Multiple Synostoses, Symphalangism, Tarsal Coalition and Stapes Ankylosis (NOG, GDF5, FGF9, GDF6)

Class of autosomal dominant disorders of joint formation due to imbalance of bone morphogenetic protein (BMP) and fibroblast growth factor 9 (FGF9) signalling: the NOG-related symphalangism spectrum (proximal symphalangism 1A, multiple synostoses syndrome 1, stapes ankylosis with broad thumbs and toes, tarsal-carpal coalition syndrome and brachydactyly B2) and multiple synostoses syndromes 2 to 4 and proximal symphalangism 1B (GDF5, FGF9, GDF6).

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

0.1. Entities of the class and identifiers

0.2. Clinical summary of the class

1. Introduction

1.1. Common syndromic description

The entities brought together in this article share a defect in the development of synovial joints: the interzone, a band of mesenchymal cells that separates two cartilaginous anlagen and should cavitate to form the joint cavity, fails to differentiate or to cavitate, and the two skeletal elements remain in cartilaginous continuity, which subsequently ossifies. The result is a synostosis, that is, a bony fusion between bones that normally articulate. When the fusion affects the interphalangeal joints, it is called symphalangism; when it affects the carpal or tarsal bones, it is called carpal or tarsal coalition; when it affects the joint between the stapes footplate and the otic capsule, it is called stapes ankylosis and results in conductive hearing loss [23, 32, 45]. All entities of the class are autosomal dominant (AD) and result from an imbalance of signalling by bone morphogenetic proteins (BMP) and growth and differentiation factors (GDF) of the transforming growth factor beta (TGF-β) superfamily, or of fibroblast growth factor 9 (FGF9) signalling [32, 37]. The common picture combines proximal symphalangism present from birth, carpal and tarsal fusions, elbow synostosis, vertebral fusions, conductive hearing loss, hypermetropia and a subtle facial dysmorphism centred on a broad, hemicylindrical nose with hypoplastic alae; expression varies greatly within each family, and the same variant may produce different clinical labels in different families [24, 46, 47].

1.2. Historical overview

The first systematic description is due to Harvey Cushing, who in 1916 published, in the journal Genetics, "hereditary ankylosis of the proximal phalangeal joints" in a Virginia family with stiff fingers, and coined the term "symphalangism"; a preliminary note had appeared in 1915 [48, 49]. Strasburger and colleagues reassessed this family in 1965 and found early-onset conductive hearing loss in enough affected individuals to attribute it to the same gene [12]. In 1917, Drinkwater described the British Talbot family, descended from John Talbot, first Earl of Shrewsbury (1388–1453); because of the genealogical depth of these two families, proximal symphalangism is considered probably the oldest dominant trait ever studied [49]. This genealogical depth has been disputed: the reanalysis by Elkington and Huntsman, in 1967, concluded that the first Earl probably did not have symphalangism and that the mutation would have arisen later in the lineage [12]. Brachydactyly, frequently associated with symphalangism, had been the first human trait interpreted as Mendelian dominant (Farabee, 1903), and Julia Bell entitled her 1951 classification "On brachydactyly and symphalangism" [38]. Vesell described in 1960 a mother and daughter with symphalangism, strabismus and hearing loss, anticipating the association between the digital defect and the middle ear defect [37]. In 1974, Spoendlin described a family of Italian origin with carpal and tarsal fusions transmitted dominantly over several generations, in which several women had hearing loss due to congenital stapes ankylosis and more severe hand and foot deformities, and in 1985 Cremers and colleagues published the first histological description of the stapes in proximal symphalangism [12, 15]. In 1972, Maroteaux, Bouvet and Briard published the "maladie des synostoses multiples", which separated from isolated symphalangism a picture with a characteristic facies and more extensive joint involvement, especially of the vertebrae and hips [37, 50]. Herrmann proposed in 1974 a classification of symphalangism-brachydactyly (WL syndrome), and the name "Herrmann syndrome" came to designate the forms with multiple synostoses and hearing loss [32, 51]. In Herrmann's family, a woman transmitted the condition to five children by two partners, whose initials (W and L) gave the syndrome its name; all had hypoplastic or absent nails, absence of flexion creases and of middle phalanges, short broad metacarpals, conductive hearing loss and radial head dislocation, and Lehmann and colleagues acknowledged in 2007 that this family and some of Maroteaux's patients may in fact have had BDB2 [1, 19]. Higashi and Inoue described in 1983 a Japanese family with a broad nose and pectus carinatum, and Hurvitz and colleagues proposed in 1985 the designation "facioaudiosymphalangism syndrome" [1]. In 1987, Gaal and colleagues published a large Hawaiian family with multiple synostoses, whose first known affected member was a Cherokee Indian who arrived in the archipelago in the 1870s; this family later served for mapping and for the identification of the first gene [1]. In 1990, Teunissen and Cremers, in Nijmegen, described an AD syndrome with congenital conductive hearing loss due to stapes ankylosis, hypermetropia, broad thumbs and halluces, short distal phalanges and syndactyly, without evident symphalangism; two patients also had ankylosis of the short process of the incus, and stapedectomy improved hearing [52].

1.3. Milestones of molecular discovery

Linkage of proximal symphalangism to 17q21–q22 was demonstrated in 1995 in Cushing's historical family, and in 1998 the Hawaiian family with multiple synostoses was linked to the same region, which pointed from the outset to allelic conditions [1, 12]. In 1999, Gong and colleagues identified heterozygous mutations in the NOG gene, which encodes noggin, in five families with proximal symphalangism, in one de novo case and in one family with multiple synostoses; all altered conserved residues, and noggin-deficient mice died at birth with bony fusions of the appendicular skeleton [53]. The NOG variants published in patients with fibrodysplasia ossificans progressiva between 1999 and 2007 were attributed to artefacts, and the disease is due to ACVR1. In Cushing's family, the variant identified was p.(Tyr222Cys), and in the Hawaiian family the variant segregated with the multiple synostoses [1, 12]. There followed the demonstration that the same NOG variant could cause tarsal-carpal coalition in one family and proximal symphalangism in another [46]; the identification of truncating NOG variants in stapes ankylosis with broad thumbs and toes, in a family that had been labelled as having otosclerosis [54]; and the description of a subtype of brachydactyly B caused by NOG missense variants in patients without a ROR2 variant [55]. In 2005 and 2006, gain-of-function GDF5 missense variants were associated with symphalangism and multiple synostoses (SYM1B and SYNS2) [56–58]; localisation to 20q11.2 had been obtained in 1999 in a large Iranian family (maximum LOD score of 13.58), and the four-generation Ashkenazi family studied by Dawson and colleagues, in which linkage to 17q21–q22 had been excluded, confirmed GDF5 as the second locus [3]; in 2009, a Chinese family with 12 affected members defined FGF9 as the third gene (SYNS3), after linkage had delimited at 13q11–q12 an 8.6 Mb interval with 22 candidate genes and the variant had not been found in 250 controls of the same origin [4, 59]; and in 2016 a noggin-resistant GDF6 variant defined SYNS4 [7]. In 2011, Potti, Petty and Lesperance reviewed the NOG-related syndromes and proposed the unifying term NOG-SSD, with a locus-specific variant database (LOVD, https://NOG.lovd.nl) [24]. The SYNS4 and SYNS3 families published between 2018 and 2023 broadened the phenotype of these forms and made it possible to resolve divergences between reference works (section 3) [5, 8, 9].

1.4. Current nomenclature and classifications

Four classification systems coexist that do not fully overlap. The Nosology of Genetic Skeletal Disorders, in its 2023 revision (11th revision, 771 entries and 552 genes), places the class in group 41, "joint formation defects and synostoses", with one entry per gene; the NOG entry (41-0010) groups SYNS1, SABTT, TCC and SYM1A, and assigns BDB2 to group 18 of the isolated brachydactylies [21]. OMIM maintains separate entries by historical phenotype (SYM1A 185800, SYNS1 186500, SABTT 184460, TCC 186570, BDB2 611377, SYM1B 615298, SYNS2 610017, SYNS3 612961, SYNS4 617898) [1, 3–6, 12, 14, 15, 17, 19, 41, 60]. All these entries, except %186400, have the "#" symbol and mapping key 3, that is, a known molecular basis, and all record AD transmission [1, 3, 4, 6, 12, 14, 15, 17, 19]. Orphanet aggregates the four forms of SYNS in ORPHA:3237 and the two forms of proximal symphalangism in ORPHA:3250, and keeps TCC (ORPHA:1412) and SABTT (ORPHA:140917) as separate entities [2, 13, 16, 18]. The Bone Dysplasias atlas organises the class by allele function and zygosity (Table 1.1) [32]. The term NOG-SSD is clinically useful because the historical labels do not predict the features of each carrier: the same variant p.(Pro35Ser) has been described in BDB2, in SYM1 and in Teunissen-Cremers syndrome [23, 47, 55].

Table 1.1. Nosology of the multiple synostoses by gene, function and zygosity (adapted from Bone Dysplasias, Table 26.1.1, supplemented by the 2023 Nosology).

The grouping request includes the designation "proximal symphalangeal chondrodysplasia". None of the reference works or classifications consulted uses this term; the content that corresponds to it is proximal symphalangism (SYM1A and SYM1B) and, at the severe pole of the GDF5 allelic series, the recessive acromesomelic chondrodysplasias [21, 25, 32].

1.5. Definition of each entity

Proximal symphalangism 1A (SYM1A) is the mildest form of the NOG spectrum: congenital fusion of the proximal interphalangeal (PIP) joints, most frequent in the fourth and fifth fingers, with the thumb spared, sometimes accompanied by tarsal coalition and conductive hearing loss [32, 38, 62]. Multiple synostoses syndrome 1 (SYNS1), also called facioaudiosymphalangism syndrome, adds to symphalangism facial dysmorphism, progressive conductive hearing loss and progressive fusions of the carpus, tarsus, elbow and spine [32, 63]. Stapes ankylosis with broad thumbs and toes (SABTT), or Teunissen-Cremers syndrome, has as its dominant feature conductive hearing loss due to congenital stapes ankylosis, with hypermetropia, broad thumbs and halluces, short distal phalanges and syndactyly, and symphalangism usually absent or limited to the fifth fingers; it corresponds to the designation "isolated stapes ankylosis" [42, 52, 64]. Tarsal-carpal coalition syndrome (TCC) is characterised by fusion of the carpus, tarsus and phalanges, short first metacarpals and humeroradial fusion, as a rule with normal hearing [46, 65]. Brachydactyly B2 (BDB2) combines hypoplasia or absence of the distal and middle phalanges, syndactyly, proximal symphalangism and carpal synostosis, in patients without a ROR2 variant [38, 55]. Proximal symphalangism 1B (SYM1B) and SYNS2 are the gain-of-function allelic forms of GDF5, and SYNS3 (FGF9) and SYNS4 (GDF6) complete the genetic heterogeneity of SYNS [21, 60]. OMIM entry %186400, "tarsal, carpal and digital synostoses", is a phenotype without an established molecular basis, distinct from TCC (OMIM 186570), although Orphanet links it to ORPHA:1412 as a narrower term [16, 22].

1.6. Scope of the article

This article covers the whole class with the same structure: common description, classifications, a table of all types and genes (section 3.1) and in-depth coverage of the forms most frequent in the literature, which are those related to NOG. The allelic disorders of GDF5, GDF6 and BMPR1B that do not belong to the class appear in the differential diagnosis: the Grebe, Hunter-Thompson and Du Pan acromesomelic dysplasias, GDF6 Klippel-Feil syndrome and FLNB spondylocarpotarsal synostosis; the isolated brachydactylies (A1, A2, B1, C and others) are summarised in section 6.

2. Molecular Genetics and Pathophysiology

2.1. Joint formation and the balance between BMP/GDF and noggin

The formation of a synovial joint depends on a local balance between prochondrogenic signals and their antagonists. BMPs and GDFs (especially GDF5 and GDF6) bind to complexes of type I (BMPR1A and BMPR1B) and type II (BMPR2, ACVR2A) receptors, which phosphorylate the SMAD1, SMAD5 and SMAD8 proteins and induce chondrocyte differentiation [25, 27]. In the interzone, where the joint will cavitate, this signalling has to be contained: noggin, a secreted protein that binds BMPs and GDFs and prevents them from reaching their receptors, diffuses through the extracellular matrix more efficiently than the ligands themselves and shapes morphogen gradients that allow joint cavitation [23, 53]. When noggin is lacking or when the ligand escapes its inhibition, BMP/GDF signalling is unopposed, recruitment of cells to the cartilaginous lineage increases, growth plates widen and the interzone fails to form; the joint is replaced by continuous cartilage that ossifies [37, 49]. The same mechanism operates between the stapes footplate and the otic capsule, at the stapediovestibular joint, which explains why the conductive hearing loss shares the pathophysiology of the digital fusions [23, 45]. The four genes of the class thus act on the same pathway: NOG through loss of function of the antagonist, GDF5 and GDF6 through gain of function of the ligands, and FGF9 through disturbance of a parallel pathway which, when altered, shifts the differentiation of mesenchymal cells towards the osteogenic lineage [32, 59].

