Dyggve–Melchior–Clausen, Smith–McCort, X-Linked Spondyloepiphyseal Dysplasia Tarda and Progressive Pseudorheumatoid Dysplasia

Five autosomal recessive or X-linked spondyloepi(meta)physeal dysplasias: the vesicular-trafficking Golgipathies due to DYM, RAB33B and TRAPPC2, and the progressive pseudorheumatoid arthropathy due to CCN6

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1 A class defined by intracellular trafficking

This article covers five entities of group 13 of the Nosology: DMC, the two forms of SMC, X-linked SEDT and progressive pseudorheumatoid dysplasia (PPRD) due to CCN6, which shares with SEDT the vertebral morphology and the early arthropathy, was called for decades «spondyloepiphyseal dysplasia tarda with progressive arthropathy» and, unlike the other four, has a mechanism of extracellular signalling rather than intracellular trafficking [1, 6, 13].

DMC, the two forms of SMC and SEDT are spondyloepi(meta)physeal dysplasias that share the same pathogenic principle: a defect in the machinery that transports matrix proteins between the endoplasmic reticulum, the Golgi apparatus and the cell surface of chondrocytes. Dyggve–Melchior–Clausen dysplasia (DMC) and Smith–McCort dysplasia type 1 (SMC1) result from biallelic variants in DYM, which encodes dymeclin; Smith–McCort dysplasia type 2 (SMC2) results from biallelic variants in RAB33B, which encodes a Golgi GTPase; X-linked spondyloepiphyseal dysplasia tarda (SEDT) results from hemizygous variants in TRAPPC2, which encodes sedlin, a subunit of the TRAPP complex required for the exit of procollagen from the endoplasmic reticulum [7, 8, 33]. In the 2023 revision of the Nosology of Genetic Skeletal Disorders, the four entities are in group 13, the spondyloepi(meta)physeal dysplasias (SE(M)D), with the dyadic «gene-related» designations that link phenotype to gene [1]. Recent cohorts use the expression «skeletal Golgipathies» for DMC and SMC, and the chapter on disorders of cellular trafficking in Saudubray's textbook lists DMC and SEDT among the trafficking disorders with skeletal changes, alongside multiple sulfatase deficiency and Yunis–Varón syndrome [22, 34].

The grouping also has a historical and clinical rationale. OMIM entry 304950, «X-linked Dyggve-Melchior-Clausen», still associated with ORPHA:239, corresponded to a family that, when restudied by Yunis and Yunis (Bogotá), revealed a frameshift variant in TRAPPC2, that is, SEDT [14, 35]. The confusion shows that the two conditions overlap at initial clinical recognition (short-trunk short stature, barrel chest, platyspondyly), although radiographs distinguish them [26].

1.2 Dyggve–Melchior–Clausen dysplasia and Smith–McCort dysplasia

In 1962, Dyggve, Melchior and Clausen described, in a sibship born of an uncle–niece marriage in Greenland, three children with a picture reminiscent of Hurler and Morquio syndromes: claw hands with limited extension, intellectual disability, generalised platyspondyly and iliac crests with a «lace-like» contour; the title of the article asked whether this was an inborn error of metabolism, and the interpretation at the time included the presence of urinary mucopolysaccharides [11, 36]. Four years earlier, Smith and McCort had published, as «osteochondrodystrophy of the Morquio–Brailsford type», a family from Guam with the same skeleton and normal intelligence [37, 38]. Spranger, Maroteaux and Der Kaloustian systematised the clinical and radiological picture of DMC in 1975 and, in 1976, Spranger, Bierbaum and Herrmann proposed separating the form without intellectual disability as «Smith–McCort dwarfism» [24, 39, 40]. Biochemical analysis at the time, including the study of Brazilian siblings by Toledo et al. in 1979, found no abnormality of mucopolysaccharide metabolism, and family segregation confirmed that both forms were autosomal recessive [41].

Molecular genetics arrived in 2002 and 2003. Ehtesham et al. linked SMC in a consanguineous family from Guam and three small families with DMC to the same region of 18q12, suggesting allelism [42]. In 2003, two independent groups identified the gene: Cohn et al. found variants in FLJ90130 in families with DMC and with SMC, with homozygosity for premature termination codons in the families with DMC, and concluded that DMC represents the null phenotype; El Ghouzzi et al., by positional cloning, described seven deleterious variants in ten families with DMC and proposed the name dymeclin [43, 44]. In 2006, a Turkish family with SMC without a DYM variant suggested genetic heterogeneity [45]. In 2012, Alshammari et al. mapped a locus at 4q31.1 in a consanguineous Saudi family with a DMC picture and normal intelligence and identified, by exome sequencing, a missense variant in RAB33B; in 2013, the DYM-negative Turkish patient revealed another variant in RAB33B, establishing SMC2 [3, 46].

1.3 X-linked spondyloepiphyseal dysplasia tarda

The first recognisable description is by Jacobsen, in 1939, in an American family of English origin with 20 affected individuals over five generations [25]. Maroteaux, Lamy and Bernard delineated «dysplasie spondylo-épiphysaire tardive» in 1957 in three families with 11 affected individuals, and Langer described the characteristic vertebral configuration of the adult in 1964 [47, 48]. Bannerman et al. reviewed the Jacobsen family in 1971 and characterised the X-linked recessive transmission [49]. Linkage studies placed the gene at Xp22, and in 1999 Gedeon et al. narrowed the interval to less than 170 kb and identified SEDL, with three dinucleotide deletions in three Australian families [9, 23]. The gene was renamed TRAPPC2 when sedlin was shown to be homologous to the Trs20 subunit of the yeast TRAPP complex [9]. In 2012, Venditti et al. showed that sedlin is recruited by TANGO1 and regulates the cycle of the SAR1 GTPase, allowing the carriers leaving the endoplasmic reticulum to grow large enough to accommodate procollagen [33].

1.4 Progressive pseudorheumatoid dysplasia

The history of this entity is one of a repeated category error. In 1970, Kahn et al. published cases under the designation «chondrodysplastic rheumatism»; in 1972, Laplane et al. described a familial «syndesmodysplastic dwarfism» [50]. In 1981, Perri described the radiological findings of what he considered a new bone dysplasia, and in 1982 Wynne-Davies, Hall and Ansell published 15 patients from 9 families, four of them Arab, under the name «spondyloepiphyseal dysplasia tarda with progressive arthropathy», insisting that the resemblance to rheumatoid arthritis was clinical and not radiological and that platyspondyly was the additional element [6, 51]. In 1983, Spranger, Albert, Schilling, Bartsocas and Stöss consolidated the entity as «progressive pseudorheumatoid arthritis of childhood» (PPAC), described the clustering of chondrocytes in nests in the resting and growth cartilage and concluded that this was a primary disease of articular cartilage [6, 28]. El-Shanti, Omari and Qubain reviewed the picture in 1997, added six patients with histological study of the iliac crest — dilated endoplasmic reticulum cisternae, large Golgi complexes, tortuous collagen fibres and defective columnisation — and proposed including the term «spondyloepiphyseal» in the name [6].

The molecular basis was found in two stages. El-Shanti et al. mapped the locus to 6q in a consanguineous Jordanian family by homozygosity mapping and excluded COL10A1; Fischer et al. narrowed the interval to 3 cM at 6q22 in three families of different origins, without a shared haplotype [6]. In 1999, Hurvitz et al., using a positional candidate approach, identified nine different variants in WISP3, a gene cloned the previous year by Pennica et al. as a member of the Wnt pathway, and showed that it is essential for postnatal skeletal growth and cartilage homeostasis [10, 52]. The approved symbol has since become CCN6, and the 2023 revision of the Nosology designates the disease «progressive pseudorheumatoid dysplasia (PPRD), WISP3-related» [1, 13].

1.5 Nomenclature and operational definitions

«Spondyloepiphyseal dysplasia» is a descriptive term denoting involvement of the spine and epiphyses; the «congenital» form is evident at birth and the «tarda» form becomes evident at school age [4]. The term «SED tarda» generally refers to the X-linked recessive form, but there are rare descriptions of autosomal dominant and recessive forms, and the Orphanet entity ORPHA:93284 groups all three (OMIM 184100, 271600 and 313400) [4, 16]. Spondyloepiphyseal dysplasia tarda with progressive arthropathy corresponds today to progressive pseudorheumatoid dysplasia due to CCN6 (WISP3), which is not a form of SEDT and is defined by its own criteria [13, 28]. Here DMC is defined as the spondyloepimetaphyseal dysplasia with intellectual disability and microcephaly associated with biallelic variants in DYM; SMC as the same skeletal phenotype with normal intelligence and no microcephaly, due to DYM (SMC1) or RAB33B (SMC2); SEDT as the dysplasia of late postnatal onset in boys due to a hemizygous variant in TRAPPC2; and PPRD as the non-inflammatory arthropathy with onset between 3 and 6 years, with bony swelling of the interphalangeal joints and spondyloepiphyseal dysplasia, due to biallelic variants in CCN6 [4, 13, 26]. Spranger's atlas recommends reserving the name DMC for patients with intellectual disability, because of the difference in prognosis [26]. This clinical separation is not absolute: a 13-year-old Moroccan boy with the DYM variant recurrent in that population had the typical skeleton and had neither developmental delay nor intellectual disability [53].

2. Molecular Genetics and Pathophysiology

2.1 Common mechanism: secretion of the cartilage matrix

Growth cartilage depends on the secretion of large amounts of type II procollagen, proteoglycans and other matrix proteins, which pass through the endoplasmic reticulum (ER) and the Golgi apparatus before reaching the extracellular space. Procollagen forms pre-fibrils too large for conventional COPII vesicles, and its export requires additional mechanisms at ER exit sites [33]. The three proteins of this class act at different points of this pathway: sedlin at ER exit and in the link between the ER and the Golgi; dymeclin in Golgi organisation and Golgi-associated secretion; and RAB33B in intra-Golgi and Golgi-to-ER retrograde trafficking [3, 33, 54]. The common histological observation is dilatation of the rough ER cisternae of chondrocytes with granular material, described in DMC and SMC, and disorganisation of the growth plate without chondrocyte columns [11, 55]. Saudubray's textbook classifies these diseases within the group of disorders of cellular trafficking, which covers more than 300 genes, and places DYM and RAB33B among the genes of inter-organelle trafficking [34]. PPRD does not belong to this mechanism: CCN6 encodes a secreted matricellular protein that regulates, from outside the cell, the expression of type II collagen and aggrecan and the BMP and WNT pathways of the chondrocyte; the histological outcome, however, converges with that of the Golgipathies, with clustering of chondrocytes in nests, loss of columnar organisation and, in El-Shanti's ultrastructural studies, dilated endoplasmic reticulum cisternae and large Golgi complexes [6, 10].

2.2 DYM and dymeclin

DYM lies at 18q21.1, has 17 exons spread over more than 400 kb and encodes, in the historically used transcript (NM_017653), a 669-amino-acid protein highly conserved across species, with no homology to known protein families, with a cluster of conserved dileucine motifs at the C-terminus [7, 44]. The transcript is ubiquitous but abundant in chondrocytes, osteoblasts and the developing brain (cortex, hippocampus and cerebellum) [7, 24]. Dimitrov et al. showed that dymeclin is not a transmembrane protein, as the initial prediction suggested, but a peripheral protein that shuttles dynamically between the cytosol and a subset of mature Golgi membranes and ER–Golgi transition vesicles [54]. In fibroblasts from patients with DMC there are fewer collagen fibrils at the surface, distended Golgi cisternae and greater susceptibility to apoptosis; re-expression of normal dymeclin corrects Golgi morphology, and the protein interacts with PPIB (cyclophilin B) and GOLM1 [56]. Electron microscopy of the skin of a child with DMC showed dilated rough ER, aberrant vacuoles and numerous vesicles [44].

The relationship between DMC and SMC1 is explained by the amount of residual function. The variants that cause DMC are mainly loss-of-function variants (premature termination codons, frameshift, splicing) and lead to mislocalisation and degradation of the protein; the missense variant p.(Glu87Lys) of SMC1 from Guam does not alter the localisation or stability of dymeclin, which suggests residual activity sufficient for the brain [45, 54]. Smith's textbook summarises the threshold hypothesis: reduced levels of dymeclin affect cartilage and bone first, and only below a lower threshold is the brain affected [24]. The correlation is not perfect: the intron 7 splicing variant is homozygous in patients with DMC from Argentina and Chile and is compound heterozygous with p.(Glu87Lys) in the patients with SMC from Guam [7, 57], and the Moroccan boy with a variant typically associated with DMC and normal cognition shows that as yet unidentified factors modulate the neurological phenotype [53].

