Spondylocostal Dysostosis 1, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spondylocostal dysostosis-1 (SCDO1) is caused by homozygous or compound heterozygous mutation in the DLL3 gene (602768) on chromosome 19q13.

Description

The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. The term 'spondylocostal dysostosis' is best applied to those phenotypes with generalized SDV and a broadly symmetric thoracic cage (summary by Gucev et al., 2010).

Genetic Heterogeneity of Spondylocostal Dysostosis

Other forms of SCDO include SCDO2 (608681), caused by mutation in the MESP2 gene (605195) on chromosome 15q26; SCDO3 (609813), caused by mutation in the LFNG gene (602576) on chromosome 7p22; SCDO4 (613686), caused by mutation in the HES7 gene (608059) on chromosome 17p13; SCDO5 (122600), caused by mutation in the TBX6 gene (602427) on chromosome 16p11; and SCDO6 (616566), caused by mutation in the RIPPLY2 gene (609891) on chromosome 6q14.

Clinical Features

Lavy et al. (1966) observed 4 of 7 offspring of a third-cousin marriage who had characteristic vertebral anomalies including hemivertebrae and block vertebrae accompanied by deformity of the ribs. All affected children died of respiratory infection under 1 year of age. Moseley and Bonforte (1969) described the same disorder in 2 apparently unrelated children of nonconsanguineous Puerto Rican parents. Caffey (1967) described brother and sister with short neck and trunk in contrast to extremities of normal length. Both showed 'hemivertebrae at practically all levels in the spine.' The skeletons were otherwise normal. Norum (1969) observed 4 similar cases in 2 related sibships in an inbred community in eastern Kentucky. Fused ribs also occurred in affected persons. See 122600 for an autosomal dominant form of spondylocostal dysostosis.

Eller and Morton (1970) described similar deformity of the chest and spine, with additional craniolacunia, rachischisis, and urinary tract anomalies, in the offspring of a woman who admitted to a single exposure to LSD about the time of conception.

Cantu et al. (1971) described 5 cases in an inbred kindred. Castroviejo et al. (1973) reported spondylothoracic dysplasia in 3 Spanish sisters who showed the typically short thorax, short neck with limited mobility, winged scapulae, and scoliosis or kyphoscoliosis. Particularly noteworthy were the vertebral anomalies, including hemivertebrae and vertebral fusions affecting the whole vertebral column. Rib abnormalities in form and number were seen. One sister showed decreased mental function and another showed incompletely formed odontoid process. Bartsocas et al. (1974) described 3 affected sibs (2 of them identical twin sisters). Satar et al. (1992) described this disorder in identical twins whose parents were first cousins. Van Thienen and Van der Auwera (1994) described monozygotic twins discordant for this syndrome, either due to a postzygotic mutation or to a phenocopy.

Jarcho and Levin (1938) are credited with first describing this syndrome, in a black brother and sister in Baltimore, but they mistakenly spoke of the condition as the same as the Klippel-Feil syndrome (118100). Perez-Comas and Garcia-Castro (1974) described 6 cases in Puerto Ricans, including 2 affected sibs. Their designation, occipito-facial-cervico-thoracic-abdomino-digital dysplasia, seems in the first place ridiculously long, but really unwarranted since all changes seem to be secondary or tertiary to the primary changes in the spine. Several authors refer to a typical 'crab-like' radiologic appearance of the thoracic skeleton. Conceivably the early lethal form represented by the cases of Jarcho and Levin (1938) and the cases with survival to a later age, e.g., the cases of Norum (1969) and Cantu et al. (1971) are produced by homozygosity for alleles at the same locus. Devos et al. (1978) described associated abnormalities of ureters and renal pelvis.

