Dysplasias with Congenital Joint Dislocations (FLNB Spectrum and Larsen Syndrome)

Larsen syndrome, atelosteogenesis type 1 (with boomerang dysplasia and Piepkorn dysplasia), atelosteogenesis type 3, spondylocarpotarsal synostosis and FLNB-related clubfoot; the dysplasias with multiple joint dislocations group of the 2023 Nosology and recessive "Larsen-like" forms

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

This article covers a class of skeletal disorders whose common presentation is congenital dislocation of large joints (hip, knee, elbow, radial head) associated with bone dysplasia. The core is the spectrum of the FLNB gene, which encodes filamin B: monoallelic gain-of-function variants cause a continuum of decreasing severity from atelosteogenesis type 1 (AO1, perinatally lethal, which includes boomerang dysplasia and Piepkorn dysplasia) to atelosteogenesis type 3 (AO3), Larsen syndrome and apparently isolated clubfoot; biallelic loss of function causes spondylocarpotarsal synostosis syndrome (SCT) [1, 2]. Around this core, the 2023 Nosology of Genetic Skeletal Disorders brings together in group 5 ("dysplasias with multiple joint dislocations") the disorders of glycosaminoglycan synthesis and related conditions that, over decades, were labelled "recessive Larsen syndrome"; CHST3 deficiency and IMPAD1 deficiency belong to group 4 (sulfation defects) but share the same presentation [2, 3]. Larsen syndrome is treated as the main entity of the FLNB spectrum. SLC26A2-related atelosteogenesis (formerly AO2) and diastrophic dysplasia, the general prenatal assessment of lethal dysplasias, the spondylodysplastic and musculocontractural forms of Ehlers-Danlos syndrome (EDS), congenital disorders of glycosylation (CDG), FLNA-related disorders, MYH3 arthrogryposes and nail-patella syndrome enter the differential diagnosis; only the features that distinguish them are given here. The relevant European reference network is ERN BOND (European Reference Network on Rare Bone Diseases); in the tables, SD denotes standard deviation, NGS next-generation sequencing, SED spondyloepiphyseal dysplasia, SEMD spondyloepimetaphyseal dysplasia and JL joint laxity, and "Bone Dysplasias" the Bone Dysplasias atlas by Spranger and colleagues.

0.1. FLNB spectrum

Sources for Table 0.1: [1, 2, 4–15].

0.2. Dysplasias with multiple joint dislocations group and related recessive forms

For all entities in Table 0.2 there is no approved specific treatment, the first-line test is the skeletal dysplasia with dislocations panel or the exome (with copy number variant, CNV, analysis), the Orphanet prevalence is below 1/1,000,000 where recorded, and the European reference network is ERN BOND. The cytobands of IMPAD1 (8q12.1) and EXOC6B (2p13) come from the OMIM entries; those of SLC10A7 and NIN are not given in the sources consulted. Sources for Table 0.2: [2, 3, 16–64].

1. Introduction

1.1. From Larsen's description to the breakdown of "recessive Larsen"

In 1950, Loren Larsen, Edward Schottstaedt and Frederic Bost described six patients with multiple congenital dislocations, a characteristic face (prominent forehead, depressed nasal bridge and midface flattening), equinovarus feet and, occasionally, cleft palate [65, 66]. The cases were sporadic, and autosomal dominant transmission was recognised in families published over the following decades; Latta and colleagues, in 1971, characterised the entity as a skeletal dysplasia, and Steel and Kohl, in 1972, described three affected siblings [67, 68]. Throughout the 1980s and 1990s, reports accumulated of an "autosomal recessive Larsen syndrome" (Clayton-Smith and Donnai in 1988, Bonaventure in 1992, Laville in 1994, Yamaguchi in 1996), phenotypically heterogeneous and bearing little resemblance to the dominant form [1]. Molecular genetics showed that this label covered several distinct chondrodysplasias: CHST3 deficiency (2008), the Réunion Island form due to B4GALT7 (2015), the Desbuquois dysplasias due to CANT1 and XYLT1, the B3GAT3 form designated "Larsen-like" (2011) and the GZF1 form described in Saudi families (2017) [1, 69–72]. Bicknell and colleagues, in their 2007 series, found no clinical, radiographic or histological marker that separated the supposedly recessive reports from the dominant phenotype, and acknowledged that some of them would correspond to parental germline mosaicism for an FLNB variant [73]. OMIM entry 245600, which brings together historical reports of "recessive Larsen" (the three siblings of Steel and Kohl, from 1972, and the two siblings of Strisciuglio and colleagues, from 1983, all of whom died of heart failure), now has B3GAT3 deficiency as its molecular basis, without molecular confirmation of these old reports; the family of Bloch and Peck (1965), cited as an example of a recessive form, was reinterpreted as dominant with germline mosaicism when an affected sister had an affected daughter [4, 30].

1.2. Atelosteogeneses, boomerang dysplasia and Piepkorn dysplasia

The term "atelosteogenesis", from the Greek for incomplete ossification, was proposed by Maroteaux, Spranger and Stanescu in 1982 for lethal dysplasias with lack of ossification of skeletal segments; Sillence described, in the same year, "spondylohumerofemoral hypoplasia", and growth plate histology, with hypocellular areas and multinucleated giant chondrocytes, gave rise to the synonym "giant cell chondrodysplasia" [74–76]. Stern and colleagues, in 1990, separated atelosteogenesis type 3, and Schultz and colleagues, in 1999, documented a woman with AO3 surviving into adulthood who transmitted the disease to her son, demonstrating dominant transmission [77, 78]. The designation "atelosteogenesis type 2" came to refer to a genetically distinct disease, caused by SLC26A2 [77, 79]. Kozlowski and colleagues, in 1985, named boomerang dysplasia the lethal form in which the bowed femora resemble a boomerang; Bicknell and colleagues, in 2005, found FLNB variants in it, confirming that it belongs to the atelosteogenesis spectrum [80, 81]. Piepkorn dysplasia (1977), previously considered identical to boomerang dysplasia, was redefined by Rehder and colleagues, in 2018, as the most severe end of the FLNB spectrum, on the basis of three fetuses and an anatomical specimen 106 years old [80, 82]. The 2025 GeneReviews and the 2023 Nosology include boomerang dysplasia, Piepkorn dysplasia and spondylohumerofemoral dysplasia within AO1 [1, 2].

1.3. Spondylocarpotarsal synostosis

SCT was delineated by Jones and colleagues in 1973 and received its current name from Langer, Gorlin, Donnai and colleagues in 1994, who proposed autosomal recessive inheritance on the basis of recurrence in siblings [14, 83]. Coelho and colleagues, in a 1998 Brazilian study, proposed as criteria fusion of multiple cervical, thoracic or lumbar vertebral bodies, carpal and/or tarsal synostosis, short stature with scoliosis and/or lordosis, and absence of rib anomalies [84, 85].

1.4. The 2004 molecular milestone

Before the gene was identified, Vujic and colleagues (1995) studied a Swedish kindred with 49 presumed carriers, 26 of whom were affected, and mapped the locus (LAR1) to 3p21.1–p14.1; none of the 26 affected individuals who had received medical care had been correctly diagnosed, and Becker and colleagues (2000) described a father with unrecognised mild Larsen syndrome, identified only after ultrasound of a severely affected fetus, possibly owing to mosaicism [4]. Steiner and colleagues (2004) mapped SCT to 3p14 by homozygosity in four families, three of them consanguineous [7]. Krakow, Robertson, Cohn and colleagues identified in 2004 the FLNB gene as the cause of four diseases: homozygous or compound heterozygous stop codon mutations in SCT, and missense mutations in dominant Larsen syndrome and in atelosteogenesis types 1 and 3 [86]. Expression of filamin B in growth plate chondrocytes and in developing vertebral bodies revealed a hitherto unsuspected role of this cytoskeletal protein in vertebral segmentation, joint formation and endochondral ossification [86]. There followed the 2007 clinical-molecular series of 20 probands with Larsen syndrome, the definition of the two variant clusters of AO1 and AO3 in 2006 and, later, the association of FLNB variants with apparently isolated clubfoot (2016 and 2022) and of multi-exon deletions with SCT (2021) [73, 87–90].

1.5. Current classification and definitions

The 2023 Nosology of the International Skeletal Dysplasia Society (ISDS), prepared in collaboration with ERN BOND and Orphanet, adopted the dyadic nomenclature "phenotype, GENE-related", recognised 771 disorders associated with 552 genes in 41 groups and assigned each entity a "NOS group–number" [2]. Three groups are relevant to this article. Group 6, "filamins and related disorders", contains the FLNB spectrum (Larsen, AO1, AO3 and SCT), RFLNA-related SCT, MYH3-related SCT with contractures and pterygia, the FLNA disorders (otopalatodigital, Melnick-Needles, frontometaphyseal dysplasia, terminal osseous dysplasia), MAP3K7-related cardiospondylocarpofacial syndrome and Frank-ter Haar syndrome [2]. Group 5, "dysplasias with multiple joint dislocations", is named after a clinical feature but mainly contains disorders of glycosaminoglycan synthesis, whose phenotypic proximity to groups 4 and 6 justifies their position in the classification [2]. Group 4, sulfation defects, includes CHST3-related chondrodysplasia with congenital dislocations (which absorbs recessive Larsen syndrome, humerospinal dysostosis and Omani-type spondyloepiphyseal dysplasia) and the IMPAD1-related form [2, 3]. Pseudodiastrophic dysplasia no longer has its own row and appears as an expression of B3GAT3, Steel syndrome is in group 13, Catel-Manzke syndrome and Temtamy brachydactyly in group 19, and the GZF1, NIN and FAM20B forms are not in the table [2, 63].

For the purposes of this article, the entities of the FLNB spectrum are defined as follows. Larsen syndrome is the autosomal dominant disease due to a gain-of-function FLNB variant compatible with survival, with congenital dislocations of large joints, a characteristic face, spatulate distal phalanges and supernumerary ossification centres in the carpus and tarsus [1, 73]. AO1 is the perinatally lethal form, with absent or incomplete ossification of multiple elements; AO3 is the semilethal form, with no qualitative difference from Larsen syndrome, distinguished by its severity, incomplete ossification and distally tapering humerus [1, 73]. SCT is the recessive loss-of-function form, without dislocations as a dominant feature, defined by vertebral fusions, carpal synostosis and short-trunk short stature [1, 14]. There are no validated formal diagnostic criteria for any of these entities [1].

2. Molecular Genetics and Pathophysiology

2.1. The FLNB gene and filamin B

The FLNB gene is located at 3p14.3 and encodes filamin B, an actin cross-linking protein; the reference sequence used by GeneReviews and ClinVar is NM_001457.4 (protein NP_001448.2) [1, 91, 92]. The protein has an N-terminal actin-binding domain formed by two calponin homology domains (CH1 and CH2), followed by 24 rod-shaped filamin repeats, interrupted by two "hinge" regions (between repeats 15–16 and 23–24) that give the molecule flexibility [1]. Filamins organise actin into three-dimensional networks, link transmembrane proteins to the cytoskeleton and act as a scaffold for signalling and intracellular trafficking pathways [86]. Filamin B is expressed by endothelial cells and chondrocytes during development, including growth plate chondrocytes and the developing vertebral bodies [1, 86]. It interacts with presenilins 1 and 2 of the Notch pathway, a mechanism proposed for the vertebral anomalies, and the Flnb-deficient mouse reproduces the loss-of-function phenotype, with vertebral anomalies, distal limb shortening and spinal curvature [66, 73]. In situ hybridisation in human bone showed FLNB expression in osteoclasts, pre-osteoclasts, reversal cells, osteoblasts and lining cells, with little expression in osteocytes [93].

2.2. Two mechanisms for two groups of diseases

Biallelic loss of function causes SCT. The variants are nonsense, frameshift, splicing or multi-exon intragenic deletions, associated with absence of the protein, and the pathogenic effect results, at least in part, from derepression of transforming growth factor beta (TGF-β) signalling [1, 14, 90]. Although SCT is described as a segmentation defect, initial vertebral segmentation is normal and fusion results from a later pathological process in development [1].

Monoallelic gain of function causes the dominant spectrum. The variants are missense or small in-frame deletions, which preserve a full-length protein [1]. Daniel and colleagues showed that substitutions in the actin-binding domain form focal cytoplasmic accumulations with actin, to a degree correlated with phenotype severity, which is compatible with increased actin binding; substitutions around hinge 1 do not form these foci and probably act by dysregulating the flexibility of the molecule [66, 94]. In a chondrogenic model (ATDC5 cells), the boomerang dysplasia variant p.(Leu171Arg) caused globular aggregation of filamin B and more apoptosis, and the p.(Gly1586Arg) variant from a family with Larsen syndrome gave a uniform distribution and reduced cell migration; both increased Runx2 expression (preclinical in vitro data) [95]. Histology from patients showed collagen-poor joint capsules, thin and hypocellular tracheal cartilage and disorganised chondrocyte columns in the epiphyseal plate, which helps to explain the tracheobronchomalacia and the dislocations [73, 80]. Historical claims that Larsen syndrome was a collagen defect, or that FLNB lay in a "type VII collagen" region, have no support: FLNB encodes a cytoskeletal protein [86, 96].

2.3. Variant spectrum and genotype-phenotype correlation

Larsen syndrome variants cluster in exons 2–5 (CH2 domain) and exons 25–33 (repeats 13–17), with repeats 13–17 as the most frequent location; those of AO3 in exons 2–5, 13 and 27–33; and those of AO1, in the great majority, in exons 2–5, with three cases of Piepkorn dysplasia with variants in exons 28 and 29 [1, 73, 87]. At discovery, the same actin-binding domain substitution (M202V in OMIM notation) was found de novo in a patient with AO3 and in another with AO1, and the two fetuses with boomerang dysplasia studied by Bicknell had the substitutions p.(Leu171Arg) and p.(Ser235Pro), one of them proven de novo [5, 6]. Farrington-Rock and colleagues described 14 new missense variants in 15 patients with AO1 or AO3, most in exons 2–3 and the remainder in exons 28–29 [87]. The same variant can be associated with phenotypes of different severity: c.502G>A p.(Gly168Ser) was observed in AO1, AO3 and Larsen syndrome, and c.5071G>A p.(Gly1691Ser), the most common recurrent substitution, present in 6 of Bicknell's 20 probands, ranges from isolated bilateral dislocation of the knees, with stature above the 97th centile and a normal cervical spine, to cervical myelopathy and a phenotype overlapping AO3 [1, 73]. Some FLNA and FLNB variants occur at exactly homologous residues with the same substitution, which reinforces the similarity between Larsen syndrome and the otopalatodigital disorders [73]. No genotype-phenotype correlation has been described in SCT [1, 14].

The following table brings together the variants cited in this article, normalised by ClinVar (searched on 28 October 2026). VariantValidator confirms NM_001457.4 as the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript of FLNB [97]; no conversion was made manually, and variants without a ClinVar record retain the notation and transcript of the article [92].

2.4. Mosaicism, penetrance and expressivity

Germline variants of the syndromic forms have complete penetrance and variable expressivity [1]. In Bicknell's family 5, 30 individuals across three to four generations carried p.(Glu227Lys) and one of them had no large-joint dislocations, although all of their children were affected to different degrees [73]. In FLNB-associated idiopathic congenital clubfoot, some families suggest reduced penetrance, and in others carriers have subtle signs of the spectrum (elbow and thumb hypermobility, broad flat thumbs) [1, 88, 89].

