Collagen XII-Related Disorder (Myopathic Ehlers–Danlos)

Overlap disorder of muscle and connective tissue caused by variants in COL12A1, with autosomal dominant and autosomal recessive inheritance, described in the literature as myopathic Ehlers–Danlos syndrome, Bethlem myopathy 2 and Ullrich congenital muscular dystrophy 2.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Background and founding articles

For two decades the collagen VI-related myopathies occupied the clinical space of disorders combining muscle weakness with signs of connective tissue disease, in the forms of Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy. Some patients with this phenotype had no variants in COL6A1, COL6A2 or COL6A3: in a Newcastle group, about half of the cases with a Bethlem picture remained without a molecular diagnosis [19]. In 2014, two articles published in the same issue of Human Molecular Genetics linked this phenotype to the collagen XII gene. Zou and colleagues, starting from immunocytochemical screening of fibroblast cultures from patients with weakness, hyperlaxity and normal collagen VI, described three patients in two families: two siblings of consanguineous parents of Turkish origin, homozygous for a splicing variant with complete loss of function, with generalised hyperlaxity and weakness that prevented walking, and a boy with a de novo missense variant, more mildly affected, who achieved walking [20]. In the same issue, Hicks and colleagues studied about 24 patients with a Bethlem-like phenotype, sequenced 12 candidate genes and then the exome, and found dominant COL12A1 variants in five individuals from two families, with intracellular retention of collagen XII in fibroblasts [19]. Zou and colleagues named the entity «Ehlers-Danlos/myopathy overlap syndrome» and showed that the collagen XII-null mouse has weakness and reduced passive force generation [20].

1.2. Milestones of molecular discovery

Collagen XII was discovered in 1987 by Gordon and colleagues, who cloned from chick tendon fibroblasts a complementary DNA homologous to the short chains of collagen IX; the human gene was mapped to chromosome 6 in 1992 and the complete sequence, with a long variant of 3063 amino acids and a short one of 1899, was described by Gerecke and colleagues in 1997 [5, 7]. The mouse with deletion of exons 2 to 5, created by Izu and colleagues in 2011, showed fragile bones with disorganised collagen fibres before any human disease was known [5]. After 2014, the disorder was broadened by successive series: the intermediate-onset form in a Polish girl in 2017 [21], adult distal myopathy in dominant families in 2019 [14], the screening of 78 patients meeting criteria for myopathic EDS in Belgium in 2020 [22], the in-frame 10-exon deletion detected only by copy-number analysis in 2022 [23], the mild recessive form affecting only the long isoform in 2023 [24], and the 2025 reviews by McCarty and colleagues, on the recessive forms, and by Merlini and colleagues, on all published families [4, 13].

1.3. Current nomenclature and classifications

The same disorder has three designations, reflecting the clinical field from which each originated. In the 2017 international classification of the Ehlers–Danlos syndromes, which recognises 13 types, myopathic EDS (mEDS) is type 12, with AD or AR inheritance, caused by COL12A1 and with collagen XII as the affected protein; the consortium included it in the classification because these patients are clinically suspected of having EDS, despite the overlap with Bethlem myopathy [1, 25]. OMIM records two phenotypes: Bethlem myopathy 2 (BTHLM2, 616471), with AD inheritance, with the alternative title «EDS, myopathic type», and UCMD2 (616470), with AR inheritance, still with the phenotype–gene relationship marked as provisional because it rests on a single family [2, 3]. The recent neuromuscular literature uses the term «collagen XII-related myopathy» (COL12-RM), justified by the biopsy not showing the dystrophic pattern [4]. McCarty and colleagues proposed that the OMIM division into Ullrich and Bethlem be reconsidered, because the phenotypes differ from those of collagen VI disease, and that the spectrum be treated as myopathic EDS [13]. Orphanet adopts the designation Myopathic Ehlers-Danlos syndrome (ORPHA:536516) as the main entity and includes the OMIM numbers in the Bethlem and Ullrich records [9–11].

The distinction between UCMD and Bethlem follows, by analogy, the ambulation criteria proposed at the 166th European Neuromuscular Centre (ENMC) workshop for collagen VI: UCMD for those who never walked or lost ambulation by 12 years, the intermediate form for those who lose it in adolescence and Bethlem for those who walk in adulthood. Applying these criteria to the 33 people with dominant variants published by 2025, Merlini and colleagues found that 31 walked, but only 14 were adults, so 17 should be classified as «currently Bethlem 2 or intermediate» until they reach 18 years [4].

