Klippel-Feil Syndrome

A class of malformations caused by congenital failure of segmentation of the cervical spine, isolated or syndromic, with four numbered monogenic forms (KFS1–KFS4: GDF6, MEOX1, GDF3, MYO18B), a recessive form linked to RIPPLY2 classified as spondylocostal dysostosis type 6, and Wildervanck cervico-oculo-acoustic syndrome as a syndromic form of unknown cause.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding description and evolution of the concept

In 1912, Maurice Klippel and André Feil published in the Nouvelle Iconographie de la Salpêtrière the case of a patient with a short neck, low posterior hairline and severe restriction of cervical mobility due to complete fusion of the cervical vertebrae, with a thoracic cage that, according to the title of the article, rose to the base of the skull [1, 46]. The original article was not read for this review; its citation and content come from Smith's Recognizable Patterns of Human Malformation and from secondary historical sources, which also mention a probable earlier description by Jonathan Hutchinson in 1893 and Feil's later thesis, which brought together 14 cases under the designation of numerical reduction of the cervical spine [46]. The combination of the three external signs (short neck, low hairline and limited mobility) became known as the classic triad. In 1919, Feil proposed the classification into three types that is still cited today, based on the extent of fusion and on the presence of segmentation defects in other segments of the spine [1, 35, 47].

Over the 20th century, orthopaedic series showed that the triad is the exception rather than the rule. Hensinger and colleagues, in 1974, described 50 patients and found that fewer than half had all three signs, that more than half had scoliosis and that one third had renal anomalies; they concluded that detection of one of the associated lesions should prompt a systematic search for the others [37]. In 1986, Bouwes Bavinck and Weaver proposed that the Poland sequence, the Möbius sequence and the Klippel-Feil anomaly share a vascular mechanism, disruption of the blood supply of the subclavian or vertebral artery or their branches around the 6th week of development, with the pattern of defects depending on the territory affected; this is a hypothesis rather than a demonstrated mechanism [48–50]. Tracy and colleagues summarised in 2004 the nosological doubt that persists: KFS brings together a heterogeneous group of patients unified only by a congenital defect of formation or segmentation of the cervical spine, and it is unclear whether it constitutes a discrete entity or a point on a spectrum of congenital spinal deformities [4].

1.2. From radiological anomaly to class of syndromes

The term Klippel-Feil anomaly (KFA) designates cervical vertebral fusion as a finding; the GeneReviews entry on spondylocostal dysostosis stresses that the designation is used broadly for diverse phenotypes [2]. The Oxford Desk Reference defines the anomaly as fusion of one or more cervical vertebrae, whereas the definition most used in clinical series requires fusion of at least two vertebral bodies, which is equivalent to one or more unsegmented intervertebral spaces [5, 40]. The difference is not trivial: an isolated block vertebra between C2 and C4, without other anomalies, is considered by some authors to be a variant rather than a syndrome, a debate expressed in a 2026 letter entitled "Isolated C2-C4 cervical block vertebra: not Klippel-Feil syndrome", of which only the title was read [51]. Smith treats the condition as a sequence, because the primary defect (the early abnormal development of the cervical vertebrae) explains the cascade of secondary changes, and notes that it may form part of severe disorders of neural tube development, such as iniencephaly, cervical meningomyelocele, syringomyelia or syringobulbia [1].

Recent literature suggests a higher prevalence than classically estimated, with a high proportion of asymptomatic people, owing mainly to the greater use of CT and MRI [5, 33]. The levels most affected are C2–C3 and C5–C6 [5, 43].

1.3. Molecular milestones

The first molecular clue came in 1995, when Clarke and colleagues described a family with AD KFS over four generations, carrying a paracentric inversion inv(8)(q22.2q23.3), with fusion always at C2–C3 and lesser expression at C4–C5 and C6–C7, associated with malformation of the laryngeal cartilages and vocal impairment [52]. Follow-up of the same family showed that the C2–C3 fusion forms after birth: in a new proband, vertebrae C2 and C3 were separate at 10 weeks of life, the space ossified progressively and fusion of the bodies was complete by 4 years; of the 11 relatives with radiographically confirmed C2–C3 fusion, 70% also had C4–C5 fusion with a free level in between and 20% had interspersed C2–C3, C4–C5 and C6–C7 fusions, and all those with two or more fusions had vocal impairment due to malformation of the laryngeal cartilages, as well as microtia, mild conductive hearing loss and limited supination and elbow flexion [14, 53]. Extended to five generations, the family also showed scoliosis, carpal and tarsal fusions and Sprengel anomaly in about half of those affected [14, 54]. In 2008, Tassabehji and colleagues identified variants at the GDF6 locus (8q22.1) in familial and sporadic cases, which defined KFS1 [54]. There followed GDF3 in 2010 (KFS3), described in patients with ocular and skeletal anomalies [55], and MEOX1 in 2013 (KFS2), identified independently in consanguineous Saudi and Turkish families, which established the first recessive form [56, 57]. In 2015, Alazami and colleagues associated biallelic null variants of MYO18B with a syndrome of Klippel-Feil anomaly, myopathy and characteristic facies (KFS4) [58], and Karaca and colleagues proposed RIPPLY2 as the gene of a new AR form of KFS, in a boy with situs inversus totalis [9]. At the same time, McInerney-Leo and colleagues linked RIPPLY2 to vertebral segmentation defects, and the entity was catalogued as spondylocostal dysostosis type 6 [7, 59].

1.4. Scope of the article and definition of each entity

This article covers the whole class uniformly. Isolated KFS (ORPHA:2345) is congenital fusion of cervical vertebrae without a recognisable syndrome, which may or may not have a monogenic cause [25]. KFS1 is the AD form attributed to GDF6, whose validity is disputed among curators and whose role the 2023 Nosology still considers unclear [8, 60]. KFS2 is the AR form due to biallelic loss of function of MEOX1, with fusions limited to the craniocervical and cervical region [56, 57]. KFS3 is the AD form attributed to GDF3, with incomplete penetrance and ocular overlap [31, 55]. KFS4 is the AR Klippel-Feil anomaly–myopathy–facial dysmorphism syndrome due to loss of function of MYO18B [58, 61]. The RIPPLY2-linked form (SCDO6, OMIM 616566) is an AR malformation of the posterior cervical and cervicothoracic spine, which GeneReviews considers might be better classified as a form of Klippel-Feil anomaly, whereas the Nosology keeps it in the group of spondylocostal dysostoses [2, 8]. Wildervanck syndrome (cervico-oculo-acoustic, OMIM 314600) combines KFA, Duane anomaly and deafness, has no known gene and is treated as a syndromic form and as a differential diagnosis [8, 32].

2. Molecular Genetics and Pathophysiology

2.1. Embryology of cervical segmentation

The vertebrae form from the somites, blocks of paraxial mesoderm that separate rhythmically under the control of a molecular oscillator (the segmentation clock) involving the Notch, Wnt and FGF pathways; each somite divides into a ventral compartment, the sclerotome, which gives rise to the vertebral body and arches, and the new vertebra results from fusion of the caudal half of one sclerotome with the cranial half of the next (resegmentation) [2, 62]. The critical period for KFS lies between the 3rd and 8th week of gestation, and the proposed aetiological hypotheses are abnormal somitic segmentation, vascular disruption, abnormal development of the neural tube and genetic factors [5, 35]. The genes of the class act at different points in this cascade: RIPPLY2 in the segmentation clock itself; MEOX1 in the specification and polarity of the sclerotome; GDF6 and GDF3 in the BMP signalling that defines the boundaries between skeletal elements; MYO18B outside the skeleton, in sarcomere assembly [12, 60, 62, 63].

2.2. GDF6 and KFS1

GDF6 (also called BMP13 or CDMP2; gene OMIM 601147; 8q22.1) encodes a secreted ligand of the TGF-β superfamily that signals through the BMPR1A, BMPR1B, BMPR2 and ACVR2A receptors, activates SMAD1/5/8 and is antagonised by noggin; it is required for the formation of joints and bones of the limbs, skull and axial skeleton, where it defines the boundaries between skeletal elements, and for retinal development [60]. Tassabehji and colleagues found that GDF6 is expressed at the boundaries of the developing carpals, tarsals and vertebrae and in the adult intervertebral disc, that the Gdf6-null mouse has carpal and tarsal fusions and that knockdown in Xenopus produces anterior axial defects [54]. In the same work, they described a recurrent missense variant at a conserved residue, associated with mirror movements, and a breakpoint of an inversion downstream of the gene in a family with carpal, tarsal and vertebral fusions [54]. In that family (Clarke's inversion family), the proximal breakpoint lies 623 kb 3′ of GDF6, in a region with long-range enhancers of the gene, and no coding variant of GDF6 was found; the distal breakpoint is intergenic [14]. In another three-generation family with AD KFS and C2–C3 fusion (Clarke class 2), affected members were heterozygous for p.Ala249Glu, which on the MANE transcript corresponds to NM_001001557.4:c.746C>A, p.(Ala249Glu) (GRCh38 NC_000008.11:g.96145185G>T, validated in VariantValidator); the two sporadic cases with p.(Leu289Pro) were an adult man with mirror movements, relative macrocephaly and left Sprengel anomaly, and a female fetus, whose pregnancy was terminated, with segmentation defects of the whole spine and ribs, failure of lumbar and sacral development, rocker-bottom feet, Chiari type II malformation and urological anomalies, both corresponding to Clarke class 1 [14, 64]. Neither variant was present in 708 control chromosomes, and the authors attributed the disease to functional haploinsufficiency; in the family with p.(Ala249Glu), the phenotype consisted mainly of fusion of the C2 and C3 bodies [20]. That variant corresponds to NM_001001557.4:c.866T>C, p.(Leu289Pro) (GRCh38 NC_000008.11:g.96145065A>G, validated in VariantValidator), and has conflicting classifications of pathogenicity in ClinVar for isolated microphthalmia with coloboma, isolated microphthalmia and KFS1, so it should not be presented as established pathogenic [64, 65]. In October 2026, ClinVar contained a single GDF6 variant classified as likely pathogenic for KFS1 — NM_001001557.4:c.986_1005del, p.(Pro329fs), from a single submitter — and dozens of variants of uncertain significance (VUS) submitted by panels [66].

Among the numbered forms, KFS1 is the one whose evidence is most debated: GeneGuidance curation notes that the evidence for GDF6 in this association is disputed among submitters, and the 2023 Nosology states that the role of GDF6 variants in KFS, as in AD spondylothoracic dysostosis, remains unclear [8, 60]. Loss of function of GDF6 has pleiotropic expression and incomplete penetrance. Asai-Coakwell and colleagues described an 8q21.2-q22.1 deletion encompassing GDF6 in a patient with chorioretinal coloboma and, later, seven heterozygous variants in patients with ocular and vertebral anomalies, with variable expressivity, incomplete penetrance and zebrafish and Gdf6+/− mouse models with variable ocular phenotypes [30, 67]. The patient with the deletion, with karyotype 46,XX,del(8)(q21.2q22.1) absent in both parents, had bilateral retinochoroidal colobomas involving the optic nerve and unilateral iris coloboma (acuity of counting fingers in one eye and 20/50 in the other), neurodevelopmental impairment (achievement quotient 74), bilateral cutaneous syndactyly between the 2nd and 3rd toes and atrial septal defect; the father, without complaints, showed on ophthalmological examination mild optic nerve dysplasia, anomalous retinal vascular branching and small retinochoroidal colobomas, and inhibition of gdf6a in zebrafish reproduced the phenotype, with microphthalmia and anophthalmia at the highest doses [20]. The screening covered 489 patients with ocular anomalies (microphthalmia, clinical anophthalmia and coloboma) and 81 with vertebral segmentation anomalies; the seven missense variants were found in nine patients: five with isolated microphthalmia, three with skeletal anomalies (among them one with spondylothoracic dysostosis and another with hemivertebra, rib malformations and horseshoe kidney) and one with coloboma and polydactyly; in the two microphthalmia cases with parental DNA available, the variant had been inherited from an unaffected parent, and none of the variants was present in 366 controls [14, 68]. The variants in this cohort, validated in VariantValidator on NM_001001557.4, include c.1271A>G, p.(Lys424Arg), in the patient with hemivertebrae, rib malformations and horseshoe kidney; c.125G>T, p.(Gly42Val), in the patient classified as having spondylothoracic dysostosis; c.758A>T, p.(Gln253Leu), in a patient with isolated microphthalmia and a single testis, inherited from the unaffected mother; and c.980C>A, p.(Pro327His), in a patient with unilateral microphthalmia, inherited from the father; p.(Ala249Glu) and p.(Lys424Arg) reduced reporter gene activity and the amount of mature ligand, which characterises them as hypomorphic alleles [20, 64]. The mouse with simultaneous loss of Gdf5 and Gdf6 has skeletal defects absent in the single mutants, with reduced or absent limb bones, unformed joints and severe scoliosis in 2 of 7 animals [14]. The catalogued ocular associations are isolated microphthalmia 4 (OMIM 613094), microphthalmia with coloboma 6 (OMIM 613703, of digenic inheritance) and Leber congenital amaurosis 17 (OMIM 615360, AR, the weakest). LCA17 rests on a single patient, found among 279 patients with Leber congenital amaurosis or juvenile retinitis pigmentosa without a cause in the known genes: compound heterozygous for NM_001001557.4:c.746C>A, p.(Ala249Glu) and c.169G>C, p.(Asp57His), she had vision limited to perception of hand movements and an extinguished electroretinogram, without other ocular or systemic findings, but without skeletal imaging; the clinically unaffected parents had subtle electroretinogram changes [64, 69]. In functional assays, p.(Asp57His) reduced the pre-proprotein and the mature ligand by 80% to 99%, depending on the cell fraction, and retained 24% of reporter activity, whereas p.(Ala249Glu) retained about 50%; p.(Asp57His) was absent in 1500 control chromosomes, but p.(Ala249Glu) was found in 4, a finding compatible with a hypomorphic allele with incomplete penetrance [20]. The same p.(Ala249Glu) had been found in the KFS family, in a patient with isolated microphthalmia and in a patient with coloboma and polydactyly without vertebral defects, and three other patients in the cohort were heterozygous for p.(Ala249Glu), c.595G>A, p.(Ala199Thr) or c.876G>T, p.(Glu292Asp) (MANE transcript, validated in VariantValidator) [64, 69]. The last two had been inherited from a clinically unaffected parent (p.(Ala199Thr) from the father, p.(Glu292Asp) from the mother) and, despite normal or increased protein expression, reduced reporter activation by 56% and 69%, respectively [20]. In the mouse heterozygous for deletion of exon 2 of Gdf6, the electroretinogram b-wave amplitude fell by up to 66% and that of the a-wave by up to 54%, and in zebrafish homozygous for gdf6 p.Ser55Ter retinal apoptosis was reversed by the anti-apoptotic compound P7C3 (preclinical data) [69]. In the historical GeneReviews chapter on microphthalmia, anophthalmia and coloboma, GDF6 accounted for about 1% of these cases [60, 70].