2.2. NOG and noggin

The NOG gene is located at 17q22 (about chr17:54.67 Mb in GRCh37) and is a single-exon gene, which has two practical consequences: truncating variants are not degraded by nonsense-mediated messenger RNA decay (NMD), and loss of function is assessed through secretion and dimerisation of the protein, not through transcript stability [41, 66]. The MANE reference transcript is NM_005450.6, which encodes NP_005441.1 [67, 68]. Noggin is secreted as a homodimer stabilised by disulfide bridges in a cysteine-rich C-terminal domain (cystine knot), and binds and inactivates BMP4 and other BMPs, GDF5 and GDF6 [23, 42].

Functional studies show that most pathogenic variants reduce the amount of functional noggin secreted. In COS-7 cells, one SYNS1 missense variant abolished and two SYM1 missense variants reduced secretion of functional dimers, and coexpression with normal noggin revealed no dominant-negative effect: the variants behave as hypomorphic or null alleles [33]. In HEK293T cells, the signal peptide variant p.(Leu14Pro) completely prevented production of detectable noggin, despite a normal transcript, and p.(Pro170Leu) reduced the protein in the lysate (0.47 arbitrary units) and in the supernatant (0.14), while retaining some secretion, contrary to what had previously been described [41, 69]. A different group of variants, the BDB2 missense variants (NM_005450.6: c.103C>G p.(Pro35Ala), c.103C>T p.(Pro35Ser), c.106G>C p.(Ala36Pro), c.142G>A p.(Glu48Lys), c.499C>G p.(Arg167Gly) and c.559C>T p.(Pro187Ser)), does not cause major loss of function; modelling of the noggin-GDF5 complex and micromass cultures suggest a subtle alteration of binding to BMPs and GDFs, and the authors propose a functional link between the BMP pathway and the ROR2 receptor, the cause of brachydactyly B1 [55]. The review by Carlson and colleagues, in 2021, counted more than 60 NOG variants (missense and nonsense) associated with NOG-SSD, most with reduced secretion or altered dimerisation [41]; in October 2026, ClinVar recorded 73 NOG variants classified as pathogenic or likely pathogenic [67].

The animal model reproduces the phenotype in a manner dependent on dose and genetic background. The Nog−/− mouse dies at birth with short bones, absence of multiple joints and appendicular bony fusions, owing to excess BMP activity and cartilage [41, 53]. Nog+/− heterozygotes were described as normal in one study [33], but in another, depending on genetic background, they showed mild conductive hearing loss due to an ectopic bony bridge between the stapes and the posterior wall of the tympanic cavity, resulting from chondrocyte hyperplasia with unopposed Bmp4 and Gdf5 activity; as the gene has a single exon, this model supports the view that the human disease results from haploinsufficiency [66].

Human temporal bone histopathology confirmed the mechanism. In a patient with the p.(Gln110Ter) variant, both temporal bones showed fixation of the stapes footplate to the otic capsule by a circumferential bridge of calcified cartilage that replaced the annular ligament of the stapediovestibular joint; the unoperated ear had no other ossicular anomaly, and the cochlea and spiral ganglion were normal [45]. In stapes removed at surgery, bony fusion of the footplate, thickened bone in the oval window niche and calcification of the annular ligament are the findings described [70]. Smith's Recognizable Patterns of Human Malformation refers to fusion of the stapes "to the round window"; the primary sources consulted always describe fixation of the footplate in the oval window, and none describes fusion to the round window, so this wording corresponds to an error in the reference work [37, 45, 66, 70].

2.3. GDF5: gain of function in SYNS2 and SYM1B

GDF5 (also designated BMP14 or CDMP1, cartilage-derived morphogenetic protein 1) is a TGF-β superfamily ligand processed into a mature disulfide-bonded homodimer, which signals mainly through BMPR1B and, to a lesser extent, BMPR1A, and is antagonised by noggin [25]. The gene lies at 20q11.22 (MANE NM_000557.5) [25, 67]. GDF5 variants are distributed along a dose-dependent continuum: biallelic loss of function causes the Grebe, Hunter-Thompson and Du Pan acromesomelic dysplasias; heterozygous loss of function causes brachydactylies C, A2 and A1C; and gain of function causes SYM1B and SYNS2 [25, 32]. A 2021 systematic review, cited by the GeneGuidance curation, counted 49 pathogenic GDF5 variants in eight phenotypes, with dominant and recessive transmission; the ClinGen dosage panel assigns the gene a haploinsufficiency score of 3 and a triplosensitivity score of 0 [25].

The gain-of-function mechanisms have been dissected in detail. The p.(Arg438Leu) variant, described in SYNS2 and SYM1B, maintains binding to BMPR1B and to noggin, but increases binding to BMPR1A, giving GDF5 properties similar to those of BMP2; the p.(Leu441Pro) variant, at the same receptor interaction site, almost inactivates the protein and causes brachydactyly A2, which illustrates opposite mechanisms in the same segment [56]. In the Ashkenazi family with p.(Arg438Leu), the mutant protein is secreted as a mature dimer, unlike the loss-of-function variants that cause brachydactyly C [3]. Variants of asparagine 445 (described as N445K and N445T in patients with SYNS) confer resistance to noggin; this asparagine is conserved throughout the BMP family, except in BMP9 and BMP10, which have a lysine at this position and are insensitive to noggin [34]. A variant of the "knuckle" epitope, where GDF5 contacts BMPR2, reduces binding to this receptor but reduces affinity for noggin much more, whose expression increases during chondrogenic differentiation, and the net effect is a gain of function through absence of inhibition [71]. The authors numbered it S94N, according to the mature protein; the correspondence with the pre-protein variant NM_000557.5:c.1424G>A p.(Ser475Asn), described in 2024 in Chinese and Iranian families, is not recorded as a synonym in ClinVar and was not converted manually [67, 72, 73]. OMIM, in the SYNS2 entry, associates the large Iranian family of Akarsu and colleagues (1999) with the variant S475N (allele 601146.0013), designated in pre-protein numbering, and ClinVar record VCV000008388 corresponds to NM_000557.5:c.1424G>A p.(Ser475Asn) without the synonym S94N; the equivalence between the two designations remains unconfirmed in a variant database [3, 29, 67]. The p.(Trp414Arg) variant, in a family with SYNS2 and brachydactyly A1, acts by two simultaneous mechanisms: insensitivity to noggin (gain of function, SYNS2) and reduced signalling through BMPR1A (loss of function, brachydactyly A1) [74]; p.(Ser475Asn) also combines the two expressions, by disrupting a salt bridge at the interface of the antagonist- and receptor-binding sites [72]. The p.(Glu491Lys) variant was the second GDF5 variant described in symphalangism, in two five-generation Chinese families [57]. Unlike the haploinsufficiency variants that cause brachydactyly C, the SYNS2 protein is secreted as a normal mature dimer [58].

The common regulatory variant rs143383, in the 5' untranslated region of GDF5, is a replicated susceptibility allele for osteoarthritis, with an odds ratio (OR) of about 1.17 in the overall analysis and 1.19 to 1.31 in subgroups, in a meta-analysis that included 23,995 individuals for knee osteoarthritis; this is a small effect of a common variant, which is not a Mendelian result and has no individual predictive value [25].

2.4. FGF9: SYNS3

FGF9 (13q12.11; MANE NM_002010.3) encodes a secreted fibroblast growth factor, originally isolated as glia-activating factor [26]. The variant of the Chinese family that defined SYNS3 is written in two forms in the original abstract ("Ser99Asp" and "S99N"); the correct form, confirmed in ClinVar and in the table of Schmetz and colleagues, is NM_002010.3:c.296G>A p.(Ser99Asn) (VCV000008705) [5, 59, 67]. The mutant protein is expressed, secreted and dimerises like the normal one, but receptor binding is severely impaired; ERK1/2 signalling, β-catenin and c-Myc decrease, chondrocyte proliferation and differentiation are impaired and osteogenic differentiation and mineralisation of mesenchymal stem cells increase, which provides a plausible mechanism for the fusion [26, 59]. The subsequent variants mainly affect dimerisation: p.(Arg62Gly) impairs homodimerisation and binding to FGFR3 and was associated for the first time with craniosynostosis [75], p.(Pro189Arg) impairs homodimerisation without affecting binding to FGFR3c [60], and p.(Asn143Tyr) affects the same amino acid as the spontaneous mutant mouse Eks (elbow-knee synostosis, p.Asn143Thr) [76]. In the Eks mouse, the variant impairs homodimerisation, reduces affinity for heparin and increases diffusion of FGF9, creating ectopic signalling; heterozygotes have constant elbow fusion and knee dysplasia, and homozygotes have short limbs and tail, vertebral and thoracic abnormalities, premature suture fusion and cleft secondary palate [5]. As heterozygous deletions that include FGF9 do not cause SYNS3, the most likely mechanism is a dominant-negative effect of the missense variants within a multimeric complex, and not the haploinsufficiency attributed to it by the Bone Dysplasias atlas [5, 32]. The GeneGuidance curation states that OMIM classified the relationship between FGF9 and SYNS3 as provisional, but the current phenotype entry (612961, revised in March 2026) presents it with mapping key 3 (known molecular basis), supported by the Chinese family of Wu and the Spanish family of Rodriguez-Zabala [4, 26]. The mouse carrying the variant equivalent to p.(Ser99Asn) also shows XY sex reversal, with no described counterpart in patients [60]. In mice with the substitution equivalent to p.(Ser99Asn) introduced by knock-in (Tang and colleagues, 2017), heterozygotes and homozygotes have a curly tail and partial or complete joint fusions; in homozygotes, the synostosis results from failure of formation of the joint interzone with excessive chondrogenesis, because mutant Fgf9 loses the ability to repress the chondrogenic factors Sox6 and Sox9 and no longer maintains Gdf5 expression in the elbow and knee, and the conformational change reduces its affinity for the receptors [4].

2.5. GDF6: SYNS4 and allelic disorders

GDF6 (BMP13, CDMP2; 8q22.1; MANE NM_001001557.4) signals through BMPR1A, BMPR1B, BMPR2 and ACVR2A, is antagonised by noggin and defines the boundaries between skeletal elements in the limbs, skull, digits and axial skeleton; in the retina it controls proliferation, apoptosis and dorsoventral patterning [27]. SYNS4 was defined in a six-generation Chinese family with the variant c.1330T>A p.(Tyr444Asn), at a conserved residue of the receptor- and noggin-binding region; the mutant protein is a more potent stimulator of the canonical BMP pathway owing to resistance to antagonism by noggin [7, 8]. The second family, Dutch, had the variant c.1287C>A p.(Ser429Arg), at the interface with the type II receptor [8], and the third, Norwegian, c.1197C>A p.(Asn399Lys), in a hydrophobic pocket critical for noggin binding, which makes GDF6 similar to GDF2 and BMP10, which are resistant to noggin because they have a lysine at this position [9]. The mouse with the orthologous variant p.Tyr443Asn develops fusions in the wrists, ankles, phalanges and ossicles, with defects of interzone formation, excessive chondrogenesis and increased SMAD1/5/8 signalling, which shows that hyperactive GDF6 disturbs both prenatal joint formation and postnatal joint maintenance [77]. A five-generation Australian family with SYNS4 has a chromosomal breakpoint 3' of GDF6 and reduced expression of the gene, that is, a mechanism in the opposite direction to gain of function; the causal relationship with GDF6 is an interpretation by the authors, who also found markedly reduced expression of other genes (NOMO3, RBMXL1, NEIL2) [10].

The other GDF6 associations differ greatly in strength of evidence. SYNS4 is the most robust; Klippel-Feil syndrome 1 (OMIM 118100) is disputed among submitters; isolated microphthalmia 4 (613094) and microphthalmia with coloboma 6 (613703, digenic) form a spectrum of ocular developmental anomalies; Leber congenital amaurosis 17 (615360, recessive) is the weakest association; and biallelic deletions of cis-regulatory elements about 350 kb downstream of the gene cause profound congenital sensorineural hearing loss with cochlear aplasia (DFNB118, 619553), described in three individuals from two families, without any coding variant being interpretable as the cause of this form [27]. Léri pleonosteosis (151200) results from duplications at 8q22.1 that include GDF6 and SDC2 [21].

The OMIM entries for these associations specify the basis of each. Klippel-Feil syndrome 1 appears in OMIM with a known molecular basis (key 3) and AD transmission, supported by a three-generation family with C2–C3 fusion and the missense variant NM_001001557.4:c.746C>A p.(Ala249Glu) and by two isolated patients with the missense variant c.866T>C p.(Leu289Pro), both with conflicting classifications in ClinVar (VCV000008371 and VCV000008372); the divergence between submitters noted by GeneGuidance coexists with this classification [27, 78]. The family of Clarke and colleagues with Klippel-Feil syndrome, malformation of the laryngeal cartilages and pericentric inversion inv(8)(q22.2q23.3), followed up to the fifth generation, also had carpal and tarsal fusions, mild to moderate conductive hearing loss, limited supination and, in about half of the affected individuals, Sprengel deformity; the proximal breakpoint lies 623 kb 3' of GDF6, in a region with long-range enhancers of the gene, and no coding variant was found [78]. The same Sydney group published in 2021, as SYNS4 with reduced GDF6 expression, a five-generation Australian family with a breakpoint 3' of the gene, progressive vertebral fusions and speech disturbance; the coincidence of these features suggests that this is the same lineage, classified in OMIM as Klippel-Feil 1 and in the 2021 publication as SYNS4, but the sources read do not state this explicitly [10, 78]. The mouse lacking both Gdf5 and Gdf6 has defects that neither single mutant shows (very reduced or absent limb bones, unformed joints and severe scoliosis in two of seven animals), which indicates partially redundant functions of the two ligands in joint formation [78].

