Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, ...MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. ...Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance.
Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine ...formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a “crab-like” configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the
mesoderm posterior 2 homolog (
MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the
MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the
MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS.
Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and ...functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.
In 1938, Saul Jarcho and Paul Levin from Johns Hopkins Hospital reported cases of thoracic insufficiency due to vertebral and rib anomalies. Nearly 30 years later, in 1966, Norman Lavy and associates ...from Indiana University reported a similar syndrome in a family from Puerto Rico. Lavy’s description was followed by a report by John E. Moseley from New York City, where the name spondylothoracic dysplasia (dysostosis) was first used. For more than half a century, there has been confusion regarding the distinction between these two phenotypically similar syndromes that cause thoracic insufficiency. Spondylocostal dysostosis (SCD), or Jarcho-Levin syndrome, causes mild to moderate respiratory insufficiency, is panethnic and has been linked to genes such as
DLL3
, which is known to be associated with the Notch pathway. In contrast, spondylothoracic dysostosis (STD), or Lavy-Moseley syndrome, results in more severe respiratory compromise, is largely linked to Puerto Rican cohorts and is thought to be associated to the
MESP2
gene, also a Notch pathway gene. Long-term studies of Puerto Rican cohorts with STD contradicts the previously held belief that individuals affected with STD have markedly diminished life expectancy with as many as 25% surviving into later childhood and adult life.
The Vertical Expandable Prosthetic Titanium Rib (VEPTR) is a technique developed for the treatment of progressive early onset scoliosis. This vertically placed device uses distraction to indirectly ...elongate the spine and chest, stabilizing the progression of the spinal deformity while preserving spinal growth. Thoracic spine and chest wall deformity are usually correlated; therefore, elongation of the chest wall will increase the space available for the lung and improve respiratory mechanics in patients with early onset scoliosis. We conducted a retrospective study of 17 patients with early onset scoliosis treated with the VEPTR technique. The medical records, imaging studies, and follow-up physical examinations were evaluated. The patient population consisted of 17 primary VEPTR implantations and 33 expansion surgeries with a mean follow-up of 25 months. Our results show that there was an improvement in the coronal plane deformity between the presurgical and postsurgical Cobb angles, preoperative Cobb angle of 59 degrees (range 38-77) to postoperative 35 degrees (range 10-70), resulting in an average decrease of 59% in the Cobb angle (P<0.001). The thoracic kyphosis was maintained at anatomically normal values. The surgical technique preserved the space available for the lung. The complication rate was 13%, which includes infection, device migration, and rib fracture. The analysis of the data shows that the natural history of the progressive spinal deformity was improved in all patients. This preliminary report reaffirms that the VEPTR implantation is a safe and efficient method for the treatment of early onset scoliosis.
Spondylothoracic dysplasia is a condition in which bilateral chest wall deformity due to costovertebral rib fusion with shortening of the thoracic spine results in severe thoracic insufficiency ...syndrome and early death. Little is known about the long-term respiratory natural history of this disorder and the specific anatomic deformity.
We conducted a multicenter prospective and retrospective study of patients with spondylothoracic dysplasia. Medical evaluations, respiratory history, physical examination findings, radiographs, computed tomographic scans, and pulmonary function tests were studied. Anatomic, radiographic, and functional parameters for the disorder were established to determine the natural history of the thoracic insufficiency syndrome.
Twenty-eight patients were identified. Eight patients had died in the neonatal period, and twenty were evaluated (eleven prospectively and nine retrospectively). The survivors were doing well clinically, but the average spirometric values were 27.9% of the predicted normal value for the forced vital capacity (FVC), 29.5% of the predicted normal value for the forced expiratory volume in the first second (FEV1), and 0.92 for the FEV1/FVC ratio, demonstrating a severe restrictive respiratory pattern. The computed tomographic scan lung volumes were an average of 28% of the expected values for age and gender. The thorax was stiff from rib fusion and was severely shortened posteriorly, averaging 24.2% of the predicted normal length. The thoracic spine was predominantly composed of block vertebrae, whereas in the lumbar region there were multiple hemivertebrae. Minimal scoliosis was seen, and there were no neurological deficits.
Spondylothoracic dysplasia has a unique pathoanatomy of volume depletion deformity of the thorax with chest wall stiffness, resulting in thoracic insufficiency syndrome. Clinical tolerance of the restrictive lung disease in this disorder is impressive, but no clear reason has yet been identified for the clinical pulmonary health in the face of severe restrictive lung disease. Patients who survive infancy show no progression of congenital anomalies and can have a good quality of life. This disease may serve as a model of the natural history of thoracic insufficiency syndrome due to growth inhibition of the thoracic spine either as a result of congenital causes or secondary to surgical fusion early in life.
A syndrome of children with short stature, bilateral hip dislocations, radial head dislocations, carpal coalitions, scoliosis, and cavus feet in Puerto Rican children, was reported by Steel et al in ...1993. The syndrome was described as a unique entity with dismal results after conventional treatment of dislocated hips. The purpose of this study is to reevaluate this patient population with a longer follow-up and delineate the clinical and radiologic features, treatment outcomes, and the genetic characteristics.
This is a retrospective cohort study of 32 patients in whom we evaluated the clinical, imaging data, and genetic characteristics. We compare the findings and quality of life in patients with this syndrome who have had attempts at reduction of the hips versus those who did not have the treatment.
Congenital hip dislocations were present in 100% of the patients. There was no attempt at reduction in 39% (25/64) of the hips. In the remaining 61% (39/64), the hips were treated with a variety of modalities fraught with complications. Of those treated, 85% (33/39) remain dislocated, the rest of the hips continue subluxated with acetabular dysplasia and pain. The group of hips that were not treated reported fewer complaints and limitation in daily activities compared with the hips that had attempts at reduction.
Steel syndrome is a distinct clinical entity characterized by short stature, bilateral hip and radial head dislocation, carpal coalition, scoliosis, cavus feet, and characteristic facial features with dismal results for attempts at reduction of the hips.
Prognostic Study Level II.
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