2.3. GDF6 allelism: two opposing dominant mechanisms

The same gene causes, by gain of function, multiple synostoses syndrome type 4 (SYNS4, OMIM 617898, AD), which is the GDF6 association with the strongest support in GenCC curation [60, 71]. Wang and colleagues described in 2016 a six-generation Chinese family, with 46 affected members, with the variant NM_001001557.4:c.1330T>A, p.(Tyr444Asn) (validated in VariantValidator), located at the binding interface between GDF6 and noggin and absent in 105 Chinese controls, bilateral carpal and tarsal synostoses from birth (on CT, absence of almost all intertarsal joints and fusion of all tarsometatarsal joints except cuboid–5th metatarsal, with pain and walking difficulty; hands of normal appearance, with variable carpal fusion on radiography) and progressive conductive deafness after the age of 40; the mutant protein has reduced sensitivity to noggin and greater potency as a BMP signal [20, 64, 72]. In C2C12 cells, the variant increased alkaline phosphatase activity and SMAD1/5/8 reporter activity and chondrogenic activity in limb bud cultures, and noggin, which inhibits normal GDF6 in a dose-dependent manner, had no effect on the mutant protein [20]. A second, four-generation family, with NM_001001557.4:c.1287C>A, p.(Ser429Arg) (in the C-terminal TGF-β domain; validated in VariantValidator), had mild to moderate hearing loss in at least 6 of 10 affected members, otosclerosis in 4 and severe stapes fixation at 6 years in one patient [73]. In this family, the cervical radiograph was normal in two affected members, and a third, aged 65, had only degenerative uncovertebral and intervertebral changes from C5 to C7, which separates SYNS4 from KFS; the ophthalmological examination, performed in three patients, was normal, except for mild Fuchs dystrophy in the oldest [74]. The mouse with the orthologous variant p.Tyr443Asn reproduces the fusions of the wrists, ankles, phalanges and ossicles [75]. The nosological table of multiple synostoses in Bone Dysplasias summarises this duality: GDF6 with gain of function causes SYNS4; GDF6 with loss of function causes microphthalmia and vertebral segmentation defects [76].

Long-range regulation of the gene adds further phenotypes. Clarke and colleagues described in 2021 a five-generation family with multiple synostoses and speech impairment due to reduced GDF6 expression (breakpoint 3′ of the gene): bilateral carpotarsal coalition in about half of those affected, otosclerosis only in women and vertebral fusion in all affected members, acquired after birth and progressive, from thinning of C2–C3 in infancy to block fusion of C2–C7 and T3–T7 [77]. Homozygous non-coding deletions of 221 kb and 338 kb, located about 350 kb downstream of GDF6, cause congenital non-syndromic profound sensorineural deafness with cochlear aplasia (DFNB118, OMIM 619553) in three patients from two families; a coding variant of GDF6 should not be interpreted as the cause of this form [60, 78]. The three patients were boys from consanguineous Turkish families (two cousins and one unrelated patient), with complete absence of the cochlea and a normal vestibular system on CT and MRI; the deletions overlap in a region of about 200 kb, were not present in 1025 Turkish controls or in the gnomAD, DGV and DECIPHER databases, and, of the 14 genes located within 1 Mb, only GDF6 had altered expression in early otic cells derived from the patients' stem cells; the Gdf6-null mouse has no cochlea and retains a normal vestibule [79]. In 2026, Zafeer and colleagues showed in mice, inner ear organoids and CRISPR interference that a distal enhancer-insulator module of GDF6 is essential for cochlear formation (preclinical work) [80]. In the same year, Bologa and colleagues analysed 30 published individuals and a Romanian patient with Nablus mask-like facial syndrome (8q22.1 microdeletions) and proposed, as a candidate mechanism, fusion of topologically associating domains bringing ultraconserved non-coding elements close to GDF6 [81]. The Nosology also lists Leri pleonosteosis, which OMIM designates 8q22.1 duplication syndrome, a third mechanism linked to GDF6 (increased dosage) [8, 82]. In the Hilton and Wentzel family, with seven affected members, the disease segregated with a heterozygous duplication of about 1 Mb, and the British proband of a second family had an overlapping duplication of 1.2 Mb; the common region, of 0.95 Mb, contains six genes, but in fibroblasts from two affected individuals, aged 77 and 20, only GDF6 was overexpressed in both (40.2-fold and 13.2-fold), whereas SDC2 was increased (2.8-fold) only in the older one; neither duplication was present in public databases or in 190 control microarrays [20, 82]. The phenotype is described in the differential diagnosis (section 6.4).

2.4. GDF3 and KFS3

GDF3 (gene OMIM 606522; 12p13.31) encodes another ligand of the TGF-β/BMP family, processed into a dimer, which signals through ACVR1B and ACVR1C with the co-receptor CRIPTO and is involved in early embryonic patterning and in ocular and skeletal development [11]. Ye and colleagues described in 2010 heterozygous missense variants in patients with microphthalmia, iris and retinal coloboma and Klippel-Feil anomaly with cervical fusion, scoliosis and rib anomalies; the effects were demonstrated by western blot, luciferase assays and knockdown in zebrafish, and one patient had heterozygous changes in both GDF3 and GDF6, which led the authors to consider multiallelic inheritance of BMP pathway variants [55]. In the screening of 449 probands with isolated microphthalmia or coloboma and 23 with skeletal or oculoskeletal phenotypes, microphthalmia with bilateral coloboma was associated with p.(Arg266Cys) in two probands and with NM_020634.3:c.820C>T, p.(Arg274Trp) (validated in VariantValidator) in a third; in one of the families with p.(Arg266Cys), the mother had mild iris colobomas, mild microphthalmia and visual acuity of 20/40, and the daughter, with nystagmus, severe colobomatous microphthalmia, foveal hypoplasia, small optic discs and acuity of 20/200, was also heterozygous for GDF6 NM_001001557.4:c.595G>A, p.(Ala199Thr), the basis for the digenic classification of microphthalmia with coloboma 6 [64, 83]. The family defining KFS3, North American and three-generation, segregated NM_020634.3:c.796C>T, p.(Arg266Cys) with the skeletal phenotype in four members: the proband had unilateral iris and retinal coloboma, rudimentary 12th ribs and mild scoliosis, the mother C5–C6 fusion, an aunt C3–C4 fusion and the grandfather thoracic and lumbar scoliosis; the variant, absent in 480 controls, adds a cysteine to the mature TGF-β domain and reduces secretion of the mature ligand in COS-7 cells [16, 22]. The same variant was found in a European man, the son of consanguineous parents, with isolated microphthalmia and bilateral coloboma, whose only bony change was an anomalous right temporal bone [22]. Isolated microphthalmia 7 rests on two probands with unilateral microphthalmia: an Asian boy, the son of consanguineous parents, with c.914T>C, p.(Leu305Pro), shared with his father without ocular anomalies (incomplete penetrance, without exclusion of digenic inheritance), and a patient of European ancestry with c.584G>A, p.(Arg195Gln), whose affected mother was not genotyped; both variants, validated in VariantValidator on NM_020634.3, reduced the amount of mature protein in COS-7 cells [22, 64, 84]. Knockdown of the orthologue dvr1 in zebrafish produced coloboma, small eyes and lenses and curvature and shortening of the tail [16]. OMIM lists three AD phenotypes for the gene: KFS3 (613702), microphthalmia with coloboma 6 (613703) and isolated microphthalmia 7 (613704) [11, 22]. The evidence is limited: there is no ClinGen curation, all GenCC submissions are graded Limited and Orphanet classifies the relationship as supportive [11]. Non-penetrance is documented: the variant NM_020634.3:c.796C>T, p.(Arg266Cys) was found in a woman with unilateral anophthalmia, kyphoscoliosis and other skeletal anomalies and in her mother, who was unaffected [31]. In ClinVar, in October 2026, the GDF3 variants associated with KFS3 were only VUS or likely benign, for example c.890G>T p.(Cys297Phe), c.236G>T p.(Arg79Leu) and c.958G>A p.(Val320Ile) [66].

2.5. MEOX1 and KFS2

MEOX1 (gene OMIM 600147; 17q21.31) encodes a homeodomain transcription factor expressed in the paraxial mesoderm, essential for development of the somites and, in particular, of the sclerotome; it maintains sclerotome polarity, activates NKX3-2 and is required for formation of the craniocervical joints [62]. The Meox1-null mouse has a cervical and craniocervical defect similar to the human one, and Mohamed and colleagues interpreted KFS2 as the human equivalent of a sclerotome polarity defect [56]. The meox1-deficient zebrafish has skeletal malformations resembling KFS (only the title of this work was read) [85].

Mohamed and colleagues studied a consanguineous Saudi family with several affected members and isolated KFS, with linkage to 17q21.31, in which they found a homozygous frameshift deletion, and a second consanguineous family with two siblings carrying a homozygous nonsense variant; in both, the transcript was completely degraded [56]. In the Saudi family, the 10-year-old proband had the complete triad, could not flex, extend or rotate her neck or bring her right hand to the back of her neck, and the skeletal survey showed C2–C3 fusion and Sprengel anomaly, without other defects; the only region of homozygosity shared solely by affected members lay on chromosome 17, and the deletion was absent in 210 Saudi controls [15, 21]. In the second family, with parents who were first cousins, the brother was born with Pierre Robin sequence and U-shaped cleft palate, repaired surgically, and had a short neck with very limited mobility, low hairline, scoliosis, ptosis, omovertebral bones, Sprengel anomaly and thoracic dextroscoliosis from T2 to T11; the sister had the same findings, without cleft palate [21]. The two variants correspond to NM_004527.4:c.94del, p.(Ala32ProfsTer165) (ClinVar VCV 39507, likely pathogenic) and NM_004527.4:c.664C>T, p.(Arg222Ter) (VCV 39508, likely pathogenic) [64, 66]. Simultaneously, Bayrakli and colleagues described a consanguineous Turkish family from western Turkey with seven affected members, linkage to 17q12-q33 (LOD 4.2) and a homozygous nonsense variant that the article designates "670G→A, Q84X" with transcript NM_001083961 [57]. Normalised in VariantValidator on the MANE transcript, the variant is NM_004527.4:c.250C>T, NP_004518.1:p.(Gln84Ter) (GRCh38 NC_000017.11:g.43661285G>A); the article's "G>A" notation describes the genomic strand, because the gene is on the reverse strand, and the numbering 670 is not the current cDNA numbering. In ClinVar, this variant (VCV 162132) is classified as pathogenic, without assertion criteria [64, 66]. The parents and an unaffected sibling were heterozygous, without phenotype, which is consistent with a loss-of-function mechanism without dominant effect [57]. ClinVar records other truncating MEOX1 variants classified as likely pathogenic or pathogenic for KFS2, such as c.268C>T p.(Gln90Ter), c.282G>A p.(Trp94Ter) and the missense c.514C>T p.(Arg172Cys) [66]. GenCC curation classifies the relationship as strong (Labcorp, G2P, PanelApp Australia) or moderate (Ambry), without ClinGen curation [62]. MEOX1 is a rare cause: in a Chinese cohort of 37 patients with KFS no pathogenic variant was found in the gene [86].

Before the gene was identified, the recessive form rested on affected siblings and consanguinity, without molecular study: two of 11 siblings with C5–C6 fusion and a third with narrowing of the intervertebral space, from probably consanguineous parents (Lubs, 1963); a patient of consanguineous parents with C1 anomalies, C2–C3 and C3–C4 fusions and hearing loss (Juberg and Gershanik, 1976); and a pedigree with four sibships, totalling seven affected women and five affected men, all children of unaffected first cousins, in which six had massive fusion of several cervical vertebrae and two had cervical, upper thoracic and lumbar fusions (da-Silva, 1982) [15]. The same OMIM entry gathers isolated reports with associated malformations, whose relationship with MEOX1 was not studied: bilateral agenesis of the ulna and ulnar ray in a female infant of Iraqi Jewish parents; frontonasal dysplasia with Sprengel anomaly, widely spaced nipples and postaxial polydactyly of one foot in an 8-year-old girl; the Clarke family in which the proband had C1–C4 and C5–C7 fusions, cleft palate, large pointed ears and ventricular septal defect, and the maternal grandmother cleft lip and palate without vertebral fusion; and a 7-year-old Turkish girl with C1–C2 fusion and Poland anomaly, without cardiac, vascular or renal anomalies [15]. A balanced de novo translocation t(5;17)(q11.2;q23) was described in a 6-year-old girl with a KFS-like phenotype (C5–C7 fusion, midface hypoplasia, micrognathia, brachydactyly and hypoplastic nails) and normal psychomotor development [15].