In the eye, GDF6 screening of 489 patients with microphthalmia, clinical anophthalmia or coloboma and of 81 patients with vertebral segmentation anomalies identified seven heterozygous missense variants in nine patients, five of them in isolated microphthalmia, one patient with spondylothoracic dysostosis and another with hemivertebra, rib malformations and horseshoe kidney; in the two microphthalmias with parents studied, the variant came from an unaffected parent, which demonstrates incomplete penetrance, and none of the variants was present in 366 controls [78, 79]. In microphthalmia with coloboma 6, the main gene is GDF3: in a mother with mild iris colobomas and microphthalmia, the daughter, with severe colobomatous microphthalmia, nystagmus, foveal hypoplasia and optic nerves of reduced diameter, had the same GDF3 missense variant and also the GDF6 missense variant NM_001001557.4:c.595G>A p.(Ala199Thr), which underpins the digenic designation [80]. Leber congenital amaurosis 17 rests on a single patient, compound heterozygous for c.746C>A p.(Ala249Glu) and c.169G>C p.(Asp57His), with vision limited to perception of hand movements and an extinguished electroretinogram, without other anomalies, although she had not had a radiological study of the skeleton; the parents, without complaints, had subtle electroretinogram changes, and three other patients from a cohort of 279 with Leber amaurosis or juvenile retinitis pigmentosa were heterozygous for a single GDF6 missense variant [81]. The mouse heterozygous for deletion of exon 2 of Gdf6 has reduced electroretinogram a- and b-wave amplitudes (down to 54% and 66%), and the homozygous zebrafish has microphthalmia, retinal disorganisation and loss of cones by apoptosis [81]. The p.(Ala249Glu) variant thus appears in Klippel-Feil syndrome, isolated microphthalmia, coloboma and Leber amaurosis [81].

In DFNB118, the three patients, from two consanguineous Turkish families, had profound sensorineural hearing loss from birth and complete absence of the cochlea with a normal vestibule on computed tomography (CT) and magnetic resonance imaging; the homozygous deletions, of about 222 kb and 338 kb, overlap in a region of about 200 kb downstream of GDF6, were not present in 1,025 Turkish controls or in population databases, and, in otic lineage cells derived from the patients' stem cells, GDF6 was the only one of the 14 genes located within 1 Mb with altered expression; the Gdf6-null mouse also fails to form the cochlea [82]. In Léri pleonosteosis, of AD transmission, flexion contractures of the interphalangeal joints, limitation of several joints and short broad metacarpals, metatarsals and phalanges are associated with short stature, blepharophimosis, thickening of the palmar and plantar skin, chronic joint pain and, in some patients, block vertebrae or C2–C3 fusion and laryngeal stenosis; two British families had duplications of 1 and 1.2 Mb at 8q22.1, and in fibroblasts from two patients aged 20 and 77 years only GDF6 was overexpressed (13 and 40 times), with overexpression of SDC2 only in the older patient [83].

2.6. BMPR1B

The BMPR1B receptor is the preferred receptor for GDF5. The heterozygous missense variant NM_001203.3:c.1457G>A p.(Arg486Gln) (VCV000006558, likely pathogenic) causes a brachydactyly C or symphalangism-type phenotype, or brachydactyly A2, and biallelic variants cause Grebe- and Du Pan-type acromesomelic dysplasias [21, 32, 67]. BMPR1B enters the molecular differential diagnosis of symphalangism and has been tested without result in patients with SYNS without a variant in the known genes [84].

2.7. Haploinsufficiency or gain of function: an inconsistency in the sources

The Bone Dysplasias atlas describes SYNS and proximal symphalangism as "variant expressions of haploinsufficiency" of the genes in its Table 26.1.1, but the same table assigns gain of function to the GDF5 and GDF6 variants that cause SYNS2 and SYNS4 [32]. The primary literature resolves the inconsistency: only NOG acts through loss of function (hypomorphic or null alleles, including deletions that span only NOG and ANKFN1) [33, 41]; GDF5 and GDF6 act through gain of function, demonstrated in noggin- and receptor-binding assays [7, 34, 56, 71]; and FGF9 probably acts through a dominant-negative effect [5]. The common denominator is a relative excess of BMP/GDF signalling in the interzone, not haploinsufficiency. The Australian SYNS4 family with reduced GDF6 expression is the described exception and remains to be replicated [10].

2.8. Variant spectrum and nomenclature

The historical nomenclature of NOG variants mixes genomic positions (g.551G>A), coding positions and one-letter amino acid designations, and some publications contain typographical errors. The variant of Usami and colleagues written in the text as "C155F" is, according to the article's own table and VariantValidator, c.463T>A p.(Cys155Ser) [42, 68]; the insertion "c.252-253insC" of Brown and colleagues corresponds to c.252dup p.(Glu85ArgfsTer97) [54, 67]; and the deletion "p.Cys230_Cys232delins11" of Westergaard-Nielsen and colleagues corresponds to c.688_699del p.(Cys230AsnfsTer12), because the 12-nucleotide deletion includes the stop codon and extends the protein [68, 85]. Table 2.1 brings together the clinically relevant variants normalised in ClinVar or VariantValidator in October 2026.

Table 2.1. Published variants, historical nomenclature and normalised form (GRCh38, MANE transcripts).

The GDF5 variants designated N445K and N445T and S94N (mature protein numbering) have no ClinVar record and remained without normalisation [34, 71]. Recent ClinVar submissions for "NOG-related disorder" (2025–2026) include NM_005450.6:c.1A>G p.(Met1Val), c.124C>A p.(Pro42Thr), c.215del p.(Gly72AlafsTer52), c.343dup p.(Ala115GlyfsTer67), c.544C>T p.(Arg182Cys), c.608del p.(Leu203ArgfsTer61), c.679G>T p.(Glu227Ter) and c.687del p.(Lys229AsnfsTer35), classified as pathogenic or likely pathogenic, and the variant c.4G>T p.(Glu2Ter) [67]. Up to 2012, the NOG variants reviewed (41) were concentrated in conserved and functionally critical regions, without an ethnic founder mutation and without a relationship between the location or type of variant and the clinical label [42]. The 2020 Chinese review confirmed regional concentration at conserved residues and absence of genotype-phenotype correlation between ethnic groups [89].

2.9. Genotype-phenotype correlations, penetrance and expressivity

Expressivity is the rule that dominates the class. Within a family, the same genotype produces anything from isolated conductive hearing loss to multiple synostoses with vertebral fusion, and the same variant gives different labels in different families: p.(Pro35Ser) in BDB2, SYM1 and Teunissen-Cremers syndrome, and p.(Tyr222Cys) and p.(Pro35Arg) in SYM1 and TCC [23, 46, 47]. Dixon and colleagues interpreted this variability as an effect of epistatic modifiers [46]. Some trends have been described, without individual predictive value: truncating variants predominate in families with SABTT (four of five families known in 2005), whereas missense variants, with possible residual activity, predominate in the other forms [97]; BDB2 variants alter ligand binding without major loss of function [55]; and the p.(Pro170Leu) variant has been associated with poor results of stapes surgery, which led a Korean centre to exclude its carriers from surgery [88]. Penetrance of the conductive hearing loss was complete in the Michigan SABTT family, and penetrance of SYNS3 appeared complete in the German family of 29 affected individuals, but expression varied greatly in both [5, 45]. In Korea, Lee and colleagues observed, in three families, that expression differed between and within families independently of age, and concluded that every carrier should be monitored for the whole spectrum [98].

2.10. 17q22 deletions and contiguous gene syndrome

17q22 microdeletions that include NOG produce the features of NOG-SSD accompanied, depending on their extent, by intellectual disability, attention deficit hyperactivity disorder (ADHD), visual impairment, low-set ears and other anomalies; in a series of five deletions of 1.8 to 2.5 Mb and one of 8.2 Mb, the smallest region of overlap (0.24 Mb) contained NOG and C17ORF67, and all patients had bone and joint features of the NOG spectrum [99]. The smallest deletion described in 2015 (1.34 Mb, in a female patient and her affected mother) included MMD, TMEM100, PCTP, ANKFN1 and NOG; the authors proposed the name "NOG spectrum contiguous gene syndrome" and recommended searching for a microdeletion when NOG features coexist with anomalies that NOG does not explain [39]. A 555 kb deletion spanning only NOG and ANKFN1 gave, in an Israeli family, a phenotype comparable to that of point variants and much milder than that of the larger microdeletions [41]. A Japanese boy with SYNS1 and hypogonadotrophic hypogonadism had an apparently balanced translocation t(10;17)(p15.3;q22) with a cryptic deletion of 2.2 to 3.9 Mb that included NOG [100]. In 2026, analysis of a de novo deletion distal to NOG, detected in a fetus with increased nuchal translucency, and of 24 postnatal cases with overlapping deletions, all with neurological abnormalities, attributed the neurodevelopmental phenotype to haploinsufficiency of SRSF1, which reinforces that the severe features of 17q22 deletions depend on genes other than NOG [41, 101].

2.11. Unexplained heterogeneity

Not all patients have a variant in the known genes. A Belgian patient with a complete SYNS phenotype had no variant in NOG, BMPR1B, GDF5 or FGF9 [84]; a Japanese family with SABTT had no variant in the coding regions, exon-intron boundaries or promoter of NOG, GDF5 and FGF9 [102]; and, in a cohort of six probands with SYNS, only one had a NOG variant [58]. These data indicate additional heterogeneity not yet identified and justify copy number variation analysis and exome or genome sequencing when panels are negative.

3. Clinical Spectrum and Manifestations by System

3.1. Table of all types of the class

Table 3.1. Types of the class, genes and distinguishing features.

3.2. Craniofacial manifestations

The facial dysmorphism of SYNS is subtle and best recognised in profile. The Bone Dysplasias atlas describes a narrow face, a broad hemicylindrical nose with hypoplastic alae nasi, a short philtrum and a thin upper lip [32]. Smith's adds a sloping forehead, prominent supraorbital ridges, a broad nasal root, hypoplastic nasal septum, bulbous nasal tip, malar flattening and an asymmetric mouth, and records on imaging fusion of the nasal bone with the frontal process of the maxilla [37]. The hemicylindrical nose with a bulbous tip is the most constant facial feature of NOG-SSD and also appears in families with SABTT and without symphalangism; in a Belgian family with p.(Trp205Cys), all five carriers had the typical facies [24, 54, 91, 103]. In SYNS3, sagittal craniosynostosis (3 of 46 individuals, 7%) and cleft palate (4 of 46, 9%) are the characteristic craniofacial findings, with bifid uvula and crowded teeth described in isolated patients [5, 60]. In families with gain-of-function SYNS4, facial dysmorphism is not described in the published abstracts [7–9].

3.3. Hands and feet

Proximal symphalangism is the hallmark of NOG-SSD: the PIP joint is absent or fused from birth, and the finger is immobile and straight, with faint or absent interphalangeal creases, rather than showing a flexion deformity [23, 37]. Fusion is most frequent in the 4th and 5th fingers and as a rule spares the thumb; the distal interphalangeal (DIP) joints are affected less frequently [32, 62]. Symphalangism is not always evident in the infant and may only become apparent with ossification [37]. It is accompanied by brachydactyly with brachymesophalangy or brachytelephalangy, hypoplasia or aplasia of the distal phalanges, clinodactyly, hypoplastic, short or absent nails, partial cutaneous syndactyly, broad short thumbs, a short first metacarpal, short feet with a broad hallux, inability to flex the toes and heel deformity with a waddling gait [32, 37]. In the carpus, capitate-hamate fusion and a carpal block are the patterns described; in the tarsus, talonavicular fusion is the most frequent according to Smith's, and the Bone Dysplasias atlas illustrates talocalcaneocuboid, intertarsal and tarsometatarsal patterns, with bilateral fusion of the talus, calcaneus, cuboid, navicular and lateral cuneiform at six years of age [32, 37]. In adults, foot stiffness transfers load to the fourth metatarsal, which shows cortical thickening [32]. In the French series of 14 patients with SYNS followed up for a mean of 18.6 years (1972–2017), all had tarsal synostoses, nine carpal, seven elbow and two vertebral; the fusions started at the distal phalanx and progressed proximally to the carpus, tarsus and the radioulnar and humeroradial joints [35]. In the Hawaiian family of Gaal and colleagues, the first joint affected was the PIP of the 5th finger, in early childhood or already at birth, and fusion advanced from the ulnar to the radial side and from proximal to distal; symphalangism was the most constant finding, and most adults could not close their hand [1]. In TCC, all affected individuals have at birth stiffness of the PIP of the 5th finger, with or without bony synostosis, and fusion then extends, in this order, to the PIP joints of the 4th, 3rd and 2nd fingers, with less frequent involvement of the DIP joints [15]. The direction of progression described thus differs between the French series and these families. In a family with proximal symphalangism and talonavicular fusion, several affected individuals had two accessory bones of the foot, the os paranaviculare and the os tibiale externum (Wildervanck, 1967) [12]. A 10-year-old girl with TCC had bilateral congenital pes varus, with hindfoot varus and forefoot supination, and pain and gait abnormality were the main complaints [104].