Gassner and Grabs (1982) described 8 affected persons in 4 interrelated families. One also had Down syndrome and died at the age of 7 days. The others showed no decrease in life expectancy and no other malformations. Autosomal recessive inheritance was well documented. Young and Moore (1984) reported a case in a child of first-cousin parents. They claimed it to be the first report of the condition in the United Kingdom. Cassidy et al. (1984) reported observations on a Puerto Rican child living in Connecticut. Giacoia and Say (1991) found diastematomyelia, spina bifida, and open meningocele in an American Indian infant with the features of the Jarcho-Levin syndrome. Turnpenny et al. (1991) indicated the wide variability in 7 affected members of an inbred Israeli-Arab family. Romeo et al. (1991) reported 2 affected brothers and 2 affected sisters related to each other as first cousins once removed. Karnes et al. (1991) reported 4 new cases. They supported the classification of Solomon et al. (1978) into 2 subtypes: spondylocostal dysostosis and spondylothoracic dysostosis. McCall et al. (1994) described the case of a Puerto Rican child with unusually long survival to age 11 years. Aurora et al. (1996) reported a newborn with characteristic features of Jarcho-Levin syndrome in addition to complex congenital heart disease (situs solitus, double outlet right ventricle, atrial septal defect) and hypospadias.

Mortier et al. (1996) analyzed 26 new patients with multiple vertebral segmentation defects and reviewed 115 previously reported cases. They recognized 3 distinct entities based on radiographic and clinical findings: Jarcho-Levin syndrome, a lethal autosomal recessive form, characterized by a symmetric crab-chest; spondylocostal dysostosis (122600), a benign autosomal dominant condition; and spondylothoracic dysostosis, which shows considerable clinical and radiographic overlap with spondylocostal dysostosis and has an autosomal recessive mode of inheritance. The authors noted that intrafamilial variability is striking (Cantu et al., 1971; Franceschini et al., 1974; Trindade and de Nobrega, 1977; Turnpenny et al., 1991); affected individuals either die in infancy of respiratory failure or survive into adulthood with minimal symptoms. Associated anomalies are not common and are only observed in lethal cases. Mortier et al. (1996) stated that sporadic cases of vertebral segmentation defects are difficult to classify as to etiology, genetic versus nongenetic, and concluded that they probably represent a heterogeneous group. Associated anomalies are more common in this group than in the familial types and may involve both mesodermally and ectodermally derived structures. Mortier et al. (1996) also concluded that the body segment in which the nonvertebral malformations occur corresponds to the site of the vertebral segmentation defects.

Bannykh et al. (2003) reported 2 affected Caucasian sibs and provided a review of the Jarcho-Levin syndrome and related disorders.

Biochemical Features

Because vertebral development is controlled by a limited number of master genes including PAX1 (167411) and PAX9 (167416), Bannykh et al. (2003) analyzed protein expression from these genes in 2 sibs with Jarcho-Levin syndrome and in age-matched controls. Immunochemical analysis showed a significant reduction in levels of protein expression on chondrocytes of the vertebral column.

Molecular Genetics

Turnpenny et al. (1999) performed genomewide scanning by homozygosity mapping in a large consanguineous Arab-Israeli family in which there were 6 definite cases of autosomal recessive spondylocostal dysostosis. Significant linkage was found to 19q13, with a lod score of 6.9. This was confirmed in a second Pakistani family with 3 affected members, with a lod score of 2.4. The combined haplotype data identified a critical region between D19S570 and D19S908, an interval of 8.5 cM on 19q13.1-q13.3.

Using homology of synteny and linkage data suggesting that the SCDO1 locus is on chromosome 19q13.1-q13.3 and that a mouse region containing the Notch ligand delta-like-3 gene is mutated in the x-ray-induced mouse mutant 'pudgy,' causing a variety of vertebral costal defects similar to the SCDO1 phenotype, Bulman et al. (2000) cloned and sequenced human DLL3 to evaluate it as a candidate gene for SCDO1. They identified mutations in 3 autosomal recessive SCDO1 families. Two of the mutations (602768.0001 and 602768.0002) predicted truncations within conserved extracellular domains; the third (602768.0003) was a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor repeat, which revealed an important functional role for this domain. These were the first mutations in a human delta homolog, thus highlighting the critical role of the Notch signaling pathway and its components in patterning the mammalian axial skeleton.

