Genetic Scoliosis — Approach

Idiopathic scoliosis, congenital scoliosis due to vertebral segmentation defects, and syndromic and neuromuscular scoliosis of monogenic basis

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Scoliosis is a three-dimensional deformity of the spine in which curvature in the frontal plane is accompanied by axial rotation of the vertebrae. The Scoliosis Research Society (SRS) considers the diagnosis confirmed when the Cobb angle, measured on the standing anteroposterior radiograph between the upper end vertebra and the lower end vertebra, reaches 10° or more and there is recognisable rotation; below 10° the diagnosis is not established, although smaller structural curves may progress [1]. The error of manual Cobb angle measurement is about 5°, and computer-assisted methods reduce it to 1.22–3.6°, values that must be taken into account whenever a clinical decision depends on a difference of a few degrees [1]. About 80% of scolioses are idiopathic and 20% are secondary to another pathological process [1].

Progressive scoliosis, in its syndromic and monogenic forms, is not a disease but a clinical problem that cuts across medical genetics, orthopaedics, neurology and physical medicine. This article treats it as a class, with a common structure: idiopathic scoliosis, whose genetic basis is polygenic; congenital scoliosis due to defects of vertebral formation or segmentation, in which compound inheritance of TBX6 explains about one in ten sporadic forms; and syndromic scoliosis, in which the spinal deformity is a manifestation of a monogenic disease of the connective tissue, skeleton, nervous system or muscle. Diseases with their own description (neurofibromatosis type 1, Marfan syndrome and hereditary aortopathies, Ehlers-Danlos syndromes, spinal muscular atrophy, dystrophinopathies, Rett syndrome, Prader-Willi syndrome, Friedreich ataxia, COL6-related disorders, Klippel-Feil syndrome, oculo-auriculo-vertebral spectrum, osteogenesis imperfecta, homocystinuria and spondylocostal dysostosis) appear here only insofar as scoliosis is concerned. Horizontal gaze palsy with progressive scoliosis, the only Mendelian entity with scoliosis in its very name, is covered in greater detail.

1.2. Classifications in use

James's chronological classification, adopted by the International Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT), divides idiopathic scoliosis by age at diagnosis into infantile (0–2 years), juvenile (3–9 years), adolescent (10–17 years) and adult (18 years or more) [1]. The term early-onset scoliosis (EOS) designates any scoliosis with onset before 10 years, regardless of cause, and is the term that guides growth-friendly surgery [2, 67]; SOSORT prefers to keep the distinction between infantile and juvenile, because the infantile form has its own prognosis [1]. The same guideline proposes an angular classification (low up to 20°, moderate 21–35°, moderate to severe 36–40°, severe 41–50°, severe to very severe 51–55° and very severe from 56°) and a topographic classification by the apical vertebra, from cervical to lumbar [1].

The 2022 French National Diagnosis and Care Protocol (PNDS) on early spinal deformities defines EOS as a three-dimensional (axial, frontal and sagittal) curvature whose main curve has a Cobb angle greater than 10°, of any cause, developing before 10 years, and groups the causes into four classes: congenital or structural («malformative»), resulting from a structural anomaly or asymmetry of the spine or thoracic cage; neuromuscular, divided into involvement of the upper motor neurone (cerebral palsy, hereditary ataxias, encephalopathies such as Rett syndrome), of the lower motor neurone (SMA, acute anterior poliomyelitis, hereditary neuropathies), mixed involvement (spinal cord injury, myelodysplasia, myelomeningocele) and muscular causes (myopathies and dystrophies); syndromic, when the syndrome has a known or possible association with scoliosis without being primarily congenital or neuromuscular; and idiopathic [74]. To organise such a heterogeneous population, the same document adopts the C-EOS classification (Classification of Early-Onset Scoliosis) of Williams and colleagues, which combines age, aetiology, the Cobb angle of the main curve, maximum kyphosis and the annual rate of progression of the main curve, calculated as (Cobb at time T2 − Cobb at time T1) × 12 / interval between T1 and T2 in months; in the studies cited, the classification showed inter- and intraobserver reproducibility and prognostic value [74]. Growth-friendly implants are classified, according to Skaggs and colleagues, by the force they exert on the spine: distraction systems (traditional growing rods, magnetic rods and VEPTR), convex-side compression systems (stapling and vertebral body tethering) and guided-growth systems (Shilla technique and modified Luque trolley) [74].

In congenital scoliosis, the orthopaedic description distinguishes failure of formation (hemivertebra, wedge or butterfly vertebra), failure of segmentation (vertebral bar or block) and mixed forms [58, 77]. The Bone Dysplasias Atlas stresses that «congenital scoliosis» is an orthopaedic description of trunk asymmetry caused by vertebral segmentation defects and does not cover congenital scolioses of neurogenic, neuromuscular or connective tissue origin [78]. For multiple segmentation defects of the vertebrae (SDV), the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS), now part of the International Consortium for Scoliosis Genetics Development and Disease (ICSGDD), proposed a clinical reporting algorithm with seven categories and a research algorithm with an ontology applicable to humans and animal models; in that system, «spondylocostal dysostosis» designates generalised segmentation defects with rib involvement [5]. The 2023 revision of the Nosology of Genetic Skeletal Disorders renamed spondylothoracic dysostosis «vertebral segmentation defect (congenital scoliosis) with variable penetrance», a designation with which the GeneReviews authors disagree, because congenital scoliosis usually results from defects of one or a few vertebrae in one region, whereas spondylothoracic dysostosis is generalised and scoliosis is not a dominant feature [5].

In the syndromic scolioses, the relevant classification is that of the underlying disease. The 2017 international nosology of the Ehlers-Danlos syndromes renamed the former «oculo-scoliotic» form described by Pinnell and colleagues in 1972 as kyphoscoliotic Ehlers-Danlos syndrome (kEDS), now divided by the PLOD1 and FKBP14 genes [22, 23]. In NF1, scoliosis is divided into dystrophic, associated with vertebral dysplasia, and non-dystrophic, similar to idiopathic [26].

1.3. Historical milestones in the genetics of scoliosis

Familial aggregation of idiopathic scoliosis has been known for decades, and the first twin study large enough to estimate heritability, based on the Swedish Twin Registry, attributed 38% of the variance in susceptibility to additive genetic effects [34]. The first robust susceptibility locus was identified in 2011 by a Japanese genome-wide association study (GWAS), which located the signal near the LBX1 gene [13]; this was followed by GPR126 (ADGRG6) in 2013 [14], an enhancer near PAX1 with an effect restricted to females in 2015 [15] and the first multi-ancestry GWAS meta-analysis in 2018 [16]. In 2014, rare-variant analysis by exome sequencing associated FBN1 and FBN2 with the severe forms [18].

In congenital scoliosis, the milestone was the demonstration, in 2015, that the combination of a rare TBX6 null allele with a common hypomorphic haplotype on the other allele explains up to 11% of sporadic cases [3], followed by the clinical definition of TACS and a recognition score in 2019 [4]. Among the Mendelian forms, horizontal gaze palsy with progressive scoliosis was linked to ROBO3 in 2004, in work that showed for the first time in humans that an axon guidance receptor is required for the crossing of motor and sensory pathways at the midline of the brainstem [33]. In 2009, homozygosity mapping in a consanguineous Israeli Arab family led to the description of MACS syndrome and the identification of RIN2, a regulator of Rab5-dependent endocytic trafficking, as the cause of a connective tissue disorder with scoliosis [35]. In 2015, the exome of four siblings from an Old Order Mennonite community, studied by the Canadian FORGE consortium, linked biallelic variants of EXT2, a gene known for dominant multiple exostoses, to a neurodevelopmental disorder with scoliosis, SSMS [36].

2. Molecular Genetics and Pathophysiology

2.1. Idiopathic scoliosis: a complex trait

Adolescent idiopathic scoliosis behaves as a multifactorial trait. In the Swedish Twin Registry, with self-reported data from 64,578 twins, prevalence was 4%, pairwise and probandwise concordance were 0.11 and 0.17 in monozygotic twins and 0.04 and 0.08 in same-sex dizygotic twins, and the best-fitting model attributed 0.38 (95% confidence interval [CI] 0.18–0.46) of the variance to additive genetic effects and 0.62 to unique environmental factors, with no significant effect of shared environment [34]. The low concordance in monozygotic twins shows that genotype does not, by itself, determine the appearance of the curve.

GWAS have identified loci of modest effect. The 2011 Japanese study, with 1376 affected girls and 11,297 controls, located at 10q24.31, near LBX1, the variant rs11190870 (combined P 1.24×10⁻¹⁹; odds ratio [OR] 1.56) [13]. LBX1 (ladybird homeobox 1) encodes a homeodomain transcription factor that specifies GABAergic interneurones of the dorsal horn of the spinal cord and neuronal subtypes of the brainstem and that guides the migration of hypaxial muscle precursors [79]. The following study, with 1819 cases and 25,939 Japanese controls, identified rs6570507 in GPR126 (6q24.1; P 2.25×10⁻¹⁰; OR 1.28), with replication in Han Chinese and Europeans (combined P 1.27×10⁻¹⁴; OR 1.27); the gene is highly expressed in cartilage and its knockdown in zebrafish delays spinal ossification [14]. GPR126, now ADGRG6, encodes an adhesion G protein-coupled receptor required for myelination by Schwann cells, whose biallelic loss causes a severe form of arthrogryposis multiplex congenita [80]. A GWAS of 3102 individuals detected at 20p11.22 a signal significant in girls (P 6.89×10⁻⁹) and absent in boys (P 0.71), replicated in female cohorts from the United States and Japan (overall P 2.15×10⁻¹⁰; OR 1.30; rs6137473); the locus lies upstream of PAX1 and contains an enhancer active in somitic muscle and the spinal cord of zebrafish whose activity is abolished by the risk alleles [15]. The first GWAS meta-analysis, with 7956 cases and 88,459 controls of three ancestries, added loci in CDH13 (rs4513093; P 1.7×10⁻¹⁵), ABO (rs687621; P 7.3×10⁻¹⁰) and SOX6 (rs1455114; P 2.98×10⁻⁸), with stronger associations when the analysis was restricted to females and with enrichment in cartilage and connective tissue developmental pathways [16].

Before GWAS, linkage studies in multiplex families had mapped susceptibility loci at 19p13.3 (IS1), 17p11.2 (IS2), 8q12 (IS3), 9q31.2-q34.2 (IS4) and 17q25.3 (IS5), none of them with an identified gene [37–41]. A Japanese and Chinese GWAS of 2109 cases and 11,140 controls also located a signal in intron 3 of BNC2 (9p22.2; OR 1.21), a gene encoding basonuclin 2, with expression data compatible with a regulatory effect [37]. Later syntheses confirm this pattern. A systematic review of 33 studies (nine GWAS, four exome studies and 20 validation studies), with more than 35,000 cases and 67,000 controls, almost all of East Asian or European ancestry, found the largest number of associations in LBX1, LBX1-AS1, GPR126/ADGRG6 and BNC2, and concluded that the clinical translation of these findings is unknown [17]. A meta-analysis of 43 publications (19,412 cases and 22,005 controls) confirmed the association of LBX1 rs11190870 and of MATN1 variants and did not confirm those of IGF1, oestrogen receptor alpha and MTNR1B [81]. A LBX1 risk allele neither diagnoses nor predicts scoliosis in an individual; the same gene region is linked, by a different mechanism, to a rare recessive form of congenital central hypoventilation described in a single family, unrelated to the scoliosis signal [79].

Rare variants explain a fraction of the severe forms. In the 2014 exome analysis, FBN1 was the gene with the greatest burden of rare variants; after sequencing of FBN1 and FBN2 in 852 cases and 669 controls, rare variants were present in 7.6% of severe cases of European ancestry, compared with 2.4% of internal controls (OR 3.5) and 2.3% of Exome Sequencing Project controls, were associated with curve severity (with replication in a Chinese cohort) and with tall stature, and most carriers did not meet criteria for Marfan syndrome [18]. Whole-genome sequencing in 119 patients from 103 families identified known pathogenic or truncating variants in 15 probands and candidate variants in a further 69, in genes such as COL11A2, FBN1 and RYR1, clustering in pathways of muscle contraction, extracellular matrix and regulation of gene expression [82]. There is also a Mendelian form of susceptibility, IS6 (OMIM 621428): in 26 patients from five families with autosomal dominant AIS, two heterozygous variants were identified in SLC6A9, the gene for the glycine transporter GLYT1 (described in OMIM as R662W and Y206F); plasma glycine was elevated in 15 patients compared with 36 controls, surface electromyography showed abnormal paravertebral activity in two affected children, and the mutant proteins were retained inside the cell and prevented membrane localisation of the normal protein, a dominant-negative effect [12, 83]. In zebrafish, loss of function of slc6a9 caused lateral axial curvature, corrected by expression of the normal gene and moderately attenuated by benzoate, a glycine-lowering agent; this is a preclinical result [12]. POC5 missense variants were described in 13 of 40 probands with scoliosis, with familial segregation, but also in unaffected relatives and in the gnomAD population database, so their role remains uncertain [84]. These data place idiopathic scoliosis on a continuum between polygenic susceptibility and the Mendelian disorders of connective tissue and muscle.

2.2. Congenital scoliosis: TBX6 and the gene dosage model

TBX6 (16p11.2; MANE transcript NM_004608.4) encodes a T-box family transcription factor that patterns the paraxial mesoderm, from which the somites and, through them, the vertebrae and ribs are derived; it activates expression of DLL1 and MESP2, and RIPPLY2 acts as its negative regulator [5]. Reduced TBX6 dosage disturbs somite segmentation.

The 2015 study assessed 161 Han Chinese patients with sporadic congenital scoliosis and 166 controls. It found 17 heterozygous TBX6 null variants in patients (11%) and none in controls (P<3.8×10⁻⁶): 12 recurrent 16p11.2 deletions including TBX6, one nonsense variant and four frameshift variants [3]. As carriers of the same deletion in the same family were discordant for scoliosis, the null allele alone was not sufficient; in all 17 patients, the other allele carried a common haplotype, T-C-A, defined by the non-reference alleles of three TBX6 polymorphisms (rs2289292 C/T, rs3809624 T/C and rs3809627 C/A), with P<1.1×10⁻⁶ [3]. The model was repeated in a second series (6 of 76 patients, 8%) and, among 42 carriers of the 16p11.2 deletion, the T-C-A haplotype was present in five of six with congenital scoliosis and in five of 30 without scoliosis (P 0.004) [3]. Luciferase assays showed that the two polymorphisms in the 5' non-coding region reduce expression, which makes the haplotype a hypomorphic allele [3]. GeneReviews writes the third polymorphism as «rs38090627»; the original article identifies it as rs3809627 [3, 5].

The result is compound inheritance: a rare null allele (16p11.2 deletion or loss-of-function variant) in trans with a common hypomorphic allele reduces TBX6 function below the threshold required for segmentation. The Tbx6−/mh mouse model (null allele with a mild hypomorphic allele) reproduces the malformations, unlike simple heterozygotes [4]. The proximal 16p11.2 deletion has a population frequency of about 0.03% and is associated, independently of the spine, with speech, language and coordination disorders, psychiatric disorders and autistic traits [3, 5]. In the Chinese (n=345) and Japanese (n=142) cohorts, compound inheritance of TBX6 explained 9.6% and 10.6% of congenital scolioses [4]; in a surgical series of 473 Chinese patients, 48 (10.1%) had TACS, 37 due to a 16p11.2 deletion and 11 due to point null variants with the T-C-A haplotype [85]. The null variants described include 16p11.2 deletions, frameshift, nonsense, splicing and missense variants, and more recently a single amino acid deletion in the T-box domain, NM_004608.4:c.338_340del p.(Ile113del), which abolished almost all transcriptional activity in an assay with the MESP2 promoter [64, 86].

