Campomelic Dysplasia

A skeletal dysplasia of the bent-bone group caused by SOX9 insufficiency, with Pierre Robin sequence, tracheobronchomalacia, scapular hypoplasia and, in most 46,XY individuals, female or atypical sexual differentiation; includes the acampomelic form, the mild form with an ischiopubic-patellar phenotype and the spectrum of regulatory rearrangements upstream of SOX9 (isolated Pierre Robin sequence and 46,XX and 46,XY differences of sex development).

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From descriptions of “bowed femora” to delineation of the syndrome

Neonates with bowed femora and tibiae were described long before campomelic dysplasia had a name. In 1954, Angle reviewed fourteen studies published between 1915 and 1952, comprising 37 cases of neonates with a bowed femur or tibia, and added a case of his own [5]. Reports by Bound and colleagues (1952) and Bain and Barrett (1959) are usually cited as the earliest descriptions compatible with the entity [3]. Recognition as a distinct syndrome came in the early 1970s. In October 1970, Spranger, Langer and Maroteaux described nine patients with “a syndrome of multiple skeletal defects”; in May 1971, Bianchine and colleagues in Baltimore used the designation camptomelic dwarfism, and Maroteaux and colleagues in France syndrome campomélique, from the Greek for “bent limb” [1, 3, 5]. Hoefnagel and colleagues (1972) spoke of “campomelic dwarfism”, and Hall and Spranger (1980) and Houston and colleagues (1983) consolidated the clinical description [3]. The name “campomelic dysplasia” was established at the international nomenclature meeting in Paris in 1977 [5].

The review by Houston and colleagues (1983) included 97 patients, seventeen of their own, and follow-up of the boy described by Maroteaux in 1971, then aged 17 years. That review established the radiological triad of short bowed femora and tibiae, small scapulae “without a blade” and hypoplastic thoracic pedicles, and showed that respiratory distress is not explained solely by the bell-shaped thorax: narrow airways due to defective tracheobronchial cartilage, micrognathia, retroglossia, cleft palate, pulmonary hypoplasia and central hypotonia contribute [32]. In 1979–1980, Lindgren and Ringertz described “campomelic syndrome without campomelia”, the first reference to the acampomelic form [5]; Glass and Rosenbaum (1997) used the designation acampomelic campomelic dysplasia for cases without long-bone bowing but with the remaining major features [4, 33].

1.2. From the recessive hypothesis to dominant inheritance

During the 1970s, reports of affected siblings led to consideration of autosomal recessive inheritance. Mellows and colleagues (1980) described two 46,XX sisters with the long-limb variant, both dying minutes after birth [34]. In the same year, Moedjono and colleagues reported three phenotypically female patients with a 46,XY karyotype, two monozygotic twins, and Pauli and Pagon drew attention to sexual differentiation abnormalities in these patients [35, 36]. In 1993, Lynch and colleagues described a mother and daughter with clinical and radiological campomelic dysplasia, milder tibial bowing and marked phalangeal shortening, the first evidence of autosomal dominant transmission [37]. In 1995, Mansour and colleagues studied 36 UK patients ascertained through genetics, radiology and pathology centres: among the 41 siblings of index cases, only two were affected, and the segregation proportion of 0.05 (95% confidence interval approximately 0.00 to 0.11) excluded the recessive hypothesis and suggested a sporadic autosomal dominant disorder [38]. Sibling recurrences are now explained mainly by parental mosaicism, documented in several families (section 8) [1, 15].

1.3. Molecular discovery

In 1993, Tommerup and colleagues used three apparently balanced de novo reciprocal translocations to map the autosomal sex reversal (SRA1) and campomelic dysplasia (CMPD1) locus to 17q24.3–q25.1, between GH and TK1, excluding HOX2 and COL1A1 [39]. In 1994, two groups published identification of the gene in parallel. Foster and colleagues cloned a translocation breakpoint in a patient with campomelic dysplasia and sex reversal and identified the adjacent gene, SOX9, an SRY-related gene involved in bone formation and control of testicular development [40]. Wagner and colleagues isolated SOX9 as a positional candidate, demonstrated inactivating variants in a single allele in patients without translocations and concluded that SOX9 haploinsufficiency causes dysplasia and autosomal XY sex reversal; the three translocation breakpoints lay 50 kb or more from the gene [41]. Kwok and colleagues (1995) confirmed the coding variant spectrum and absence of coding variants in patients with 17q rearrangements, indicating that translocations alter gene expression without disrupting it [42]. This was followed by demonstration of an upstream control domain with breakpoints dispersed over approximately 1 Mb [43], its association with isolated PRS [8] and isolated DSD due to testicular enhancer duplication or deletion [11].

1.4. Current nomenclature and classification

The term “campomelic” may mislead: not all children with the disease have bowed limbs, as in ACD, and most children with bowed limbs do not have campomelic dysplasia but osteogenesis imperfecta, hypophosphatasia or other dysplasias [1]. In the 2023 revision of the Nosology of Genetic Skeletal Disorders (771 entries and 552 genes), which adopted dyadic gene–phenotype nomenclature, the entity was renamed SOX9-related campomelic dysplasia and included in the bent-bone dysplasia group [1, 2]. The Bone Dysplasias atlas (4th edition) classifies it among polytopic dysostoses and includes the classical, long-bone and camptomelic forms in the same entry [4]. Differences of sex development terminology follows the 2005 Chicago consensus: “XX male” became “46,XX testicular DSD” and “true hermaphroditism” became “46,XX ovotesticular DSD” [10].

1.5. Definition of entities within scope

Classical campomelic dysplasia is a prenatal-onset skeletal dysplasia characterised by distinctive facies, PRS with cleft palate, long-bone shortening and bowing and clubfeet, accompanied by laryngotracheomalacia with respiratory compromise and, in most 46,XY individuals, atypical or female external genitalia [1]. ACD shares all major findings except long-bone bowing; when bones are straight, scapular hypoplasia is the next finding to seek [4, 5]. No published consensus clinical criteria exist, and no single sign is mandatory [1].

The mild form with an ischiopubic-patellar phenotype designates survivors whose findings are limited to or predominate in the pelvis and lower limbs (hypoplastic patellae, hypoplastic lesser trochanters, defective ischiopubic ossification), initially described as ischiopubic-patellar syndrome and now recognised as a mild form of campomelic dysplasia with survival into adulthood [1, 7]. The ischiopubic-patellar phenotype is genetically heterogeneous: some cases are due to TBX4 (small patella syndrome) and others to SOX9 [6].

The regulatory spectrum includes three phenotypes without full campomelic dysplasia, defined by the position and type of structural alteration in the region upstream of SOX9: isolated PRS, associated with translocations and deletions more than 1 Mb from the gene [8, 15]; 46,XX testicular or ovotesticular DSD, associated with duplications or triplications of upstream testicular enhancers, leading to SOX9 overexpression in the absence of SRY [10, 11]; and 46,XY DSD with gonadal dysgenesis, associated with deletions of these enhancers [11, 12]. Cooks syndrome (brachydactyly-anonychia), associated with non-coding microduplications 5′ of SOX9, is addressed as an allelic entity with limited evidence [9, 15].

Outside the scope are Robin sequence as a general entity and its aetiological differential diagnosis, 46,XY gonadal dysgenesis of other causes, the general approach to lethal skeletal dysplasias diagnosed prenatally and orofacial clefts.

2. Molecular Genetics and Pathophysiology

2.1. The SOX9 gene and protein

SOX9 lies at 17q24.3, has three exons and encodes a 509-amino-acid transcription factor of the SOX family, related to SRY through the DNA-binding HMG (high mobility group) domain [1, 5, 15]. The MANE Select reference transcript is NM_000346.4 (ENST00000245479.3), encoding NP_000337.1 [14]. Historical aliases SRA1, CMD1 and CMPD1 reflect the designations of the autosomal sex reversal and campomelic dysplasia loci before gene cloning [13, 39].

The protein is organised into functional domains with clinical significance. The HMG domain occupies approximately codons 101 to 180; the preceding 39 to 40 codons form the dimerisation domain (DIM), enabling cooperative DNA binding; these are followed by two transactivation domains, middle (TAM) and C-terminal (TAC, residues 402 to 509), separated by a proline-, glutamine- and alanine-rich region (PQA) [5, 44]. Sock and colleagues (2003) demonstrated that DNA-dependent dimerisation is a third essential domain: substitution p.(Ala76Glu), found in a long-term survivor with ACD, and an in-frame deletion of residues 66 to 75, in a patient with severe dysplasia, abolished dimerisation and activation of targets such as Col11a2 and CD-RAP [45].

2.2. SOX9 function in chondrogenesis, testicular determination and other organs

SOX9 is the master regulator of chondrogenesis. It binds the ACAAAG motif in enhancers and super-enhancers and activates COL2A1, COL9A1, COL11A2, ACAN (aggrecan), CD-RAP, SOX5 and SOX6; it directs precartilaginous condensation, chondrocyte differentiation and hypertrophic maturation and blocks their conversion into osteoblasts [1, 13]. COL2A1 regulation helps explain phenotypic overlap with spondyloepiphyseal dysplasia congenita and Stickler syndrome, two type 2 collagenopathies [1]. Tracheobronchial cartilage is among the affected tissues, providing the basis of the tracheobronchomalacia that dominates neonatal mortality [1, 32].

In the bipotential 46,XY gonad, SOX9 is the immediate downstream target of SRY: it induces Sertoli cell differentiation and, together with SF1 (NR5A1), activates anti-Müllerian hormone (AMH) [1, 13]. Forced Sox9 expression in transgenic XX mice suffices to induce testicular development (Vidal and colleagues, 2001, cited by GeneReviews) [1], and conditional heterozygous Sox9 inactivation in XY mouse gonadal somatic cells, reducing mRNA by 50%, produces ovotestes, reproducing human dosage sensitivity [46]. In animal models the gene also participates in pancreas, heart, intestine and inner ear formation, corresponding to pancreatic, cardiac and auditory abnormalities described in human disease; sox9 crispants in Xenopus tropicalis reproduce part of the mandibular, branchial, auditory, cardiac and intestinal phenotype [1, 47].

2.3. Molecular mechanisms

Campomelic dysplasia results from haploinsufficiency in most cases. Nonsense and most frameshift variants predict truncated proteins and act as loss-of-function alleles [1, 41]. Some distal truncating variants preserving the DIM and HMG domains produce a stable protein that binds DNA without transactivating and acts as a dominant negative: Csukasi and colleagues (2019) studied four unrelated patients, showed truncated SOX9 synthesis in chondrocytes from three and COL2A1 transactivation below that expected from simple haploinsufficiency, with one case of very severe vertebral and limb dysplasia [48]. Conversely, the recurrent variant p.(Tyr440Ter), the most frequent in campomelic dysplasia, retains some transactivation activity in transfection assays and was associated in several patients with a milder phenotype and longer survival (four and over nine years in Meyer and colleagues' two cases) [44, 49]. A frameshift variant at codon 507, extending the protein by 70 residues, was associated with death shortly after birth, possibly due to protein instability [44].

Missense variants cluster in the HMG domain and reduce or abolish DNA binding; a minority lie in the dimerisation domain [15, 44]. Staffler and colleagues (2010) showed that two new DNA-binding domain missense variants, p.(His165Gln) and p.(Met113Val), retained residual binding and transactivation and caused non-lethal ACD, proposing that variants with residual function determine mild forms in which campomelia and sex reversal may be absent [50]. A 2026 biophysical study showed that p.(Ala76Glu) preserves folding and secondary structure but reduces thermal stability and may disrupt higher-order complex formation with DNA [51]. Two rare mechanisms produce homozygosity in a dominant disorder: mitotic gene conversion of a maternal allele with de novo p.(Tyr440Ter), leaving approximately 80% of leucocytes homozygous in a patient who lived three months [49], and a homozygous deletion in a Taiwanese patient with ACD, 46,XY sex reversal and mild skeletal involvement, for which the authors considered gene conversion, uniparental disomy or somatic crossing over [52].