Postzygotic mosaicism has clinical and reproductive consequences. In a mosaic parent, the variant gives an asymmetric or milder phenotype, compatible with Larsen syndrome, whereas the same variant in the constitutional state in the child may give AO3 or lethal AO1 [1, 103]. Meira and colleagues described, in Brazil, a female newborn with AO1 and neonatal death whose father, with limb deformities and body asymmetry, had an FLNB missense variant in about 20% of cells [103]. Bernkopf and colleagues quantified by deep sequencing the p.(Tyr233Cys) variant in a man with asymmetric Larsen syndrome: 10.24% in saliva, 9.79% in fibroblasts, 9.47% in blood and 7.08% in sperm, which corresponds to about 20% of heterozygous somatic cells and a transmission risk of about 7% per conception [101]. Sanger sequencing has a detection limit of about 10% and blood analysis does not detect exclusively gonadal mosaicism [1, 101].

2.5. Allelic disorders and modifiers

No other Mendelian phenotype associated with germline FLNB variants is known [1]. One study implicated FLNB as a contributing factor in a proposed oligogenic aetiology for some cases of adolescent idiopathic scoliosis, without independent corroboration, and common variation at the locus contributes modestly to stature in the general population; loss-of-function heterozygotes may have slightly reduced stature [1]. Wang and colleagues published in 2024 cases of short stature associated with FLNB haploinsufficiency, discussing whether they constitute a new syndrome or an extension of the Larsen spectrum; only the title was consulted [104].

2.6. Non-FLNB spondylocarpotarsal synostosis: MYH3 and RFLNA

The MYH3 gene (17p13.1) encodes the embryonic myosin heavy chain. Zieba and colleagues described three patients with SCT without an FLNB variant and with heterozygous missense or nonsense variants in MYH3, with reduced TGF-β signalling and persistent postnatal expression of embryonic myosin in the small muscles between the neural arches [105]. Cameron-Christie and colleagues found, in 16 patients with SCT without FLNB, a recessive form: 9 had truncating variants inherited from unaffected parents and 6 the hypomorphic variant rs557849165 (splicing in the 5′ untranslated region) in trans; the truncating variants only cause disease in compound heterozygosity with the hypomorphic allele, and the 5′UTR variant is not captured by exome sequencing [106]. The Nosology classifies this entity as "SCT with contractures and pterygia, MYH3-related", AD and AR (OMIM 178110 and 618469); monoallelic missense variants of MYH3 also cause distal arthrogryposes 2A (Freeman-Sheldon) and 2B3 (Sheldon-Hall) [2, 107]. In the dominant forms, intrafamilial variability is marked: in one family, the mother had normal stature and mobility with C1–C2 and C6–C7 fusions, while the daughter had short stature, pterygia of the neck, knees and ankles, a bicuspid aortic valve and restrictive respiratory failure; in another, French, family, the son with scoliosis and thoracic fusions still had no carpal fusions at 8.5 years, which was attributed to delayed bone age, and the Australian girl of the initial description of "congenital synspondylism" turned out to carry an MYH3 variant [7, 108]. The RFLNA gene (refilin A, a filamin-binding protein) was associated with SCT in a single Japanese patient homozygous for c.241delC p.(Leu81CysfsTer111); refilins, filamins and myosins take part in the "perinuclear actin cap" [109].

2.7. Proteoglycan biosynthesis: the basis of the recessive forms

Proteoglycans, the main components of the cartilage extracellular matrix, are formed by a core protein to which glycosaminoglycan (GAG) chains are attached; chondroitin sulfate, dermatan sulfate and heparan sulfate bind to serine residues through a linker tetrasaccharide (xylose–galactose–galactose–glucuronic acid), synthesised in the Golgi apparatus by successive enzymes [110, 111]. Sulfation depends on the universal donor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) and on specific sulfotransferases; the intracellular sulfate pool depends mainly on the SLC26A2 transporter [110]. These defects should be suspected when more than one connective tissue compartment is affected simultaneously (bone and cartilage, ligaments, skin and sclerae) [110]. In cartilage, deficiency of tetrasaccharide enzymes, such as those encoded by xylt1 and fam20b, accelerates chondrocyte maturation through a matrix feedback circuit, which explains the advanced bone age associated with short stature [111]. The disorders of the group share hypoplasia of the distal humerus, deformed proximal femora ("monkey wrench"), accelerated carpal ossification, poor modelling of the short tubular bones, joint laxity or restriction, radioulnar involvement, clubfoot and EDS-type skin; all are autosomal recessive [112, 113].

CHST3 deficiency is a loss of function without hotspots; most variants cluster in the sulfotransferase domain, the phenotype is homogeneous and missense homozygotes are no less severe than carriers of nonsense variants [3]. The variant NM_004273.5:c.1298C>T p.(Pro433Leu) is a founder variant in the Amish community; it was not found in ClinVar by its protein designation, and the GeneReviews notation is retained [3, 92]. In B4GALT7 deficiency, the variant NM_007255.3:c.808C>T p.(Arg270Cys) (VCV000005613, pathogenic) is homozygous in all 22 patients with Réunion Island Larsen syndrome, with a founder effect [70, 92]. In B3GAT3 deficiency, the consanguineous kindred from Nias Island (Indonesia) is homozygous for NM_012200.4:c.419C>T p.(Pro140Leu) (VCV000225764) and has no heart disease, whereas the variant described at discovery, c.830G>A p.(Arg277Gln) (VCV000030573), was associated with bicuspid aortic valve and aortic root dilatation; the more severe phenotypes are associated with variants in the acceptor subdomain of the catalytic domain and the milder ones with the nucleotide-sugar donor-binding subdomain [56, 71, 92, 125]. The variant c.416C>T p.(Thr139Met), recurrent in Turkey, is classified as of uncertain significance in ClinVar [56, 92]. In Desbuquois dysplasia, arginine 300 of CANT1 was substituted in 5 of 9 families at discovery, and the mild allelic form, multiple epiphyseal dysplasia type 7, is associated, in the six patients from five families described more recently, with NM_001159773.2:c.375G>C p.(Trp125Cys) (VCV000031017), whereas the three earlier patients were homozygous for NM_001159773.2:c.511A>T p.(Ile171Phe) (VCV000441248; two siblings of Latino ancestry) or V226M (OMIM notation; one Latino patient) [23, 92, 121, 126]. In Baratela-Scott syndrome, when only one sequence variant is found in XYLT1, the GGC repeat expansion and methylation of exon 1, which constitute a common pathogenic variant, should be sought [115, 127].

CANT1 (17q25.3) encodes a calcium-dependent nucleotidase of the endoplasmic reticulum and Golgi, which preferentially hydrolyses UDP, a by-product of glycosyltransferases, to uridine monophosphate and phosphate; the MANE Select transcript is NM_001159773.2 (NP_001153245.1), confirmed in VariantValidator [92, 121, 128]. Desbuquois variants are loss-of-function, missense or truncating, in homozygosity or compound heterozygosity. The two substitutions of the catalytic residue Arg300 in the initial series correspond to NM_001159773.2:c.898C>T p.(Arg300Cys) (VCV000000279) and c.899G>A p.(Arg300His) (VCV000000280); the founder allele of the Kim variant, V226M in OMIM notation, is c.676G>A p.(Val226Met) (VCV000031018); the variant of the six Turkish patients with multiple epiphyseal dysplasia type 7 is c.375G>C p.(Trp125Cys) (VCV000031017); and the duplication c.902_906dup p.(Ser303AlafsTer21) (VCV000031013) was found in homozygosity in a fetus with severe dysplasia [23, 92, 129, 130]. The Cant1-null mouse, obtained by CRISPR/Cas9 editing, reproduces the short stature, thoracic kyphosis and type 1 delta phalanx, with reduced GAG content and extracellular space in the growth cartilage, rounded proliferative chondrocytes and impaired terminal hypertrophic differentiation [128]. In the same type of model, decorin and aggrecan are synthesised and secreted with shorter GAG chains, but not in the glycan-free form, and skin decorin also has a smaller hydrodynamic size, which shows that the defect is not confined to cartilage [131]. In chicken chondrocytes with thiram-induced tibial dyschondroplasia, CANT1 stabilised β-catenin, with activation of the TCF4–CHSY1 axis and of GAG, aggrecan and type II collagen synthesis; these are preclinical data in an avian model, without demonstration in patients [132].

2.8. Other entities of the group: KIF22, EXOC6B, NIN, COL27A1, GZF1, TGDS and CHSY1

Leptodactylic-type SEMD with joint laxity is the only dominant form in group 5: it results from monoallelic missense variants at two adjacent residues of the motor domain of the monomeric kinesin KIF22, NM_007317.3:c.442C>T p.(Pro148Ser), c.443C>T p.(Pro148Leu) and c.446G>A p.(Arg149Gln); the abstract of Min 2011 swaps the c.442/c.443 pairs, and the correspondence adopted is that of ClinVar, which matches that of the OMIM allelic entries [25, 92, 133, 134]. Boyden and colleagues also described a de novo substitution at the same codon, R149L (c.446G>T in OMIM notation), and found exon 4 variants in all 32 patients studied [24, 25]. At discovery, Boyden and colleagues studied 20 familial cases from 8 families and 12 sporadic cases, and Min and colleagues 7 of 8 individuals from 6 Korean families; sequencing targeted at codons 148–149 is a reasonable first line when the radiological phenotype is typical [133–135]. Three pairs of affected siblings with unaffected parents suggest relatively frequent germline mosaicism or genetic heterogeneity [136]. The EXOC6B form results from biallelic loss of function of an exocyst subunit, with impaired primary ciliogenesis; the discovery variant was NM_015189.3:c.906T>A p.(Tyr302Ter) (VCV000625845) in two Indian siblings [92, 137, 138]. EXOC6B alterations (deletions, translocations) have been described in intellectual disability without skeletal anomalies, without proof of causality [16]. The NIN form was described in a single family; the EXOC6B GeneReviews classifies it as AR, and the Bone Dysplasias atlas refers to monoallelic variants, a divergence that the sources consulted do not resolve [16, 136].

Steel syndrome results from biallelic variants in COL27A1, which encodes the pro-α chain of fibrillar collagen XXVII; the Puerto Rican founder variant is NM_032888.4:c.2089G>C p.(Gly697Arg) (VCV000143245), and the notation "p.Gly679Arg" in the Bone Dysplasias atlas is a typographical error [62, 92, 139]. COL27A1 (9q32–q33, 61 exons; MANE Select transcript NM_032888.4, NP_116277.2, confirmed in VariantValidator) encodes the proα1(XXVII) chain, of 1860 amino acids, with a triple-helix domain of Gly-Xaa-Yaa repeats; in the embryo it is expressed in cartilage, eye, inner ear, bronchial epithelium, ameloblasts and large arteries, and later becomes almost restricted to growth cartilage, a distribution compatible with the hearing loss, dental anomalies and septal defects described [140]. Unlike glycine substitutions in the triple helix of the classical fibrillar collagens, which act by a dominant negative effect, those of COL27A1 (clade C collagen) only cause disease in the biallelic state, and heterozygotes for p.(Gly697Arg) do not have the phenotype [140, 141]. The knock-in mouse with the orthologous substitution p.(Gly682Arg) has shorter body length, scoliosis and a more rounded skull, with abnormal collagen deposition in the matrix and disorganisation of the proliferative zone of the growth cartilage [141]. Identity-by-descent analysis in the BioMe biobank in New York placed the origin of the founder allele on an Amerindian haplotype, probably at the beginning of European colonisation of Puerto Rico, with a population bottleneck 9–14 generations ago [142]. Outside Puerto Rico, about 21 variants are distributed along the gene, half of them truncating (frameshift or nonsense), and the consanguineous Turkish families with rare and distinct alleles illustrate homozygosity by recent descent rather than a founder effect [140, 141]. Examples verified in ClinVar on NM_032888.4 are c.3556-2A>G (VCV000559511, patient from the United Arab Emirates), c.3249+1G>T (VCV001346078, fetuses from a Caucasian family), c.93del p.(Phe32fs) with c.3075del p.(Lys1026fs) (VCV000807556 and VCV000807557; p.Phe32LeufsTer71 and p.Lys1026ArgfsTer33 in the report of the Syrian patient), c.2619+1G>A with c.2673+4A>G (VCV004530701 and VCV004530698; skipping of exons 17 and 18 demonstrated in fibroblast RNA, with in-frame deletions of 18 amino acids) and c.3988G>C p.(Gly1330Arg) in homozygosity (VCV004685562) [92, 140, 143]. In the monozygotic twins of Girisha and colleagues, the variants c.295G>A p.(Ala99Thr) and c.3056C>A p.(Pro1019His) are listed in ClinVar with conflicting classifications and as likely benign, respectively, so their causality should be read with caution [92, 144]. The genotype-phenotype correlation proposed from 63 patients associates biallelic glycine substitutions of the triple helix with the classical Steel phenotype and truncating variants with more severe short stature and more extraskeletal manifestations; the age at onset of hearing loss did not correlate with the type or location of the variant [140]. The GZF1 phenotype results from biallelic truncating variants in the transcription factor GDNF-inducible zinc finger protein 1, such as NM_022482.5:c.1440del p.(His481IlefsTer26) (VCV001687511), observed in homozygosity and in compound heterozygosity with c.1451_1452del in Mexican patients [61, 72, 92]. Catel-Manzke syndrome results from biallelic variants in TGDS (thymidine diphosphate-glucose 4,6-dehydratase), with a probable founder allele NM_014305.4:c.298G>T p.(Ala100Ser) (VCV000162455); Jacobs and colleagues showed in 2025 that TGDS produces an "enzyme rescue metabolite" that regenerates NAD+ at the catalytic centre of UXS1, without which skeletal glycan synthesis fails (preclinical mechanistic study) [92, 145, 146]. Temtamy brachydactyly results from loss of function of CHSY1 (chondroitin synthase 1), a potential target of bone morphogenetic protein (BMP) signalling [147].

3. Clinical Spectrum and Manifestations by System

3.1. Common syndromic description

The dysplasias with congenital dislocations share a clinical core: dislocation or subluxation of large joints present at birth (knees, often in genu recurvatum, hips, elbows and radial heads), clubfoot, short stature of variable severity, vertebral deformity (cervical kyphosis, kyphoscoliosis, coronal clefts) and, in several entities, cleft palate, hearing loss and airway abnormalities [1, 3, 111]. The entities are distinguished by the face (flat in Larsen syndrome, normal in CHST3 deficiency, round with prominent eyes in Desbuquois dysplasia and the linkeropathies), the hands (spatulate thumbs in Larsen syndrome, hyperphalangism in Desbuquois dysplasia, brachydactyly in the IMPAD1 form, leptodactyly in the KIF22 and EXOC6B forms), bone age (advanced in the disorders of GAG synthesis, normal or delayed in CHST3 deficiency and markedly delayed in the EXOC6B form) and extraskeletal involvement (heart disease in B3GAT3 deficiency, hyperextensible skin in the B4GALT7 and B3GALT6 forms, myopia in the GZF1 form, amelogenesis imperfecta in the SLC10A7 form) [3, 60, 148, 149]. In the forms associated with proteoglycan synthesis, the dislocations coexist with progression towards restricted joint mobility, most evident in CHST3 deficiency [3].

3.2. FLNB-related Larsen syndrome

3.2.1. Reference cohorts

The series of Bicknell and colleagues (J Med Genet 2007) brought together, through international medical referral coordinated from Otago (New Zealand), 20 probands (8 male, 12 female), 16 isolated and 4 familial, with 52 affected individuals in total; 10 variants were proven de novo and all were missense variants or in-frame deletions of FLNB [1, 73]. The table summarises the frequencies; this is a clinically ascertained cohort, biased towards recognisable phenotypes, and not a population estimate.