The same gene causes other allelic presentations, and Smith's Recognizable Patterns stresses that TBX6 causes both classic spondylocostal dysostosis and congenital scoliosis without rib defects [87]; OMIM records both modes of inheritance for SCDO5, autosomal dominant and recessive [42, 43]. Spondylocostal dysostosis 5 due to biallelic TBX6 has been described in six families and is the second most frequent form of spondylocostal dysostosis, after the DLL3-related form [5]. A three-generation family with autosomal dominant spondylocostal dysostosis (all affected individuals male) segregates the variant NM_004608.4:c.1311A>T p.(Ter437CysextTer81), which abolishes the stop codon and extends the protein by 81 residues, with about half the transcriptional activation of the normal allele [5, 86]. TBX6 deletions with a hypomorphic allele also occur in patients with Müllerian aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) or renal malformations [5]. Spondylocostal dysostosis as a whole (DLL3, MESP2, LFNG, HES7, RIPPLY2, TBX6) belongs to the group of spondylocostal and spondylothoracic dysostoses.

2.3. Syndromic scoliosis: mechanisms by disease group

In the connective tissue disorders, scoliosis results from alterations of the extracellular matrix. In Marfan syndrome, the neonatal and severe early-onset forms usually result from de novo variants in the central region of FBN1 (exons 24–32) and present with hypotonia, laxity, significant scoliosis, arachnodactyly, contractures and rapidly progressive valvular and aortic disease [88]. In Loeys-Dietz syndrome, caused by variants in genes of the transforming growth factor beta (TGF-β) pathway, scoliosis and spondylolisthesis occur, mild or severe and progressive, as well as malformations or instability of the cervical spine [20]. Congenital contractural arachnodactyly (FBN2) and Shprintzen-Goldberg syndrome (SKI) complete the group of fibrillinopathies and marfanoid syndromes [21, 89]. In PLOD1-related kEDS, lysyl hydroxylase 1 deficiency reduces hydroxylysine-derived pyridinoline cross-links in collagen; about 30% of pathogenic variants are a recurrent intragenic duplication generated by Alu-Alu recombination between introns 9 and 16, which should be sought in first-line analysis [22]. FKBP14-related kEDS, mcEDS (CHST14 and DSE) and the spondylodysplastic form due to B3GALT6 (spondyloepimetaphyseal dysplasia with joint laxity, Beighton type, due to defective synthesis of the glycosaminoglycan linker region, affecting heparan sulfate and chondroitin sulfate) are autosomal recessive [23–25].

In the skeletal dysplasias, scoliosis derives from the abnormal shape and growth of the vertebrae. In diastrophic dysplasia, biallelic SLC26A2 variants prevent sulfate entry into cells and give rise to undersulfated cartilage proteoglycans, with severity proportional to the degree of transport impairment [31]. In metatropic dysplasia, gain-of-function variants of TRPV4, a cation channel mediating calcium entry, cause autosomal dominant disease; germline mosaicism explains affected siblings of unaffected parents, and the same gene causes a spectrum of neuromuscular disorders [32].

In NF1, vertebral dysplasia may be primary or secondary to an adjacent plexiform neurofibroma or to dural ectasia, and bone healing of these lesions is deficient [26]. Missense variants at NF1 codons 844–848 (NM_000267.3), in the cysteine- and serine-rich domain, are associated with a severe phenotype with frequent plexiform and spinal neurofibromas and skeletal anomalies, and variants at p.Arg1276 are associated with symptomatic spinal neurofibromas [26].

In the neuromuscular and neurodevelopmental disorders, scoliosis is a consequence of weakness, hypotonia or tone imbalance acting on a growing spine. In Friedreich ataxia, the length of the shorter GAA repeat allele (GAA1) correlates with disease severity, including the presence and severity of scoliosis, which is less frequent in the late-onset forms [30]. In Prader-Willi syndrome, scoliosis is attributed to hypotonia, without structural vertebral anomalies [59]. In Rett syndrome, the type of MECP2 variant modulates the age at onset and the progression of the curve [90].

2.4. HGPPS: failure of axonal crossing at the midline

ROBO3 (11q24.2) encodes an axon guidance receptor of the roundabout family which, unlike the other members, is required for commissural axons to cross the midline of the hindbrain [33]. Biallelic loss prevents decussation of the corticospinal tracts and of the medial lemniscus in the medulla, so motor control and proprioceptive sensation become predominantly ipsilateral; the horizontal gaze palsy results from involvement of the tegmentum and the medial longitudinal fasciculus [33, 91]. The defect is structural and fixed from development, with no biochemical marker. In 20 years, more than 60 pathogenic or likely pathogenic ROBO3 variants have been described in almost 100 patients [6]. The HGPPS2 form, also called developmental split-brain syndrome, results from biallelic DCC variants and is associated with intellectual disability; by 2024 eight patients had been described, with three homozygous frameshift variants, one homozygous missense variant and one intragenic duplication, which justifies including analysis of DCC deletions and duplications in the study of these patients [7].

2.5. RIN2 syndrome: endosomal trafficking and elastic fibres

RIN2 (Ras and Rab interactor 2), at 20p11.23, encodes a ubiquitously expressed protein that interacts with Rab5 and participates in the regulation of early endocytic trafficking [35, 92]. The disease results from biallelic loss of function: the variants described in patients with the full phenotype are truncating; in the original family, the mRNA was reduced and the protein absent from fibroblasts, and in the Algerian family the variant led to nonsense-mediated mRNA decay [8, 35, 92]. In the skin, RIN2 deficiency is associated with a paucity of dermal microfibrils and oxytalan fibres in the papillary dermis and with reduced fibulin-5, a component of elastic microfibrils, with normal elastic and collagen fibres in the reticular dermis [35]. In other patients, electron microscopy showed altered collagen fibril morphology, and fibroblasts had dilated endoplasmic reticulum, a Golgi apparatus with sparse and dilated cisternae and accumulation of vacuoles, which places the disease among the intracellular trafficking defects that affect collagen and elastin together [92, 93]. The mechanism of the scoliosis has not been established; the ligamentous hyperlaxity and osteoporosis described in several patients are plausible contributors, without experimental demonstration [9, 35].

RIN2 variant nomenclature requires care, because the articles used two transcripts whose numbering differs by 147 nucleotides. Normalised to the MANE transcript NM_018993.4 (VariantValidator, GRCh38), the published variants are: c.1731del p.(Ile578SerfsTer4), homozygous in the Israeli Arab family and in a Lebanese patient, recorded in OMIM as c.1878delC according to NM_001242581 [8, 35, 93, 94]; c.1914_1915del p.(Glu638AspfsTer9), in the Algerian family, c.2061_2062delGC in OMIM [8, 92, 95]; c.1731dup p.(Ile578HisfsTer7), in the Turkish family and the Italian patient, published as c.1878dupC (or c.1878_1879insC) p.(Ile627HisfsTer7) according to NM_001242581 [9, 60, 94]; and c.2104dup p.(Leu702ProfsTer9), in the Iranian child, published as NM_001242581.1:c.2251dup p.(Leu751ProfsTer9) [61, 94, 95]. The deletion and the duplication affect the same nucleotide in families of different origins, with no founder effect demonstrated. No genotype-phenotype correlation has been established and expressivity varies: macrocephaly, alopecia and cutis laxa, which gave the syndrome its name, are absent in some patients, whereas progressive scoliosis and buccofacial dysmorphism are the most constant features [8, 92]. In 2017 a patient was published with intellectual disability, cataract and a biallelic RIN2 frameshift variant, without the features of the syndrome [96], and in a consanguineous Pakistani family a patient with a mixed phenotype was homozygous for variants in RIN2 and BBS7, an example of dual diagnosis, while relatives homozygous for only one of the variants had only the corresponding disease [62].

2.6. SSMS: hypomorphic deficiency of heparan sulfate synthesis

EXT2 (exostosin 2), at 11p11.2, encodes a transmembrane glycosyltransferase of the Golgi apparatus that forms with EXT1 a hetero-oligomeric complex with heparan sulfate polymerase activity, responsible for elongation of the glucuronic acid and N-acetylglucosamine disaccharide chain of heparan sulfate proteoglycans [56, 97]. These proteoglycans participate in Wnt and fibroblast growth factor (FGF) signalling in skeletal and brain development [97]. Heterozygous loss of function of EXT2 causes hereditary multiple exostoses type 2, of autosomal dominant inheritance [56]. SSMS, in contrast, results from biallelic variants, almost all missense, that reduce the expression and function of the enzyme without abolishing it. In the original family, the two variants were in cis on the same allele, in the homozygous state; the patients' fibroblasts had less EXT2 protein and mRNA and absence of the NDST1 protein, which interacts with EXT2, despite a normal transcript; and, in in vitro expression, each variant reduced the protein, with a synergistic effect when combined [10, 36]. The disease is understood as a multisystem congenital disorder of glycosylation, caused by a significant but non-lethal reduction in heparan sulfate synthesis [98]; the low blood heparan sulfate concentration in one patient supports this model [63].

In the MANE transcript NM_207122.2 (VariantValidator, GRCh38), the published variants are: c.260T>G p.(Met87Arg) and c.283C>T p.(Arg95Cys), in cis and homozygous in the Mennonite family [36, 63, 94]; c.11C>T p.(Ser4Leu), homozygous in the Syrian siblings [11]; c.679G>A p.(Asp227Asn) and c.1823A>G p.(Tyr608Cys), compound heterozygous in the Italian siblings [95, 98]; and c.1019T>A p.(Val340Asp) and c.1916C>T p.(Thr639Met), compound heterozygous in a North American patient and her dizygotic twin, described in the original article as c.1118T>A p.(Val373Asp) and c.2015C>T p.(Thr672Met) according to transcript NM_000401.3, which encodes an isoform 33 amino acids longer [63, 94]. The p.(Asp227Asn) variant had already been described in patients with multiple exostoses; in the Italian siblings, who had exostoses, it was inherited from the mother, who also had exostoses and a family history of exostoses, whereas the father, a carrier of p.(Tyr608Cys), did not have them [10, 98]. The authors proposed a genotype-phenotype correlation: exostoses occur when one of the alleles is, by itself, a cause of multiple exostoses, and are absent when both alleles are hypomorphic [98]. Expressivity varies within the same family: the twin of the North American patient, with the same variants, had autism spectrum disorder and mild delays, without seizures [63]. ClinVar contains mainly variants of uncertain significance (VUS) in EXT2 with joint annotation of exostoses and SSMS, which reflects the difficulty of assigning each variant to one of the two diseases [95].

3. Clinical Spectrum and Manifestations by System

3.1. Idiopathic scoliosis: natural history

Idiopathic scoliosis can arise at any stage of growth and appears mainly during periods of rapid growth: between 6 and 24 months, between 5 and 8 years and during the pubertal spurt, usually between 11 and 14 years [1]. The rate of worsening is greatest at the onset of puberty, which corresponds to Tanner stages S2/P2 in girls and T2/P2 in boys; menarche occurs when about two-thirds of the spurt has passed, and from then on the risk of progression decreases [1]. According to Bunnell's data reproduced by SOSORT, the risk of progression at the onset of puberty is 20% for a 10° curve, 60% for 20° and 90% for 30°; at the age of peak growth (bone age 13 years in girls) it falls to 10%, 30% and 60%; and in the final phase of puberty (Risser II or more) to 2%, 20% and 30% [1]. The prognosis is more favourable in boys [1]. Female predominance increases with magnitude: the girl-to-boy ratio is 1.3:1 for curves of 10–20°, 5.4:1 for 20–30° and 7:1 above 30° [1].

After the end of growth, smaller curves tend to stabilise. The risk of progression in adulthood begins to increase above 30° and is almost certain above 50°, a magnitude from which scoliosis is associated with health problems, reduced quality of life, visible deformity, pain and progressive functional limitation [1]. Differences in the prevalence of pain are already detectable between 20 and 30 years, and in a follow-up of more than 40 years the prevalence of chronic pain complaints was three times that of the comparison population [1]. Factors associated with a greater risk of progression include a positive family history, skin and joint laxity (suggestive of a connective tissue defect), thoracic hypokyphosis, an angle of trunk rotation greater than 10° and the growth spurt [1]. In a cohort of 5891 Japanese patients, family history was associated with curve severity with an effect dependent on the number of affected relatives, and later menarche was linearly associated with larger Cobb angles; even so, age at menarche and family history explained only 2.7% and 0.2% of the variance in the angle [99].

In early-onset idiopathic scoliosis, progression is concentrated between birth and 5 years and resumes at the onset of puberty, at around 10 years; as the remaining trunk growth is large, the risk of worsening is high, and untreated EOS is associated with significant morbidity and mortality [74]. Below 2 years, Mehta's rib-vertebra angle difference (RVAD), measured at the apical vertebra between the concave and convex ribs, and the phase of the convex rib (phase 1: the rib head does not overlap the apical vertebral body; phase 2: it overlaps) distinguish resolving from progressive forms: a difference of 20° favours the progressive form, and in the original series 83% of children with an initial RVAD below 20° and phase 1 had resolution of the curve [74].

3.2. Congenital scoliosis and TACS

Congenital scoliosis has a heterogeneous course: in a synthesis of series, about a quarter of curves do not progress, another quarter progress slowly and about half eventually require surgery [58]. Progression depends on the type and location of the anomalies and on the asymmetry of growth between the convex and concave sides. A unilateral unsegmented bar tethers one side and causes asymmetric growth, and the combination of hemivertebra with a contralateral bar progresses fastest; multiple or mixed anomalies and location at the thoracolumbar junction are factors for rapid progression, whereas curves of 25° or less rarely progress [58].

TACS has its own profile. In the Chinese cohort of 345 patients, the 33 patients with TACS had earlier onset, presented with one or more hemivertebrae or butterfly vertebrae, with malformations concentrated in the lower half of the spine (from T8 to S5), had simple rib anomalies more often and intraspinal anomalies less often than the other congenital scolioses; the same features were repeated in the Japanese and North American cohorts [4]. In the original series, all 23 patients with a TBX6 null variant had at least one hemivertebra, and the number of hemivertebrae was greater than in patients without a variant [3]. The generalised spondylocostal dysostoses, which include the biallelic TBX6 form, mostly have mild, non-progressive or self-limiting scoliosis, and only rarely require surgery; the LFNG-related form is the most severe [5]. In general, neurological complications of the vertebral anomalies of the spondylocostal dysostoses are rare [78].

3.3. Syndromic scoliosis: frequency and character by entity

The table brings together the frequency and pattern of scoliosis in the main monogenic diseases, with the sources for each value. The frequencies come from series and reviews with different denominators and are not comparable with one another as though they were prevalences.

3.4. Syndromic forms with clinical particularities

In NF1, dystrophic scoliosis is characterised by sharp angulation of a short segment of the spine, appears much earlier than common adolescent scoliosis and may worsen within a few months of becoming evident; the non-dystrophic form resembles idiopathic scoliosis in age at onset and course [26]. In a systematic review of 761 patients operated on for dystrophic scoliosis, the mean age per study ranged from 7 to 22 years and the mean preoperative Cobb angle was 75.2°, which reflects the severity with which these curves reach surgery [104].

In the kyphoscoliotic forms of Ehlers-Danlos, the deformity is present at birth or in the first year of life and is associated with congenital hypotonia; adults with severe kyphoscoliosis are at risk of restrictive lung disease, recurrent pneumonia and heart failure, and rupture of medium-sized arteries is the most important fatal complication [22]. In FKBP14-kEDS, congenital hypotonia and weakness tend to improve during childhood, but the kyphoscoliosis progresses [23]. In congenital contractural arachnodactyly, kyphoscoliosis may be congenital, progresses and is the manifestation that weighs most on morbidity [21].

In EOS, neuromuscular scoliosis is, in the great majority of cases, progressive and becomes rigid over time; in congenital scoliosis, progression depends on the type and location of the structural anomaly; in syndromic scoliosis it is less predictable and depends on the syndrome, age at onset and remaining growth [74]. Pelvic obliquity, frequent in the neuromuscular forms, unbalances the spine and creates points of ischial skin hyperpressure, and major coronal deformities may cause painful costo-iliac impingement [74]. In the neuromuscular disorders, the pattern of scoliosis depends on walking ability. In SMA, non-ambulant patients may also develop thoracic kyphosis at a late stage [27]. In Rett syndrome, maintenance of walking, independent or assisted, is associated with less progression, and the Cobb angle and walking ability at 10 years make it possible to identify those who will develop very severe scoliosis (greater than 60°) by 16 years [90]. In Duchenne dystrophy, the risk increases when the patient starts to use a wheelchair (at 12 years most depend on the wheelchair and have contractures, scoliosis and thoracic deformity; at 20 years, kyphoscoliosis and respiratory failure) [105], and corticosteroid treatment is associated with milder curves and less need for surgery [28, 70].