A non-coding variant may likewise reduce SOX9 dosage. Von Bohlen and colleagues (2017) described de novo c.-185G>A in the 5′ untranslated region, creating an upstream initiation codon with a better Kozak context; translation of a short peptide ending immediately after the normal AUG reduces normal protein synthesis and caused ACD [53]. The practical consequence is that sequencing should include untranslated regions [1].

2.4. The upstream regulatory domain and position effect

SOX9 lies at the centre of an extensive gene desert, and its expression in each tissue depends on enhancers up to approximately 2 Mb upstream and, to a lesser extent, downstream [10, 54]. Translocations, inversions and deletions leaving the coding region intact but separating the gene from these elements reduce expression through a position effect [1, 55]. Wunderle and colleagues (1998) demonstrated in transgenic mice with a human SOX9-lacZ yeast artificial chromosome (YAC) that an upstream rearrangement resembling those in campomelic dysplasia reduces expression particularly in chondrogenic tissue [56], and Pfeifer and colleagues (1999) showed that translocation breakpoints were dispersed between 140 and 950 kb upstream, in a 1063 kb sequence without identifiable genes, and that translocation cases were generally less severe than cases with coding variants [43]. The region between −350 and −50 kb contains several cartilage enhancers active at successive stages of chondrocyte differentiation (E250 in condensed prechondrocytes, E195 in proliferating chondrocytes, E84 in all differentiated chondrocytes, synergising with E70), activated by SOX9 and SOX5/SOX6 [57].

Breakpoint position defines clusters with different phenotypes. Leipoldt and colleagues (2007) delineated a proximal cluster between 50 and 300 kb, whose centromeric boundary was extended to 375 kb by a t(1;17) with mild tibial bowing, cryptorchidism and hypospadias in a 46,XY patient, and a distal cluster between 899 and 932 kb, whose telomeric boundary was extended to 789 kb by a t(Y;17) with ACD and complete XY sex reversal [58]. The Brazilian cohort of Fonseca and colleagues (2013) moved the distal cluster boundary to 601–585 kb [59]. The most recent synthesis distinguishes four upstream clusters: proximal (50–375 kb), the RevSex sex-determination interval (517–595 kb), distal (601–932 kb) and the PRS-associated cluster (1.03–1.26 Mb) [60]. Generally, the further the breakpoint is from SOX9, the milder the skeletal phenotype and effect on male external genitalia [1, 61]. Velagaleti and colleagues (2005) described the first downstream breakpoint, at approximately 1.3 Mb, in a fetus with ACD and sex reversal, and a familial t(4;17) with a breakpoint approximately 900 kb upstream in a family with mild ACD and PRS; the SOX9cre1 element, at approximately 1.1 Mb, colocalises with SOX9 in the nucleus [62]. Hill-Harfe and colleagues (2005) described a five-generation family with a balanced t(13;17), a breakpoint at approximately 932 kb and a mild skeletal spectrum (PRS, hypoplastic scapulae, absence of one rib pair), transmitted across several generations [1, 63].

Gonadal determination depends on specific enhancers. Croft and colleagues (2018) identified, in four patients with DSD and overlapping duplications or deletions upstream of SOX9, three synergistic testicular enhancers responding to different regulator combinations: duplication leads to 46,XX DSD with sex reversal and deletion to 46,XY DSD with sex reversal [11]. In mice, the 557 bp Enh13 enhancer, located 565 kb from the transcription start, is indispensable for testis initiation; its deletion produces XY females, and the element is conserved in a 32.5 kb human region whose deletion is associated with XY sex reversal [64]. Fonseca and colleagues located a testicular enhancer at 517–595 kb, in addition to the TESCO enhancer 10–15 kb from the gene [59]. In the face, two enhancer clusters in the PRS region regulate SOX9 in neural crest progenitors at distances up to 1.45 Mb (EC1.45 cluster); facial specificity in PRS results from these elements' contextual activity and the mandible's greater sensitivity to reduced Sox9, hence PRS has been described as an “enhanceropathy” [65]. Table 2.1 summarises known enhancers in the SOX9 topological domain.

Table 2.1. Selected enhancers in the SOX9 topological domain (GRCh38 coordinates, distance from gene) [60]

2.5. Variant spectrum and nomenclature

SOX9 variants in campomelic dysplasia are mostly private. The Brazilian cohort of Mattos and colleagues (2015) compiled approximately 70 variants: premature termination codons accounted for approximately 45% and splice variants approximately 4% [66]; a 2026 Indonesian series reports more than 200 documented variants [23]. EuroGentest describes the spectrum as mainly point variants (missense, nonsense, splice) and small frameshifting insertions or deletions; missense variants cluster in the HMG domain, with two exceptions in the dimerisation domain; large deletions including SOX9 or the upstream region are occasional; and inversions or translocations disrupting the regulatory domain explain “a few per cent” of cases [15]. Table 2.2 presents variants cited in this article, normalised on the MANE transcript using VariantValidator.

Table 2.2. Cited SOX9 variants, normalised on NM_000346.4 / NP_000337.1 (GRCh38, NC_000017.11) [14]

Several reports predating systematic adoption of Human Genome Variation Society (HGVS) nomenclature use old cDNA numbering whose origin is not always the A of ATG; original nomenclature is therefore retained without manual conversion: “261-262insG” and “888-889insC” (Okamoto 2010) [74], C insertion at nucleotide 1096 (Cameron 1996) [75] and “972delC (P200fsX218)” (Cost 2009) [76]. In the Brazilian cohort, variants were described on reference sequence CCDS11689.1: three nonsense (p.Lys151Ter, p.Ser41Ter, p.Gln232Ter), three frameshift and one intron 1 acceptor alteration (IVS1-2A>G) [66]. Source correction notes: one article describes the upstream region as “19q24.3–25”, a typographical error for 17q24.3–q25 [66], and another assigns campomelic dysplasia OMIM number 608160, which belongs to the gene, whereas the phenotype is 114290 [1, 60].

2.6. Genotype–phenotype correlations

Early series found no clear correlations: Meyer and colleagues (1997) studied twelve patients, found missense and nonsense variants with and without sex reversal and concluded that sex reversal had variable penetrance [44]. The same frameshift variant was found in two unrelated 46,XY patients, one with a male phenotype and the other with sex reversal [42], and the same SOX9 insertion produced, in three siblings, one 46,XY individual with ovotesticular DSD and atypical genitalia, and one 46,XY and one 46,XX individual both with bilateral ovaries and female genitalia [75]. The same allele may therefore give CD or ACD, different degrees of DSD and very different survival [4, 66].

There are, however, partial correlations of clinical value. Upstream translocations or inversions are more frequent than coding variants in long-term survivors and ACD [1]. Mild campomelia and ACD are overrepresented among translocation and inversion carriers (nine of fifteen cases with well-defined breakpoints in Leipoldt's series); only approximately 10% of individuals with coding variants have ACD, mainly missense variants in the HMG or dimerisation domain; and all described upstream deletions were associated with ACD, such as the de novo 1.5 Mb deletion identified by array comparative genomic hybridisation (array-CGH) in a case with XY sex reversal [1, 58, 77, 78]. In Towers and colleagues' review (2026), among 21 ACD cases with missense variants, six lay in the dimerisation domain and fifteen in HMG, whereas among 18 CD cases with missense variants all lay in HMG except one in TAC [5]. A 2022 review stated that dimerisation domain variants do not cause sex reversal, but that generalisation rests on few cases [79].

The review by Towers and colleagues is the most comprehensive source on the relationship between alteration class and survival. The authors analysed more than 1500 abstracts and more than 500 articles (264 references up to 2025), reclassified as ACD cases described as CD with straight bones and calculated survival excluding pregnancy terminations and cases without outcomes [5]. Results (Table 2.3) come from published cases, with likely bias favouring survivors and patient duplication impossible to exclude in pre-1990 cases, and internal proportions vary slightly between article sections; they do not constitute a population survival estimate [5].

Table 2.3. Outcome by SOX9 alteration class in published cases (review up to 2025, excluding terminations and cases without outcomes) [5]

The authors summarise survival beyond the first year in CD as approximately 25% or less for deletions, insertions, nonsense and splice variants (22% for nonsense and 0% for splice variants), approximately 40% for missense and approximately 75–80% for 17q rearrangements [5]. Mansour and colleagues (1995) had already observed in the UK series that patients with 17q rearrangements had a milder phenotype and two of the three survivors carried such rearrangements [38]. The Brazilian cohort found no correlation between truncating variant position and survival [66], and two Japanese patients with severe truncating variants survived over five years [74].

There are two discrepancies between sources regarding ACD severity. EuroGentest (2013) considers most ACD clinically as severe as the classical form [15], whereas the 2026 review finds approximately 90% survival in genetically confirmed ACD [5]; a 2025 article cites 65% survival beyond the first year in ACD, attributing this to another source [60]. Differences may reflect era, publication bias and ACD definition (absent versus mild bowing).

2.7. Penetrance, expressivity and mosaicism

SOX9 coding region variants have complete penetrance for dysplasia; breakpoints very distant from the gene may not have complete penetrance [1]. Expressivity varies within families: a father with mild dysplasia and normal intelligence had a more severely affected 46,XY daughter [80]; a mother with the p.(His169Gln) allele and mild phenotype had a son with ACD [5, 81]; a deletion of approximately 1 Mb upstream segregated over three generations with isolated PRS in one member, ACD in others and learning difficulties in affected males [82]. Sex reversal in 46,XY individuals has incomplete penetrance, and the same alteration may be associated with different gonadal morphologies [4, 44].

Mosaicism has variable clinical expression. Documented examples include paternal germline mosaicism (normal parental blood, three affected children) [75], paternal somatic mosaicism for a SOX9 deletion in a phenotypically normal father with two affected children [83], maternal somatic and germline mosaicism with mild skeletal abnormalities in the mother of two children with classical CD [68], paternal somatic mosaicism without clinical or radiological signs [84], maternal lymphocyte mosaicism for p.(Glu148Ter) without physical abnormalities [5] and somatic mosaicism with a germline component identified by single-nucleotide polymorphism (SNP) microarray in the context of preimplantation diagnosis [85]. Counselling implications are addressed in section 8.

2.8. Allelic and regulatory entities

Isolated Pierre Robin sequence. Benko and colleagues (2009) linked isolated PRS to 17q24 and found a cluster of translocation breakpoints between 1.06 and 1.23 Mb upstream of SOX9, approximately 1.5 Mb microdeletions centromeric and telomeric to the gene and a point variant in a conserved enhancer element altering MSX1 binding [8]. Gordon and colleagues (2014) described two new upstream deletions in PRS families, validated craniofacial enhancers in mice and zebrafish and located the PRS locus at approximately 1.2–1.5 Mb; they noted that PRS is frequently an endophenotype of campomelic dysplasia and that translocations, deletions and duplications across approximately 2 Mb reproduce all or part of the CD-DSD spectrum [54]. Two families with an approximately 1 Mb upstream deletion had isolated PRS, isolated congenital heart disease or both, suggesting cardiac enhancers in this region [86]. In 2025, EC1.45 cluster deletions caused PRS in zebrafish, and Neanderthal-derived variants in this cluster increased activity in neural crest progenitors [87]; a genome-wide association study in the Finnish FinnGen cohort (2647 mandibular retrognathia cases and 497,020 controls) found a SOX9 signal (rs7225448), with variants in linkage disequilibrium in distal enhancers, and another in NOG [88]. The ClinGen expert panel classified the SOX9–isolated PRS relationship as limited (0 to 6 points), because of few cases and difficulty interpreting non-coding variation; this classification means insufficient evidence to include the gene in isolated PRS diagnostic panels, not absence of a relationship [9]. EuroGentest states that translocations or deletions more than 1 Mb upstream may produce only isolated PRS without other CD or ACD signs [15].