The international consortium announced for December 2026 the publication of a new classification of all EDS types and of the hypermobility spectrum disorders (HSD), developed by literature review, Delphi consensus and peer review, which will replace the previous criteria; information on the assessment and treatment of the monogenic types is planned for the same date and the diagnostic pathway for March 2027. At the date of this update this is an announcement by The Ehlers-Danlos Society, and the 2017 criteria remain in force [26].

1.4. Definition of the entity

Collagen XII-related disorder is a single entity, with two modes of transmission that should not be confused. The dominant form results from heterozygous variants, often de novo, with a dominant-negative effect on the homotrimer, and on average occupies the milder end of the spectrum; the recessive form results from biallelic loss-of-function variants and is, on average, more severe, although mild recessive forms exist when only the long isoform is affected [13, 24, 27]. Orphanet defines myopathic EDS as a rare systemic disorder with congenital muscle hypotonia and/or atrophy that improve with age, proximal joint contractures (knee, hip, elbow) and hypermobility of the distal joints, together with soft, doughy skin, atrophic scars, delayed motor development, myopathic findings on biopsy and, in some patients, craniofacial changes; molecular confirmation is mandatory [9].

1.5. Related entities

The collagen VI-related disorders (Bethlem myopathy and Ullrich congenital muscular dystrophy) are the main differential diagnosis of COL12A1 disease. The general classification of the Ehlers–Danlos syndromes and the remaining types also enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The gene and the isoforms

COL12A1 is located at 6q13-q14.1 (the first mapping by in situ hybridisation placed it at 6q12-q13), close to two other FACIT collagen genes, COL9A1 and COL19A1 [5, 7]. The MANE Select reference transcript, NM_004370.6, corresponds to the long isoform: it has 66 exons, 11 725 nucleotides and a coding sequence of 9192 nucleotides, encoding 3063 amino acids (about 331 kDa). The short isoform, NM_080645.3, has 51 exons and encodes 1899 amino acids [5–7]. Both result from alternative splicing and differ in the NC3 domain: the long one (XIIA) has 18 fibronectin type III repeats and four von Willebrand factor type A (vWA) domains, and the short one (XIIB) lacks the first two vWA domains and eight fibronectin repeats, that is, about half of NC3 [8, 24]. In the mouse, the long isoform predominates in the early embryo and the short one in late stages and after birth, the long one becoming restricted to dense connective tissues (bone, tendon, ligament, dermis, cornea, vascular wall, meninges, periodontium and periosteum) [8, 20]. In humans, both variants have been detected in amnion, chorion, skeletal muscle, small intestine, dermal fibroblasts, keratinocytes and endothelial cells, and only the short one in lung, placenta and kidney [5].

2.2. Structure and function of collagen XII

Collagen XII is a homotrimer of three α1(XII) chains, with two short triple-helical domains (COL1 and COL2) separated by non-collagenous domains (NC1 and NC2) and a large amino-terminal NC3 domain, which includes an N-terminal thrombospondin (TSPN) domain, the vWA domains and the fibronectin repeats [20, 24]. Heterotrimers between the long and short isoforms also form [8, 24]. On electron microscopy, molecules extracted from tendon are cross-shaped, with three arms of 60 nm and a tail of 75 nm [7]. The collagenous domain binds to the surface of collagen I fibrils and regulates fibrillogenesis, and the NC3 arms project into the perifibrillar matrix and bind tenascin-X, decorin and fibromodulin, bridging the fibrils and the other components of the extracellular matrix (ECM) [7, 8, 20]. Expression is induced by mechanical tension and inflammation, and collagen XII is produced mainly by fibroblasts, as is collagen VI in muscle, where it derives from interstitial fibroblasts and not from the muscle fibre [14, 20]. In normal muscle, collagen XII strongly marks the perimysium and, less intensely, the endomysium, but, unlike collagen VI, it does not overlap the basement membrane of the fibre [20].