The only invariable feature in patients assessed at a sufficient age was the accessory ossification centres of the carpus and/or tarsus; there were carriers without large-joint dislocations (the mildest case had only subluxable shoulders), without spatulate digits, without midface hypoplasia or with stature at or above the 10th centile (one patient measured 179 cm, above the 97th centile) [73]. Short stature, chest wall deformity and spatulate thumb increase the specificity of the diagnosis [73]. In family 5, with 13 members examined between 2 and 40 years of age and the p.(Glu227Lys) variant, intrafamilial expressivity was broad: prominent forehead, depressed nasal bridge and flat midface in 13/13, congenital dislocation of the knees in 11/13 (85%), of the hips in 6/13 (46%) and of the elbows in 4/13 (31%), clubfoot in 7/12 (58%), short stature in 7/12 (58%), spatulate thumbs in 9/13 (69%), vertebral anomalies in 4/12, hearing loss in 3/13 (23%), cleft palate in 1/13 (8%) and no developmental delay [73]. Metacarpophalangeal pattern profile analysis showed a distal acral patterning defect similar to that of men with otopalatodigital syndrome type 1 [73].

3.2.2. Musculoskeletal system

The dislocations are present at birth and mainly affect the hips, knees and elbows; knee dislocation often presents as genu recurvatum [67]. Postnatal development of hip dislocations has not been described, which makes neonatal assessment decisive [1]. Equinovarus foot with forefoot torsion, or equinovalgus, is often refractory to orthopaedic measures [1, 67]. The hands have cylindrical fingers without distal tapering, relatively short metacarpals, short broad distal phalanges and spatulate thumbs with premature epiphyseal-diaphyseal fusion of the distal phalanx, sometimes bifid [67, 68]. The characteristic radiological signs are supernumerary carpal bones, the accessory ossification centre of the calcaneus that appears at the end of the first year, fuses in childhood and may persist as a plantar notch, epiphyseal separation at the elbow (trochlea and capitulum, with pseudarthrosis), bipartite or tripartite patella and premature ossification of the proximal humeral epiphysis [67, 150]. Secondary osteoarthritis of the large joints is expected in adulthood, and final height is normal or slightly reduced [67, 68].

3.2.3. Cervical spine and spinal cord

The cervical spine is the main source of severe morbidity. In Bicknell's series, 10 of 16 probands assessed had cervical anomalies, typically C2–C3 fusion, sometimes with subluxation of C3 on C4, and posterior arch defects; 3 of 20 (15%) developed myelopathy, and GeneReviews gives an incidence of myelopathy of at least 15% [1, 73]. Cervical kyphosis results from hypoplasia of the mid-cervical vertebral bodies, hypermobility of the small vertebral joints and ligamentous laxity, and may cause spinal cord compression and early death [67]. Johnston and colleagues (1996) found cervical kyphosis in 5 of 9 infants followed up, always with marked hypoplasia of one or two vertebral bodies at the apex (usually C4 and/or C5), and considered its frequency underestimated, because documentation does not require dynamic studies or patient cooperation [4]. In the series of Singh and colleagues (Lucknow, India, 2011–2019), 10 children with Larsen syndrome operated on for craniovertebral instability all had atlantoaxial dislocation (reducible in 8) and hypoplasia of the subaxial vertebral bodies, 7 presented before 5 years of age with moderate to severe myelopathy, and 4 of 7 initially asymptomatic children followed up in the genetics clinic developed myelopathy; the diagnosis of Larsen syndrome was clinical, without individual genetic confirmation [151]. Singh's review describes two patterns: neonatal presentation with cervical or thoracic kyphosis that frequently progresses, and presentation in adolescence or adulthood with tetraparesis, sometimes after minor trauma [151].

3.2.4. Airway and breathing

Laryngotracheomalacia is described in Larsen syndrome, but few patients with a documented FLNB variant have a severe form; when present, it may require prolonged ventilatory support and overlaps with the AO3 end of the spectrum [1, 67]. Rock and colleagues documented tracheomalacia in three children with Larsen syndrome, one with diffuse bronchomalacia, with stridor, cyanosis, apnoea and recurrent pneumonia [152]. Abnormally mobile arytenoid cartilage, tracheal stenosis and bronchomalacia are listed as occasional findings [68]. Hall (1978) observed, in the mother of a two-generation family, polychondritis of the tracheobronchial cartilages from the age of 30, with airway stenosis and recurrent pulmonary problems, and Le Marec and colleagues (1994) described an infant with laryngomalacia and apnoea associated with cervical kyphosis, segmentation defects and atlantoaxial dislocation [4]. In adults, severe kyphoscoliosis may reduce lung function to about 40% of predicted, as in the index patient of Juul and colleagues [93].

3.2.5. Face, palate, hearing and teeth

The face combines a prominent forehead, depressed nasal bridge, malar flattening and hypertelorism; midline cleft palate or bifid uvula occurs in 15% of Bicknell's probands and in about half of the cases in the Bone Dysplasias atlas, a difference that reflects different inclusion criteria [67, 73]. Hearing loss is mainly conductive, owing to ossicular chain malformation, middle ear effusion, Eustachian tube dysfunction or cleft palate; in a systematic review of 15 studies, 7 described hearing loss (4 conductive, 3 mixed), and hearing aids were safe and effective [1, 153]. Hypodontia, supernumerary teeth, gingival hyperplasia and periodontitis are occasional [68].

3.2.6. Heart and vessels

Heart disease is rare in the molecular era (1/20 in Bicknell's series) [73]. Kiel and colleagues, in 1983, reviewed more than 80 clinical cases and described septal defects and acquired abnormalities of the aorta and mitral valve, including aortic dilatation and regurgitation, but these diagnoses predate molecular confirmation [154]. The OrphanAnesthesia recommendation lists aortopathy, valvular disease and congenital shunts [96]. A clinical diagnosis of Larsen syndrome with arterial dissections should prompt a search for another connective tissue disorder, such as FKBP14-related kyphoscoliotic EDS [155].

3.2.7. Bone and mineral density

Juul and colleagues described, in Denmark, a mother and daughter with Larsen syndrome and the variant NM_001457.3:c.688G>T p.(Val230Phe) with severe osteoporosis: spine T-score of −5.2 and hip T-score of −3.1 at 46 years in the mother, and −5.6 and −4.1 at 27 years in the daughter, without low-energy fractures; high-resolution peripheral tomography showed low trabecular bone volume fraction and increased trabecular separation compared with 262 healthy women, and transiliac biopsy showed reduced trabecular bone with remodelling similar to that of controls [93]. Corticosteroid therapy, early menopause and a restrictive diet coexisted, so the contribution of FLNB has not been isolated; this is a report of two cases [93].

3.2.8. Neurodevelopment and other findings

Intelligence is normal [1]. Neurodevelopmental delay was recorded in 3/20 probands, partly secondary to neurological and respiratory complications [73]. Intellectual disability, cleft lip, entropion, cortical lens opacities, cryptorchidism and hypoplastic humerus occur occasionally [68]. Malignant hyperthermia appears as an occasional finding in Smith's atlas, but the association has not been proven (see section 7) [68, 96].

3.2.9. Apparently isolated clubfoot

Clubfoot is the most common congenital malformation (1–2 per 1000 live births) and is multifactorial [1]. Yang and colleagues, in China, described three FLNB missense variants in isolated congenital talipes equinovarus, and Quiggle and colleagues, in the USA, identified by exome sequencing a recurrent FLNB deletion in individuals with idiopathic clubfoot; some had mild signs of Larsen syndrome, and larger cohorts are needed [1, 88, 89]. Hickey and colleagues showed that Larsen syndrome can present with single-joint pathology: a three-generation family with congenital dislocation of the knees, clubfeet and neither a typical face nor spatulate thumbs, initially investigated for nail-patella syndrome [66].

3.3. Atelosteogenesis type 3

AO3 manifests as a neonatal short-limbed dysplasia with a small thorax, flat face with hypertelorism and micrognathia, cleft palate, multiple dislocations of elbows, hips and knees, broad distal phalanges, syndactyly, camptodactyly and talipes equinovarus [77, 156]. Radiologically, the distinguishing features are cervical kyphosis or double curve, a broad odontoid process, coronal clefts throughout the thoracolumbar spine, short and distally tapering humeri and femora, hypoplastic but usually ossified fibulae, "tombstone" proximal phalanges and a calcaneus with double ossification [77, 156]. Laryngotracheobronchomalacia is the main cause of death and morbidity; ventilation is often required and respiratory infections recur in childhood [1, 77]. Survival beyond the first year is rare, but has been documented into adulthood: Schultz's patient, followed up from 6 months to 21 years, intellectually normal, reached 135 cm and had an affected son, who required invasive ventilatory support for laryngotracheomalacia and thoracic hypoplasia [77, 78, 156]. Stern and colleagues delineated AO3 from five isolated cases, one of them with advanced paternal age, and Pyeritz (1993) reported affected siblings; in the cases reviewed by Schultz, respiratory complications and cervical spine instability were the apparent causes of death [6]. In some long-term survivors neurodevelopment was mildly affected, presumably owing to orthopaedic and respiratory complications [1]. A distally tapering humerus indicates AO3 and a greater likelihood of significant laryngotracheobronchomalacia, the main feature that differentiates it from Larsen syndrome [1, 73].

3.4. Atelosteogenesis type 1, boomerang dysplasia and Piepkorn dysplasia

AO1 is lethal in the perinatal period: second-trimester ultrasound shows polyhydramnios, a narrow thorax, very short limbs and absent or delayed ossification of vertebrae and long bones, and death results from cardiorespiratory failure due to pulmonary hypoplasia [1, 75, 76]. Radiological findings include absent, segmented or distally tapering humeri, absent fibulae, short pointed femora, bowed tibiae, platyspondyly with coronal clefts, 11 pairs of ribs, ischiopubic hypoplasia and lack of ossification of the proximal and middle phalanges with ossified distal phalanges [75, 76]. Laryngeal hypoplasia or stenosis, encephalocele, omphalocele, retinal dysplasia and renal microcysts are occasional [1, 76]. Li and colleagues described two patients with AO1 and substitutions of residue 181, one of whom had airway instability and bronchopulmonary dysplasia that prevented weaning from ventilation [102]. Boomerang dysplasia is distinguished by a more severe mineralisation defect, with complete absence of ossification of some long bones and vertebrae, relative sparing of the thorax, clavicles and iliac wings, limbs often with a single segment and boomerang-shaped femora [80]. The first cases had a broad nasal root with severe hypoplasia of the nostrils and septum, absent radii and fibulae and neonatal death; one fetus was diagnosed by ultrasound at 16 weeks, with vertebral ossification limited to T11–T12 and L1–L3, and another had generalised alopecia and multinucleated giant chondrocytes in the cartilage [5]. Piepkorn dysplasia (fewer than five individuals published) has extremely short flipper-like limbs, complete syndactyly of all digits with duplication of the middle and distal phalanges ("distal octodactyly"), hypoplastic or absent thumbs and halluces, and occasionally omphalocele, heart disease and sex reversal; oligosyndactyly may be the only feature that separates it from AO1 [1, 82].

3.5. FLNB-related spondylocarpotarsal synostosis

Birth length is normal or nearly normal; progressive vertebral fusion compromises trunk growth and postnatal stature is typically 3 to 6 standard deviations (SD) below the mean [1]. The systematic review by Gobbetto and colleagues (search in June 2026) included 11 studies (Taiwan, Argentina, Pakistan, Italy, Germany, India) with 38 molecularly confirmed patients, plus one new case; the frequencies depend on what each series assessed [14].

The "core" (≥85% of those assessable) and "supportive" categories are descriptive proposals and not validated criteria; publication bias is likely [14]. Fusion of the posterior elements is mainly thoracic and contiguous, and asymmetry gives rise to the unilateral unsegmented bar which, without treatment, leads to severe scoliosis and restrictive pulmonary dysfunction [1, 85, 99]. Cervical instability, basilar impression and foramen magnum stenosis, with cervical myelopathy, have been described [1, 85]. Tarsal coalition may become painful in adolescence, and tarsal fusion may be a late finding, so its absence at an early assessment does not exclude the diagnosis [14, 99]. The face is normal or mildly dysmorphic (round face, frontal bossing, anteverted nares); enamel hypoplasia, retinal anomalies without visual loss, renal cysts and femoral epiphyseal dysplasia have been described [1, 85, 157]. In seven Argentinian cases, facial dysmorphism was present in 7/7 [14, 158].

Salian and colleagues described 10 patients from 7 families (7 months to 15 years), all with disproportionate short stature between −2.4 and −9.5 SD, contiguous vertebral fusion mainly at T5–T7, capitate-hamate fusion in 9/10, lunotriquetral in 3/10 and tarsal in 5/10, with marked intrafamilial variability; all variants were nonsense or frameshift in homozygosity [7, 159]. Seaver and Boyd documented cervical instability in a 5-year-old girl, with hypoplasia of C1 and of the odontoid process and subluxation of C2 on C3 [7]. Brunetti-Pierri and colleagues described an Italian girl with documented growth hormone deficiency and no response to treatment, platybasia, basilar impression and foramen magnum stenosis without cervicomedullary compression; her heterozygous brother had short stature and transient growth hormone deficiency [7]. Mitter and colleagues recorded delayed ossification of multiple epiphyses and dysplasia of the proximal femoral epiphyses, and, among the 18 patients published up to 1998, 10 were sibling pairs from 5 families, with first-cousin parents in 3 [7].

3.6. CHST3-related chondrodysplasia with congenital dislocations

Most patients are identified at birth as having a generalised skeletal disorder; birth length is 39 to 44 cm, the great majority have bilateral dislocation or subluxation of the knees, followed by the radial heads and hips, and clubfeet are frequent [3]. The face is normal, and the thumbs are not spatulate [3, 148]. In the series of Unger and colleagues (24 patients from 23 families, 2010), the previous working diagnoses had been Larsen syndrome in 15 families, humerospinal dysostosis in 4, Mégarbané-type chondrodysplasia with dislocations in 2, Desbuquois dysplasia in 1 and spondyloepiphyseal dysplasia in 1; the common picture included dislocation of knees and/or hips, clubfoot, elbow dysplasia with limited extension, short stature and progressive kyphosis in late childhood, and the most useful radiographic clue was the changes in the lumbar vertebrae [160]. Despite the dislocations, the overall phenotype is one of restricted mobility, and many children undergo multiple operations with limited benefit [3, 148]. Radiologically, the coronal clefts of infancy persist as notches in the vertebral bodies, the interpedicular distance increases conspicuously between T12 and L1–L2, the distal humerus may be bifid in the newborn (the origin of the name humerospinal dysostosis), bone age is normal or delayed and the hand is practically normal [3, 148].