Turnpenny et al. (2003) sequenced the DLL3 gene in a series of spondylocostal dysostosis patients from 14 families and identified 12 mutations, 2 of which occurred twice. The patients represented diverse ethnic backgrounds and 6 came from traditionally consanguineous communities. In all affected individuals, the radiologic phenotype was abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which Turnpenny et al. (2003) suggested the term 'pebble beach sign.' This appeared to be a very consistent phenotype-genotype correlation. Turnpenny et al. (2003) suggested the designation SCD type 1 for the autosomal recessive form caused by mutation in the DLL3 gene.

Day and Fryer (2003) reported 2 pregnancies in 1 family in which diaphragmatic hernia and preaxial polydactyly accompanied spondylothoracic dysplasia. The first pregnancy was monozygous male twins and the second was a female sib. The pregnancies were terminated. The authors suggested that spondylothoracic dysplasia and spondylocostal dysostosis may be allelic.

In a family with spondylocostal dysostosis, previously reported by Floor et al. (1989) and believed to represent autosomal dominant inheritance, Whittock et al. (2004) performed haplotype analysis which suggested pseudodominant transmission with segregation of 2 distinct disease alleles. Direct sequencing of the DLL3 gene revealed that the affected father was homozygous and all 4 sibs were heterozygous for a 1440delG mutation (602768.0007), whereas the unaffected mother and 2 affected sibs were heterozygous for a G504D substitution (602768.0008), thus confirming autosomal recessive inheritance in all affected members of the family.

Heterogeneity

In a family segregating autosomal recessive spondylocostal dysplasia, Iughetti et al. (2000) could find no evidence of linkage to 19q, indicating genetic heterogeneity in this disorder.

Whittock et al. (2004) demonstrated a mutation in the basic helix-loop-helix transcription factor gene, MESP2 (605195), in a consanguineous family with 2 children affected by spondylocostal dysostosis (SCDO2; 608681). The phenotype was milder than that of DLL3 mutation-positive spondylocostal dysostosis, and not all vertebrae were affected.

Both the DLL3 and MESP2 genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Sparrow et al. (2006) used a candidate-gene approach to identify mutation in a third Notch pathway gene, lunatic fringe (LFNG; 602576.0001), in a family with autosomal recessive spondylocostal dysostosis (SCDO3; 609813).

In 5 children with short stature and congenital scoliosis from 4 Taiwanese Han Chinese families, Wang et al. (2011) analyzed the DLL3, MESP2, LFNG, and HES7 genes but identified no causative mutations. Apart from abnormal vertebral segmentation defects, the children had no other systemic anomalies, and all achieved normal developmental milestones. Two sisters whose parents were descendants of the same minor aboriginal tribe in Taiwan showed marked phenotypic similarity, including decreased size of vertebral bodies, hypoplasia of disc spaces throughout the thoracic spine, thoracic scoliosis, and block lumbar vertebrae. The other 3 unrelated patients displayed varying degrees of block vertebrae and hemivertebrae in the thoracic spine, with asymmetric fusion, bifid ribs, and butterfly vertebrae. Noting that none of their patients completely fulfilled the criteria for the strictest definition of SCD, which requires contiguous involvement of at least 10 spinal segments and aberrant rib alignment, with some asymmetry in rib alignment and irregular points of rib fusions, but basic overall symmetry in the shape of the thorax, Wang et al. (2011) suggested that these patients might represent a subtype of SCD occurring in the Taiwanese population.

Nomenclature

The terms dysostosis and dysplasia are used here interchangeably. Both words refer to abnormal development or formation. A distinction between the 2 terms has some usefulness, however. The dysostoses, in the usage and interpretation of Spranger (1997), referred to disorders due to defects in genes that are active predominantly in early stages of development and only at that stage are likely to result in the 'frozen' type of malformation. On the other hand, defects in genes that are active later in development or in extrauterine life cause dysplasia. Some disorders, such as fibrodysplasia ossificans progressiva (135100), show characteristics of a malformation (dysostosis) in the malformation of the thumbs and toes and characteristics of a dysplasia in the form of the ectopic ossification which develops in the first decade of life.