In HGPPS, the absence of conjugate horizontal movements is present from birth, with preserved vertical gaze and convergence; children compensate with head turning, and vision, visual fields and pupils are normal [66, 91]. Scoliosis appears in childhood or adolescence and progresses, but is not obligatory: in a series of five patients it was present in two, and two siblings aged 5 and 2 years with confirmed ROBO3 variants did not have it [66, 103]. OMIM describes cognition as normal in HGPPS1 [47], but there are reports of delay: the two siblings mentioned had moderate and mild psychomotor delay [66]. As the motor and sensory tracts do not decussate, a unilateral hemispheric lesion may cause ipsilateral hemiparesis, and three cases with hemiplegia ipsilateral to the brain lesion have been published [91].

Two series from populations with consanguinity refine the picture of HGPPS. In the Turkish series of six patients, the median age at symptom onset was 1.5 years (0.5–4) and at diagnosis 11 years (2–16); oculomotor signs were the presentation in four and scoliosis in two; scoliosis was progressive, accompanied by kyphosis, with intrafamilial variability, and was corrected surgically in three; mild intellectual disability in four, hypergonadotrophic hypogonadism in two, hearing loss in two and transient movement disorders in one were also described, as well as nystagmus and head titubation in some patients [106]. In the Tunisian series of 13 patients from six consanguineous families, the deformity was detected in early childhood in all, torticollis accompanied the picture or prompted the consultation in five, Cobb angles at diagnosis ranged from 10° to 120°, and seven patients underwent surgery (two with growing rods and five with arthrodesis), with an eighth awaiting surgery [107]. HGPPS2 (DCC) is distinguished by intellectual disability and generalised loss of the commissures of the central nervous system at several levels of the neuraxis; heterozygous DCC variants are associated with congenital mirror movements, not with HGPPS [108].

3.5. Respiratory impact and other complications

Severe scoliosis limits the capacity of the thoracic cage, respiratory mechanics, exercise tolerance and work capacity [1]. In the severe spondylocostal dysostoses, the small thorax may compromise neonatal respiratory function; by 2 years lung growth usually allows almost normal development, but in patients with severe restriction pulmonary hypertension may eventually affect cardiac function [5]. In operated congenital scolioses, the presence of heart disease was associated with lower forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak expiratory flow [109].

In EOS, a curve with a Cobb angle greater than 45° may cause a restrictive ventilatory syndrome; in the neuromuscular disorders, the restrictive component is compounded by an obstructive component (asthma, accumulation of bronchial secretions, gastro-oesophageal reflux) and a central component (apnoeas) [74]. Thoracic deformity may mask the objective signs of heart failure, such as crackles and hepatomegaly, and in the neuromuscular forms swallowing disorders, gastro-oesophageal reflux and paralytic constipation compromise nutritional status [74].

3.6. RIN2 syndrome: clinical picture

In the original family, three patients aged 15, 32 and 35 years, with normal psychomotor development, had macrocephaly (head circumference +3 and +2 standard deviations, SD, in the two measured), downslanting palpebral fissures, oedematous and drooping eyelids, sagging cheeks, everted lower lip, retrognathia, gingival hyperplasia, irregular dentition with impacted teeth, sparse hair with a receding frontal hairline, high-pitched voice, severe joint hyperlaxity and flat feet; the skin was soft and redundant, especially on the face, without easy bruising, atrophic scars or blue sclerae [35]. Scoliosis was severe in the youngest patient and mild in the other two, and short stature resulted mainly from it; the 15-year-old patient had severe kyphoscoliosis with back pain, mild aortic dilatation and an umbilical hernia, and one of the adults had generalised osteoporosis, more marked in the spine, and a fracture [35]. Facial sagging was more marked in the two older patients, which indicates a progressive phenotype; there was no visceral involvement [8, 35].

In the patients described later, progressive coarse facies, gingival hyperplasia, sparse hair, skin and joint hyperextensibility and scoliosis remained core features, and head circumference was normal or increased: true macrocephaly (+3 SD) was initially observed in two of five patients and regressed in one of them [8, 60, 92]. The three Algerian siblings had sparse hair instead of alopecia, did not have cutis laxa and had a dermatological and ultrastructural phenotype closer to the Ehlers-Danlos spectrum [92]. The following were added to the spectrum: bronchiectasis, osteoporosis and hypergonadotrophic hypogonadism in two Turkish siblings with normal intelligence and progressive scoliosis [9]; cervical vertebral fusion, mild hearing loss and colonic fibrosis in the Italian patient, the first of European origin and the oldest described [60]; and white matter changes on magnetic resonance imaging (MRI), with periventricular cystic lesions and sparing of the U fibres in an 18-year-old patient with the c.1731del variant [68] and with diffuse abnormal signal, anterior temporal subcortical cysts and enlarged perivascular spaces in a 4-year-old Iranian child with normal development, with no change on follow-up MRI at 5 years [8, 61]. Cognition is as a rule normal, but an 18-year-old Lebanese patient had intellectual disability (intelligence quotient of 62), macrocephaly of +3.5 SD, short stature (156 cm), cutis laxa of the hands, ankles, wrists and neck, thoracic deformity without scoliosis and brachydactyly [8, 93]. The Iranian child also had easy bruising and an umbilical hernia [8]. No vascular ruptures or severe visceral complications have been described, but aortic dilatation in one patient justifies cardiovascular assessment [35].

3.7. SSMS: clinical picture

The four Mennonite siblings, young adults, had psychomotor delay from childhood, poor speech, seizures of various types beginning between 2 and 5 years (one had status epilepticus with brain injury and hemiparesis), macrocephaly and scoliosis, as well as hypotonia, coarse facies with hypertelorism, cutaneous hypersensitivity, low bone density, gastro-oesophageal reflux, intestinal malrotation, diarrhoea or constipation and cryptorchidism in the boys; apart from scoliosis, they had no evident skeletal anomalies or exostoses [10, 36]. Two had cerebral haemorrhage and two haematuria with proteinuria, in one case with haemolytic uraemic syndrome and need for dialysis; one or two had a broad-based gait, ventricular septal defect, arterial hypertension, liver dysfunction, overlapping toes or tremor [10]. The Syrian siblings had a more severe picture: severe global delay without walking or speech at 8 and 5 years, microcephaly, hypotonia, feeding difficulties with tube feeding in one of them, constipation, osteopenia, neurological regression and refractory epilepsy from the first years, with generalised and multifocal discharges and hypsarrhythmia in one of them; a probably affected sister died at 7 years of respiratory distress [10, 11]. The Italian siblings, aged 21 and 15 years, had a patent ductus arteriosus at birth, seizures in the first years, global delay and intellectual disability (severe in the brother, with walking at 3 years, limited language, repetitive behaviour and a thin corpus callosum; milder in the sister, who attended mainstream school with support), dysmorphism (large head with high forehead, hypertelorism, bulbous nasal tip, long philtrum, prominent lower lip, large ears, preauricular tags, sparse hair), distal anomalies of the hands and feet, osteopenia, scoliosis and multiple exostoses at the knees and elbows [10, 98]. The North American patient, aged 14 years, had developmental delay with language regression at 27 months, autism, focal seizures from 10 years, macrocephaly, high forehead, hypertelorism, long philtrum, preauricular pits, strabismus, reflux and constipation, with normal brain MRI, without scoliosis or exostoses [63].

In the comparison of the ten patients published up to 2019, developmental delay, intellectual disability and speech delay were present in all, seizures in nine, hypotonia in seven, macrocephaly in six and microcephaly in two, scoliosis in five, cardiovascular anomalies in four, autism in three and exostoses in two [63]. Scoliosis is not obligatory; the name of the syndrome reflects the first family, and the designation AREXT2 was proposed to cover the whole spectrum [11, 98]. The age of the scoliosis, its severity and orthopaedic treatment are not described in detail in the publications.

4. Clinical Recognition and Warning Signs

4.1. Screening for adolescent idiopathic scoliosis

Screening for AIS is the point on which societies diverge most. The United States Preventive Services Task Force (USPSTF) concluded in 2018 that the evidence is insufficient to assess the balance of benefits and harms of screening in asymptomatic children and adolescents aged 10 to 18 years (I statement), updating the 2004 recommendation; it found no direct evidence on the effect of screening on health outcomes or on its harms, considered adequate the evidence that bracing can slow the progression of mild to moderate curves and inadequate the evidence on exercise and surgery [110]. The evidence report that supported it included 14 studies with 448,276 participants: accuracy was highest in a clinical programme combining the forward bending test, the scoliometer and Moiré topography (306,082 participants; sensitivity 93.8% and specificity 99.2%) and was lower in programmes with fewer modalities [111].

The American Academy of Orthopaedic Surgeons (AAOS), the SRS, the Pediatric Orthopaedic Society of North America (POSNA) and the American Academy of Pediatrics (AAP) jointly published a statement in favour of early detection, with screening of girls at 10 and 12 years and of boys once at 13 or 14 years [112]. SOSORT likewise recommends screening of asymptomatic adolescents and notes that the contrary recommendations rest on evidence of lower quality than the favourable ones; it also records that some US states make it mandatory, that British and Canadian recommendations do not mention scoliosis and that Australian bodies advise against it [1]. Adams's forward bending test used alone is insufficient, as it generates many referrals (OR 2.91) with a low positive predictive value for curves of 10° or more (OR 0.49) and of 20° or more (OR 0.34), so objective measurement with a scoliometer is recommended; with a trunk rotation threshold of 5°, the referral rate for radiography was 5.2% in one of the series cited [1].

4.2. When to suspect a genetic or secondary cause

Idiopathic scoliosis is a diagnosis of exclusion. The data in the sources point to the following elements as indicators that the curve may have an underlying cause that changes management:

The initial examination of EOS begins with a history covering prenatal and birth history, allergies, personal and family history and, in children with disabilities, the orthoses and school adaptations already in place; the physical examination records height and weight, looks for café-au-lait macules, a sacrococcygeal dimple and generalised hyperlaxity, measures joint ranges, tests sensation, motor function and limb and abdominal cutaneous reflexes, and includes Adams's forward bending test, because the rib hump, a consequence of axial rotation of the trunk, is the pathognomonic sign of scoliosis; it also assesses, standing, coronal and sagittal balance, the pelvis, the shoulders and the chest wall [74].

4.3. Emergency signs

In some entities, the spine may cause spinal cord compression, and detection of this complication changes the urgency of assessment. In diastrophic dysplasia, cervical kyphosis present at birth may progress in childhood and cause spinal cord compression with tetraparesis and death, an indication for surgical stabilisation [31]. In metatropic dysplasia, hypoplasia of the upper cervical vertebral bodies and of the odontoid may give rise to cervical hypermobility and spinal stenosis, which requires special care during anaesthesia [32]. In SEMD with joint laxity, Beighton type, the spinal deformity may lead to spinal cord compression [25]. In RIPPLY2-related spondylocostal dysostosis, C2-C3 cervical kyphosis was associated with spinal cord compression [5]. In Loeys-Dietz syndrome and in mcEDS there is cervical or atlantoaxial instability [20, 24]. Dystrophic scoliosis of NF1 may progress within months [26].

4.4. Prenatal detection

Vertebral anomalies can be detected on first- and second-trimester ultrasound. In the published case of prenatal TACS, the spinal anomaly was suspected at 13 weeks and characterised at 17 weeks as an abnormal arrangement of the thoracic and sacrococcygeal vertebrae with scoliosis [64]. Prenatal detection of vertebral anomalies justifies a search for associated anomalies and genetic study by microarray and sequencing (section 5.7).

In France, fetal spinal anomalies are relatively frequent (1 in 500–600 births, according to the obstetric source cited by the PNDS), but not all progress to deformity; the PNDS recommends that prenatal suspicion of vertebral malformation, neuromuscular disease or syndrome should lead to a prenatal consultation with a specialist surgeon, to discuss the natural history and the consequences of a possible deformity [74]. After birth, the usual reasons for consultation are postural disturbance, asymmetry of the trunk or shoulders and torticollis noticed by the parents [74].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnosis of scoliosis and its magnitude

The diagnosis rests on the standing anteroposterior radiograph, with measurement of the Cobb angle, and requires a curve of 10° or more with rotation [1, 110]. Skeletal maturity, assessed by the Risser classification (0 to 5, according to ossification of the iliac apophysis), enters into every decision, because it defines the remaining growth [69]. When the decision depends on a variation of a few degrees, measurement error must be taken into account [1]. In obese patients, clinical assessment of the curve is unreliable and radiography is required, both in Prader-Willi syndrome and in Duchenne dystrophy [59, 70].

In the criteria for the connective tissue disorders, scoliosis is counted with its own definitions. In the revised Ghent nosology for Marfan syndrome, scoliosis or thoracolumbar kyphosis is worth 1 point in the systemic score [19]. The same criteria define scoliosis radiographically as a Cobb angle of 20° or more and consider an increased arm span/height ratio (greater than 1.05 in the adult) only in the absence of significant scoliosis, because the curve reduces height [21].

Children with EOS accumulate radiographs over years of treatment. The EOS low-dose biplanar radiography system (EOS Imaging, Paris) reduces exposure 6 to 9 times compared with conventional radiography, and the «micro-dose» protocol up to about 45 times; the image should be obtained in a functional position, standing or, in patients who do not walk, sitting, and the system allows frontal and lateral views in the sitting position [74]. Whole-body biplanar radiography is the reference examination for diagnosis and follow-up and can be performed from 6 years, or earlier if the child tolerates standing still during acquisition [74]. Previous images should be retrieved to document progression, especially during periods of rapid growth; CT is reserved for structural anomalies, such as congenital scoliosis, with age-adapted low-dose protocols; and MRI explores the spinal cord from the craniocervical junction to the conus medullaris [74]. As curves exceeding 20° before 10 years have neuraxis anomalies in 17.6–26% of series, the PNDS recommends screening MRI in all EOS with curves greater than 20°, even with a normal neurological examination; in idiopathic scoliosis, MRI is accepted for atypical curves (associated kyphosis, left thoracic curve), rapid progression, back pain and abnormal neurological examination [74].

5.2. Assessment of congenital scoliosis

Congenital scoliosis requires assessment of the whole neuraxis and of other systems, because associated anomalies are frequent and alter the surgical plan.

On the basis of these data, MRI of the neuraxis is recommended in all patients with congenital scoliosis, to be repeated with growth because some anomalies are not visible at very early ages, together with renal ultrasound even without symptoms and cardiac assessment [58]. Computed tomography (CT) with three-dimensional reconstruction is used in surgical planning and may show up to 50% more anomalies than plain radiography, but the radiation dose weighs on children who will have serial imaging [58]. In patients with associated heart disease, assessment of respiratory function before surgery becomes more important, as they have lower FEV1 and FVC [109].

5.3. Recognition and confirmation of TACS

The TACScore integrates four variables: segmented hemivertebrae or butterfly vertebrae in the lower half of the spine (T8–S5), number of vertebral malformations, presence of intraspinal defects and type of rib defect. The score ranges from −8 to 4; with a threshold of 3 or more, sensitivity, specificity and accuracy were greater than 90% in the derivation cohort (area under the curve [AUC] 0.9; 95% CI 0.9–1.0) and the AUC was 0.8 (0.7–0.9) in the Japanese validation [4]. The score serves to choose whom to test and does not replace the test.

Confirmation requires identification of both alleles. The 16p11.2 deletion is the most frequent null variant and is detected only by copy number analysis (chromosomal microarray or CNV analysis from exome data); sequencing detects point variants; and the T-C-A haplotype has to be genotyped, which may not appear in panel or exome reports that filter out common variants [3, 4]. An isolated heterozygous null allele does not, by itself, explain the scoliosis, and the report should state the phase (cis or trans) when it can be determined by study of the parents [3, 64]. GeneReviews points out that large deletions and duplications of TBX6 have not been described in recessive spondylocostal dysostosis, but are the rule in congenital scoliosis due to compound inheritance [5].