Adult height is severely affected, with great variability between families: 110–130 cm in a family from Oman, a mean of 84 cm in a Pakistani family and 117, 121 and 134.5 cm in three adults from one review [3, 160–162]. For the Omani family, the OMIM summary of the same report gives 110–139 cm [17]. In adults, joint stiffness, osteoarthritis, kyphosis (often cervical) and reduced lung capacity due to thoracic shortening predominate [3, 148]. Minor valvular dysplasia with regurgitation has been described in multiple reports, including the Omani family and 14 Egyptian patients; structural malformations such as atrial septal defect (ASD) were occasional, without an established causal link [3, 163]. Microdontia and delayed tooth eruption were observed in Oman and Egypt [3]. Intellect, vision and hearing are usually normal, but in a Pakistani family at least six affected individuals had mixed hearing loss [3, 162]. Sagittal craniosynostosis and "sclerosis of the sutures" have been described in isolation [3]. There are exceptions to the typical signs: two Turkish siblings had narrowing, rather than widening, of the lumbar interpedicular distance; in another Turkish family, the affected individuals had only elbow dysplasia with radial subluxation, without multiple dislocations, and a 33-year-old uncle had mitral, tricuspid and aortic regurgitation with aortic stenosis; in two Somali half-siblings, the girl presented at 5.5 years with short stature and genu valgum, with no recollection of neonatal dislocations, and used a wheelchair for most of the day at 10 years, while her brother was born with bilateral knee dislocation and clubfoot; both had conductive hearing loss [17].

3.7. CANT1-related Desbuquois dysplasia and multiple epiphyseal dysplasia type 7

Desbuquois dysplasia was described in 1966 in two sisters with short stature, dislocations, glaucoma, heart disease and severe psychomotor delay [122, 149]. The historical classification separated type 1, with hyperphalangism of the index finger (extra ossification centre distal to the 2nd metacarpal), delta phalanx and bifid distal phalanx of the thumb, from type 2, without these changes; the "Kim variant" has short metacarpals and elongated phalanges, with fingers 2–5 of almost equal length [122, 149]. The 2023 Nosology reserves the name for the CANT1 forms and calls the former XYLT1 form Baratela-Scott syndrome [2]. The review by Piwar and colleagues brought together 111 cases published up to 2023 (54 type 1, 39 type 2, 14 Kim variant): median birth weight 2505 g, median length 40 cm, median head circumference 33 cm, consanguinity in about 60%, prenatal diagnosis in 28%, intellectual disability in 20 and motor delay in 15 of the 111 [41, 126]. Among the 54 type 1 patients, 28% died early and 26% had respiratory difficulty, failure or arrest; the "Swedish key" femur was present in almost all patients of all subtypes and advanced carpal and tarsal bone age in about 80% [41, 126].

Five findings occur in more than 90% of patients: "Swedish key" proximal femur (short neck, medial metaphyseal beak, exaggerated lesser trochanter), flat acetabular roof, elevated greater trochanter, overgrowth of the proximal fibula and advanced carpal and tarsal bone age [122]. Stature lies between −4 and −10 SD in adolescence; sleep apnoea and respiratory difficulty may lead to respiratory failure and early death, and cervical kyphosis, progressive scoliosis and early osteoarthritis occur (hip joint space narrowing at 22 years in a patient with the Kim variant) [122, 149]. In a single-centre retrospective cohort of 9 patients with biallelic CANT1 and a median follow-up of 7.7 years, 7/9 had mitral prolapse, 7/9 dilatation of the ascending aorta (median Z 5; 2.3–8.5), 6/9 aortic root enlargement, 5/9 small ASD, 2/9 bicuspid aortic valve and 1/9 ventricular septal defect (VSD) [126, 164]. The mild allelic form, multiple epiphyseal dysplasia type 7, causes arthralgia, early osteoarthropathy, small irregular epiphyses and mild short stature in some, with features of Desbuquois dysplasia [126].

Faivre and colleagues described the radiology of 35 patients: 46% had the typical hand changes and 54% did not, and the first group had more long-bone dislocations (62% versus 28%) and more kyphoscoliosis (50% versus 12%); these hand changes may no longer be recognisable after the first year, as may the vertebral coronal clefts [22]. In the follow-up of four patients up to 16–22 years of age, mean adult height was 114 cm (−8.5 SD), with generalised osteoporosis, scoliosis and marked lordosis in three, walking difficulty in three and acute open-angle glaucoma in one, which led the authors to propose an ophthalmological examination with intraocular pressure measurement in routine follow-up; glaucoma was already part of the original description and was congenital and bilateral in a Saudi infant [22]. In the initial molecular series, truncating variants were associated with early death from cardiorespiratory failure, and two substitutions of residue Arg300, at the catalytic centre, accounted for 5 of 9 families [22, 23]. There are hydropic fetal forms, with hands with widely spaced fingers in the shape of a capital "Y", renal anomalies (pelvicalyceal dilatation, horseshoe kidney, cysts) and recurrence in non-consanguineous couples [22]. The Kim variant is associated with V226M (OMIM notation) on at least one allele, with a founder effect in Japanese and Korean families and an estimated variant age of about 1420 years; the same variant in homozygosity was found in a Latino patient with multiple epiphyseal dysplasia type 7, a form initially described in two Latino siblings with p.(Ile171Phe) [22, 23]. PGM3 deficiency (immunodeficiency 23) may produce skeletal changes reminiscent of Desbuquois dysplasia [22].

Daşar and colleagues described six patients from five unrelated Turkish families, all with p.(Trp125Cys), with multiple epiphyseal dysplasia and some features of Desbuquois dysplasia, which raised to nine the number of published patients with the mild allelic form [129]. At the severe end of the spectrum, a Thai newborn of non-consanguineous parents, with short long bones and a small thorax on ultrasound at 33 weeks, was born measuring 38 cm (Z −4.80), with a round flat face, micrognathia, "hitchhiker" thumbs, multiple dislocations, "Swedish key" femur, coronal clefts and wavy ribs; he was ventilated from birth for thoracic dysplasia and died at 7 months, with two compound heterozygous missense variants, NM_001159773.2:c.505G>A p.(Asp169Asn) (VCV002439717, uncertain significance in ClinVar), at a calcium-binding residue, and c.1028G>T p.(Gly343Val), without a ClinVar record, both classified by the authors as of uncertain significance [92, 165]. In a fetus of consanguineous parents, ultrasound showed short femur and humerus, hypoplastic thorax, brachydactyly, overlapping fingers, clubfoot, rocker-bottom foot and VSD, and homozygosity for c.902_906dup p.(Ser303AlafsTer21) led the family to opt for termination of pregnancy [130].

3.8. XYLT1-related Baratela-Scott syndrome

XYLT1 deficiency causes short stature of prenatal onset, a round face with depressed nasal bridge and micrognathia, occasional cleft palate, moderate laxity, lateral patellar dislocation in most, brachydactyly, clubfeet and developmental delay in practically all cases described [166]. The radiology overlaps with that of Desbuquois dysplasia ("monkey wrench" femur, high greater trochanter, accelerated carpotarsal ossification, coronal clefts in infancy), but the type 1 phalangeal changes are lacking [114, 166]. The Bone Dysplasias atlas lists synophrys among the findings and, in the differential diagnosis, states that it is not observed, an internal contradiction that the sources consulted do not resolve [166]. Some patients died in childhood [166]. The case illustrated in the atlas is that of a girl from Recife, Brazil, with cleft palate, marked short stature and intellectual disability, with coronal clefts at 6 months and, at 8 years, dislocated patella and radial head, osteopenia and advanced carpal age [166].

Baratela and colleagues described in 2012 seven male patients from six families, with dislocated patella, brachydactyly with short thumbs, "monkey wrench" femur, flat midface and cognitive delay with attention deficit, tempered by a warm and sociable personality; the initial hypothesis of X-linked inheritance was ruled out by the brother-sister pairs of Schreml and of Bui, both from 2014 [20]. In Bui's series, 5 of the 7 patients with a variant had intellectual disability and 2 truncal obesity; in Schreml's Turkish siblings, homozygous for a hypomorphic allele, the phenotype was milder, without "monkey wrench" femur or advanced bone age (signs that attenuate with time), with acne and hirsutism [20]. LaCroix and colleagues identified in 10 of 12 patients from 10 families a (GGC)n expansion in the promoter that hypermethylates and silences exon 1; the second most frequent alteration, in 6 patients, was a 3.1 Mb deletion at 16p13 that includes XYLT1, and in two families the expansion increased when transmitted by the unaffected mother; 11 of the 12 patients were male, a skew whose reality requires larger cohorts [20, 21]. OMIM still designates this entity "Desbuquois dysplasia type 2", with "Baratela-Scott syndrome" as an alternative title [20].

3.9. Linkeropathies: B3GAT3, B4GALT7 and B3GALT6

The linkeropathies form a continuum between EDS and the skeletal dysplasias, with hypoplasia of the distal humerus, deformed proximal femora, accelerated carpal ossification and poor modelling of the short tubular bones [112, 113]. Radioulnar synostosis is frequent in the B3GAT3 and B4GALT7 forms and not in the others [111].

In B3GAT3 deficiency, the 2019 review (25 patients from 12 families, 7 variants) found skeletal dysplasia in 26/26, facial dysmorphism in 25/25, spatulate distal phalanges in 16/17, disproportionate short stature in 19/23, contractures in 11/16, bone fragility with fractures and osteopenia in 8/12, hypermobility with dislocations of elbows, hips and knees in 10/19 and intellectual disability in 2/14 [56, 57, 167]. Cardiovascular involvement, in 12/20 (60%), includes bicuspid aortic valve, dilatation of the root and ascending aorta, mitral prolapse, ASD, VSD, patent ductus arteriosus and pulmonary stenosis, and depends on genotype [71, 125, 167]. Blue sclerae, fractures and osteopenia raise the possibility of osteogenesis imperfecta; congenital diaphragmatic hernia, cutis laxa, glaucoma and corneal opacification have also been described [111, 167]. Some cases published as pseudodiastrophic dysplasia have B3GAT3 variants [63]. A Mexican boy homozygous for a missense variant had femoral fractures at birth and about 25 fractures in the first year, some during blood pressure measurement, with bilateral glaucoma and no dislocations; a boy from the United Arab Emirates additionally had atlantoaxial and atlanto-occipital instability, mild developmental delay and refractive errors, and in the Nias kindred one of the sibships was more severely affected, which suggests a modifier gene [30, 31].

B4GALT7 deficiency (spondylodysplastic EDS type 1) causes often severe short stature, hypotonia, hypermobility, soft hyperextensible skin with slow wound healing, a face with prominent eyes and forehead, radioulnar synostosis, hypermetropia and cognitive delay; sensorineural hearing loss, lymphoedema of the limbs and recurrent pneumothorax have also been described [113, 168, 169]. The term "progeroid EDS" should be abandoned [168]. Réunion Island Larsen syndrome, described in 1975, has dwarfism (about −5 SD), multiple dislocations, hyperlaxity, a round flat face with prominent eyes and microstomia, advanced carpal ossification, radioulnar synostosis and absence of accessory carpal bones [68, 70, 73]. Alessandri and colleagues described the perinatal phenotype in 12 patients: all had prenatal growth restriction and short limbs, increased nuchal translucency at 10–12 weeks in 50%, foot abnormalities and dislocation of at least one large joint in 25% on ultrasound, radioulnar synostosis in 75% and "Swedish key" proximal femur [170]. On Réunion, Bonaventure and colleagues counted more than 40 affected children over 20 years in a population of 600,000 inhabitants, about 1 in 1500 births, compared with about 1 in 100,000 in France; the p.(Arg270Cys) allele frequency of 2% in 500 local controls corresponds to about 1 in 2500 births [28]. Patients from Réunion have delta phalanx, phalangeal dislocations and advanced carpal ossification and no hypermetropia has been described, unlike those of other origins, which suggests modifier genes in this Creole population; a non-Réunionese boy did not respond to a growth hormone trial, and a lethal phenotype was described, with cystic hygroma and perinatal death in three consecutive pregnancies, associated with an allele with practically no enzyme activity [28, 29].

B3GALT6 deficiency (Beighton-type SEMD with joint laxity; spondylodysplastic EDS type 2) has as its main problem congenital or early-onset progressive kyphoscoliosis, refractory to treatment, which may cause spinal cord compression and cardiorespiratory compromise; adult height may be below 120 cm in men and 100 cm in women [117, 171]. Severe laxity with hypotonia dominates in infancy and this is the form most often confused with EDS; the skin is hyperextensible, thin and translucent, there are blue sclerae, osteopenia with fractures in some and, in the series of 12 patients, dilatation or aneurysm of the ascending aorta, cervical instability and respiratory failure as potentially fatal complications [117, 171, 172]. In a review of 18 live births (2025), scoliosis was present in 16/18, hypotonia in 15/18, soft lax skin in 12/18, skeletal abnormalities on prenatal ultrasound in 4/18 and cervical instability in 3/18; one child died at 18 months from hypoxia with tracheomalacia and tracheal compression by the scoliosis [173]. Al-Gazali syndrome, which is lethal, is the extreme neonatal form [2, 171]. The evidence does not support transposing the precautions of vascular EDS, because arterial, hollow organ or uterine ruptures have not been described [171]. Beighton, who described the form in South Africa, reported in 1994 that orthoses are usually ineffective, that internal fixation is often necessary and that a significant proportion of patients develop spinal cord compression and paraplegia; most died in the first or second decade and no affected individual over 25 years had been published by then, but Tsirikos and colleagues described in 2003 a 35-year-old patient with a favourable course after multiple operations [26]. Malfait and colleagues described, in Iranian families, a form with multiple early fractures, skin fragility and intellectual disability [26, 27].

3.10. IMPAD1-related chondrodysplasia with dislocations

The IMPAD1 form (gPAPP deficiency) causes short-limbed dwarfism detectable at 24 weeks, prominent forehead, protruding eyes, Pierre Robin sequence with cleft palate, hearing loss, dislocations mainly of hips, knees and patellae, marked brachydactyly with asymmetry of the hands and, sometimes, a "hitchhiker" thumb or 5th toe [1, 40, 124]. Bone age is not advanced, intellectual development appears normal and the final height of one woman was 125 cm [40]. The four patients at discovery were a German girl and two Turkish sisters, from consanguineous families, and a patient whose parents were from Kerala (India) [19]. Nizon and colleagues found loss-of-function IMPAD1 variants in two unrelated Turkish patients with a phenotype similar to Catel-Manzke syndrome, one of them a boy already described by Kiper (2011), whose two sisters had died in the neonatal period with similar features; these patients had only knee hyperlaxity, without recurrent dislocations, with accessory bones and carpal synostosis [19, 174]. The Bone Dysplasias atlas refers to these patients as "two sisters", which does not match OMIM or the title of the article [40].

3.11. CSGALNACT1 and SLC10A7 forms

CSGALNACT1 deficiency, described in 4 patients, causes a mild, non-progressive skeletal dysplasia, with disproportionate short stature of prenatal onset, generalised laxity that may exist without dislocations, advanced bone age, mild dysmorphism, axial malalignment of the lower limbs and mild language delay in two patients; the radiographs of the index case resemble Desbuquois dysplasia [64, 120, 175]. One of the index patient's alleles was an intragenic deletion of about 55 kb (exons 5 to 8), and another patient had a deletion of about 85 kb that removes the exon containing the initiation codon, which makes CNV analysis necessary; one of Mizumoto's patients also had mosaic trisomy 8, with its own features, which limits attribution of the phenotype [32]. SLC10A7 deficiency, described in 6 homozygous individuals, causes severe disproportionate short stature, micro-retrognathia, multiple dislocations, advanced carpal ossification, osteoporosis and amelogenesis imperfecta [60, 110].