46,XX testicular or ovotesticular DSD due to upstream duplication. Small duplications or triplications, mosaic or otherwise, of SOX9 regulatory regions cause sufficient overexpression to override ovarian pathway repression and lead to testes or ovotestes formation without SRY; balanced translocations involving 17q24.3 and whole-gene duplication have also been described [10]. Huang and colleagues (1999) described an SRY-negative neonate with severe penoscrotal hypospadias and palpable gonads, a mosaic 46,XX,dup(17)(q23.1q24.3)/46,XX karyotype, de novo and maternal in origin [89], and Cox and colleagues (2011) familial 46,XX testicular DSD with SOX9 duplication [90]. SOX9-associated duplications appear more frequently associated with ovotesticular than testicular DSD, and the two phenotypes have not been described in the same family [10]. In a 2025 Turkish-German series, twelve SRY-negative 46,XX individuals with upstream duplications of 107 to 941 kb, diagnosed between 0.1 and 55 years, included seven (58%) with testicular or ovotesticular DSD and five (41%) asymptomatic carriers identified by family screening, without correlation between duplication size and phenotype [91]. In a 2026 mouse model, subtle Enh13 enhancer alterations, including a single nucleotide insertion, caused complete XX-to-male reversal by disrupting RUNX1, NR5A1 and GATA4 repression [92]. SOX9 duplication causes only XX sex reversal, without dysplasia [1]. 46,XX DSD is not characteristic of 46,XX individuals with campomelic dysplasia [10].

46,XY DSD due to upstream deletion or coding variants without dysplasia. Bhagavath and colleagues (2014) described three 46,XY sisters with sex reversal without campomelic dysplasia, carrying a heterozygous 349 kb deletion located 353 kb upstream of SOX9, inherited from their father and absent in their mother, with reduced SOX9 expression and gonadoblastoma in two of the three; SRY and NR5A1 were normal [12]. The GeneReviews chapter on non-syndromic 46,XY DSD classifies the SOX9 regulatory regions as a rare cause of complete and partial gonadal dysgenesis, with autosomal dominant inheritance [22]. In 1997, none of 18 women with XY gonadal dysgenesis (Swyer syndrome) had a SOX9 alteration detectable by single-strand conformation polymorphism (SSCP) analysis, indicating that coding variants rarely cause XY reversal without skeletal malformation [44]; the 2026 review nevertheless includes two missense variants, p.R394G and p.R437C, described in isolated 46,XY DSD [5]. 46,XY gonadal dysgenesis of other causes is part of the differential diagnosis.

Mild form with an ischiopubic-patellar phenotype. Ischiopubic-patellar syndrome is heterogeneous: with TBX4 (17q21–q22), the course is benign except for recurrent patellar dislocation or instability; with SOX9, developmental delay may occur, ischiopubic synchondroses are wide and ischia broad and vertical [6]. Offiah and colleagues (2002) showed that campomelic dysplasia survivors have the radiological features of the syndrome previously described as ischiopubic-patellar [7]. Matsushita and colleagues (2013) described a Japanese family with a phenotype overlapping mild campomelic dysplasia and small patella syndrome (defective ischiopubic ossification, elongated femoral neck, hypoplastic patellae, gap between first and second toes), with SOX9 p.(His169Gln), negative TBX4 and reduced but not abolished transactivation [81].

Cooks syndrome and other associations. Microduplications of non-coding elements 5′ of SOX9 are associated with brachydactyly-anonychia, compatible with Cooks syndrome [15, 93]. ClinGen classified the SOX9–Cooks syndrome relationship as limited; in these duplications, including KCNJ2 and KCNJ16, the proposed mechanism is co-option of SOX9 regulatory elements by other genes, and no animal model exists [9]. The 2026 review also cites isolated missense variants in congenital vertebral malformations (p.M469V) and an odontogenesis defect (p.T240P), whose causal relationship has not been evaluated by curation panels [5].

2.9. Gene–disease validity and dosage

The ClinGen skeletal disorders expert panel curated nine genes and 26 gene–disease relationships; SOX9–campomelic dysplasia received a definitive classification (12 points or more), and the panel separated the three SOX9-associated entities by mechanism: coding loss of function in dysplasia, non-coding deletions reducing expression in PRS and rearrangements co-opting regulatory elements in Cooks syndrome [9, 94]. The ClinGen SOX9 haploinsufficiency score is 3 (sufficient evidence), and there is no actionability assessment [13].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and data sources

Clinical information comes from case reports and small series: at the GeneReviews review date, approximately one hundred individuals, including fetuses, had an identified pathogenic SOX9 variant, with scattered data [1]. Series with denominators are Houston and colleagues' review (97 patients, 1983) [32], Mansour and colleagues' UK national study (36 patients, 1995) [38], Mattos and colleagues' Brazilian cohort (nine patients, 2015) [66] and Towers and colleagues' published-case review (over 250 CD and 85 ACD cases, 2026) [5]. Mansour and colleagues' study of the survivor phenotype (2002) is cited by GeneReviews, but its text was not obtained for this article [1, 71]. Table 3.1 compares manifestations according to the main reference works.

Table 3.1. Manifestations by domain according to reference works

3.2. Appendicular and axial skeleton

Long-bone bowing is most marked in the tibia, which bows anteriorly, with a skin dimple over maximal bowing; femora also bow, fibulae are short and upper limbs are usually normal on prenatal imaging [3, 55]. At birth, limbs are short and the trunk normal in length; as kyphoscoliosis progresses, the trunk becomes short relative to the arms [3]. Dislocated hips and talipes equinovarus are frequent [32].

Axial abnormalities determine survivor morbidity. In a series of eight patients with a mean age of six years and five months, delayed mid-thoracic pedicle ossification was present in all, mean scoliosis was 63° in the seven non-tetraplegic patients, mean thoracic hyperkyphosis 126° in six (75%) and mean cervical kyphosis 66° in three (38%); vertebral body hypoplasia was considered the main cause of deformity [97]. Vertebral hypoplasia or malformation, particularly cervical, may lead to spinal cord compression unless surgically stabilised and may cause death in neonatal survivors [1]. Lekovic and colleagues described incomplete cervical pedicle ossification with instability and congenital cervical kyphosis that progressed to complete spinal cord injury despite closed reduction and a custom orthosis [98]. Absent cervical and thoracic pedicles complicate surgical instrumentation (section 7) [3, 99].

3.3. Airway and respiratory system

Many neonates die shortly after birth from respiratory failure; unlike other lethal dysplasias, the cause is not thoracic cage hypoplasia but airway instability (tracheobronchomalacia) or cervical spine instability [1]. Bronchoscopy in two infants showed anatomical upper airway compromise and diffuse laryngotracheobronchomalacia, with severe inspiratory and expiratory obstruction that, combined with the restrictive chest wall defect, rapidly leads to respiratory failure; tracheostomy may temporarily improve the situation, but further respiratory insults may be fatal [95, 100]. Obstruction is multilevel: it combines PRS micrognathia and glossoptosis, laryngeal and tracheobronchial malacia, subglottic stenosis in some cases and a small thorax [32, 101, 102]. The Cincinnati series, with six tracheostomised or ventilator-dependent patients followed for a mean of 12.2 years, shows that long-term survival is possible with airway reconstruction (section 7) [103]. Recurrent apnoea and respiratory problems persist in survivors, and severe scoliosis may maintain ventilator dependence even after airway correction [3, 103].

3.4. Sexual differentiation, gonads and endocrine function

The proportion of 46,XY individuals with female or atypical genitalia differs between sources: approximately 75% according to GeneReviews, Bone Dysplasias and Síndromes Genéticas: Reconhecer para Tratar [1, 4, 104], “approximately two-thirds” according to Smith [3] and the “majority” according to Oxford Desk Reference [96]. The figures are similar: in the UK series, the chromosomal sex ratio was approximately 1:1, with a predominance of female phenotype, and three-quarters of 46,XY individuals had sex reversal or atypical genitalia [38]; a 2025 article states that approximately two-thirds of 46,XY individuals have gonadal dysgenesis [60]; in the Brazilian cohort, only one of three 46,XY patients had sex reversal [66]. Differences reflect small samples and differing criteria (external genitalia versus gonadal histology), and none of the sources specifies a comparable denominator.

The sexual differentiation spectrum ranges from female phenotype to atypical genitalia, and gonadal morphology resembles XY gonadal dysgenesis, from dysgenetic testes to ovotestes and dysgenetic ovaries [4]; ovotesticular DSD has been described in a fetus with ACD [105]. Internal genitalia are variable, with mixed Müllerian and Wolffian structures [1]. Dysgenetic gonads with a Y chromosome carry a risk of germ cell tumours: bilateral gonadoblastoma has been described in a three-year-old 46,XY girl (the first documented case) [106], bilateral gonadoblastoma, one with foci of “dissecting” gonadoblastoma, in a one-year-old girl [107] and dysgerminoma in an eight-year-old girl with medullary nephrocalcinosis, urolithiasis and renal malrotation [76]. In the family with an upstream deletion without dysplasia, two of the three 46,XY sisters had gonadoblastoma [12].

Endocrine function has particular features described in recent reports. In a 46,XY girl with ACD and complete gonadal dysgenesis, minipuberty was absent, with low gonadotrophins at five and eight weeks, followed later by a rise in follicle-stimulating hormone (FSH) to 38.2 IU/L, consistent with hypergonadotrophic hypogonadism [60]. A long-term surviving 46,XY adolescent presented with primary amenorrhoea and hypogonadotrophic hypogonadism (low gonadotrophins and minimally detectable sex steroids), an unexpected finding in a primary gonadal dysgenesis disorder [108]. A 34-year-old Japanese woman with ACD, t(11;17) translocation and a Y chromosome with SRY present experienced menarche at 33 years and four months, following oestrogen and then oestrogen–progestogen therapy [109]. Olfactory bulb agenesis, described in several patients, evokes Kallmann syndrome, but the subsequent gonadotrophin rise in the Polish case suggests normal gonadotrophin-releasing hormone (GnRH) neurons; the authors attributed absent minipuberty to concomitant severe illness [60, 110].

3.5. Neurological development and cognition

Survivors' intellectual development is described differently. GeneReviews states that intellect is normal [1]; Smith reports that although some survivors have normal intelligence, most have mild to moderate intellectual disability [3]; Bone Dysplasias states that some survivors had delay and others normal intelligence, and that developmental delay is common in SOX9-related ischiopubic-patellar phenotypes [4, 6]. Individual reports span the spectrum: normal psychomotor and intellectual development in a Brazilian woman with translocation-associated ACD [59], normal intellectual and social development at four years with initial speech delay in the Polish girl [60], language delay alone at three years in Towers' case [5], motor delay and attention deficit in an Indonesian patient [23], learning difficulties in males from a family with an upstream deletion including KCNJ2 and KCNJ16 [82] and profound intellectual disability in a Japanese woman with translocation-associated ACD [109]. A six-and-a-half-year-old patient with classical CD attended the first year of mainstream school [111]. Central hypotonia contributes to early respiratory distress [32]. Without the 2002 survivor series, whose text was not obtained, a proportion with a denominator cannot be given; the discrepancy remains and should be explained to families.

