In 1938, Jarcho and Levin first described a syndrome of mal- formations with abnormal fusion of thoracic vertebrae and ribs associated with a short trunk and respiratory insufficiency. At present, Jarcho-Levin syndrome is an eponym used to describe a variety of clinical phenotypes, consisting of short-trunk dwarfism associated with rib and vertebral anomalies. Two phenotypic sub- types of spondylothoracic dysplasia and spondylocostal dysosto- sis have recently been proposed.
GENETICS/BASIC DEFECTS
1. Inheritance and molecular defects
a. Presence of considerable genetic heterogeneity with var- ied clinical presentations and associated abnormalities b. Spondylothoracic dysplasia
i. Autosomal recessive inheritance ii. Linked to chromosome 2q32.1 iii. No mutations found in the DLL3 gene c. Spondylocostal dysostosis
i. Inheritance: either autosomal recessive or auto- somal dominant
ii. Mutations in the Delta-like 3 (DLL3) gene on chromosome 19q13.1-q13
a) As the major cause of autosomal recessive spondylocostal dysostosis
b) DLL3 encodes a ligand in the Notch gene sig- nal pathway. When mutated, defective somi- togenesis occurs resulting in a consistent and distinctive pattern of abnormal vertebral seg- mentation affecting the entire spine
iii. Mutated MESP2 gene that codes for a basic helix-loop-helix transcription factor was found to cause spondylocostal dysostosis in one con- sanguineous family with two affected children (linkage to 15q21.3-15q26.1)
2. Pathogenesis
a. Vertebral anomalies: probably attributed to defective segmentation of the somite at about the 4th or 5th week of intrauterine life
b. Costal anomalies: probably secondary to the vertebral anomalies
c. Pax1 and Pax9 might be required for the phenotypic expression of Jarcho-Levin syndrome
CLINICAL FEATURES
1. Spondylothoracic dysplasia
a. Vertebral segmentation and formation defects throughout cervical, thoracic, and lumbar spine
i. Hemivertebrae ii. Block vertebrae iii. Unsegmented bars
b. Fusion of all the ribs at the costovertebral joints bilaterally
c. Absence of intrinsic rib anomalies d. Other clinical features
i. Short-trunk dwarfism ii. Craniofacial features
a) Brachycephaly b) Low posterior hairline c) Prominent nasal bridge d) High-arched palate iii. Short and rigid neck
iv. Short thorax
v. Protuberant abdomen
vi. Inguinal and umbilical hernias vii. Urinary tract abnormalities viii. Talipes equinovarus
e. Prognosis: poor but not an invariably lethal condition with 56% of survival among the prospectively evalu- ated patients
i. Normal intelligence
ii. Respiratory complications such as pneumonia iii. Congestive heart failure
iv. Pulmonary hypertension 2. Spondylocostal dysostosis
a. Constitutes a heterogeneous group of radiologic phe- notypes with axial skeletal malformations
b. Generally milder phenotype
c. Multiple vertebral segmentation and formation defects d. Typical findings
i. Intrinsic asymmetric rib anomalies a) Broadening
b) Bifurcation c) Fusion
ii. No symmetric fusion of the ribs
iii. Do not display a fan-like configuration of the thorax iv. No cervical spine anomalies in some patients
v. Short-trunk dwarfism e. Associate anomalies
i. Congenital heart disease ii. Urogenital and anal anomalies iii. Limb abnormalities
iv. Torticolis
v. Diaphragmatic, umbilical, and inguinal hernias f. Prognosis
i. A good prognosis, due in part to the asymmetry of the thoracic anomalies resulting in a less restric- tive thorax
ii. Normal intelligence
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Spondylothoracic dysplasia
i. Bilateral fanning of the ribs with posterior
fusion, giving the appearance of a common ori-
gin of ribs at the posterior thoracic spine
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ii. A decreased number of cervical, thoracic, and lumbar vertebrae
iii. Multiple vertebral segmentation and formation defects
a) Block and wedge vertebrae b) Unsegmented bars
c) Hemivertebrae
d) Anterior–posterior–lateral failure of closure b. Spondylocostal dysostosis
i. Multiple vertebral formations and segmentation defects along the entire spine
a) A decreased number of cervical, thoracic, and lumbar vertebrae
b) Block and wedge vertebrae c) Agenesis of the coccygeal region
d) Progressive scoliosis of the thoracic spine due to tethering effect secondary to the rib anomalies
ii. Asymmetric rib malformations
2. Reconstructed tridimensional CT scan of the chest a. Spondylothoracic dysplasia
i. Bilateral rib fusion at the costovertebral junction ii. Segmentation and formation defects in all cervical, thoracic, and lumbar vertebrae. Sacrococcygeal regions are spared from any abnormality
iii. Increase in the coronal diameter of the thoracic and lumbar vertebrae, which acquire a sickle- like appearance
b. Spondylocostal dysostosis
i. Varying extent of the thoracic fusion
ii. Thoracic fusion always asymmetric with respect to each side of the thorax
iii. Increase in the coronal diameter of the thoracic and lumbar vertebrae, which acquire a sickle- like appearance
3. Pulmonary function tests for restrictive lung disease 4. Molecular genetic analysis: DLL3 mutations in spondylo-
costal dysplasia (homozygous or compound heterozygous mutations)
GENETIC COUNSELING
1. Recurrence risk
a. Autosomal recessive inheritance (spondylothoracic dysplasia and spondylocostal dysostosis)
i. Patient’s sib: 25%
ii. Patient’s offspring: not increased unless the spouse is also a carrier, in which case there is a 50% risk of having an affected offspring b. Autosomal dominant inheritance (spondylocostal
dysostosis)
i. Patient’s sib: not increased unless a parent is affected in which case, there is a 50% risk of having an affected sibling
ii. Patient’s offspring: 50%
2. Prenatal diagnosis a. Ultrasonography
i. Grossly distorted thoracic and lumbar spine ii. Marked kyphoscoliosis
iii. Multiple vertebral segmentation anomalies
iv. Fanned ribs
v. A small chest with foreshortened spine vi. Increased fetal nuchal translucency thickness b. Molecular genetic diagnosis of DLL3 gene mutation
is available clinically by sequencing the entire coding region of fetal DNA obtained from amniocytes or CVS, provided the disease-causing allele has been previously identified.
3. Management
a. Minimize positive end-expiratory pressure to avoid bronchopulmonary dysplasia
b. Continuous feeding instead of in boluses to avoid stomach distension that will lead to increase diaphrag- matic pressure
c. Aggressive treatment of infections d. Treat the spinal deformities
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Fig. 1. Two infants with spondylocostal dysostosis with typical crab- like deformities of the chest with fused ribs (radiographs).
Fig. 2. Radiographs of another infant with spondylocostal dysostosis showing fused ribs and fused vertebrae.
Fig. 3. Radiograph of an infant with spondylothoracic dysplasia showing severe chest deformity.