3.12. SEMD with joint laxity: KIF22, EXOC6B and NIN

In the KIF22 form, laxity and dysmorphism (midface hypoplasia, short nose, long upper lip) are present from birth, with dislocation of hips and elbows suggestive of EDS; in early childhood genu valgum or varum, slow growth and scoliosis appear, and the specific hand changes (long slender tubular bones, markedly delayed carpal ossification) appear from 3 years of age [135, 136]. About one third of patients have laryngeal stenosis due to fibrotic cricoarytenoid joints, with respiratory compromise; intellect is normal [136]. Park and colleagues counted upper airway obstruction in 5 of the 13 cases published up to 2007 and described an infant with stridor from 4 months of age, failure of vocal cord abduction and tracheostomy at 22 months; laryngotracheomalacia occurred in 2 of 4 patients in another series, which also recorded stellate ossification of the calcaneus and mild platyspondyly in infancy, and several cases were initially classified as sponastrime dysplasia [24]. In adults, laxity progresses to joint limitation: the oldest individual described, a 66-year-old man, had stiffness of the knees and elbows from the age of 20, of the shoulders, hips, ankles and wrists at around 40, early retirement at 45 and dependence on assisted living at 65 [135].

In the EXOC6B form, the 7 individuals described had dislocations of hips and knees at birth, leptodactyly and generalised laxity (7/7), genu valgum (6/7), vertebral changes (6/7), postnatal growth deficiency with normal size at birth (5/7) and markedly delayed carpal and tarsal ossification (7/7); the vertebral changes evolve with age, and a normal spine in adulthood does not exclude the diagnosis [16, 137]. The NIN form combines microcephalic primordial dwarfism, flat face, laxity, dislocations, genu valgum and pes cavus [16].

3.13. COL27A1-related Steel syndrome

Described in 1993 in Puerto Rican children with dislocation of the hips and radial heads, carpal coalition and short stature, Steel syndrome has a long oval face with prominent forehead, hearing loss (perhaps due to fusion of the ossicles), pes cavus and scoliosis; 47 patients had been published up to 2022, with a molecular diagnosis in 20 Puerto Rican and 9 non-Puerto Rican families [139, 176, 177]. The hip dislocation is classically resistant to surgical reduction, and atlantoaxial subluxation is rare but may produce upper motor neuron signs; adult height is below the 5th centile [139, 177]. The FLNB GeneReviews states that cleft palate is not part of Steel syndrome, and GeneGuidance lists it as a described finding [1, 139].

In the original description, 8 of the 23 Puerto Rican children had bilateral pes cavus and 3 cervical spine anomalies; in the series of Flynn and colleagues (32 patients, 18 of them from the original series), hip dislocation was present in all, radial head dislocation in 29/32, carpal coalition in 73% of wrists, scoliosis in 17/32 and pes cavus in 34% of feet, and all had short stature [34]. Belbin and colleagues, in a New York biobank linked to clinical records, found among 4397 people of Puerto Rican ancestry 5 homozygotes for p.(Gly697Arg), aged 34 to 74 years and none with a previous diagnosis of Steel syndrome: all had short stature and hip dislocation, four cervical anomalies (three operated on), three hip replacements and two, both under 50 years of age, knee replacements [34, 35]. Among the 34 heterozygotes under 55 years of age there was no short stature or dislocation, but carpal coalition (15%), scoliosis (24%), cervical anomalies (21%) and vertebral degeneration (38%, versus 13% in 31 non-carriers) were frequent, an observational association in a single sample [34]. Outside Puerto Rico, patients with severe sensorineural hearing loss (United Arab Emirates) and with developmental delay and hearing loss (India) have been described [34].

The review by Gorodilova and colleagues (2026) brought together 63 patients with clinical data (32 Puerto Ricans from Flynn's series, 14 Puerto Ricans from other studies, 15 non-Puerto Ricans and 2 new): short stature in 55/61, congenital hip dislocation in 53/62, radial head dislocation in 51/61, carpal coalition in 38/52, scoliosis in 37/62, oval face in 44/48, prominent forehead in 50/53, hypertelorism in 46/50, hearing loss in 18/56, developmental delay in 10/23 and cervical anomalies in 12/47, with the limitation that many reports do not state the presence or absence of each sign [140]. Pes cavus and carpal coalition predominate in Puerto Ricans, while talipes equinovarus or planovalgus, vertical talus, cryptorchidism, hernias, bilateral clinodactyly of the 5th finger, partial cutaneous syndactyly and hearing loss are more frequent in patients of other origins; the hip ranges from acetabular dysplasia to complete dislocation, and the first European patient, like one of the Russian patients, had no dislocation [140]. Cervical anomalies, stenosis and spinal cord compression manifest mainly in adults, and in homozygotes for p.(Gly697Arg) hearing loss was diagnosed after 30 years of age, whereas patients with other alleles had it from childhood [140, 141]. Girisha and colleagues described cleft palate and delayed carpal ossification for the first time; in the hand, pseudoepiphyses may be seen at the base of the 2nd metacarpal, and capitate-hamate coalition is the easiest fusion to recognise before ossification is complete [140, 144]. In a Puerto Rican family from New York with three homozygous adult siblings, the proband measured 1.47 m (−2.46 SD) and had multiple dislocations, severe scoliosis, diffuse osteoarthritis, hearing loss from the fourth decade, loss of 7.6 cm in height over 20 years and walked with a walking frame; in the DiscovEHR cohort (Geisinger), a homozygous woman measuring 1.50 m had developmental dysplasia of the hip, scoliosis, radial head subluxation, sensorineural hearing loss recorded at 38 years and failure of hip arthroplasties [141]. Among the 28 adult heterozygotes in the same cohort, the recorded joint and spinal complaints showed no statistically significant association, unlike the enrichment observed by Belbin and colleagues [141, 142]. In a non-consanguineous couple, two consecutive pregnancies were terminated for severe fetal anomalies; both fetuses were compound heterozygous for c.2548G>A p.(Gly850Arg) (notation of the report) and c.3249+1G>T, and autopsy showed bilateral absence of the humeral capitulum, which explains the radial head dislocation, markedly disorganised metaphyseal cartilage and hypercellular resting cartilage in irregular nests, in the first histological description of the syndrome [143].

3.14. GZF1-related phenotype

Patel and colleagues described two consanguineous Saudi families, one with severe recurrent dislocations of the large joints and severe myopia, the other with severe myopia, retinal detachment and milder skeletal involvement [72]. The variants were NM_022482.5:c.865G>T p.(Glu289Ter) (NM_022482.4 in OMIM notation; identical position, confirmed in VariantValidator), in two siblings (the sister with respiratory compromise due to severe kyphoscoliosis), and c.1054dup p.(Thr352AsnfsTer50), in three siblings, two of them with retinal detachment and iris and chorioretinal coloboma; in the patients' lymphoblastoid lines, P3H2, associated with severe myopia and an elongated eyeball, was expressed about 8 times less, a proposed mechanism for the ocular phenotype [33]. Yokoyama-Rebollar and colleagues added in 2026 three Mexican patients with congenital glaucoma and abnormal iris, cervical segmentation defects, carpal shortening, lumbar sacralisation, umbilical hernia and congenital heart disease, and proposed the GZF1 phenotype as an entity distinct from FLNB Larsen syndrome, characterised by severe ocular defects, short stature, hypermobility with dislocations, scoliosis, chest deformity, progressive hearing loss, umbilical hernia and hypodontia [61].

3.15. Pseudodiastrophic dysplasia

Pseudodiastrophic dysplasia, described by Burgio and colleagues in 1974 in two newborn sisters, combines midface hypoplasia, blue sclerae, micrognathia with cleft palate, rhizomelic shortening, dislocations of the proximal interphalangeal joints and of the large joints, especially the elbow, and clubfoot [178]. Bowing of the long bones is conspicuous in the second trimester and regresses in the third [178]. Most patients died in infancy or early childhood, from respiratory difficulty or unexplained hyperthermia [178]. Byrne and colleagues identified biallelic variants in B3GAT3 in one family and in CANT1 in another, with abolished or inhibited GAG synthesis [63]. On this basis, they proposed that pseudodiastrophic dysplasia is not a distinct genetic disease but the most severe end of the proteoglycan biosynthesis dysplasias, and OMIM retains entry 264180 without its own molecular basis [36]. Eteson and colleagues described four patients, all with elbow dislocation, scoliosis and clubfoot, two alive after 4 years of age and one with odontoid hypoplasia and C1–C2 dislocation in flexion; the clubfoot responded better to physical and surgical treatment than in diastrophic dysplasia, and sulfate uptake and proteoglycan sulfation were normal in one patient studied [36]. Omphalocele and complex heart disease have been described, and three unrelated probands came from a mountainous and relatively isolated region of Slovenia [36].

3.16. Related members: Catel-Manzke and Temtamy

Catel-Manzke syndrome combines Pierre Robin sequence with bilateral hyperphalangism of the index finger (accessory ossicle at the base of the proximal phalanx), with radial deviation at the metacarpophalangeal joint and ulnar clinodactyly; neonatal respiratory obstruction and heart disease determine the initial prognosis, and intelligence is normal in most [179, 180]. Manzke and colleagues estimated that about 70% of children have other severe congenital anomalies, mainly cardiac, as well as clubfoot, knee dislocation and laxity; the original patient, reassessed at 47 years, ran his own business, with an almost normal mandibular profile, hypernasal voice due to a residual palatal defect and reduced mobility of the index fingers [37]. The A100S variant (OMIM notation) was present in homozygosity or compound heterozygosity in 6 of the 7 patients at discovery, on a common 50 kb haplotype compatible with a founder effect, and a Dutch patient had bilateral Perthes disease and subluxation of the knees [38]. Temtamy preaxial brachydactyly combines brachydactyly with hyperphalangism and delta phalanges, congenital dislocations of hips and knees in some, sensorineural hearing loss, developmental delay and dental anomalies, almost always in consanguineous families [147, 181]. Talon cusps of the upper central incisors, proximal radioulnar synostosis, carpal and tarsal fusions and, in a Jordanian family, macrophthalmia with blue sclerae have also been described; the 15q26-qter deletion, which removes one copy of CHSY1, shares some features [39].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

On second-trimester ultrasound, AO1 and boomerang dysplasia present with polyhydramnios, a narrow thorax, very short limbs and absent or delayed ossification of vertebrae and long bones, which allows a definitive ultrasound diagnosis; fetal three-dimensional computed tomography (CT) added detail in one case of boomerang dysplasia [1, 182]. In AO3, a specific diagnosis is rarely possible by ultrasound alone [1]. In Larsen syndrome, second-trimester ultrasound may show abnormally positioned limbs, especially hyperextended knees [67, 183]. Short limbs with dislocations often lead to a provisional diagnosis of arthrogryposis in CHST3 deficiency [3, 148]. On Réunion Island, fetal growth restriction with micromelia should raise the possibility of the B4GALT7 form [170]. Abnormal vertebral bone density and abnormal segmentation on ultrasound suggested MYH3-related SCT in an Italian fetus [184]. Delivery of a fetus with dislocated hips and knees may be complicated by breech presentation with extended limbs [1].

4.2. Newborn and infant

Suspicion arises with congenital dislocations of large joints, especially bilateral knee dislocations, with clubfoot. The guiding features are a flat face with prominent forehead and spatulate thumbs (Larsen syndrome), a normal face with short stature of 39–44 cm (CHST3 deficiency), a round face with prominent eyes and hands with deviated fingers (Desbuquois dysplasia), prominent eyes with heart disease (B3GAT3 deficiency), lax hyperextensible skin (B4GALT7 and B3GALT6 forms) and Pierre Robin sequence (IMPAD1 and TGDS forms) [3, 67, 111, 149, 180]. In a child with Pierre Robin sequence, the index fingers should be examined and X-rayed [180]. In a hypermobile child with multiple dislocations, a skeletal survey is necessary, and a bifid calcaneus in infancy suggests Larsen syndrome [150]. In the family history of a child with contractures or dislocations, one should ask specifically about clubfeet, congenital hip dislocation, joint dislocations and hyperextensibility in relatives [185]. Mild Larsen syndrome may present with dislocation of a single joint or with clubfoot only, and be confused with arthrogryposis or nail-patella syndrome [1, 66].

4.3. Child, adolescent and adult

In SCT, the usual presentation is progressive scoliosis in early childhood, with a short trunk and neck and postnatal short stature [1, 99]. In the linkeropathies and the SEMD forms, progressive short stature, kyphoscoliosis, fractures and blue sclerae may lead to a diagnosis of osteogenesis imperfecta or EDS [111, 117, 136]. In adults, severe osteoporosis with kyphoscoliosis and spatulate thumbs may reveal undiagnosed Larsen syndrome, as in Juul's family [93].

4.4. Warning and emergency signs

There is no newborn screening for these disorders.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no established formal diagnostic criteria for the FLNB disorders; GeneReviews proposes suggestive findings [1]. For Larsen syndrome: combinations of congenital dislocations of the hip, knee and elbow (occasionally shoulder), clubfoot, scoliosis and cervical kyphosis, short spatulate distal phalanges, a characteristic face, midline cleft palate, hearing loss and, on radiology in early childhood, hypoplastic vertebrae, hemivertebrae, spondylolisthesis, bifid posterior processes and supernumerary carpal and tarsal centres [1]. For AO1: lethal short-limbed dwarfism, severe dislocations, clubfoot, platyspondyly, hypoplastic pelvis and thorax, incomplete or tapering humeri and femora, absent or bowed radii, absent fibulae and unossified metacarpals and middle and proximal phalanges [1]. For SCT, Coelho's criteria (multiple vertebral fusion, carpal and/or tarsal synostosis, short stature with scoliosis/lordosis and absence of rib anomalies) and Gobbetto's categories continue to serve as guidance, without formal validation [14, 84]. For CHST3 deficiency: dislocations at birth with short stature, clubfeet, limited mobility, kyphosis in childhood, coronal clefts, increased T12–L1/L2 interpedicular distance, normal thumbs, normal or slightly advanced bone age and a family compatible with recessive inheritance; absence of a family history does not exclude it [3].

5.2. Skeletal survey

The complete skeletal survey (skull, anteroposterior and lateral spine, including cervical, pelvis, limbs, hands and feet) is the central examination, and the age at radiography determines the reading: the accessory calcaneal centres and tarsal fusion only appear after the first year, the unsegmented bar is cartilaginous and poorly visible on early radiographs (CT is useful) and the vertebral changes of the EXOC6B form fade in adulthood [14, 16, 67, 85]. Even so, differentiation on neonatal radiographs is difficult, and a genetic panel or exome sequencing is more efficient [148].

5.3. Molecular tests

For all entities, the recommended strategy is a multigene panel for skeletal dysplasias or for dysplasias with multiple dislocations that includes FLNB, the group 5 genes and those of the differential diagnosis, or exome sequencing, which is now the most widely used approach when the phenotype does not distinguish between the entities; genome sequencing is an alternative [1, 3]. In the series of Ranza and colleagues (30 patients with chondrodysplasia with multiple dislocations), exome sequencing combined with targeted analysis of 15 genes gave a molecular diagnosis in 60% (18/30), the previous clinical hypothesis was confirmed in 53% of the cases in which one existed and 40% remained without an aetiology [190]. Single-gene testing is justified when the phenotype is typical: FLNB sequencing and, in an SCT phenotype with no or only one variant, deletion/duplication analysis; CHST3 sequencing followed by deletion/duplication analysis; sequencing targeted at codons 148–149 of KIF22; targeted Sanger for B4GALT7 c.808C>T on Réunion Island when a SNP array shows loss of heterozygosity that includes the gene [1, 3, 135, 170].

The proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test for the phenotype; a negative result does not exclude the diagnosis. The limitations to consider are intragenic deletions (SCT), deep intronic and untranslated region variants, repeat expansions (XYLT1) and mosaicism: Sanger sequencing has a detection limit of about 10%, leucocyte DNA may not reflect somatic mosaicism and does not detect gonadal mosaicism, and an asymmetric picture should lead to deep sequencing of another tissue (fibroblasts, buccal mucosa, saliva) [1, 101]. In Bernkopf's patient, blood analysis by denaturing high-performance liquid chromatography (dHPLC) had been negative five years earlier, and the variant was found in fibroblasts and buccal mucosa [101]. Apparent homozygosity should raise the possibility of an undetected deletion of the other allele (false homozygosity) or uniparental isodisomy [1, 3]. The presence of a variant in gnomAD in a few carriers does not exclude pathogenicity in a mild phenotype with variable penetrance [66].

5.4. Biochemical tests

In CHST3 deficiency, incubation of cultured fibroblasts with sulfur-35-labelled sulfate and chondroitin shows, in all patients studied, drastically reduced incorporation of sulfate at position 6, with normal (or increased) incorporation at position 4; this assay requires a skin biopsy and a specialised laboratory, is useful when no variants are identified or there are variants of uncertain significance (VUS), and reduced C6 sulfation is unequivocal proof of the deficiency [3, 69]. In SLC10A7 deficiency, the abnormal electrophoretic profile of serum N-glycoproteins is a CDG marker useful for guiding interpretation [60].

5.5. Report content, classification and segregation

The report should state the gene, the transcript with version (NM_001457.4 for FLNB), the variant in HGVS, zygosity, allele fraction when mosaicism is suspected and the classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). Pathogenic and likely pathogenic variants have the same value for clinical decision-making; a VUS neither confirms nor excludes the diagnosis [1]. In SCT and CHST3 deficiency, two VUS or one pathogenic variant with one VUS do not establish the diagnosis [3]. Parental testing is recommended to confirm the phase of variants in the recessive forms and to distinguish de novo, inherited and mosaic variants in the dominant forms, with detailed clinical and radiographic examination of the parents [1]. Hickey's variant was classified as a VUS (PM4, PP1) and considered causal by the authors on the basis of segregation across three generations; ClinVar retains conflicting classifications, an example of how family segregation strengthens interpretation [66, 92].

5.6. Prenatal and preimplantation diagnosis

In pregnancies at known risk, prenatal testing and preimplantation genetic testing are possible once the familial variants have been identified [1, 3]. In low-risk pregnancies, limb changes suggestive of multiple dislocations or the AO1 hypo-ossification pattern should prompt molecular testing of FLNB or fetal exome sequencing; several genes cause lethal dysplasias similar to AO, which favours exome sequencing [1, 98]. In CHST3 deficiency, prenatal homozygosity mapping was used in one family [148].

5.7. Algorithm

Sources for the algorithm: [1, 3, 101, 106, 115, 190].

6. Differential Diagnosis

6.1. Comparative table

Sources for the table: [1–3, 14, 16, 20, 36, 40, 60, 61, 66, 67, 73, 79, 99, 111, 117, 122, 136, 148, 149, 155, 177, 178, 192–197].

6.2. Differential within the FLNB spectrum

The distinction between AO1, AO3 and Larsen syndrome is one of severity and degree of ossification: in AO1, the fibulae do not ossify, the phalanges and metacarpals, except the distal ones, are unossified or incompletely ossified and death is perinatal; in AO3, the spine and short tubular bones are better ossified and survival is possible [75, 77]. Between AO3 and Larsen syndrome there are no qualitative differences; the distally tapering humerus and the predominance of incomplete ossification justify the AO3 label, which remains appropriate because there are survivors [1, 73]. The same variant (for example, p.(Gly1691Ser) or p.(Gly168Ser)) may give different phenotypes, so the label describes severity and not genotype [1].

6.3. FLNB Larsen versus the recessive forms

CHST3 deficiency is distinguished from Larsen syndrome by the normal face, non-spatulate thumbs, more marked short stature, normal bone age, vertebral coronal clefts early in life and less pronounced laxity, with progression to stiffness; bilateral knee dislocation at birth is much more frequent in this deficiency than in the B4GALT7 form, which is why the name "recessive Larsen" applies better to it [3, 148, 160]. Desbuquois dysplasia has more severe growth deficiency, less prominent dislocations, accessory metacarpophalangeal rather than carpal ossicles and only rarely a double calcaneus [73, 149]. The linkeropathies share short stature, laxity, dislocations, pectus and prominent eyes; molecular analysis is usually needed to separate them, but heart disease points to B3GAT3, lax skin and hypermetropia to B4GALT7 and early kyphoscoliosis with platyspondyly to B3GALT6 [111, 117]. The B4GALT7 and B3GALT6 forms may be clinically indistinguishable [117, 168]. The GZF1 form is distinguished by severe myopia and excessive laxity, which are rare in FLNB Larsen syndrome [1, 61].

6.4. Larsen syndrome versus the FLNA disorders

Otopalatodigital syndrome type 1 and frontometaphyseal dysplasia share with Larsen syndrome the spatulate thumbs and craniofacial dysmorphism, but have neither accessory carpal bones nor cervical dysplasia, have fewer dislocated joints, a less frequent extra calcaneal centre and a frontal torus at least in males [1, 67, 193]. OMIM, citing Kozlowski (1993), describes in OPD1 extracarpal bones as in Larsen syndrome and a deepened proximal ulnar fossa, along with the secondary ossification centre at the base of the 2nd metacarpal and metatarsal and a long 2nd metacarpal and 5th metatarsal; the presence of accessory carpal bones therefore does not exclude OPD1, whose expression may be so subtle that it is only recognised after the diagnosis of a more severely affected relative [195]. In Rosenbaum's family (1986), with OPD1, three related children, offspring of first cousins, had a clinical diagnosis of Larsen syndrome [195]. AO3 was delineated precisely because of its overlap with OPD2, caused by gain-of-function FLNA variants [6, 196]. OPD2 has less frequent dislocations of the large joints, more pronounced bowing of the long bones and an unshortened distal humerus, which separates it from AO3 [77, 194]. Confusion is mainly possible in a male with Larsen syndrome without dislocations [73]. In Juul's family, the initial diagnosis in adolescence was frontometaphyseal dysplasia, with a negative MAP3K7, TAB2 and FLNA panel before exome sequencing identified the FLNB variant [93].

6.5. Differential diagnosis of spondylocarpotarsal synostosis

Absence of rib anomalies, carpal and/or tarsal fusion and absence of symphalangism are the main radiological discriminators between SCT and the spondylocostal dysostoses, the Klippel-Feil anomaly and multiple synostoses syndrome [1, 14, 99]. In the spondylocostal dysostoses there are true segmentation defects with rib anomalies and normal hands; in multiple synostoses syndrome, the segmental anomalies are less extensive and there is symphalangism; in GDF6 Klippel-Feil there are no carpal or tarsal fusions, and isolated cervical fusions do not occur in FLNB SCT [1, 99]. Cardiospondylocarpofacial syndrome is radiologically indistinguishable and is differentiated by dysmorphism, hearing loss and heart disease [99]. MYH3 SCT is accompanied by contractures and pterygia; the recessive form may require genome sequencing [1, 105, 106].

6.6. The multiple dislocations group among themselves and other differentials

CANT1 Desbuquois dysplasia, the XYLT1 form, the B4GALT7 form and the CSGALNACT1 form share the "monkey wrench" femur and advanced bone age; the type 1 phalangeal changes only occur with CANT1, and intellectual disability was observed in all XYLT1 cases in the Bone Dysplasias atlas, but in 5 of the 7 patients with a variant in Bui's series [20, 149, 166, 168]. The IMPAD1 form is distinguished by brachydactyly without advanced ossification, and Catel-Manzke syndrome has index finger changes similar to those of Desbuquois dysplasia, but without generalised laxity, "monkey wrench" femur, coronal clefts or advanced carpal age [40, 179]. Chitayat syndrome (ERF, AD) has hyperphalangism of the index finger with ulnar angulation, hallux valgus and respiratory difficulty from birth, and Devriendt syndrome has an accessory ossicle at the distal end of the metacarpal [179]. Leptodactylic SEMD differs from the Beighton form by more frequent dislocated hips, more severe genu valgum and slender hands, and from sponastrime dysplasia by small epiphyses, slender tubular bones and dislocations [136]. Pseudodiastrophic dysplasia is distinguished from diastrophic dysplasia by the absence of a "hitchhiker" thumb and of cystic swelling of the pinnae, and from Reardon-Kozlowski mesomelic dysplasia by platyspondyly [178]. Steel syndrome is distinguished from Larsen syndrome by carpal coalition (fused bones and not merely supernumerary ones) and from CHST3 deficiency by pronounced laxity [177]. Frank-ter Haar syndrome, originally published as a recessive form of Melnick-Needles syndrome, is distinguished by megalocornea, prominent coccyx and rapidly progressive valvular disease [192]. Borrone syndrome, with thick skin, acne conglobata, osteolysis, gingival hypertrophy and mitral prolapse, is the same disease, with biallelic SH3PXD2B variants [197]. In the presence of fractures, blue sclerae and osteopenia, osteogenesis imperfecta enters the differential diagnosis of the linkeropathies [111]. The multiple synostoses syndromes (NOG, GDF5, GDF6, FGF9, AD), with progressive proximal symphalangism, carpal and tarsal fusions, humeroradial or radioulnar synostoses, hemicylindrical nose and conductive hearing loss due to stapes ankylosis, and the other causes of carpal fusion do not have multiple dislocations, and Steel syndrome without hip dislocation, described outside Puerto Rico, is recognised by the combination of carpal coalition, radial head dislocation and facial dysmorphism [140, 177, 198].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of recommendations

There is no approved disease-modifying treatment, nor any registered clinical trial, for any entity in this article; a ClinicalTrials.gov search on 28 October 2026 (conditions "Larsen syndrome", "FLNB", "atelosteogenesis", "Desbuquois", "Larsen-like", "B3GAT3", "CHST3", "spondylocarpotarsal") returned no relevant studies, which does not prove the absence of research [1, 3]. The FLNB and CHST3 GeneReviews state that there are no specific clinical practice guidelines and base their recommendations on the authors' experience [1, 3]. Cross-cutting recommendations come from the Delphi consensus statements of the Skeletal Dysplasia Management Consortium, which apply to skeletal dysplasias in general and mention Larsen syndrome and AO3 among the dysplasias with significant spinal involvement, and from the OrphanAnesthesia anaesthetic recommendation, which states that it does not meet the formal criteria of a guideline [96, 186, 188, 189, 199]. Management is multidisciplinary and, in Europe, should involve an ERN BOND centre [15].

7.2. Cervical spine

The initial assessment of every patient with Larsen syndrome includes lateral cervical spine radiographs and, as soon as the child can cooperate (typically at 2–3 years), flexion and extension views; the 2020 consensus recommends dynamic radiographs in all patients with a known risk of C1–C2 instability (90% full agreement) and considers flexion-extension CT or MRI useful adjuncts [1, 186, 187]. Incomplete ossification, overlap and abnormal anatomy (hypoplastic dens, os odontoideum) make interpretation difficult, and the panel did not reach consensus on routine MRI (70% agreement) [151, 186]. Myelopathic signs require urgent assessment and treatment (100% agreement), and cervical kyphosis should be reassessed because it may progress and cause spinal cord injury [186].

Surgical treatment depends on the degree of deformity and the neurological status. Johnston and colleagues operated on four children with kyphosis of 35° to 65°, by isolated posterior cervical arthrodesis at a mean age of 14 months: in three, the kyphosis stabilised or reverted to lordosis through anterior growth with solid posterior fusion; in the fourth, a pseudarthrosis led to progression to 110° and an acute neurological deficit, treated by anterior decompression and arthrodesis (mean follow-up 70 months) [200]. Sakaura and colleagues concluded, in three infants, that isolated posterior fusion is suitable for mild, flexible kyphosis and that severe structural kyphosis with myelopathy requires anterior decompression with circumferential arthrodesis, with a halo [187]. GeneReviews summarises that instability in asymptomatic infants can be successfully treated by early posterior arthrodesis, that in infants with myelopathic signs function can be stabilised or improved by anterior decompression and circumferential arthrodesis, and that intraoperative cervical extension should be minimised [1, 201]. Isolated anterior fusion is not advised in young children because of the risk of spinal cord injury and of arrest of anterior growth [151]. Before upper cervical surgery, three-dimensional CT angiography or MR angiography is essential because of variations in the course of the vertebral artery; one of Singh's patients had hypoplasia of the right vertebral artery [151, 186].

There is an explicit divergence regarding prophylactic fixation. The 2020 Delphi consensus considers prophylactic C1–C2 arthrodesis without spinal cord compression or myelopathic signs not indicated (recommendation 13, 70% full agreement and 30% agreement) and reserves surgery for demonstrable pathology [186]. Singh and colleagues, on the basis of 10 operated children (6 C1–C2 fixations by the Goel-Harms technique, 4 long posterior cervical fixations and 2 staged transoral decompressions; mean follow-up 23 months), advocate early fixation also in asymptomatic patients with progression, because many published cases present with acute tetraparesis after falls and 4 of 7 asymptomatic children in their series developed myelopathy [151]. In Singh's series, the median Nurick grade went from 4 to 3 at the last visit, neck pain improved in 9, fusion was complete in 3 of 4 assessed and three children remained bedridden [151]. The practice that reconciles the sources is close surveillance, documentation of instability or progression of kyphosis and surgery when there is demonstrable instability, progressive kyphosis or spinal cord compromise, within a team experienced in syndromic paediatric spine surgery; the decision in asymptomatic patients with documented instability has no consensus.

7.3. Thoracolumbar spine and scoliosis

No drug has reduced spinal disease in the skeletal dysplasias, and non-operative measures include physiotherapy, weight control and appropriate non-steroidal anti-inflammatory drugs (NSAIDs) [186]. In the young child with progressive flexible scoliosis, bracing or serial casting are appropriate, and early-onset scoliosis can be treated with growth-preserving techniques; scoliosis or kyphosis surgery has more complications than in the general population, and advanced imaging is strongly recommended before spinal instrumentation [186]. Stabilisation of thoracolumbar kyphosis is indicated if it is progressive, with neurological compromise or refractory pain (70% full agreement) [186]. In SCT, an untreated unilateral unsegmented bar leads to severe scoliosis and pulmonary dysfunction; GeneReviews describes no surgical intervention of proven efficacy and leaves the scoliosis to the orthopaedic surgeon [1, 99]. In B3GALT6 deficiency, Maheshati and colleagues recommend choosing the "substantially touched vertebra" as the lowest instrumented vertebra (because of hypermobility), after coronal imbalance at 18 months in a patient with a shorter fusion; preoperative halo-pelvic traction was used without complications in one patient, and the systematic review (63 published patients) found treatment of kyphoscoliosis described in only 12, with frequent complications, including death, which advises surgery in an experienced centre and preoperative molecular diagnosis [59, 171]. In recessive MYH3 SCT, a patient with 100° scoliosis and thoracic lordosis was treated with halo-gravity traction (1 week) and halo-pelvic traction (7 weeks) followed by Smith-Petersen osteotomies, with correction to 54° [202]. In CHST3 deficiency, surgical treatment of kyphosis is also difficult [148].