2.6. MYO18B and KFS4

MYO18B (gene OMIM 607295; 22q12.1) encodes an unconventional myosin with nucleocytoplasmic localisation, required for sarcomere assembly in fast skeletal muscle in animal models; its loss disorganises sarcomeres and gives rise to nemaline rods [12]. The gene has 43 exons spanning about 286 kb and encodes a protein of 2567 amino acids (about 285 kDa), with an N-terminal motor domain, an IQ motif and a tail with a coiled-coil domain allowing dimerisation; it is expressed mainly in skeletal muscle and heart and, in the myocyte, is located at and near the Z-lines [23]. The Myo18b-null mouse dies between embryonic days 10.5 and 13.5, with cardiac and ventral body wall haemorrhage or pericardial dilatation and disorganised assembly of cardiac sarcomeres; heterozygotes are healthy and fertile [23]. Alazami and colleagues described in 2015 two patients from two apparently unrelated consanguineous families, with Klippel-Feil anomaly, myopathy, mild short stature, microcephaly and characteristic facies, sharing a founder autozygous interval with a truncating MYO18B variant, almost complete loss of the transcript through nonsense-mediated decay and abnormal myosin filaments on electron microscopy [58]. Altuame and colleagues expanded the series to seven patients (six Saudi and one American of European ancestry), with the Saudi founder variant NM_032608.5:c.6905C>A, p.(Ser2302*) in the first six and c.6660_6670del, p.(Arg2220Serfs*74) in homozygosity in the American patient [61]. On the MANE transcript, the founder variant is NM_032608.7:c.6905C>A, NP_115997.5:p.(Ser2302Ter) (GRCh38 NC_000022.11:g.26026879C>A; ClinVar VCV 208842, pathogenic/likely pathogenic with several submitters); the deletion c.6660_6670del is VCV 590293, with the same classification [64, 66]. ClinVar gathers more than 35 truncating or splicing variants classified as pathogenic or likely pathogenic for this syndrome [66]. A homozygous nonsense variant in the last exon, with stable mRNA but no full-length protein, was found in a sporadic case of severe nemaline myopathy with cardiomyopathy, the severe end of the spectrum [87]. The patient was the daughter of consanguineous Portuguese parents and the variant, described as p.Glu2166Ter, corresponds on the MANE transcript to NM_032608.7:c.6496G>T, p.(Glu2166Ter) (validated in VariantValidator); the authors considered that the truncated protein detected in muscle might have a toxic effect, different from the complete loss in the Saudi patients, which would explain the cardiomyopathy [17, 64]. The variant lies in the last of the 42 coding exons, was not listed in the dbSNP, EVS and ExAC databases or in 676 in-house exomes, and the patient was part of an exome series of 34 patients with mild nemaline myopathy and 17 with the severe form, without variants in the main genes of this myopathy [23]. In a boy of consanguineous parents from Afghanistan, trio exome sequencing identified NM_032608.7:c.6433C>T, p.(Arg2145Ter) in homozygosity (validated in VariantValidator), with heterozygous parents, and in a 4-year-old boy of non-consanguineous parents of European ancestry, with KFS4 and medulloblastoma, compound heterozygous NM_032608.7:c.6768del, p.(Leu2257SerfsTer16), inherited from the mother, and c.6660_6670del, p.(Arg2220SerfsTer74), inherited from the father (validated in VariantValidator), were found, both in the penultimate exon [17, 23, 64]. On RNA sequencing, both variants were present in about half of the transcripts (48.5% and 50.0%), suggesting absence of nonsense-mediated decay in brain tissue, and MYO18B expression was higher in medulloblastoma, especially group 3, than in other paediatric central nervous system tumours [23]. The deletion c.6660_6670del is also the variant described in homozygosity in Altuame's American patient; the sources read do not indicate whether this is the same patient [23, 61]. In 2026, Zaharieva and colleagues described six patients from four families with early-onset myopathy, of whom only one had radiological KFS, which shows that cervical fusion is not required for the diagnosis of MYO18B-related disease [88]. Orphanet records two cases or families in the 2015 source and a prevalence below 1/1,000,000 [26]. The somatic role of MYO18B as a tumour suppressor in lung cancer has no significance for germline predisposition [12].

2.7. RIPPLY2: recessive KFS or spondylocostal dysostosis type 6

RIPPLY2 (gene OMIM 609891; 6q14.2) encodes a transcriptional repressor with the WRPW tetrapeptide, which recruits Groucho/TLE corepressors; in the segmentation clock, it binds the DNA-binding domain of TBX6, converts T-box proteins from activators into repressors and promotes degradation of TBX6 at the segment boundary, being in turn a direct transcriptional target of MESP2 and TBX6, in a negative feedback loop [9, 63]. The Ripply2−/− mouse has severe malformations of the vertebrae and ribs and dies in the perinatal period [9]. The human protein has 128 amino acids, with the WRPW tetrapeptide near the amino terminus and a Ripply homology domain of about 50 amino acids, and is expressed in the presomitic mesoderm during somite formation [24]. The homozygous mouse is born in the expected Mendelian proportion, but dies soon after birth without breathing, with a short tail, truncated axis, defects of the vertebral bodies, discs and neural arches, fused or absent pedicles and fused, bifurcated, asymmetric and fewer ribs, with normal skull and limbs and altered expression of Notch2 and Uncx4.1; in heterozygotes, a mild vertebral defect appeared in 1 of 33 embryos (0 of 40 in wild type), and brief maternal hypoxia did not significantly increase penetrance (4 of 30 versus 1 of 35) [24].

McInerney-Leo and colleagues described in 2015 two siblings compound heterozygous for p.(Arg80Ter) and c.240-4T>G (a rare variant, with allele frequency below 0.002, next to the splice acceptor site of the last exon), with failure of formation of the posterior elements from C1 to C4, descent of the occiput, and cervical and thoracic hemivertebrae and butterfly vertebra; the mutant protein had reduced repressive capacity in C2C12 myoblasts [59]. Among 991 individuals sequenced for other diseases there were no compound heterozygotes, and the probability of two rare variants coinciding by chance was estimated at 2.54 × 10⁻⁷; p.(Arg80Ter) eliminates the 49 C-terminal amino acids, including the Ripply homology domain required for binding to the T-box domain of TBX6, and the heterozygous maternal grandmother was unaffected, whereas the unaffected sister had neither variant [24]. Neither sibling had the cervical fusion typical of KFS [9]. In the same year, Karaca and colleagues described the case that prompted the proposal of an AR KFS linked to RIPPLY2 (see section 10) [9]. Serey-Gaut and colleagues studied in 2020 three patients from two families homozygous for c.240-4T>G, with complex cervicothoracic segmentation defects and major atlantoaxial malformation with risk to the spinal cord, and considered this pattern a discrete entity, distinct from classic KFS; one patient had overlap with the oculo-auriculo-vertebral spectrum [89]. The parents of these patients were heterozygous and the variant has a low allele frequency in gnomAD, with no homozygotes recorded [18]. Mokhateb-Rafii and colleagues had described in 2019 the same variant in homozygosity in a 7-year-old Salvadoran boy, the son of second cousins (without published segregation study) [18]. Wegler and colleagues added in 2021 two sisters aged 15 and 20 with p.(Arg80Ter) and c.240-4T>G and an 8-year-old boy homozygous for p.(Arg80Ter), with malformation of multiple cervical and thoracic vertebral bodies, small or absent rib involvement, myelopathy, scoliosis, spasticity and mild facial asymmetry; they classified the nonsense variant as likely pathogenic and the splicing variant as VUS [90]. In 2024, van der Vlis and colleagues described two Dutch siblings homozygous for p.(Arg80Ter) and, taking into account that Wegler's homozygous German boy also required cervical stabilisation, proposed that homozygosity for this variant is associated with a malformation pattern with a risk of progressive deformity and spinal cord injury [18].

Normalised in VariantValidator on the MANE transcript, the variants are NM_001009994.3:c.238A>T, p.(Arg80Ter) (NC_000006.12:g.83854160A>T; ClinVar VCV 221271, with conflicting classifications), NM_001009994.3:c.240-4T>G, p.? (NC_000006.12:g.83857238T>G) and NM_001009994.3:c.299del, NP_001009994.1:p.(Leu100ArgfsTer25) (NC_000006.12:g.83857301del; VCV 218314, likely pathogenic) [64, 66]. Karaca's variant is associated in ClinVar with the trait "Klippel-Feil syndrome 2, autosomal recessive", a label that in OMIM belongs to MEOX1; the designation KFS2 should not be used for RIPPLY2-related disease [7, 66]. In the gene entry, reviewed in October 2026, OMIM does not include c.299del in SCDO6 and classifies it as a variant of uncertain significance with respect to KFS, in the list of associations not yet confirmed, because its contribution to the disease has not been demonstrated; this position differs from ClinVar's likely pathogenic classification and is a reminder that the association of RIPPLY2 with KFS with situs inversus rests on a single patient [24, 66]. In 2026, an evidence-level assessment classified the biallelic RIPPLY2–SCDO6 relationship with a cervical or cervicothoracic phenotype as established, on the basis of six non-duplicated families, stressing that gene-disease validity does not settle the classification of each allele [13]. GeneReviews and Bone Dysplasias describe SCDO6 as similar to SCDO1 but extending to the cervical spine and without rib fusions; there are no known genotype-phenotype correlations and no deletions or duplications described in the gene [2, 91]. In AR spondylocostal dysostosis in general, DLL3 accounts for about 60% of cases, TBX6 for about 20% and HES7, LFNG, MESP2 and RIPPLY2 for about 5% each [63].

2.8. Other genes, oligogenism and copy number variation

Most patients with isolated KFS have no pathogenic variant in the numbered genes. In the Chinese cohort of Li and colleagues (37 patients, exome sequencing), the five known genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) showed only three VUS in MYO18B; rare variant burden analysis in 96 candidate segmentation genes highlighted BAZ1B, followed by FREM2, SUFU, VANGL1 and KMT2D, and seven patients had possible oligogenic inheritance, at a higher frequency than in-house controls [86]. In the sandwich fusion subtype (simultaneous C0–C1 and C2–C3 fusions), exome sequencing of 21 patients found two novel FGFR2 variants, one of them (c.1750A>G in exon 13, in the tyrosine kinase domain; on the MANE transcript, NM_000141.5:c.1750A>G, p.(Met584Val)) with a functional effect in vitro, and candidate heterozygous variants in PAX1 and MYO18B in two patients, with a low overall yield [92]. The VANGL1 variant NM_138959.3:c.1151C>G, p.(Pro384Arg) was described in a patient with KFS and in a fetus with a neural tube defect, the mother being an unaffected carrier [93]. The 16p11.2 BP4–BP5 duplication, which increases TBX6 dosage to about 150%, was associated with congenital vertebral malformations, mainly cervical, in 4 of 7 carriers (57%), and the mouse with Tbx6 expression of about 160% has malformations, mainly cervical, in 60% [94]. Biallelic PAX1 causes otofaciocervical syndrome 2, but PAX1 heterozygosity in isolated vertebral malformation (2 of 48 patients, with variants inherited from unaffected mothers) remains a hypothesis [13]. Smith mentions GDF1 variants in some AD cases of KFS, but no OMIM entry links GDF1 to KFS, its catalogued phenotypes being right atrial isomerism and congenital heart defects; a patient with KFS and situs inversus had no variants in GDF1, GDF3 or GDF6 [1, 95, 96]. A 2024 review identified 118 genes linked to vertebral malformations, 98 of them in pathways of spinal formation [97]. Two cytogenetic reports and one of twins illustrate the heterogeneity: a translocation t(5;8)(q35.1;p21.1) segregated with KFS in five affected members of three generations (the 9-year-old proband had C2–C7 fusion, short stature and microcephaly), and was absent in the three unaffected relatives studied; and monozygotic twin girls were discordant, with C1–C4 fusion in one of them, suggesting post-zygotic mutation or intrauterine factors [14].

Outside genetics, Bone Dysplasias notes that enzyme deficiencies of the kynurenine pathway, which synthesises nicotinamide adenine dinucleotide (NAD), cause some vertebral segmentation defects with other malformations, and that, in mice, these malformations were prevented with niacin during pregnancy; these are preclinical data, without established application to KFS [98]. The Nosology groups these forms as NAD deficiency syndrome (HAAO, KYNU, NADSYN1), with a VACTERL-like phenotype [8].

2.9. Pathophysiology of the manifestations

Fusion of cervical segments transfers movement to the spaces that remain open. Pizzutillo and colleagues studied the kinematics of 111 patients on lateral flexion-extension radiographs and found increased mobility per open space in the upper cervical segment and decreased total mobility of the lower segment; upper hypermobility predisposes to neurological sequelae and alteration of the lower segment predisposes to degenerative disease [39]. Superior migration of the odontoid process increases with the number of fused segments and with occipitalisation of the atlas [99]. Mirror movements are associated with cervicomedullary neuroschisis, a failure of decussation of the motor pathways [3, 100]. Deafness results from malformations of the middle and inner ear, including anomalies of the skull base and labyrinth [32, 98]. A complementary hypothesis comes from lineage mapping in the mouse: Matsuoka and colleagues showed that part of the skeleton of the neck and shoulder (cervical spinous processes, spine of the scapula, occipital attachments) derives from the post-otic neural crest, and interpreted Sprengel anomaly, with the omovertebral bone, and part of the cervical hypomobility as defects in the fate of these cells (ectopic ossification of the connective tissues of the trapezius territory and of the prevertebral ligaments), rather than of segmentation; this is an interpretation derived from animal models, without demonstration in patients [14].