5.4. Tests in the syndromic forms

When kEDS-PLOD1 is suspected, the major criteria are congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or not) and generalised joint hypermobility with dislocations or subluxations; the minor criteria include skin hyperextensibility and fragility, rupture or aneurysm of a medium-sized artery, osteopenia, blue sclerae with ocular fragility, hernia, pectus, marfanoid habitus, clubfoot, refractive errors and microcornea; the minimal suggestive picture is congenital hypotonia and early kyphoscoliosis associated with generalised hypermobility or three minor criteria [22]. Confirmation is molecular (biallelic PLOD1 variants, including a search for the Alu-Alu duplication); if only one variant or a variant of uncertain significance (VUS) is found, the urinary deoxypyridinoline to pyridinoline ratio by high-performance liquid chromatography, about 0.2 in normal individuals and about 6.0 in kEDS-PLOD1, is a highly sensitive, specific and inexpensive test that distinguishes the disease from all other entities in the differential diagnosis, which maintain a normal ratio [22]. In FKBP14-kEDS, confirmation requires biallelic FKBP14 variants [23]. In Loeys-Dietz syndrome, the initial assessment includes spinal radiographs with cervical flexion and extension views [20]; in Marfan syndrome lumbar MRI may be considered for dural ectasia [19].

In undiagnosed EOS, exome sequencing is a reasonable first-line test: in a cohort of 447 operated Chinese patients, it identified the molecular diagnosis in 92 (20.6%), of whom 84 had a clinically unrecognised disease; in a North American group of 13 patients with idiopathic EOS, it identified one [67]. The predictors of a molecular diagnosis were age at presentation, number of systems involved and magnitude of the curve [67]. In AIS, genome sequencing finds clinically relevant variants in a minority [82], and GWAS risk polymorphisms have no individual diagnostic utility [17].

5.5. HGPPS

MRI is usually the first examination to suggest the diagnosis, which should be confirmed by ROBO3 analysis [65]. The characteristic findings are brainstem hypoplasia with a midline cleft in the pontine tegmentum (the «split pons» sign) and a butterfly configuration of the medulla [91, 103]. Diffusion tensor imaging (DTI) and tractography show uncrossed corticospinal tracts and absent decussation of the superior cerebellar peduncles, and somatosensory evoked potentials are predominantly ipsilateral [66, 91]. In patients with intellectual disability and the same picture, DCC should be included, with deletion and duplication analysis [7].

5.6. RIN2 syndrome and SSMS

There are no formal diagnostic criteria for either entity, and the diagnosis is molecular. In RIN2 syndrome, the facial gestalt is considered characteristic and the cutis laxa is mild, manifesting mainly as redundant facial skin; in a series of cutis laxa with neurological involvement, the association of scoliosis and alopecia was used to direct RIN2 sequencing [57, 68]. Exome sequencing, or an extended panel of connective tissue disorders (cutis laxa and Ehlers-Danlos), with copy number analysis, is the first-line test. Transferrin isoelectric focusing and the apolipoprotein C-III profile were normal in the original family, which helps to exclude the cutis laxas with a glycosylation defect, such as ATP6V0A2-CDG [35, 57]. Skin biopsy with electron microscopy is not required for the diagnosis, but shows a paucity of microfibrils and oxytalan fibres in the papillary dermis or alterations of the collagen fibrils [35, 92].

In SSMS, the diagnosis usually emerges from exome sequencing requested for developmental delay and epilepsy, and scoliosis and exostoses may be absent [63]. Interpretation of the variants is difficult for three reasons: almost all are missense; EXT2 is known mainly as a gene for dominant exostoses, so an isolated heterozygous variant in a patient with intellectual disability does not explain the picture; and the variants of the North American patient were initially classified as VUS, in a gene then considered of uncertain significance for neurodevelopmental disease [63]. Parental segregation, with demonstration of two variants in trans, is indispensable. In the same patient there was a heterozygous variant of uncertain significance in NDST1, the gene of another recessive disorder of heparan sulfate synthesis, without a second variant or deletion, and its contribution remained unresolved [63]. Heparan sulfate, measured in the mucopolysaccharidosis screening requested because of the coarse facies, was low in dried blood (12 nmol/L, at the 1st percentile of the paediatric reference) and in serum (4.46 ng/mL, below the 1st percentile), and was described as low in urine; the finding supports pathogenicity, but has not been validated as a diagnostic test [63]. Once the variants have been identified in the parents, prenatal and preimplantation diagnosis are possible in both entities.

5.7. Algorithm

5.8. Limitations of the tests and report content

A negative result does not exclude a genetic cause. Sequencing alone does not detect the 16p11.2 deletion or the intragenic PLOD1 duplication if CNV analysis is not performed [3, 22]; the hypomorphic TBX6 haplotype may be filtered out as a common variant [3]; and most idiopathic scolioses have no identifiable monogenic cause [17]. The report should state the gene, the transcript with version (for example NM_004608.4 for TBX6), the HGVS nomenclature, the zygosity, the phase when known and the classification according to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); VUS should not guide clinical decisions and benefit from segregation studies [22].

5.9. Prenatal diagnosis

When a fetal vertebral anomaly is suspected on ultrasound, the work-up includes karyotype, microarray and, when available, trio exome, because a combination of alterations is possible: in the published case of prenatal TACS, trio exome identified the TBX6 null variant and the hypomorphic haplotype, and CNV analysis also revealed a maternally inherited 17q12 deletion, which complicated counselling [64]. GeneReviews considers molecular testing the standard for prenatal diagnosis in families with spondylocostal dysostosis in which the variants are known [5].

The French PNDS recommends genetic counselling for couples when a spinal malformation associated with other anomalies (cardiac, renal, urinary, genital or musculoskeletal) is suspected or confirmed in the prenatal period, with the possibility of karyotyping on amniotic fluid [74]; karyotype alone does not detect the 16p11.2 deletion or TBX6 variants, so, when TACS or another monogenic cause is suspected, the work-up should include microarray and sequencing [3, 64].

5.10. Initial assessment of comorbidities in early-onset scoliosis

The French PNDS makes the extent of the assessment depend on the severity and cause of the deformity and allows it to be carried out in a multidisciplinary clinic or during a short admission to a reference centre [74].

6. Differential Diagnosis

6.1. Principle

The differential diagnosis of scoliosis is made on two levels: first, distinguishing structural from postural scoliosis and idiopathic from secondary scoliosis; then, faced with a secondary cause, identifying the entity. SOSORT points out that there are congenital postural curves in the newborn, resulting from intrauterine compression due to fetal malposition, which are not three-dimensional deformities [1].

The French EOS PNDS includes among the congenital and structural causes several acquired or non-Mendelian entities that enter the differential diagnosis: thoracogenic curves after thoracotomy, tumours (before or after resection), amniotic band sequence, hemihypertrophy, congenital diaphragmatic hernia, congenital heart disease after repair, Proteus syndrome, Jeune syndrome, constrictive chest wall syndrome, Jarcho-Levin syndrome and the spondylothoracic and spondylocostal dysostoses, Klippel-Feil syndrome and the VATER/VACTERL association [74]. Among the syndromic forms, in addition to the entities in the table, it lists achondroplasia, arthrogryposis, Ellis-van Creveld syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia, Down syndrome and Goldenhar syndrome [74]. Among the neuromuscular forms, it adds to the hereditary causes, such as the hereditary neuropathies and myelomeningocele, acquired causes such as cerebral palsy, acute anterior poliomyelitis and spinal cord injury [74].

6.2. Table of the main entities

6.3. Differentials with the greatest impact

The distinction between idiopathic scoliosis and syndromic scoliosis with vascular risk is the one that most changes management, because an adolescent with scoliosis and marfanoid features who has Marfan syndrome, Loeys-Dietz syndrome or kEDS needs cardiovascular surveillance and specific anaesthetic and surgical precautions [19, 20, 22]. Some severe AIS with rare FBN1 variants do not meet the Marfan criteria, which shows that there is a continuum and that the absence of criteria does not exclude a fibrillin alteration [18].

Within the congenital scolioses, TACS is distinguished from the syndromic forms by the usual absence of anomalies of other organs apart from simple rib anomalies and by the low location of the hemivertebrae, and from the spondylocostal dysostoses by involving few vertebrae rather than the whole spine [4, 5]. Sporadic segmentation defects, which are more frequent, are as a rule unilateral and restricted to a few vertebrae or to one region [78].

In the differential diagnosis of congenital horizontal gaze palsy, Möbius syndrome and Duane syndrome usually present other signs of cranial nerve nucleus agenesis and lack the split pons sign; congenital fibrosis of the extraocular muscles presents with ptosis and downward-deviated eyes; and chronic progressive external ophthalmoplegia, of mitochondrial origin, combines ptosis, visual deficits, weakness and cardiac involvement [91].

RIN2 syndrome overlaps with the recessive cutis laxas and with the kyphoscoliotic and dermatosparaxis forms of Ehlers-Danlos [60]. It is distinguished from the recessive cutis laxas by skin laxity predominating on the face and becoming more marked with age, by normal glycosylation and by the absence of cortical malformations and epilepsy (ATP6V0A2), frequent fractures (GORAB) or dystonia and a progeroid appearance (PYCR1, ALDH18A1) [35, 57, 68]. The coarse facies and gingival hyperplasia may suggest a lysosomal disorder, but the patients in the original family had no hepatosplenomegaly, thrombocytopenia, dysostosis multiplex or progressive neurological course [35]. Costello syndrome may also present with cutis laxa and should be considered [68]. Scoliosis or kyphoscoliosis also occurs in other hereditary cutis laxas, dominant and recessive, including the De Barsy forms, which makes the facial pattern, the evolution with age and molecular testing the discriminating elements [116].

In SSMS, the differential diagnosis includes the other disorders of heparan sulfate biosynthesis, in particular recessive intellectual disability due to NDST1, with hypotonia, epilepsy and speech delay, and the contiguous deletion syndromes with multiple exostoses and intellectual disability (Potocki-Shaffer and Langer-Giedion), which justifies CNV analysis [56, 97]. The other defects of glycosaminoglycan synthesis (for example, B3GALT6, B3GAT3, CHST3, CHST14) combine kyphoscoliosis with skeletal dysplasia, dislocations or skin laxity, without the dominant epileptic picture of SSMS [117]. In the mucopolysaccharidoses with heparan sulfate accumulation the concentration is increased, in contrast to the low value described in SSMS [63].

In kEDS, all the differentials (other forms of Ehlers-Danlos, Marfan, Loeys-Dietz, mcEDS, the spondylodysplastic form, brittle cornea syndrome) maintain a normal urinary Dpyr/Pyr ratio, which makes this test the main biochemical discriminator [22]. SEMD with joint laxity, Beighton type, may be mistaken for a pure form of Ehlers-Danlos in childhood and overlaps with B4GALT7 deficiency, which is usually less severe; the autosomal dominant (FLNB) and recessive (CHST3) forms of Larsen syndrome are distinguished by radiographic signs in the carpals, calcaneus and vertebrae [25].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no pharmacological treatment directed at scoliosis, whether idiopathic or of genetic cause. Treatment is conservative (observation, specific exercises, bracing or casting) or surgical (fusion, growth-preserving or growth-modulating techniques), and in the syndromic forms treatment of the underlying disease is added, which may modify the evolution of the curve, as happens with corticosteroids in Duchenne dystrophy [1, 70]. The goals of conservative treatment during growth were set by SOSORT consensus (level of evidence VI, strength C), with a minimum and a maximum goal for each clinical situation [1]. Conservative treatment should be delivered by a team with a physician, physiotherapist, orthotist and, ideally, psychologist, and all methods require the active participation of the patient and family [1].

In EOS, the French PNDS sets the goal of limiting curve progression while preserving growth of the trunk and thoracic cage, because the deformity appears or worsens while the chest wall and pulmonary alveoli are developing; the decision weighs age, skeletal maturity and growth potential, curve magnitude and global balance, the underlying diagnosis, pulmonary status and comorbidities [74]. Confirmation of the diagnosis and the therapeutic decision should take place in a reference or competence centre for paediatric spinal disorders, with multidisciplinary assessment (obstetrics, neurology, genetics, physical and rehabilitation medicine, neurosurgery, respiratory medicine, nutrition, psychiatry, radiology, physiotherapy, orthotics, therapeutic education nursing, dietetics, psychology and social work) coordinated by the orthopaedic surgeon; the attending physician is responsible for ensuring confirmation at a centre, follow-up by a qualified team and surveillance of complications in liaison with that team [74].

7.2. Idiopathic scoliosis: conservative treatment

SOSORT organises the options on a scale of increasing intensity: observation at intervals of 36, 12, 8, 6 or 3 months; physiotherapeutic scoliosis-specific exercises (PSSE); night-time rigid brace (8–12 hours a day); specific rehabilitation inpatient programme; soft brace (for example SpineCor); part-time rigid brace (12–20 hours); full-time rigid brace (20–24 hours) or cast; very rigid brace; and surgery [1]. For each combination of age, maturity and angle, the guideline defines a minimum and maximum admissible treatment; for example, for a low-magnitude curve, a juvenile child is observed every 3 months and an adolescent with Risser 0–3 every 6 months, whereas an adolescent with Risser 4 is observed every 12 months [1]. Casting is considered the standard in infantile scoliosis [1].

The main SOSORT recommendations on bracing, with the strength of recommendation and the level of evidence, are as follows [1]:

The evidence supporting bracing comes mainly from the BrAIST trial (Bracing in Adolescent Idiopathic Scoliosis Trial). The trial included adolescents aged 10 to 15 years, with Risser 0–2 and a main curve of 20° to 40°, at 25 centres in the United States and Canada, with a randomised cohort and a preference cohort; of the 242 patients analysed, 116 were randomised [69]. The trial was stopped early for efficacy: the success rate (skeletal maturity without progression to 50° or more) was 72% with bracing and 48% with observation in the combined analysis (adjusted OR 1.93; 95% CI 1.08–3.46) and 75% versus 42% in the intention-to-treat (ITT) analysis of the randomised cohort (OR 4.11; 95% CI 1.85–9.16) [69]. The benefit depended on hours of wear, measured by temperature sensors: the lowest wear quartile (0–6 hours a day) had a success rate of 41%, similar to observation, and a mean wear of at least 12.9 hours a day was associated with a success rate of 90–93% [69]. The Cochrane review cited by SOSORT rated the evidence in favour of bracing as of very low quality, largely because randomised trials fail owing to parents' refusal to accept randomisation [1].

7.3. Early-onset scoliosis

In infantile idiopathic scoliosis, serial derotation casting is the most widely used treatment [1]. In a series of 21 children without syndromes or developmental delay, with a mean Cobb angle of 48° (24–72°) and first cast at a mean of 2.1 years, followed for 3.5 years, a higher body mass index (BMI) was associated with response (each unit increased the probability of improvement 2.38 times), and onset before 1.8 years and derotation were considered determinants of success [118]. When surgery is needed before the end of growth, magnetically controlled growing rods (MCGR) allow outpatient distraction by external remote control and avoid repeated surgery; a systematic review of 23 studies (504 children under 10 years with Cobb greater than 40°, mean age 8.7 years, mean follow-up 28.9 months) showed reduction of the Cobb angle and of kyphosis [2]. There is an expert consensus on contraindications to MCGR [119]. In forms with thoracic insufficiency, such as the spondylocostal dysostoses, the vertical expandable prosthetic titanium rib (VEPTR) is used [5].

The French PNDS defines the therapeutic sequence for EOS. Simple observation is reserved for patients with a mature skeleton and balanced, non-evolutive curves, and some forms, such as the isolated vertebral block, have a lower tendency to worsen; in the others, the suggested protocol includes biplanar radiographs every 6 to 12 months, according to age and growth phase, with repeated measurement of the Cobb angle, and observation continues until the coronal curve exceeds 25° with documented progression greater than 10°, at which point a brace or cast is applied according to age [74]. Physiotherapy has not been shown to influence the progression of the deformity in this population, but remains indispensable to prevent and treat complications, especially respiratory ones, and the comorbidities of the underlying disease [74]. Bracing is recommended in skeletally immature patients with curves of 25° to 40° [74].