3.6. Acampomelic form

ACD represents approximately 10% of campomelic dysplasia cases [52, 60, 78]. It shares the facies, PRS, hypoplastic scapulae, narrow iliac wings, hypomineralised thoracic pedicles, 11 rib pairs, clubfeet, tracheomalacia and sex reversal in most XY individuals, but without or with only mild long-bone bowing [1, 112]. Half of cases with 17q rearrangements have no or mild campomelia [112]. ACD is often overlooked or misdiagnosed because the sign naming the disease is absent [15, 113]. Glass and Rosenbaum added shallow orbits to the phenotype in two sisters [33], and olfactory bulb agenesis has been proposed as a diagnostic indicator [110]. In an ACD case with p.(Lys106Glu), bowing was visible on ultrasound until the 18th week and then disappeared [3, 67]. A homozygous deletion in a 46,XY patient with sex reversal and minimal skeletal involvement led the authors to recommend considering ACD in 46,XY sex reversal with subtle skeletal abnormalities [52].

3.7. Mild forms and adult survivors

Survivors show variably affected height (some neonates with significant short stature, others within the normal range), usually progressive scoliosis contributing to short stature and potentially causing neurological signs, cervical instability, hearing loss sometimes requiring hearing aids, and heart defects in a minority [1]. Unger's letter on “the mildest form of campomelic dysplasia” discussed this end of the spectrum [114]. The mild ischiopubic-patellar form has been described in survivors with subtle CD findings and without typical facies, cleft palate, small scapulae or vertebral abnormalities [4, 7]. A 10.5-year-old girl with mild CD and de novo p.(Pro170Leu) had prenatal-onset short stature, facial dysmorphism, limited pronation–supination, dysplastic nails, cone-shaped epiphyses of the second finger middle phalanx, brachydactyly, short fourth metacarpals, radial and femoral head subluxation, hypoplastic scapulae, an unossified pubic symphysis and delayed bone age [69]. The same variant was found in a patient of Mansour and colleagues alive at 21 years [5, 71].

Adults with delayed diagnosis exist. An 18-year-old woman was diagnosed after giving birth to a daughter with classical CD [4], and other adults were identified following the birth of an affected child [1]. Adult survivors with translocations include patients alive at 32, 35, 29, 28, 23 and 15 years at last follow-up [5]. An Australian woman with ACD due to t(2;17), ventilatory failure and severe kyphoscoliosis carried a pregnancy to term [115]. Described late complications are conductive hearing loss, myopia, dental caries, recurrent apnoea and respiratory problems [3].

3.8. Natural history and treated disease

Most survival data come from published cases with heterogeneous and rarely described care. In the Brazilian cohort (2000–2013), two patients were stillborn and all liveborn patients died in the first three months, with recorded survivals of 1, 7, 11 and 82 days [66]. In the 2026 review, 87% of 164 CD cases without genetic testing died by the first year [5]. By contrast, series of patients treated at centres providing airway reconstruction and spinal surgery include adolescents and young adults (mean age 19.4 years in the Cincinnati series) [103, 116]. Survival figures therefore cannot be transferred across eras and settings: neonatal survival depends on malacia severity, genetic class and availability of tracheostomy, prolonged ventilation and specialist surgery.

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

In the first trimester, suspicion may arise with increased nuchal translucency or cystic hygroma associated with lower-limb abnormalities. Massardier and colleagues described two fetuses with hygroma and lower- but not upper-limb abnormalities, with campomelic dysplasia confirmed by fetal pathology, and proposed SOX9 analysis for this association [24]; Zhen and colleagues highlighted hygroma and micromelic lower limbs as first-trimester markers [117]. A fetus with ACD had nuchal translucency of 5.6 mm at 13 weeks, normal femora at 22 weeks and long-bone growth retardation only at 32 weeks [118]. On second-trimester anomaly ultrasound, symmetrical femoral and particularly tibial bowing, with clubfeet and micrognathia, suggests the diagnosis [1, 55]. Hypoplastic scapulae are the most specific finding but require targeted assessment [15]. Discordance between chromosomal sex (chorionic villi, amniocentesis or cell-free fetal DNA sex determination) and female genitalia on ultrasound in a fetus with short or bowed limbs is a specific warning sign [55, 96, 118]. Polyhydramnios, relative macrocephaly and micrognathia complete the presentation [3, 5].

4.2. Neonate

Campomelic dysplasia should be suspected in a neonate with short bowed lower limbs and pretibial dimples, PRS with cleft palate, relative macrocephaly, a small thorax, clubfeet and dislocatable hips, particularly with respiratory distress [1]. A child with female or atypical genitalia and a 46,XY karyotype, or a phenotypically female neonate with skeletal dysplasia, should prompt consideration of the disease, and karyotyping is mandatory in any female phenotype with suggestive dysplasia [13, 106]. With straight bones, PRS combined with small scapulae is the clue: in an 18-month-old child without campomelia, palpation of small scapulae and PRS suggested the disease [4]. In a neonate with apparently isolated PRS, 11 rib pairs, hypoplastic scapulae, hypomineralised thoracic pedicles or cervical abnormalities on chest radiography point to ACD [5, 59].

4.3. Childhood, adolescence and adulthood

In childhood, mild forms present with short stature, scoliosis or kyphoscoliosis, delayed bone age, hypoplastic scapulae and 11 rib pairs, as in the Brazilian patient referred at 12 years for short stature [59]. In adolescence, a girl with primary amenorrhoea, a 46,XY karyotype and a history of PRS or skeletal abnormalities may have a survivor form [108]. In adults, diagnosis is sometimes made retrospectively following an affected child's birth, and careful clinical and radiological examination of apparently healthy parents identifies minimal manifestations or mosaicism [4, 68, 80]. An ischiopubic-patellar phenotype with broad vertical ischia, scapular hypoplasia or developmental delay points to SOX9 rather than TBX4 [6].

4.4. Emergency signs

Signs requiring immediate action are respiratory distress with stridor, apnoea, desaturation or extubation failure in neonates, suggesting laryngotracheobronchomalacia or PRS obstruction [1, 95]; signs of spinal cord compression (weakness, altered reflexes, urinary retention) in a patient with cervical kyphosis, because of complete spinal cord injury risk [1, 98]; and the need for anaesthesia or airway manipulation, because of cervical injury and postoperative apnoea risks [1, 119]. In a 46,XY girl with dysgenetic gonads still present, elevated tumour markers or a gonadal mass require surgical assessment [60, 76].

4.5. Neonatal screening

There is no biochemical or molecular neonatal screening for campomelic dysplasia. Detection depends on prenatal ultrasound and neonatal examination [1, 120].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and suggestive findings

No published consensus clinical diagnostic criteria exist. Diagnosis is usually established clinically and radiologically; no single sign is mandatory, and radiographic findings, consistent between patients, are the most reliable clues [1]. Identification of a heterozygous pathogenic or likely pathogenic variant involving SOX9 establishes diagnosis when clinical and radiological findings are inconclusive [1]. EuroGentest considers definitive diagnosis possible in most cases by radiology, but molecular analysis of SOX9 and its regulatory domain important because regulatory and chromosomal alterations tend to have a better prognosis and some patients have only partial skeletal abnormalities, such as brachydactyly or PRS [15]. Table 5.1 compiles suggestive findings.

Table 5.1. Findings suggestive of campomelic dysplasia

5.2. Initial assessment

Assessment of a suspected case includes a full skeletal survey (frontal and lateral skull and spine, thorax, pelvis, limbs, hands and feet), karyotype or another test determining chromosomal sex, airway examination and hearing assessment [1, 120]. Karyotyping is mandatory in all female phenotypes to identify 46,XY individuals, because the result determines gonadectomy [13, 106]. Pelvic and renal ultrasound, echocardiography and, if a central nervous system abnormality is suspected, brain imaging complete characterisation; cranial and renal ultrasound and echocardiography were used in recent published cases [5, 60].

5.3. Genetic testing strategy

GeneReviews proposes two pathways according to phenotype [1]. When distinctive, testing begins with SOX9 sequencing (detecting small insertions and deletions, missense, nonsense and splice variants); if negative, gene-targeted deletion and duplication analysis follows; chromosomal microarray (CMA) detects large deletions and duplications including SOX9 and its upstream region; and karyotyping is performed if SOX9 analysis is non-diagnostic, to detect copy-number-neutral reciprocal translocations of 17q24.3–q25.1. Alternatively, a skeletal dysplasia panel including SOX9 has a composition adapted to presentation (bowed limbs in a fetus, PRS in a neonate). When phenotype is not distinctive, exome sequencing (most commonly used) or genome sequencing is used and, if the exome is non-diagnostic and dominant inheritance is suggested, an exome array for exonic deletions and duplications [1]. EuroGentest recommends sequencing the three exons and exon–intron junctions, detecting approximately 90% of variants in CD and ACD, followed by large deletion analysis using quantitative polymerase chain reaction (PCR) or array-CGH and cytogenetics for translocations and inversions, raising detection to approximately 95%, with confirmation using a second independent PCR product [15]. The 2026 review recommends SOX9 analysis including the upstream region or whole-genome sequencing [5]. Oxford Desk Reference notes that chromosome 17 translocation disrupting SOX9 is among the specific cytogenetic alterations in skeletal dysplasias, justifying karyotyping [121].

5.4. Method yields

GeneReviews presents two non-concordant sets of figures [1]. In the text, a heterozygous pathogenic variant involving SOX9 is found in approximately 90% of affected individuals and an interstitial deletion or reciprocal translocation of 17q24.3–q25.1 in 5% (unpublished G. Scherer data). In Table 1 of the same chapter, proportions attributed to each method are those in Table 5.2. Both are author estimates; they should neither be added nor interpreted as clinical sensitivity, because they measure the proportion of probands with a variant detectable by each method in reference series.

Table 5.2. Proportion of probands with a detectable variant by method (GeneReviews, Table 1) [1]

EuroGentest estimates analytical and clinical sensitivity of approximately 95%, specificity of 100% and a positive predictive value of “almost 100%” [15]. That 95% corresponds to the proportion of cases with an alteration detectable by the full strategy in reference series, not an independent clinical sensitivity study. In a Brazilian cohort investigated only by Sanger sequencing, detection was 7/9 (78%), and the two negative cases were not investigated for intragenic deletions or regulatory copy-number variants (CNVs) [66]. A Chinese series of 100 fetuses with postural abnormalities (2020–2025) obtained 12% diagnoses by CMA or low-coverage CNV sequencing and 19.3% by exome (17/88; 95% confidence interval 11.7% to 29.1%), without any SOX9 case [122].

5.5. Test limitations

A negative result does not exclude campomelic dysplasia. SOX9 sequencing does not detect whole-gene deletions, upstream deletions and translocations, inversions or balanced rearrangements [1, 15]. The exome generally does not detect a 606 kb deletion containing SOX9, as in the Chinese fetus with hygroma in whom only chorionic villus CMA identified the alteration; the authors proposed combining CMA and exome in fetuses with hygroma and skeletal dysplasia [123]. CMA does not detect balanced translocations, and its resolution in the SOX9 gene desert depends on platform; CNVs in this region may not be identified by automated algorithms, so the laboratory should confirm that it analyses and reports variants in this interval [1, 10]. In a 46,XX DSD series, a duplication undetected by a 300,000-probe microarray was identified by MLPA and confirmed by a 750,000-probe microarray, and the authors recommended high-resolution microarrays (over 500,000 probes) as the primary test in SRY-negative 46,XX DSD [91]. Apparently balanced translocations require karyotyping, and breakpoints are defined only by fluorescence in situ hybridisation (FISH), genome sequencing or optical genome mapping (OGM): in a 46,XY child with PRS, skeletal abnormalities and female genitalia, exome sequencing was uninformative and SOX9 had no variants, but karyotyping showed a de novo t(5;17)(q22;q23.1), and genome sequencing and OGM located the breakpoint upstream of the gene [124]. A 17q23.1 breakpoint, outside the usually accepted region, was also described in a 46,XY girl with bilateral gonadoblastoma [107]. Non-coding 5′ untranslated region variants require sequencing to include this region [53]. Parental somatic mosaicism may escape blood analysis, and germline mosaicism is undetectable in blood [15, 84].