2.3 RAB33B

RAB33B, at 4q31.1, encodes a small GTPase of the Rab family that alternates between GDP-bound and GTP-bound forms and that, in the Golgi, regulates intra-Golgi and Golgi-to-ER retrograde trafficking, with an additional role in autophagy [3, 18]. The founder variant of the Saudi family, p.(Lys46Gln), replaces the invariant lysine of the guanine nucleotide-binding domain and markedly reduces the amount of protein; the same occurs with NP_112586.1:p.(Asn148Lys) [3, 46]. In 2026, expression of five pathogenic variants in cultured cells showed that all lose Golgi localisation and are prematurely degraded, and that the missense variants reduce the number of autophagosomes; these are preclinical data [58]. A mouse carrying p.(Lys46Gln) reproduces only part of the disease, only in males, with a slight increase in trabecular and cortical thickness, a fourfold increase in osteoclastic parameters and altered protein glycosylation, which suggests a role for RAB33B in osteoclast function [59]. The variant spectrum includes mainly truncating variants (NM_031296.3:c.211C>T p.(Arg71Ter), c.490C>T p.(Gln164Ter), c.253C>T p.(Gln85Ter), c.144C>A p.(Cys48Ter), c.280C>T p.(Arg94Ter), c.400C>T p.(Gln134Ter), and the published protein designation NP_112586.1:p.(Gly17ValfsTer58)) and some missense variants (NM_031296.3:c.365T>C p.(Phe122Ser)) [20, 60].

2.4 TRAPPC2 and sedlin

TRAPPC2 lies at Xp22.2, has six exons over about 20 kb, with translation starting in exon 3, and encodes sedlin, of 140 amino acids, ubiquitously expressed, including in fetal cartilage [4, 9, 23]. Sedlin is part of the TRAPP complexes, which tether vesicles coming from the ER to the target compartment; silencing of TRAPP components fragments the Golgi and blocks anterograde trafficking [9]. Its specific role in cartilage is explained by procollagen export: recruited by TANGO1, sedlin binds SAR1 and promotes its cycling, which allows carriers to grow and incorporate procollagen pre-fibrils [33]. The crystal structure of mouse sedlin resembles the N-terminal regulatory domain of SNAREs (Ykt6p, SEC22B); of the first four known missense variants, three are located in the interior of the protein and destabilise the structure [9]. The disease mechanism is loss of function [4].

Two molecular facts have laboratory consequences. The first is the existence of an expressed, intronless processed pseudogene on chromosome 19 (and of several other pseudogenes), which requires sequencing of the flanking introns and designing assays so as not to amplify the pseudogene [4, 9]. The second is that TRAPPC2 escapes X inactivation, as do the neighbouring genes at Xp22.2; heterozygous females therefore have two active alleles in all cells, and haploinsufficiency does not, as a rule, produce a phenotype [61]. Despite this, Whyte et al. described subtle radiographic changes and middle-age arthralgias in obligate carriers of the Arkansas family, and a Brazilian woman with a 46,XX karyotype and classic SEDT radiology has been published [5, 12].

2.5 CCN6 and the WISP3 protein

CCN6 occupies 6q21, between positions 112,052,813 and 112,069,686 of the GRCh38 reference genome, and encodes a 354-amino-acid protein with five functional domains: signal peptide, insulin-like growth factor binding protein (IGFBP)-like domain, von Willebrand factor type C repeat (VWC) domain, thrombospondin type I domain and C-terminal cystine knot [10, 13]. The protein belongs to the CCN family (connective tissue growth factor, CYR61 and NOV), a set of secreted cysteine-rich proteins with functions in cell growth and differentiation that are not redundant with each other; the gene was cloned by Pennica et al. in 1998 as the third member of the «WNT1-inducible signaling pathway», alongside WISP1 and WISP2 [10, 13].

Its function in cartilage has three documented aspects. The first is transcriptional regulation of the matrix: WISP3 controls the expression of type II collagen and aggrecan by chondrocytes through activation of SOX9 factors and inhibits cell proliferation while promoting differentiation of precursor cells [13, 62, 63]. The second is control of oxidative stress: in human chondrocyte lines, reduction of WISP3 by RNA interference increased reactive oxygen species, whereas soluble WISP3 reduced them in chondrocytes and in umbilical vein endothelial cells, and two pathogenic variants, NM_003880.4:c.232T>C p.(Cys78Arg) and c.993G>A p.(Trp331Ter), were associated with high levels [10, 64]. The third is modulation of BMP and WNT signalling: in zebrafish, overexpression of Wisp3 inhibited both pathways, and the human and fish proteins bound BMPs and the LRP6 and frizzled co-receptors; the PPRD-causing variants lost this activity, and morpholino knockdown altered the size and shape of the pharyngeal cartilage [10].

The disease mechanism is not fully established, but the data converge on loss of function with consequences for chondrocyte maturation. CCN6 expression is greatly reduced in patients' chondrocytes; mutant articular chondrocytes proliferate more, have greater viability and less apoptosis, which corresponds to an immature, hyperproliferative state and may explain the metaphyseal widening; the mutant protein aggregates abnormally in the cytoplasm and membrane, delays intracellular collagen synthesis and inhibits its secretion, with loss of cartilage flexibility [13, 63, 65]. A 2025 study expressed four variants of the IGFBP domain in chondrocytes and showed that the consequences do not depend only on the variant type: p.(Cys52Ter) led to rapid degradation of the protein, with complete loss of function; p.(Tyr109Ter) disrupted matrix regulation, reduced protein interaction capacity and raised mitochondrial reactive oxygen species to the point of programmed cell death; NM_198239.2:c.248G>A p.(Gly83Glu) produced minimal cellular changes; and c.342T>G p.(Cys114Trp) severely destabilised the protein, accumulated reactive oxygen species, induced endoplasmic reticulum stress and acquired new interaction partners, which suggests a gain-of-function component [64, 66]. These are overexpression data in culture, not data from patient tissue. In 2026, functional analysis of CCN6 variants also pointed to ferroptosis and apoptosis of chondrocytes as cell-death pathways involved, likewise in a cell model [67].

The animal model was a long-standing obstacle: the Ccn6 knockout mouse has no skeletal phenotype. In 2026, Ramirez et al. generated sheep with CRISPR–Cas9 inactivation of CCN6, on the premise that a larger, longer-lived animal would better reproduce the human disease; the juvenile sheep developed clinical signs of joint disease that worsened with age, histology showed early cartilage damage, and the cartilage of the knockout animals differed from that of controls biomechanically, biochemically and transcriptomically, sharing features with cartilage derived from patients' induced pluripotent stem cells [68]. This is a preclinical study, presented by the authors as a platform to clarify the mechanism and test therapies.

2.6 Variant spectrum and nomenclature

In SEDT, Gedeon et al. found variants in 30 of 36 unrelated cases of various origins: 21 variants distributed throughout the gene, with deletions in 57% (17/30) and frameshifts in 43% (13/30), half of them due to dinucleotide deletions; four recurrent variants (IVS3+5G>A, historical numbering, = NM_001011658.4:c.93+5G>A; 157–158delAT, = c.157_158del; 191–192delTG, = c.191_192del p.(Val64GlyfsTer24); and 271–275del, published designation) accounted for 43% (13/30) of cases, and the haplotypes indicated independent recurrence rather than a founder effect [69]. In 13 European families, all variants were exon deletions, premature terminations or splicing defects, and c.93+5G>A was present in three families [70]. There are rare missense variants, such as NM_001011658.4:c.248T>C p.(Phe83Ser), associated in one family with later onset and a mild phenotype, but overall there is no genotype–phenotype correlation: null variants and the others produce almost identical pictures [4, 71]. In recent years non-canonical intronic variants have accumulated, such as NM_001011658.4:c.94-11C>G, which creates an aberrant acceptor site with a 10-nucleotide insertion, and the deep intronic variant NM_001011658.4:c.239-20_239-12delinsAATGAA, which only genome sequencing detected [72, 73]. TRAPPC2 variants are not a frequent cause of early primary osteoarthritis in men: none was found in 37 men with early end-stage osteoarthritis of the hip or knee [74].

The older DYM literature uses transcript NM_017653 and a cDNA numbering that does not always match the current one. The most frequent variant in Morocco, described as 1877delA in 2003, corresponds to NM_017653.6:c.1878del, p.(Lys626AsnfsTer94); the MANE Select transcript of DYM is, however, NM_001353214.3, in which the same variant is written c.2043del, p.(Lys681AsnfsTer94) [7, 19, 64]. The Portuguese variant from Madeira, p.(Cys542Arg) in NM_017653.6 (c.1624T>C), is c.1789T>C, p.(Cys597Arg) in the MANE transcript; variants upstream of the additional exon of the MANE transcript keep their numbering, such as c.48C>G, p.(Tyr16Ter), and c.259G>A, p.(Glu87Lys) [64]. In TRAPPC2 the MANE transcript is NM_001011658.4, and the recurrent variant IVS3+5G>A is written c.93+5G>A (NC_000023.11:g.13719866C>T); 157–158delAT corresponds to c.157_158del, p.(Met53ValfsTer35) [64, 70]. In RAB33B, the MANE transcript is NM_031296.3 and the Saudi variant is c.136A>C, p.(Lys46Gln) [59, 64]. A report should state the transcript with its version and, when the literature uses another numbering, the correspondence.

In CCN6, the literature and GeneReviews use NM_003880.3 (protein NP_003871.1), whose current version is NM_003880.4, but the MANE Select transcript is NM_198239.2, transcript variant 3, with protein NP_937882.2; the two have the same coding region and the cDNA numbering coincides, so published variants transpose without change of numbers, as was confirmed for c.156C>A, c.172A>T, c.233G>A, c.248G>A, c.347-1G>A, c.624dup, c.740_741del, c.866dup and c.1010G>A [13, 64]. The spectrum is dominated by loss-of-function variants distributed throughout the gene: in the 36 Turkish patients and the 23 Egyptian patients, 13 and 11 distinct variants were identified, respectively, and in the 105 Chinese patients 33 variants, of which 26 (79%) were described only in that population [75–77]. Verified examples include NM_198239.2:c.80T>A p.(Leu27Ter), c.161del p.(Cys54SerfsTer12), c.172A>T p.(Lys58Ter), c.376C>T p.(Gln126Ter), c.536_537del p.(Cys179Ter), c.737T>C p.(Leu246Pro), c.740_741del p.(Cys247LeufsTer31), c.866dup p.(Ser290GlufsTer13) and c.947_951del p.(Gln316ArgfsTer5) [64, 76, 78–80]. The variant c.589G>C, described by Delague et al. as causing a processing defect because it affects the last nucleotide of exon 3, is a case in which the protein-level prediction, p.(Ala197Pro), does not reflect the molecular effect described [64, 78]. In HGMD data, sequencing detects almost 100% of pathogenic variants and targeted deletion/duplication analysis about 1%; three intronic alleles, two of them deep intronic, were identified only by sequencing of fibroblast cDNA [13]. The two deletions described are a 9 kb deletion spanning the 5' untranslated region and exon 1, detected by quantitative real-time PCR in two siblings, and a 7 kb deletion spanning exon 2, detected by genome sequencing [13, 81, 82].

Genotype–phenotype correlations in PPRD are scarce and limited. Most studies find no correlation, and the slight variation in age at onset, severity and rate of progression between families is not explained by the type or location of the variants; intrafamilial variability is documented [13, 75, 76]. Three exceptions have been described. The variant NM_198239.2:c.624dup p.(Cys209MetfsTer21) is associated with later onset and, in the Chinese cohort, with more extensive joint involvement and a greater likelihood of affecting the elbows [13, 64, 77, 83]. Biallelic null variants with at least one in exon 2 were associated, in three Chinese patients, with shortening of the long bones and severe deformities, and biallelic null variants with greater shoulder involvement (p = 0.027) [77]. The combination of a nonsense variant with a frameshift, NM_198239.2:c.172A>T p.(Lys58Ter) and c.740_741del p.(Cys247LeufsTer31), has been proposed as the explanation for the severe phenotype of three Indian sisters with crouch gait and marked muscle atrophy, in an association inferred from a single family [64, 80].

2.7 Recurrent variants and founder effect

Variants marked «not converted» are published intronic designations without an unambiguous correspondence in the MANE transcript.