3.4. Large joints and spine

The large joints progressively lose mobility. The elbow is the most affected: limitation of flexion, extension and pronation-supination, humeroradial and radioulnar synostosis, anterior dislocation of the radial head and, when the coalition is not yet bony, severe cubitus valgus [32, 37]. The hips and shoulders lose rotation and abduction, and pectus excavatum or carinatum with prominent costochondral junctions has been described [37, 51]. In the spine, the cervical or lumbar vertebral bodies frequently fuse (sometimes described as Klippel-Feil malformation), the thoracolumbar disc spaces narrow and there may be stenosis of the cervical and lumbar canal [32]. Smith's states that neurological complications due to canal stenosis are frequent and that cervical fusion may be disabling [37]; the Bone Dysplasias atlas illustrates L4–L5 disc narrowing, L5–S1 spondylolisthesis and marked stenosis in an adult [32]. A young Australian man was diagnosed with SYNS1 after a cervical injury with spinal cord contusion, which revealed canal stenosis from C3 to C6 with spinal cord compression, an anteroposteriorly flattened canal and vertebral fusions [51]. In the Hawaiian family, cervical vertebral fusions began in early childhood and eventually limited neck flexion and extension, and with age ankylosis of the hips and humeroradial joints appeared [1]. In TCC, humeroradial fusion is absent in the infant but appears soon afterwards, the elbow is the most variable feature, and ankle and foot abnormalities may make walking painful and difficult to the point of requiring palliative or surgical treatment [15]. A North American child with SYNS1 had limited cervical mobility due to C2–C3 fusion [41]. The frequency of vertebral fusion varies between series: 2 of 14 in the French series and 9 of 46 (20%) in SYNS3, a figure the authors consider underestimated owing to lack of systematic spinal study [5, 35].

3.5. Ear and hearing

The conductive hearing loss is congenital or of onset in early childhood and results from fixation of the stapes footplate; it may be the presenting feature or the only evident finding, and is often labelled otosclerosis [23, 54, 92]. Severity ranges between 20 and 80 dB, usually moderate, with a normal tympanogram, absent stapedial reflexes and absent otoacoustic emissions; computed tomography (CT) and magnetic resonance imaging are often normal, with occasional narrowing of the oval window or deformity of the stapes [42, 70]. Besides the footplate, there may be fixation of the incudomalleolar joint, of the short process of the incus in the fossa incudis or of the malleus-incus complex, and the stapes superstructure may be abnormally high [41, 47, 94, 97]. Progression is variable. In the Michigan SABTT family, the eight affected individuals had bilateral low-frequency conductive hearing loss and two had maximal conductive hearing loss documented at four years of age [105]; in a Belgian family with SYNS1, 5 of 10 ears had early-onset progressive conductive hearing loss [91]; in a Danish family, 7 of 8 affected individuals had bilateral conductive hearing loss [85]; and in a Korean paediatric series of 11 patients from five families the hearing loss did not progress in any, although two had cochlear and vestibular dysplasia [88]. A Danish family with SYNS1 and NM_005450.6:c.689G>A p.(Cys230Tyr) had no hearing loss, which shows that not even this feature is constant [103]. Mixed hearing loss has also been described: a Croatian mother and daughter with SABTT had a sensorineural component, whose cause remains uncertain, and in SYNS3 a German patient had moderate and profound mixed hearing loss [5, 70]. A Japanese child from a SABTT family had normal auditory brainstem responses (ABR) at 9 months, 1 year and 2 years and later developed progressive conductive hearing loss, and a Chinese girl who had passed newborn hearing screening by otoacoustic emissions and had normal speech presented at 6 years with progressive bilateral conductive hearing loss of 2 years' duration; both cases suggest that the ankylosis may be incomplete at birth [36, 95]. In the original family of Teunissen and Cremers, stapes ankylosis was bilateral in most affected individuals and produced conductive hearing loss of 40 to 60 dB [17]. In a child with symphalangism, surgery showed fixation of all the joints of the ossicular chain, which required total reconstruction of the chain (Stephan, 2006) [12]. In the Hawaiian family, all affected individuals examined had some degree of hearing loss, from mild to severe [1].

3.6. Eyes

Hypermetropia is frequent and may be severe; it should be sought early [24, 37]. In a Belgian family, 4 of 5 carriers had hypermetropia, and a North American child had worn +8 dioptre glasses since 2.5 years of age, with strabismus corrected by optical correction [41, 91]. An Israeli family with p.(Pro35Ser) also had lens opacities [47].

3.7. Growth, bone and other systems

Short stature is not part of the NOG picture. In two Scottish families, carrier children were tall (up to +3.5 standard deviations), but adults not necessarily, and appendicular bone mineral content was low in childhood and tended to normalise in adulthood [106]. A 10-year-old German boy with SYNS1 had height above the 97th centile since 3.5 years of age and markers of activated bone metabolism [93]. This boy's father, never followed up in clinic, had been one of the tallest boys until 15 years of age, when growth velocity slowed, and reached 185 cm (75th centile); the authors related the accelerated growth to the acceleration of osteogenesis observed experimentally when noggin is suppressed [1]. A muscular build and good muscle development are mentioned in classical and case descriptions [37, 51]. Smith's mentions as occasional anomalies moderate intellectual disability, Klippel-Feil anomaly, short sternum and humeroradial synostosis [37]; intellectual disability, when present, should raise suspicion of a 17q22 microdeletion [39, 99]. Isolated cases of association with premature ovarian insufficiency have been published (a 33-year-old Japanese woman with p.(Glu48Lys) and a Moroccan patient) [86, 107], as well as oesophageal atresia with tracheo-oesophageal fistula in a newborn with a de novo nonsense variant [108], hypogonadotrophic hypogonadism in a cryptic 17q22 deletion [100] and a colloid cyst of the third ventricle in a nine-year-old Saudi girl [109]; none of these associations is established, and some may be coincidental. Recurrent pain in the affected joints has been reported as a secondary feature of NOG-SSD [103].

3.8. Phenotype by NOG entity

SYM1A. Isolated proximal symphalangism is the mildest expression; even so, tarsal coalition and conductive hearing loss appear in several patients, and the same variant gives SYNS1 in another relative [32, 87]. SYNS1. It brings together the signs of sections 3.2 to 3.6; a four-generation Belgian family showed the variable expression and progressive nature of the condition [63]. A large Brazilian family with 28 affected individuals in AD transmission (Da-Silva and colleagues, 1984) had mainly symphalangism and carpal and tarsal synostoses, and some members had other synostoses, absence of phalanges and nails, short metacarpals and hypoplastic alae nasi; the sources consulted do not mention a molecular study of this family [1]. SABTT. The founding family had five males in three generations, with no sex predominance in subsequent families [70]; symphalangism, when present, is limited to the 5th finger or to one foot, and the minor skeletal features (broad thumbs and halluces, brachytelephalangy) are the clue that distinguishes SABTT from otosclerosis [42, 45, 97]. Among the five males of the original family there was father-to-son transmission, all had hypermetropia, broad thumbs and halluces and syndactyly, two had fused cervical vertebrae, and no carpal or tarsal fusions or symphalangism were found [17]. In the family of Milunsky and colleagues (1999), mother and daughter had stapes ankylosis, hypermetropia and short broad thumbs, features also present in earlier generations, and both had a cylindrical nose with hypoplastic alae nasi, without symphalangism; the Italian family of Brown and colleagues had conductive hearing loss with complete penetrance, attributed to non-syndromic otosclerosis in each affected individual before the molecular diagnosis [17]. An Israeli family with p.(Pro35Ser) added to the hearing loss and incus fixation symphalangism, syndactyly, brachydactyly and contractures of the elbows and knees, which links SABTT to the other forms [47]. The proband, a 22-year-old Ashkenazi woman with seven affected relatives, could not bring her hand to her ear to use her hearing aid because of limited elbow flexion and pronation-supination, and her father had a more severe phenotype [17]. In Hiroshima, a Japanese family with SABTT and congenital stapes ankylosis had the variant NM_005450.6:c.682T>G p.(Cys228Gly), at the same codon at which c.682T>A p.(Cys228Ser) was described in an atypical SYNS1 in Okinawa [102, 110]. TCC. An Argentinian family and an Indian family (mother and two children, with p.(Arg204Gln)) showed carpal, tarsal and phalangeal fusions with short first metacarpals and humeroradial fusion and mild intrafamilial variability [65, 90]; a Belgian family with NM_005450.6:c.110C>G p.(Pro37Arg) and two siblings with a de novo double variant also had transverse reduction defects of the toes [111, 112]. In the OMIM description, TCC presents with normal stature, facies and intelligence and, unlike SYM1A and SYNS1, with hearing usually normal; the molecular basis was identified in 2001 in three families, including that of Drawbert and colleagues (1985) [15]. A four-generation Danish family with medial talocalcaneal synostosis, a bulky valgus talus and short stature (Gregersen and Petersen, 1977) is included in the same entry without a molecular study, and the short stature contrasts with the normal stature of families with a NOG variant [15]. In 2026, TCC was published as a rare cause of peripheral joint pain in a rheumatology clinical image [113]. BDB2. Patients have brachydactyly B (hypoplastic distal and middle phalanges, syndactyly) with additional proximal symphalangism and carpal synostosis, without a ROR2 variant [55].

3.9. GDF5 forms: SYM1B and SYNS2

A British family with p.(Arg438Leu) (mother and three children) was referred to orthopaedics mainly for foot problems, with multiple tarsal coalitions and brachydactyly or symphalangism of the PIP of the 5th finger; the authors recommend a three-generation family tree in children with rigid planovalgus foot [62]. The two five-generation Chinese families with p.(Glu491Lys) had bony fusion of the PIP joints of the 2nd to 4th fingers, absence of the cuboid, flat feet and first and fifth metacarpals of normal length [57]. OMIM adds that these two families comprised 17 affected individuals, who also had fusions of the distal interphalangeal joints, and that the fusions and deformities worsened with age; in the family in which p.(Arg438Leu) was described in SYM1B, patients could not flex the interphalangeal joints of the 4th and 5th fingers, without the corresponding flexion creases, and the radiograph showed complete bony fusion between the proximal and middle phalanges of the 5th finger and less marked fusion in the 4th; a third family, Han Chinese, had p.(Leu373Arg) [14]. The Iranian family described in 2024 as "Farhud-type" SYNS2 (58 affected and 62 unaffected individuals over five generations, observed between 1982 and 2022) had tarsal-carpal coalition, humeroradial synostosis, brachydactyly and proximal symphalangism; the p.(Ser475Asn) variant was present in the 16 patients tested and absent in the 40 healthy relatives [73]. The Iranian family in which SYNS2 was mapped in 1999 (Akarsu and colleagues) had the same combination of tarsal-carpal coalition, humeroradial synostosis, brachydactyly and proximal symphalangism, and the authors likened it to the Pearlman picture (OMIM %186400); the sources read do not make explicit whether this is the same lineage described in 2024 [3]. The four-generation Ashkenazi family with p.(Arg438Leu) had a broad hemicylindrical nose, progressive symphalangism and carpal, tarsal and vertebral fusions, with variation between members in the extent of the fusions and the presence of talipes equinovarus [3]. The same variant combined brachydactyly A1 and SYNS2 in a Chinese family [72], and p.(Trp414Arg) had the same dual effect in another family [74]. SYNS2 has been described as a syndrome with progressive symphalangism, carpotarsal fusions, hearing loss and mild facial dysmorphism [58], and the GeneGuidance curation refers to conductive hearing loss due to stapes fixation in SYM1B and SYNS2 [25].

3.10. SYNS3 (FGF9)

SYNS3 has its own pattern, centred on the elbow. Table 3.2 summarises the 47 individuals from seven families published up to 2023.

Table 3.2. Frequency of SYNS3 features in 47 individuals from 7 families (Schmetz 2023, which includes the families of Wu 2009, Rodriguez-Zabala 2017, Sentchordi-Montané 2021, Thuresson 2021 and Dobson 2022).

Source: [5].

In the original Chinese family (12 individuals aged 5 to 68 years), the elbow was affected in all, the fingers in 10, the toes in 8 and the spine in 3 [59, 60]. Hearing, stature and intelligence were normal in all, and the four patients aged 11 years or less had only mild subluxation or cubitus valgus and limited finger flexion, which indicates an age-dependent phenotype [4]. In the Spanish family with p.(Arg62Gly), the son had premature closure of the sagittal suture at 2 months, with dolichocephaly and mild proptosis, and at 5 years had broad thumbs and halluces without joint limitation or fusions; the father, investigated in childhood for craniosynostosis, had cleft palate, broad radially deviated thumbs with fixed contractures of the interphalangeal joints, cutaneous syndactyly of the toes and progressively worsening carpal, tarsal and lumbar limitation with bony fusions, and the variant arose de novo in him, being absent in the paternal grandparents with confirmed biological paternity [4, 75]. In the German family of 29 affected individuals over five generations, first described in 1930, the 25-year-old proband had operated sagittal craniosynostosis, cleft palate, thumb surgery in childhood, almost complete ankylosis of the elbows at 70° of flexion, pectus carinatum and absent DIP creases; his dizygotic twin had mildly limited elbows, broad valgus halluces corrected in childhood, bilateral calcaneonavicular coalition operated on in adolescence, partial L3–L4 synostosis and mild right-sided conductive hearing loss (20–30 dB) with a Carhart notch at 2 kHz; the father had elbows fixed at 45° without pronation, humeroradial synostosis documented as progressive between three and six years of age and mixed hearing loss. Intelligence was normal in all, and radiological progression in childhood was not accompanied by progression reported by the patients [5]. A 16-year-old Swedish boy with p.(Pro189Arg), probably de novo, had reduced mobility of the elbows, thumbs and halluces, bilateral radial head dislocation, interphalangeal fusions of the thumbs and toes, suspected calcaneonavicular coalition, fusion of the posterior elements from L3 to S1, high palate, bifid uvula, large hands and feet and normal hearing [60]. A Canadian patient with p.(Arg190Thr) had an unstable elbow, bilateral radial head deformity, carpotarsal fusions, brachydactyly and sacroiliac osteoarthritis, and the authors described SYNS3 as a form with normal cognition and hearing [96].