2.10. Table of types in the class

3. Clinical Spectrum and Manifestations by System

3.1. Current clinical and radiological classifications

Feil's classification (1919), reproduced in Smith without explicit attribution, distinguishes three types: in type 1, elements of many cervical vertebrae are incorporated into a single block; in type 2, segmentation fails at only one or two cervical levels, possibly including occipito-atlantal fusion; in type 3, a type 1 or 2 fusion coexists with segmentation defects in the lower dorsal or lumbar spine [1]. Gunderson and colleagues recognised in 1967 three equivalent morphological types (type I, massive fusion of many cervical and upper thoracic vertebrae into bony blocks; type II, fusion at one or two spaces, sometimes with hemivertebrae or occipito-atlantal fusion; type III, cervical fusion with lower thoracic or lumbar fusion) and, from the observation of families, suggested that C2–C3 fusion, the most frequent of the congenital cervical fusions, is transmitted as a simple dominant trait and C5–C6 fusion as a recessive trait [14]. Torg took up this classification in two categories for sports decisions: type I corresponds to massive fusion of the cervical and upper thoracic vertebrae and type II to fusion of only one or two intervertebral spaces [47].

The Samartzis classification (2006), derived from a retrospective single-institution cohort of 28 patients, is based on the fusion pattern: type I corresponds to a single fused cervical segment, type II to multiple non-contiguous fused segments and type III to multiple contiguous fused segments; in the original cohort, the distribution was 25%, 50% and 25% [36]. It is the classification most used in recent series on surgery, prevalence and degeneration [33, 43, 101]. The Clarke classification (1998), in four classes (KF1 to KF4), was based on the position of the cervical fusions and on how they were distributed within three families, and is now considered historical [35, 53]. In class 1, the most rostral fusion is at C1, the associated anomalies are severe and inheritance is AR; in class 2, C2–C3 fusion is dominant and forms after birth; in class 3, there is a single isolated fusion, the most rostral at C3, with reduced penetrance; and in class 4, vertebral fusion is associated with the ocular anomalies of Wildervanck syndrome, with possible X-linked inheritance; thoracic and lumbar fusions do not count towards the class [14]. In one of Clarke's families, the daughter had C4–C5 fusion and the father C5–C6 fusion, both complete along the spinous processes, laminae and bodies and with reduced height of the fused vertebrae, suggesting a fusion already present before birth, with mild cervical stiffness and without short neck or low hairline [14]. Raas-Rothschild and colleagues proposed in 1988 a type IV (Klippel-Feil anomaly with sacral agenesis), based on one child and a review of published cases; the proposal was not generally adopted [102]. Xu and colleagues defined in 2024 the sandwich fusion subtype (simultaneous C0–C1 and C2–C3 fusion, leaving the C1–C2 segment mobile), with an increased risk of atlantoaxial dislocation [92]. A 2026 neurosurgical series uses the designation "KFA type 3" for fusion at the level of C3 and below, a group-specific definition that does not coincide with Samartzis type III [103].

A 2026 case review presents a table associating Feil type I with sporadic mutation, type II with GDF3/GDF6 (AD) and type III with MEOX1 (AR) [35]. This association has no support in the primary sources: in the Turkish family with KFS2, for example, the anomalies were limited to the cervical spine, which would correspond to type 1 or 2 and not to type 3 [57]. The morphological types do not predict the gene. For reporting vertebral segmentation defects in general, the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) proposed a clinical algorithm with seven broad categories and an investigation algorithm supported by an ontology [2].

3.2. Classic triad and frequency of manifestations

The triad is insensitive. In Hensinger's series (50 patients, published in 1974), fewer than half had all three signs; more than half had scoliosis, one third had renal anomalies, 21 had Sprengel anomaly, 15 hearing impairment, 9 synkinesis (mirror movements) and 7 congenital heart disease [37]. Samartzis and colleagues studied 31 paediatric patients (mean age 9.7 years at first visit; 12 boys and 19 girls) at one institution: 35.5% had no component of the triad, 38.7% had one, 16.2% two and 9.7% all three; limited cervical mobility was the most frequent finding (64.5%) [6]. Patients with any finding had on average 3.9 fused segments, versus 2.5 in the others (p=0.028), and the proportion with at least one component of the triad rose from 16.7% in Samartzis type I to 73.3% in type II and 80.0% in type III [6]. A 2025 report states that about half of patients have the complete triad, a figure that does not match the paediatric series and reflects the heterogeneity of the samples [105]. Smith reports that about 65% of patients are female, without stating the source population; in Royal's series, 17 of 23 patients (74%) were female [1, 100].

3.3. Cervical spine and craniocervical junction

The natural history of the spine depends on the fusion pattern. In the Samartzis cohort (28 patients, 12 male, mean clinical follow-up of 8.5 years), the mean age at presentation was 7.1 years and the mean age at onset of cervical symptoms 11.9 years; 64% never had cervical complaints and 36% had symptoms, mainly axial [36]. Axial symptoms were associated with type I, whereas radiculopathy and myelopathy appeared in types II and III; at the end of follow-up, two patients were myelopathic and two radiculopathic, all of types II or III. Mean onset was 10.6 years for myelopathic symptoms, 13.0 for axial and 18.6 for radiculopathic (difference not statistically significant), and 3 of the 28 patients (11%) underwent surgery [36]. Type III, although generally asymptomatic, had the highest risk of radiculopathy or myelopathy; type I predominated in females and type III in males [36]. Smith summarises the same pattern: about one third of patients have symptoms related to the cervical spine, axial symptoms associated mainly with type 1 and radicular and myelopathic symptoms with types 2 and 3 [1].

Superior odontoid migration (SOM), measured relative to McGregor's line, was studied in 27 patients without previous surgery (mean age 13.5 years): the mean value was 5.0 mm (−1.0 to 19.0 mm), and C2–C3 was the most frequently fused segment (74.1%) [99]. SOM correlated with the number of fused segments (r=0.589), with occipitalisation (r=0.616) and with coronal alignment (r=0.413); the presence of four or more fused segments was associated with a crude relative risk of 7.20 (95% confidence interval, 95% CI, 1.05–49.18) of SOM greater than 4.5 mm, and, adjusting for a coronal deviation greater than 10°, five or more segments had a relative risk of 4.54 (95% CI 1.07–19.50) [99]. Eight of the 27 patients (29.6%) were symptomatic, two after trauma, and symptoms did not correlate statistically with SOM [99]. Sandwich fusion concentrates movement at C1–C2 and is associated with atlantoaxial dislocation [92]. In a neurosurgical series of 99 patients with fusion at the level of C3 and below (2004–2024, 4–54 years), all had spastic quadriparesis of variable degree, with coexisting Chiari malformation (30), syringomyelia (17), basilar invagination (70), atlas assimilation (49) and torticollis (29), a composition that reflects the referral of symptomatic patients to a craniocervical junction surgery centre [103].

3.4. Adulthood: degeneration and myelopathy

Guille and colleagues reassessed 22 adults (15 women; mean age 35 years, 26–57) diagnosed at a mean age of 9 years: clinical examination was abnormal in 45% (10/22) and 68% (15/22) had at least one complaint attributable to the syndrome; no radiograph showed subluxation or stenosis, but MRI showed degenerative disc changes (T2 hypointensity) in all and other findings in 86% (19/22): disc protrusion in 16, osteophytes in 4, syringomyelia in 4 and narrowing at the craniovertebral junction in 6 [107]. In a 2026 Chinese retrospective cohort, with 70 patients with congenital C5–C6 fusion (Samartzis type I) and 140 age- and sex-matched controls, fusion was associated with higher Pfirrmann grades at adjacent and non-adjacent segments, greater disc biological age and a higher dural sac compression index, especially in young and middle-aged adults [101]. In the prospective multicentre AOSpine North America study on cervical spondylotic myelopathy, 5 of 131 operated patients (3.82%) had single-level congenital fusion; all had adjacent segment changes and T2 cord hyperintensity, with greater canal compromise and a larger area of hyperintensity than patients without KFS, and 4 of the 5 with postoperative follow-up were stable or improved [108]. Minor trauma can cause severe deficits in a spine with hypermobile segments: cases of tetraplegia and of Brown-Séquard syndrome after minor trauma have been published (reports read only by title or abstract) [109, 110].

3.5. Neurological manifestations

Smith mentions primary or secondary neurological deficits (paraplegia, hemiplegia, cranial or cervical nerve palsies) and synkinesis [1]. Royal and colleagues studied 23 patients with KFS and found cervicomedullary neuroschisis in 6 of 16 with adequate axial imaging (38%); the five of these assessed clinically had mirror movements, and none of the six patients without neuroschisis who were assessed had them [100]. The GeneReviews entry on congenital mirror movements indicates that these occur in a minority of people with KFS and are probably linked to neuroschisis, and recommends looking for KFS in people with mirror movements [3, 100]. Chiari malformation, hydrocephalus, meningocele or encephalocele and dermoid cysts of the posterior fossa are among the non-random associated anomalies [1]. A 2025 report described a discrepancy between severe cervico-occipital involvement on MRI and a mild clinical picture, with visuospatial impairment on neuropsychological tests; the proposed link to GDF6 is speculative [105]. Intellectual disability is among the non-randomly associated anomalies [1].

3.6. Ear, nose and throat and airway

The Boston otolaryngology series (95 children, 1989–2015; mean age 5.8 years at first visit) recorded on average eight visits and five diagnoses per patient: conductive hearing loss in 52%, sensorineural in 40% and dysphagia in 39%; 65% underwent procedures, 38% ventilation tube insertion and 24% flexible endoscopy [38]. In 12 direct laryngoscopies with documented Cormack-Lehane grade, 5 (42%) had compromised view (grades 2 to 4), and three patients required tracheotomy for severe upper airway obstruction [38]. A systematic review of case reports added cleft palate, mandibular and thyroid abnormalities and pinna malformations, with more severe symptoms in extensive fusions [111, 112]. Cleft palate, pinna anomalies and voice changes are also listed in Smith; malformation of the laryngeal cartilages with vocal impairment was described in the family with inv(8) [1, 52]. McGaughran and colleagues assessed 44 patients and found audiological abnormalities in 35 (80%), with a slight female excess: sensorineural hearing loss in 15, mixed in 10 and conductive in 7, without a characteristic audiometric profile and without a relationship between conductive hearing loss and serous otitis; malformations of the external ear, ossicular chain and inner ear are described, and vestibular function was not studied [14]. In a family with 31 affected members over five generations, the 24-year-old proband had unilateral sensorineural hearing loss since adolescence, head tilt, scoliosis, mild Sprengel and facial asymmetry, with C2–C3 fusion, and 5 of the 12 relatives examined had hearing loss, scoliosis with Sprengel and facial asymmetry; in another family, with six affected members in AD transmission, four had cleft palate [14].

3.7. Heart and vessels

Ventricular septal defect is the most frequent heart defect, and Smith includes anomalies of the supra-aortic trunks and situs inversus totalis among the associations [1]. A systematic review of 46 case reports published over ten years found at least one finding compatible with congenital heart disease in 72%, with Samartzis type III as the most frequent fusion pattern; the percentage reflects publication bias and not the frequency in the population with KFS, but the authors recommend including cardiology in the team and considering cardiovascular screening [106]. Published cases include posterior circulation ischaemic strokes in an adolescent with atlanto-occipital assimilation and C2–C3 fusion, with vertebrobasilar stenosis or occlusion and cerebellar and pontine infarcts after neck movements [113], multiple arterial dissections [114], fatal rupture of a posterior communicating artery aneurysm in a 33-year-old woman with undiagnosed KFS [115] and the coexistence of an aberrant right subclavian (lusoria) artery and a bicarotid trunk [116]. These are case reports, without an estimate of frequency.

3.8. Kidneys, genital tract, appendicular skeleton and other associations

Renal anomalies (agenesis, ectopia, horseshoe kidney) occurred in one third of Hensinger's series [35, 37]. The association with Müllerian aplasia defines the MURCS association (see section 6) [117, 118]. Sprengel anomaly, sometimes with an omovertebral bone between the scapula and the cervical arches, is the most characteristic appendicular anomaly [37, 57]. Smith adds rib defects, carpal and tarsal fusions, scoliosis and secondary webbed neck, torticollis or facial asymmetry [1]. A patient with KFS and Caroli disease, scoliosis and aphasia and a patient with end-stage chronic kidney disease who underwent kidney transplantation illustrate the diversity of published associations (case reports) [119, 120].