2.8 Inheritance, penetrance and expressivity

DMC, SMC1 and SMC2 are autosomal recessive, with a high proportion of parental consanguinity in the series (79% in the Indian cohort; ten of ten families in the Turkish cohort) [21, 22]. In a 12-year-old Spanish child with DMC, the DYM variant NM_001353214.3:c.62C>G p.(Ser21Ter), in homozygosity, had been inherited only from the father, through paternal uniparental isodisomy and heterodisomy of chromosome 18; a single carrier parent therefore does not exclude the diagnosis [84]. In another child, detection of a region of homozygosity on the long arm of chromosome 18 by microarray was the first clue to a recessive disease [85]. SEDT is X-linked recessive, with complete penetrance in hemizygous males and variable expressivity within the same family: a 24-year-old relative carrying the variant measured 1.61 m and had minimal signs, and two Korean brothers had different rates of radiological appearance [73, 86]. GeneReviews describes heterozygous females as usually without changes; Spranger's atlas and Smith's textbook acknowledge mild osteoarthritis, subtle radiographic changes of the pelvis and knees and middle-age arthralgias in some carriers [4, 25, 27].

PPRD is autosomal recessive, with complete penetrance in homozygotes and compound heterozygotes and asymptomatic heterozygotes with no risk of disease [13]. The series come mainly from populations with frequent consanguinity, and the disease affects both sexes: the three Indian sisters with a severe phenotype and the Turkish cohort, in which all patients had biallelic variants in CCN6, illustrate the sex distribution and the mild to moderate intrafamilial variability [13, 75, 80, 87]. In the Chinese monozygotic twins, the deletion of about 6.5 kb (published designation g.112057664_112064205del) in trans with c.624dup escaped three successive genetic tests and was identified only by genome sequencing with detailed phenotyping, ending a 13-year diagnostic odyssey; the scenarios to consider when the variant is found in only one parent are dealt with under counselling [13, 82].

2.9 Allelic disorders and related entities

No germline TRAPPC2 phenotypes other than SEDT are known [4]. Other genes of the TRAPP complex cause neurological diseases without typical skeletal dysplasia: TRAPPC2L (encephalopathy with rhabdomyolysis) and TRAPPC11 (muscular dystrophy and encephalopathy spectrum), in a group designated «TRAPPopathies», which has been joined by TRAPPC12 (progressive childhood encephalopathy with Golgi dysfunction) [34, 88]. For DYM, the DMC/SMC1 distinction is the only allelic relationship described. In group 13 of the Nosology, other dysplasias due to glycosylation or trafficking defects, such as TMEM165 (congenital disorder of glycosylation IIk) and BNIP1, constitute the closest molecular differential [1]. For CCN6, no germline phenotype other than PPRD is known [13]. The gene's relationship with oncology is somatic and not germline: loss or reduction of CCN6 expression is associated with breast, colon and rectal cancer and hepatocellular carcinoma, with about 1290 somatic variants recorded in the COSMIC database in tumour tissues, and heterozygous carriers of PPRD variants have, in the sources consulted, no described oncological risk [13].

3. Clinical Spectrum and Manifestations by System

3.1 DMC and SMC: natural history

The manifestations of DMC become evident between 1 and 18 months and are progressive; short-trunk dwarfism is present before 18 months, and feeding difficulties are common in infancy [24]. In the Turkish cohort of 17 patients (10 DMC and 7 SMC2, from 10 consanguineous families), symptoms appeared from infancy to early childhood, but age at diagnosis was 9.61 ± 9.72 years (20 months to 34 years), with a mean height of 92.85 ± 15.50 cm at that time; all had a short trunk, barrel chest, prominent abdomen, hyperlordosis and reduced joint mobility [22]. In the Indian cohort of 24 patients from seven centres (18 DMC and 6 SMC2), 20 had height below −3 standard deviations (SD) and 14 had gait abnormalities [21]. Spranger's atlas reports adult heights between 82 and 128 cm, and Smith's textbook records three adults measuring 128, 127 and 119 cm [24, 26]. These figures come from small series, with ascertainment bias towards severe cases, and do not describe the distribution in a population.

The radiological evolution is age-dependent. At 5 months the vertebrae are already flat with minimal notches; at 18 months there is anterior wedging; between 3 and 5 years the central notches of the upper and lower endplates appear, the «double hump»; in the second decade the platyspondyly becomes less marked, and in adolescence the appositional bone fuses and the vertebrae become rectangular [11, 26]. In the Turkish series, central notches were present from 20 months and the rectangular configuration appeared at around 15 years; in the Tüysüz series, the double hump was present in patients under 12 years and disappeared after puberty [20, 22]. Lace-like iliac crests and double-humped vertebrae were found in 96% and 88% of the Indian patients, and the authors stress that the findings become less marked with age [21]. In the adult, the lace-like crest evolves into a marginal irregularity [24]. Histology shows that the lace-like appearance corresponds to bone deposited in an undulating pattern at the osteochondral junction [55].

Joint involvement dominates long-term morbidity. The hips tend towards bilateral subluxation and degeneration; in a French review, degeneration and dislocation of the hips were described as almost constant [89]. Of the seven patients with SMC2 followed for 5 to 9 years by Tüysüz, six walked independently at diagnosis, all had severe hip pain, hip and knee stiffness and walking difficulty after 10 years, and only two still walked independently at the last examination [20]. Atlantoaxial instability due to odontoid hypoplasia occurs in DMC and SMC and may cause spinal cord compression; it is described as a serious and preventable complication, and Toledo et al. warned as early as 1979 of spinal cord injury and early death in both forms [26, 41, 90].

The neurological phenotype of DMC includes global developmental delay and intellectual disability of variable degree. In the Ecuadorian case, the intelligence quotient on the Wechsler Adult Intelligence Scale (WAIS-IV) was 68 [19]. There are descriptions of seizures and of unrelated associations, such as Hirschsprung disease and trisomy 21 in a Turkish sibship, or Kearns–Sayre syndrome in an Omani adolescent girl, which should not be interpreted as part of the spectrum [30, 91].

3.2 SEDT: natural history

Affected boys have normal length and proportions at birth, and radiographs are normal until about 5 years [4, 5]. Linear growth delay begins at around 6 to 8 years, and radiological diagnosis is not possible before 4 to 6 years [4, 5]. The initial complaint is often vague low back pain in adolescence, and the vertebral changes are most marked during periods of rapid growth [25]. The adult has disproportionate short stature, a short trunk and neck, barrel chest, thoracic kyphosis and lumbar hyperlordosis; the upper-to-lower segment ratio is about 0.8 and arm span exceeds height by 10 to 20 cm [4]. Final height is 137 to 163 cm according to GeneReviews and Spranger's atlas, 132 to 157.5 cm (mean 138 cm) according to Smith's textbook, and mean adult height in the series of Heuertz et al. was 1.45 m [4, 5, 25, 27]. Intelligence, motor development and life expectancy are normal [4].

The study of the Arkansas family showed that the initial lesion is a disturbance of endochondral ossification that manifests as a radiologically absent ring apophysis; this results in malformation of the anterior margins of the lumbar vertebrae in childhood, followed by disc degeneration and destruction of the facet joints [12]. The femoral head, neck and condyles become deformed, and hip osteoarthritis is common; total arthroplasty is often required before 40 years [12, 25]. The interphalangeal joints are spared, which separates SEDT from progressive pseudorheumatoid dysplasia [4]. Odontoid hypoplasia and scoliosis/kyphoscoliosis have been described, but there are no published data on their frequency or severity [4]. There are reports of occasional corneal opacities, and Saudubray's textbook includes TRAPPC2 among the trafficking genes associated with corneal anomalies [25, 34]. One missense variant has been associated with a later-onset, less severe picture [71].

Expression in heterozygous females is discordant between sources. GeneReviews states that carriers do not, as a rule, show changes; Spranger's atlas mentions mild osteoarthritis; Smith's textbook mentions minimal radiographic changes of the pelvis and knees, early vertebral degeneration and middle-age arthralgias; Bannerman described a woman, daughter and mother of affected men, with «arthritis» from age 33 and bony fusion of the left hip at 51 [4, 5, 25, 27]. In the 2026 Korean family, the heterozygous sister had a normal spine [73]. The explanation proposed for the rarity of manifestations is the escape of TRAPPC2 from X inactivation [61].

3.3 PPRD: natural history

The child with PPRD is healthy at birth and during early childhood, and has no extraskeletal manifestations: no craniofacial features, no cognitive impairment, no corneal clouding and no visceromegaly [13]. Onset lies between 3 and 6 years in most series, with a published range of 1 to 16 years; in the Turkish cohort of 44 patients, the median age at onset was 4 years and the median age at diagnosis 9.7 years, a difference of almost six years that sums up the clinical problem of this disease [13, 75]. More than 400 families with biallelic variants in CCN6 had been identified by 2026 [13].

The usual presentation is swelling of the interphalangeal joints, accompanied by gait abnormality; pain is rarely the initial symptom and is disproportionately mild relative to the severity of the arthropathy, which distinguishes the disease from arthritis [13]. The swelling is neither synovial nor of the soft tissues, but bony enlargement of the ends of the phalanges, and the joints appear swollen without being tender on palpation [6, 13]. A fraction of patients present differently: in the Turkish cohort, 15 of the 44 had their first symptoms before 3 years and, in this early-onset group, the initial symptom was genu varum rather than interphalangeal swelling [75]. There are descriptions of muscle weakness, easy fatigability and difficulty walking between 3 and 8 years that led to consideration of polymyositis or muscular dystrophy [28].

The frequencies compiled in GeneReviews from the published series are: interphalangeal involvement in 100%, large-joint involvement in 100% (knees, hips, wrists and elbows), spinal involvement in 93% (scoliosis and/or kyphosis, platyspondyly on radiographs) and short stature in 50% [13]. Hand involvement begins in the proximal interphalangeal joints and progresses to the distal ones, with swelling, stiffness and reduced range of motion that evolve into contractures; camptodactyly is always present in adulthood [13]. The large joints are affected gradually; the hip manifests late with coxa vara, the knees with genu varum or genu valgum, and the shoulders are not, as a rule, severely affected, although they are more so in patients with two null variants [13, 77]. The Turkish cohort documented the age sequence: the median age at appearance of stiffness was 5 years in the interphalangeal joints, 9 years in the elbows, 9 years in the knees and 12.2 years in the hips [75].

The spine is affected in late childhood and adolescence, with scoliosis, kyphosis and sometimes lordosis; the neck is only occasionally involved [13]. The radiological sequence described by Garcia Segarra et al. in 63 patients is as follows: platyspondyly develops in late childhood and may be the first clue to the diagnosis; widening of the phalangeal metaphyses sets in subtly and is usually recognisable by 10 years; the femoral heads are large and the acetabulum forms a «lip» that overhangs the femoral head; and there is progressive narrowing of all joint spaces as cartilage is lost [92]. Anterior beaking of the vertebral bodies is seen in late childhood, and diffuse osteoporosis appears in advanced disease; osteophytes and periarticular calcifications may form in the shoulders and knees [13].

Stature is initially normal and deviates progressively to a short-trunk pattern in late childhood and adolescence; adult stature falls below the third centile in about half of patients, with published values of 1.36 to 1.56 m in the Wynne-Davies series and 135 to 150 cm in Spranger's atlas [6, 13, 28]. Flexion deformities of the hips and knees and spinal changes contribute to the short stature, which is therefore not only a deficit of linear growth [13].

Functional outcome is the most important element of prognosis and was quantified in the Turkish cohort: waddling gait occurred in 97.7% of patients, and 47.7% lost the ability to walk without support, at a median age of 12 years; in the early-onset group, waddling gait appeared earlier than in the classic group (p < 0.001) [75]. Loss of articular cartilage continues after skeletal growth is complete, and adults become severely limited by generalised contractures, with normal life expectancy [13, 28]. Arthroplasty is required in several patients before 30 years [6, 68]. There are reports of atypical evolution: two patients in the Turkish cohort had late onset and mild or absent interphalangeal involvement, and Legius et al. described two brothers and a sister with normal adult stature, mild platyspondyly and severe osteoarthritis with extensive synovial osteochondromatosis [6, 75].

Two complications described in isolated cases change management: secondary osteoporosis with vertebral fractures, favoured by prolonged immobilisation and by corticosteroid therapy given for a mistaken diagnosis of arthritis, and compression of neural structures by degenerative spinal disease, described as acute cauda equina syndrome in a 21-year-old man [93, 94].

