenesis, type II

De la Chapelle dysplasia

Deficient ossification in the L vertebrae, C kyphosis, scoliosis, and lumbar hyperlordosis with horizontal sacrum, flattened vertebrae with coronal clefts

SD (shortened limbs, small chest, clubfoot), respiratory insufficiency

SLC29A3

602782

H Syndrome

“Sandwich” vertebrae and platyspondyly

Anemia, bilateral femoral fractures

SLC35D1

610804

Schneckenbecken dysplasia

Retardation of the VBs ossification

SD (handle bar clavicle, bell shaped thorax, ossification of the posterior arch, interpediculate distance narrowing, sacral, pubic, tarsal ossification)

SOX9

608160

Campomelic dysplasia

Hypoplastic pedicles of Th vertebrae

SD (very small scapulas, dislocated hips, talipes equinovarus deformities, small thoracic cage), respiratory distress, renal and heart malformations

SUMF1

607939

Multiple sulfatase deficiency

VMs (ND)

Bilateral cataracts, retinal atrophy, ichthyosis, hepatosplenomegaly, psychomotor retardation

TNFRSF11A

602080

Paget disease of bone 2, early-onset

“Sandwich” vertebra

Osteoporosis

TRPV4

605427

Spondylometaphyseal dysplasia

Platyspondyly, dense wafer vertebrae

SD (congenital scoliosis, rib abnormalities, flared iliac wings, halberd pelvis, irregular proximal femoral growth plate, brachydactyly, carpal ossification delay), contracture