Derotation casting is potentially curative in infantile idiopathic scoliosis, but its effect in non-idiopathic forms remains uncertain, because structural anomalies reduce the efficacy of casting and bracing; in a series of 55 children with progressive infantile scoliosis, 89% had a reduction of the curve [74]. Earlier onset, a curve below 60° and idiopathic aetiology are associated with a better result [74]. Classic application under general anaesthesia and in traction carries a risk of spinal cord injury, so the PNDS recommends neurophysiological monitoring during the procedure, and application with the child awake is becoming widespread to reduce neurological risk; the complications described include pressure ulcers under the cast, gastro-oesophageal reflux, vomiting and respiratory decompensation and, among the serious ones, subclavian vein thrombosis and spinal cord trauma during traction [74]. Data on bracing in EOS are scarce and come from small series (following table); the PNDS considers it an option in idiopathic scolioses, because of the flexibility of these spines and because it is better tolerated than casting, and notes that few studies have compared the two methods [74].

In severe deformities, halo traction (halo-gravity) reduces curve magnitude and improves respiratory mechanics and nutritional status before surgery. It usually lasts 2 to 12 weeks, according to general condition and radiographic improvement, and achieves 30–44% of the correction in the sagittal and coronal planes before placement of growing rods or definitive fusion; the traction weight is increased slowly up to 30–50% of body weight, according to tolerance, with daily neurological examination at each increase; the most frequent complications are pin infection and halo loosening, and neck and trapezius pain, which is common, eases with slow progression of the weight [74].

When non-operative treatment fails, early thoracic fusion should be avoided so as not to restrict the chest wall or cardiopulmonary development during growth; the historical idea that a short, straight spine would be preferable to a long, crooked one has been abandoned [74]. The exception is congenital scoliosis caused by a single anomalous vertebra, such as a hemivertebra, in which osteotomy or excision with short-segment fusion at an early age may be curative [74]. In the other cases, techniques that allow some spinal growth are preferred, at the cost of a high complication rate, prolonged treatment and additional costs [74].

In traditional growing rods, the dual-rod technique is now preferred: distal anchorage with, as a rule, four pedicle screws, proximal anchorage at three levels with at least five fixation points, rods contoured for the sagittal plane and placed submuscularly, and connectors near the thoracolumbar junction; the choice of distal levels takes into account pelvic obliquity and the magnitude and location of the curve, and screw-only constructs showed, in biomechanical studies, greater stability and fewer implant complications than hook constructs [74]. Lengthening is usually performed every 6 to 12 months, and more frequent lengthenings (interval of 6 months or less) were associated with greater correction, better quality of life and greater T1–S1 growth [74]. As neuromonitoring changes occurred in 0.9% of rod placements or exchanges and in 0.5% of lengthenings, systematic intraoperative monitoring is recommended in primary surgery and in exchanges [74]. Magnetic rods, with indications and surgical technique similar to those of traditional rods, allow lengthening in clinic, without anaesthesia or sedation, with confirmation by radiography or by ultrasound, which reduces radiation [74]. The VEPTR, developed from a chest wall prosthesis placed in 1987 in a ventilated 8-month-old infant with thoracic insufficiency syndrome, is anchored to the posterior arches of the ribs and distally to the spine; it provides more solid anchorage in extreme cases, particularly neuromuscular ones, and avoids the verticalisation of the ribs seen with growing rods («Christmas tree effect»), but the complication rate requires case-by-case decisions in expert centres [74]. Guided-growth techniques (Shilla and modern Luque trolley) avoid repeated surgical lengthenings, but remain marginal; the classic Luque trolley, with sublaminar wires, fell into disuse because of complications, spontaneous fusion and insufficient preservation of growth, and with the Shilla technique controversy arose over metal ions in the blood and peri-implant tissues [74].

These series are small, mostly retrospective and with different definitions of success, and the values were extracted as summarised by the PNDS; the document itself stresses that there are few studies with a high level of evidence and that part of the management, including the surveillance schedule, rests on expert consensus [74].

7.4. Surgery and growth modulation in idiopathic scoliosis

Curves greater than 50° at the end of growth carry a high risk of progression in adulthood and are the usual indication for surgery [69]. Growth modulation by vertebral body tethering (VBT) has a single device authorised in the United States, through a humanitarian device exemption (HDE), a process for small populations that requires demonstration of safety and probable benefit, not of effectiveness:

These studies do not allow indirect comparison with one another: populations, inclusion thresholds, duration of follow-up and definitions of success differ. BrAIST is the only randomised trial and measures an intermediate outcome (the 50° threshold), not health in adulthood; the USPSTF considered that there is no evidence on the long-term outcomes of treatment in adolescence [69, 110, 111]. The VBT meta-analyses bring together mainly observational series and show that neither VBT nor ApiFix exceeded, on average, 50% correction, with frequent tether breakage and reoperations; isolated breakage, however, should not be taken as failure or as an automatic indication for revision [121, 122]. The comparison between TACS and non-TACS is retrospective, single-centre and with 28 pairs, and the differences in the main curve were not significant [85].

In instrumentation, pedicle screws are considered safe in the paediatric spine; in an analysis of 19,360 paediatric scoliosis operations from the SRS morbidity and mortality database, the rate of neurological deficit in AIS was 0.8%; one systematic review found 4.2% of screws malpositioned, 15.7% in studies with CT assessment, and another showed, with moderate evidence, less malpositioning with CT guidance (7.9%) than freehand (9.7–17.1%) [74]. The PNDS authors prefer the freehand technique, reserve CT navigation for complex anatomies, weighing the radiation, and consider robot-assisted placement still under evaluation in children [74].

Compression techniques apply the Hueter-Volkmann principle: compression of the convex side slows growth on that side while the concave side continues to grow; they are placed by thoracoscopy or, below the diaphragm, by a mini-open retroperitoneal approach [74]. In vertebral body stapling (VBS), in a series of 28 patients with idiopathic scoliosis followed for 2 years, success (final curve up to 10° or reduction greater than 10°) was 77% in thoracic curves below 35°, 25% in those of 35° or more and 86.7% in lumbar curves, and 85.7% in thoracic curves that were 20° or less on the first standing radiograph; the proposed criteria are age below 13 years in girls and 15 years in boys, Risser 0–1, at least 1 year of remaining growth (or Sanders ≤4), flexible thoracic curve of 25–35° (lumbar below 45°), minimal apical rotation and thoracic kyphosis below 40° [74]. In another series of 31 patients with curves of 25–40° and Risser 0–2, overall curve control at 2 years was 61%, 75% below 35° and 22% from 35°, and 83% of thoracic curves of 35° or more progressed to more than 50° [74]. In vertebral body tethering, a series of 11 patients with AIS had 70% correction of the thoracic Cobb angle at 2 years without serious complications; the authors proposed it in immature skeletons (Risser 0–1, Sanders ≤4) with thoracic curves of 35–60° that reduce to less than 30° on bending, and considered thoracic kyphosis greater than 40° and apical rotation greater than 20° to be contraindications [74]. The PNDS accepts the compression techniques as an alternative in patients who refuse or do not comply with bracing, but considers it difficult to recommend them as first line, especially in EOS [74].

7.5. Congenital scoliosis

Conservative treatment is often ineffective in congenital scoliosis [58]. Surgery is considered when the curve progresses more than 10° per year or reaches 40–50°, and the timing also depends on magnitude, associated anomalies and general condition [58]. The options include in situ fusion, hemiepiphysiodesis, hemivertebra resection (by a posterior or combined approach, with neurological complications described in 10–20%), conventional or magnetic growing rods, VEPTR in thoracic insufficiency syndrome and posterior vertebral column resection in rigid deformities [58]. During surgical exposure, unrecognised posterior laminar defects may cause neurological injury [58]. In the spondylocostal dysostoses, the Bone Dysplasias Atlas recommends physiotherapy for mild asymmetries and notes that congenital scolioses with marked asymmetry almost always end up being operated on, without solid evidence on the results [78]; GeneReviews indicates surgery if the scoliosis is significant and allows VEPTR, growing rods and other devices [5]. In TACS, the matched series suggests surgical results at least equivalent to those of the other congenital scolioses, with better correction of the compensatory curves, which the authors attribute to more normal development of the paravertebral tissues [85].

7.6. Syndromic scoliosis: recommendations by entity

In Duchenne dystrophy, the recommendation of posterior fusion rests on prospective non-randomised cohort studies that showed benefit in function, balance and sitting tolerance, pain and quality of life, and the goal of surgery is to halt progression, improve sitting tolerance and reduce pain [70]. Respiratory and cardiological assessment before surgery is mandatory [70]. The dosing of corticosteroids, which modify the natural history of scoliosis, follows the recommendations for the dystrophinopathies.

In NF1, dystrophic curves reach surgery with high magnitude. In the systematic review of 30 studies, 69.6% of curves were thoracic; 51.5% of patients were treated with pedicle-screw-only constructs, 42.5% with hybrid constructs and 6.0% with hooks; 0.9% underwent vertebral column resection; loss of correction in the coronal and sagittal planes was frequent during follow-up [104]. A meta-analysis of 16 studies found no differences in efficacy, long-term stability or safety between combined anterior and posterior fusion and posterior-only fusion with modern instrumentation [123]. In a series of seven Chinese patients, upper thoracic involvement predominated and the maximum correction was 85.3% [124].

In SMA, a series of 11 children with types I and II treated with VEPTR, operated on at a mean age of 6 years and followed for a mean of 43 months, had no surgical complications and two medical complications (pneumonia and anaemia); in a small series of neuromuscular patients (two with SMA), MCGR improved FVC and FEV1 with few complications [27].

7.7. Perioperative and anaesthetic precautions

Underlying diseases condition spinal surgery. In kEDS-PLOD1, arteriography should be avoided and reserved for localising life-threatening haemorrhage before surgery, because of the risk of vascular injury; wounds should be closed without tension, preferably in two layers, with abundant deep sutures and skin sutures left in place twice the usual time; blood pressure control is recommended [22]. In metatropic dysplasia, cervical instability requires the utmost care during anaesthesia [32]. In Loeys-Dietz syndrome, the initial assessment includes cervical flexion and extension radiographs [20]. In SMA, surgery should preserve intrathecal access [27]. In Duchenne dystrophy, surgery should take place in centres with full cardiac assessment capability, because it is high-risk [28, 70]. In Rett syndrome, anaesthesia, analgesia and seizure control require specialised management [72]. In NF1, the most frequent non-neurological complications were dural tears and wound infections [104]. In HGPPS, as the motor and sensory pathways do not decussate, a new neurological deficit may be ipsilateral to the lesion, which should be considered in postoperative assessment [91].

In HGPPS, absent decussation of the motor and sensory tracts has also been observed on neurophysiological monitoring during scoliosis surgery, and the somatosensory evoked potentials of the operated patients were ipsilateral; the neuromonitoring team must know the diagnosis to interpret the responses [106, 107]. In RIN2 syndrome, the aortic dilatation described in one patient and the osteoporosis justify echocardiography and densitometry before arthrodesis [9, 35]. In SSMS, the epilepsy, renal dysfunction, arterial hypertension and heart defects described justify neurological, renal and cardiological assessment before surgery [10, 36, 98].

In the EOS techniques, the PNDS recommends neurophysiological monitoring during cast application under anaesthesia and traction, systematic intraoperative monitoring during placement and exchange of growing rods and daily neurological examination during halo traction [74]; in HGPPS, this monitoring is interpreted in the light of the ipsilateral pattern of evoked potentials characteristic of the disease [106].

7.8. Pregnancy, lactation and transition

In women with SMA, published series report preterm delivery in 27% and caesarean section in 41–100%; regional anaesthesia is preferred, but epidural may be difficult with severe scoliosis or spinal fusion, and 32% report persistent worsening of weakness after delivery [27]. In the kyphoscoliotic forms of Ehlers-Danlos, there is an increased risk of miscarriage, premature rupture of membranes and arterial rupture, echocardiographic surveillance of the aortic root is recommended in kEDS-PLOD1 and delivery should take place in a centre with a high-risk perinatologist [22, 23]. Idiopathic scoliosis tends to stabilise after the end of growth, but curves greater than 50° may progress in adulthood and severe scoliosis in Marfan syndrome may require surveillance after skeletal maturity, so the transition to adult services should include the spine [1, 19].

The EOS PNDS includes among the goals of follow-up the transition, at the end of adolescence, to adult services, so as to avoid interruption of follow-up [74].

7.9. Investigational therapies and recent developments

There are no drugs in clinical development directed at genetic scoliosis. On ClinicalTrials.gov, the search of 29 October 2026 found trials of adjunctive interventions in AIS: botulinum toxin (Dysport®) combined with bracing (NCT03935295, phase 4, recruiting since 2020), vitamin D in rehabilitation (NCT03582917, phase 2, recruiting since 2018), intravenous iron in children with iron deficiency and scoliosis (NCT07217873, phase 2/3, since November 2025) and perioperative anaesthetic studies (opioid-free anaesthesia, tranexamic acid); the registered studies on scoliosis in NF1 are observational and completed [125]. None of these trials had published results in the sources consulted, and their existence does not indicate efficacy.

Among the publications of the last 12 months, with their respective level of evidence: a UK Biobank GWAS that measured curvature by deep learning on densitometry scans of 57,588 individuals (correlation 0.83 with clinical Cobb in a subsample of 150) and identified two new loci in Europeans, in SEM1/SHFM1 and in a long non-coding RNA between EDEM1 and GRM7 (association study, without clinical application) [126]; the analysis of 5891 Japanese patients on family history and age at menarche (cohort with suggestive Mendelian randomisation) [99]; the meta-analysis of intraspinal anomalies in congenital scoliosis (35%) [77]; two meta-analyses of observational studies on VBT and ApiFix [121, 122]; the matched study of surgical results in TACS [85]; a series of five patients with HGPPS [103]; and genome sequencing in families with AIS [82]. None resulted in a change of guideline or authorisation.

For RIN2 syndrome, SSMS and HGPPS there are no targeted therapies. The ClinicalTrials.gov search of 1 November 2026 found no interventional trials for RIN2 or biallelic EXT2; the only active study covering HGPPS is an observational genetic study of the congenital cranial dysinnervation disorders (NCT03059420), recruiting [125].

7.10. Divergences between guidelines

The main divergence concerns screening: the USPSTF neither recommends it nor advises against it (I statement), whereas the North American orthopaedic and paediatric societies and SOSORT recommend it [1, 110, 112]. As for bracing, the USPSTF considers adequate the evidence that it slows progression, but not the evidence that it improves long-term health outcomes, and SOSORT recommends it with strength B [1, 110]. In the neuromuscular disorders, orthoses are not recommended in Duchenne dystrophy and have no evidence of efficacy in SMA, although they are used before surgery [27, 70]; in growing idiopathic scoliosis, by contrast, they are the first-line treatment for moderate curves [1].

The 2022 French PNDS diverges from the other sources on several points. It defines EOS by a Cobb angle greater than 10°, whereas the SRS and SOSORT confirm scoliosis from 10° [1, 74]. In EOS, it continues observation until the curve exceeds 25° with progression greater than 10° and recommends bracing between 25° and 40°, whereas SOSORT, in growing idiopathic scoliosis, allows bracing from 20° ± 5° with demonstrated progression or high risk and recommends it in evolutive curves above 25° [1, 74]. It considers that physiotherapy does not alter progression in EOS, whereas SOSORT recommends specific exercises (PSSE) in AIS, with strength B [1, 74]. For vertebral body tethering, the criteria the PNDS reproduces (thoracic curves of 35–60°, flexible to less than 30°) are more restrictive than the indication of the FDA HDE approval (major curve of 30–65°), and the PNDS does not recommend it as first line [74, 120]. For surveillance, the PNDS indicates visits every 3 months to once a year and biplanar radiographs every 6 to 12 months, without fixing them by age and maturity as SOSORT does (3, 6 or 12 months), and acknowledges that the schedule varies between teams and rests on expert opinion [1, 74]. For MRI, the PNDS recommends it in all EOS with a curve greater than 20°, an age and magnitude criterion, whereas the review on congenital scoliosis recommends it in all congenital scolioses, regardless of magnitude [58, 74]; the two criteria are additive. The PNDS does not address school screening or recommend medicines [74].