4. Clinical Recognition and Warning Signs

4.1 When to suspect DMC or SMC

Suspicion arises in a young child with short-trunk short stature, barrel chest and protruding sternum, joint stiffness, short broad hands and, in DMC, developmental delay and microcephaly [24, 26]. The first diagnosis considered is often a mucopolysaccharidosis, especially type IV (Morquio) or VI; the Ecuadorian case was initially investigated as mucopolysaccharidosis type VI, and in the Turkish sibship MPS IV was excluded biochemically before genetic testing [19, 30]. The most useful radiological sign is the lace-like iliac crest, accompanied by the vertebral double hump; both are most evident between 3–4 years and the end of the first decade and become less marked thereafter [21, 85]. In an adult, the absence of these signs does not exclude DMC [21]. Parental consanguinity and a region of homozygosity on chromosome 18 on a microarray strengthen the hypothesis [21, 85].

4.2 When to suspect SEDT

SEDT should be considered in a school-age or adolescent boy with growth deceleration, progressive shortening of the trunk, barrel chest and low back pain, especially if there are maternal uncles, a maternal grandfather or maternal-line cousins who are short and have early osteoarthritis [4, 73]. The absence of a family history does not exclude the diagnosis [4]. In an adult, early osteoarthritis of the hips with platyspondyly and a hump of the lumbar endplates is the typical presentation [27]. The absence of cleft palate, severe myopia and retinal detachment argues against spondyloepiphyseal dysplasia congenita [4].

A frequent error is the diagnosis of growth hormone (GH) deficiency. In early stages, the only abnormality may be reduced growth velocity, without disproportion or definitive radiographic changes, and GH stimulation tests may give borderline values [73]. In the Korean case, GH peaks were 5.89 ng/mL with glucagon and 4.33 ng/mL with arginine, and the patient was treated for about five years before the truncal disproportion was recognised [73]. A growth response below that expected on GH should prompt review of the diagnosis and a skeletal survey [73].

4.3 When to suspect PPRD

PPRD should be suspected in a child healthy at birth who, between 3 and 6 years, develops swelling of the interphalangeal joints of the hands, progressive stiffness of all joints, gait abnormality, genu valgum or genu varum, mild joint pain, motor weakness and fatigability, without signs of inflammation; the erythrocyte sedimentation rate and C-reactive protein are normal, and rheumatoid factor and anti-cyclic citrullinated peptide antibodies are negative [13, 50]. The family history is compatible with autosomal recessive inheritance, with affected siblings or parental consanguinity, but its absence does not exclude the diagnosis [13]. In children under 3 years, the presenting sign may be only genu varum, and the Turkish cohort proposes that genu varum before 3 years, in a child who later develops joint stiffness, be considered an early sign of PPRD [75]. There is an isolated report questioning whether lumbar scoliosis observed at 7 months may be an inaugural manifestation; this is a hypothesis raised by a single case, without molecular confirmation, and not a criterion [95].

The step of greatest diagnostic yield is radiography of the hands. It shows enlarged epiphyses, wide metaphyses and loss or narrowing of the joint spaces in the metacarpophalangeal and interphalangeal joints, especially the proximal ones, with flat articular surfaces indented in the centre at the distal ends of the proximal phalanges [13, 28, 79]. The pelvis shows large, flattened femoral heads, short and broad femoral necks, widened ilia and irregular acetabular roofs with lateral extensions due to ossification of the capsular insertions [13, 28]. The spine shows progressive irregularity of endplate ossification and platyspondyly with loss or narrowing of the disc spaces in all patients [13]. The radiological picture separates PPRD from juvenile idiopathic arthritis, in which there is bone erosion and soft-tissue involvement rather than dysplasia with enlarged epiphyses and platyspondyly [13, 28].

The combination of «rheumatoid arthritis with Scheuermann disease» in a young patient is, in the formulation of Spranger's atlas and the OMIM entry, a direct reason to consider PPRD [6, 28]. The diagnosis has immediate consequences: in a Turkish series of 25 patients initially suspected of juvenile idiopathic arthritis and later reclassified as monogenic diseases, 12 had PPRD and 8 camptodactyly–arthropathy–coxa vara–pericarditis syndrome, and the errors led to inappropriate use of methotrexate or biological agents [87].

4.4 Warning and emergency signs

4.5 Newborn screening

There is no newborn screening for these dysplasias. SEDT is normal at birth and DMC/SMC manifests after the neonatal period [4, 24]. In a child with SMC2, ultrasound at 34–35 weeks of gestation was normal [8].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no published consensus diagnostic criteria for any of the five entities [4, 13, 18]. For SEDT, GeneReviews allows a clinical diagnosis in a boy with characteristic clinical and radiological findings and defines the molecular diagnosis by identification of a hemizygous pathogenic or likely pathogenic variant in TRAPPC2; a hemizygous variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [4]. For DMC and SMC, the radiology is very characteristic (lace-like crests and double-humped vertebrae), but does not distinguish DYM from RAB33B, so molecular testing is necessary [18, 21]. The separation between DMC and SMC is made by cognitive assessment and head circumference, not by the skeleton [26]. For PPRD, GeneReviews establishes the diagnosis in a proband with the characteristic radiographic findings and/or biallelic pathogenic or likely pathogenic variants in CCN6; identification of two variants of uncertain significance, or of one pathogenic variant and one of uncertain significance, neither establishes nor excludes the diagnosis [13]. The formulation therefore allows a clinical–radiological diagnosis without molecular confirmation, a possibility with practical consequences in settings with limited access to genetic testing [13, 50].

5.2 Radiological skeletal survey

The Oxford Desk Reference recommends, when a skeletal dysplasia is suspected, anteroposterior and lateral views of the skull, chest, anteroposterior and lateral views of the spine, pelvis with hips and one example of each limb segment (humerus, forearm, hand with carpals and phalanges; femur, leg, foot), with expert interpretation [29]. Many changes evolve with age and may not be visible in early childhood, and SEDT is radiologically normal until 4–6 years [5, 29]. A normal survey in a young child should therefore be repeated if suspicion persists. When mucopolysaccharidosis is suspected, the same book recommends urinary glycosaminoglycans; in DMC these are normal [29, 30]. The dysplasia table of the Oxford Desk Reference records delayed bone maturation and intellectual disability for DMC, and the SEDL gene for X-linked SED tarda [98]. When PPRD is suspected, the survey must include radiographs of both hands, because that is where the signs appear first and with the greatest specificity, and GeneReviews adds a complete skeletal survey to the evaluations recommended after diagnosis [13, 92]. Early radiographs may show only subtle metaphyseal widening of the interphalangeal joints, so a normal survey in a child of 4 or 5 years does not exclude the diagnosis and should be repeated [50, 92].

5.3 Molecular tests

For SEDT, the single-gene strategy begins with sequencing of TRAPPC2, including the flanking introns; if negative, gene-targeted deletion/duplication analysis follows. In HGMD data, 84% of pathogenic variants were detected by sequencing and 16% by deletion/duplication analysis; an unknown fraction of patients remain without a variant, which may reflect locus heterogeneity or diagnostic error [4]. These percentages are proportions of variants detectable by each method, not the clinical sensitivity of the test. In the Gedeon series, 30 of 36 clinically diagnosed cases had a variant identified with the methods of the time [69]. A multigene skeletal dysplasia panel including TRAPPC2, DYM and RAB33B allows the differentials to be covered [4].

For PPRD, the single-gene strategy begins with sequencing of CCN6, which detects missense, nonsense and splice-site variants and small intragenic deletions and insertions, and accounts for almost 100% of the pathogenic variants recorded in HGMD; if one or no variant is found, targeted deletion/duplication analysis follows, responsible for about 1% [13]. Targeted variant analysis may be useful in populations with recurrent variants: c.156C>A in patients of Turkish and Middle Eastern ethnicity, c.1010G>A and c.233G>A in India [13, 75, 79]. When genomic sequencing reveals no variants in a patient with typical signs and symptoms, skin biopsy for sequencing of fibroblast or peripheral blood cDNA is indicated, because intronic variants causing splicing aberrations are only detected in this way; Garcia Segarra et al. identified three intronic alleles in this way, two of them deep intronic [13, 92]. A multigene panel including CCN6 and the genes of the differential, or exome sequencing when the phenotype is atypical, are the alternatives [13]. Garcia Segarra et al. confirmed the variant in 63 of 64 clinically typical cases, a rate that measures the yield of the test in a series selected by phenotype and not the sensitivity of the test in a population of suspected cases [92].

Technical limits constrain interpretation. The processed pseudogene of TRAPPC2 may contaminate the analysis if the primers are not specific [4]. Exon deletions of TRAPPC2 are not detected by sequencing in heterozygous women, because the normal allele masks the deletion [4]. Deep intronic variants escape the exome: in the Korean case, the exome was negative and the genome identified the variant c.239-20_239-12delinsAATGAA [73]. In DYM, a homozygous deletion of exon 16 was identified only after standard sequencing was inconclusive, which justifies requesting CNV analysis from exome data or a targeted test when the phenotype is typical and no variant is found [30]. The exome and genome detect CNVs by read depth with lower sensitivity than targeted tests [4]. In CCN6, the story of the Chinese monozygotic twins exemplifies the cumulative limits: the 7 kb deletion spanning exon 2 escaped three tests and was identified only by genome sequencing, whereas the 9 kb deletion of the 5' untranslated region and exon 1 in another family was detected by quantitative real-time PCR [81, 82]. An apparently isolated heterozygous CCN6 variant in a patient with a typical phenotype therefore requires a search for a copy-number variant and an intronic variant before abandoning the diagnosis [13].

5.4 Interpretation and report

The report should state the gene, the transcript with its version (NM_001011658.4 for TRAPPC2; NM_001353214.3, MANE Select, for DYM, with the correspondence to NM_017653.6 when the variant was published in that transcript; NM_031296.3 for RAB33B), the HGVS cDNA and protein nomenclature, the zygosity (hemizygosity, homozygosity, compound heterozygosity with phase confirmation) and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [4, 64]. In the Ecuadorian case, the DYM variant c.1878del was classified as pathogenic with criteria PVS1, PM2, PM3 and PP5, and phase was confirmed by study of the parents and sister; gnomAD v4.1.0 recorded 8 alleles in 34,586 individuals, with no homozygotes [19]. In the Korean SEDT case, the intronic variant was first a VUS and became likely pathogenic with PM2, PP3 (SpliceAI 0.31) and PP1, through segregation with the phenotype in several affected men and carrier women [73]. Large panels produce VUS in other dysplasia genes (in the Ecuadorian case, in CCN6, CSPP1, GNPTAB and FLNB) that should not be interpreted outside the clinical context [19]. In CCN6 reports, the transcript to state is NM_198239.2 (MANE Select, protein NP_937882.2), with a note that the cDNA numbering coincides with that of NM_003880.3, used in the literature and in GeneReviews, which avoids unnecessary corrections of published variants [13, 64]. Apparent homozygosity without consanguinity and with only one carrier parent may correspond to uniparental disomy or deletion of the other allele, which requires parental testing [84].

5.5 Algorithm

5.6 Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible once the family's variants have been identified [4]. Fetal ultrasound is not useful for these dysplasias, because the manifestations are postnatal; in a child with SMC2, ultrasound at 34–35 weeks was normal [8]. The decision is conditioned by the late onset and variable expressivity of SEDT, a dilemma already pointed out in 2004 [86]. In PPRD, prenatal diagnosis and preimplantation genetic testing are possible provided the CCN6 variants have been identified in an affected relative, and GeneReviews acknowledges that there may be different perspectives on their use among professionals and within families, regarding it as a personal decision that benefits from prior discussion [13].

6. Differential Diagnosis

6.1 Main differentials

The most important differential of DMC is mucopolysaccharidosis IV (Morquio syndrome). In MPS IV, intelligence is normal, there are no lace-like crests, the platyspondyly is more severe and without central notches, and there are corneal opacities, deafness, valvular disease and keratan sulfaturia, all absent in DMC [19, 26]. Historically, the resemblance led DMC to be considered a metabolic disease, and the first description called it «Morquio–Ullrich disease» [36]. MPS VI and mucolipidoses II and III enter the differential because of dysostosis multiplex, coarse facies and joint stiffness; normal arylsulfatase B activity excluded MPS VI in the Ecuadorian case [19]. Spondyloepiphyseal dysplasia congenita due to COL2A1 manifests at birth, with myopia, deafness and risk of retinal detachment, and is the most common form of spondyloepiphyseal dysplasia [4].