2.3. From collagen XII deficiency to weakness and laxity

The Col12a1−/− mouse has reduced grip strength, reduced hindlimb splaying when suspended by the tail, delayed fibre-type transition in the soleus, an 18% reduction in isometric tetanic force and a 16% reduction in specific force in the extensor digitorum longus muscle, lower passive force when the muscle is stretched and, by contrast, protection from force drop during eccentric contractions [20]. The authors interpreted this set of findings as a more compliant matrix, which transmits less force and mechanically unloads the muscle fibre, and not as a primary defect of the contractile apparatus, which distinguishes the model from the mdx mouse [20]. The same logic explains the ring fibres found in a biopsy from an adult patient, which Mohassel and colleagues compared to a mild chronic functional tenotomy [14]. Brady and colleagues summarise the mechanism as a mechanical problem of the ECM: in muscle, abnormal organisation and force transmission; in skin and tendons, the EDS-type manifestations [15].

In connective tissues, the collagen XII-null mouse has fragile bones with disorganised fibres, reduced expression of bone matrix proteins and reduced bone-forming activity, through loss of osteoblast polarity [5, 8]. In tendon, pericellular collagen XII links neighbouring tenocytes and regulates collagen I synthesis, and its absence disorganises the cellular network and increases the stiffness of the flexor tendon [5]. In the developing knee joint, lack of collagen XII destabilises the tendons and the femoral trochlear groove and causes patellar subluxation, with secondary degeneration of the quadriceps, a finding that led to the identification of the same problem in patients [28]. In the dermis of a patient with skipping of exon 54, electron microscopy showed slightly wider collagen fibrils (92.1 versus 84.7 nm), increased interfibrillar space (42% versus 32%) and elastin with frayed edges [22]. Studies from 2025 and 2026 with tendon-targeted deletion of Col12a1 showed cellular disorganisation from birth, abnormal tibial insertion and, in the Achilles tendon, lower maximum load, stiffness and modulus, with thinner fibrils and persistent remodelling [29, 30]. In the subcutaneous adipose tissue of the collagen XII-null mouse, expression of muscle genes and myostatin-positive cells appear, a still preclinical hypothesis of a contribution to the myopathy [31]. In gingival fibroblasts from a patient homozygous for a loss-of-function variant, hyperproliferation, reduced apoptosis and reduced osteogenic differentiation provide a basis for the gingival hypertrophy of the recessive forms [32].

2.4. Mechanism of the dominant forms

Dominant variants produce abnormal chains that enter the homotrimer and disrupt it, in a dominant-negative effect. Glycine substitutions in the repetitive Gly-X-Y sequence of the triple-helical domains, especially in the more amino-terminal COL2 domain, allow the COL1 domain to initiate the triple helix and incorporate the mutant chain; with one mutant chain in three, 7 in every 8 homotrimers contain at least one abnormal chain [14]. For the substitution p.Ile2334Thr, adjacent to a metal ion-dependent adhesion site (MIDAS) motif in the last vWA, Zou and colleagues estimated that only 25% of trimers would be normal if the mutant chain were incorporated with the same efficiency [20]. The in-frame deletion of exon 52 and the substitution p.Gly2689Arg affect a cysteine-rich laminin-G-like domain, which is thought to stabilise the trimer through disulphide bonds; exposure of unpaired cysteines may retain the protein in the endoplasmic reticulum, as proposed for p.Arg1965Cys, which activates the unfolded protein response and dilates the reticulum [14, 19]. The splicing variants with in-frame skipping described in Belgium cluster in a hinge region between NC3 and the fibril-associated portion (TSPN and COL2 domains), and those removing exons 52, 53 and 56 alter the migration of the long isoform (suggesting overmodification) and almost completely reduce the secreted short isoform, with less extracellular decorin and tenascin-X and without reticulum stress markers [22]. The exon 55 and 56 variants studied in Italy produced a filamentous extracellular network with punctate aggregates and increased collagen XII, I and VI in lysates and media [4].

2.5. Mechanism of the recessive forms

In the severe recessive forms, both variants are loss-of-function and affect the part of the gene common to both isoforms, leading to nonsense-mediated decay (NMD) of messenger RNA and an almost complete absence of collagen XII. In the siblings of Zou and colleagues, the transcript in fibroblasts was 3% of normal, and collagen XII was absent from the matrix, from within the cells and from muscle, with collagen VI and laminin γ1 preserved [20]. Haploinsufficiency is, by contrast, clinically mild or silent: the carrier parents of these siblings walked after 2 years but had normal strength in adulthood, and the heterozygous parents of the later recessive families were healthy [13, 14, 20]. This observation is the basis of the strategy of silencing the dominant allele (see 7.8). COL12A1 is constrained for loss-of-function variants in the population: the gnomAD v4.0.0 population database records 102 of 320.4 expected loss-of-function variants (probability of loss-of-function intolerance, pLI, of 0.97; loss-of-function observed/expected upper bound fraction, LOEUF, of 0.38) [13].

