Familial development of lumbar spondylolysis: a familial case report of 7- and 4-year-old brothers and their father.

The incidence of lumbar spondylolysis is affected by sex, race, and congenital abnormalities. These differences suggest a genetic component to the etiology of spondylolysis. However, no definitive evidence has been presented regarding the inheritance of lumbar spondylolysis. We report familial cases of lumbar spondylolysis in 7- and 4-year-old brothers and their father, each of whom visited our clinic complaining of low back pain. Spondylolysis in the fifth lumbar vertebra (L5) was identified in both boys and their father from clinical, radiographic, computed tomographic, and magnetic resonance imaging examinations. Conservative treatment was provided for both boys. No bony union of any spondylolytic lesions was obtained, but they returned to sports activity without low back pain. Frequent development of spondylolysis, even at younger ages, in all male family members might indicate an underlying genetic etiology in lumbar spondylolysis, primarily in the form of autosomal dominant inheritance. However, information on patients and their parents should be considered carefully, as bony union with conservative therapy is not expected in such patients.

mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications.

Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic sequence variants prioritizations from clinical exome sequencing (CES) variant data of single individual or family. The mirVAFC is able to comprehensively annotate sequence variants, filter out most irrelevant variants using custom criteria, classify variants into different categories as for estimated pathogenicity, and lastly provide pathogenic variants prioritizations based on classifications and mutation effects. Case studies using different types of datasets for different diseases from publication and our in-house data have revealed that mirVAFC can efficiently identify the right pathogenic candidates as in original work in each case. Overall, the Web server mirVAFC is specifically developed for pathogenic sequence variant identifications from family-based CES variants using classification-based prioritizations. The mirVAFC Web server is freely accessible at https://www.wzgenomics.cn/mirVAFC/.

Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene.

Spondylolysis is a fracture in part of the vertebra with a reported prevalence of about 3-6% in the general population. Genetic etiology of this disorder remains unknown. The present study was aimed at identifying genomic mutations in patients with dysplastic spondylolysis as well as the potential pathogenesis of the abnormalities. Whole-exome sequencing and functional analysis were performed for patients with spondylolysis. We identified a novel heterozygous mutation (c.2286A > T; p.D673V) in the sulfate transporter gene SLC26A2 in five affected subjects of a Chinese family. Two additional mutations (e.g., c.1922A > G; p.H641R and g.18654T > C in the intron 1) in the gene were identified by screening a cohort of 30 unrelated patients with the disease. In situ hybridization analysis showed that SLC26A2 is abundantly expressed in the lumbosacral spine of the mouse embryo at day 14.5. Sulfate uptake activities in CHO cells transfected with mutant SLC26A2 were dramatically reduced compared with the wild type, confirming the pathogenicity of the two missense mutations. Further analysis of the gene-disease network revealed a convergent pathogenic network for the development of lumbosacral spine. To our knowledge, our findings provide the first identification of autosomal dominant SLC26A2 mutations in patients with dysplastic spondylolysis, suggesting a new clinical entity in the pathogenesis of chondrodysplasia involving lumbosacral spine. The analysis of the gene-disease network may shed new light on the study of patients with dysplastic spondylolysis and spondylolisthesis as well as high-risk individuals who are asymptomatic.

BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing.

Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development.

Newly occurred L4 spondylolysis in the lumbar spine with pre-existence L5 spondylolysis among sports players: case reports and biomechanical analysis.

STUDY DESIGN: Case series and a biomechanical study using a finite element (FE) analysis. OBJECTIVES: To report three cases with multi-level spondylolysis and to understand the mechanism biomechanically. BACKGROUND: Multi-level spondylolysis is a very rare condition. There have been few reports in the literature on multi-level spondylolysis among sports players. METHODS: We reviewed three cases of the condition, clinically. These patients were very active young sports players and had newly developed fresh L4 spondylolysis and pre-existing L5 terminal stage spondylolysis. Thus, we assumed that L5 spondylolysis may have increased the pars stress at the cranial adjacent levels, leading to newly developed spondylolysis at these levels. Biomechanically, we investigated pars stress at L4 with or without spondylolysis at L5 using the finite element technique. RESULTS: L4 pars stress decreased in the presence of L5 spondylolysis, which does not support our first hypothesis. CONCLUSIONS: It seems that multi-level spondylolysis may occur due to genetic and not biomechanical reasons.

Diaphanospondylodysostosis: six new cases and exclusion of the candidate genes, PAX1 and MEOX1.

