Long-Term Follow-up of Untreated Adult Patients with Spondylothoracic Dysostosis (Jarcho-Levin Syndrome).

BACKGROUND: Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is a rare autosomal recessive disorder affecting the formation of the spine, characterized by a complete bilateral fusion of the ribs at the costovertebral junction, producing a "crablike" appearance of the thorax. Despite being declared a core indication for a V-osteotomy vertical expandable prosthetic titanium rib (VEPTR) expansion thoracoplasty of the posterior thorax, the natural history of STD in untreated subjects remains poorly documented. In this study, we report radiographic and pulmonary function findings and Patient-Reported Outcomes Measurement Information System (PROMIS) and 24-Item Early Onset Scoliosis Questionnaire (EOSQ-24) scores for untreated adult subjects with STD to gain insights into the natural history. METHODS: We identified 11 skeletally mature, untreated subjects with STD. Findings on medical evaluation, demographics, radiographic parameters, pulmonary function, genetic testing results, PROMIS measures, and EOSQ-24 scores were assessed. RESULTS: Five male and 6 female subjects (mean age, 32.3 years [range, 15 to 70 years]) with a confirmed STD diagnosis based on radiographs and genetic testing were evaluated. Mean body mass index (BMI) was 24.4 kg/m 2 (range, 18 to 38.9 kg/m 2 ), and mean thoracic height was 16 cm (range, 12 to 17 cm). Pulmonary function tests (PFTs) showed a mean forced vital capacity (FVC) of 22% of predicted, mean forced expiratory volume in 1 second (FEV1) of 24% of predicted, and FEV1/FVC ratio of 107% of predicted. The mean PROMIS dyspnea score was 40 ± 8 points (range, 27.7 to 52.1 points). The mean total EOSQ-24 score was 77.3 ± 18 points (range, 43.9 to 93.2 points). CONCLUSIONS: Our study characterizes the natural history of STD in untreated subjects. We confirmed the expected restrictive pattern in pulmonary function, but interestingly, our subjects exhibited better EOSQ scores compared with those reported in neuromuscular populations. PFT results and thoracic height did not correspond to PROMIS and EOSQ scores, questioning the use of those parameters as a surgical indication. We therefore suggest that the STD diagnosis as an absolute indication for VEPTR expansion thoracoplasty surgery be reconsidered. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Homozygous TRPV4 Mutation Broadens the Phenotypic Spectrum of Congenital Spinal Muscular Atrophy and Arthrogryposis: A Case Report.

Transient receptor potential vanilloid 4 (TRPV4) mutations are known to cause inherited axonal neuropathies and skeletal dysplasia. TRPV4 mutations are associated with distal hereditary motor neuropathies (dHMN), which distinctly involve motor deficits. A 1 ½-year-old boy presented at the clinic with diminished lower limb movement and ambulatory limitations. The patient was born with bilateral knee arthrogryposis and bilateral talipes equinovarus, which required surgical intervention. A gross neurologic exam was unremarkable, with normal vision and hearing. A bone survey radiograph showed no evidence of skeletal dysplasia. Genetic tests revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L), leading to the diagnosis of congenital spinal muscular atrophy and arthrogryposis (CSMAA). Hence, this presents the first case of CSMAA caused by a TRPV4 mutation (p.S94L), with a different presentation from the one previously described in the literature, thus broadening the phenotypic variability and clinical spectrum of TRPV4 mutations.

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

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.

Vitamin D levels and fracture risk among Hispanic children.

PURPOSE: There is a lack of knowledge about whether low vitamin D levels increase the risk of pediatric low-energy fractures among Hispanic population. The objective of this study is to determine whether there is a direct relationship between low vitamin D levels and the incidence of low-energy fractures in Hispanic children. METHOD: Cases included all consecutive patients evaluated with low-energy fractures in the pediatric orthopedic clinic. The control group consisted of all pediatric patients evaluated, without fractures, who had bone and joint pain complaints in the general pediatric clinic. The main focus was to compare cases and controls in relation to their vitamin D levels. Cases and controls were compared using t tests for means of quantitative variables and Chi-square tests. RESULTS: A total of 201 subjects, distributed as cases (n = 107) and controls (n = 94), were included in this study. One hundred twelve (55.7%) of the total study population were males. The mean age for the study population was 8.6 years old ranging from 1 year to 18 years, and standard deviation = 4.0 years. The median age for the study population was 9 years. The mean vitamin D level for the cases was 32.6 ng/dl (SD = 10.9); the mean vitamin D level for controls was 32.3 ng/dl (SD = 13.4). This difference was not statistically significant (t = 0.18, 95% CI - 3.2 to 3.9; p = 0.854). CONCLUSION: A direct relationship between low vitamin D levels and fracture risk in a Hispanic pediatric population was not established. LEVELS OF EVIDENCE: III.

Steel syndrome: dislocated hips and radial heads, carpal coalition, scoliosis, short stature, and characteristic facial features.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: Prognostic Study Level II.

Natural history of thoracic insufficiency syndrome: a spondylothoracic dysplasia perspective.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Controversies surrounding Jarcho-Levin syndrome.

PURPOSE OF THE REVIEW: Jarcho-Levin syndrome is an eponym that has been used to describe a variety of clinical phenotypes consisting of short-trunk dwarfism associated with rib and vertebral anomalies. This admixture of phenotypes under Jarcho-Levin syndrome has allowed some confusion in terms of phenotype, prognosis, and mortality. In the past 2 years, few papers have provided more insight into the clinical diagnosis, prognosis, and management of patient with these phenotypes. RECENT FINDINGS: Recently molecular, clinical, and radiologic data have allowed further characterization of these phenotypes. Based on these findings, we have divided these phenotypes into spondylothoracic dysplasia and spondylocostal dysostosis. SUMMARY: A better understanding of the distinct phenotypes under Jarcho-Levin syndrome will help clinicians to understand the pathological factors of the disease, establish mode of inheritance, provide adequate genetic counseling, prognosis, molecular diagnosis, and clinical management recommendations.