2.6. Genotype–phenotype correlation and isoforms

Severity follows the quantity and type of collagen XII that remains. Almost complete absence through biallelic loss of function in both isoforms is associated with the most severe congenital phenotype; haploinsufficiency, with a minimal phenotype; qualitatively abnormal chains in the dominant forms, with variable and on average moderate phenotypes [22]. In the series of McCarty and colleagues, the five severe patients had biallelic loss-of-function variants affecting the long and the short isoform; a patient homozygous for a loss of function only in the long isoform and two siblings with a missense in the long isoform and a loss of function in both had milder disease and walked, and the authors described a trend in which loss of the short isoform is associated with the severe congenital form [13]. The 47-year-old Japanese man homozygous for c.395-1G>A, which removes exon 6 (present only in the long isoform) and part of the first vWA, worked without physical limitations [24], and the patient of Shinmi and colleagues, with a nonsense variant outside the short-isoform region and a splicing variant common to both, had almost only the short isoform in muscle (20% to 30% of normal) and was walking at 30 years [33]. These observations come from few patients and the correlation is described by the authors as a trend.

Brady and colleagues found no documented cases of non-penetrance in the dominant forms, but formal penetrance is unknown and intrafamilial variability is large: in the three-generation Danish family and in the North American family of Mohassel and colleagues, adults with the same variant had different degrees of weakness and hyperlaxity [14, 15, 34]. Arginine-to-cysteine substitutions in fibronectin III domains are the group most difficult to interpret: patients with these variants were diagnosed later and had no hypermobility, 23 of the 157 arginines of the chain have cysteine substitutions in gnomAD, p.Arg1965Cys has a frequency of about 1/4009 in gnomAD and p.Arg1863Cys of 1/2095 in the Japanese population panel, and both currently have conflicting classifications in ClinVar [22, 24, 35]. Furuhata-Yoshimura and colleagues excluded these families from their review for this reason, and Delbaere and colleagues allowed that they may be modifiers rather than causal [22, 24].

2.7. Published variants and normalisation

The literature uses two numberings for the first variants. Zou and colleagues counted from another origin of the transcript, and their variants, transcribed this way by OMIM and by Brady and colleagues, are shifted by 166 nucleotides relative to MANE Select: «c.8006+1G>A» corresponds to NM_004370.6:c.7840+1G>A and «c.7167T>C» to NM_004370.6:c.7001T>C; the historical forms give a reference error in VariantValidator, which confirmed the current forms [5, 6, 24]. The table of Merlini and colleagues corrects the second but keeps the first in the historical form and has two typographical errors (c.5893C>T and c.5794+2T>A) [4, 13]. Table 2.1 brings together the published variants, with those of uncertain significance (VUS) flagged, normalised in VariantValidator with transcript NM_004370.6 and protein NP_004361.3.

Table 2.1. COL12A1 variants published in patients, normalised (NM_004370.6; NP_004361.3) [6, 35].

2.8. Mosaicism, allelic disorders and associations

In the Polish girl with p.Gly2777Arg, the variant was absent in the mother and somatic mosaicism was excluded by analysis of blood, buccal mucosa and hair follicles; the father was not tested [21]. Germline mosaicism has not been described in the sources consulted. To date, there are no established allelic disorders of COL12A1 outside the mEDS/BTHLM2/UCMD2 spectrum in OMIM [5]. A Chinese study from 2026 found COL12A1 variants classified as pathogenic in 3 of 32 patients with isolated spontaneous dissection of the superior mesenteric artery; this is a small association study, without replication, which does not establish a vascular manifestation of myopathic EDS [44]. A COL12A1 VUS, p.(Val1051Leu), with reduced RNA and protein in fibroblasts, was found in a Pakistani family with a limb-girdle muscular dystrophy phenotype, in a cohort of 29 families [45].