3.9. Monogenic subtypes: what differs

In KFS2, the seven affected members of the Turkish family had a short neck, low hairline, limited mobility and elevated scapula; imaging showed a foramen magnum anomaly, occipitalisation of the atlas, atlas-axis fusion, anterior and posterior fusions, omovertebral bone, neural arch fusion defects, scoliosis and a reduced cervical count, without brain anomalies [57]. In the Saudi family with the deletion, KFS was isolated, with C2–C3 fusion and Sprengel anomaly in the proband; in the second family, the two siblings had omovertebral bones, Sprengel anomaly, scoliosis and ptosis, and the brother also Pierre Robin sequence with cleft palate [15, 21, 56]. In KFS4, myopathy is present in all patients, of variable severity, slowly progressive or non-progressive and predominantly proximal in the lower limbs; there is distal arthrogryposis of the hands and abnormal interphalangeal creases in some patients, and Klippel-Feil anomaly and dysmorphism (ptosis, bulbous nose) were present in five of Altuame's seven patients [61]. Other findings are hypotonia, microcephaly, high palate, low-set ears, long philtrum, pectus excavatum, clinodactyly and short stature, and muscle biopsy shows nemaline bodies [12, 58]. In the 2026 series, weakness was facial, axial and proximal, three patients had congenital findings (hip dislocation, reduced fetal movements, arthrogryposis with hypotonia), there was marked intrafamilial variability, no cardiac involvement, selective involvement of the semitendinosus and tibialis anterior on muscle MRI and, on histology, type I fibre predominance and cores, without nemaline bodies [88]. OMIM describes KFS4 mainly by severe hypotonia from infancy and gathers reports showing that cervical fusion is not the presenting sign: in Alazami's Saudi boy, motor delay and short stature were noted at 16 months (he sat at 1 year and walked at 2), and biopsy at 12.5 years showed myofibrillar disorganisation with loss of myosin filaments and deposits resembling nemaline rods; the Saudi girl also had thoracolumbar scoliosis and bilateral acetabular dysplasia [17]. In a boy of Afghan origin, ultrasound showed lateral cervical cysts at 15 weeks and micrognathia, cleft palate, clinodactyly and a small left ventricle at 18 weeks; he was intubated at birth for respiratory depression, had distal arthrogryposis, a perimembranous ventricular septal defect that closed and a patent foramen ovale, required gastrostomy at 1 year and had recurrent obstructive bronchitis, and at 16 months had bilateral ptosis, facial weakness, thoracolumbar scoliosis and progressive microcephaly (−3.8 standard deviations), with clinical signs of KFA but without a cervical radiograph [17]. In another boy, with micrognathia and mild congenital hip dislocation, MRI at 6 months, performed for torticollis, showed partial fusion of the C2–C3 posterior elements; at 2 years and 4 months he had severe scoliosis with an orthosis, and at 3 years and 8 months an anaplastic large-cell group 3 medulloblastoma was diagnosed, the cause of death at 4 years and 9 months; this is a single case, which does not establish tumour predisposition [17]. Malfatti's Portuguese infant had, from 22 weeks, reduced growth of the left ventricle and aortic valve; after birth, hypotonia with reduced spontaneous movements, tendon contractures, feeding difficulty and dysmorphism (broad skull, small palpebral fissures, high palate, low-set ears, pectus excavatum, large low-set thumbs), cardiomyopathy with hypertrophic left chambers, atrial septal defect and pulmonary hypertension, nemaline bodies in about 40% of fibres, and she died at 4.5 months; Klippel-Feil anomaly could not be assessed because no radiographs were taken [17]. In the RIPPLY2-linked form, failure of formation of the posterior elements from C1 to C4 predominates, with marked cervical kyphosis at C2–C3 and spinal cord compression, as well as hemivertebrae and butterfly vertebrae from T2 to T7 [2, 90, 121]. According to the OMIM synopsis, the most common cervical malformations are agenesis of the posterior elements, cervical fusions and hypoplasia or dysplasia of C1–C3, and most patients have myelopathy, mainly due to canal stenosis [18]. The reports show that minor trauma can reveal the disease: the 7-year-old Salvadoran boy had a cardiac arrest after going down a slide, and imaging showed incomplete atlanto-occipital assimilation, hypoplastic odontoid, absence of the C2 and C3 posterior elements, C4 hypoplasia with canal narrowing and a whiplash-type injury with rupture of the posterior longitudinal ligament and spinal cord injury up to C3; after surgery and rehabilitation, he recovered completely from the upper limb paresis and the left vocal cord paresis [18]. Of the French sisters, the elder had occipitalisation of the atlas, superior dislocation of a hypoplastic odontoid and agenesis of the posterior arches and pedicles from C2 to C4, and the younger, with spasticity at 6 months and progressive flaccid tetraplegia due to compression at C2, did not improve with decompression and at 22 years was incontinent and in a wheelchair; the Italian boy, with cervical kyphosis and spastic tetraparesis, improved after cervical stabilisation and removal of the anterior occipital bone, with residual mild spastic tetraparesis [18]. In the Dutch siblings, the sister's MRI at 2 months showed agenesis of C1 and of the posterior elements from C2 to C4, with kyphosis centred on C3, and at 3 years spasticity triggered by axial loading appeared; the brother had torticollis after minor trauma at 8 months and, at 3 years, an incomplete spinal cord injury after a fall from a chair, with resolution within 24 hours; both had incomplete spinal cord injuries after falls and underwent surgical stabilisation (the sister at 5 years), regaining independent walking [18]. In KFS1 and KFS3, the ocular findings (microphthalmia, coloboma) and carpal and tarsal fusions are the signs pointing to these genes [54, 55].

3.10. Wildervanck syndrome

Described in 1952, it was reviewed by Wildervanck in 1978 in a series of 62 patients [32]. It combines craniofacial asymmetry, short neck, low hairline and preauricular tags or pits; Duane anomaly (abducens palsy with retraction of the globe and narrowing of the palpebral fissure on adduction) and epibulbar dermoids; sensorineural, conductive or mixed deafness, with a usually malformed vestibular labyrinth and sometimes a malformed cochlea; and Klippel-Feil anomaly, which may extend to the thoracic vertebrae, with torticollis, scoliosis and Sprengel anomaly [32]. Occasional findings include intellectual disability, growth deficiency, occipital meningocele, cerebellar and brainstem hypoplasia, cervical diastematomyelia, pseudopapilloedema, lacrimation during feeding, Mondini malformation, absence of the cochlea, rudimentary semicircular canals and vestibule, absence of the internal carotid artery, hydrocephalus, cleft palate, cardiac anomalies, cervical ribs, renal agenesis and cholelithiasis [32]. Intelligence is normal in the great majority; craniofacial deformities may progress with severe torticollis and an immobile neck [32]. Duane anomaly accounts for about 1% of strabismus and is bilateral in 20%; amblyopia is a frequent complication [40]. OMIM describes the deafness as sensorineural, due to bony malformation of the inner ear, and allows that the syndrome (at least the combination of profound childhood deafness with Klippel-Feil malformation) might account for at least 1% of deafness in females, an old estimate without a defined population or method [19]. In one child, MRI showed diastematomyelia of the lower medulla oblongata and cervical cord, vermis hypoplasia, cerebellar tonsillar herniation and triventricular hydrocephalus, and the authors suggested MRI study of the craniospinal axis in all children with the syndrome [19]. In a male patient with bilateral Duane type 1, almost complete fusion of the cervical bodies and bilateral deafness with malformation of the cochlea, vestibules and semicircular canals, there was also malformation of the lower brainstem and cervical cord with incomplete diastematomyelia and ventricular and atrial septal defects repaired at 2.5 years [19].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In the newborn and infant, suspicion arises in the presence of a short neck, torticollis, facial asymmetry, Sprengel anomaly or associated malformations (heart disease, renal anomaly, cleft palate, microtia, rib anomalies), and also in the presence of vertebral defects identified on prenatal ultrasound [1, 122]. In the child, limited cervical mobility is the most frequent sign, and assessment should not depend on the complete triad; congenital scoliosis warrants an active search for cervical fusions, which were present in 25% of 1215 patients with congenital scoliosis or kyphosis in the Minnesota series [6, 123]. Hearing loss, mirror movements, Duane anomaly (especially with deafness, which suggests Wildervanck) and Sprengel anomaly are entry points in clinics of other specialties [38, 40, 100]. In the adolescent and adult, KFS is often an incidental finding on CT or MRI, or presents with neck pain, radiculopathy or myelopathy; it may be confused with axial spondyloarthritis or with previous surgical fusion [33, 124, 125]. In anaesthesia, the first manifestation may be a difficult airway [42]. A congenital myopathy with ptosis, bulbous nose and short neck suggests KFS4 [61]; parental consanguinity, recurrence in siblings or ocular anomalies point to the monogenic forms [55, 56].

4.2. Warning and emergency signs

Warning signs are myelopathic symptoms, progressive radiculopathy, neurological deficits after minor trauma, posterior circulation neurological symptoms triggered by neck movements and signs of craniocervical junction compression (Chiari malformation, basilar invagination, syringomyelia) [36, 103, 109, 113]. In the emergency setting, an acute neurological deficit after trauma, even minor, requires immobilisation and imaging, and a posterior circulation deficit requires vascular imaging [110, 113]. Upper airway obstruction with respiratory failure occurred in three children in the Boston series [38]. In KFS4, respiratory weakness and cardiomyopathy are the potentially serious complications [12, 87]. In the RIPPLY2-linked form, high cervical kyphosis with spinal cord compression is the main risk, and cardiac arrest after going down a slide and incomplete spinal cord injuries after minor falls have been described in children not yet diagnosed or awaiting stabilisation [2, 18, 90].

4.3. Newborn screening

There is no newborn screening for KFS. Prenatal detection of vertebral segmentation defects is possible by detailed ultrasound from 13 weeks, when they are looked for; in the fetal series of Xie and colleagues, the defects detected in the 2nd and 3rd trimesters were not Klippel-Feil-type cervical fusions [2, 122].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no validated formal diagnostic criteria for KFS. The diagnosis is radiological: demonstration of congenital fusion of cervical vertebrae (most authors require at least two vertebral bodies) distinguishes it from acquired fusion, the clinical triad being unreliable [5, 6, 33]. The monogenic forms require identification of heterozygous (KFS1, KFS3) or biallelic (KFS2, KFS4, RIPPLY2) variants classified as pathogenic or likely pathogenic, with a compatible phenotype [7, 8]. Wildervanck syndrome is a clinical diagnosis based on the association of KFA, Duane anomaly and deafness [8, 32].

5.2. Imaging

Cervical spine radiographs document fusions, block vertebrae, hemivertebrae, scoliosis and secondary degeneration; Smith recommends lateral flexion-extension radiographs in all patients, to assess the mobility of each intervertebral space that has remained open, and notes that flexion-extension is often preserved when there is a single functioning space [1, 35]. CT defines the number and level of the fused segments and the anatomy of the craniocervical junction; CT angiography studies the vascular anatomy; MRI assesses the cord, roots, discs, foramina, syringomyelia, stenosis and root compression; imaging of the whole spine is recommended, because there may be anomalies below the cervical level [35, 62, 126]. At the craniocervical junction, SOM relative to McGregor's line, the anterior and posterior atlanto-dental intervals, the number of fused segments between C1 and T1, occipitalisation and coronal and sagittal alignment are measured [99]; a 2026 review systematises the linear and angular craniometric measurements and the anomalies to look for (platybasia, basilar invagination, atlanto-occipital assimilation) [127]. The unsegmented bar of spondylocarpotarsal synostosis is cartilaginous and poorly visible on early radiographs, and CT helps in this differential [128].

5.3. Assessment of associated anomalies

At diagnosis, renal and abdominal ultrasound, echocardiogram, audiological assessment and, in the presence of hearing loss, inner ear imaging are recommended [1, 32, 40]. Ultrasound may identify horseshoe kidney and uterine duplication [35]. In forms with suspected GDF6 involvement, ophthalmological examination with electroretinography and ocular imaging and audiological assessment with temporal bone imaging are added [60]. When KFS4 is suspected, muscle biopsy (histology and electron microscopy, with nemaline bodies in some cases), muscle MRI, echocardiogram and respiratory function support but do not confirm the diagnosis [12, 88]. In Wildervanck syndrome, MRI of the craniospinal axis has been suggested to look for diastematomyelia, cerebellar hypoplasia, tonsillar herniation and hydrocephalus [19]. There is no biochemical test for any of the forms [60, 62].

5.4. Genetic testing: indications, strategy and yield

The Oxford Desk Reference recommends genomic analysis (chromosomal microarray, panel, exome or genome) when a chromosomal or syndromic diagnosis is suspected [40]. The yield is higher in vertebral defects associated with other malformations than in isolated ones, and the monogenic forms of the class are concentrated in consanguineous families, in those with myopathy or in those with ocular anomalies [55, 56, 61, 122]. For generalised segmentation defects, GeneReviews recommends a multigene panel that includes DLL3, HES7, LFNG, MESP2, RIPPLY2, TBX6 and the genes of the differential diagnosis [2]. In a Polish cohort of 34 patients with congenital vertebral malformations, a three-step strategy (microarray, panel and exome or genome) gave a diagnosis in 12%: a deletion upstream of SOX9 and pathogenic or likely pathogenic variants in FLNB and KMT2D, most detected by exome or genome, with NSD2 and TBXT as candidates [41]. In the Chinese cohort of 37 patients with KFS, no patient had a diagnosis in the known genes [86], and in the sandwich subtype the yield of the six "KFS-related" genes was low [92]. Microarray detects the 16p11.2 duplication or deletion (TBX6) and the 8q24.3 deletions that include PUF60 [94, 129].

5.5. Limitations of the tests

A negative result in the genes of the class does not exclude KFS: most isolated cases remain without a molecular diagnosis, and the contribution of oligogenic inheritance, copy number variation and regulatory variants is unresolved [41, 86]. Panels and exome do not, as a rule, detect balanced rearrangements such as the inversion inv(8)(q22.2q23.3) or breakpoints downstream of GDF6, nor distant non-coding deletions such as those causing cochlear aplasia, which require karyotype, high-resolution microarray or genome [52, 54, 78]. The RIPPLY2 intronic variant c.240-4T>G lies outside the canonical splicing dinucleotides; its effect was predicted and not demonstrated in patient RNA, and in 2021 it was classified as VUS, which requires the laboratory to report and interpret it rather than filter it out [89, 90]. For GDF6 and GDF3, incomplete penetrance means that a variant inherited from an unaffected parent has limited diagnostic or predictive value, and most recorded variants are VUS [11, 31, 66]. The clinical sensitivity of testing for isolated KFS is not established, and the proportion of cases explained by the numbered genes should not be presented as sensitivity.