5.6. Interpretation and report content

The report should state the gene, versioned transcript (NM_000346.4), HGVS cDNA and protein nomenclature, zygosity, classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, origin when parents have been tested and, for CNVs and rearrangements, genomic coordinates with reference genome build and distance from SOX9 [1, 14]. Pathogenic and likely pathogenic classes are equivalent for clinical decisions [1]. A heterozygous SOX9 VUS neither establishes nor excludes diagnosis; this applies to p.(Ala116Val), classified as a VUS (criteria PM2, PM1 and PP3) in an Indonesian boy with a typical clinical presentation whose parents were not tested [1, 23]. In the same series, p.(Arg107Gly) was classified as likely pathogenic (PM1, PM2, PM5 and PP3) [23]. Family segregation and demonstration of de novo occurrence are the most useful steps for reclassification. For rearrangements, breakpoint distance from the gene has prognostic value (section 2.6) [1, 5].

5.7. Diagnosis of regulatory entities without dysplasia

In SRY-negative 46,XX DSD, duplications or triplications upstream of SOX9 are a very rare cause when the genitalia are typically male and a rare cause when they are atypical; SRY explains approximately 80% of cases with typical male genitalia [10]. Sequencing does not detect them; CMA detects them with a sensitivity below 100%, depending on the platform, and that of genome sequencing has not been established [10]. In 46,XY gonadal dysgenesis, deletion of upstream enhancers is a rare cause of complete or partial dysgenesis [11, 22], and its investigation requires high-resolution CMA of the region. In isolated PRS, the relationship with SOX9 has limited evidence, and ClinGen does not recommend including the gene in panels for this phenotype [9].

5.8. Prenatal diagnosis

The ACMG and International Skeletal Dysplasia Society guideline (2009) recommends that fetuses with long bones at or below the 5th percentile, or more than 3 standard deviations below the mean, be assessed at a centre experienced in skeletal dysplasias (in the text, femur or humerus below the 5th percentile or −2 standard deviations before 24 weeks), with genetic counselling [120]. Assessment should measure and compare with norms the skull, facial profile, mandible, clavicles, scapulae, thoracic circumference, vertebral bodies, all long bones, hands and feet; the femur-to-foot ratio is approximately 1.0 throughout gestation, and long bones more than 3 standard deviations below the mean with head circumference above the 75th percentile strongly suggest dysplasia [120]. A thoracic-to-abdominal circumference ratio below 0.6 (0.618 in the text) or femoral length-to-abdominal circumference ratio below 0.16 strongly suggests perinatal lethality, with exceptions [120]. Because lethality in campomelic dysplasia arises mainly from the airway rather than thoracic hypoplasia, these indices are less informative in this disease [1]. Routine ultrasound diagnostic accuracy for dysplasias is approximately 40%, so diagnosis should always be confirmed after delivery [120]. The guideline predates routine exome and genome use.

In campomelic dysplasia, gestational detection age varies. In the Italian series of five prenatally diagnosed cases, dysplasia was seen in the first trimester in one, the second in three and the third in one, with de novo SOX9 variants in the four terminated fetuses and paternal somatic mosaicism without clinical or radiological signs in the case carried to term [84]. Ultrasound distinction from osteogenesis imperfecta is difficult: in a series of eight cases, three osteogenesis imperfecta cases mimicked campomelic dysplasia and the only campomelic dysplasia case was diagnosed as osteogenesis imperfecta [125]. ACD is difficult to recognise prenatally, because ultrasound does not reliably assess ossification and micrognathia and clubfeet are non-specific and tend to be attributed to isolated PRS [5]. Fetal magnetic resonance imaging is useful for the spine and three-dimensional ultrasound for the face [120]. Olfactory bulb agenesis has been proposed as an indicator, with unknown prevalence [110].

Oxford Desk Reference suggests considering cell-free DNA fetal sex determination, because an apparently female fetus on ultrasound may be 46,XY with sex reversal [55]. With chromosomal–phenotypic sex discordance, maternal cell contamination (the most likely cause), sample mix-up and vanishing-twin chimerism should first be excluded before accepting true discordance [96]. Michel-Calemard and colleagues used amniotic fluid testosterone measurement to document the female phenotype in a 46,XY fetus [118].

In prenatal molecular investigation, Towers and colleagues suggest, as author opinion, offering amniotic fluid genome sequencing for bowed femora or tibiae without a firm diagnosis and, once campomelic dysplasia is confirmed, characterising the SOX9 alteration to guide class-based counselling [5]. GeneReviews notes that a multigene panel or exome may be more efficient with non-specific signs [1], and combining CMA with exome covers deletions [123]. Fetal DNA should be stored with consent for future diagnosis [55, 120]. Following termination or perinatal death, the 2009 guideline recommends anteroposterior radiographs of the entire appendicular skeleton, including hands and feet, frontal and lateral skull and spine radiographs, photographs, autopsy, cartilage and bone sampling for histomorphology and tissue or DNA storage [120]. The 2018 international consensus on prenatal assessment and delivery in skeletal dysplasias (Delphi method with 13 experts, 40 consensus recommendations) was not read in full, and its individual recommendations are not reproduced [126]. No International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guideline specific to skeletal dysplasias was found.

5.9. Practical algorithm

Table 5.3. Diagnostic algorithm by setting

6. Differential Diagnosis

6.1. Bowed limbs prenatally

Femoral bowing is a frequent non-specific finding [4]. Because osteogenesis imperfecta is more common than campomelic dysplasia, it is the most frequent cause of bowed limbs on prenatal ultrasound [1]. Oxford Desk Reference distinguishes symmetrical bowing, predominantly tibial, pointing to campomelic dysplasia (with clubfeet, sex reversal and heart disease), osteogenesis imperfecta type IIB or Beemer–Langer syndrome, from asymmetrical or single-bone involvement, more likely sporadic, vascular or environmental [55]. The 2026 review lists the prenatal differential for bowed femora or tibiae as achondroplasia, Antley–Bixler syndrome, campomelic dysplasia, Cumming syndrome, diastrophic dysplasia, hypophosphatasia, Kniest dysplasia, kyphomelic dysplasia, Langer mesomelic dysplasia, Larsen syndrome, osteogenesis imperfecta types 2 and 3, Schwartz–Jampel syndrome, spondyloepiphyseal dysplasia congenita (SEDC), Stüve–Wiedemann syndrome, thanatophoric dysplasia and Weismann–Netter–Stuhl syndrome; and for hypoplastic scapulae, ACD, Antley–Bixler syndrome, campomelic dysplasia and cleidocranial dysplasia [5]. Table 6.1 compares the main differentials.

Table 6.1. Differential diagnosis of bowed limbs and the campomelic phenotype (AD, autosomal dominant; AR, autosomal recessive)

6.2. Postnatal differential

After birth, the main differentials are SEDC and Stickler syndrome, both due to COL2A1 with dominant inheritance, sharing facies, cleft palate and, in SEDC, short limbs; radiographs distinguish them [1]. In a skeleton without campomelia, the combination of hypoplastic scapulae, 11 rib pairs, narrow vertical iliac wings and hypomineralised thoracic pedicles distinguishes ACD from isolated PRS and other dysplasias [4, 5]. Cousin dysplasia shares scapular and iliac hypoplasia but lacks PRS and thoracic pedicle hypoplasia [129]. Survivors with mild campomelic findings, without typical facies, cleft palate, small scapulae or vertebral abnormalities, were designated as having ischiopubic-patellar syndrome [4, 7].

6.3. Differential of sex reversal and atypical genitalia

In a newborn with atypical genitalia or in a 46,XY female phenotype, the differential includes Smith–Lemli–Opitz syndrome (DHCR7), WAGR syndrome (11p13 deletion), Denys–Drash and Frasier syndromes (WT1), 5α-reductase deficiency, 17β-hydroxysteroid dehydrogenase deficiency, partial androgen insensitivity (AR) and 9p24.3 (DMRT1/2) or 10q26 deletions [96]. In 46,XY women, SRY variants or deletions explain only 15% to 20% of cases; further causes are complete androgen insensitivity, campomelic dysplasia, 9p24 monosomy and Xp21.2–p22.2 duplication (dosage-sensitive reversal), and approximately 80% of XY women with gonadal dysgenesis remain without a defined aetiology [96]. Among short-limb dysplasias, campomelic dysplasia, Smith–Lemli–Opitz syndrome and some short-rib polydactyly dysplasias may show sex reversal, which makes assessment of the external genitalia on ultrasound mandatory [128]. The distinction rests on skeletal radiology and molecular investigation.

6.4. Pierre Robin sequence

PRS is frequently an endophenotype of campomelic dysplasia [54]; the genes of interest in PRS include SOX9, and the chromosomal aberrations include 17q deletion [133]. In a patient with PRS, campomelic dysplasia should be considered when there are small scapulae, bowed bones, 11 pairs of ribs, cervical abnormalities or genitalia discordant with the karyotype [4, 5]. Even without these signs, rearrangements or deletions far upstream of SOX9 may cause isolated PRS, and a family with a deletion of approximately 1 Mb showed phenotypic continuity between isolated PRS and ACD [8, 82].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no disease-modifying treatment, and the GeneReviews investigational therapies section names no candidate [1, 13]. Management is supportive and multidisciplinary, addressing manifestations determining survival and function: airway, cervical and thoracolumbar spine, cleft palate and feeding, hips and feet, hearing and, in 46,XY individuals with gonadal dysgenesis, germ cell tumour risk and endocrine function [1]. Neonatal airway management is the main determinant of early survival [13]. Neonatal resuscitation and intensive care decisions should consider that survival depends on genetic class and malacia severity, and lethality is lower than described in public information sources quoting “90%” lethality, which does not reflect ACD [5]. For viable fetuses with skeletal dysplasia, the 2009 guideline recommends a predelivery plan involving obstetrics, neonatology, anaesthesiology and genetics, because many neonates with non-lethal dysplasias have immediate respiratory compromise and relative macrocephaly may complicate vaginal delivery [120]. In Towers and colleagues' ACD case, delivery-room intubation was necessary for moderate respiratory compromise [5].

Table 7.1. Recommended assessments after diagnosis in infants surviving the neonatal period (GeneReviews, Table 3) [1]

Table 7.2. Treatment of manifestations (GeneReviews, Table 4, supplemented with published series)

7.2. Airway and breathing

Airway obstruction in campomelic dysplasia is multilevel and combines PRS, laryngomalacia, diffuse tracheobronchomalacia, subglottic stenosis in some patients and the restrictive chest wall defect [32, 95, 101]. Bronchoscopy characterises malacia: it documented tracheobronchomalacia in the earliest cases [95, 100] and, in the Polish case, laryngotracheoscopy on the third day showed tracheomalacia over two-thirds of tracheal length, while CT angiography identified a vascular ring formed by the brachiocephalic trunk compressing the trachea and left bronchus, treated by brachiocephalic trunk suspension [60]. Tracheostomy and gastrostomy were needed at six months in the Brazilian patient with t(17;20), after failed ventilator weaning and an apnoeic episode with severe bradycardia requiring chest compressions [59], and at three months in a Korean patient with severe laryngomalacia who died at four months from progressive respiratory failure [135].