7.4. Hips, knees, elbows and feet

In Larsen syndrome, hip dislocation generally requires surgical reduction, and conservative management is often ineffective [1]. Congenital knee dislocation was treated, in a patient of Dobbs and colleagues, by manipulation and serial casting followed by open quadriceps tenotomy, as an alternative to the traditional extensive reconstructions (isolated report, without long-term follow-up) [100]. In Hickey's family, the child underwent staged open reductions of the knees with femoral shortening from 6 months of age [66]. Clubfeet are treated with the usual orthopaedic approach, bearing in mind that in Larsen syndrome they are often refractory [1, 67]. In CHST3 deficiency, surgical correction of the dislocations is often only partial, most patients undergo multiple procedures until adulthood and physiotherapy has not been shown to be effective; high-impact joint activities (for example, running) and obesity should be avoided [3, 160]. In Steel syndrome, the hips tend to redislocate after surgery, and in one patient there was progressive acetabular destruction with replacement of the proximal femur at 26 years [177]. Steel and colleagues advised against hip surgery because of poor results in almost all those operated on, and Flynn and colleagues observed fewer complaints and less limitation of daily activities in patients whose hips were not operated on [34]. In an Uzbek boy with a dislocation irreducible under anaesthesia, splinting at 6 months, skeletal traction at 2 years and three hip operations between 2 and 4 years of age brought no substantial benefit; the authors of the 2026 review advocate early recognition of the core picture to avoid unnecessary hip surgery, and failures of hip arthroplasty are documented in the homozygous adult [140, 141]. In B3GAT3 deficiency, the hips improved with conservative treatment in one patient at 2 years [111]. In Desbuquois dysplasia, regular physiotherapy is used for laxity and to delay osteoarthritis, and severe dislocations and spinal deformity are managed surgically [126]. In the EXOC6B form, dislocations are operated on to improve mobility, with a wheelchair and walking aids as needed [16]. Secondary osteoarthritis in adults is treated according to the usual rules [67].

7.5. Airway, anaesthesia and perioperative care

The 2017 perioperative consensus recommends, before surgery in patients with skeletal dysplasia, pulmonary assessment with polysomnography, cardiac and neurological assessment, cervical spine imaging and a difficult airway plan for intubation and extubation; the risks identified are upper airway anatomy, tracheobronchial morphology and function, chest wall deformity and abnormal mobility of the upper cervical spine [189]. The OrphanAnesthesia recommendation for Larsen syndrome (revised in February 2026) organises management by system [96]. For the airway, the risk of difficult intubation is high (cleft palate, midface hypoplasia, macroglossia), cervical instability is the main concern and requires manual in-line stabilisation even without neurological signs, videolaryngoscopy or fibreoptic intubation are preferred and supraglottic devices or a face mask are acceptable for short procedures [96]. Cervical radiography is the first examination, followed by CT or MRI if abnormal or if there are neurological signs; nasendoscopy assesses airway dynamics, and the threshold for echocardiography should be low [96]. In patients with laryngotracheomalacia, agents with rapid induction and recovery are preferred, because the risk of airway complications is higher [1]. General and regional anaesthesia are possible, intravenous or inhalational induction is safe and there is no contraindication to common anaesthetics; caudal block has been described [96]. Positioning may dislocate large joints, and the prone position with a poorly compliant chest wall increases intrathoracic pressure and reduces venous return, with cardiac arrests described [96]. Postoperative complications include stridor due to post-extubation oedema, laryngotracheomalacia, subglottic stenosis and bronchomalacia, and severe kyphoscoliosis may require prolonged ventilatory support in an intensive care unit [96, 152, 203]. Neurophysiological monitoring (somatosensory and motor evoked potentials) is recommended in spinal surgery, and the 2020 consensus suggests considering it in any procedure under prolonged anaesthesia (more than 1 hour) in patients with "spine at risk" findings (30% full agreement, 70% agreement) [96, 186]. An intraoperative cardiac arrest under sevoflurane, during scoliosis surgery in a patient with Larsen syndrome, was attributed to pre-existing heart disease and surgical stress [96, 204]. There is no proven association with malignant hyperthermia: the only report with volatile anaesthetics has been disputed, and OrphanAnesthesia concludes that no association has been demonstrated [96]. In Desbuquois dysplasia, intubation may be difficult and supraglottic devices have been used successfully [126]. In leptodactylic SEMD with laryngeal stenosis, early intubation or tracheostomy followed by laryngotracheal reconstruction may be necessary [136]. In Steel syndrome and B3GALT6 deficiency, atlantoaxial or cervical instability should be investigated before anaesthesia [171, 177].

For surgical bleeding, OrphanAnesthesia allows tranexamic acid if there is no contraindication, without stating a dose; no source consulted gives a dose for this population, and use in orthopaedic or spinal surgery in Larsen syndrome is an extrapolation [96]. The reference dosage is that of the labels of the US Food and Drug Administration (FDA) and of the Summary of Product Characteristics (SmPC) approved by INFARMED (the Portuguese National Authority of Medicines and Health Products), which differ from each other:

Sources: [205, 206]. The label of the Brazilian Health Regulatory Agency (ANVISA) was not consulted.

7.6. Cleft palate, hearing, sleep and teeth

Cleft palate and hearing loss should be managed by multidisciplinary craniofacial teams [1]. Hearing loss is treated with hearing aids, vibrotactile devices or cochlear implants according to type, with paediatric otolaryngology and audiology; otological surgery is possible in selected cases, weighing the anaesthetic risk [1, 153]. The 2021 craniofacial consensus recommends assessing at each visit for signs of upper airway obstruction and sleep-disordered breathing, polysomnography in the presence of snoring or signs of apnoea, polysomnography before adenotonsillectomy, adenoidectomy and/or tonsillectomy as first line in obstructive sleep apnoea syndrome (OSAS), non-invasive ventilation (NIV) as an alternative, overnight inpatient monitoring after adenotonsillectomy for OSAS, ventilation tubes for otitis media with effusion (OME) persisting for at least 3 months or with a type B tympanogram, and laryngeal assessment in the presence of stridor or hoarseness [188]. Specialised dental and orthodontic care should begin in early childhood [188]. The enamel hypoplasia of SCT is treated with sealants, and the microdontia and delayed eruption of CHST3 deficiency with a dentist and orthodontist [1, 3]. Non-invasive ventilation was used for obstructive sleep apnoea in B4GALT7 deficiency [113].

In a Turkish series of 27 children with genetic skeletal disorders who underwent polysomnography (one with Desbuquois dysplasia), 19 had obstructive sleep apnoea (9 severe), 2 central apnoeas and 4 nocturnal hypoventilation; non-ambulation was associated with the apnoea-hypopnoea index, and in the 9 children titrated, positive airway pressure normalised the obstructive index, data that support polysomnography in Desbuquois dysplasia, in which sleep apnoea is part of the natural history [149, 207].

7.7. Heart and aorta

In B3GAT3 deficiency, the high rate of valvular and structural anomalies justifies echocardiography at diagnosis with measurement and Z-score of the root and ascending aorta and periodic follow-up; management of aortic dilatation and valvular disease follows usual cardiological practice, with no specific published threshold [111, 167]. In CANT1 Desbuquois dysplasia, the frequency of mitral prolapse and aortic dilatation (7/9 each) justifies echocardiography and follow-up, with medical treatment when abnormalities appear [126, 164]. In B3GALT6 deficiency, dilatation or aneurysm of the ascending aorta justifies imaging surveillance, without transposing the restrictions of vascular EDS [171]. In CHST3 deficiency, echocardiography is part of the initial assessment and is repeated as advised by the cardiologist, or about every 5 years if normal [3]. In Larsen syndrome, echocardiography is justified in the presence of a murmur, symptoms or cardiac history, and before surgery [96, 154].

7.8. Bone health, growth and rehabilitation

In the linkeropathies with fragility (two thirds of B3GAT3 patients, some of the B3GALT6 and B4GALT7 patients), densitometry (DXA), optimisation of calcium and vitamin D and fracture prevention are recommended [167, 171]. No source consulted evaluated bisphosphonates in these diseases. Treatment by analogy with severe osteogenesis imperfecta is an off-label extrapolation: in the uncontrolled observational series of Glorieux and colleagues (30 children aged 3 to 16 years), intravenous pamidronate in cycles every 4–6 months, at a mean dose of 6.8 ± 1.1 mg/kg/year for 1.3 to 5.0 years, increased bone mineral density by 41.9 ± 29.0% per year and reduced fracture incidence by 1.7 per year, without altering fracture healing or growth [208]. The FDA label for pamidronate disodium includes no paediatric indication and states that safety and efficacy in children have not been established [209]. The FDA label for alendronic acid with colecalciferol (Fosamax Plus D®) describes a randomised trial in 139 children aged 4 to 18 years with severe osteogenesis imperfecta (5 mg/day below 40 kg, 10 mg/day from 40 kg, for 2 years): the lumbar Z-score increased by 1.3 versus 0.1 with placebo, without reduction in fracture risk and with more delayed fracture healing (16% versus 9%) [210]. In the adult with Larsen syndrome and osteoporosis, Juul's patient took alendronic acid 70 mg weekly with calcium and vitamin D for about one year, then intravenous zoledronic acid (dose not stated) because of adverse effects, for a total of 13 years of bisphosphonates, with a slight increase in spinal density and no effect at the hip; the dose of 70 mg weekly matches the approved dosage for postmenopausal and male osteoporosis [93, 210]. The authors raise the possibility of anabolic agents (teriparatide, romosozumab), without data [93].

For growth, a response to growth hormone was described in two siblings with B4GALT7 deficiency; the dose and results are not given in the abstract consulted [58]. Conversely, a boy with B4GALT7 deficiency did not respond to a therapeutic trial of growth hormone, and a girl with FLNB SCT and documented growth hormone deficiency did not respond to its administration [7, 28]. The use of somatropin in these dysplasias is off-label and the reference doses are those of the labels:

Sources: [58, 211, 212]. In CHST3 deficiency, physiotherapy has not been shown to be effective, but physiotherapy and occupational therapy are recommended in B3GALT6 deficiency, Desbuquois dysplasia and the EXOC6B form [3, 16, 126, 171]. After craniovertebral surgery, antispasticity drugs could be reduced: in Singh's paediatric series, five patients taking baclofen 30 mg/day no longer needed it, and two taking baclofen 60 mg/day and tizanidine 6 mg/day were switched to baclofen 20 mg/day (reported doses, not a recommendation) [151].

7.9. Pregnancy and delivery

The first pregnancy described in a woman with Larsen syndrome was managed with serial ultrasound, paediatric and anaesthetic consultations and caesarean section, with immediate stabilisation of the newborn's neck [183]. OrphanAnesthesia allows planned caesarean section for pelvic and hip anomalies, recommends avoiding general anaesthesia, accepts the technically difficult neuraxial technique with an epidural catheter and gradual titration of local anaesthetic, and requires difficult airway equipment and neonatal cervical protection at delivery if the fetus may have Larsen syndrome [96]. The 2018 prenatal consensus establishes minimum recommendations for the pregnant woman with skeletal dysplasia and for the fetus with suspected dysplasia, whose individual items were not consulted [199]. In the affected fetus, delivery may be complicated by breech presentation with extended limbs [1].

7.10. Evidence for interventions

Sources: [58, 59, 151, 187, 200, 208, 210]. There are no randomised trials in the diseases covered in this article; the surgical series are retrospective, small, without a comparison group and with a diagnosis that is sometimes only clinical, and confidence intervals are not reported. The bisphosphonate data come from another disease and cannot be compared between studies; the alendronic acid trial showed improved mineral density without benefit for fractures, which illustrates that a favourable surrogate outcome does not guarantee clinical benefit. No negative, suspended or withdrawn trials were identified for these entities.

7.11. Developments in the last 12 months

There were no authorisations, regulatory opinions or trial announcements for these diseases in the period.

7.12. Regulatory status

Sources: [205, 206, 209–212]. The ANVISA registrations were not consulted.

7.13. Transition to adulthood

The adult with Larsen syndrome, CHST3 deficiency, Desbuquois dysplasia or SEMD needs continued orthopaedic follow-up for early osteoarthritis, kyphosis and joint restriction, respiratory assessment when chest deformity progresses, cardiac surveillance in the forms with aortopathy and reproductive counselling before pregnancy [1, 3, 135, 148]. The progression of the KIF22 form to joint stiffness with loss of independence in adulthood illustrates the need for social and occupational planning [135].

8. Reproductive Options and Family Counselling

8.1. Autosomal dominant forms of the FLNB spectrum

FLNB-associated Larsen syndrome, AO1, AO3 and apparently isolated clubfoot are autosomal dominant. Some patients inherit the variant from a heterozygous or mosaic parent, others have a de novo variant; the great majority of the lethal forms are de novo [1]. Mild (Larsen) and severe (AO3) forms may coexist in the same family, and a heterozygous parent may be more or less affected than the child [1]. In an apparently isolated case, molecular testing of the parents and a detailed clinical examination, with radiographs when indicated, are recommended; the variant is only considered de novo if neither parent has it, with maternity and paternity confirmed [1].

In a man with known somatic mosaicism, quantification of the allele fraction in sperm by deep sequencing allows the theoretical range of 0–50% to be replaced by a personalised risk, and may avoid unnecessary in vitro fertilisation, preimplantation testing or prenatal diagnosis if the germline is not involved [101]. Simultaneous involvement of tissues of mesodermal and ectodermal origin indicates an early event, prior to the separation between soma and germline, and increases the likelihood of gonadal involvement [101]. Recurrence in the offspring of unaffected parents due to gonadal mosaicism has been documented in Larsen syndrome since the descriptions of Petrella and of Frints [67].

8.2. Autosomal recessive forms

FLNB SCT, CHST3 deficiency and all the recessive entities of group 5 follow the usual pattern: with both parents heterozygous, each sibling has a 25% chance of being affected, 50% of being heterozygous and 25% of not being a carrier; the offspring of an affected individual are obligate heterozygotes, unless the partner is a carrier; the parents' siblings have a 50% chance of being carriers [1, 3]. Parental testing is recommended; if only one parent is a carrier, a de novo variant in the proband or a postzygotic variant in a mosaic parent is considered, and apparent homozygosity requires exclusion of an undetected deletion or uniparental isodisomy [1, 3]. CHST3 heterozygotes are asymptomatic and have no known increased risk of degenerative joint disease [3]. Loss-of-function FLNB heterozygotes may have slightly reduced stature; one parent of a child with SCT measured −2.2 SD and had mild unilateral hip dysplasia [1, 14]. Carrier testing of partners is especially useful when there is consanguinity or shared ancestry, as in the Amish community (CHST3 p.(Pro433Leu)), on Réunion Island (B4GALT7 p.(Arg270Cys)), in Puerto Rico (COL27A1 p.(Gly697Arg)) or on Nias Island (B3GAT3 p.(Pro140Leu)) [3, 62, 70, 125]. In recessive MYH3 SCT, the parents are usually unaffected heterozygotes for a truncating variant and for the hypomorphic 5′UTR allele [106]. In Baratela-Scott syndrome, the XYLT1 GGC expansion should be sought in the parents when it is identified in the proband [115]. For Steel syndrome, Belbin and colleagues proposed targeted population screening for p.(Gly697Arg) in people of Puerto Rican ancestry, for surveillance and reproductive choice, a proposal without prospective evaluation; heterozygotes have neither short stature nor dislocations [34, 142]. The 25% recurrence materialised in two consecutive pregnancies of a non-consanguineous couple with affected fetuses, which makes it useful to discuss prenatal or preimplantation diagnosis soon after the first diagnosis [143, 165].

8.3. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing are possible; the decision is personal and should be discussed before pregnancy [1, 3]. In low-risk pregnancies, the ultrasound findings described in section 4.1 should prompt molecular study [1]. For the pregnant woman with Larsen syndrome, delivery planning includes early anaesthetic assessment, consideration of caesarean section and preparation for cervical protection of the newborn [96, 183].