We report on six cases from four families with the newly described skeletal disorder diaphanospondylodysostosis (DSD). The characteristic radiographic findings included abnormal ossification of vertebral bodies, posterior rib gaps, missing ribs, and a downward tilt of the pubic rami, but normal long bones. The typical facial features of DSD cases were ocular hypertelorism, a short nose, depressed nasal bridge, and low set ears. Other distinctive findings included a short neck with bell-shaped thorax, and nephroblastomatosis. A history of consanguinity and affected siblings with unaffected parents supports autosomal recessive inheritance. Skeletal histology showed incomplete ossification of the ribs, vertebral bodies, and sacrum as well as incomplete formation of intervertebral discs. The posterior ribs were comprised of bone with intervening cartilage interrupted by dense fibrous tissue and skeletal muscle fascicles. These findings suggest abnormal development and differentiation of the paraxial mesoderm. Because of phenotypic similarities of DSD to Pax1 and Meox1 deficient mice, we sequenced genomic DNA from three unrelated DSD cases. No mutations were identified in the PAX1 and MEOX1 exons or flanking intronic sequences, excluding them as likely causative genes.

High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K.

INTRODUCTION: Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT. METHODS: Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced. RESULTS: The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 +/- 28 mg/cm(3) in patients vs. 290 +/- 6 mg/cm(3) in controls; p = 0.001), especially in the trabecular compartment (733 +/- 26 mg/cm(3) in patients vs. 195 +/- 8 mg/cm(3) in controls; p < 0.001), but also in the cortical bone (1108 +/- 22 in patients vs. 1020 +/- 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W). CONCLUSION: We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.

Spondylolytic spondylolisthesis: a study of pelvic and lumbosacral parameters of possible etiologic effect in two genetically and geographically distinct groups with high occurrence.

STUDY DESIGN: An anatomic and radiographic study of archeological skeletal remains from two genetically and geographically distinct groups with high occurrence rates of spondylolytic spondylolisthesis was done. Specimens were Aleut (27% known occurrence rate, n = 48) and Arikara Plains Indians (9% occurrence, n = 250+ of 1,062). OBJECTIVE: To evaluate three radiographic parameters highly correlated with spondylolisthesis (pelvic incidence [PI], sacral table angle [STA], and lumbar index [LI]) in genetically homogeneous populations to determine which may be etiologic or most predictive for lysis. SUMMARY OF BACKGROUND DATA: LI has been known to vary with the percentage of slip in lytic spondylolisthesis. Recent clinical studies have shown that PI is also significantly higher in high-grade slips, and a possible etiologic effect has been ascribed to this association. STA has also been shown to vary between normals, those with only lysis, and those with lysis and slip. The etiologic significance of STA is unknown. METHODS: Radiographic and direct morphologic measurement of PI, LI, and STA was done on L5 and reassembled sacra and ilia. Statistical analysis of these three parameters among all groups was done. RESULTS: 1) There is a genetically determined difference in the upper sacral tilt (STA) that may be etiologic. 2) Genetically homogeneous groups with a lower STA in normal specimens have an increased occurrence rate of spondylolysis. 3) When there has been pars lysis, changes in the STA occur as well as deformity more caudal in the sacrum. 4) These changes are likely related to remodeling with epiphyseal growth related to changed axial stresses secondary to pars lysis. 5) PI is not a primary etiologic factor in the process. CONCLUSIONS: The STA in the normal population for each genetic group varies and relates significantly to the occurrence rate and is thus probably etiologic. STA is more highly associated with the occurrence of pars defect than is PI. Upper sacral deformities appear due to the growth plate response to the changed pressure gradients across the epiphyseal plate rather than interosseous remodeling of the ilium and acetabular area. Thus, changes in PI would be secondary.

Dissociation between back pain and bone stress reaction as measured by CT scan in young cricket fast bowlers.

BACKGROUND: Bone stress reaction is prevalent among cricket fast bowlers. Few studies have addressed the sensitivity and specificity of imaging for diagnosis, and follow up assessment has been poorly investigated. OBJECTIVE: To determine whether there was an association between back pain and bone stress reaction as measured by computed tomography (CT) scan in young cricket fast bowlers. METHODS: Ten young cricket fast bowlers were included in the study. Nine bowlers presented to a physiotherapy practice with low back pain and were later diagnosed with lumbar stress fractures, while one was an experienced bowler with no pain. All players had a CT scan after presenting to the physiotherapy practice. Pain was assessed according to a subjective scale (0-10) where 10 represented the player's subjective, maximum pain score. Recovery and rehabilitation of all players was monitored until they returned to full participation. RESULTS: There was no consistency in the relationship between pain and CT scan results. For example, one subject had evidence of un-united stress fractures after 15 months of rest but had experienced moderate pain for only 2 weeks after the onset of symptoms, in contrast to another subject who had intermittent pain for 11 months even though CT scan showed multiple stress fractures ranging from partially healed to fully healed status at 3 months. CONCLUSION: There is dissociation between back pain and bone stress reaction as measured by CT scan. Therefore, CT scan does not provide objective evidence for ongoing management or decision concerning return to sport in cricket fast bowlers.