3.11. SYNS4 (GDF6)

The core of SYNS4 is carpal and tarsal coalitions. In the six-generation Chinese family, affected individuals had bilateral deformities of the wrists and ankles at birth and progressive conductive hearing loss after 40 years of age, with profound functional disability [7]. In the Dutch family, at least 6 of 10 affected individuals had mild to moderate hearing loss; in four "otosclerosis" had been diagnosed, one child had severe stapes fixation at six years and two adults underwent surgery for stapes fixation [8]. In the four-generation Norwegian family, six of nine affected individuals examined had carpal and tarsal synostoses with foot pain after walking, the condition could be asymptomatic and there was no hearing loss: a 73-year-old carrier had normal audiometry for age [9]. In the Australian family with reduced GDF6 expression, bilateral carpotarsal coalition was present in about half of the affected individuals, hearing loss associated with otosclerosis occurred only in women, all had acquired and progressive vertebral fusions (from C2–C3 in childhood to a C2–C7 and T3–T7 block later) and most had a speech disorder [10]. A four-generation family with SYNS4 followed up in London, published in 2026, was described from the point of view of clinical management, with no abstract available [11]. The OMIM summary adds details of the first two families: in the Chinese family, with 46 affected individuals, three-dimensional CT reconstruction showed absence of almost all intertarsal joints and fusion of all tarsometatarsal joints except that of the cuboid with the 5th metatarsal, and the hands, of normal appearance, had variable carpal fusions on radiography; in the Dutch family, five affected individuals examined had a broad forefoot with overlapping toes and a low plantar arch, several had brachydactyly and clinodactyly of the 5th finger, the cervical spine was normal in two and showed degenerative changes from C5 to C7 in a 65-year-old patient, and ophthalmological examination of three was normal, except for mild Fuchs dystrophy in the oldest [6]. OMIM counts five of the ten affected individuals of the Dutch family with hearing loss attributed to otosclerosis, a count that differs from the at least six with hearing loss reported by the authors [6, 8].

3.12. Divergence between reference works on SYNS3 and SYNS4

Smith's states that the picture is similar in the four genotypes, but that FGF9 carriers do not have hearing loss and GDF6 carriers do not have facial dysmorphism, symphalangism, humeroradial synostosis or vertebral fusions [37]. The GeneGuidance curation states the opposite for both forms: progressive conductive hearing loss and facial dysmorphism in SYNS3, and PIP, tarsal, carpal, humeroradial and cervical fusions with frequent hearing loss and dysmorphism in SYNS4 [26, 27]. The primary sources partly support each. In SYNS3, hearing loss is rare: absent in Wu's family, in the Swedish patient and in the Canadian patient, and present in two members of the German family, which the authors only propose as a possible part of the picture; on the other hand, vertebral fusions do occur (20%), which contradicts their implicit absence in Smith's [5, 60, 96]. In SYNS4, conductive hearing loss is present in three of the four families with an audiological description, so the statement in Smith's that only SYNS3 lacks hearing loss is compatible with the data; facial dysmorphism and symphalangism are not described in the abstracts of the human families (the mouse has phalangeal fusions), and vertebral fusions have only been described in the family with reduced expression [7–10, 77]. Brachydactyly and clinodactyly of the 5th finger are, however, recorded in several members of the Dutch family [6]. The GeneGuidance description applies the generic SYNS1 phenotype to SYNS3 and SYNS4 and should not be used for these forms.

3.13. Natural history

The disease is congenital but progressive. Symphalangism and joint ankylosis progress with age and increase stiffness; adult radiographs show fusions absent in childhood, and in the French series radiological progression was observed in all adults [23, 32, 35]. Vertebral fusion may cause myelopathy, and hearing loss worsens with progression of stapes ankylosis, although the Korean paediatric series did not document progression [32, 88]. Bony fusions may be painful, and foot deformities have the greatest impact on quality of life [35, 37]. Life expectancy is not described as reduced in the sources consulted; severe morbidity is concentrated in spinal cord compression and untreated hearing loss [32, 51]. Natural history data come from families and small series, not prospective cohorts, and mix treated and untreated patients; the frequencies by NOG entity compiled in Potti's 2011 review were not accessible in full text.

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the newborn and infant, the earliest sign is a finger that does not bend: a straight finger, with an absent interphalangeal crease, which does not follow the flexion of the others when the child grasps; this is associated with broad thumbs and halluces, cutaneous syndactyly of the toes, hypoplastic nails and, in SYNS4, deformities of the wrists and ankles [7, 23, 37]. In SYNS3, sagittal craniosynostosis, cleft palate or an elbow with reduced mobility may be the first finding [5]. At preschool and school age, the most frequent presentation is conductive hearing loss with a normal tympanogram, detected by the family or at school, often after normal newborn screening; hypermetropia and strabismus lead to an ophthalmology consultation [36, 41, 95]. In adolescence and adulthood, the presentation is orthopaedic (rigid planovalgus foot, tarsal pain after walking, an elbow that does not extend, cervical stiffness) or otological (conductive hearing loss labelled otosclerosis) [9, 62, 92].

4.2. Warning signs for the otolaryngologist

Congenital or childhood-onset bilateral conductive hearing loss, with a normal tympanic membrane and absent stapedial reflexes, should prompt examination of the hands, feet and nose of the patient and parents. Many patients labelled as having non-syndromic otosclerosis have NOG syndromes, a negative family history does not exclude the diagnosis because there are de novo variants, and the minor skeletal features (broad thumbs and halluces, symphalangism of the 5th finger, brachytelephalangy) are often the only clue [42, 92, 105]. Identifying the syndrome before surgery changes planning, because the distance between the incus and the footplate is greater than in otosclerosis and there may be fixation of the malleus or incus [41, 94].

4.3. Warning signs for the orthopaedic surgeon and paediatrician

A child with bilateral or multiple tarsal coalition, with associated carpal coalition, with elbow synostosis or with symphalangism should have a three-generation family tree, an examination of the parents' hands, feet and face and a hearing assessment [38, 62]. The association of symphalangism or fusions with intellectual disability, ADHD, visual impairment or anomalies of other organs suggests a 17q22 microdeletion [39, 99].

4.4. Emergency signs

Cervical canal stenosis with vertebral fusions exposes the patient to spinal cord injury after trauma that, in another person, would be benign. Cervical or lumbar pain with neurological deficit, paraesthesia, weakness or sphincter disturbance, especially after a fall or contact sport, requires urgent spinal imaging [32, 51]. After stapes surgery, severe vertigo or a sudden drop in sensorineural hearing suggests a prosthesis that is too long or a perilymphatic fistula [41, 70].

4.5. Newborn screening

There is no specific newborn screening. Universal newborn hearing screening may fail to detect the conductive hearing loss of NOG-SSD, because stapes ankylosis may be incomplete at birth and progress in early childhood; a normal result does not exclude hearing loss in a child with a family history or a congenital joint anomaly [36, 95].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no validated formal diagnostic criteria for any entity of the class. The clinical diagnosis rests on the combination of proximal symphalangism, carpal or tarsal coalitions, synostoses of the large joints, conductive hearing loss and facial features, and the aetiological diagnosis on identification of a variant in NOG, GDF5, FGF9 or GDF6 [24, 32]. As an operational research definition, the French series included patients with more than three synostoses, of which at least one was in a joint of the hand [35]. For NOG-SSD, the key finding is proximal symphalangism, but its absence does not exclude the diagnosis, as the families with SABTT show [24, 54].

5.2. Clinical examination

The examination should include active flexion of each interphalangeal joint and the search for skin creases, the shape and length of the distal phalanges and nails, the width of the thumbs and halluces, syndactyly, the mobility of the wrists, elbows (flexion, extension and pronation-supination), shoulders, hips and cervical spine, and the nasal profile. In the approach to brachydactyly, the Oxford Desk Reference recommends a family tree of at least three generations (because the rule is variable expressivity rather than incomplete penetrance), the parents' stature, measurement of height, arm span and segments, hand measurements (total length, middle finger and palm), observation of the palmar creases, camptodactyly, nails and syndactyly, examination of both feet, a search for dysmorphic features and measurement of blood pressure (because of brachydactyly with hypertension) [38]. Examination of the parents looks for minimal carrier signs [64].

5.3. Skeletal imaging

Radiographs of the hands and feet are essential and allow recognition of the brachydactyly and synostosis patterns [38, 64]. The Bone Dysplasias atlas lists as major radiological findings symphalangism, with or without brachymesophalangy or brachytelephalangy; mild undertubulation of the metacarpals; a short first metacarpal; carpal and tarsal fusion; humeroradial and radioulnar synostosis; fusion of cervical or lumbar vertebral bodies; narrowing of the thoracolumbar disc spaces; and stenosis of the cervical and lumbar canal [32]. The figures in this atlas, from a Korean series of five patients, show in the infant absent or rudimentary middle phalanges and capitate-hamate fusion; at three years, proximal symphalangism with brachymesophalangy and PIP fusion of the 2nd to 4th fingers; at ten years, deformity of the capitate and hamate preceding fusion; and in the adult distal symphalangism, metacarpophalangeal fusion and a carpal block. In the foot, the hourglass calcaneus of the infant corresponds to a calcaneocuboid fusion [32]. Before ossification, a cartilaginous coalition may not be visible, and only serial radiographs document progression [23, 32]. At least one spinal imaging examination in childhood is recommended [35].

5.4. Audiological and temporal bone assessment

Pure-tone audiometry with tympanometry shows conductive hearing loss with an intact membrane, a normal tympanogram and an absent stapedial reflex; otoacoustic emissions are absent [23, 70]. High-resolution CT of the petrous bones is often normal, but may show narrowing of the oval window, stapes deformity, an enlarged incus, an elongated stapes superstructure or indistinctness of the incudomalleolar joint, and is useful for planning the prosthesis and for excluding other causes [70, 94, 105]. In a Chinese series of 98 patients with conductive or mixed hearing loss, temporal bone anomalies on CT were absent in NOG-SSD, unlike branchio-oto-renal syndrome (87.5%) [40]. Surgical inspection confirms the fixed footplate. None of these examinations is specific: otosclerosis gives the same audiogram, and NOG-SSD overlaps clinically with 17q22 microdeletions [23]. The Teunissen and Cremers classification of congenital middle ear malformations, determined during surgery, organises the findings (section 7.3) [114].

5.5. Genetic testing

Genetic testing is the only means of distinguishing the forms from one another and of distinguishing syndromic stapes ankylosis from otosclerosis. In a Japanese series, none of 33 patients with typical otosclerosis without symphalangism had a NOG variant, whereas the three families with symphalangism did [42]. In the Chinese series of 98 patients, the genetic yield of next-generation sequencing was 96.6% in the syndromic forms (branchio-oto-renal syndrome, Treacher Collins, Van der Hoeve, NOG-SSD) and 1.5% in the non-syndromic forms; none of the 55 patients with otosclerosis had a genetic explanation [40]. The data indicate that testing should be targeted at patients with syndromic features, even mild ones.

The strategy depends on the clinical picture. With a typical NOG-SSD picture, NOG can be sequenced (a single-exon gene, simple sequencing) with deletion analysis; in current practice, a skeletal dysplasia, dysostosis or hearing loss panel that includes NOG, GDF5, FGF9, GDF6, BMPR1B, ROR2 and FLNB, with copy number variation (CNV) detection, is preferred [38, 41, 60]. With features not explained by NOG (intellectual disability, ADHD, malformations of other organs), chromosomal microarray is the first test [39, 99]. If the panel is negative, exome or genome sequencing increases the probability of diagnosis [38, 94].

5.6. Limitations of the tests

A negative result does not exclude the diagnosis. Panel and exome sequencing may fail to detect single-gene deletions, especially of a single-exon gene such as NOG, if CNV analysis has not been validated for that region; cryptic 17q22 deletions and apparently balanced translocations with a deletion at the breakpoint require microarray or genome sequencing [41, 88, 100]. Regulatory and structural alterations (such as the breakpoint 3' of GDF6 in the Australian family) escape sequencing of the coding regions [10]. Low-level mosaicism in a parent may not be detected in blood or buccal mucosa [112]. There are families with a complete phenotype and no variant in the known genes [84, 102]. The proportion of variants detectable by sequencing is not equivalent to the clinical sensitivity of the test, which has not been measured for any entity of the class.