7.11. Therapeutic education and daily life

The French PNDS considers it essential that parents understand the importance of regular follow-up at a reference centre, whatever the treatment. Casting and bracing require strict adherence and teaching parents about fitting and maintaining the brace, to maximise efficacy and reduce morbidity, including recognition of skin lesions caused by the brace; surgical treatments likewise depend on the family's adherence to the visits monitoring thoracic growth and correction and to successive lengthenings [74]. As normal a life as possible should be promoted, facilitating schooling and sporting activity, which the PNDS considers beneficial whatever the aetiology or severity of the deformity, for general health, to combat a sedentary lifestyle and respiratory insufficiency and for socialisation [74]. The duration of follow-up and the burden of treatment generate anxiety and adherence difficulties, and contact with patient associations, at face-to-face meetings or through social networks, helps families share experiences and fears [74].

8. Reproductive Options and Family Counselling

8.1. Idiopathic scoliosis

In idiopathic scoliosis there is no Mendelian recurrence risk. The available data describe familial aggregation and moderate heritability: in the Swedish registry, 38% of the variance in susceptibility was attributed to additive genetic effects, and concordance in monozygotic twins was only 0.11 pairwise and 0.17 probandwise [34]. In a study of 69 extended Utah families with 247 affected individuals, cited by OMIM, the analysis concluded in favour of a polygenic and multifactorial disease, with estimated penetrance of about 9% in men and 29% in women at risk (assuming a dominant allele transmitted by an affected parent) and with a recurrence risk of about 9% even in third-degree relatives, above the general population risk; age at onset appeared to be inherited separately from the pattern and severity of the curve [37]. Family history is associated with curve severity with an effect dependent on the number of affected relatives [99] and is one of the risk factors for progression recognised by SOSORT [1]. Useful counselling is therefore clinical surveillance of the siblings and children of affected people during growth, without recourse to polymorphism testing, whose individual application has not been validated [17]. In the rare IS6 form, transmission is autosomal dominant [12]. When severe AIS reveals a rare FBN1 or FBN2 variant, or when the family has signs of connective tissue disease, counselling becomes that of the corresponding Mendelian disease [18].

8.2. TACS and spondylocostal dysostoses

TACS follows a compound inheritance model. The patient has a rare null allele (16p11.2 deletion or loss-of-function variant), often inherited from an unaffected parent, and the hypomorphic T-C-A haplotype on the other allele [3]. Consequently, carriers of the same deletion in a family may not have scoliosis, and recurrence in a sibling depends on inheriting the null allele from one parent and the hypomorphic haplotype from the other; as the haplotype is common, it may be present in one or both parents, as in the case described in section 10 [3, 64]. The sources consulted do not provide empirical recurrence risks for TACS, and the estimate for each couple should be based on genotyping of the parents for the null allele and the haplotype. If the null allele is the 16p11.2 deletion, counselling must include the neurodevelopmental phenotype associated with the deletion, independent of the spine [5]. In the autosomal recessive spondylocostal dysostoses, the risk for each sibling is 25% when both parents are heterozygous, and carrier testing and prenatal or preimplantation diagnosis are possible once the variants have been identified [5]; in the family with the dominant TBX6 form, the risk for the offspring of an affected individual is 50% [5].

The prenatal case described in section 10 illustrates the practical difficulties: the null variant was inherited from the mother, both parents were heterozygous for the T-C-A haplotype, and simultaneous detection of a maternal 17q12 deletion, with a variable phenotype, made counselling more complex [64].

8.3. Syndromic scolioses and HGPPS

In the autosomal recessive forms (kEDS-PLOD1, kEDS-FKBP14, mcEDS, diastrophic dysplasia, HGPPS1 and HGPPS2, SMA), each sibling of an affected individual has a 25% risk of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier, when both parents are heterozygous; once the variants have been identified, carrier testing in relatives and prenatal or preimplantation diagnosis are possible [22, 23, 65]. In kEDS-PLOD1 it is recommended to clarify the genetic status of apparently asymptomatic siblings, younger or older, so as to start prevention early [22]. In the autosomal dominant forms (Marfan syndrome, Loeys-Dietz, congenital contractural arachnodactyly, NF1, metatropic dysplasia), the risk for the offspring of an affected individual is 50%, with variable expressivity; in metatropic dysplasia, germline mosaicism explains recurrence in siblings of unaffected parents [32]. In congenital contractural arachnodactyly, the diagnosis in one of the parents is often made retrospectively, after the child, because the mild signs persist into adulthood [21]. In the X-linked and genomic imprinting disorders, counselling follows the specific rules for the dystrophinopathies, Rett syndrome and Prader-Willi syndrome.

In RIN2 syndrome and SSMS, inheritance is autosomal recessive, with a risk of 25% per pregnancy for siblings when both parents are heterozygous; almost all published families were consanguineous, and the Turkish family, without known consanguinity, came from the same village [9, 10, 35]. No manifestations have been described in heterozygotes for RIN2 variants [35]. In SSMS, counselling has a particularity: a heterozygous parent may have hereditary multiple exostoses if their variant is, by itself, exostosis-causing, like the mother of the Italian siblings; in that situation, each child has a 50% probability of inheriting that allele and developing exostoses, independently of the 25% risk of SSMS, which justifies clinical and radiological examination of parents carrying EXT2 variants [56, 98]. In the Old Order Mennonite community, the p.(Met87Arg) variant was found in the heterozygous state in 3.85% of individuals tested, whereas p.(Arg95Cys), which accompanies it in cis on the patients' allele, was not found in that population [10]. In the dizygotic twin of the North American patient, with the same variants and a mild picture, variable expressivity makes it difficult to predict the phenotype of an affected sibling [63].

8.4. Testing of minors

Genetic testing of a minor is justified when it changes surveillance or treatment in childhood. This is the case for syndromic scolioses with vascular or neurological risk (kEDS, Loeys-Dietz, Marfan) and for clarifying the status of siblings in kEDS [19, 22]. In TACS, study of the parents serves to establish the phase of the variants and the reproductive risk [3]; testing of siblings without vertebral anomalies has no established clinical utility in the sources consulted.

8.5. Disclosure of the diagnosis and family support

The French PNDS recommends that the diagnosis of EOS be disclosed in a dedicated consultation with a paediatric orthopaedic surgeon, who explains the natural history, prognosis, the need for regular clinical and radiological follow-up, the possible treatments, screening for comorbidities and the multidisciplinary team that will provide them [74]. In prenatal disclosure, the following are added: the possibility of requesting the opinion of the specialists who will treat the child after birth, the mode of transmission and genetic counselling, and information on possible termination of pregnancy for medical reasons, after discussion at the multidisciplinary prenatal diagnosis centre (CPDPN); in postnatal disclosure, genetic counselling when applicable, the care plan, screening for complications and social aspects, including the care protocol and applications to the MDPH (Maison départementale des personnes handicapées); in both, the family is informed about patient associations [74]. A second consultation a few weeks later allows the information, difficult to assimilate in the shock of disclosure, to be revisited and the follow-up team, including the social worker, to be introduced; psychological support can be offered to the parents and siblings, and the content of the consultation is communicated by letter to the doctors caring for the child [74].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Idiopathic scoliosis

The prevalence of AIS with a Cobb angle greater than 10° ranges from 0.93% to 12% across studies, with 2–3% as the most frequent value, and a variation with latitude has been suggested [1]. About 10% of diagnosed cases need conservative treatment and 0.1–0.3% surgical correction [1]. In the United States, BrAIST reports scoliosis in about 3% of children under 16 years, with 0.3–0.5% progressive curves requiring treatment [69], and one review estimated the costs associated with AIS at about 3 billion dollars per year in the United States [17]. In the Swedish twin registry, self-reported prevalence was 4% [34]. These values measure different things (radiographic screening, self-report, treated curves) and should not be taken as comparable national prevalences.

The prevalence of EOS is unknown; according to the Boston genetic survey cited by the French PNDS, early-onset idiopathic curves account for less than 1% of all scolioses [74].

The genetics of AIS has been studied almost exclusively in populations of East Asian and European ancestry, which limits the transfer of findings to other populations [17]. The LBX1 signal was discovered in Japanese individuals and the GPR126 signal was replicated in Han Chinese and Europeans [13, 14]; the PAX1 locus has an effect restricted to females [15]; and the new UK Biobank loci come from a European population [126].

9.2. Congenital scoliosis and TACS

Congenital scoliosis affects 0.5–1 per 1000 live births and accounts for almost 10% of paediatric scolioses [58]; vertebral segmentation defects in general have the same estimated frequency [5]. In France, the obstetric source cited by the PNDS estimates fetal spinal anomalies at 1 per 500–600 births, a figure that includes anomalies that do not progress to deformity [74]. The proportion of TACS was 9.6–11% in Han Chinese and 10.6% in Japanese individuals, and TACS has also been described in European and North American patients, but the North American cohorts were small (10 patients) [3, 4, 64]. The proximal 16p11.2 deletion has a frequency of about 0.03% worldwide [3]. In DLL3-related spondylocostal dysostosis, 75% of patients in the Exeter laboratory's experience were children of consanguineous unions, mainly from the Middle East and Pakistan, and the carrier frequency in the United Kingdom was estimated at about 1:350 [5].

9.3. Syndromic and Mendelian forms

Marfan syndrome has an estimated prevalence of 1:5000 to 1:10,000, without ethnic enrichment [19]. kEDS-PLOD1 has an estimated incidence of about 1:100,000 live births, and many of the patients described originate from Turkey, the Middle East and Greece [22]. SMA has an incidence of about 1:11,000 live births [71]. HGPPS is concentrated in populations with consanguinity: the largest series brings together 13 patients from six consanguineous Tunisian families, with two ROBO3 variants already described in other Tunisian patients [107]. From Brazil, the sources consulted include a case of HGPPS in a 13-year-old girl from São Paulo, with pontine hypoplasia and a butterfly medulla on MRI and uncrossed tracts on tractography, treated with posterior arthrodesis from T2 to T11 [127], and a family with distal arthrogryposis type 4 and autosomal dominant inheritance (three members; the proband, aged 5 years, had congenital camptodactyly, bilateral talipes equinovarus and severe intellectual disability, with normal spinal radiographs), described by Pagnan and Gollop in 1987 and summarised in OMIM [115]; they do not include data from Portugal, which does not demonstrate the absence of published data.

In the Turkish HGPPS series, a truncating ROBO3 variant found only in patients of Turkish origin raised the hypothesis of a founder effect [106]. RIN2 syndrome has been described in Israeli Arab, Algerian, Lebanese, Turkish, Iranian and Pakistani families and in an Italian patient, the first of European origin [9, 35, 60–62, 92, 93]. SSMS has been described in an Old Order Mennonite family, a Syrian family, an Italian family and a North American family [11, 36, 63, 98]. These numbers are of published cases and do not allow prevalence to be estimated; the sources consulted do not include patients from Portugal or Brazil with these two syndromes.

9.4. European networks and associations

ERN BOND (European Reference Network on Rare Bone Diseases) covers the skeletal dysplasias and vertebral anomalies [73], and ERN ITHACA covers congenital anomalies and malformation syndromes [75]; rare epilepsies, such as that of SSMS, belong to ERN EpiCARE [76]. The neuromuscular, vascular and tumour forms belong to the EURO-NMD, VASCERN and GENTURIS networks. The reference scientific societies are the SRS and SOSORT [128, 129]. Patient associations include Scoliosis Association UK (https://www.sauk.org.uk/) and the National Scoliosis Foundation in the United States (https://www.scoliosis.org/).

In France, the PNDS «Déformations précoces du rachis» was drawn up under the coordination of C-MAVEM, the national reference centre for Chiari malformations, syringomyelias, dysraphisms and other rare vertebral and spinal cord malformations (https://www.c-mavem.fr/), following the 2012 HAS method, and published by the HAS in October 2022 [74]. The document names as contacts the reference centres for developmental anomalies and malformation syndromes of eight regions (Île-de-France, South-West, North, West, South-PACA, South-Languedoc-Roussillon, East and Auvergne-Rhône-Alpes, with associated centres), the patient association Scoliose et Partage (https://www.scoliose.org) and the Fondation Cotrel (https://www.fondationcotrel.org) [74]. The PNDS serves as a reference for the attending physician to establish the care protocol with the health insurance medical adviser, in an application for exemption from the ticket modérateur as an off-list condition, and social and school needs go through the MDPH and the individualised care plan (PAI) at school [74].

10. Illustrative Clinical Case

10.1. Fetal congenital scoliosis due to compound inheritance of TBX6

Li and colleagues described in 2024 a 33-year-old primigravida of Han ethnicity, married to a 32-year-old man, without consanguinity and without a family history of spinal disorders [64]. The 13-week ultrasound, at a local hospital, suggested abnormal development of the fetal spine. At 17 weeks, detailed ultrasound showed abnormal development of the spinal cord, abnormal arrangement of the vertebrae in the thoracic and sacrococcygeal segments and scoliosis, without anomalies of other organs (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC11218386/figure/Fig1/) [64]. At 19 weeks amniocentesis was performed, with karyotype, chromosomal microarray and trio exome.

Exome sequencing identified in the fetus the TBX6 variant NM_004608.4:c.338_340del p.(Ile113del), a single amino acid deletion in the T-box domain, absent from population and clinical databases and inherited from the mother, and the hypomorphic T-C-A haplotype in the homozygous state, with both parents heterozygous for the haplotype (figure 2, pedigree and Sanger sequencing: https://pmc.ncbi.nlm.nih.gov/articles/PMC11218386/figure/Fig2/) [64, 86]. The Ile113 residue is conserved across species and, in a luciferase assay with the MESP2 promoter, the variant almost abolished the transcriptional activity of TBX6, without reducing protein expression [64]. Copy number analysis, confirmed by microarray, also identified a 1.85 Mb 17q12 deletion (hg19 chr17:34493374–36346847) in the fetus and the mother; the mother had multiple medullary renal cysts with lithiasis, compatible with medullary sponge kidney [64].

After genetic counselling on the exome and microarray results, the pregnant woman opted for termination of pregnancy at 23 weeks. Autopsy confirmed left scoliosis between T8 and L5, with hypertrophy of L5 [64]. The case brings together the features that define TACS (malformation in the lower half of the spine and combination of a null allele with the hypomorphic haplotype) and shows two limits of prenatal diagnosis: the need to genotype the common haplotype and the possibility of additional findings that are difficult to interpret, such as the 17q12 deletion, which is associated with renal anomalies, MODY5-type diabetes and neurodevelopmental disorders [64]. The decision to terminate the pregnancy was the family's and does not constitute recommended management; congenital scolioses due to TACS diagnosed after birth have, in surgical series, results at least equivalent to those of the other congenital scolioses [85].

10.2. Horizontal gaze palsy with progressive scoliosis in the adult

Lin and colleagues described a 55-year-old woman with limitation of eye movements since childhood, who compensated by turning her neck, and with progressive scoliosis since early adolescence [91]. Examination showed conjugate horizontal gaze palsy with normal vertical gaze, isocoric pupils reactive to light and convergence, normal visual acuity and fields and no motor, reflex or coordination signs; there was no consanguinity or family history. The radiograph showed an S-shaped thoracic and lumbar scoliosis; bracing in adolescence had been of limited benefit. MRI showed a dorsal midline pontine cleft and a butterfly medulla, and DTI and tractography demonstrated uncrossed corticospinal tracts, absent decussation of the superior cerebellar peduncles and apparent agenesis of the pontocerebellar tracts; somatosensory evoked potentials were predominantly ipsilateral [91]. The report does not describe genetic testing, so the diagnosis is clinical and radiological; it illustrates the natural course of scoliosis in HGPPS and the value of MRI in guiding the diagnosis.

