Idiopathic Coliosis (AIS) - Pediatric Spinal Deformity Information
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Synopsis and Key Points:
Information regarding AIS a common form of pediatric spinal deformity affecting 3% of children in the world.
Main DigestIdiopathic scoliosis (AIS) is the most common form of pediatric spinal deformity. It is one that affects around 3% of children around the world. AIS has a significant impact on national health in America alone, creating disfigurement and disability for more than 10% of people at a cost of billions of dollars each year for treatment. Despite a number of investigations, the underlying etiology of AIS remains poorly understood.
Twin studies and observations of familial aggregation reveal significant genetic contributions to AIS. Many features of the disease, including potentially strong genetic effects, the early onset of disease, and standardized diagnostic criteria, make AIS ideal for genomic approaches to finding risk factors for it.
The word, 'scoliosis,' is derived from the Greek word for, 'crooked,' and describes a lateral S-shaped spinal deformity. Different pathological conditions may present with an associated scoliosis in people. For example; scoliosis might be secondary to neuromuscular/neurological disease such as spinal muscular atrophy, Duchenne's muscular dystrophy, or polio. In other instances, a person's spinal deformity is a direct result of vertebral anomalies which are easily visualized through radiography and are usually present at the time of the person's birth.
The majority of scoliosis; however, develops in apparent isolation in an otherwise healthy and pre-adolescent child. The idiopathic form of scoliosis is usually seen during two periods of quick growth - at infancy and at the onset of adolescence. The vast majority of people with AIS experienced adolescent onset. While estimates differ, adolescent idiopathic scoliosis (AIS) usually affects 2-3% of school age children and it seems that no ethnic population remains unaffected. Due to the fairly high frequency and possible risks of the disease, a number of children participate in screenings at schools with the goal of early detection.
AIS is perhaps best described as a three-dimensional deformity because of the rotation of a person's vertebrae within the curve. Progression of the rotational deformity may ultimately evoke pulmonary compromise. The natural history of untreated AIS involves spinal osteoarthritis and increasing back pain. Due to this, the central clinical issue in treatment of AIS is anticipating and controlling the progression of the deformity.
Risk factors for progression in a child who is unaffected are well-documented. The most obvious AIS risk factor is gender. Girls who are affected are at least five times more likely to have progressive curves when compared with boys who are affected; the reasons why remain unknown. Additional risk factors are the person's initial curve pattern and the severity of the curvature in relation to the person's remaining growth.
Certain curve patterns, such as in the thoracic region, are more likely to progress in severity and must be carefully monitored. How the person's growth provokes progression of the disease is not clear, yet the two remain very correlated. Due to the relationship, several measures are usually used to monitor the remaining growth of an affected child. The measures include bone age, 'menarchal status,' in girls, or peak height velocity.
'Peak height velocity,' refers to the point at which the child is at maximum growth, which is taken from the child's sequential height measurements. Historical data permits an estimation of this point, beyond which the child is at decreased risk for progression of spinal curvature. If curve progression is minimal or controlled through the child's high-risk period, such as through bracing, the child might avoid surgical intervention. Surgery is warranted; however, for spinal curvature that continues to progress before their high-risk period is over. Management of AIS, from screening and monitoring to intervention, is therefore a considerable health care concern to not only the child, but their family members and health care providers.
Chart showing diseases researchers have had success with finding the genetic loci of
Several clinical investigations of AIS have revealed interesting phenomena associated with the disease, yet have failed to produce underlying susceptibility factors or disease modifiers. The aetiological understanding of AIS remains poor because of this. Recently, successes in the identification of genetic loci underlying common disease such as:
- Type 2 diabetes
- Coronary heart disease
- Inflammatory bowel disease
- Age-related macular degeneration
have generated an increased interest in applying similar genome-wide approaches in large scale studies of AIS. Strategies like these are appealing in part because they are agnostic to disease aetiology. AIS might be particularly amenable to these types of analyses for a number of reasons.
One of the reasons why is because of its significant genetic underpinnings, something established by literature that has existed for more than seventy years. Another reason is because AIS is routinely phenotyped using standardized objective measures which reduce clinical heterogeneity and may substantially increase power to detect genetic associations. Still another reason why is the onset in childhood enables collection of entire families that may provide information on linkages, association, as well as inheritance. The recent association of AIS susceptibility with variants in the CHD7 gene presents proof of concept for the approaches.
Genetic Evidence and AIS
Recognition of genetic influences in AIS is well-documented. Familial forms of AIS were described as early as the year 1922. Since that time, reports of multiple twin sets and twin series have consistently shown higher concordance in monozygotic (MZ) compared with dizygotic (DZ) twins. A meta-analysis of clinical twin studies shows 73% MZ compared to 36% DZ concordances. Interestingly, in this series there was a significant correlation with spinal curve severity in MZ twins, yet not DZ twins. No correlation with curve pattern was discovered, suggesting the importance of genetic factors in controlling both susceptibility and disease course, but not necessarily disease pattern.