5.6. Report content and reclassification

The report should state the gene, the reference transcript with version (preferably the MANE Select: NM_001001557.4 for GDF6, NM_004527.4 for MEOX1, NM_020634.3 for GDF3, NM_032608.7 for MYO18B and NM_001009994.3 for RIPPLY2), the HGVS DNA and protein nomenclature, zygosity, the ACMG/AMP class and the correspondence with historical nomenclature where it exists, such as "670G→A, Q84X" = c.250C>T, p.(Gln84Ter) in MEOX1 [10, 57, 64]. For a VUS, segregation study in the parents confirms the trans configuration of biallelic variants and segregation with the disease in dominant families, with the limitation of incomplete penetrance in the GDF6 and GDF3 forms [9, 31]. Inconsistent phenotype labels in databases (for example, the RIPPLY2 variant associated in ClinVar with "KFS2") should be corrected in the report [66].

5.7. Prenatal and preimplantation diagnosis

A Chinese series of 12 fetuses with vertebral defects on 2nd- or 3rd-trimester ultrasound (2020–2024, one centre) obtained a genetic diagnosis in 5 (41.7%): de novo 16p11.2 deletion in three, 7q36.1-q36.3 deletion in one and, on exome, the TBX6 variant NM_004608.4:c.989_990dup, p.(Gly331ProfsTer168) in trans with the hypomorphic T-C-A haplotype [122]. The yield was 25% (2/8) in isolated defects and 75% (3/4) in non-isolated defects (p=0.141); there were six terminations of pregnancy, three live births with normal development and three without follow-up [122]. These fetuses did not have cervical KFS, and the figures cannot be transposed to KFS. When the familial variants are identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible, and molecular testing is the gold standard in the recessive forms [2].

5.8. Algorithm

6. Differential Diagnosis

6.1. Comparative table

6.2. Wildervanck, Duane and Okihiro

Wildervanck syndrome is the main syndromic differential diagnosis and the form most frequently named together with KFS. It is distinguished by Duane anomaly and deafness, almost always with vestibular malformation, and by almost exclusive female predominance; the aetiology is unknown, cases are sporadic and a single male patient, the son of consanguineous parents, has been described [32, 40]. The GeneReviews entry on mirror movements suggests possible X-linked inheritance and records one patient with mirror movements [3]. OMIM records three interpretations: the almost exclusive limitation to females raises the hypothesis of X-linked dominant inheritance with lethality in hemizygous males; Konigsmark and Gorlin preferred multifactorial inheritance; and Wildervanck, in the 1978 review, polygenic inheritance limited to females; a family with sensorineural deafness over five generations included two members with Duane anomaly [19]. In the male patient described in 2014, microarray (CGH) showed a deletion of about 3 kb at Xq26.3 encompassing FGF13, absent in the mother and in the only unaffected sibling studied; the deceased father did not have the signs of the syndrome; this is a finding in a single patient, which does not define a gene for the syndrome [19]. No SALL4 variants have been found in patients meeting the criteria, which separates Wildervanck from Okihiro syndrome, in which Duane anomaly is associated with radial ray defects [130, 136]. In isolated Duane anomaly, about 10% of cases are familial AD [40]. The Duane GeneReviews entry places Wildervanck and the Goldenhar spectrum in the differential diagnosis [144].

6.3. Vertebral and costal dysostoses

The 2023 Nosology brings together the vertebral and costal dysostoses in group 36, where KFS occupies entries 36–0110 to 36–0140, Wildervanck 36–0150 and RIPPLY2-linked SCDO 36–0070; the same group includes Currarino syndrome (MNX1), the SCDOs linked to DLL3, MESP2, LFNG, HES7 and TBX6, the AD segmentation defects with variable penetrance due to MESP2 and HES7, the syndrome with short stature, cervical segmentation defects and developmental delay due to CDK10, cerebro-costo-mandibular syndrome (SNRPB, COG1), diaphanospondylodysostosis (BMPER), spondylo-mega-epiphyseal-metaphyseal dysplasia (SMMD, NKX3-2), NAD deficiency syndrome, the VATER/VACTERL association and its forms linked to FANCB and ZIC3, and paternal uniparental disomy of chromosome 14 [8]. In the classic SCDOs, the malformation is generalised and involves the ribs, whereas in KFS the anomalies predominate in the cervical region; the RIPPLY2-linked form lies between the two groups [2, 91].

Source: Nosology of genetic skeletal disorders, 2023 revision [8]; designation of entry 617694 according to OMIM [145].

Three of these entities have features that separate them from KFS. Al Kaissi syndrome (CDK10, AR) was defined in nine patients from five consanguineous families of Tunisian, Algerian, Saudi or Turkish origin, with intrauterine growth restriction, severe hypotonia, growth deficiency, developmental delay with moderate to severe intellectual disability and language delay, and cervical malformations (clefts, segmentation defects and fusions) in all but one; there were also a sacral dimple in five, facial dysmorphism (synophrys, hypertelorism, ptosis, downslanting palpebral fissures, long philtrum, low-set posteriorly rotated ears), small hands with deep palmar creases, a thin corpus callosum in three of the six patients with MRI and atrial septal defect in two; the variants were loss-of-function, and the Cdk10-null mouse has C1 or C2 clefts, absence of the odontoid and longer cilia [145]. Diaphanospondylodysostosis (BMPER, AR) is lethal in the perinatal period, with a small thorax, absent or very delayed ossification of the vertebral bodies (below T12 in some cases), posterior rib gaps filled with poorly differentiated mesenchyme, hypertelorism, short nose, low-set ears and nephroblastomatosis with cystic kidneys; one survivor at 9 months has been described, with severe delay and hypotonia, and in a Jewish family of Balkan origin three pregnancies were terminated between 12 and 16 weeks for malformation of the spine and thorax, reduced ossification, horseshoe kidney and increased nuchal translucency; PAX1 and MEOX1 had been excluded before BMPER was identified [146]. In the VACTERL association, usually sporadic in occurrence, a birth defects registry found 400 cases with two or more components (29 expected by chance) and 76 with three or more (fewer than 1 expected); of these 76, 7 had a chromosomal or monogenic cause and 19 another recognised condition, and in the remaining 50 ventricular septal defect (30%), renal agenesis (30%), limb reduction defects (34%) and polydactyly (20%) predominated [147]. In a series of 78 probands, 7 (9%) had a first-degree relative with at least one component, and 4 of 141 first-degree relatives (5.0%) had a major component, mainly vertebral defects; the VATER picture has been described in several Fanconi anaemia complementation groups, and 5 of 27 patients in group D1 had three or more anomalies [141, 147].

6.4. Synostoses and spondylocarpotarsal synostosis

In the multiple synostoses, cervical vertebral fusion is sometimes described as Klippel-Feil malformation, but proximal symphalangism and progressive ankylosis predominate, together with conductive deafness due to stapes fixation, surgically correctable in many patients, and neurological complications due to canal stenosis; NOG causes most cases [71, 131]. Spondylocarpotarsal synostosis (about 50 cases published in Smith) meets the Coelho criteria (1998): fusion of multiple cervical, thoracic or lumbar vertebral bodies, carpal and/or tarsal synostosis, short stature with scoliosis and/or lordosis and absence of rib anomalies [128]. Upper cervical instability with myelopathy has been described, and the untreated bar progresses to severe scoliosis and pulmonary dysfunction [132]. The AR form results from absence or truncation of filamin B due to nonsense or frameshift FLNB variants in homozygosity or compound heterozygosity; the spondylocarpotarsal fusions with contractures and pterygia linked to MYH3 have their own OMIM entries [134]. The first documented cervical instability was that of a 5-year-old girl with hypoplasia of C1 and the odontoid and subluxation of C2 on C3, and an Italian girl had platybasia, basilar invagination and foramen magnum stenosis without medullary compression, as well as growth hormone deficiency unresponsive to treatment [134]. In Salian's series (10 patients from 7 families, 7 months to 15 years), all had disproportionate short stature (−2.4 to −9.5 standard deviations); contiguous vertebral fusion was most frequent at T5–T7, there was cervical or lumbar fusion in 4, scoliosis in 9 and capitate-hamate fusion in 9, and intrafamilial variability was marked [134]. In Brazil, a family of first-cousin parents was described with 5 affected among 10 children, short-trunk dwarfism of postnatal onset, scoliosis, unilateral thoracic bar and carpal fusion; two had lens opacities and retinal pigmentary and vascular changes, of uncertain significance [134]. The GeneReviews entry on FLNB-related disorders includes GDF6-linked KFS in its differential diagnosis [133].

In Leri pleonosteosis (8q22.1 duplication, AD), flexion contractures of the interphalangeal joints, limitation of multiple joints and short, broad metacarpals, metatarsals and phalanges predominate, with chronic joint pain, short stature, thickening of the palmar and forearm fasciae and of the skin, blepharophimosis, genu recurvatum and a short-stepped gait; in the cervical spine, enlarged posterior neural arches, block vertebrae in some family members, spinal cord compression and, in a 27-year-old British man, C2–C3 fusion have been described [82]. A father and son had laryngeal stenosis, and the differential diagnosis includes Myhre syndrome and geleophysic dysplasia [82]. The short hands and feet with contractures, progressive joint stiffness and thickened skin separate it from KFS, and the duplication was identified by microarray [20, 82].

6.5. Other conditions with cervical fusion

In fibrodysplasia ossificans progressiva, fusion of the cervical facet joints produces a KFS-like anomaly; the absence of heterotopic ossification and hallux malformation excludes it [138, 139]. In Fanconi anaemia, neck anomalies (Sprengel, KF, short or webbed neck, low hairline) occur in 1% and spinal anomalies in 2% [141]. In Diamond-Blackfan anaemia, a short neck due to cervical fusion and Sprengel anomaly warrant orthopaedic and haematological assessment [142]. In PUF60-related disorders, KF is a less common finding; a 6-year-old girl with clinical KFS and normal cognition had the de novo variant NM_078480.3:c.1179del, p.(Ile394SerfsTer7), which led the authors to propose PUF60 in the differential diagnosis even without intellectual disability [29, 129]. The combination of coronal craniosynostosis, KF and Sprengel with and without the FGFR3 variant NM_000142.5:c.749C>G, p.(Pro250Arg) (Muenke syndrome), 22q11 duplication and 12q13.2-q13.3 microdeletion with KF have been described (reports read only by title) [148–150]. In the syndromic craniosynostoses, cervical fusion is occasional in Apert syndrome (FGFR2), mainly as single C5–C6 fusion, and Klippel-Feil anomaly is illustrated in an infant with Pfeiffer syndrome (FGFR2, FGFR1) and in a 4.5-year-old child with Baller-Gerold syndrome (RECQL4, biallelic variants), the latter with radial aplasia and absent thumbs; craniosynostosis and the hand and foot anomalies separate these syndromes from KFS [151–153]. The GeneReviews entry on spondylocostal dysostosis also lists, among the conditions with multiple vertebral segmentation defects, CHARGE (CHD7), KBG (ANKRD11), Alagille (JAG1, NOTCH2), Kabuki (KMT2D, KDM6A), Robinow (ROR2, WNT5A) and Simpson-Golabi-Behmel (GPC3) syndromes, campomelic dysplasia (SOX9), incontinentia pigmenti (IKBKG), 22q11.2 deletion and maternal diabetes [2]. In the adult, axial spondyloarthritis and acquired ankylosis are rheumatological differential diagnoses, with cases of KFS misdiagnosed as spondyloarthropathy [124, 125].

7. Treatments and Risk Management Strategies

7.1. General principles and evidence base

There is no treatment directed at the cause and no clinical guideline from a scientific society specific to KFS; management rests on reviews, retrospective series, sports medicine expert consensus statements and general airway guidelines [4, 5, 47, 154, 155]. The 2026 guideline search was negative, which does not prove that unindexed institutional documents do not exist. GeneGuidance identified no guideline for KFS, MEOX1 or MYO18B, nor any ClinGen actionability curation [12, 62]. Management depends on the extent and level of the fusions and on the presence of instability, stenosis or neurological deficit, and ranges from observation and activity modification to spinal surgery [4, 5]. Complex presentations require a multidisciplinary team (spinal orthopaedics or neurosurgery, medical genetics, otolaryngology, cardiology, nephrology, anaesthesiology, physical and rehabilitation medicine and, in KFS4, neuromuscular medicine) [5, 12, 106].

7.2. Asymptomatic patients and activity modification

In asymptomatic patients, the approach is observation [5]. Smith recommends that patients with hypermobility of the upper cervical segment be assessed at least once a year and avoid violent activities, because of the risk of neurological deficit; hypermobility of the lower segment increases the risk of degenerative disc disease and is treated symptomatically [1]. Samartzis and colleagues stress that activity modification should be emphasised in patients at high risk of neurological compromise (type II and III patterns, increased SOM, occipitalisation or extensive fusions) [36, 99]. Education of the patient and family should include the risk of spinal cord injury after minor trauma and the need to inform the anaesthetist before any procedure [42, 109].

7.3. Conservative pain management and rehabilitation

Treatment of neck pain and radiculopathy without progressive deficit is conservative. In an 18-year-old man with a type II pattern and no neurological deficit, a corrective collar, 5 kg cervical traction and targeted physiotherapy for 12 months were associated with reduced pain and increased mobility (single case) [156]. In a 45-year-old woman with radiculopathy, carpal tunnel syndrome and T1 root compression, wrist splints, physiotherapy and a topical non-steroidal anti-inflammatory drug (NSAID) gel two to three times a day were used, and epidural injections and botulinum toxin were discussed; the dose of the topical product was not stated [35]. The combination of incobotulinumtoxinA with physiotherapy in a 7-year-old child with paraparesis and KFS with an MYH3 variant, and intrathecal baclofen therapy combined with occipitocervical fixation in basilar invagination with KFS, have been published, both read only by title [157, 158]. These drugs treat pain, spasticity or radiculopathy according to the indications and doses specific to those situations; they are not treatments for KFS, and the sources consulted do not describe specific doses for patients with the syndrome.