10.3. RIN2 syndrome in a consanguineous family

Basel-Vanagaite and colleagues described in 2009 three patients from two related, consanguineous Israeli Arab families [35]. The youngest, a 15-year-old boy born at term weighing 3500 g and with normal psychomotor development, had a height of 149 cm (−2 SD), weight of 44 kg (−2 SD) and head circumference of 59.5 cm (+3 SD), with parents of normal height and head circumference. Examination showed downslanting palpebral fissures, oedematous eyelids, everted lower lip, gingival hyperplasia and malpositioned teeth, short and sparse hair, mild ichthyosis of the lower limbs, high palate, severe joint hyperlaxity, flat feet, umbilical hernia, urethral stenosis, undescended testis and high-pitched voice (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC2725231/figure/fig1/) [35]. He complained of severe back pain, and the skeletal radiograph showed severe kyphoscoliosis; the echocardiogram revealed mild aortic dilatation. Full blood count, renal and liver function, thyroid-stimulating hormone, transferrin isoelectric focusing and the apolipoprotein C-III profile were normal. Skin biopsy showed a normal epidermis, a paucity of elastic fibres and almost complete absence of oxytalan fibres in the papillary dermis, a normal reticular dermis, a diminished peripheral microfibrillar component on electron microscopy and reduced fibulin-5 on immunohistochemistry (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC2725231/figure/fig2/) [35].

Homozygosity mapping delimited a 6.8 Mb region at 20p11.21-p11.23; comparison of gene expression in the patients' fibroblasts with that of controls pointed to RIN2, with reduced mRNA, and sequencing identified in the homozygous state the deletion now designated NM_018993.4:c.1731del p.(Ile578SerfsTer4), with segregation confirmed in the family and absence in 182 controls of the same ethnicity; the RIN2 protein was absent from fibroblasts [8, 35, 94]. The two older patients, aged 32 and 35 years, had more marked facial sagging and mild scoliosis, and one of them generalised osteoporosis and a fracture, which illustrates the progression of the skin changes and the variability of scoliosis within the same family [35]. The article does not describe the treatment of the kyphoscoliosis or the subsequent course.

10.4. SSMS with EXT2 variants initially classified as uncertain

Gupta and colleagues described a 14-year-old girl, born of a dizygotic twin pregnancy at 36 weeks and 5 days, who sat at 7–8 months and walked at 14 months, with language delay at 2 years, verbal, social and cognitive regression at 27 months, autism, aggressive behaviour, stereotypies and focal seizures from 10 years [63]. She had macrocephaly, a high and prominent forehead, hypertelorism, a long and hypoplastic philtrum, bilateral preauricular pits and a broad, rounded nasal tip, and had undergone strabismus surgery at 5 years. Karyotype, microarray and tests for fragile X, Rett, Angelman and Prader-Willi had been normal; brain MRI was normal and the electroencephalogram showed midline occipital spike-waves. Mucopolysaccharidosis screening showed low heparan sulfate in dried blood and in serum. Trio exome identified two compound heterozygous EXT2 missense variants, one from each parent, now designated NM_207122.2:c.1019T>A p.(Val340Asp) and c.1916C>T p.(Thr639Met), rare in gnomAD and with damaging predictions, initially classified as VUS, and a heterozygous VUS in NDST1 inherited from the mother (pedigree in figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC6452521/figure/ccr32010-fig-0001/) [63, 94]. The twin, with Asperger disorder and mild delays that improved over time, had the same three variants, and the healthy brother only the paternal EXT2 variant [63]. The case shows that scoliosis may be absent, that expressivity varies between siblings with the same genotype and that the attribution of EXT2 missense variants to SSMS depends on segregation and phenotypic comparison with the published patients.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In idiopathic scoliosis, the prognosis depends on the magnitude of the curve at the end of growth. Curves below 30° tend to remain stable in adulthood; above 30° the risk of progression, health problems and poorer quality of life increases, and above 50° progression is almost certain [1]. Bracing reduces progression to the surgical threshold in proportion to the hours of wear [69].

In EOS, the prognosis depends mainly on the aetiology and associated conditions; untreated, it is associated with significant morbidity and mortality, early thoracic fusion leaves reduced respiratory function (50–60% of predicted in a series of 28 patients fused before 9 years), and the C-EOS classification has prognostic value [74].

In congenital scoliosis, about half of curves eventually require surgery [58]; in TACS, surgical results in the matched series were at least equivalent to those of the other forms [85]. In the spondylocostal dysostoses, most scolioses are mild and the prognosis is determined by respiratory function [5].

In the syndromic forms, the prognosis is that of the underlying disease, and the spine contributes mainly through respiratory restriction. In kEDS-PLOD1, life expectancy may be normal, but adults with severe kyphoscoliosis are at risk of restrictive lung disease, recurrent pneumonia and heart failure, and vascular rupture is the most important fatal complication [22]. In diastrophic dysplasia, once infancy has passed and without severe spinal complications, life expectancy is normal; median adult height is 136 cm (114–158) in men and 129 cm (98–143) in women [31]. In SEMD with joint laxity, Beighton type, spinal deformity, thoracic deformity and possible heart defects make the overall prognosis unfavourable [25]. In NF1, surgery for dystrophic scoliosis has 21.5% revisions and frequent loss of correction [104]. In Rett syndrome, the Cobb angle and walking ability at 10 years allow prediction of progression to very severe scoliosis by 16 years [90]. In HGPPS, the neurological deficit is fixed and non-progressive, and morbidity depends on the scoliosis [33, 65]. In RIN2 syndrome, the patients described reached adulthood, up to the fourth decade in the original family, without severe visceral complications, and morbidity arises from the scoliosis, osteoporosis and the progressive facial, gingival and dental changes [35, 60]. In SSMS, the prognosis is that of the neurological disease: intellectual disability is permanent, epilepsy may be refractory, and there were deaths in childhood and young adulthood in the Syrian and Mennonite families, with causes not detailed in the sources consulted, except for the respiratory distress of the Syrian sister who died at 7 years [11, 63].

11.2. Surveillance

12. Summary and Final Considerations

Scoliosis of genetic cause encompasses three realities with different logic. Adolescent idiopathic scoliosis, which affects 2–3% of children, is a complex trait with a heritability of about 38%, in which the loci identified by GWAS (LBX1, ADGRG6, the PAX1 region, CDH13, SOX6, BNC2) explain little of the individual risk and have no diagnostic utility; rare FBN1 and FBN2 variants mark a fraction of the severe forms and link AIS to the fibrillin disorders. Treatment remains orthopaedic and guided by age, maturity and Cobb angle, with bracing supported by BrAIST and the SOSORT recommendations, and screening remains a matter of divergence between the USPSTF and the specialist societies.

Congenital scoliosis requires assessment of the whole neuraxis, the kidneys and the heart, because about one-third of patients have intraspinal anomalies and almost a quarter genitourinary anomalies. Compound inheritance of TBX6, with a null allele (often the 16p11.2 deletion) and the hypomorphic T-C-A haplotype, explains about 10% of sporadic forms, has a recognisable phenotype (hemivertebrae in the lower half of the spine, simple rib anomalies) and requires a laboratory strategy that includes copy number and haplotype genotyping.

In the syndromic scolioses, the curve is a signal to look for the underlying disease, especially when onset is early, angulation is short, or there are connective tissue signs, hypotonia or weakness, or a horizontal gaze palsy. Exome sequencing identifies the cause in about one-fifth of operated early-onset scolioses. Diagnosis of the underlying disease changes cardiovascular surveillance, surgical and anaesthetic precautions, reproductive counselling and, in diseases such as Duchenne dystrophy and SMA, the very indication for and technique of spinal surgery. In early-onset scoliosis of any cause, the 2022 French PNDS summarises the common principles: decision at a reference centre, MRI of the neuraxis for curves greater than 20°, brace or cast from 25° with progression, preservation of thoracic growth and growth-friendly techniques when surgery is unavoidable, with frequent complications.

RIN2 syndrome and SSMS illustrate two rare mechanisms of recessive syndromic scoliosis: a defect of endosomal trafficking that affects elastic fibres and collagen, with progressive coarse facies, gingival hyperplasia and redundant facial skin, and a hypomorphic reduction of heparan sulfate synthesis due to EXT2, with intellectual disability and epilepsy. Both have little more than ten published families, diagnosis by exome, variants whose nomenclature should be normalised to the MANE transcript and symptomatic treatment; in SSMS, a carrier parent may have dominant multiple exostoses, which changes counselling.