8.4. Testing of minors and young adults

Testing of at-risk relatives is carried out with the identified familial variant; in minors, it is justified when it alters surveillance (cervical spine, hips, hearing), and carrier testing for recessive forms should, as a rule, await the age at which the person can decide. GeneReviews recommends offering counselling to affected, carrier or at-risk young adults, ideally before pregnancy [1, 3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

GeneReviews states that there are no prevalence figures for any of the FLNB disorders, and records more than 100 published individuals with pathogenic variants [1]. Orphanet assigns Larsen syndrome a birth prevalence class of 1–9 per 1,000,000 in Europe, based on the EUROCAT congenital anomaly registry, and records a mean value of 0.4 for Europe and 0.65 for France [8, 91]. This figure measures the birth prevalence of a diagnosis of Larsen syndrome in congenital anomaly registries, not restricted to FLNB, and the values are only compatible with the assigned class if they are expressed per 100,000 births. The estimate of 1:100,000 live births cited in the anaesthetic recommendation refers to an otological review and is not a validated population estimate [96, 153]. The remaining entities have, in Orphanet, a prevalence below 1/1,000,000, which is an upper limit and not a rate: about 35 cases of SCT, 25 of AO3, 10 of boomerang dysplasia, 50 of Desbuquois dysplasia, 34 of B4GALT7 deficiency, 33 of Catel-Manzke syndrome and 18 of Temtamy brachydactyly; for CHST3 deficiency, Orphanet records "2 families", a figure that is out of date compared with more than 100 published probands [3, 91, 113, 126, 180, 213, 214]. Unger and colleagues considered CHST3 deficiency probably more frequent than had been supposed, and Boyden and colleagues described the KIF22 form as relatively common among the skeletal dysplasias [134, 160]. Clubfoot, of all causes, occurs in 1–2 per 1000 live births, but the fraction attributable to FLNB is unknown [1].

9.2. Geography, ancestry and founder effect

FLNB Larsen syndrome and AO1 are mostly de novo and show no known population clustering; the recessive forms are concentrated in consanguineous or isolated populations, where a panel or exome should first consider the local founder variant [1, 170].

9.3. Brazil and Portugal

The sources consulted include Brazilian contributions: the definition of the SCT criteria from three cases (Coêlho and colleagues, 1998), SCT with ocular findings (Steiner and colleagues, 2000), AO1 with paternal mosaicism diagnosed from fetal ultrasound and examination of the father (Meira and colleagues, 2018), the otological review with a 14-year-old case (Marques and colleagues, 2017) and the XYLT1 deficiency case from Recife illustrated in the Bone Dysplasias atlas [84, 103, 153, 157, 166]. OMIM also records a Brazilian case of Beighton-type SEMD with laxity (Pina-Neto and colleagues, 1996) and a sporadic Brazilian patient with the KIF22 variant P148L in Boyden's series [25, 26]. ERN BOND includes Portuguese authors (Lisbon) [15]. The sources consulted do not describe Portuguese or Brazilian epidemiological data; this does not demonstrate that none exist.

9.4. Special populations

In the pregnancy of an affected woman, the abnormal pelvis and hips, spine and airway determine the delivery and anaesthesia (section 7.9) [96]. In adopted children or those without an available family history, as in Gobbetto's case, segregation is impossible and the diagnosis depends on the isolated interpretation of the variant [14]. Patients with intellectual disability (Baratela-Scott, some with Desbuquois dysplasia) need educational support, and children with hearing loss need a specialised educator [1, 166].

9.5. Reference networks and patient organisations

ERN BOND, one of the 24 European reference networks, coordinated by the Istituto Ortopedico Rizzoli (Bologna), brought together in 2023 53 centres from 20 countries, diagnosed about 2800 patients per year and maintained a registry with more than 2300 mapped cases; patients are represented through 8 representatives of patient organisations (ePAG) [15, 216]. GeneReviews lists American resources: Little People of America, Children's Craniofacial Association, National Scoliosis Foundation, Helping After Neonatal Death, Compassionate Friends and the UCLA International Skeletal Dysplasia Registry [1, 3]. OrphanAnesthesia refers to the National Organization for Rare Disorders (NORD) and to Contact a Family (United Kingdom) [96]. No patient organisation specific to Larsen syndrome or the FLNB spectrum was identified in the sources consulted.

10. Illustrative Clinical Case

10.1. FLNB spondylocarpotarsal synostosis in an adopted child (Gobbetto and colleagues, Genes, 2026)

A girl of Indian origin, adopted by an Italian couple, was born preterm weighing 1560 g and required neonatal intensive care with ventilation; gestational age, pregnancy history, family history and consanguinity were unknown, and she spent her first months in an Indian paediatric institution with a mainly milk-based diet and little stimulation [14]. A spinal MRI at 7 months, performed in India, showed fusion of the posterior elements, including the spinous processes, from T7 to T9 [14]. On arrival in Italy, at 15 months, she had severe short stature (−5.19 SD on the Centers for Disease Control and Prevention, CDC, charts) and global developmental delay [14]. At 18 months, MRI and CT of the spine showed a left-convex thoracolumbar scoliotic curve, kyphosis from T10 to L2, straightening of the thoracic kyphosis, clefts of the posterior arches of C1–C2, T1–T2, T5–T11 and the sacrum, fusion of the posterior elements of C4–C5, T1–T11 and L1–S2 and coccygeal dysgenesis (Figure 2 of the article); brain MRI suggested periventricular leucomalacia, attributed to prematurity and possible hypoxic-ischaemic injury [14]. Orthopaedics found no vertebral rotation or rapidly progressive scoliosis, and neurosurgery did not indicate surgery [14]. There was intermittent convergent strabismus, delayed tooth eruption with a supernumerary tooth and bilateral otitis media with effusion, with normal serial audiometry; metabolic screening, cardiological assessment and abdominal ultrasound were normal [14].

Array CGH (comparative genomic hybridisation) was normal; a next-generation sequencing skeletal dysplasia panel identified NM_001457.4:c.7332dup p.(Met2445HisfsTer5) in homozygosity in FLNB, classified as likely pathogenic (PVS1, PM2) and confirmed by Sanger sequencing, with no possibility of segregation [14]. At 2 years and 4 months she measured 70 cm (−5 SD), weighed 7.2 kg (−6.6 SD), had a head circumference of 45 cm (−1.9 SD) and an arm span/height ratio of 0.93; she had walked independently since 2 years of age with a broad base and only babbled [14]. She had a triangular face with a pointed chin, broad nose, thin upper lip, short neck, synophrys and café-au-lait spots under investigation [14]. The hand radiograph showed a bone age of 9 months (Greulich-Pyle) and fusion of the capitate and hamate ossification centres (Figure 4), and the foot radiograph absence of the navicular ossification centre without documented tarsal synostosis (Figure 5) [14]. The figures were consulted through their legends on the article page (https://pmc.ncbi.nlm.nih.gov/articles/PMC13606696/).

The case illustrates the core triad of SCT (short-trunk short stature, posterior vertebral fusions and capitate-hamate synostosis), the absence of tarsal fusion at an early assessment and the difficulty of attributing the developmental delay, which the authors related mainly to prematurity, hypoxic-ischaemic injury and institutionalisation, rather than to SCT, in which cognition is usually normal [14]. The follow-up proposed by the authors (orthopaedics and physiatry, neurosurgical surveillance of the craniocervical junction, auxology, audiology, ophthalmology, rehabilitation, dentistry, lung function when age permits and renal imaging) is the authors' opinion and largely coincides with the surveillance described in section 11 [14].

10.2. Larsen syndrome with severe osteoporosis in a mother and daughter (Juul and colleagues, 2025)

A 63-year-old Danish woman, 150 cm tall, had severe kyphoscoliosis progressive since adolescence, pectus carinatum, flat feet, spatulate thumb, hypermobility, conductive hearing loss with hearing aids since the age of 40 and lung function of about 40% of predicted, with recurrent pneumonia [93]. At 46 years, DXA showed T-scores of −5.2 at the spine and −3.1 at the hip; she had had early menopause at 35 years and oral and inhaled corticosteroid therapy, and took bisphosphonates for 13 years with a slight vertebral gain and none at the hip [93]. Her daughter, 33 years old and 158 cm tall, had congenital right-sided hearing loss, congenital dislocation of the right hip, prominent supraorbital ridges and kyphoscoliosis; she was diagnosed at 15 years with frontometaphyseal dysplasia, with a negative FLNA, MAP3K7 and TAB2 panel, and at 27 years had T-scores of −5.6 and −4.1, with severe vitamin D deficiency [93]. Exome sequencing identified in both NM_001457.3:c.688G>T p.(Val230Phe) in the actin-binding domain, absent from gnomAD; the grandmother had had congenital dislocation of one knee treated with a cast, and other relatives had pectus carinatum (Figure 3 of the article, pedigree; legends consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC12507938/) [93]. The report shows Larsen syndrome diagnosed only in adulthood and raises the question of bone health, without allowing the effect of FLNB to be separated from secondary factors; the choice of bisphosphonates in this family does not constitute a recommendation [93].

10.3. Steel syndrome with irreducible hip dislocation in an Uzbek boy (Gorodilova and colleagues, Frontiers in Medicine, 2026)

The first child of healthy parents, consanguineous in the third generation, of Uzbek origin, he was born at term weighing 3600 g and measuring 50 cm; shortly after birth, left torticollis, acetabular dysplasia and congenital hip dislocation were identified [140]. Splinting at 6 months, skeletal traction at 2 years and hip operations at 2, 3 and 4 years brought no substantial benefit; motor and cognitive development were appropriate, but independent walking only began at 4 years, because of orthopaedic limitation [140]. At 6 years, mild conductive hearing loss was diagnosed and attributed to severe adenoid hypertrophy, not to the syndrome [140]. At 7 years he measured 111 cm (−1.74 SD) and weighed 18 kg (−2.01 SD), with an oval face, prominent forehead, hypertelorism, midface hypoplasia, broad nasal bridge, cup-shaped right pinna, pectus excavatum, scoliosis, genu valgum, shortening of the 4th and 5th toes, planovalgus foot, interphalangeal hypermobility and contractures of the elbows and knees [140]. The radiographs (figure 1 of the article) showed at 1 year bilateral dislocation with an acetabular index of 45°, irreducible on attempted closed reduction under anaesthesia, and at 6 years residual dislocation with empty acetabular cavities, dislocation of the radial heads, multiple carpal fusions, pseudoepiphyses at the base of the 2nd metacarpals, lateral dislocation of the patellae and subluxation of the tibiae [140]. Exome sequencing identified in homozygosity NM_032888.4:c.3988G>C p.(Gly1330Arg), in the triple-helix domain, inherited from both parents, with a frequency of 6.2 × 10⁻⁷ in gnomAD v4.1.0 and classified as likely pathogenic [92, 140]. The case brings together the classical Steel phenotype associated with a glycine substitution, without the extraskeletal manifestations of the syndrome, and the lack of response of the hip dislocation to repeated interventions, which underpins the surgical caution set out in section 7.4 [140].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

AO1, boomerang dysplasia and Piepkorn dysplasia are lethal in the perinatal period [1, 80]. AO3 is semilethal, with survival beyond the first year rare and dependent on intensive respiratory support, but documented into adulthood with a height of 135 cm and reproduction [1, 77, 78]. Larsen syndrome is compatible with survival into adulthood and normal intelligence; prognosis depends on the cervical spine (myelopathy in at least 15%), the airway, the dislocations and kyphoscoliosis, with often late walking and early osteoarthritis [1, 68, 73]. SCT has normal cognition in most patients and morbidity determined by progressive scoliosis, restrictive lung disease and cervical instability [1, 85]. In CHST3 deficiency, adult height is severely reduced (84–134.5 cm in the series described) and the main problem in adults is reduced lung capacity due to kyphosis, with joint stiffness [3, 148]. In Desbuquois type 1, 28% died early, mainly from respiratory causes, and stature lies between −4 and −10 SD [122, 126]. In B3GALT6 deficiency, refractory spinal deformity and cardiorespiratory compromise make the prognosis unfavourable, with adult height that may be below 100–120 cm [117, 171]. In pseudodiastrophic dysplasia, most died in infancy or early childhood [178]. The KIF22 and EXOC6B forms have normal intellect and progress to osteoarthritis and, in KIF22, to disabling joint stiffness [16, 135]. In the follow-up of four adults with Desbuquois dysplasia, mean height was 114 cm (−8.5 SD), with osteoporosis and walking difficulty in three [22]. In Beighton-type SEMD with laxity, most patients described up to 1994 died in the first or second decade, but survival up to 35 years has been documented [26]. In Steel syndrome, homozygous adults identified in a biobank required hip and knee replacements, some before 50 years of age [34]. The review of 63 patients with Steel syndrome associates truncating variants with more severe short stature (−7.9 SD in a 9-year-old Syrian patient) and with extraskeletal manifestations, and the cervical anomalies and hearing loss of p.(Gly697Arg) homozygotes appear mainly in adulthood [140]. In Desbuquois type 1, the forms with a narrow thorax may be lethal in the first year due to respiratory failure, as in the Thai infant ventilated until his death at 7 months [165].

11.2. Surveillance

There is a divergence regarding hearing: the FLNB GeneReviews recommends annual audiological assessment, whereas the craniofacial consensus approved assessment at diagnosis and at 5 years and did not reach consensus for annual assessment up to 5 years of age (30.8% agreement) [1, 188]. In patients with conductive hearing loss or cleft palate, the annual follow-up of GeneReviews is the more prudent. The 2020 consensus did not set intervals for radiographic surveillance of the spine, which are left to the judgement of the orthopaedic surgeon [186].

12. Summary and Final Considerations

The dysplasias with congenital joint dislocations form a class defined by clinical presentation and reorganised by molecular genetics. Their core is the FLNB gene: gain-of-function variants in the actin-binding domain and in repeats 13–17 cause a continuum that runs from lethal AO1 to AO3, Larsen syndrome and apparently isolated clubfoot, whereas biallelic loss of function causes SCT, a disease of vertebral and carpal fusions without dominant dislocations. The former "recessive Larsen syndrome" has broken down into disorders of proteoglycan synthesis and sulfation, mainly CHST3 deficiency, the B3GAT3, B4GALT7 and B3GALT6 linkeropathies, the CANT1 and XYLT1 dysplasias, and into entities such as the GZF1 form, grouped in the 2023 Nosology in groups 4, 5 and 6.

Diagnosis rests on dysmorphological examination, a skeletal survey read according to age and an extended panel or exome with CNV analysis; conventional sequencing misses intragenic deletions, repeat expansions, non-coding variants and low-level mosaicism, which has direct consequences for counselling in the dominant forms. The cervical spine is the main determinant of prognosis in Larsen syndrome: myelopathy affects at least 15% of patients, and a cervical radiograph at the first visit and before any anaesthesia is the central preventive measure. The indication for prophylactic cervical fixation in asymptomatic patients remains without consensus between the Delphi panel and the surgical series. There is no specific pharmacological treatment and no ongoing trials; the drugs used (antifibrinolytics, bisphosphonates, somatropin) are extrapolations from other conditions. The recessive forms are concentrated in populations with a founder effect (Réunion, Amish, Puerto Rico, Nias) and in consanguineous families, and cardiac, bone and ophthalmological surveillance depends on the gene. Organising care in centres with experience in skeletal dysplasias, such as those of ERN BOND, makes it possible to apply these recommendations to diseases in which each centre sees few patients.

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