7.4. Cervical spine surgery

The surgical indications are neurological deficits, instability, deformity and concomitant spinal anomalies [5]. In the largest published cohort, 718 patients with KFS from a tertiary hospital in Beijing (2010–2017; 391 women; mean age 46.8 years), 86.5% had a Samartzis type I pattern, 6.7% type II and 6.8% type III; the most frequent fused segments were C2–C3 (54.9%) and C5–C6 (9.3%) [43]. A total of 133 patients (18.5%) underwent surgery, mainly by the posterior approach (69.9%), and male sex and instability were independent risk factors for surgery; as this is a hospital cohort, the proportion does not represent the surgical risk in the population with KFS [43]. In the Samartzis paediatric cohort, surgery was required in 11% [36].

In spondylotic myelopathy with single-level congenital fusion, four of five operated patients with follow-up in the AOSpine series remained stable or improved [108]. Goel and colleagues treated 99 patients with fusion at the level of C3 and below by atlantoaxial fixation without bony decompression, with follow-up of 3 to 189 months and clinical improvement reported in all; the authors' interpretation, according to which chronic atlantoaxial instability would be the cause of the fusions, is the hypothesis of a single group, in a retrospective uncontrolled series without an outcome scale described in the abstract read [103]. Anterior cervical discectomy and fusion (ACDF) next to a congenital fusion creates an intercalated mobile segment subject to overload: in a 44-year-old woman with congenital C4–C5 fusion and C6–C7 ACDF, adjacent segment disease at C5–C6 became symptomatic at 40 months and required revision, and the authors recommend individualised planning and lifelong imaging surveillance [159]. Reports have also been published of two-level disc arthroplasty, simple decompression without fixation in myelopathy and transmandibular corpectomy, which illustrate technical options without comparative data [160–162].

7.5. Associated anomalies

For surgical correction of Sprengel anomaly, recent series describe the modified Woodward and modified Green techniques, with functional and patient-reported outcome analyses (read only by title) [163–166]. Conductive hearing loss is treated according to otolaryngology standards; in the Boston series, 38% of children received ventilation tubes and 65% underwent some procedure [38]. In the multiple synostoses in the differential diagnosis, otological management is mandatory and conductive deafness is surgically correctable in many patients [76, 131]. In Wildervanck syndrome and Duane anomaly, surveillance and treatment of amblyopia are necessary [40].

7.6. Management of the specific forms

In KFS4, there is no specific treatment; care includes neuromuscular assessment and physiotherapy for the proximal myopathy and distal arthrogryposis, orthopaedic and spinal assessment, respiratory monitoring as in other congenital myopathies, baseline and periodic cardiac assessment (because of the cardiomyopathy described) and assessment of cervical instability before any cervical manipulation or intubation [12, 87]. In the RIPPLY2-linked form, the SCDO GeneReviews entry recommends maintaining weight appropriate for height, scoliosis surgery when significant (with orthoses, VEPTR or growing rods when indicated), respiratory support according to pulmonary compromise with assessment for pulmonary hypertension and heart failure, treatment of neurological findings (in the RIPPLY2 form, cervical kyphosis and spinal cord compression) and education of the parents of boys about the signs of inguinal hernia; these recommendations are expert consensus for the SCDO group [2, 63].

7.7. Sport

Recommendations on contact sport differ between sources. Torg, based on data from the National Football Head and Neck Injury Registry (more than 1200 injuries), considers type I (massive cervical and upper thoracic fusion) an absolute contraindication to contact or collision sports; type II with limited mobility or with occipitocervical anomalies, instability, disc disease or degeneration is also an absolute contraindication; type II with fusion of one or two spaces at C3 and below, full cervical mobility and without these anomalies does not constitute a contraindication [47, 104]. Atlanto-occipital fusion is, for Torg, an absolute contraindication, and return is only allowed in asymptomatic, pain-free, neurologically intact athletes with full cervical strength and mobility [47]. The international Delphi consensus of Zuckerman and colleagues (2025; 34 spine surgeons with sports experience, consensus defined as at least 70%) concluded that an athlete with KFS of one motion segment, with or without kyphosis, may return to high-impact, high-frequency sports, as may athletes with occipitalised C1 or a C1 ring anomaly without neurapraxia; in the remaining KFS scenarios, including multilevel fusion, there was no consensus (only the abstract was read) [154]. The divergence is concrete: Torg's criterion requires location at C3 or below and full mobility, whereas the 2025 consensus does not make return depend on the level of the single fusion. A 2026 narrative review proposes a synthesis: absolute or near-absolute contraindication in upper or multilevel cervical instability, symptomatic stenosis or neurological deficit; relative contraindication in stable single-level fusion in collision sports; requirements of stability, absence of symptoms, normal neurological examination, adequate canal, absence of associated high-risk anomalies and shared multidisciplinary decision-making, supported by complete cervical imaging, MRI and dynamic assessment when indicated [167]. In combat sports (wrestling, judo, martial arts), symptomatic KFS argues against exposure to contact until specialist assessment [167]. All this evidence comes from cases and expert opinion [167].

7.8. Airway and anaesthesia

Cervical fusion, limited extension, mandibular anomalies and upper instability make the airway potentially difficult. A systematic review of 30 case reports of intubation in patients with KFS (27 articles over ten years; mean age 25.4 years; 73.3% women) found first-attempt success of 83% with fibreoptic intubation and with videolaryngoscopy, versus 50% with direct laryngoscopy and with a laryngeal mask; success was 70% in two-segment fusions and 33% in fusions of three or more, and 100% in low fusions (C5–T1) versus 33% in mid fusions (C3–C5) [42]. The authors propose fibreoptic intubation as the standard approach, with the limitation that the data are case reports [42]. In the Boston paediatric series, 42% of direct laryngoscopies with a recorded grade had a compromised view [38]. The observational study NCT03741790 (Boston Children's Hospital), which retrospectively assesses the prevalence of difficult airway in about 300 children with KFS anaesthetised between 2012 and 2018, remained active, not recruiting and without published results in April 2026; the investigators' statement that difficulty increases with age is a hypothesis in the registry entry and not a result [168]. The 2025 Difficult Airway Society guidelines for unanticipated difficult tracheal intubation in adults (65 recommendations; algorithm with plan A intubation, plan B supraglottic device, plan C face mask and plan D emergency front-of-neck access, continuous oxygenation, maximisation of first-attempt success and capnography) apply in general; they are not specific to KFS and, in known KFS, the difficulty is anticipable and should be planned [155]. The importance of videolaryngoscopy in paediatric surgery, a modified tracheostomy technique in an adult and airway compression by the cervical fusion itself have been published (reports read only by title) [169–171].

7.9. Dexmedetomidine in awake intubation

Dexmedetomidine (Precedex® in the USA; Dexdor® in the European Union), an α2-adrenergic receptor agonist, was used for awake fibreoptic intubation in a pregnant woman with KFS and Chiari type I malformation (report read only by title) [172, 173]. There is no published dose for KFS; the doses in the official labels apply. The FDA label expressly includes awake fibreoptic intubation in adults, whereas the EMA summary of product characteristics (SmPC) covers it within procedural and awake sedation and describes a trial in that setting [173, 174].

7.10. Regulatory status

7.11. Trials and intervention studies

There is no therapeutic trial in KFS: on ClinicalTrials.gov, on 28 October 2026, the search "Klippel-Feil" returned 27 records, of which only NCT03741790 was specific, the rest being trials of cervical fusion devices for degenerative disease [168]. The SmPC trial was conducted in patients without KFS, and its extrapolation assumes that the pharmacology of sedation does not depend on the malformation; Fisher's review compares techniques chosen by the operator in published reports, with selection and publication bias, and its figures are not expected success rates [42, 174]. The Goel series does not allow inference of benefit compared with other techniques or with the natural course [103]. No negative trials, suspensions or withdrawals were identified.

7.12. Developments in the last 12 months

Between November 2025 and October 2026 there were no regulatory applications, opinions or authorisations relating to KFS. The human studies published were the series of 99 patients treated by atlantoaxial fixation (retrospective series) [103], the cohort on degeneration of the segments adjacent to congenital C5–C6 fusion (retrospective cohort with matched controls) [101], the series of six patients with MYO18B-related myopathy (case series) [88], the 12% yield of a three-step genetic approach in congenital vertebral malformations (diagnostic cohort) [41], the scoping review of obstetric neuraxial anaesthesia in rare spinal disorders [175], the evidence-level framework for vertebral malformation genes [13] and the narrative review on cervical variants in athletes [167]. At the preclinical level, the role of a distal regulatory module of GDF6 in cochlear formation was demonstrated and a mechanism of rearrangement of the genomic architecture of GDF6 in Nablus syndrome was proposed [80, 81]. The 2025 Difficult Airway Society guidelines were published in January 2026 [155], and the Delphi consensus on return to sport was published at the end of 2025 [154].

7.13. Agents and situations to avoid

Before any procedure involving cervical manipulation or intubation, cervical instability should be assessed [12]. Direct laryngoscopy had lower first-attempt success than fibreoptic intubation and videolaryngoscopy in published reports [42]. Patients with upper cervical hypermobility should avoid violent activities, and massive fusions or those with instability contraindicate collision sports [1, 47]. In KFS4, the anaesthetic precautions for congenital myopathies apply, with respiratory monitoring [12].

7.14. Pregnancy, delivery and lactation

A scoping review (2012–2024) on anaesthesia in pregnant women with rare spinal disorders brought together 121 cases: 33 vaginal deliveries and 88 caesarean sections, 68 successful neuraxial techniques, 46 primary general anaesthetics and 7 failed neuraxial techniques converted to general anaesthesia; the failures included cases of KFS, mainly due to inadequate analgesia or anaesthesia, and the complications were multiple attempts and operators, high block, resistance to local anaesthetic and spinal cord injury [175]. The authors conclude that the neuraxial technique is feasible with planning, an individualised technique, imaging guidance and preparation for general anaesthesia [175]. A primigravida with KFS had an elective caesarean section under spinal anaesthesia, with preparation for a difficult airway, and the authors note that there is no consensus on the optimal technique [176]. Early anaesthetic planning, with spinal imaging (which may show anomalies below the cervical level) and preparation for a difficult airway, is the common element of these reports [126, 175, 176]. In women with the MURCS association, specific preoperative considerations in gynaecological surgery have been described (reports read only by title) [118, 177]. As regards dexmedetomidine, the European SmPC advises against use in pregnancy unless clinically necessary, and states that the drug passes into breast milk, falling below the limit of detection 24 hours after discontinuation [174].

7.15. Transition to adulthood

Cervical symptoms appear at a mean age of 11.9 years and radiculopathy or myelopathy is diagnosed at a mean age of 17.9 years, which places transition in the period of greatest risk [36]. Degeneration of the adjacent segments progresses in young and middle-aged adults [101, 107]. Transition should transfer to the adult team the map of fusions, the results of dynamic assessments, recommendations on activity and sport, the anaesthetic airway record and, in the monogenic forms, reproductive information [36, 42].

8. Reproductive Options and Family Counselling

8.1. Isolated KFS without identified cause

Most cases are sporadic and of unknown aetiology; recurrence in siblings is rare, but AD inheritance with variable expression, presumably rare, has been described, which justifies examining the immediate family [1]. Examination of parents and siblings should include cervical mobility, hearing and, when there are signs, cervical spine imaging, because single-level fusions are often asymptomatic [1, 33]. The possible oligogenic contribution and the 16p11.2 duplication (with 57% of carriers affected in Ren's series) make the risk empirical in families without a molecular diagnosis, and the sources consulted do not provide a validated empirical recurrence risk for isolated KFS [86, 94]. The discordance of monozygotic twins and the segregation of a balanced t(5;8) translocation with KFS over three generations show that both post-zygotic events and familial chromosomal rearrangements may be involved, which justifies karyotype or microarray when there are several affected members [14].

8.2. Autosomal dominant forms (KFS1, KFS3)

In KFS1 and KFS3, each child of a carrier has a 50% probability of inheriting the variant, but incomplete penetrance and variable expressivity make it impossible to predict whether there will be a phenotype and which (vertebral fusions, ocular anomalies or both) [30, 31]. Non-penetrance is documented for GDF3, with p.(Leu305Pro) shared by a patient with unilateral microphthalmia and his father without ocular anomalies, and for GDF6, with p.(Gln253Leu) and p.(Pro327His) inherited from unaffected parents [20, 22]. A variant inherited from an unaffected parent has limited diagnostic and predictive certainty, and possible multiallelic inheritance (variants in GDF3 and GDF6 in the same patient) adds uncertainty [11, 55]. Counselling should address the pleiotropy of GDF6: loss of function is associated with KFS and microphthalmia, gain of function with multiple synostoses with progressive conductive deafness, and biallelic regulatory deletions with cochlear aplasia [60, 72, 78]. Families with chromosomal rearrangements near GDF6 (inversion inv(8)(q22.2q23.3), 3′ breakpoints) show dominant transmission over four to five generations and fusions that may progress after birth, which makes surveillance of carrier children necessary even without fusions at birth [52, 77].