The differential of SEDT includes the non-X-linked tarda forms, which affect both sexes, have more epiphyseal changes of the long bones and uniform platyspondyly with increased anteroposterior diameter of the vertebrae [27]. Progressive pseudorheumatoid dysplasia (CCN6/WISP3), formerly called SED tarda with progressive arthropathy, begins at 3–6 years in the interphalangeal joints, with joint swelling, bony enlargement of the ends of the phalanges and progressive contractures, without laboratory inflammation and with a poor response to antirheumatic drugs [4, 28]. Multiple epiphyseal dysplasia has a normal spine by definition [4]. Scheuermann disease has irregular endplates without a hump [27]. In brachyolmia, the vertebral contour is irregular, and the autosomal dominant form has pedicles with an «overlapping» appearance on the anteroposterior view and a variant in TRPV4 [27]. Early primary osteoarthritis in men from short families is not, as a rule, explained by TRAPPC2 [74]. The aggrecan-associated dysplasias, due to variants in ACAN (15q26.1), enter the differential of the two entities with arthropathy: spondyloepiphyseal dysplasia Kimberley type, autosomal dominant through haploinsufficiency, causes almost proportionate short stature, a stocky habitus and progressive osteoarthropathy of the weight-bearing joints, with platyspondyly of slightly elongated bodies and irregular, sclerotic endplates, and is separated from X-linked SEDT by the absence of the posterior hump characteristic of the vertebral bodies; autosomal recessive spondyloepiphyseal dysplasia tarda and mild spondyloarthropathy due to COL2A1 cause similar changes and are distinguished by molecular analysis [99]. Axial spondylometaphyseal dysplasia, autosomal recessive due to variants in C21orf2 or NEK1, shares lace-like ilia with DMC, but differs in the appearance of the proximal femora, the absence of hand and foot involvement, the bell-shaped chest and pigmentary retinal degeneration with progressive visual impairment [100].

The differential of PPRD is organised along two axes: the inflammatory arthritides and the other dysplasias with epiphyseal and vertebral involvement [13]. The first axis is dominated by juvenile idiopathic arthritis, the disease with which PPRD is most often confused. It is distinguished by joint inflammation, with tenderness on palpation and local warmth, raised erythrocyte sedimentation rate and C-reactive protein, which are always normal in PPRD, and bone destruction with erosions on radiographs, in contrast to the dysplasia, epiphyseal enlargement and platyspondyly of PPRD [13]. The rise in acute-phase reactants in juvenile idiopathic arthritis may, however, be minimal, so normal laboratory results alone do not resolve the problem [13]. A poor response to antirheumatic drugs is a clinical finding with discriminating value recognised since Spranger's descriptions [6, 28]. The Adana series, with 25 children initially suspected of juvenile idiopathic arthritis and reclassified, identified five monogenic mimics — PPRD (12 patients), camptodactyly–arthropathy–coxa vara–pericarditis syndrome due to PRG4 (8), mucolipidosis type III gamma, primary hypertrophic osteoarthropathy and multicentric carpotarsal osteolysis — and pointed to camptodactyly, skeletal deformities, digital clubbing, median nerve neuropathy and lack of response to treatment as warning signs [87].

The second axis includes the dysplasias that share features with PPRD. The COL2A1 forms are the closest: spondyloepimetaphyseal dysplasia presents in infancy, with a flat facial profile, ocular anomalies, delayed ossification and metaphyseal widening, without large epiphyses; mild spondyloepiphyseal dysplasia with premature osteoarthritis begins in adolescence or adulthood and has neither early platyspondyly nor large epiphyses; and spondyloepiphyseal dysplasia with metatarsal shortening, associated with the COL2A1 variant NM_001844.5:c.823C>T p.(Arg275Cys), has average stature and shortening of the postaxial toes [13]. Spranger's atlas adds that myopia and its complications and hearing loss are frequent in the COL2A1 chondrodysplasias and not in PPRD, and highlights the Stanescu type in particular [28]. In 2015, a COL2A1 variant c.619G>A p.(Gly207Arg) was described with a phenotype similar to PPRD and to spondyloepiphyseal dysplasia Stanescu type [28]. Spondylometaphyseal dysplasia «corner fracture» type, due to COL2A1 or FN1, shares short stature, scoliosis, coxa vara, genu varum or valgum and joint pain, but the epiphyses are normal [13]. Mucopolysaccharidoses types I, II, III, IVA and IVB share the vertebral deformities and progressive joint limitation, but have extraskeletal manifestations — coarse facies, corneal clouding, hepatomegaly, intellectual disability — absent in PPRD; mucolipidosis type III shares joint pain and stiffness, with coarse facies and dysostosis multiplex [13]. Spranger's atlas separates them by the skeleton: in PPRD the vertebral change is mild, the lower ilia are broad and the ends of the short tubular bones are swollen, whereas DMC has more regular platyspondyly with central notches and broad, irregularly calcified iliac crests [101].

Three non-dysplastic monogenic arthropathies complete the differential. Camptodactyly–arthropathy–coxa vara–pericarditis syndrome due to PRG4 is the most similar, with non-inflammatory arthropathy, camptodactyly and progressive hip deformity, but it affects the large joints, especially the hips, earlier in the course of the disease and may be associated with pericarditis [13]. LACC1-related juvenile arthritis begins in childhood with deformities, contractures, pain and joint swelling, but it is erosive, has raised inflammatory markers and may present with fever, erythematous rash, generalised lymphadenopathy and hepatosplenomegaly [13]. Multicentric carpotarsal osteolysis due to MAFB, with or without nephropathy, and multicentric osteolysis, nodulosis and arthropathy due to MMP2 present with arthritis, but osteolysis of the carpal and tarsal bones distinguishes them, and the latter adds subcutaneous nodules [13].

6.2 Differential table

6.3 Changing diagnoses

The classification is still being adjusted. The former «X-linked DMC» (OMIM 304950) was reinterpreted as SEDT [35]. The DMC versus SMC designation by cognitive criterion has exceptions, such as the Moroccan patient with a variant usually associated with DMC and normal cognition [53]. The 2023 Nosology recommends dyadic names («DYM-related», «RAB33B-related», «TRAPPC2-related», «WISP3-related»), which make the genetic basis explicit and avoid these ambiguities [1]. PPRD is the clearest example of this nomenclature problem: it was successively called chondrodysplastic rheumatism, syndesmodysplastic dwarfism, spondyloepiphyseal dysplasia tarda with progressive arthropathy, progressive pseudorheumatoid arthropathy of childhood and progressive pseudorheumatoid chondrodysplasia, and the current name retains the prefix «pseudo» precisely to mark the misleading appearance of the picture in childhood [6, 13, 28, 50]. Orphanet retains as synonyms «PPD», «progressive pseudorheumatoid arthropathy of childhood» and «spondyloepiphyseal dysplasia tarda–progressive arthropathy syndrome», with codes ICD-10 Q77.7 and ICD-11 LD24.3 [17, 18].

7. Treatments and Risk Management Strategies

7.1 Principles and sources of recommendations

There is no targeted treatment for any of the five entities, no drug has an approved indication for them and there are no specific guidelines; the GeneReviews chapters on SEDT and PPRD base their recommendations on the authors' experience, and GeneGuidance classifies the evidence for DYM and RAB33B as case reports and small series [4, 13, 18]. The applicable cross-cutting recommendations come from the best-practice guidelines of the Skeletal Dysplasia Management Consortium, developed by the Delphi method with an 80% agreement threshold: spine (2020; 11 experts; 31 statements), perioperative care (2017; 13 experts; 19 recommendations) and pregnancy and delivery (2018; 13 experts; 40 statements) [31, 97, 103]. These are expert consensus recommendations for skeletal dysplasias in general, not specifically validated in DMC, SMC or SEDT. Follow-up by a multidisciplinary team with genetics, orthopaedics, neurosurgery or spinal surgery, anaesthesiology, physical medicine and rehabilitation, developmental paediatrics and, in DMC, educational support, is the basis of management [4]. European patients can be referred to ERN BOND centres [32].

7.2 Craniovertebral junction

Odontoid hypoplasia with atlantoaxial instability is the potentially fatal complication of DMC and SMC and also occurs in SEDT [4, 26]. The GeneReviews chapter on SEDT recommends flexion–extension radiographs of the cervical spine at initial evaluation and before school age, and flexion–extension MRI when there is instability or compression on radiographs or when interpretation is limited by delayed ossification of the upper cervical spine [4]. The 2020 guidelines recommend considering flexion–extension radiographs in all patients with a known risk of C1–C2 instability or with a dysplasia not yet classified, accept dynamic CT or MRI as adjuncts, indicate surgery when there is instability or spinal cord compression with signs of myelopathy and state that prophylactic C1–C2 arthrodesis is not indicated without compression or myelopathy [31]. The same guidelines draw attention to the difficulty of interpreting radiographs in children with incomplete ossification, to the variability of the course of the vertebral artery and to the need for advanced imaging (CT and CT or MR angiography) before upper cervical surgery [31].

Surgical reports in DMC confirm these difficulties. In a 17-year-old man with severe atlantoaxial instability, the irregular course of the vertebral artery at C2 prevented posterior fixation and insufficient mouth opening prevented the transoral approach; fixation with anterior transarticular screws achieved solid fusion at 36 weeks [90]. Two brothers with DMC and atlantoaxial instability had neurological recovery after posterior atlantoaxial fixation by the Goel technique, and the authors advocate early stabilisation when instability is demonstrated [96]. In SMC from Guam, posterior cervical arthrodeses were performed [38]. Divergence between sources: case reports tend to advocate early stabilisation, whereas the 2020 consensus reserves surgery for demonstrated instability with compression or myelopathy and recommends serial surveillance with careful neurological examination in the others [31, 96].

7.3 Thoracolumbar spine

Kyphosis, scoliosis and hyperlordosis are frequent [4, 26]. GeneReviews recommends treatment by the orthopaedic surgeon, with surgical correction when indicated, and annual clinical evaluation with radiographs if clinically justified [4]. The 2020 guidelines recommend reassessing cervical and upper thoracic kyphosis, because of the risk of spinal cord injury during procedures under anaesthesia; considering bracing or casting for flexible, progressive scoliosis at young ages and growth-preserving techniques for early-onset scoliosis; operating on thoracolumbar kyphosis when it is progressive, causes neurological compromise or refractory pain; obtaining advanced imaging before any instrumentation; and monitoring respiratory function when there is chest deformity [31]. Spinal surgery in skeletal dysplasias has more complications than in the general population [31]. Lumbar hyperlordosis may be associated with hip flexion contracture, and correcting the hip deformity may improve sagittal alignment [31]. The panel did not reach consensus on surveillance MRI of the whole spine (70% agreement) [31].

7.4 Hips and other joints

In DMC/SMC, the hip is the most affected joint. In two brothers with DMC treated with triple pelvic osteotomy and femoral varus osteotomy, or with bilateral Pemberton osteotomy and varus osteotomy, the subluxation recurred and degeneration was severe at 5 and 3 years of follow-up; the authors advise against operating on these hips in childhood unless justified by pain, consider total arthroplasty in the adult the only reliable solution and warn that previous osteotomies make the prosthesis more difficult [89]. A bilateral total arthroplasty at 31 years, planned by CT and with a small porous cup and a version-control stem, had an outcome considered safe and effective by the authors [104]. In the Guam series, femoral osteotomy, total hip arthroplasty, early meniscectomy and realignment osteotomies of the lower limbs were performed [38]. These data come from series of one to seven patients, without comparison.

In SEDT, treatment of osteoarthritis follows general principles: control of chronic pain and hip, knee or shoulder arthroplasty when osteoarthritis is disabling; hip arthroplasty is often necessary before 40 years [4, 25]. Spranger's atlas mentions orthopaedic procedures for disabling hip osteoarthritis and for scoliosis [27]. Pharmacological pain control has no particularities described in these dysplasias and follows the protocols for osteoarthritis and chronic pain.

7.5 PPRD: symptomatic treatment and treatment of bone complications

In PPRD too there is no targeted treatment and there are no published clinical practice guidelines; the GeneReviews recommendations are based on the authors' personal experience in following these patients [13]. The evaluations recommended after diagnosis are a complete skeletal survey, referral to a paediatric orthopaedic surgeon or a bone dysplasia specialist, measurement of blood 25-hydroxyvitamin D to identify a coincident deficiency and genetic counselling by genetics professionals [13].