More recent series show that airway reconstruction is possible. In Cincinnati, six patients with campomelic dysplasia, tracheostomised or ventilator-dependent due to multilevel obstruction (mean age 19.4 years; mean follow-up 12.2 years), were treated by an airway team: four underwent open reconstruction and were decannulated; one underwent reconstruction of complete subglottic stenosis, improving but remaining ventilator-dependent because of severe scoliosis; and two required no reconstruction, were weaned from ventilation and were being assessed for decannulation [103]. The authors proposed clinical airway management guidelines, whose text was not consulted [103]. In 1996, Ruan and colleagues described the first single-stage laryngotracheal reconstruction with a rib graft for diffuse laryngotracheomalacia and moderate subglottic stenosis [102].

Robin sequence consensuses apply to the oropharyngeal component of obstruction. The 2016 international clinical consensus defines PRS as micrognathia, glossoptosis and upper airway obstruction, describes obstruction as multilevel and intermittent, particularly during sleep, and recommends sleep studies and initial assessment of respiratory severity and feeding problems [136]. A 2025 commentary discussed seeking consensus in infant Robin sequence diagnosis and management [137]. The International Pediatric Otorhinolaryngology Group (IPOG) published expert recommendations in 2020 on postnatal assessment, antenatal obstruction and perinatal airway management in PRS [138]. The ERN CRANIO European Robin sequence guideline (2024) was not obtained in full, and its recommendations are not reproduced [29, 139]. These consensuses do not address tracheobronchomalacia, which may maintain obstruction in campomelic dysplasia after the mandibular component has been corrected; in Towers and colleagues' case, positional respiratory events due to micrognathia led to mandibular distraction two weeks after neonatal intensive care discharge [5].

7.3. Cleft palate and feeding

Cleft palate is treated by a craniofacial team, and closure timing depends on respiratory stability [1, 134]. Narimatsu and colleagues performed Furlow palatoplasty at two years and nine months, after respiratory stabilisation, and reviewed literature on timing and technique [134]. In recent cases, palatoplasty was performed at ten months [60] and seven months after neonatal discharge [5]. Feeding difficulties, worsened by the cleft, are frequent in PRS [136]; gastrostomy was used in several patients and could be removed at 16 months in Towers' case [5, 59]. In an Indian child with ACD, the neurosurgeon advised against cervical extension during palatoplasty because of canal narrowing on MRI, and surgery proceeded uneventfully with these precautions [140].

7.4. Spine

The spine is survivors' main orthopaedic problem. Cervicothoracic kyphoscoliosis progresses, compromises pulmonary function and may cause spinal cord compression; surgery is often needed in childhood and bracing generally does not help [1, 116]. In a retrospective Minneapolis series of eight patients (mean follow-up three years and nine months), five initially received an orthosis and six ultimately required surgery; complications included pseudarthrosis in 50% and neurological problems in 33%, and the authors recommended non-instrumented anterior and posterior fusion with postoperative halo-cast immobilisation to prevent progression and potentially fatal sequelae [116]. Coscia and colleagues recommended active deformity treatment because patients survive longer than previously thought [97]. Absent pedicles often preclude fixation: in a ten-year-old girl with progressive kyphoscoliosis, neurological compromise and thoracic stenosis, C2–L4 decompression and fusion used pedicle screws where possible and sublaminar cables, because pedicle fixation was impossible in the lower cervical and upper and mid-thoracic spine and “floating” posterior elements precluded lower cervical laminar fixation; with a cervicothoracolumbosacral orthosis, there was neurological improvement and no hardware failure at two years [99]. In a neonate with severe cervical and thoracic kyphoscoliosis and respiratory compromise, the authors considered intervention potentially appropriate in selected patients [141]. Neonatal cervical instability has a guarded prognosis: closed reduction with a custom orthosis did not prevent complete spinal cord injury in one patient [98]. A six-and-a-half-year-old girl underwent two posterior cervical and two thoracic fusions, with significant perioperative complications [111].

7.5. Hips, feet and limbs

Hip dislocation or subluxation and clubfeet are treated by orthopaedics, with surgical foot correction [1]. In Ray and Bowen's case, a Pavlik harness was used in infancy for hip subluxation, and release of complex foot deformities and tibial osteotomy were required [111]. In a two-year-old girl undergoing hip dislocation surgery, the postoperative course was complicated by several tracheobronchomalacia-related apnoeic episodes, with paediatric intensive care admission [119]. In mild forms with an ischiopubic-patellar phenotype, patellar instability and foot deformities are treated with orthopaedic measures [6].

7.6. Hearing, vision and teeth

Conductive or sensorineural hearing loss is followed by audiology, with hearing aids when needed [1, 3]. Myopia and dental caries described in survivors warrant ophthalmological and dental surveillance, without a source-defined interval [3]. A four-year-old Ecuadorian girl had bilateral conductive hearing loss and Chiari type 1 malformation [79].

7.7. Gonads: sex assignment, gonadectomy and tumour risk

Sex assignment in a neonate with truly atypical genitalia should be discussed by a DSD team at a tertiary centre [96]. Minto and colleagues (2003) questioned childhood genital surgery and advocated a conservative approach deferring surgery to allow the individual's participation, a position also discussed by Reiner and Gearhart (2004) [96]. The 2016 international DSD consensus updates, including gender assignment, exist but were not consulted in full for this article [142, 143]. DSD Families supports families with differences of sex development [31].

In 46,XY individuals with undervirilised or female genitalia, GeneReviews recommends gonadal removal because of increased gonadoblastoma risk, recognising no data on appropriate intervention age [1]. In 1995, Hong and colleagues, describing the first bilateral gonadoblastoma in the disease, recommended karyotyping all phenotypic girls with campomelic dysplasia as soon as dysplasia is recognised and gonadectomy if the karyotype contains a Y chromosome or fragment [106]. Witchel and Reyes-Múgica's 2025 review of tumours in DSD does not specifically mention SOX9 but considers germ cell tumour risk high in complete 46,XY gonadal dysgenesis and recommends bilateral gonadectomy after confirmed diagnosis; in partial gonadal dysgenesis risk is poorly established and higher with intra-abdominal gonads [25]. The same review emphasises that neither ultrasound nor MRI provides histological detail, no reliable serum markers exist, laparoscopy is useful, biopsies should include the gonadal surface, histology with immunohistochemistry should be interpreted by a specialist, decisions should be shared with patient and family and fertility preservation considered when testicular tissue is present [25].

Published cases support this recommendation: bilateral gonadoblastoma at three years [106] and one year [107], dysgerminoma at eight years with an enlarged gonad [76] and gonadoblastoma in two of three sisters with an upstream deletion without dysplasia [12]. In the Polish case, tumour markers (alpha-fetoprotein, beta human chorionic gonadotrophin, or βhCG, and lactate dehydrogenase) were monitored until gonadectomy, performed after an isolated βhCG elevation at 24 months; histology showed no tumour [60]. The authors note that marker elevation typically indicates already invasive disease, oncological surveillance is ineffective as an alternative to surgery and gonadectomy is justified even with negative histology, because dysgenetic gonads have no hormonal or germline potential [60]. In the Indonesian series, parents declined laparoscopy to locate the gonads despite the recommendation of prepubertal gonadectomy [23].

Sources differ regarding timing. GeneReviews specifies no age [1]; the 2025 review recommends gonadectomy after confirmed complete dysgenesis diagnosis [25]; case reports performed it between one and eight years or recommended it before puberty [23, 76, 107]. Bilateral gonadoblastoma at one year and dysgerminoma at eight years demonstrate that risk exists in early childhood [76, 107]. In 46,XY individuals with a male phenotype and descended testes, such as the Indonesian boy with p.(Ala116Val), sources define no specific tumour surveillance [23].

7.8. Pubertal induction and hormone therapy

In complete 46,XY gonadal dysgenesis, puberty is delayed and primary amenorrhoea with hypergonadotrophic hypogonadism occurs in adolescence [25]. Campomelic dysplasia-specific sources on pubertal induction are case reports. Harrison and Millington (2025) treated a 46,XY adolescent with primary amenorrhoea and hypogonadotrophic hypogonadism using one-quarter of a 0.025 mg transdermal oestradiol patch (equivalent dose 0.00625 mg), with planned titration to increasing doses over one year, to induce puberty, promote bone growth and allow concordance with gender identity [108]. This is a case-report dose, used outside a disease-specific indication, not a validated regimen; the report does not state the brand, and consulted sources do not include oestradiol labels for pubertal induction. In the Japanese woman with ACD and a translocation, menarche occurred at 33 years and four months after oestrogen followed by oestrogen–progestogen, without doses described in the abstract [109]. Consulted sources define no disease-specific pubertal induction regimen; general endocrine protocols apply, which are outside this article's sources.

7.9. Anaesthesia, perioperative care and activities to avoid

Anaesthesia for imaging or surgery carries risks, and any procedure in a patient with a cervical spine abnormality requires special care with cervical manipulation and the airway [1]. Assessment of the cervical spine and spinal canal by radiography and, if needed, MRI before anaesthesia allowed cervical extension to be avoided during palatoplasty [140]. Tracheobronchomalacia predisposes to postoperative apnoea, as in the child undergoing hip surgery who required intensive care [119], and acute apnoea complicated recovery after vascular surgery in the Polish case [60]. In Funchal, a boy with campomelic dysplasia died at 16 months from malignant hyperthermia; the authors note that malignant hyperthermia is rare but has been associated with skeletal dysplasias, without an established causal relationship with campomelic dysplasia [144]. Ray and Bowen's orthopaedic procedures and McDowell and colleagues' spinal surgery involved significant perioperative complications [99, 111]. There are no known circumstances to avoid, but in survivors with cervical malformations it is reasonable to limit activities involving extreme flexion or extension, such as somersaults [1].

7.10. Pregnancy, lactation and transition

Some affected women have reproduced [1]. An Australian woman with ACD due to t(2;17), ventilatory failure and severe kyphoscoliosis had a successful pregnancy [115]. Sources consulted describe no specific pregnancy, delivery or lactation protocols; reproductive risk and prenatal diagnosis are addressed in section 8. Transition to adult care mainly involves the spine, airway and ventilation, hearing and, in 46,XY women, hormone replacement therapy; sources describe no disease-specific transition model [1, 103].

7.11. Regulatory status

Table 7.3. Regulatory status

Absence of records was checked by searching ClinicalTrials.gov and literature up to 10 October 2026; a negative search does not prove absence of unpublished programmes [26].

7.12. Clinical trials and intervention studies

There is no registered therapeutic clinical trial for campomelic dysplasia or ACD; the ClinicalTrials.gov search (terms “campomelic”, “campomelic dysplasia” and “SOX9 dysplasia”, 10 October 2026) returned only unrelated studies [26]. Intervention evidence comes from retrospective series and case reports, summarised in Table 7.4.

Table 7.4. Available intervention studies (no randomised trials)

These studies cannot estimate effects with confidence intervals or compare techniques: they are small, retrospective, single-centre series without comparison groups, with selection bias towards patients surviving to intervention. There are no published negative trials because there are no trials; author conclusions (for example, preference for non-instrumented fusion with halo casting) are experience-based opinions, and the instrumentation technique described in 2017 shows that approaches have evolved [99, 116].

7.13. Developments in the last twelve months

Table 7.5. Developments from October 2025 to October 2026, by evidence level

Searches identified no gene therapies, pharmacological SOX9 modulators, company announcements, opinions or regulatory procedures for the disease [26].

7.14. Guidelines and consensus documents

There is no campomelic dysplasia-specific clinical guideline. Management rests on GeneReviews, expressing expert opinion, and documents from adjacent fields, listed in Table 7.6.