Anderson and associates reported their findings more recently using the Danish Twin Registry. They found 25% proband-wise concordance in MZ twins compared to 0% in DZ twins with an overall prevalence of around 1%. The lower concordances in both groups of twins as compared with previous results might be explained by differences in study design - specifically ascertainment in clinics versus by registry, as well as screening by examination instead of through questionnaires.
The overall trend obtained for all studies suggests strong genetic effects in AIS. Interestingly, measured concordances in MZ twins were below 100%, reflecting the complexity of disease and suggesting the involvement of as yet unknown stochastic or environmental factors in disease susceptibility.
How AIS Susceptibility is Inherited
Granted, genes contribute to AIS; yet how is disease susceptibility inherited? Autosomal dominant inheritance has been suggested from evaluation of single families, or small family collections. 'X-linked dominant inheritance,' has been a prevailing theory to explain apparent lack of male-male transmission; however, this was disputed after re-evaluation of X-ray data from original study participants. Different studies have found that AIS disease risk decreases rapidly comparing first-degree relatives of a proband to subsequent generations.
Chart showing the risk percentages to family members of persons with AIS
Other studies found similar trends. Specifically, in their comprehensive population study, Riseborough and associates reported overall risk to first-degree relatives of 11%, compared to 2.4% and 1.4% in second and third degree relatives. Notably, some - yet not all studies, have found advanced maternal age for mothers of probands with AIS. The observations might be most consistent with a multifactoral inheritance model involving several to a number of genes, interplaying with unknown environmental factors. The general consensus gathered from all of this is that while families with dominant inheritance might exist, AIS is generally a complex genetic disease that is not easily explained by existing inheritance models.
Familial risk values might be used to estimate and compare the genetic effects across diseases. Prior sibling risk studies of AIS have reported 19% and 11.5% of siblings affected for 10, 20-degree curves respectively, compared to population recurrence risks of 2%. In a cohort of 305 AIS families it was found that 16% of siblings were affected. The percentage was compared to the incidence of AIS in the general population in order to estimate the sibling risk ratio for AIS, yielding overall values ranging from 8-23 depending upon spinal curve severity. The values represent significant genetic effects that are comparable to those for other, well-described complex genetic diseases such as:
- Crohn's disease (CD)
- Type 1 diabetes (T1D)
- Rheumatoid arthritis (RA)
The possibility of a major gene contributing to AIS, analogous to human leukocyte antigen (HLA) genes in the listed inflammatory diseases, has been suggested - yet has not been unproven.
Identification of Susceptibility Genes
Candidate gene studies of AIS have not been revealing in general. In a previous linkage study of 53 families, a large region of chromosome 8q12 linked with AIS (locus IS3) apparently near the SNTG1 gene was described. Further study revealed that this signal was due at least in part to a different gene encoding with the chromodomain helicase DNA binding protein 7 (CHD7) that was both linked and associated with AIS. Specifically, multiple single nucleotide polymorphisms (SNP's) in CHD7 were significantly associated with increased risk of developing AIS. The study also produced more observations.
One of the observations revealed associations within CHD7 gene, detected for various inheritance models, underscoring difficulties with specifying any single model for AIS. Affected members within individual AIS families commonly differed in severity and pattern of the disease, potentially indicating that disease susceptibility and expression were controlled by distinct genetic factors. It might also be possible that the presence of disease in other affected family members was a, 'phenocopy,' or genetically unrelated.
When these alternative explanations were tested using the, 'FBAT,' statistic that considers all affected family members in a pedigree, p-values were significant for the SNP's used in the previously published study. The results supported the conclusion that presence of disease in siblings in this cohort was genetically related and that separate factors might influence the severity of the disease and its course.
Future Studies and Analyses
In the near term, researchers expect that genomic studies will find factors with strongest effects on susceptibility to AIS, revealing insights into disease pathogenesis. One of the most important questions is how such factors - either separately or together, contribute quantitatively to risk of disease. Quantitative analyses and stratification of datasets might also enable improved definition of clinical subtypes within the diagnosis. Identification of genetic factors underlying AIS will enable further research, enhancing the prospect for alternative and less invasive forms of therapies.
The genetic (heritable) basis of adolescent idiopathic scoliosis (AIS)
Severe scoliosis linked to rare mutations
Researchers Identify Genetic Mutation Associated with Scoliosis
- 1: Research on Severe Spinal Cord Injuries : University of Copenhagen - The Faculty of Health and Medical Sciences (2014/09/05)
- 2: Neuralstem Spinal Cord Injury Stem Cell Trial : Neuralstem, Inc. (2014/10/10)
- 3: What is Quadriplegia and Paraplegia? : Disabled World (2017/11/25)
- 4: Procedure for SCI Patients to Breathe on Their Own : Case Western Reserve University (2014/11/18)
- 5: Photons Versus Protons for Spinal Cord Gliomas Treatment : Ohio State University Medical Center (2010/12/22)
- 6: Is a Brace Necessary for Spinal Fractures : American Academy of Orthopaedic Surgeons (2014/12/03)
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