[Spondylolisthesis in athletes]. / Le spondylolisthésis du sportif.

Isthmic spondylolysis is a fatigue fracture which mostly affects athletes. It is acquired between the ages of 5 and 15 years and is directly related to the type of sport practised. Ethnic and racial factors are also involved. It is of interest to identify the first symptoms of isthmic damage at the initial stage. The practice of sports must be interrupted to facilitate isthmic repair. Sporting activities can be resumed, but the initial therapeutic procedure (hyperlordosis) must be modified. Once spondylolysis has been constituted, few sports are contra-indicated in adolescents. Major displacements towards spondyloptosis are rare, but surveillance is necessary. Isthmic spondylolysis is usually well tolerated by adults.

Aspartylglucosaminuria in a Puerto Rican family: additional features of a panethnic disorder.

We report on 3 Puerto Rican brothers with the clinical and laboratory findings of aspartylglucosaminuria (AGU). Their parents were first cousins. The affected sibs have the "cardinal" manifestations of AGU, including developmental disabilities, progressive "coarsening" of the face, and early onset of hepatosplenomegaly. Biochemical studies showed elevated levels of urinary aspartylglucosamine and very low activity of aspartylglucosaminidase(AGA) in cultured fibroblasts. With long term follow-up, previously undescribed manifestations were noted, including radiographic evidence of spondylolysis and spondylolisthesis in early childhood and development of macro-orchidism during puberty. This family shows that AGU is not limited to individuals of Finnish background, but that the gene is panethnic in distribution and that additional changes, not previously noted, may present with advancing age.

Familial spondylolisthesis of the axis vertebra.

This report describes a nine-year-old girl with a spondylolisthesis of the C2 vertebra allowing 14 mm of slip. Her father had very similar vertebral anomalies.

Spondylolysis in Eskimo skeletons.

Spondylolysis was found in 25 of 46 spines of Eskimos from Greenland, at L1 in one case, at L3 in five cases and at L4 and L5 in 14 cases each. Two spondylolytic vertebrae were seen in the same spine in nine cases. Among young individuals, spondylolysis was found in 2 out of 15 spines and in older in 23 out of 31. The prevalence of spondylolysis was higher, the fourth vertebra was more commonly affected, and spondylolysis occurred at an older age in Eskimos than in other ethnic groups.

Family study of spondylolysis and spondylolisthesis.

Seventy index patients and 222 first-degree relatives with spondylolysis or spondylolisthesis have been studied by means of interview and clinical and radiological examinations. The index patients had an average age of 18 years, and included 43 females and 27 males. Following Wiltse's classification, 18 patients had dysplastic lesions and 52 had isthmic defects. The first-degree relatives included 99 parents and 125 siblings and children of the index patients. Both isthmic and dysplastic defects occurred in most families, regardless of the classification of the index patient. Isthmic defects were consistently more frequent than dysplastic defects. Spina bifida occulta occurred at the lumbosacral area in 61% of the index patients; in the first-degree relatives, spina bifida occulta was most common among the siblings and children of index patients, and occurred more often in relatives of index patients with dysplastic lesions than in those with isthmic lesions.

Familial occurrence of lumbar spondylolysis and spondylolisthesis.

In a Finnish kindred consisting of 192 descendants from two marriages of a male ancestor born in 1868, the lumbar spines of 105 of the 170 living members were X-rayed. Spondylolysis was found in 22 individuals. In addition, six of them had spondylolisthesis, four had spina bifida occulta, and two had a transitional lumbar/sacral vertebra. Seven members of the kindred without spondylolysis had spina bifida occulta and 10 had transitional lumbar vertebrae. The pedigree is consistent with autosomal dominant inheritance and incomplete (about 75%) penetrance for spondylolysis. It raises the question of a common aetiology for several congenital disturbances in the formation of lumbar vertebrae and possibly supports the concept of variable expressivity of a "spondylolysis gene".

Fatigue fracture: the basic lesion is inthmic spondylolisthesis.

The defect in the pars interarticularis in spondylolysis and spondylolisthesis is most often the result of repeated trauma, stress, and factors other than acute fracture. These fatigue fractures develop early in life, may have a strong hereditary basis, and most often represent incidental roentgenographic findings. Attention should be given to the youngster or adolescent with low-back pain and paraspinal muscle spasm. If these patients are followed closely, the incidence of pars interarticularis defect is higher than appreciated. The lesion in some of these individuals may progress to significant vertebral slipping. If the developing defect is recognized early, treatment can be quite satisfactory.