Table 7.6. Applicable guidelines and consensus documents

There are three relevant discrepancies between sources. Regarding gonadectomy timing, GeneReviews specifies no age, the 2025 review recommends it after confirmed diagnosis and case reports propose the prepubertal period [1, 23, 25]. Regarding orthoses in kyphoscoliosis, GeneReviews states that bracing generally does not help, and the Minneapolis series showed that five of eight patients initially received an orthosis and six required surgery [1, 116]. Regarding invasive prenatal diagnosis following a child with de novo disease, the 2009 guideline considers the issue controversial because of relatively low germline mosaicism risk, whereas EuroGentest considers it indicated with a recurrence risk of approximately 5% [15, 120].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

Campomelic dysplasia is autosomal dominant and typically results from a de novo SOX9 variant; rarely, from a de novo or inherited chromosomal rearrangement [1]. Most parents are unaffected, but some adults have been diagnosed after an affected child's birth, so testing parents for the proband's variant or rearrangement and clinical and radiological examination are recommended [1, 68, 80]. Table 8.1 summarises risks by scenario.

Table 8.1. Recurrence risks by scenario

Empirical data confirm a low but non-zero risk. In the UK study, among 41 siblings of 36 index cases, two were affected (segregation proportion 0.05; 95% confidence interval approximately 0.00 to 0.11) [38]. Most cases are de novo, and the small number of recurrences arises from gonadal mosaicism [3, 55].

8.2. Parental mosaicism

Parental mosaicism has different forms with distinct counselling consequences. Parents may have exclusively germline mosaicism without blood abnormalities: in Cameron and colleagues' family, three children were affected with normal parental blood [75]. They may have blood-detectable somatic mosaicism without clinical or radiological signs, as in the father of an Italian fetus [84], the phenotypically normal father with a mosaic SOX9 deletion and two affected children [83] and the mother with lymphocyte mosaicism for p.(Glu148Ter) without physical abnormalities [5]. Or they may have mild manifestations, like the mother with subtle skeletal abnormalities and somatic c.441del mosaicism, with two children with classical CD; the authors recommended meticulous clinical and radiological examination of apparently healthy parents [68]. Parental blood testing detects only somatic mosaicism and does not exclude germline mosaicism [15]. A phenotypically normal couple with two previous fetal CD pregnancies and no blood variant identified by conventional methods used in vitro fertilisation with haplotype-based preimplantation genetic diagnosis (PGD): initially no embryo could be declared unaffected, because all shared a haplotype with the product of conception; peripheral blood SNP microarray identified the woman as somatically mosaic with a germline component, and one of five euploid embryos was considered unaffected and transferred, without a viable pregnancy [85].

8.3. Familial transmission in regulatory and mild forms

Vertical transmission is more frequent in mild forms. Described examples include mother-to-daughter transmission of clinical CD [37], a t(13;17) across five generations [63], a familial t(4;17) with mild ACD [62], a 960 kb upstream deletion transmitted from a mother with ACD to a 46,XY child with DSD [78], an approximately 1 Mb deletion across three generations with phenotypes ranging from isolated PRS to ACD [82] and a 349 kb deletion present in the unaffected father and three 46,XY daughters with sex reversal, demonstrating that DSD expression depends on chromosomal sex and has variable penetrance [12]. In 46,XX DSD due to upstream duplication, inheritance is sex-limited autosomal dominant: only 46,XX individuals are affected; transmission by an unaffected 46,XY father has been demonstrated in at least two testicular DSD and three ovotesticular DSD families; all described 46,XY carriers are anatomically typical fertile males; and one XY father inherited the duplication from his fertile 46,XX mother [10]. In a 2025 series, duplications were inherited from the father in three cases and an asymptomatic mother in two [91]. If parents are non-carriers, risk does not exceed the empirical risk, although theoretically higher because of paternal germline mosaicism; individuals with non-syndromic 46,XX testicular DSD are infertile [10].

8.4. Cascade testing

When the proband has a rearrangement, parental karyotyping should be performed and, if a parent has a balanced rearrangement, chromosome analysis offered to at-risk relatives [1, 55]. In families with upstream duplication or deletion, family screening identifies asymptomatic carriers, including 46,XX women carrying duplications and 46,XY men carrying deletions [12, 91]. The Brazilian woman with balanced translocation-associated ACD sought counselling at 31 years about offspring risk, illustrating the need to revisit counselling in adulthood [59].

8.5. Prenatal and preimplantation diagnosis

In a pregnancy with a known familial variant, prenatal diagnosis in chorionic villi or amniocytes and preimplantation genetic testing (PGT) are possible; for a familial rearrangement, karyotyping in amniocytes or chorionic villi [1, 15]. Predictive prenatal testing is possible only if the variant has been identified in a previous pregnancy or individual [15]. Following a child with de novo disease, the 2009 guideline considers offering invasive testing controversial because of relatively low germline mosaicism risk [120], whereas EuroGentest considers it justified with a risk of approximately 5% [15]; ultrasound targeting the scapulae, thorax and long bones is complementary [15]. Haplotype-based PGT may fail when the carrier parent is unknown [85]. DNA storage is recommended for probands without a molecular diagnosis [1, 120]. With cell-free fetal DNA sex determination, female genitalia in a fetus with Y chromosome DNA should prompt consideration of sex reversal [55].

8.6. Counselling content

Counselling before another pregnancy should address inheritance, estimated recurrence risk and its uncertainty, germline mosaicism undetectable in blood, prenatal and preimplantation diagnostic options and limitations, and prognosis by genetic class [1, 5, 15]. In prenatal counselling after diagnosis, the 2026 review authors recommend information according to alteration class and note that online information overestimates lethality [5]. Antenatal Results and Choices and Contact a Family were listed by Oxford Desk Reference as UK family resources [55]. Consulted sources do not define the appropriate age for testing asymptomatic minors; in duplication-associated 46,XX DSD, described 46,XY carriers are anatomically typical fertile males, whereas 46,XX carriers are at risk of DSD [10].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

No reliable population data exist on campomelic dysplasia prevalence. GeneReviews authors estimate prevalence at 1:40,000 to 1:80,000 [1], the same range given by EuroGentest without a specified population or method [15]. GeneGuidance records 1.9 per 100,000, the midpoint of this range, which should be read as an order of magnitude rather than a measured rate [13]. A 2026 Indonesian series cites approximately 1:200,000 births, attributing this to another source without an explicit population basis [23]. The estimates differ by a factor of two to five, and neither comes from a population-based registry. Neither includes duplication-associated 46,XX DSD or isolated PRS due to upstream rearrangement. Orphanet prevalence for isolated PRS (ORPHA:718) does not apply to campomelic dysplasia (ORPHA:140) [16, 17].

Figures for related entities measure something different. Non-syndromic 46,XX testicular DSD of all causes has a prevalence of approximately 1:20,000 males, and SRY explains approximately 80% of cases with typical male genitalia; SOX9 is a very rare to rare cause [10, 96]. Complete 46,XY gonadal dysgenesis of all causes has an incidence of approximately 1:80,000 to 1:100,000 births [25]. ACD accounts for approximately 10% of campomelic dysplasia cases [52, 78], but authors of an Indian series argued that it is among the most common skeletal dysplasias and frequently misdiagnosed, which, if true, would lead to frequency underestimation [113].

9.2. United States, Europe and other regions

Europe. Mansour and colleagues' UK study (1995) is the reference national series: 36 patients identified through multiple ascertainment at genetics, radiology and pathology centres, with a chromosomal sex ratio of approximately 1:1 and three-quarters of 46,XY individuals showing sex reversal or atypical genitalia; it is not a prevalence study [38]. Other European series include five Italian prenatally diagnosed cases [84], two French cases detected in the first trimester [24], the three-generation Italian family with an upstream deletion [82], German ACD cases with hypomorphic missense variants [50], the Lithuanian p.(Lys106Glu) case [67] and the Polish case described in section 10 [60]. A 2025 Turkish-German series included twelve 46,XX cases with upstream duplications [91], and a 2019 report described prenatal diagnosis through a SOX9 deletion in Turkey [146].

United States. The Minneapolis surgical series (eight patients with kyphoscoliosis), Cincinnati series (six patients with reconstructed airways) and Houston and colleagues' review (97 patients) are the main North American sources; they describe tertiary-centre referrals rather than population frequency [32, 103, 116]. The 2026 review, undertaken in the United States, compiles published cases from all origins [5].

Asia and other regions. Described patients include Japanese patients with long survival, maternal mosaicism and adult translocation-associated ACD [68, 70, 74, 109], Chinese prenatal diagnoses [73, 123], a Korean case without sex reversal [135], a Taiwanese case with a homozygous deletion [52], Indian ACD cases [113, 140], the first Indonesian cases [23], an Ecuadorian case [79] and an Australian woman with a successful pregnancy [115]. Consulted sources describe no founder variants or populations with increased frequency; SOX9 variants are predominantly private and de novo [1, 66].

9.3. Brazil and Portugal

Mattos and colleagues' Brazilian cohort (2015), from Hospital de Clínicas de Porto Alegre, included nine patients referred from Rio Grande do Sul, São Paulo and Pernambuco, six retrospective (2000–2011) and three prospective, assessed between April 2012 and November 2013 [66]. All had typical phenotypes; two were stillborn and the remainder died in the first three months; mean gestational age of liveborn patients was 36.4 ± 2.5 weeks, mean birth weight 2672.8 ± 699.0 g, mean length 40.7 ± 3.1 cm (below the 10th percentile in all measured) and mean head circumference 36.1 ± 1.8 cm, above the 90th percentile in most [66]. Sanger sequencing identified new variants in seven (78%): six premature termination codons and one splice variant; de novo occurrence could be confirmed in only one patient; one of three 46,XY patients had sex reversal [66]. This is a hospital referral cohort, not a measure of Brazilian frequency. In São Paulo, Fonseca and colleagues (2013) described two de novo balanced translocations with ACD, a woman followed to 31 years and a ventilator-dependent boy, alive at 32 and 3 years at last follow-up [5, 59]. The textbook Síndromes Genéticas: Reconhecer para Tratar, published in Ceará, includes campomelic dysplasia in the lethal dysplasia differential [104].

In Portugal, consulted sources include a report from Hospital Dr. Nélio Mendonça in Funchal: a boy born at 40 weeks, diagnosed with campomelic dysplasia, who died at 16 months from malignant hyperthermia [144]. Consulted sources include no Portuguese series or frequency data for Portugal; this absence does not demonstrate absence of published data.

9.4. Special populations

46,XY individuals with a female phenotype form the population with specific tumour prevention, hormone therapy and gender identity support needs [25, 108]. Adult survivors with ventilatory failure and severe kyphoscoliosis form a group at risk during pregnancy and anaesthesia [1, 115]. Parents with mosaicism or minimal expression form an often unrecognised at-risk population [68, 80].

9.5. European reference networks and patient associations

In the European Union, ERN BOND is the European reference network for rare bone diseases [27]; Endo-ERN covers rare endocrine conditions, including sexual development [28]; and ERN CRANIO covers craniofacial anomalies and rare ear, nose and throat disorders, including Robin sequence and cleft palate, and published the European Robin sequence guideline [29]. The European Skeletal Dysplasia Network (ESDN), mentioned in the 2009 guideline, did not respond during the October 2026 consultation [120]. GeneReviews lists resources including the MAGIC Foundation, Human Growth Foundation, Little People of America, the Freiburg skeletal dysplasia group and the International Skeletal Dysplasia Registry at the University of California, Los Angeles [1, 30]. DSD Families in the United Kingdom supports families with differences of sex development [31], and Contact a Family and Antenatal Results and Choices support families in the prenatal context [55].