Pain control deserves emphasis because the non-inflammatory appearance of the picture leads to its undertreatment. Spranger's atlas states that analgesic medication is essential and should not be withheld despite the absence of inflammatory signs, and that a poor response to antirheumatic drugs is characteristic [28]. In the Italian case, pain control during antifracture treatment was achieved with oral tapentadol 100 mg once daily, together with regular physiotherapy [93]. Physiotherapy to delay the development of contractures is recommended by both reference sources; four Turkish patients followed in rehabilitation suggested to the authors that patient education and an early rehabilitation programme delay the loss of joint range, an observation of four cases without comparison [28, 105].

Joint replacement is the intervention with the greatest documented impact. Spranger's atlas states that most patients benefit greatly from hip arthroplasty, and sometimes knee arthroplasty, with a significant reduction in pain; Garcia Segarra et al. consider hip arthroplasty in early adulthood effective and recommend it, with knee arthroplasty as a subsequent option, and GeneReviews places it in the second decade of life [13, 28, 92]. None of these statements comes from a comparative study, and the price of operating so early is loosening and revision: the two adult patients described in 2025 had bilateral hip prostheses, with loosening, migration of the femoral component and fracture of a fixation screw in one of them [50, 93].

Secondary osteoporosis and fragility fractures are the therapeutic problem for which there is published pharmacological experience, albeit limited to case reports. No antifracture drug has been tested in PPRD, and all uses described are off-label [93]. The cases published before 2025, compiled in a table of the Italian report, used only antiresorptives: intravenous pamidronate 1 mg/kg/day for 3 days every 3 months in three siblings aged 3, 14 and 15 years, without significant improvement in bone mineral density; alendronate 70 mg weekly in a 33-year-old man; and bisphosphonates at unspecified doses in three other patients, with undocumented response and no tolerability data [93]. The 59-year-old Italian patient, with vertebral fractures of T12, L1 and L3 on oral ibandronate 150 mg monthly and previous intolerance of alendronate, denosumab and teriparatide, received romosozumab (Evenity®) 210 mg subcutaneously once a month for 12 months, followed by intravenous zoledronic acid 5 mg, after adequate calcium intake had been ensured with calcium citrate 500 mg daily and supplementation with colecalciferol 2500 IU daily [93]. Lumbar bone mineral density increased by 24.0% in 12 months (L1–L4 from 0.622 to 0.771 g/cm², T-score from −4.7 to −3.4, Z-score from −3.1 to −1.7), distal radius density changed by −2.9%, considered non-significant, no new fragility fractures occurred and the patient reported good tolerability and benefit in spinal mobility during physiotherapy [93]. Remodelling markers showed, at 15 days, a tripling of bone alkaline phosphatase (46.5 to 111.0 µg/L) and halving of the C-terminal telopeptide of type I collagen (0.707 to 0.321 ng/mL), a rise in resorption up to the third month and an overall decline in the second half of treatment, with a generalised reduction six months after zoledronic acid [93]. This is a single patient, with short observation, without a control and without the possibility of drawing conclusions on the antifracture effect; the authors themselves state that there is no comparison allowing them to say whether the response is atypical.

The authorisation conditions of romosozumab delimit this extrapolation. In the USA, the Food and Drug Administration approved Evenity® (biologics licence BLA 761062, Amgen) on 9 April 2019 for the treatment of osteoporosis in postmenopausal women at high risk of fracture, defined as a previous osteoporotic fracture or multiple risk factors, or in patients who have failed or are intolerant of other therapies; the dose is 210 mg subcutaneously once a month, given as two separate injections of 105 mg/1.17 mL by a healthcare professional, limited to 12 monthly doses, because the anabolic effect wanes after that period, and should be followed by an antiresorptive [106]. In the EU, the European Commission authorised Evenity® (EMEA/H/C/004465, UCB Pharma S.A.) on 9 December 2019 for the treatment of severe osteoporosis in postmenopausal women at high risk of fracture, with the same posology of 210 mg monthly for 12 months, and requires treatment to be initiated and supervised by a physician experienced in the management of osteoporosis [107]. The European indication is more restrictive, as it requires severe osteoporosis. The US label carries a boxed warning for the risk of myocardial infarction, stroke and cardiovascular death: the drug should not be initiated in patients who have had one of these events in the previous year, the benefit should be weighed in patients with other cardiovascular risk factors, and it should be discontinued if such an event occurs during treatment; in addition there are hypersensitivity, including angioedema and erythema multiforme, hypocalcaemia, which requires adequate calcium and vitamin D supplementation, osteonecrosis of the jaw and atypical femoral fracture [106]. Neither label covers men, children or adolescents, which makes extrapolation to a patient with PPRD outside both labels when the patient is not a postmenopausal woman; the Italian patient, aged 59 with menopause at 43, was within the age and hormonal group of the label, though not within the indication as regards the cause of the osteoporosis [93, 106, 107].

The agents and circumstances to avoid in PPRD are immobilisation, including cast immobilisation, and steroidal anti-inflammatory drugs and immunosuppressants prescribed for a mistaken diagnosis of arthritis [13]. The Italian case documents the cost of this confusion: the patient received betamethasone for at least ten years, from 12 to 32, with prolonged periods of bed rest, and at 37 had a lumbar T-score of −4.3 [93]. The Casablanca patient received methotrexate 10 to 15 mg weekly for more than two decades without any clinical improvement [50]. In pregnancy, pelvic deformities may require caesarean section [13].

7.6 Growth hormone and other drugs

Recombinant growth hormone (somatropin) has no approved indication for these dysplasias, and there are no trials. The available data are case reports. In the Korean family with SEDT, the proband was treated as GH deficient from 11 years and 10 months, with the dose adjusted up to 0.71 IU/kg/week: growth velocity remained below 4–5 cm/year, height went from 128.5 cm (−3.12 SD) to 142.8 cm (−3.17 SD) at 14 years and 7 months and to 148 cm (−4.30 SD) at 16 years and 8 months, with an arm span of 165.5 cm; the younger brother, treated from 5 years, grew 7–8 cm/year on treatment [73]. The authors conclude that the effect of GH in SEDT is generally limited and variable between patients [73]. There is another report of three years of GH in a boy with SEDT [108]. In a girl with DMC treated with GH for six months at 10 and a half years (dose unknown), disabling bilateral pain and subluxation of the hips followed; the authors cannot determine whether there was benefit and raise the hypothesis of worsening, recommending genetic testing before starting GH for severe short stature [85]. In the absence of evidence, GH should not be presented as a treatment for these dysplasias; its use would be off-label, and a poor response to GH in a patient treated for presumed deficiency should prompt review of the diagnosis [73].

7.7 Perioperative care and anaesthesia

The 2017 guidelines recommend, before surgery, pulmonary evaluation, polysomnography, cardiac and neurological evaluation, cervical spine imaging and a plan for difficult airway at intubation and extubation [97]. The GeneReviews chapter on SEDT recommends cervical radiographs before any general anaesthesia and precautions to avoid neck hyperextension during intubation and positioning [4]. The spine guidelines describe high thoracic spinal cord infarctions after prolonged anaesthesia in patients with skeletal dysplasia (four of five with mucopolysaccharidosis, one with SEDC) and introduce the concept of the «spine at risk», which includes foramen magnum stenosis, atlantoaxial instability and thoracic kyphosis [31]. In DMC, limited mouth opening may make intubation difficult, and the respiratory restriction and mild cardiomegaly described in adults justify prior assessment [19, 90].

7.8 Rehabilitation, activity and development

GeneReviews recommends avoiding extreme flexion and extension of the neck when there is odontoid hypoplasia, and avoiding activities and occupations that overload the spine and the weight-bearing joints [4]. Presymptomatic testing in SEDT was proposed precisely to guide these choices, should avoidance of harmful activities prove beneficial [109]. Physiotherapy and gait adaptation follow the general principles of dysplasias with joint stiffness; in DMC, early developmental intervention, speech therapy and educational support are added [19, 85]. In PPRD, rehabilitation is the only component with a suggested effect on progression: stiffness of the large joints is treated with physiotherapy, activity modification and walking aids, and small-joint arthropathy with occupational therapy, adaptive devices and vocational guidance, with the express instruction to avoid immobilisation [13, 105].

7.9 Regulatory status and trials

A search of ClinicalTrials.gov for «Dyggve», «Smith-McCort», «spondyloepiphyseal dysplasia tarda» and «TRAPPC2» identified no trials of these diseases; the results returned were unrelated studies (one on the diagnosis of mucopolysaccharidoses in bilateral hip disease) [110]. The search for «pseudorheumatoid dysplasia» returned a single record, an observational study not yet recruiting at Assiut University Children's Hospital on the clinical spectrum and diagnostic approach to non-inflammatory paediatric arthropathies, and not an interventional trial; the GeneReviews chapter on PPRD refers to ClinicalTrials.gov and the European registry, warning that there may be no trials for this disease [13, 110]. A negative search does not prove that no studies are under way outside these registries. No gene therapy in preclinical or clinical development has been described for any of the five entities; the most advanced published resource is the ovine CCN6 knockout model, presented by the authors as a platform for testing therapies, with no agent under evaluation [68].

These studies are case reports without a control group and do not allow efficacy to be estimated or interventions to be compared. No randomised trial has been conducted.

7.10 Developments in the last 12 months

Between November 2025 and October 2026 the literature added mainly descriptions of cases and variants: a Turkish sibship with a homozygous deletion of exon 16 of DYM identified after inconclusive sequencing (report) [30]; a homozygous frameshift variant in DYM in a patient followed in Lanzarote, Spain (report) [111]; a deep intronic TRAPPC2 variant identified by genome sequencing after a negative exome, with reclassification by segregation (family report) [73]; a non-canonical intronic TRAPPC2 variant with functional minigene study in a four-generation Chinese family (report with functional study) [72]; and the first cellular characterisation of five RAB33B variants, with protein instability and altered autophagy (preclinical study) [58]. There were no marketing authorisation applications, regulatory opinions or clinical trials.

In PPRD, the same period was more productive and includes, for the first time, work with therapeutic relevance. The comprehensive GeneReviews update was published on 7 April 2026 (expert review) [13]. In October 2026 the first animal model with a phenotype was published, sheep with CRISPR–Cas9 inactivation of CCN6, which reproduce the clinical, histological and molecular features of the disease (preclinical study) [68]. In September 2025, the first report of treatment with romosozumab in a patient with PPRD and severe osteoporosis (case report) [93]. In September 2025 and January 2026, functional studies of CCN6 variants in chondrocytes were published, with endoplasmic reticulum stress, reactive oxygen species, apoptosis and ferroptosis (preclinical studies) [66, 67]. In November 2025, a cohort of 25 children initially diagnosed with juvenile idiopathic arthritis and reclassified as monogenic mimics, 12 of them with PPRD (retrospective observational study) [87]. In addition, there are case reports with little-described phenotypes or complications: acute cauda equina syndrome in a 21-year-old man, the severe phenotype of three Indian sisters, the 52-year-old patient with advanced joint destruction after two decades of methotrexate and the question of early scoliosis at 7 months [50, 80, 94, 95]. No marketing authorisation application, regulatory opinion or interventional trial was registered for PPRD in this period.

7.11 Pregnancy, transition and special situations

The 2018 guidelines address prenatal assessment and delivery in women with skeletal dysplasia and in fetuses with suspected dysplasia, with 40 consensus statements; the sources consulted do not describe pregnancies in women with DMC or SMC [103]. Severe short stature, chest deformity and cervical instability raise airway and neuraxial anaesthesia issues that should be planned with anaesthesiology before delivery [97, 103]. SEDT carriers do not, as a rule, have obstetric limitations [4]. In PPRD, GeneReviews indicates that pelvic deformities may require caesarean delivery, and hip contracture and kyphoscoliosis raise the same positioning and neuraxial anaesthesia issues as the other dysplasias [13, 103]. Transition to adult care should ensure continuity of cervical surveillance and referral for joint replacement surgery; in DMC, the adult retains variable dependence depending on the degree of intellectual disability [4, 24]. In PPRD, transition has its own content: loss of independent walking in adolescence, documented in almost half of the Turkish patients, requires planning of accessibility and vocational training, and the occupational therapy recommended by GeneReviews explicitly includes vocational guidance [13, 75]. From adulthood, surveillance of secondary osteoporosis and review of joint prostheses are added [50, 93].