3. Clinical Spectrum and Manifestations by System

3.1. Overview

The common picture combines three elements: hypotonia of congenital onset, with motor delay, which tends to improve; contractures of large proximal joints, which may regress in the mild forms; and hypermobility of the distal joints, often generalised and more marked than in collagen VI disease [1, 13, 15]. The review by Merlini and colleagues, which brought together 33 patients from 20 dominant families and 15 patients from 13 recessive families, showed congenital onset or onset at birth in most, onset in childhood in three patients and in adolescence in three, and difficulty running in all those for whom this information was available [4]. Hypermobility was described as distal in 15 patients, generalised in 9, distal and proximal in 10, marked in one and moderate in another; the Beighton score, recorded in few, ranged from 5 to 9 out of 9 [4]. Creatine kinase (CK) is normal or mildly elevated [4, 13]. Table 3.1 compares the two forms of inheritance.

Table 3.1. Features of the dominant and recessive forms of collagen XII-related disorder.

3.2. Severe recessive form

The two siblings of Zou and colleagues define the severe end. The elder was born weighing 2660 g, with strength barely overcoming gravity, very hypermobile distal joints, moderate proximal contractures, kyphoscoliosis, mild facial weakness, high-arched palate and absent reflexes; he had a gastrostomy before 2 years because of difficulty eating and swallowing, nocturnal non-invasive ventilation (NIV) before 3 years for documented hypoventilation, and spinal fusion at 9 years for progressive scoliosis. He could move from lying to sitting, but never stood or walked, and moved about in a powered wheelchair. The younger brother had an almost identical picture. CK and nerve conduction were normal and the biopsy showed only variation in fibre size [20]. In the extended family, several children died in early childhood with an apparently similar picture, without DNA available [20]. As young adults, the two siblings remained non-ambulant and on nocturnal respiratory support, without progression of the myopathy since birth [28].

In the series of McCarty and colleagues, five of the eight patients had this severe phenotype: profound weakness, minimal motor achievements (no head control, sitting only with support), respiratory failure and feeding difficulties; four were born with arthrogryposis, one with femoral and tibial fractures at birth and gracile ribs, and one became dependent on ventilation via tracheostomy from birth [13]. Other severe recessive cases have been described in Iran, India and Egypt (a girl homozygous for p.Arg1414Ter, non-ambulant and on NIV before 2 years) [4, 38–40]. The Iranian boy, son of first cousins and homozygous for p.(Pro2943Leu), had decreased fetal movements in the last week of gestation, was born at 37 weeks weighing 2700 g and had seizures on day 3, feeding difficulty and progressive spasticity; he never sat or spoke, and had profound weakness, proximal contractures, pectus excavatum, mild strabismus, mild microcephaly, recurrent pneumonia and difficulty swallowing solids, and died at 10 years without a described cause; the central nervous system signs do not belong to the known spectrum of the disorder, the variant was classified by the authors as of uncertain significance and has only in silico and segregation support, so the attribution of the whole picture to COL12A1 is uncertain [38]. The Indian girl, daughter of non-consanguineous parents, was seen at 4 years for isolated motor delay: she took only a few steps without support, rose with difficulty from squatting and had proximal limb-girdle weakness, distal hypotonia, knee contractures, prominent calcanei, hyperextensibility of the metacarpophalangeal and interphalangeal joints, soft, velvety palms and soles, keratosis pilaris on the legs and forearms and preserved reflexes; CK was 90 U/L and the echocardiogram, brainstem auditory evoked potentials and nerve conduction were normal; the two missense variants were in trans and the parents declined muscle biopsy, so there was no functional study [39].