5.7. Report and variant interpretation

The report should state the gene, the reference transcript with its version (for example, NM_005450.6 for NOG), the variant in HGVS nomenclature at the DNA and protein level, zygosity, the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) with the criteria applied, and the correspondence with the historical nomenclature when the variant was published under another designation [67, 68]. The ClinGen hearing loss expert panel specified the ACMG/AMP rules for hearing loss genes (three rules retained, four removed and 21 specified); in the pilot study, 19 of 51 variants (37%) changed category [115]. Two examples show the need to reassess published classifications. The variant c.291del p.(Ala98ArgfsTer26) was classified as of uncertain significance by the Croatian authors, who invoked nonsense-mediated decay, a mechanism that does not apply to a single-exon gene; moreover, the criteria that the authors themselves applied (PVS1, null variant in a gene in which loss of function is the disease mechanism; PM2, absence from population databases; PP4, specific phenotype) correspond, under the ACMG/AMP rules, to a classification of likely pathogenic [70]. The p.(Glu48Lys) variant, described as causal in SYM1 and BDB2, appears in ClinVar as of uncertain significance with a single submitter, and the p.(Arg204Gln) and p.(Ser185Cys) variants have conflicting classifications [67, 86, 89, 90]. With a variant of uncertain significance, segregation studies should include affected and unaffected relatives, taking variable expressivity into account, and targeted clinical assessment (audiometry, radiographs of the hands and feet) of so-called unaffected relatives is necessary before considering them phenotypically negative [23, 42].

5.8. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible; for the isolated brachydactylies, they are usually considered unnecessary, and for the syndromic forms counselling depends on the expected severity, which variable expressivity makes unpredictable [38, 89]. The sources consulted do not describe prenatal ultrasound diagnosis of the dominant forms of the class; ultrasound detected Grebe dysplasia at 21 weeks in a fetus of consanguineous parents [61], and a 17q22 deletion distal to NOG was diagnosed in a fetus with increased nuchal translucency [101].

5.9. Algorithm

Table 5.1. Diagnostic algorithm.

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of multiple synostoses, symphalangism and congenital stapes ankylosis.

6.2. Main differentials

The most important differential from the otological point of view is otosclerosis. Otosclerosis is an abnormal bone remodelling of the otic capsule, with a multifactorial model, nine loci of monogenic forms without identified causal genes and genomic associations such as that of RELN [135]. In the Japanese series of 33 patients operated on for otosclerosis, onset occurred between 15 and 57 years of age (mean 37.3), with 23 women and 10 men and bilateral forms in 24; all were sporadic, all had good surgical results and none had a NOG variant [42]. Onset in childhood, minor skeletal features and a dominant family history favour NOG-SSD; when hearing loss is only recognised in adulthood, the clinical distinction is difficult and the search for minor skeletal anomalies and genetic testing are decisive [42, 92]. The distance between the incus and the footplate, greater in NOG-SSD (4.62 mm in one case, compared with a mean of 3.72 ± 0.38 mm in 40 temporal bones with otosclerosis), is a difference with surgical consequences [41]. The Dutch family with SYNS4, in which four affected individuals had a diagnosis of "otosclerosis", shows that SYNS4 should also be considered [8].

From the skeletal point of view, the central differential is spondylocarpotarsal synostosis. In the recessive FLNB form, the almost constant core is disproportionate short stature, contiguous vertebral fusion and carpal synostosis (typically capitate-hamate), with variable tarsal fusion, hearing loss and facial dysmorphism, according to a systematic review of 11 publications published in 2026 [118]. Vertebral malsegmentation is more severe than in SYNS, with unsegmented bars and scoliosis, and there is no symphalangism [116, 117]. An AD form (mother and son) without a variant in NOG or FLNB showed additional heterogeneity [146]. The Bone Dysplasias atlas writes "FNLB" by typographical error, instead of FLNB [32].

The isolated brachydactylies are distinguished by the absence of synostoses and hearing loss and by Bell's radiological patterns [38]. ROR2 brachydactyly B1 has absent distal phalanges and a cleft distal phalanx of the thumb, with little disability; NOG BDB2 adds proximal symphalangism and carpal synostosis [55, 129]. Brachydactyly C is distinguished from A1 by sparing the proximal phalanx of the 4th finger, and from Catel-Manzke syndrome by the latter's supernumerary ossicle at the base of the index finger [130]. Short distal phalanges may also result from frostbite or electrical injuries, intrauterine exposure to phenytoin and acro-osteolyses [129]. Fetal hydantoin syndrome, which affects about 10% of fetuses exposed to phenytoin, includes among its occasional anomalies symphalangism, syndactyly and terminal transverse limb defects [147]. The small but structurally normal hands and feet of Prader-Willi syndrome, Smith-Magenis syndrome and uniparental disomy of chromosome 14 should not be confused with brachydactyly [38]. Brachydactyly C, due to heterozygous loss of function of GDF5, is highly variable: in the large Mormon family of Haws (86 affected among about 600 relatives examined), brachymesophalangy of the 2nd and 3rd fingers, hyperphalangism, triangulation of the middle phalanx of the 5th finger and symphalangism coexisted; four heterozygotes from three families had normal hands and feet; the homozygotes of a consanguineous Turkish family had the full picture and the heterozygotes only mild shortening of the 4th and 5th metacarpals, which suggests semidominance; and a de novo BMPR1B missense variant produced in a woman a brachydactyly C picture with SYM1 features, after coding variants of GDF5 and NOG had been excluded [131]. Entry %186400 brings together old familial descriptions without a molecular basis: Pearlman and colleagues (1964) observed in a mother and daughter multiple carpal and tarsal synostoses with radial head subluxation, aplasia or hypoplasia of the middle phalanges and metacarpophalangeal synostoses, a picture they likened to Nievergelt syndrome but which OMIM considers distinct; the same entry, whose alternative title is "calcaneonavicular coalition", includes families with massive tarsal synostosis, with calcaneonavicular coalition in three generations and with talocalcaneal coalition in a mother and three of eight children, which OMIM considers probably different from the common calcaneonavicular bars [22]. Without a published molecular study, the relationship of these families to the genetic forms of the class has not been established [3, 22].

Non-syndromic tarsal coalition is frequent (estimated incidence between 1% and 13%), bilateral in half of cases and, in 90%, calcaneonavicular or talocalcaneal, with symptoms in adolescence when the cartilaginous coalitions ossify [127]. The 2025 classification distinguishes developmental coalitions (double, triple, massive with more than three intertarsal joints or coalition outside the tarsus, and total) from syndromic coalitions, among which TCC, the phocomelias and the craniosynostoses [128]. A massive or total coalition, a tarsal coalition with carpal coalition or associated symphalangism point to a syndromic form [62, 128].

Liebenberg syndrome is a homeotic transformation of the upper limb due to ectopic activation of PITX1: the elbow resembles a knee and the carpal bones acquire the shape of tarsal bones, but the condition does not progress and the lower limbs are normal [21, 122]. The 17q22 microdeletion is distinguished by intellectual disability and anomalies of other organs, and should be sought by microarray [39, 99].

Brachydactyly A2 is genetically heterogeneous and directly involves the pathway of the class. It results from heterozygous BMPR1B variants (the first in two German families), from loss-of-function GDF5 variants, such as NM_000557.5:c.1322T>C p.(Leu441Pro), present in 22 members of the nine-generation Norwegian family of Mohr and Wriedt, three of them without signs, or from microduplications of an enhancer located about 110 kb downstream of BMP2, the first of which in a large Brazilian family of German ancestry described by Freire-Maia and colleagues in 1980 [132]. The BMPR1B variant NM_001203.3:c.1457G>A p.(Arg486Gln) gave typical brachydactyly A2 in a 26-month-old child and a brachydactyly C picture with SYM1 features in an unrelated adult woman, and the GDF5 missense variant NM_000557.5:c.1139G>A p.(Arg380Gln) produced in a six-generation family an overlap with brachydactylies A1 and C; the ligand–receptor–antagonist axis (GDF5, BMPR1B, noggin) thus generates a continuum between brachydactyly and symphalangism [132].

In two of the syndromes in which carpal or phalangeal fusion is a minor feature, the most serious consequences lie outside the skeleton. In Slovenian-type heart-hand syndrome, due to heterozygous LMNA variants, brachydactyly of the tubular bones (in the original family, mild in the hands and more marked in the feet, with terminal symphalangism, duplicated bases of the 2nd metatarsal and supernumerary ossicles) is accompanied by sinoatrial and atrioventricular conduction disease, dilated cardiomyopathy, sudden death from ventricular tachyarrhythmia and, sometimes, myopathy, with onset between the second and seventh decades; in a family of German and Irish ancestry, the hands were small from birth and there was syncope at 12 years, cardiogenic shock at 27 and sudden death at 23 [141]. In Steel syndrome, AR due to COL27A1, congenital dislocations of the hips (in all 32 patients of one series) and radial heads (29 of 32) are accompanied by carpal coalition in 73% of wrists, scoliosis in more than half, constant short stature and a long facies with a prominent forehead; hip surgery had poor results and unoperated patients had fewer limitations in daily activities [142]. Sugarman brachydactyly, described in a family of Cuban and Salvadoran origin, combines marked shortening of the proximal phalanges, absence of movement of the PIP joints, a double first metacarpal and an unarticulated hallux, implanted in a dorsal and proximal position; the original authors proposed AR inheritance and subsequent authors AD with reduced penetrance, and the sources do not resolve the divergence [143].

In spondylocarpotarsal synostosis, OMIM records only the AR form due to FLNB, caused by absence or truncation of filamin B due to nonsense or frameshift variants in homozygosity or compound heterozygosity; in a series of ten patients from seven families, aged between 7 months and 15 years, short stature ranged between −2.4 and −9.5 standard deviations, capitate-hamate fusion was present in nine, lunotriquetral fusion in three, tarsal fusion in five and scoliosis in nine, and contiguous vertebral fusion mainly affected T5–T7 [119]. There are descriptions of cervical instability (hypoplasia of the atlas and odontoid process with C2–C3 subluxation in a five-year-old child), of sensorineural or mixed hearing loss and of a consanguineous Brazilian family with five of ten children affected, two of them with lens opacities and retinal pigmentation changes of uncertain relationship to the syndrome; the forms with contractures and pterygia due to MYH3 have their own OMIM entries [119]. SAMS syndrome, due to homozygous truncating GSC variants or homozygous deletion of the gene, combines short stature, atresia of the external auditory canals with conductive hearing loss, severe mandibular hypoplasia with respiratory failure and feeding difficulty at birth, rhizomelic shortening, humeroscapular synostosis, hip dislocation, delayed ossification of the pubis and genital anomalies, and has been described in children of consanguineous Mennonite, Afghan, Pakistani and Bengali couples [125]. Giuffrè-Tsukahara syndrome (radioulnar synostosis with microcephaly) has no identified gene and the mode of transmission has not been established: the original Italian families suggested AD inheritance, a female patient born to first cousins suggested AR inheritance and a mother and son with skewed X inactivation suggested X-linked semidominant transmission; in one patient, the radioulnar synostosis recurred between 4 and 6 years of age after surgical correction performed at two and a half years [124]. The designation "Tsukahara syndrome" also applies to a different entity, with brachydactyly A1, hearing loss and ptosis (OMIM 613627) [124].

In Liebenberg syndrome, the original South African family had ten affected individuals in five generations, with triquetral-pisiform fusion and dysplasia of all components of the elbow, without tarsal coalition or other fusions; the causal rearrangements identified are deletions of 107 and 134 kb that include H2AFY and bring an enhancer (hs1473) closer to PITX1, a translocation t(5;18)(q31.1;q12.3) in twins that places chromosome 18 enhancers upstream of the gene, and an 8.5 kb deletion of the first exon of H2AFY in an Italian family with mild expression, whose promoter normally insulates PITX1 from the Pen enhancer [123]. This Italian family had been proposed as an allelic form of NOG, a hypothesis that the demonstration of the rearrangement near PITX1 ruled out [123]. In Klippel-Feil syndrome, hearing loss is frequent and of variable type: in a series of 44 patients, 35 (80%) had audiological abnormalities, sensorineural in 15, mixed in 10 and conductive in 7, so the type of hearing loss does not separate Klippel-Feil syndrome from the forms of the class [78].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment that prevents or reverses the joint fusions, nor any guideline or consensus specific to any entity of the class; the available recommendations derive from case series, histopathological studies and reviews [23, 25, 35, 41]. Management is symptomatic and multidisciplinary, with four axes: hearing (otolaryngology and audiology), vision (ophthalmology), the locomotor system (paediatric and adult orthopaedics, hand and foot surgery) and the spine (spinal orthopaedics and neurosurgery). The register of guidelines consulted contains only documents of general scope: the 2022 American College of Medical Genetics and Genomics (ACMG) clinical practice resource for the aetiological evaluation of hearing loss, of which only the abstract was read, and which states that identifying the aetiology may alter management, prognosis and counselling [148]; and the ACMG/AMP rules specified for hearing loss genes [115]. ClinGen has no actionability assertion for GDF5 [25].

7.2. Conductive hearing loss: options

The three options are conventional amplification, stapes surgery and, when surgery fails or is not possible, bone conduction devices or implantable prostheses [23, 42, 70]. Conventional hearing aids serve patients who cannot or do not wish to have surgery, young children and patients with a residual sensorineural component after surgery [70, 149]. The bone-anchored hearing aid is the alternative to be presented to patients with a NOG genotype before surgery, because the long-term surgical result is uncertain in some [42]. A 2020 Chinese review considered the results of otomicrosurgery "not encouraging" because of bony regrowth and emphasised regular follow-up and hearing aids; this opinion contrasts with the more recent surgical series, described in section 7.4 [88, 89, 102].