8. Reproductive Options and Family Counselling

8.1 DMC and SMC (autosomal recessive inheritance)

The parents of an affected child are, as a rule, heterozygous, and each new pregnancy has a 25% risk of an affected child, 50% of a carrier and 25% of a non-carrier; the series show parental consanguinity in most families [21, 22, 41]. Confirmation of variant phase by testing both parents is necessary before giving risks, because apparent homozygosity may result from uniparental disomy, as in the Spanish patient in whom only the father was a carrier; in that case, the recurrence risk for siblings is low [84]. Healthy siblings have a two-thirds probability of being carriers, and carrier testing is mainly of interest in settings of consanguinity or in populations in which the variant is recurrent, such as c.1878del in Morocco [19]. In DMC, the severity of the intellectual disability, not the skeleton, is the main determinant of prognosis, and the same genotype can give different cognitive phenotypes; this uncertainty should be explained when prenatal diagnosis is discussed [26, 53].

8.2 SEDT (X-linked recessive inheritance)

The father of an affected boy is not a carrier and does not need to be tested [4]. A woman with more than one affected son, or with a son and another affected maternal relative, is an obligate carrier [4]. In an isolated case, the mother may be a carrier, the son may have a de novo variant or the mother may have somatic or germline mosaicism; in the studies in which all mothers were tested, all were carriers, and no non-carrier mothers of affected sons, nor maternal germline mosaicism, have been published [4, 69]. Maternal testing is recommended, bearing in mind that leucocyte testing does not detect exclusively germline mosaicism [4]. A carrier mother transmits the variant in 50% of pregnancies: sons who inherit it are affected and daughters are heterozygous, usually without manifestations [4]. An affected man transmits the variant to all his daughters and to none of his sons [4]. Maternal aunts and maternal-line female cousins may be carriers [4]. Carrier detection is by the familial variant; without a testable affected male, by sequencing and, if negative, by deletion/duplication analysis, bearing in mind that exon deletions are not seen by sequencing in a heterozygous woman [4].

8.3 Testing of relatives and minors

Testing of at-risk boys in SEDT allows a diagnosis before clinical and radiological expression and avoids unnecessary endocrine investigations and treatments, such as GH for presumed deficiency [4, 73, 109]. In the Ashkenazi family of Bar-Yosef, an 8-month-old second cousin was identified as carrying the variant before any sign, and the authors raised the dilemma of prenatal counselling in a disease of late onset and variable expressivity [86]. GeneReviews recommends offering genetic counselling, including discussion of risks to offspring and reproductive options, to young adults who are affected, carriers or at risk of being carriers [4]. Anticipatory counselling of carriers includes the possibility of low back pain or osteoarthritis later in life [25, 73].

8.4 Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [4]. Ultrasound does not replace molecular testing, because these dysplasias have no recognisable fetal expression [8]. GeneReviews recommends discussing risk before pregnancy, offering counselling to young adults who are affected, carriers or at risk, and considering DNA banking for probands without a molecular diagnosis [4, 13].

8.5 PPRD (autosomal recessive inheritance)

The parents of a patient with PPRD are presumed to be heterozygous, and GeneReviews recommends testing them to confirm that both carry a pathogenic CCN6 variant, because only that confirmation allows a reliable recurrence risk to be given [13]. Once heterozygosity of both parents is confirmed, each sibling has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier; heterozygotes are asymptomatic and have no risk of developing the disease [13]. Among siblings who inherit both variants, mild to moderate phenotypic variability may be observed, which should be explained to families with more than one affected child [13]. The offspring of a patient are obligate carriers, and each sibling of the proband's parents has a 50% chance of being a carrier [13].

When the variant is identified in only one parent, and biological maternity and paternity are confirmed, the hypotheses to consider are a de novo variant in the proband, a post-zygotic de novo variant in a mosaic parent, a deletion of one or several exons not detected by sequencing that mimics homozygosity, or uniparental isodisomy of the chromosome carrying the variant [13]. The recurrence risk differs greatly between these scenarios, so a conclusion should not be given before excluding them, with targeted deletion/duplication analysis and, if necessary, homozygosity studies [13, 82].

Carrier testing of at-risk relatives requires prior identification of the family's variants [13]. The optimal time to determine genetic risk and discuss the availability of prenatal diagnosis and preimplantation testing is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk of being carriers [13]. GeneReviews further recommends offering molecular CCN6 testing to the reproductive partners of patients or known carriers, especially when consanguinity is likely, a recommendation with practical consequences in the populations in which the disease is concentrated [13]. It also recommends considering DNA banking for probands without a confirmed molecular diagnosis, because methodology and knowledge of mechanisms will improve [13]. Anticipatory counselling here has content that families value: a confirmed diagnosis makes immunosuppression unnecessary, guides surveillance of vitamin D and bone density and allows arthroplasty to be planned, which changes the functional trajectory without altering the progression of the arthropathy [13, 50, 87].

9. Special Considerations: Population Diversity and Epidemiology

9.1 SEDT

Prevalence estimates diverge and none comes from a modern population study. GeneReviews gives 1:150,000 to 1:200,000, citing the British study by Wynne-Davies and Gormley; the OMIM entry cites the same study as 1 per 100,000 in a Scottish population; and the gene identification paper mentions about two cases per million [4, 5, 23]. The study by Wynne-Davies and Gormley estimated the minimum prevalence of skeletal dysplasias in patients ascertained by five orthopaedic centres in Scotland, England and Wales between 1950 and 1979; it measures minimum prevalence in orthopaedic patients, not incidence [112]. The Orphanet class of the grouped entity is 1–9/1,000,000 [18]. TRAPPC2 variants have been described in European, North American, Canadian, Australian, Ashkenazi, Japanese, Korean, Chinese, Taiwanese, Turkish and Italian families, with no population at increased risk, and the recurrence of variants results from independent mutations [4, 9, 69, 70]. In Brazil, the only description in the sources consulted is that of a woman with a 46,XX karyotype and a classic radiological picture [5]. The sources consulted do not include data from Portugal on SEDT.

9.2 DMC and SMC

DMC and SMC have a prevalence below 1/1,000,000 (Orphanet class), with about 100 published cases; a 2002 review counted 58 cases of DMC [18, 19, 90]. The distribution is that of a rare recessive disease: concentration in populations with frequent consanguinity. DMC has been described in Greenland (first family), in Lebanon, where Naffah suggested a relatively high frequency, in Moroccan Jews and Arabs from Gaza, in Morocco, Tunisia, Egypt, India, Pakistan, Turkey and in South Africans of Indian origin [11, 19, 21, 22, 113]. The variant c.1878del (legacy 1877delA) represents 54% of the DYM variants described in Morocco [19]. SMC1 has an ancestral allele in Guam, and the intron 7 splicing variant is shared by identity by descent between Guam, Chile, Argentina and Spain, which the authors relate to European colonisation from the 16th century [57]. SMC2 has been described in Saudi Arabia, Turkey, India and Korea [3, 20, 21, 60].

In the Iberian Peninsula and Latin America, the sources record: a 6-year-old girl from Madeira, daughter of consanguineous parents, with SMC1 due to DYM c.1624T>C in homozygosity, a variant absent in 50 healthy Portuguese individuals [7, 114]; Spanish patients with DMC (compound heterozygosity for splicing variants; paternal isodisomy of chromosome 18; a homozygous frameshift variant described in 2026 in Lanzarote) [57, 84, 111]; Brazilian siblings with DMC studied by Toledo et al. in 1979 [41]; Argentine and Chilean patients [57]; and the first Ecuadorian case, a mestizo man from Quito, presented by the authors as the second in South America [19]. A Honduran child was diagnosed in the USA [85]. In the USA, the main series are the families from Guam (a US territory) and of Dominican origin [38, 43]. The lack of other data in the sources consulted does not mean there are no patients in those countries.

9.3 PPRD

The only population estimate is that of Wynne-Davies, Hall and Ansell, who in 1982 calculated a frequency of 1 per 1,000,000 in the United Kingdom; Hurvitz et al. reproduced it in 1999 as population incidence and added that it is probably higher in the Middle East and the Gulf States, an observation that Teebi and Al-Awadi had made in 1986 when noting that the disease was frequently diagnosed among Arabs [6, 51, 52]. The Orphanet class is 1–9/1,000,000 in point prevalence in Europe [17, 18]. GeneReviews warns that the disease is probably underdiagnosed because of clinical overlap with juvenile idiopathic arthritis, and that more than 400 families with molecular confirmation had been identified by 2026, a number of published families and not a prevalence estimate [13].

The known distribution is that of a recessive disease concentrated in populations with frequent consanguinity, and the largest series come from India and China [13]. The figures of the published cohorts are: 35 patients from 25 unrelated Indian families, with the variant c.1010G>A in 10 of these families, the largest series in the literature at the time; 44 Turkish patients, with c.156C>A in 53.3% of the families; 105 Chinese patients, with 33 variants of which 26 (79%) were exclusive to that population; 23 unrelated Egyptian patients, with 11 variants, five of them novel; nine families from the Middle East (three from Lebanon, five from Syria, one of Palestinian Bedouin origin), all consanguineous, with a founder effect of c.156C>A; and 63 patients from a European multicentre series coordinated in Lausanne [75–79, 92]. GeneReviews adds the observation of the disease in populations with a high rate of consanguinity in Kuwait, Lebanon, India, Iran, Jordan, Saudi Arabia, Syria, Palestine and Morocco [13]. Hurvitz et al. noted that the zygosity of the variants follows consanguinity: the families from Italy, France and the USA were compound heterozygous, and those from Saudi Arabia, Jordan and Iran homozygous [10].

Europe and North America contribute scattered patients and the methodological reference series. The series of 63 patients by Garcia Segarra et al. brought together centres in Switzerland, Turkey, Italy, France, Austria, Germany, Belgium, Poland, the United Kingdom and India and is the source of the radiological sequence used in diagnosis [92]. Hurvitz et al. included families from the USA, Italy, France and Iran [10, 52]. There are isolated descriptions in patients of European ancestry, among them the Italian patient from Bologna and the Belgian family with the exon 1 deletion [50, 81, 93]. In the sources consulted there are no prevalence data or series from Portugal or Brazil for PPRD; the patient described in Casablanca is the closest geographical reference to the Portuguese-speaking world in the Maghreb [50]. The absence of these data in the sources consulted does not demonstrate an absence of patients or publications.

9.4 Dysplasia cohorts and access to diagnosis

In an Indian cohort of 248 patients with skeletal dysplasia from 197 families, next-generation sequencing and targeted tests yielded a diagnosis in 73.6% of families, with 35% consanguinity and 60% recessive forms; RAB33B appears among the genes with an expanded spectrum [115]. These data show that, in populations with frequent consanguinity, recessive forms such as DMC and SMC are a relevant fraction of the dysplasias diagnosed. Access to testing also conditions PPRD: the Casablanca patient did not have the financial means for CCN6 testing, and the authors assumed the diagnosis on the basis of the clinical picture, normal inflammatory markers, radiology and lack of response to disease-modifying antirheumatic drugs, recommending molecular confirmation whenever feasible; in the Syrian patient, the diagnosis was likewise clinical because the test was unavailable in the country [50, 95].

9.5 Networks and associations

In Europe, the reference network is ERN BOND, dedicated to rare bone diseases [32]. GeneReviews lists the Human Growth Foundation, Little People of America, the MAGIC Foundation and the International Skeletal Dysplasia Registry of the University of California, Los Angeles (UCLA) as resources for families [4]. For PPRD, GeneReviews lists the Arthritis Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health and the same UCLA international skeletal dysplasia registry; the applicable European reference network is likewise ERN BOND [13, 32]. The choice of resources reflects the usual pathway of these patients through rheumatology, and referral to a bone dysplasia centre is, according to GeneReviews, part of the initial evaluation [13].

10. Illustrative Clinical Case

10.1 DMC: late diagnosis in Ecuador

Reyes-Silva et al. described in 2025 a man from Quito, Ecuador, referred to the genetics clinic at 17 years for suspected skeletal dysplasia and re-evaluated at 21 [19]. He was born at 38 weeks, weighing 3180 g and measuring 47 cm, without known consanguinity or family history. In early childhood he had developmental delay: he sat at 8 months, walked at 18 months with a waddling gait and achieved sphincter control at 3 years. Short stature and abdominal distension led to the initial suspicion of mucopolysaccharidosis type VI [19].