13. References

1. Negrini S, Donzelli S, Aulisa AG, Czaprowski D, Schreiber S, de Mauroy JC, et al. 2016 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis Spinal Disord. 2018;13:3. doi:10.1186/s13013-017-0145-8
2. Migliorini F, Chiu WO, Scrofani R, Chiu WK, Baroncini A, Iaconetta G, et al. Magnetically controlled growing rods in the management of early onset scoliosis: a systematic review. J Orthop Surg Res. 2022;17(1):309. doi:10.1186/s13018-022-03200-7
3. Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372(4):341-350. doi:10.1056/nejmoa1406829
4. Liu J, Wu N, Yang N, Takeda K, Chen W, et al.; Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model. Genet Med. 2019;21(7):1548-1558. doi:10.1038/s41436-018-0377-x
5. Turnpenny PD, Sloman M, Dunwoodie S. Spondylocostal Dysostosis, Autosomal Recessive. 2009 Aug 25 [updated 2023 Aug 17]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK8828/
6. Harahsheh EY, Moxley LE, Al-Amin M, Sabrowsky S, Deniz A, Osundiji M. 20 years of ROBO3-related horizontal gaze palsy with progressive scoliosis: a mini-review. Neurogenetics. 2025;26(1):30. doi:10.1007/s10048-025-00811-0
7. Rahikkala E, Väisänen T, Ojala L, Pohjola P, Toivonen M, Parkkola R, et al. Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome. Mol Syndromol. 2024;15(2):149-155. doi:10.1159/000534772
8. Online Mendelian Inheritance in Man, OMIM®. MIM Number 613075: MACS SYNDROME. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/613075
9. Aslanger AD, Altunoglu U, Aslanger E, Satkın BN, Uyguner ZO, Kayserili H. Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2. Am J Med Genet A. 2014;164A(2):484-489. doi:10.1002/ajmg.a.36277
10. Online Mendelian Inheritance in Man, OMIM®. MIM Number 616682: SEIZURES, SCOLIOSIS, AND MACROCEPHALY/MICROCEPHALY SYNDROME; SSMS. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/616682
11. El-Bazzal L, Atkinson A, Gillart AC, Obeid M, Delague V, Mégarbané A. A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2). Eur J Med Genet. 2019;62(4):259-264. doi:10.1016/j.ejmg.2018.07.025
12. Online Mendelian Inheritance in Man, OMIM®. MIM Number 621428: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 6; IS6. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/621428
13. Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011;43(12):1237-1240. doi:10.1038/ng.974
14. Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet. 2013;45(6):676-679. doi:10.1038/ng.2639
15. Sharma S, Londono D, Eckalbar WL, Gao X, Zhang D, Mauldin K, et al. A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nat Commun. 2015;6:6452. doi:10.1038/ncomms7452
16. Khanshour AM, Kou I, Fan Y, Einarsdottir E, Makki N, Kidane YH, et al. Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci. Hum Mol Genet. 2018;27(22):3986-3998. doi:10.1093/hmg/ddy306
17. Terhune E, Heyn P, Piper C, Wethey C, Monley A, Cuevas M, et al. Association between genetic polymorphisms and risk of adolescent idiopathic scoliosis in case-control studies: a systematic review. J Med Genet. 2024;61(2):196-206. doi:10.1136/jmg-2022-108993
18. Buchan JG, Alvarado DM, Haller GE, Cruchaga C, Harms MB, Zhang T, et al. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet. 2014;23(19):5271-5282. doi:10.1093/hmg/ddu224
19. Dietz H. FBN1-Related Marfan Syndrome. 2001 Apr 18 [updated 2022 Feb 17]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1335/
20. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [updated 2024 Sep 12]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1133/
21. Callewaert B. Congenital Contractural Arachnodactyly. 2001 Jan 23 [updated 2019 Oct 21]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1386/
22. Rohrbach M, Giunta C. PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome. 2000 Feb 2 [updated 2024 Jun 13]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1462/
23. Giunta C, Rohrbach M, Fauth C, Baumann M. FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome. 2019 May 23. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541503/
24. Kosho T, Yamaguchi T, Mizumoto S, Mendoza-Londono R. Musculocontractural Ehlers-Danlos Syndrome. 2025 May 15. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK614472/
25. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 287–9.
26. Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [updated 2022 Apr 21]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1109/
27. Prior TW, Leach ME, Finanger EL. Spinal Muscular Atrophy. 2000 Feb 24 [updated 2024 Sep 19]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1352/
28. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 402–5.
29. Kaur S, Christodoulou J. MECP2 Disorders. 2001 Oct 3 [updated 2019 Sep 19]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1497/
30. Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1281/
31. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 250–3.
32. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 135–9.
33. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rüb U, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304(5676):1509-1513. doi:10.1126/science.1096437
34. Grauers A, Rahman I, Gerdhem P. Heritability of scoliosis. Eur Spine J. 2012;21(6):1069-1074. doi:10.1007/s00586-011-2074-1
35. Basel-Vanagaite L, Sarig O, Hershkovitz D, Fuchs-Telem D, Rapaport D, Gat A, et al. RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. Am J Hum Genet. 2009;85(2):254-263. doi:10.1016/j.ajhg.2009.07.001
36. Farhan SM, Wang J, Robinson JF, Prasad AN, Rupar CA, Siu VM, et al. Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. J Med Genet. 2015;52(10):666-675. doi:10.1136/jmedgenet-2015-103279
37. Online Mendelian Inheritance in Man, OMIM®. MIM Number 181800: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 1; IS1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/181800
38. Online Mendelian Inheritance in Man, OMIM®. MIM Number 607354: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 2; IS2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/607354
39. Online Mendelian Inheritance in Man, OMIM®. MIM Number 608765: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 3; IS3. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/608765
40. Online Mendelian Inheritance in Man, OMIM®. MIM Number 612238: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 4; IS4. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/612238
41. Online Mendelian Inheritance in Man, OMIM®. MIM Number 612239: SCOLIOSIS, ISOLATED, SUSCEPTIBILITY TO, 5; IS5. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/612239
42. Online Mendelian Inheritance in Man, OMIM®. MIM Number 602427: T-BOX TRANSCRIPTION FACTOR 6; TBX6. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/602427
43. Online Mendelian Inheritance in Man, OMIM®. MIM Number 122600: SPONDYLOCOSTAL DYSOSTOSIS 5; SCDO5. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/122600
44. Online Mendelian Inheritance in Man, OMIM®. MIM Number 225400: EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 1; EDSKSCL1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/225400
45. Online Mendelian Inheritance in Man, OMIM®. MIM Number 614557: EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 2; EDSKSCL2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/614557
46. Online Mendelian Inheritance in Man, OMIM®. MIM Number 121050: CONTRACTURAL ARACHNODACTYLY, CONGENITAL; CCA. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/121050
47. Online Mendelian Inheritance in Man, OMIM®. MIM Number 607313: GAZE PALSY, FAMILIAL HORIZONTAL, WITH PROGRESSIVE SCOLIOSIS 1; HGPPS1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/607313
48. Online Mendelian Inheritance in Man, OMIM®. MIM Number 617542: GAZE PALSY, FAMILIAL HORIZONTAL, WITH PROGRESSIVE SCOLIOSIS 2, WITH IMPAIRED INTELLECTUAL DEVELOPMENT; HGPPS2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/617542
49. Online Mendelian Inheritance in Man, OMIM®. MIM Number 608630: ROUNDABOUT GUIDANCE RECEPTOR 3; ROBO3. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/608630
50. Orphanet. Adolescent idiopathic scoliosis (ORPHA:3153). https://www.orpha.net/en/disease/detail/3153
51. Orphanet. Juvenile idiopathic scoliosis (ORPHA:459696). https://www.orpha.net/en/disease/detail/459696
52. Orphanet. Autosomal dominant spondylocostal dysostosis (ORPHA:1797). https://www.orpha.net/en/disease/detail/1797
53. Orphanet. Horizontal gaze palsy with progressive scoliosis (ORPHA:2744). https://www.orpha.net/en/disease/detail/2744
54. Orphanet. RIN2 syndrome (ORPHA:217335). https://www.orpha.net/en/disease/detail/217335
55. Orphanet. Seizures-scoliosis-macrocephaly syndrome (ORPHA:466926). https://www.orpha.net/en/disease/detail/466926
56. Sefcik R, Earl D, Thorpe S. Hereditary Multiple Osteochondromas. 2000 Aug 3 [updated 2026 Jan 29]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1235/
57. Van Maldergem L, Dobyns W, Kornak U. ATP6V0A2-Related Cutis Laxa. 2009 Mar 19 [updated 2021 Jan 28]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK5200/
58. Grabala P. Congenital Scoliosis: A Comprehensive Review of Diagnosis, Management, and Surgical Decision-Making in Pediatric Spinal Deformity-An Expanded Narrative Review. J Clin Med. 2025;14(22):8085. doi:10.3390/jcm14228085
59. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. 1998 Oct 6 [updated 2023 Mar 9]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/
60. Rosato S, Syx D, Ivanovski I, Pollazzon M, Santodirocco D, De Marco L, et al. RIN2 syndrome: Expanding the clinical phenotype. Am J Med Genet A. 2016;170(9):2408-2415. doi:10.1002/ajmg.a.37789
61. Kameli R, Ashrafi MR, Ehya F, Alizadeh H, Hosseinpour S, Garshasbi M, et al. Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum. Eur J Med Genet. 2020;63(1):103629. doi:10.1016/j.ejmg.2019.02.002
62. Shaukat M, Ishaq T, Muhammad N, Naz S. RIN2 and BBS7 variants as cause of a coincidental syndrome. Eur J Med Genet. 2020;63(3):103755. doi:10.1016/j.ejmg.2019.103755
63. Gupta A, Ewing SA, Renaud DL, Hasadsri L, Raymond KM, Klee EW, et al. Developmental delay, coarse facial features, and epilepsy in a patient with EXT2 gene variants. Clin Case Rep. 2019;7(4):632-637. doi:10.1002/ccr3.2010
64. Li G, Chen Y, Han X, Li N, Li S. Concurrent of compound heterozygous variant of a novel in-frame deletion and the common hypomorphic haplotype in TBX6 and inherited 17q12 microdeletion in a fetus. BMC Pregnancy Childbirth. 2024;24(1):456. doi:10.1186/s12884-024-06653-2
65. Pinero-Pinto E, Pérez-Cabezas V, Tous-Rivera C, Sánchez-González JM, Ruiz-Molinero C, Jiménez-Rejano JJ, et al. Mutation in ROBO3 Gene in Patients with Horizontal Gaze Palsy with Progressive Scoliosis Syndrome: A Systematic Review. Int J Environ Res Public Health. 2020;17(12):E4467. doi:10.3390/ijerph17124467
66. Deniz A, Çomu S, Güngör M, Anık Y, Kara B. Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review. J Pediatr Genet. 2024;13(2):116-122. doi:10.1055/s-0041-1739387
67. Zhao S, Zhang Y, Chen W, Li W, Wang S, Wang L, et al. Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS). J Med Genet. 2021;58(1):41-47. doi:10.1136/jmedgenet-2019-106823
68. Gardeitchik T, Mohamed M, Fischer B, Lammens M, Lefeber D, Lace B, et al. Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa. Eur J Hum Genet. 2014;22(7):888-895. doi:10.1038/ejhg.2013.154
69. Weinstein SL, Dolan LA, Wright JG, Dobbs MB. Effects of bracing in adolescents with idiopathic scoliosis. N Engl J Med. 2013;369(16):1512-1521. doi:10.1056/nejmoa1307337
70. Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17(4):347-361. doi:10.1016/s1474-4422(18)30025-5
71. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi:10.1016/j.nmd.2017.11.005
72. Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, et al. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine (Phila Pa 1976). 2009;34(17):E607-17. doi:10.1097/brs.0b013e3181a95ca4
73. ERN BOND – European Reference Network on Rare Bone Diseases. Available from: https://ernbond.eu/
74. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Déformations précoces du rachis. Centre de référence des malformations vertébrales et médullaires (C-MAVEM). Saint-Denis La Plaine: HAS; 2022 Oct 10. Available from: https://www.has-sante.fr/jcms/p_3374135
75. ERN ITHACA – European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Available from: https://ern-ithaca.eu/
76. ERN EpiCARE – European Reference Network for rare and complex epilepsies. Available from: https://epi-care.eu/
77. Algarni N, Alrasheed K, Alkhunein F, Alorayyidh M, Alrasheed R, Marwan Y. Intraspinal abnormalities in MRI-evaluated congenital scoliosis: a systematic review and meta-analysis of prevalence, geographic variation, vertebral anomaly patterns, and Cobb angle. N Am Spine Soc J. 2026;28:100943. doi:10.1016/j.xnsj.2026.100943
78. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 857–60.
79. Hernandez-Miranda LR, Ibrahim DM, Ruffault PL, Larrosa M, Balueva K, Müller T, et al. Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice. Proc Natl Acad Sci U S A. 2018;115(51):13021-13026. doi:10.1073/pnas.1813520115
80. Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, et al. Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet. 2015;96(6):955-961. doi:10.1016/j.ajhg.2015.04.014
81. AlMekkawi AK, Caruso JP, El Ahmadieh TY, Palmisciano P, Aljardali MW, Derian AG, et al. Single Nucleotide Polymorphisms and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis of the Literature. Spine (Phila Pa 1976). 2023;48(10):695-701. doi:10.1097/brs.0000000000004623
82. Tuncay IO, Lee EK, Gustafson A, Lee Y, Jung D, Koh JY, et al. Whole genome sequencing in adolescent idiopathic scoliosis cohort implicates multiple biological pathways. NPJ Genom Med. 2025;10(1):67. doi:10.1038/s41525-025-00520-5
83. Online Mendelian Inheritance in Man, OMIM®. MIM Number 601019: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 9; SLC6A9. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/601019
84. Online Mendelian Inheritance in Man, OMIM®. MIM Number 617880: POC5 CENTRIOLAR PROTEIN; POC5. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/617880
85. Lin G, Yang Y, Chen Z, Zhao S, Niu Y, Du Y, et al. Preliminary study assessing the long-term surgical outcomes of TBX6-associated congenital scoliosis (TACS) patients using the propensity score matching method: exploring the clinical implications of genetic discoveries in congenital scoliosis. Orphanet J Rare Dis. 2025;20(1):32. doi:10.1186/s13023-024-03471-9
86. VariantValidator. NM_004608.4:c.1311A>T e NM_004608.4:c.338_340del (GRCh38). Available from: https://rest.variantvalidator.org/
87. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 848–50.
88. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 484–9.
89. Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [updated 2020 Apr 9]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1277/
90. Downs J, Torode I, Wong K, Ellaway C, Elliott EJ, Christodoulou J, et al. The Natural History of Scoliosis in Females With Rett Syndrome. Spine (Phila Pa 1976). 2016;41(10):856-863. doi:10.1097/brs.0000000000001399
91. Lin CW, Lo CP, Tu MC. Horizontal gaze palsy with progressive scoliosis: a case report with magnetic resonance tractography and electrophysiological study. BMC Neurol. 2018;18(1):75. doi:10.1186/s12883-018-1081-9
92. Syx D, Malfait F, Van Laer L, Hellemans J, Hermanns-Lê T, Willaert A, et al. The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2). Hum Genet. 2010;128(1):79-88. doi:10.1007/s00439-010-0829-0
93. Albrecht B, de Brouwer AP, Lefeber DJ, Cremer K, Hausser I, Rossen N, et al. MACS syndrome: a combined collagen and elastin disorder due to abnormal Golgi trafficking. Am J Med Genet A. 2010;152A:2916-2918. doi:10.1002/ajmg.a.33712
94. VariantValidator. Normalisation of the published variants of RIN2 (NM_018993.4), EXT2 (NM_207122.2) and MECP2 (NM_001110792.2), GRCh38. Available from: https://rest.variantvalidator.org/
95. ClinVar. National Center for Biotechnology Information. RIN2 (NM_018993.4) and EXT2 (NM_207122.2) variants, accessed 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
96. van Amen-Hellebrekers CJM, Jansen S, Stegmann APA, Stevens SJC, Pfundt R, de Vries BBA. Biallelic frameshift mutation in RIN2 in a patient with intellectual disability and cataract, without RIN2 syndrome. Am J Med Genet A. 2017;173(12):3238-3240. doi:10.1002/ajmg.a.38396
97. Mizumoto S, Yamada S. Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis. Front Genet. 2021;12:717535. doi:10.3389/fgene.2021.717535
98. Gentile M, Agolini E, Cocciadiferro D, Ficarella R, Ponzi E, Bellacchio E, et al. Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype. Clin Genet. 2019;95(1):165-171. doi:10.1111/cge.13458
99. Tanaka R, Iwami T, Yonezawa Y, Otomo N, Takeda K, Ikegawa S, et al. Clinical and genetic evidence from East Asian cohorts linking family history burden and menarche timing to curve severity in adolescent idiopathic scoliosis. Front Endocrinol (Lausanne). 2026;17:1876849. doi:10.3389/fendo.2026.1876849
100. Hakim A. Hypermobile Ehlers-Danlos Syndrome. 2004 Oct 22 [updated 2024 Feb 22]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1279/
101. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 176–7.
102. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 506–11.
103. Bhate M, Bathula S, Varma R. Horizontal Gaze Palsy and Progressive Scoliosis: Clinical Profile and Review of Literature. J Pediatr Ophthalmol Strabismus. 2026;63(3):179-185. doi:10.3928/01913913-20250724-04
104. Neifert SN, Khan HA, Kurland DB, Kim NC, Yohay K, Segal D, et al. Management and surgical outcomes of dystrophic scoliosis in neurofibromatosis type 1: a systematic review. Neurosurg Focus. 2022;52(5):E7. doi:10.3171/2022.2.focus21790
105. Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 102–5.
106. Günbey C, Çavdarlı B, Göçmen R, Yazıcı M, Temuçin ÇM, Özdemir Ö, et al. Horizontal gaze palsy with progressive scoliosis: Further expanding the ROBO3 spectrum. Ann Clin Transl Neurol. 2024;11(8):2088-2099. doi:10.1002/acn3.52129
107. Bouchoucha S, Chikhaoui A, Najjar D, Dallali H, Khammessi M, Abdelhak S, et al. Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases. Front Pediatr. 2020;8:172. doi:10.3389/fped.2020.00172
108. Jamuar SS, Schmitz-Abe K, D'Gama AM, Drottar M, Chan WM, Peeva M, et al. Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet. 2017;49(4):606-612. doi:10.1038/ng.3804
109. Wu N, Liu L, Zhang Y, Wang L, Wang S, Zhao S, et al. Retrospective Analysis of Associated Anomalies in 636 Patients with Operatively Treated Congenital Scoliosis. J Bone Joint Surg Am. 2023;105(7):537-548. doi:10.2106/jbjs.22.00277
110. US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, et al. Screening for Adolescent Idiopathic Scoliosis: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(2):165-172. doi:10.1001/jama.2017.19342
111. Dunn J, Henrikson NB, Morrison CC, Blasi PR, Nguyen M, Lin JS. Screening for Adolescent Idiopathic Scoliosis: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018;319(2):173-187. doi:10.1001/jama.2017.11669
112. Hresko MT, Talwalkar V, Schwend R, AAOS, SRS, and POSNA. Early Detection of Idiopathic Scoliosis in Adolescents. J Bone Joint Surg Am. 2016;98(16):e67. doi:10.2106/jbjs.16.00224
113. Lorente R, Mariscal G, Lorente A. Incidence of genitourinary anomalies in congenital scoliosis: systematic review and meta-analysis. Eur Spine J. 2023;32(11):3961-3969. doi:10.1007/s00586-023-07889-w
114. Wang S, Zhao Y, Du Y, Zhang J, Yu B. The incidence and interrelationship of hemivertebra and concomitant cardiac abnormalities in congenital scoliosis. BMC Musculoskelet Disord. 2023;24(1):621. doi:10.1186/s12891-023-06727-w
115. Online Mendelian Inheritance in Man, OMIM®. MIM Number 609128: ARTHROGRYPOSIS, DISTAL, TYPE 4; DA4. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/609128
116. Diniz MAN, Pinto CX, Ribeiro EM, Carvalho EDF. Cutis laxa. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 273–7.
117. Jones S, Wijburg FA. Glycosaminoglycans and oligosaccharides disorders: glycosaminoglycans synthesis defects, mucopolysaccharidoses, oligosaccharidoses and sialic acid disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 41, section 41.1 Glycosaminoglycans synthesis defects.
118. Iorio J, Orlando G, Diefenbach C, Gaughan JP, Samdani AF, Pahys JM, et al. Serial Casting for Infantile Idiopathic Scoliosis: Radiographic Outcomes and Factors Associated With Response to Treatment. J Pediatr Orthop. 2017;37(5):311-316. doi:10.1097/bpo.0000000000000654
119. Matsumoto H, Sinha R, Roye BD, Ball JR, Skaggs KF, Brooks JT, et al. Contraindications to magnetically controlled growing rods: consensus among experts in treating early onset scoliosis. Spine Deform. 2022;10(6):1289-1297. doi:10.1007/s43390-022-00543-3
120. U.S. Food and Drug Administration. Humanitarian Device Exemption H190005: The Tether™ – Vertebral Body Tethering System (Zimmer Biomet Spine). Decision date 2019 Aug 16. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H190005
121. Hevia E, Burgos J, García V, Altabbaa H, Mariscal G, Barrios C. Emerging growth modulation techniques in treatment of adolescent idiopathic scoliosis: a meta-analysis of the outcomes and safety of anterior vertebral body tethering and ApiFix. Asian Spine J. 2026. doi:10.31616/asj.2025.0612
122. Sönmez E, Ayhan L, Kapdan M. Reoperation and fusion after documented tether breakage following vertebral body tethering: a systematic review and meta-analysis. Spine Deform. 2026. doi:10.1007/s43390-026-01561-1
123. Jia F, Wang G, Sun J, Liu X. Combined Anterior-Posterior Versus Posterior-only Spinal Fusion in Treating Dystrophic Neurofibromatosis Scoliosis With Modern Instrumentation: A Systematic Review and Meta-analysis. Clin Spine Surg. 2021;34(4):132-142. doi:10.1097/bsd.0000000000001069
124. Du Y, Bai T, Song J, Zhang L, Huang H, Han P, et al. The genotypic and family characteristics and clinical intervention of neurofibromatosis type 1 gene are associated with dystrophic scoliosis by whole-exome sequencing. Front Neurol. 2025;16:1641665. doi:10.3389/fneur.2025.1641665
125. ClinicalTrials.gov. Search for studies on scoliosis (neurofibromatosis; adolescent idiopathic scoliosis, pharmacological intervention) and on RIN2, EXT2, ROBO3 and horizontal gaze palsy (1 November 2026). Available from: https://clinicaltrials.gov/
126. Zeosky M, Kun E, Reddy S, Pandey D, Xu L, Wang JY, et al. Deep learning-based precision phenotyping of spine curvature identifies novel genetic risk loci for scoliosis in the UK Biobank. NPJ Digit Med. 2026;9(1):381. doi:10.1038/s41746-026-02540-6
127. Pereira BJA, Batista UC, Bechelli Filho FN, Ribeiro CAA, Holanda CVM, Galvão PEC. Horizontal gaze palsy and progressive scoliosis: magnetic resonance imaging features and surgical treatment. Einstein (Sao Paulo). 2017;15(4):512-513. doi:10.1590/S1679-45082017AI3969
128. Scoliosis Research Society. Available from: https://www.srs.org/
129. International Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT). Available from: https://www.sosort.org/