7.3. Teunissen-Cremers classification and choice of technique

The Teunissen and Cremers classification, built on 144 ears operated on in Nijmegen between 1964 and 1990 for congenital conductive hearing loss, is the reference for middle ear malformations and is determined during surgery [114, 149]. NOG-SSD usually corresponds to classes 1 and 2, because stapes ankylosis may be accompanied by fixation of the incus or malleus [41, 94, 97].

Table 7.1. Teunissen-Cremers classification and corresponding technique.

In a Korean cohort of 49 ears with class 3 malformations (not specific to NOG, 2012–2024), closure of the air-bone gap to 10 dB or less was achieved in 80.8% of ears with a viable superstructure and in 52.2% of non-viable ones (p = 0.033), with no difference in complications [151]. In a multicentre Turkish series of 51 patients with congenital ossicular chain anomalies, also not specific to NOG, transcanal endoscopic surgery reduced the air-bone gap from 42.5 ± 10.9 to 20.3 ± 12.3 dB, without intraoperative complications, with five revisions for recurrence [152]. Endoscopic surgery gives hearing results comparable to those of microscopic surgery [149].

7.4. Stapes surgery in NOG-SSD

Planning. High-resolution CT of the petrous bones is useful for anticipating the choice of prosthesis [94]. In the temporal bone with NOG-SSD, the distance between the incus and the footplate is greater than in otosclerosis (4.62 mm in one case, more than 2.4 standard deviations above the mean of 3.72 ± 0.38 mm of 40 temporal bones with otosclerosis); the prostheses required in the patients operated on ranged between 4.5 and 5.5 mm, whereas most patients with otosclerosis use a conventional 4.25 mm prosthesis or a 4.5 mm shape-memory alloy prosthesis [41]. Four recommendations from the authors follow: have longer stapes prostheses available before surgery; consider a malleus-attachment prosthesis, available in longer lengths, when no incus-attachment prosthesis of about 5.25 mm is available; assess the mobility of the malleus-incus complex before stapedotomy; and, if the ankylosis extends beyond the stapes, consider an atticotomy [41]. A prosthesis that is too long causes severe vertigo, and one that is too short conducts sound poorly or becomes displaced [41]. A thickened long process of the incus makes clip and loop prostheses and crimping tools difficult to use [94].

Technique and timing. The series describe stapedotomy with a CO2 laser or a manual perforator and a fluoroplastic or Teflon piston, with mobilisation of the incus when it is fixed [42, 70, 94]. Bilateral surgery is performed in separate stages (six months in the Croatian case and five months in the North American case), and simultaneous bilateral surgery is not recommended [70, 94]. Given the high success rate in SABTT, the Japanese authors advocate early intervention to minimise the effect of hearing loss at school age [36]; in the North American family, the child was operated on at 7 and 8 years of age [41].

Results. Table 7.2 summarises the series with results.

Table 7.2. Results of middle ear surgery in NOG-related conductive hearing loss (observational studies).

The results diverge. The Michigan series described refixation in all those operated on with initial success, attributed to excessive bone growth [105]; the Japanese, Danish, Korean and Croatian series described lasting results in most, with late refixation in 2 of 7 patients in one of them [42, 70, 85, 88, 102]. In a patient from the same Michigan family, histopathology showed that the poor result in the operated ear was explained by previous fenestration, absence of the incus and fibroadipose tissue, and that the unoperated ear had a normal cochlea and spiral ganglion, which would have made a good result from stapedectomy predictable [45]. The complications described include bony reclosure of the oval window, piston displacement, excessive perilymph leakage and, in a few cases, progressive postoperative sensorineural hearing loss attributed to a perilymphatic fistula [70]. In all series, the result should be followed up in the long term, and the limitations and alternatives should be explained before surgery [42].

7.5. Vision

Hypermetropia, which may be severe and associated with strabismus, is corrected with glasses; in the North American child with +8 dioptres, glasses also corrected the strabismus [37, 41]. The sources consulted do not describe specific treatment of the lens opacities described in one family [47].

7.6. Hands, feet and large joints

Joint ankylosis is difficult to treat and cannot be modified [32, 35]. Attempts to create interphalangeal joints surgically in symphalangism have not been successful, according to a 1979 review of surgery for hand malformations [12]. In the French series, foot deformities had the greatest impact on quality of life; four of the 14 patients underwent surgery for tarsal synostoses, and the authors concluded that surgical arthrodesis to treat pain may have reasonable results and that, as the ankylosis is not treatable, physiotherapy is not recommended [35]. In a case of TCC with massive coalitions and pes varus, treatment was aimed at symptomatic relief, surgery was reserved for that purpose and appropriate rehabilitation gave satisfactory results, with prolonged follow-up for possible progression [104]. In non-syndromic tarsal coalition, conservative treatment of mild to moderate symptoms includes analgesia, immobilisation in a short cast or walking boot, physiotherapy, custom orthoses and activity modification, with limited data and without resolution of symptoms in most; corticosteroid injections do not reduce the need for surgery; the surgical gold standard is open resection with autologous fat interposition, with success rates of 79% (95% confidence interval, 95% CI, 75–83) in talocalcaneal coalition and 81% (75–85) in calcaneonavicular coalition in a systematic review of 1284 feet, and complications of 4% and 6%; arthroscopy had more revisions in calcaneonavicular coalition (15% versus 2%), and arthrodesis is reserved for failure or severe joint degeneration [127]. These results refer to isolated coalitions; in the massive coalitions of the syndromic forms, resection is often unfeasible, and arthrodesis or symptomatic treatment are the options described [35, 104]. In SYNS3, several patients underwent surgery on the thumbs in childhood, on valgus halluces and on calcaneonavicular coalitions in adolescence, without outcome data [5]. A 2026 review of congenital toe deformities includes symphalangism, but only the abstract was read [154]. The sources consulted do not describe results of surgery for elbow synostosis in the forms of the class.

7.7. Spine and neurosurgery

Spinal cord compression due to canal stenosis or vertebral fusions may require decompression surgery [32]. At least one spinal imaging examination in childhood is recommended, because of the risk of neurological complications [35], and it is advisable to weigh the risk of cervical or lumbar injury in certain sports when there is stenosis [51]. The sources consulted do not describe spinal surgical series in this class.

7.8. Analgesia

No drug has an approved indication or a published dose for the pain of synostoses or syndromic coalitions. Analgesia is one of the conservative measures for tarsal coalition [127], and recurrent pain in fused joints has been described in NOG-SSD [35, 103]. In the absence of a specific dose, the reference is the official label of a non-steroidal anti-inflammatory drug (NSAID) indicated for mild to moderate pain and arthropathies, ibuprofen; its application to this class is an extrapolation. The label consulted is that of the United States Food and Drug Administration (FDA) for the 100 mg/5 mL oral suspension of a generic medicinal product (text effective 15 July 2026); trade names by jurisdiction and the European or INFARMED Summary of Product Characteristics (SmPC) were not consulted [155].

Table 7.3. Ibuprofen: FDA label dosage applied by extrapolation to the pain of synostoses.

7.9. Regulatory status

Table 7.4. Regulatory status of treatments.

7.10. Clinical trials and limits of the evidence

A ClinicalTrials.gov search in October 2026 (terms "symphalangism", "multiple synostoses", "NOG", "GDF6", "tarsal coalition", "stapes fixation", "congenital stapes") found no trial directed at the entities of the class; the results were tangential: a cone-beam CT study in the diagnosis and surgery of otosclerosis and stapes fixation (NCT05921578, active, not recruiting), a study of clinical assessment and surgical results in tarsal coalition (NCT04894942) and an antisense oligonucleotide trial in FGFR-related syndromic craniosynostoses (NCT07535372, out of scope) [156]. A negative search does not demonstrate the absence of studies.

Table 7.5. Studies with available treatment outcomes (no randomised trials).

All the evidence is observational, retrospective and from single centres or few families, with selection of operated patients, heterogeneous follow-up and non-standardised audiometric outcomes. The series of middle ear malformations and non-syndromic coalitions include few or no patients with a NOG variant, and their results cannot be transposed directly; figures from different series should not be compared with one another. There are no published negative series other than the Michigan family with universal refixation [105].

7.11. Developments in the last 6 to 12 months

Table 7.6. Publications between October 2025 and October 2026 and level of evidence.

There were no marketing authorisation applications, regulatory opinions, trials or new pharmacological therapies for the class in this period [156]. Therapeutic interest related to this pathway is only preclinical: the noggin-resistant GDF5 variants identified in patients with SYNS have been studied as ligands of greater chondrogenic potency, and one of them (N445T) has been the subject of a patent for regenerative medicine [34].

7.12. Agents to avoid, pregnancy, lactation, perioperative care and transition

No drugs are contraindicated by the disease. NSAIDs follow the general contraindications of the label; in pregnancy, the FDA label requires limiting the dose and duration between 20 and 30 weeks and avoiding ibuprofen from 30 weeks onwards, because of the risk of premature closure of the ductus arteriosus and of fetal renal dysfunction with oligohydramnios, and during lactation it recommends weighing discontinuation of the drug or of breastfeeding, because excretion in milk has not been established [155]. The sources consulted do not describe pregnancy or delivery in women with the disease; lumbar fusions and canal stenosis are relevant to the planning of neuraxial anaesthesia, by extrapolation from the vertebral findings [32, 51].

In the perioperative setting, cervical fusions (C2–C3 in a child, C2–C7 in an adult of the Australian family) and cervical canal stenosis limit neck extension and increase the risk of spinal cord injury during intubation; the literature consulted contains no anaesthesia series, and this recommendation is an extrapolation from the published vertebral findings [10, 41, 51]. Assessment of the cervical spine before any general anaesthesia is prudent in patients with known cervical fusions or cervical stiffness. In stapes surgery, availability of long prostheses and assessment of malleus and incus mobility are part of the preparation [41].

Transition to adult life should ensure continuity of audiological follow-up, because refixation after surgery may occur 3 to 10 years later and hearing loss in some forms (SYNS4) only appears after 40 years of age, and of orthopaedic and spinal follow-up, because the fusions continue to progress in adults [7, 35, 42]. The sources consulted do not describe specific transition programmes.

7.13. Available recommendations and divergences

Table 7.7. Recommendations from the sources and divergences.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All entities of the class are autosomal dominant. A heterozygous carrier transmits the variant to each child with a probability of 50%, regardless of sex [32, 37]. Severity in the child cannot be predicted from that of the parent: within the same family, the same variant produces anything from isolated conductive hearing loss to multiple synostoses, and the historical labels do not predict individual features [23, 98]. Penetrance is high in the families studied, but expression may be minimal, so an apparently unaffected parent should be examined (hands, feet, nasal profile, audiometry) before being considered a non-carrier [5, 45, 64]. In the isolated forms of brachydactyly, most cases have a family history and there may be incomplete penetrance [38].

De novo variants are frequent in the NOG forms: the first molecular study included a de novo case, the p.(Leu14Pro) variant arose de novo in the mother of a North American family, and several sporadic cases of SYM1, SYNS1 and SABTT have been published; therefore, a sporadic case should also be investigated [41, 42, 53]. When the parents of a de novo case do not have the variant in blood, the recurrence risk for siblings is low but not zero, because of germline mosaicism: two Belgian siblings with carpal and tarsal synostoses had the same double NOG variant, absent from the blood and buccal mucosa of both parents, which indicates low-level gonadal or somatic mosaicism in one of them [112]. The sources consulted do not quantify this risk.

In the recessive forms of the GDF5 and BMPR1B allelic series (Grebe, Hunter-Thompson, Du Pan), the risk for siblings of an affected individual is 25%, and heterozygotes may have brachydactyly C or normal hands [61]. In 17q22 microdeletions, most cases are de novo, but a female patient with a 1.34 Mb deletion had an affected mother, and a balanced translocation in a parent increases the risk of an unbalanced deletion in the offspring [39, 100].

8.2. Cascade testing

Once the variant has been identified in the index case, targeted testing of parents, siblings and children allows recognition of carriers with minimal expression and allows them to be offered audiological, ophthalmological and radiological assessment [42, 64]. In at-risk children, periodic audiological assessment is justified even with normal newborn screening, and knowledge of the genotype allows intervention before school age [36]. The genotype may also guide surgery, as shown by the exclusion of p.(Pro170Leu) carriers at a Korean centre [88].

8.3. Prenatal and preimplantation diagnosis

With the familial variant known, prenatal diagnosis and preimplantation genetic testing are technically possible and have been mentioned as a prevention option in a Chinese review [38, 89]. For the isolated brachydactylies, prenatal diagnosis is not usually requested or considered appropriate; in the syndromic forms, the decision depends on the expected severity, which variable expressivity makes unpredictable, and on the value the couple attaches to a condition compatible with normal intelligence and a life expectancy with no described reduction [5, 38]. Ultrasound detected Grebe dysplasia at 21 weeks in a fetus of consanguineous parents [61].

8.4. Content of counselling and minors

Counselling should explain dominant inheritance, variable expressivity and the impossibility of predicting severity, the progressive nature of the fusions, the possibility of late-onset hearing loss or of refixation after surgery, the cervical risk in contact sports when there is stenosis and the availability of effective treatment for hearing loss and hypermetropia [35, 42, 51]. Testing of asymptomatic at-risk minors is justified, because there are surveillance measures with benefit in childhood (audiometry, refraction, spinal imaging) [35–37].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no population-based prevalence study for any entity of the class. Orphanet places SYNS, TCC and SABTT in the prevalence class below 1 per 1,000,000 and counts about 30, 10 and 6 cases or families, respectively; the prevalence of proximal symphalangism is unknown [2, 13, 16, 18]. The prevalence class is an upper limit derived from counts of published cases, not a measured rate, and the Orphanet counts are out of date compared with the literature: more than 60 NOG variants in 2021, 47 individuals with SYNS3 in seven families in 2023 and five families with SYNS4 [5, 23, 41]. Syndromic stapes ankylosis is a small fraction of the congenital ossicular chain anomalies, which account for 0.5–1.2% of conductive hearing losses according to the literature cited by Zrno and colleagues [70]. Non-syndromic tarsal coalition, by contrast, is frequent (1–13%) [127].