8.3. Autosomal recessive forms (KFS2, KFS4, RIPPLY2)

When both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of an unaffected non-carrier [2, 62]. Heterozygotes for MEOX1 and RIPPLY2 had no phenotype in the families studied, which is consistent with loss of function without dominant effect [9, 57]. In RIPPLY2-related disease, heterozygous parents were unaffected in all families with a segregation study, and in the heterozygous mouse vertebral defects were rare and mild [24]. The published families are mainly consanguineous (Saudi Arabia and Turkey for MEOX1; Saudi Arabia for MYO18B, with the founder variant c.6905C>A, p.(Ser2302Ter); Turkey and other origins for RIPPLY2), which justifies carrier testing in the extended family and, in consanguineous couples, testing of the spouse for the familial variant [9, 56, 57, 61, 90]. Once the variants are identified, carrier testing, prenatal diagnosis and PGT are possible [2].

8.4. Wildervanck syndrome

All cases described in Smith are sporadic and most occur in women; the Oxford Desk Reference records relatives with one or more components, and the inheritance is uncertain [32, 40]. The hypotheses under discussion (X-linked dominant with male lethality, multifactorial or polygenic limited to females) do not provide usable recurrence risks, and the FGF13 deletion described in a male patient has no predictive value [19]. There is no genetic test that confirms or excludes the diagnosis.

8.5. Cascade testing, mosaicism and minors

In the forms with an identified variant, cascade testing is directed at the parents (to establish phase and origin), the siblings and, in the recessive forms, the partners of consanguineous carriers [2]. The possibility of germline mosaicism is not documented in the sources consulted for the genes of the class, but should be mentioned when a dominant variant appears to be de novo, as in PUF60-related disease [129]. In minors, diagnostic testing is indicated when there is a phenotype; in the siblings of a patient, clinical examination and, when indicated, cervical imaging identify fusions and instability with consequences for physical activity and anaesthesia, regardless of molecular testing [1, 42].

8.6. Prenatal and preimplantation diagnosis

In families with known variants, prenatal diagnosis and PGT are technically possible [2]. Without an identified variant, detailed ultrasound can detect multiple segmentation defects from 13 weeks, but does not exclude an isolated cervical fusion [2]. In the presence of fetal vertebral defects, microarray and exome gave a diagnosis in 41.7% of a series of 12 fetuses, with a higher yield in non-isolated cases [122].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

Frequency estimates vary by more than two orders of magnitude because they measure different things. Orphanet assigns isolated KFS in Europe a point prevalence of 2/100,000 (expert estimate) and a birth prevalence of 0.6/100,000 (EUROCAT, 2010); both measure the clinically recognised syndrome [25]. The historical figure of 1 in 42,000 births, reproduced in Smith and in the NCT03741790 registry entry, comes from the old literature, without a stated population or period, and should not be presented as current prevalence [1, 33, 168]. The CT series measure radiological congenital cervical fusion, including asymptomatic single-level fusions: at a level I trauma centre in New York, 17 of 2917 emergency cervical CT scans in one year (0.58%, 1 in 172; the published abstract writes "0.0058%", a unit error), all Samartzis type I, without cervical scoliosis or fracture [33]; in Rochester, in a paediatric emergency department between 2013 and 2015, 10 of 831 CT scans of patients aged 10 to 18 years (1.2%, about 1 in 83), nine type I and one type III [34]. These emergency samples are not population-based. In selected populations, 25% of 1215 Minnesota patients with congenital scoliosis or kyphosis had cervical segmentation defects [123], and 3.82% of patients operated on for spondylotic myelopathy in the AOSpine North America study had single-level congenital fusion [108]. Vertebral segmentation defects in general, a broader category, affect 0.5 to 1.0 per 1000 live births [2, 41].

9.2. Sex, ancestry and founder populations

Clinical series show female predominance (65% in Smith; 74% in Royal's series; 19 of 31 in the Samartzis paediatric series), whereas emergency CT series, with more single-level fusions, have a balanced distribution or male predominance (8 boys out of 10 in the Rochester series) [1, 6, 34, 100]. In the Beijing cohort, male sex was a risk factor for surgery [43]. The recessive forms are concentrated in populations with frequent consanguinity: MEOX1 in Saudi and Turkish families, MYO18B with a Saudi founder variant and RIPPLY2 in Turkish families and families of other origins [9, 56, 57, 61]. In RIPPLY2-related disease, the splicing variant c.240-4T>G was found in homozygosity in French, Italian and Salvadoran families, and p.(Arg80Ter) in homozygosity in German and Dutch families, which shows that the form is not limited to consanguineous Middle Eastern populations [18]. KFS4 has also been described in Afghan and Portuguese families, both consanguineous, and in a boy of European ancestry born to non-consanguineous parents [17, 23]. Pre-molecular reports of the recessive form include a female infant of Iraqi Jewish parents and several sibships of first-cousin parents; KFS3 and GDF3-related microphthalmia have been described in North American, European and Asian families; and Al Kaissi syndrome, a recessive differential diagnosis, has been described in families from North Africa, Saudi Arabia and Turkey [15, 16, 22, 145]. Chinese cohorts provided the data on mutational burden and sandwich fusion, and a Romanian case contributed to the analysis of Nablus syndrome [81, 86, 92].

9.3. Portugal, Brazil and gaps

The sources consulted do not include prevalence estimates for Portugal or Brazil. From the Brazilian literature, a report of an occipital dermal sinus with an infected teratoma in an adult with KFS and a case of Charcot-Marie-Tooth disease associated with Klippel-Feil malformation were identified, both read only by title [178, 179]. A consanguineous Portuguese family contributed to the MYO18B spectrum: the female infant homozygous for p.(Glu2166Ter) had severe nemaline myopathy with fatal cardiomyopathy, without assessment of the cervical spine [17, 87]. From Brazil, a consanguineous family with spondylocarpotarsal synostosis, a differential diagnosis of KFS, has been published [134]. The absence of data in the sources consulted does not prove the absence of published data.

9.4. Special populations

Contact sport athletes require targeted assessment (section 7.7) [47, 154]. Pregnant women require early anaesthetic planning [175, 176]. Patients undergoing surgery unrelated to the spine, including kidney transplantation, require airway planning [42, 120]. Trauma victims, even after minor trauma, should be assessed for spinal cord injury [109, 110].

9.5. European Reference Networks and patient organisations

KFS falls within the scope of ERN BOND (rare bone diseases), which incorporates the nosological classification of genetic skeletal disorders, and of ERN ITHACA (rare malformation syndromes and neurodevelopmental disorders), especially for the syndromic forms; the ERN BOND page presents it as one of the 24 European networks, dedicated to improving access to quality care for rare bone diseases, but the nominal inclusion of KFS in the disease list of either network was not confirmed [8, 44, 45]. In the USA, the organisation Klippel-Feil Syndrome Freedom provides peer support, education and advocacy [180]. The NIH Genetic and Rare Diseases Information Center (GARD) maintains a page on the syndrome, and the CoRDS registry (NCT01793168, Sanford Health) includes isolated KFS and remains open to recruitment [181, 182]. The UCLA International Skeletal Dysplasia Registry accepts cases of vertebral dysostoses [2]. In the United Kingdom, the Oxford Desk Reference indicates the organisation Contact a Family as the point of contact for support groups for individual syndromes [40].

10. Illustrative Clinical Case

Karaca and colleagues described in 2015 a Turkish boy aged 13 years and 9 months, the son of first-cousin parents, with two healthy siblings [9]. The pregnancy was not regularly monitored and delivery was vaginal, at term and uneventful; head control appeared at 4 months, unsupported sitting at 12 months and walking at 18 months, and he was attending 7th grade with moderate to good achievement [9]. He was assessed for short stature, scoliosis and an apparently webbed neck; he was 145 cm tall (3rd centile) and weighed 35 kg (3rd to 10th centile) [9]. Examination showed a short neck with reduced mobility, low posterior hairline, Sprengel anomaly, pectus excavatum in the upper part of the sternum and pectus carinatum in the lower part [9]. Imaging revealed fusion of the cervical vertebrae, scoliosis, dextrocardia, patent foramen ovale and a single kidney, and MRI and three-dimensional CT confirmed the vertebral anomalies and situs inversus totalis [9]. Exome sequencing (mean coverage 115×) identified the homozygous RIPPLY2 variant c.299delT, p.L100fs (now NM_001009994.3:c.299del, p.(Leu100ArgfsTer25)), located in a 25.3 Mb region of absence of heterozygosity, the largest of the 54 regions identified, which together amounted to about 8.9% of the genome [9, 64]. No relevant variants were found in GDF6, GDF3 and MEOX1, in the genes for primary ciliary dyskinesia and heterotaxy (CFC1, ACVR2B, NODAL) or in the segmentation defect genes (MESP2, TBX6, HES7, DLL3, LFNG); the parents and the available sibling were heterozygous [9]. The authors considered that the variant might also explain the heterotaxy, based on the role of TBX6 in laterality in mice, but acknowledged that another undetected change might be responsible [9]. The article does not describe management or outcome. The legend of Figure 1 (pedigree and segregation, conservation profile, photographs of the short and webbed neck, the thorax and the low hairline with Sprengel, three-dimensional CT and radiographs with the cervical fusion and scoliosis, MRI with situs inversus) was consulted in the full text; the image is at https://pmc.ncbi.nlm.nih.gov/articles/PMC4837953/figure/F1/ [9].

The case illustrates three points. First, consanguinity and absence of heterozygosity directed the analysis towards a recessive cause. Second, the variant fell in a gene that, a few months earlier, had been associated with posterior cervical malformation without typical fusion, which shows the overlap between KFS and SCDO6 that leads GeneReviews to suggest reclassification and the Nosology to keep RIPPLY2 in the SCDO group [2, 8, 59]. Third, the label given to the variant in ClinVar ("KFS2") does not correspond to OMIM, which treats the variant as being of uncertain significance for KFS, which requires care in drafting the report [24, 66]. By way of contrast, the Turkish family of Bayrakli and colleagues, with seven members affected by KFS2 and the MEOX1 variant c.250C>T, p.(Gln84Ter) in homozygosity, had anomalies limited to the cervical spine and craniocervical junction with an omovertebral bone (Figure 1 of the article, legend consulted in the full text: https://pmc.ncbi.nlm.nih.gov/articles/PMC3849745/figure/F1/) [57].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Life expectancy in isolated KFS is not quantified in the sources consulted, and the functional prognosis depends on the fusion pattern, the associated anomalies and the syndromic form. In childhood, about one third of patients have cervical symptoms (36% in the Samartzis cohort), mainly axial in the single-segment pattern and radicular or myelopathic in the multiple-segment patterns; 11% of that paediatric cohort underwent surgery [1, 36]. In adulthood, 68% of Guille's patients had complaints attributable to the syndrome and all had disc degeneration on MRI at a mean age of 35 years, and congenital fusion was associated with accelerated degeneration of adjacent and non-adjacent segments in young and middle-aged adults [101, 107]. In a hospital cohort of adults with a mean age of 46.8 years, 18.5% underwent surgery [43]. Hypermobility of the upper cervical segment is associated with neurological risk and that of the lower segment with degenerative disease [39]. Four or more fused segments are associated with SOM greater than 4.5 mm (crude relative risk 7.20) [99]. Rare serious events include tetraplegia or Brown-Séquard syndrome after minor trauma and posterior circulation stroke [109, 110, 113].

In the specific forms, KFS4 has slowly progressive or non-progressive myopathy, with cardiomyopathy in one severe case but without cardiac involvement in the 2026 series [61, 87, 88]. In the RIPPLY2-linked form, the dominant risk is upper cervical spinal cord compression [2, 90]. In Wildervanck syndrome, intelligence is normal in the great majority, and craniofacial deformities may progress with torticollis [32]. The prognostic data come from tertiary centre series, with referral bias towards symptomatic cases; the single-level fusions found incidentally on emergency CT had no fracture or cervical scoliosis [33].

11.2. Surveillance

The surveillance intervals are not defined by any guideline; the annual interval for upper cervical hypermobility comes from Smith and the annual interval for the RIPPLY2-linked form comes from the GeneReviews consensus for the SCDOs [1, 2].

12. Summary and Final Considerations

Klippel-Feil syndrome is a class of cervical segmentation malformations, defined by congenital fusion of cervical vertebrae and described in 1912. The triad of short neck, low hairline and limited mobility appears in a minority (9.7% in a paediatric series), and CT series show that single-level fusion is much more frequent (0.58% to 1.2% in US emergency departments) than the clinical syndrome recorded in Europe (2/100,000). Most cases have no identified molecular cause. Four monogenic forms are numbered: KFS1 due to GDF6 and KFS3 due to GDF3, dominant, with incomplete penetrance, ocular overlap and disputed or limited evidence; KFS2 due to biallelic loss of function of MEOX1, with craniocervical and cervical fusions in consanguineous families; KFS4 due to loss of function of MYO18B, a congenital myopathy with dysmorphism in which cervical fusion may be absent. The RIPPLY2-linked form is recessive, with posterior cervical malformation and spinal cord risk, and is classified by the Nosology as spondylocostal dysostosis type 6. Wildervanck syndrome adds Duane anomaly and deafness to the fusion, and has no known gene.

The initial assessment includes flexion-extension radiographs, CT and MRI of the craniocervical junction, renal ultrasound, echocardiogram and audiological assessment. Genetic testing has a low yield in the isolated form and a higher yield in familial and consanguineous forms and in those with myopathy, ocular anomalies or associated malformations; a negative result does not exclude the condition. Neurological risk is concentrated in the hypermobile segments, extensive fusions and the craniocervical junction, and degeneration of adjacent segments accompanies adulthood. There is no targeted treatment: management combines surveillance, activity modification, rehabilitation, surgery for instability or compression and airway planning, with preference for fibreoptic intubation or videolaryngoscopy. Sports recommendations differ between the Torg criteria and the 2025 consensus regarding single-level fusion. Counselling distinguishes the low recurrence of the isolated form, the 25% of the recessive forms and the unpredictability of the dominant forms with incomplete penetrance.

13. References

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