10. Illustrative Clinical Case

10.1. 46,XY girl with ACD, complete gonadal dysgenesis and an upstream SOX9 deletion (Poland, 2025)

Szoszkiewicz and colleagues in Poznań described a girl in 2025, the first child of non-consanguineous parents (28-year-old mother with previous hypothalamic amenorrhoea, 29-year-old father), born by uncomplicated vaginal delivery at 41 weeks, weighing 2960 g (3rd–10th percentile, small for gestational age), length 50 cm (50th–75th percentile), head circumference 34 cm (50th–75th percentile) and Apgar score 9/9 [60]. After birth she had respiratory distress requiring non-invasive support; she had a flat midface and soft palate cleft. On the third day, laryngotracheoscopy showed tracheomalacia over two-thirds of tracheal length, and CT angiography a brachiocephalic trunk vascular ring compressing the trachea and left bronchus, with suspected vertebral malformation (incomplete neural tube closure at C5–C7 and in the thoracic spine). She underwent surgical brachiocephalic trunk suspension and right thymic lobe removal; postoperatively she had acute respiratory distress with apnoea and pallor, resolving with respiratory rehabilitation [60].

Dysmorphism was mild: sloping forehead, low-set ears, micrognathia, plantar crease, broad nasal root, cleft palate, long philtrum, short neck with low hairline, widely spaced nipples, gap between first and second toes and female external genitalia. Karyotype was 46,XY, prompting endocrine assessment; at two months pelvic ultrasound showed a normal uterus without visible ovaries, and complete 46,XY gonadal dysgenesis was diagnosed [60]. During minipuberty (five and eight weeks), luteinising hormone (LH) was 0.1 and below 0.03 IU/L, FSH 5.4 and 5.6 IU/L, oestradiol below 10 pg/mL, testosterone 0.24 and 0.1 nmol/L, inhibin B below 4 pg/mL and AMH 0.01 ng/mL; thyroid-stimulating hormone, corticotrophin and insulin-like growth factor 1 were normal. Gonadotrophins were unexpectedly low, but FSH later rose to 38.2 IU/L, the hypergonadotrophic hypogonadism pattern typical of gonadal dysgenesis [60].

Tumour markers were monitored periodically until gonadectomy, and palatoplasty was performed at ten months. Radiographs at 15 months showed a short neck, severe thoracic kyphoscoliosis, a narrow bell-shaped thorax, hypoplastic scapulae, poorly mineralised thoracic pedicles, narrow iliac wings and straight femora, tibiae and fibulae (article figure 1A and 1B) [60]. At 24 months an isolated βhCG elevation was detected (21.84; reference below 5, in article units), prompting bilateral gonadectomy; histology in tissue collected at three years and ten months showed a streak gonad resembling ovarian stroma and a fallopian tube, without embryonal tumour or malignancy (figure 1F and 1G) [60].

The course was marked by progressive cervicothoracolumbar kyphoscoliosis, genu valgum and pes planovalgus (figure 1C to 1E: short neck with cervical kyphoscoliosis, long philtrum and low ears at three years and three months; narrow iliac wings, pubic widening and symphyseal diastasis; pes planovalgus) [60]. CT showed scoliosis with a left C7 apex (Cobb angle 77°) and right D9–D10 apex (Cobb 93°), reduced cervical and thoracic vertebral body height, vertebral rotation, canal stenosis between D1 and D7, hypoplastic left C4 to C7 transverse processes, non-union of C1, C4, C5 and L3 arches, lumbar kyphoscoliosis of 20° and spina bifida from L3. The patient had hypotonia and mild gross motor delay, attributed by the authors to complex spinal malformation, hypotonia and joint hyperlaxity, with independent walking at 17 months; at four years intellectual and social development were normal and she spoke in sentences, following oral electrical stimulation for initial speech delay attributed to palatal surgery and hypotonia [60].

High-resolution CMA (1×1M) identified an interstitial deletion arr[GRCh38] 17q24.3(70260910_71919954)x1, with a minimum size of 1.659 Mb; quantitative PCR showed it was de novo, and breakpoint sequencing defined a 1.671 Mb deletion, chr17:70259128-71930429 (hg38), situated between 191 kb and 1.862 Mb upstream of SOX9 (figure 2A to 2C) [60]. The deletion includes one non-coding gene and eleven known SOX9 enhancers (F2, hs1467, SOX9cre1, E1, enh3, F8, enh4, enh5, enh6, enh7 and E3), encompasses two topologically associated domains (TADs) and one boundary, and preserves promoter-proximal elements (E1 at −28 kb, hTES at −12 kb and E7 at +93 kb); the figure 2D map compares it with upstream deletions already described in ACD and PRS [60]. It is the second-largest upstream deletion described in ACD; the largest, approximately 4.2 Mb, was associated with an unbalanced t(7;17) [60].

Figures were consulted through full-text legends (Figure 1, clinical, radiological and histological findings: https://pmc.ncbi.nlm.nih.gov/articles/PMC12874664/figure/Fig1/ ; Figure 2, deletion, validation and enhancer/TAD map: https://pmc.ncbi.nlm.nih.gov/articles/PMC12874664/figure/Fig2/) [60].

10.2. Lessons from the case

The case brings together this article's elements. First, upstream deletion-associated ACD may present as PRS with respiratory distress and female genitalia, without the campomelia naming the disease, and diagnosis depends on karyotype and thoracic and spinal radiographs [5, 60]. Second, the deletion was detected by high-resolution CMA and would not be detected by SOX9 sequencing [1, 60]. Third, absent minipuberty with low gonadotrophins does not exclude gonadal dysgenesis: the authors attributed it to concomitant severe illness and considered it a diagnostic pitfall [60]. Fourth, isolated βhCG elevation did not correspond to tumour, but the authors advocated gonadectomy because marker surveillance is ineffective as an alternative and dysgenetic gonads have no hormonal or germline potential [60], consistent with the gonadectomy recommendation in complete 46,XY dysgenesis [25]. Fifth, severe kyphoscoliosis dominated morbidity at four years, as predicted by survivor natural history [1]. Management in the report (vascular surgery, palatoplasty and gonadectomy timing) represents individual decisions, not a protocol; gonadectomy timing in particular is undefined in reference sources [1].

10.3. Complementary case: Brazilian adult survivor with translocation-associated ACD

Fonseca and colleagues in São Paulo described a girl born at term by caesarean section (breech presentation), with repeated acute bronchitis during her first six years, height at the 50th percentile until six years and 25th at nine, and normal psychomotor and intellectual development [59]. At 12 years she was referred for short stature (136.5 cm, 3rd percentile), with delayed bone age, hypoplastic scapulae, thoracolumbar scoliosis and 11 rib pairs with hypoplasia of the first four pairs, still prepubertal. Karyotyping showed a de novo t(7;17)(p13;q24), with normal parental karyotypes, and array-CGH showed no imbalances; the 17q breakpoint lay 855–917 kb upstream of SOX9 [59]. At 31 years she returned, at 159 cm and 54 kg, concerned about offspring risk [59]. The case illustrates the favourable-prognosis form associated with distal cluster breakpoints and the need for adult reproductive counselling (section 8) [5, 59].

11. Prognosis and Long-Term Follow-Up

11.1. Survival

Survival prognosis depends mainly on the neonatal airway and subsequently the spine. Most neonates with classical CD die neonatally from respiratory failure caused by tracheobronchomalacia or cervical instability rather than thoracic hypoplasia [1, 3, 4]. Figures with denominators come from case series, not population cohorts. In the Brazilian cohort (2000–2013), two of nine patients were stillborn and all liveborn patients died in the first three months [66]. In the 1995 UK series, there were three survivors among 36 patients, two with 17q rearrangements [38]. In the 2026 published-case review, excluding terminations and cases without outcomes, 20 of 67 patients with CD and complete SOX9 testing (30%) were alive beyond one year, versus 45 of 50 with ACD (90%) alive at last follow-up; among CD cases without genetic testing, 143 of 164 (87%) died by the first year [5]. By genetic class, survival beyond the first year in CD was approximately 25% or less for deletions, insertions, nonsense and splice variants, approximately 40% for missense and approximately 75–80% for 17q rearrangements (Table 2.3) [5]. These figures have publication and duplication bias and describe a mixture of patients with and without intensive care; they do not equate to individual risk [5].

In neonatal survivors, later death may result from spinal cord compression due to cervical instability, respiratory failure or perioperative complications [1, 98, 144]. A patient with a breakpoint at 900 kb died at six years from tracheobronchomalacia [59], and two patients with p.(Tyr440Ter) died in childhood, at four years [5]. Treated series show survival to young adulthood with tracheostomy, airway reconstruction and spinal surgery [103], and adult translocation survivors were followed to 35 years [5, 109].

11.2. Functional prognosis

Long-term morbidity includes variable short stature, progressive kyphoscoliosis with pulmonary compromise, cervical instability, hearing loss, recurrent apnoea, myopia and caries [1, 3]. Cognitive prognosis is described differently (section 3.5): GeneReviews considers intellect normal, whereas Smith reports mild to moderate impairment in most [1, 3]. Respiratory independence may be achieved after reconstruction, but severe scoliosis may maintain ventilator dependence [103]. In 46,XY individuals with gonadal dysgenesis, gonadal function is absent, fertility is not possible and hormone replacement therapy is necessary [25, 60]. Mild forms, such as ischiopubic-patellar and those associated with distant breakpoints, allow adult life and reproduction [1, 63].

11.3. Surveillance

GeneReviews defines only one surveillance interval, annual spinal assessment in long-term survivors [1]. Other assessments follow from known manifestations, without source-defined intervals, and are clinically directed. Table 11.1 compiles recommendations and their degree of definition.

Table 11.1. Surveillance in survivors

12. Summary and Final Considerations

Campomelic dysplasia is an autosomal dominant skeletal dysplasia, almost always de novo, caused by insufficiency of SOX9, the transcription factor governing chondrogenesis and, downstream of SRY, testicular differentiation. The classical phenotype combines anterior femoral and tibial bowing with skin dimples, hypoplastic scapulae, 11 rib pairs, narrow vertical iliac wings, hypomineralised thoracic pedicles, cervical abnormalities, Pierre Robin sequence with cleft palate and laryngotracheobronchomalacia; approximately three-quarters of 46,XY individuals have female or atypical genitalia, with dysgenetic gonads and germ cell tumour risk. The acampomelic form, approximately 10% of cases, differs only in absent bowing and is frequently poorly recognised; with straight bones, scapular hypoplasia is the sign to seek.

Disease genetics illustrates the role of distant enhancers. Beyond coding variants explaining approximately 90% of cases, translocations, inversions and deletions of the approximately 2 Mb region upstream of SOX9 reduce expression through position effects, with milder severity as the breakpoint lies further from the gene. Alteration position determines separate phenotypes: proximal and distal clusters associate with CD or ACD, the RevSex interval with isolated DSD (46,XY through deletion, 46,XX through duplication), and more distal elements with isolated PRS, whose SOX9 relationship has limited evidence according to ClinGen. The mild ischiopubic-patellar form represents disease expression in survivors. Molecular diagnosis requires sequencing including untranslated regions, high-resolution CNV analysis and karyotype or genome for balanced rearrangements; negative sequencing or exome results do not exclude disease.

Prognosis is determined by the neonatal airway and subsequently the spine. In published series, approximately 30% of genetically confirmed CD patients are alive beyond the first year, versus approximately 90% with ACD, and 17q rearrangements associate with the best survival; these figures come from published cases and do not replace individual assessment. There is no disease-modifying treatment or clinical trial. Management is supportive: airway care with tracheostomy and, at experienced centres, reconstruction; cleft palate closure when breathing permits; early kyphoscoliosis and cervical instability surgery; cervical and respiratory precautions during any anaesthesia; and, in 46,XY individuals with gonadal dysgenesis, early karyotyping, gonadectomy and pubertal induction, with timing still undefined by sources. Counselling should explain the 2% to 5% recurrence risk after a de novo case due to germline mosaicism, careful parental examination, 50% risk when a parent is a carrier and prenatal and preimplantation diagnostic options, whose limitations have been demonstrated in mosaic families.

13. References

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