9.2. Geography, ancestry and founder effect

The published families are distributed across all continents and no founder variant has been demonstrated [42]. In the United States, the families from Utah (TCC), Michigan (SABTT), Hawaii (SYNS1), Washington and Houston provided the first clinical and otological studies [46, 53, 54, 94, 108]. In Europe, there are families published in the Netherlands (Nijmegen and Utrecht), Belgium (Antwerp and Leuven), Denmark, Norway, Germany (Aachen and Düsseldorf), the United Kingdom (Edinburgh and London), France (Paris), Spain (Madrid, with the ECEMC network and CIBERER), Croatia, Sweden and Italy [5, 8, 9, 35, 39, 60, 62, 70, 75, 85, 91, 93, 97, 106, 112, 158]. In Asia, the largest series come from Japan, China and Korea [42, 59, 88, 89, 98, 102]. Some families are very large, but they correspond to isolated lineages and not to founder populations: 58 affected individuals over five generations in Iran (GDF5 p.(Ser475Asn)), 29 affected over five generations in Germany (FGF9 p.(Trp144Arg)), 12 affected in China (FGF9 p.(Ser99Asn)) and two five-generation Chinese families (GDF5 p.(Glu491Lys)) [5, 57, 59, 73]. Recurrence of the same variant in families of different origins, such as GDF5 p.(Ser475Asn) in China and Iran, or NOG p.(Pro35Ser) and p.(Trp205Cys) in several origins, indicates mutational hotspots and not a founder effect [42, 72, 73]. A demonstrated founder effect exists in one differential, Steel syndrome: the COL27A1 variant NM_032888.4:c.2089G>C p.(Gly697Arg) has an estimated carrier frequency of 1 in 51 among people born in Puerto Rico, 1 in 9 among those born in St. Thomas and 1 in 346 in the Hispanic and Latino population of the United States, arose on an Amerindian haplotype and, in New York cohorts of Puerto Rican ancestry (4,397 people), revealed five adult homozygotes without a previous clinical diagnosis, all with short stature and hip dislocation, and 105 heterozygotes, who had neither short stature nor dislocations [142]. The OMIM entries add families of other origins: the large Hawaiian family descended from a Cherokee Indian, Ashkenazi families with SYNS2 and with SABTT, a Japanese family with SYNS1, a Danish family with talocalcaneal coalition and families of Italian origin with stapes ankylosis [1, 3, 15, 17]. The sources consulted contain no data from Portugal. From Brazil, OMIM records a large family with 28 cases of multiple synostoses with AD transmission (Da-Silva and colleagues, 1984), without molecular characterisation in the sources read; the other Brazilian data point is historical and refers to Grebe dysplasia, described by Quelce-Salgado in 1964 as "Brazilian achondrogenesis" [1, 61]. Among the differentials, OMIM also records a large Brazilian family of German ancestry with brachydactyly A2 due to a duplication downstream of BMP2 and a consanguineous Brazilian family with spondylocarpotarsal synostosis [119, 132]. This absence in the sources consulted does not demonstrate that there are no cases in these countries.

9.3. Special populations

In children, hearing loss may not be detected by newborn screening and may appear up to school age, which justifies audiological surveillance in affected families [36, 95]. The stature of children with a NOG variant may be tall and appendicular bone mineral content low, tending to normalise in adulthood [93, 106]. In adults, the hearing loss of SYNS4 may appear after 40 years of age, and hearing loss associated with otosclerosis occurred only in the women of the Australian family [7, 10]. Athletes with cervical canal stenosis are at risk of spinal cord injury [51]. The sources consulted do not describe specific data on pregnancy or the elderly.

9.4. European reference networks, resources and organisations

The European Reference Network on Rare Bone Diseases (ERN BOND), coordinated by the Istituto Ortopedico Rizzoli in Bologna, covers the skeletal dysplasias and dysostoses; the skeletal dysplasia unit of La Paz University Hospital, in Madrid, which published two of the families with SYNS3, is a centre of the network [43, 76, 96]. ERN CRANIO covers rare craniofacial anomalies and ear, nose and throat disorders and is the relevant network for the conductive hearing loss and the craniosynostosis of SYNS3 [44]. The authors of the German SYNS3 family belong to ERN ITHACA, the network for rare congenital malformations and intellectual disability [5]. The NOG-specific LOVD database (https://NOG.lovd.nl) brings together the published variants [24]. The sources consulted did not identify patient organisations specific to NOG-SSD or the multiple synostoses; the Oxford Desk Reference lists, for the brachydactylies, the British organisation Contact a Family [38].

10. Illustrative Clinical Case

10.1. Bilateral conductive hearing loss due to a NOG initiation codon variant

A 35-year-old Caucasian man was referred to a university centre in Houston (Texas, United States) for bilateral conductive hearing loss progressive since early childhood; at ten years of age he had had an audiogram, without imaging [94]. His history included an abdominal lipoma, open-heart surgery at five years of age for an aortic valve anomaly, excision of a wrist ganglion and fractures of the shoulder and ankle in sports injuries, which the authors did not attribute to the phenotype; he had no ophthalmological history. His father and paternal grandfather had hearing loss, and the grandfather had symphalangism of both fifth fingers, unlike the father. On examination, there was symphalangism of only the two fifth fingers, without proximal symphalangism of the other fingers or brachydactyly; the tympanic membranes were normal and the malleus moved on pneumatic otoscopy. Pure-tone audiometry showed moderate bilateral conductive hearing loss, rising to mild at high frequencies (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC6679842/figure/fig1/), with speech reception thresholds of 45 dB on the right and 40 dB on the left, discrimination of 90% and 100% at 70 dB HL, normal tympanic mobility and absent ipsilateral and contralateral stapedial reflexes. CT of the temporal bones showed an enlarged incus with possible bilateral fixation, an elongated stapes superstructure (about 4.5 mm on the right and 4.8 mm on the left), thickening of the long process of the incus and thinning of the tegmen mastoideum without herniation (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC6679842/figure/fig2/) [94].

At surgery on the right ear, the incus was enlarged and slightly fixed and the stapes fixed; the incus was mobilised by gentle traction between the body and the attic wall, and a CO2 laser stapedotomy was performed, with a 5 mm Richards piston over a fascia seal of the oval window. Pure-tone and speech thresholds improved, with near closure of the air-bone gap (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC6679842/figure/fig3/). Five months later, the left ear showed identical findings, with an exceptionally high stapes and a thickened long process of the incus; the Robinson prosthesis initially chosen did not seat on the enlarged lenticular process and was replaced by a 5.5 mm Causse piston. The patient did not have an audiogram after the second operation, but reported improved and symmetrical hearing [94]. Exome sequencing (from saliva) identified in heterozygosity the NOG variant NM_005450.6:c.2T>C p.(Met1?), confirmed by Sanger sequencing, absent from gnomAD and classified as likely pathogenic according to the ACMG criteria; loss of the initiation codon prevents translation of normal noggin [68, 94]. Relatives were not available for testing.

10.2. Lessons from the case

The case brings together four points that recur in the literature. The skeletal phenotype was minimal (symphalangism of two fingers) and would have gone unnoticed without a targeted examination of the hands, which corresponds to the profile of SABTT or mild SYM1 and shows that conductive hearing loss may be the dominant manifestation [42, 94]. Expression was variable between generations: the grandfather had symphalangism and the father did not, but both had hearing loss [94]. The ankylosis was not limited to the stapes: the incus was fixed and enlarged and the stapes superstructure was elongated, which required 5 and 5.5 mm pistons, longer than those used in otosclerosis, in agreement with the measurements of Carlson and colleagues [41, 94]. And preoperative CT, although not diagnostic, made it possible to anticipate the need for long prostheses [94]. The management described (bilateral surgery in separate stages, with mobilisation of the incus) is that of one centre and one patient, and does not constitute a protocol; audiometric follow-up after the second operation was not obtained.

10.3. Complementary case with mixed hearing loss

In Zagreb, a seven-year-old girl with bilateral hearing loss detected at two years of age and progressive worsening despite hearing aids had the same facies as her mother (hemicylindrical nose), hypermetropia, strabismus, broad thumbs and halluces and partial syndactyly of the 2nd and 3rd toes. Her mother had undergone surgery at 25 years of age for bilateral stapes ankylosis, with complete closure of the air-bone gap for 10 years, but continued to use hearing aids because of the sensorineural component. Clinical exome sequencing identified NM_005450.6:c.291del p.(Ala98ArgfsTer26) in mother and daughter. The daughter had thresholds of 70–90 dB on the left and 50–80 dB on the right, with an air-bone gap of 30–40 dB, absent reflexes and otoacoustic emissions and normal CT and magnetic resonance imaging; she underwent surgery on both ears six months apart, with isolated stapes ankylosis, stapedotomy with a manual perforator and a fluoroplastic piston, without perilymph gusher, and complete closure of the air-bone gap, stable at one year [70]. The case shows that surgery resolves the conductive component but not the sensorineural one, whose origin in NOG-SSD remains uncertain.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Intelligence is normal in the monogenic forms, except in 17q22 microdeletions that include other genes, and the sources consulted do not describe reduced life expectancy [5, 32, 99]. Functional prognosis depends on three factors. The first is progression of the fusions: in the French series, radiological progression was observed in all adults, and foot deformities were the main determinant of quality of life [35]; in SYNS3, radiological progression in childhood was not accompanied by progression reported by the patients [5]. The second is hearing: conductive hearing loss is treatable with surgery or amplification, with lasting results in most series but with refixation in 2 of 7 patients in a Japanese series (3 to 10 years later) and in all those operated on in a Michigan family (within 2 years), and the sensorineural component, when present, persists [42, 70, 105]. The third is the spine: canal stenosis and cervical fusions expose the patient to spinal cord compression, which is the most serious complication described [32, 51]. The sources do not give probabilities of each outcome by age.

11.2. Surveillance

The sources consulted do not define validated surveillance intervals for any entity of the class; Table 11.1 indicates the recommended examinations and the starting point described in the sources, and the intervals are left to the judgement of the team according to the findings.

Table 11.1. Recommended surveillance.

11.3. Long-term follow-up

Follow-up should be shared between the otolaryngologist, ophthalmologist, orthopaedic surgeon and geneticist, with organised transition to adult services, because progression of the fusions continues after adolescence and some forms of hearing loss begin in adulthood [7, 35, 42]. Patients with cervical fusions or canal stenosis should know the signs of spinal cord compression and the risk of cervical trauma [51].

12. Summary and Final Considerations

Multiple synostoses, proximal symphalangism, tarsal-carpal coalition, stapes ankylosis with broad thumbs and toes and brachydactyly B2 form a class of autosomal dominant disorders of joint formation, caused by a relative excess of BMP/GDF signalling in the joint interzone: loss of function of the antagonist noggin (NOG), gain of function of the ligands GDF5 and GDF6 through resistance to noggin or altered receptor specificity, and a probably dominant-negative effect of FGF9 missense variants. The NOG-related entities constitute a continuous spectrum (NOG-SSD), in which the same variant produces different clinical labels and in which expressivity, not penetrance, explains the variability.

The condition is recognised by the combination of a stiff finger without an interphalangeal crease from birth, carpal and tarsal coalitions, elbow synostosis, vertebral fusions, conductive hearing loss with a normal tympanic membrane, hypermetropia and a hemicylindrical nose. SYNS3 is centred on the elbow and may be associated with craniosynostosis and cleft palate, with rare hearing loss; SYNS4 is centred on the carpus and tarsus, with variable conductive hearing loss and without the facial dysmorphism of the NOG forms. The divergence between Smith's and GeneGuidance on these two forms is resolved in favour of the descriptions of the published families, and the fusion of the stapes "to the round window" mentioned in Smith's has no support in the primary sources, which describe fixation of the footplate in the oval window.

Diagnosis rests on radiographs of the hands, feet, elbows and spine, audiometry and genetic testing by panel with CNV analysis, with microarray when there are features that NOG does not explain. Testing distinguishes syndromic stapes ankylosis from otosclerosis, which has no NOG variants, and guides surgery. A negative result does not exclude the diagnosis, because there is genetic heterogeneity yet to be identified.

There is no disease-modifying treatment or specific guideline. Conductive hearing loss is treated with stapedotomy, planned with prostheses longer than those used in otosclerosis and with assessment of incus and malleus mobility, or with amplification; results are lasting in most series, but late refixation justifies long-term follow-up. Hypermetropia is corrected with glasses. Painful foot fusions are treated symptomatically and, if necessary, by arthrodesis; physiotherapy does not modify the ankylosis. The spine should be studied at least once in childhood, because of the risk of stenosis and spinal cord compression. Genetic counselling should convey the 50% risk of transmission, the unpredictability of severity, the frequency of de novo variants and the possibility of germline mosaicism, and offer testing and audiological surveillance to at-risk relatives.

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