At 17 years he measured 137 cm (−3 SD), weighed 42 kg (body mass index 22.4) and had a head circumference of 45 cm. He had coarse facies, macroglossia, prognathism, a short neck, a disproportionately short trunk, pectus carinatum, thoracic kyphosis of 62°, flat feet and an unsteady gait with adduction and restriction of the hips. The WAIS-IV scale gave an intelligence quotient of 68, compatible with mild intellectual disability. Spirometry showed mild restriction (forced vital capacity 0.93 L, 58% of predicted; forced expiratory volume in one second 0.93 L, 57%), and cardiac evaluation showed grade I cardiomegaly with an ejection fraction of 58%. Arylsulfatase B activity was normal (11.6 µmol/L/h; reference ≥8.8), excluding MPS VI [19]. Figure 1 of the article shows the phenotype, the acetabular dysplasia on the pelvic radiograph and the platyspondyly on the lateral radiograph of the thoracic spine (https://pmc.ncbi.nlm.nih.gov/articles/PMC12110845/figure/genes-16-00490-f001/) [19].

A panel of 358 skeletal dysplasia genes identified, in homozygosity, the DYM variant NM_017653.6:c.1878del, p.(Lys626AsnfsTer94), which in the MANE transcript corresponds to NM_001353214.3:c.2043del, p.(Lys681AsnfsTer94); classified as pathogenic (PVS1, PM2, PM3, PP5), it lengthens the protein to 718 amino acids [19, 64]. Sanger sequencing confirmed that the parents and sister were heterozygous. The panel also found VUS in CCN6, CSPP1, GNPTAB and FLNB, which the authors considered unrelated to the phenotype [19]. This is the most frequent variant in Morocco, here found in a mestizo patient without known consanguinity, which the authors interpret as a sign that DMC is not restricted to specific ethnic groups [19].

At follow-up, the patient had mild tricuspid regurgitation, worsening thoracic kyphosis, bilateral coxarthrosis, narrowing of the femorotibial joint space and chronic bone pain, and remained on multidisciplinary supportive treatment [19]. The report does not describe dynamic assessment of the cervical spine; the spine guidelines recommend considering flexion–extension radiographs in patients with dysplasia and a risk of C1–C2 instability [31]. The case illustrates the diagnostic delay, the initial confusion with a mucopolysaccharidosis, the mild intellectual disability possible in DMC and the joint degeneration of the young adult [19].

10.2 PPRD: two decades of methotrexate for a mistaken diagnosis

Ridah et al. described in 2025, in the rheumatology department of the Ibn Rochd University Hospital Centre in Casablanca, a 52-year-old woman with PPRD [50]. She had a history of hypertension, diabetes, vitiligo, early menopause and two total hip prostheses. Her parents were not consanguineous and there were no similar cases among her siblings. From the age of 7 she had polyarthralgia and non-synovial swelling of the metacarpophalangeal joints, proximal interphalangeal joints, wrists, elbows, shoulders, knees and ankles. She was initially classified as having seronegative polyarticular juvenile idiopathic arthritis, then seronegative rheumatoid arthritis, and received methotrexate at doses of 10 to 15 mg weekly for more than two decades, without any clinical improvement; the reason given for continuation was the persistence of symptoms under the initial diagnosis, which led clinicians to expect delayed efficacy and prevention of further joint damage [50].

On examination she measured 1.49 m and weighed 54 kg (body mass index 24.3 kg/m²). She had joint pain, non-synovial swelling, limited range of motion, amyotrophy of the hands, deltoids and right thigh, and deformities of the hands, elbows and feet, with symmetrical involvement of the upper and lower limbs; there was shortening of the left forearm and of the right lower limb, the latter due to removal of the hip prosthesis. The erythrocyte sedimentation rate and C-reactive protein were normal, and rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative [50].

Radiographs of the hands showed bilateral epimetaphyseal flattening and widening of the metacarpophalangeal and proximal interphalangeal joints, with ankylosis of the radiocarpal, intercarpal and carpometacarpal joints on the left; those of the feet showed subluxation of the metatarsophalangeal joints and brachymetatarsia; the pelvic radiograph showed both prostheses, with loosening of the right one, superior migration of the femoral component and fracture of a fixation screw, confirmed by coronal computed tomography with marked periacetabular bone loss; radiographs of the thoracic and lumbar spine showed vertebral fractures from T7 to T10, reduced disc height and endplate irregularity, and densitometry showed lumbar osteopenia with a T-score of −2.1 [50]. The article's figures document the amyotrophy of the hands with Z-thumb and boutonnière deformities, bilateral hallux valgus and claw toes, the radiographs of the hands and feet, the radiograph and CT of the pelvis and the lateral radiograph of the spine (https://pmc.ncbi.nlm.nih.gov/articles/PMC12533980/figure/FIG1/) [50].

The patient did not have the financial means for molecular testing of CCN6. The authors considered the diagnosis highly reliable through the combination of clinical, laboratory and radiological findings with the lack of response to disease-modifying antirheumatic drugs, but recommend molecular confirmation whenever possible, because it establishes the diagnosis definitively and allows genetic counselling [50]. She was treated with analgesics, rehabilitation and bisphosphonates, indicated for osteopenia with vertebral fractures, and reassessment of the right arthroplasty was proposed [50]. The management in this report is not routine: GeneReviews recommends assessing vitamin D and supplementing in deficiency, without routinely recommending bisphosphonates, and no antiresorptive has demonstrated antifracture efficacy in PPRD [13, 93].

A second report completes the picture of complications in the young adult with molecular confirmation. Udayakumar et al. described in 2026, at the Jawaharlal Institute of Postgraduate Medical Education and Research in Puducherry, a 21-year-old man with pain in both legs and acute progressive weakness of the lower limbs with gait disturbance; he had asymmetric motor weakness, absent knee and ankle reflexes and preserved bladder and bowel function. Radiographs showed generalised platyspondyly, scoliosis and epiphyseal widening of the long bones, and inflammatory markers were negative. Magnetic resonance imaging showed a right paracentral disc extrusion at L1–L2 with severe central canal stenosis and compression and displacement of the cauda equina roots. Exome sequencing identified in homozygosity the CCN6 variant c.1010G>A, p.(Cys337Tyr), which is one of the two most frequent variants in the Indian population. He underwent posterior decompressive laminectomy with stabilisation, with complete neurological recovery at six weeks [13, 64, 94].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

In DMC, prognosis is determined by the intellectual disability, moderate to severe in most patients described, by final stature (82–128 cm), by hip degeneration and by the risk of cervical spinal cord compression [24, 26]. Spinal cord compression and early death have been described in both forms, DMC and SMC [41]. In SMC, cognition is normal, but motor function deteriorates: in the Tüysüz series, only two of seven patients walked independently after 5 to 9 years of follow-up [20]. The sources consulted do not provide life-expectancy data for DMC or SMC. In SEDT, intelligence and life expectancy are normal; morbidity results from low back pain, early osteoarthritis, frequently disabling by 60 years, and the need for arthroplasties, often before 40 years [4, 25].

In PPRD, intelligence is normal, there are no extraskeletal manifestations and life expectancy is normal; the prognosis is entirely functional [13, 28]. The most useful quantitative data come from the Turkish cohort of 44 patients, with a mean follow-up of 5.6 years: 97.7% developed a waddling gait and 47.7% lost the ability to walk without support, at a median age of 12 years [75]. This is a cohort from a referral centre, with probable overrepresentation of severe forms and of the founder variant c.156C>A, and not a population estimate. Adult stature falls below the third centile in about half of patients, between 135 and 156 cm in the older series [6, 13, 28]. Cartilage loss continues after the end of growth, and adults become severely limited by contractures; hip arthroplasty, and sometimes knee arthroplasty, is required in several patients before 30 years and is the intervention that most alters the trajectory, with an added risk of loosening and revision in prostheses implanted so early [6, 28, 50, 92]. There are no published life-expectancy or mortality data specific to PPRD, and the natural history figures refer to patients who received, for the most part, symptomatic treatment and, in many cases, inappropriate immunosuppression for years [13, 50].

11.2 Surveillance

11.3 Lifelong follow-up

In the child with DMC, follow-up includes cervical surveillance, developmental stimulation and conservative orthopaedic management of the hips, avoiding osteotomies in childhood unless there is pain [31, 89]. In adolescence and adulthood, the focus shifts to pain, mobility and arthroplasty [104]. In the boy with SEDT, follow-up begins with confirmation of the diagnosis, which avoids useless treatments, and continues throughout life with annual assessment of the spine and joints and cervical radiographs before anaesthesia [4, 73]. Carriers do not need specific surveillance, but should know that arthralgias or early degeneration may occur [25, 73]. In the child with PPRD, follow-up is organised around function: orthopaedic assessment at each visit, an annual visit at a bone dysplasia centre, continued physiotherapy and occupational therapy, correction of vitamin D deficiency and avoidance of immobilisation and immunosuppression [13]. In adolescence, bracing for scoliosis and mild kyphosis, correction of angular deformities of the lower limbs and the decision on hip arthroplasty, which may be performed in the second decade, are added [13]. In the adult, follow-up shifts to chronic pain, revision of prostheses, secondary osteoporosis and surveillance of the degenerative spine; delivery, when the pelvis is deformed, may require caesarean section [13, 50, 93, 94].

12. Summary and Concluding Remarks

Dyggve–Melchior–Clausen dysplasia, Smith–McCort dysplasias types 1 and 2 and X-linked spondyloepiphyseal dysplasia tarda form a group of spondyloepi(meta)physeal dysplasias in which the primary defect lies in the trafficking of matrix proteins between the endoplasmic reticulum, the Golgi apparatus and the chondrocyte surface. DYM and RAB33B cause autosomal recessive diseases with an identical skeleton, defined by lace-like iliac crests and double-humped vertebrae, and are distinguished by the presence of intellectual disability and microcephaly in DMC; TRAPPC2 causes an X-linked recessive dysplasia, invisible at birth, that manifests at school age with a short trunk, a central and posterior hump of the lumbar endplates and early osteoarthritis of the hips.

Diagnosis rests on the radiological skeletal survey interpreted by someone familiar with the evolution of the signs with age, on exclusion of the mucopolysaccharidoses and on molecular confirmation with attention to technical limits: the pseudogene and exon deletions in TRAPPC2, deep intronic variants that escape the exome, exon deletions in DYM and the difference in numbering between the historical transcript NM_017653 and the MANE transcript NM_001353214.3 of DYM. In SEDT, the most common error is the diagnosis of growth hormone deficiency.

PPRD adds a disease with a different mechanism and equally difficult recognition. CCN6 does not belong to the trafficking machinery: it encodes a secreted matricellular protein that regulates the expression of type II collagen and aggrecan through SOX9, controls the chondrocyte's reactive oxygen species and modulates the BMP and WNT pathways. The disease sets in between 3 and 6 years with painless bony swelling of the interphalangeal joints and progressive stiffness of all joints without any sign of inflammation, and the dominant diagnostic error is not growth hormone deficiency but juvenile idiopathic arthritis, with years of ineffective methotrexate, corticosteroids or biologics and the added cost of osteoporosis and immobilisation. Radiographs of the hands, pelvis and spine, together with a normal erythrocyte sedimentation rate and C-reactive protein, resolve most cases, and CCN6 sequencing confirms them, with the caveat of exon deletions and deep intronic variants, which require copy-number analysis and sequencing of fibroblast cDNA.

There is no targeted treatment and there are no ongoing trials. Management follows the consensus recommendations for skeletal dysplasias: surveillance of the craniovertebral junction, cervical imaging before anaesthesia, cervical surgery when there is instability with compression or myelopathy, caution with hip osteotomies in childhood, arthroplasty in the adult and developmental follow-up in DMC. Genetic counselling differs between the recessive forms, in which consanguinity and the recurrent variants in Morocco, Guam, the Iberian Peninsula and Latin America guide carrier testing, and the X-linked form, in which the mothers of affected boys are, in the published studies, always carriers. In PPRD, treatment is symptomatic: analgesia that should not be withheld because of the absence of inflammation, physiotherapy and occupational therapy, avoidance of immobilisation and immunosuppressants, spinal bracing, correction of angular deformities, vitamin D supplementation in deficiency and early arthroplasty. The published pharmacological experience in secondary osteoporosis is limited to case reports and includes a report of romosozumab followed by zoledronic acid with a 24% gain in lumbar bone mineral density, an off-label use without demonstrated antifracture efficacy in the disease. The first animal model with a phenotype, sheep with CCN6 inactivation, was published in 2026 and is presented as a platform for testing future therapies.

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