3.3. Mild recessive forms

Not all recessive forms are severe. Three patients in the series of McCarty and colleagues, all with congenital onset and hip dysplasia, walked at 3 years, 15 months and 16 months; one of them, at 13 years, ran, jumped and climbed stairs, with mild proximal and axial weakness [13]. The Japanese man of Furuhata-Yoshimura and colleagues had hypotonia, scoliosis, weak spontaneous movements and torticollis at birth, was followed as possible Marfan syndrome, walked at 3 years, had frequent dislocations of both knees, orchidopexy, surgery for congenital muscular torticollis at 11 years and spinal fusion for scoliosis in adolescence; at 47 years he had short stature (158.4 cm, −2.2 standard deviations), long thin fingers, flat feet and hallux valgus, normal hand strength, CK of 93 U/L and worked without limitations [24]. The Japanese patient of Shinmi and colleagues needed oxygen and had feeding difficulties at birth, but walked at 2 years and ran at 4; he had slow healing, keloids, recurrent dislocations of the shoulders and knees, scoliosis and hearing loss, and at 30 years walked without support, with distal weakness in the upper limbs (grip of 7.4 and 5.9 kg) and mild proximal weakness in the lower limbs, vital capacity of 88% and normal cardiac function [33]. In Turkey, a girl aged 2 years and 10 months homozygous for a variant classified as of uncertain significance had distal laxity, frequent falls, strength 4/5, flat feet and keratosis pilaris, with normal CK and echocardiogram, although the article designates her as UCMD [41].

3.4. Dominant form with onset in childhood

The boy of Zou and colleagues with p.Ile2334Thr had hypotonia, proximal contractures and distal hyperlaxity in the first year, began walking shortly before 2 years with a stooped posture and did not run; the knee contractures disappeared and those of the elbows improved, with mild kyphosis and normal cognition [20]. The Polish girl of Punetha and colleagues, with p.Gly2777Arg, was born from a pregnancy with oligohydramnios and growth restriction, with severe hypotonia, scoliosis, proximal contractures, facial asymmetry with cranial flattening, micrognathia, large dysplastic ears, high-arched palate, pectus excavatum and long fingers; she sat at 1 year, walked at 3 years, and at 7 years fell frequently, had marked hypermobility, no longer with contractures, and scoliosis with Cobb angles of 52° and 43°, operated on at 8 years [21]. She was classified as an intermediate form in the 2025 review [4]. The Belgian boy of Coppens and colleagues, with a de novo deletion of exons 45 to 54, had fetal hypokinesia, severe neonatal hypotonia, clubfeet, retrognathia and pectus excavatum, sat at 11 months and walked at 2.5 years; strength improved, but hyperlaxity remained very severe, with recurrent subluxations and spontaneous dislocation of the scapula at 13 years [2, 23]. He was born at term weighing 3350 g, with a weak cry, generalised muscle atrophy and distal and proximal hyperlaxity, breastfed but tired, and the karyotype and tests for Prader-Willi syndrome, myotonic dystrophy type 1 and spinal muscular atrophy were normal; he crawled at 2 years and, later, had genu valgum, flat valgus feet with prominent calcanei and atrophy of the shoulder girdle. The authors considered the phenotype somewhat more severe than that of the other dominant cases published at the time, because of the fetal hypokinesia, not previously described [23]. In China, a female newborn heterozygous for p.Ser2541Phe had hypotonia, seizures and respiratory failure at birth, with failure of ventilator weaning, the only dominant case with a severe UCMD2 phenotype in the 2025 review [4, 42]. She was the first daughter of non-consanguineous parents, born at 39 weeks with an Apgar score of 10, and had intermittent seizures from day 1, followed by dyspnoea and cyanosis; she remained hypoxaemic on continuous positive airway pressure and then on invasive ventilation, with greatly reduced responsiveness and scant spontaneous movements, and CK was 380 U/L. Imaging excluded structural anomalies of the airways and lungs, the variant arose de novo and the subsequent course was not described [42].

The five Belgian and French patients of Delbaere and colleagues illustrate the typical paediatric dominant phenotype: neonatal hypotonia, walking between 12 and 27 months, generalised hypermobility (Beighton 7 to 9 out of 9), bilateral congenital hip dislocation in three, congenital clubfoot in two, congenital adducted thumbs in one, congenital torticollis in one, flat feet, soft, pale skin, light-blue sclerae and micrognathia, with CK between 73 and 258 U/L; a carrier father had a milder picture, with patellar dislocation and congenital clubfoot [22]. The authors' synthesis of the 19 patients then known included hypotonia with variable motor delay, reduced muscle mass, distal or generalised hypermobility, congenital and/or progressive contractures (equinovarus foot, adducted thumbs, fingers and, at times, large joints), soft, smooth or translucent skin with somewhat slow healing and, at times, atrophic or hypertrophic scars, and mild dysmorphic features (light-blue sclerae, micrognathia, high-arched palate) [22].

3.5. Adult dominant form and distal myopathy

Adults with dominant variants almost always recall hypotonia or motor delay in childhood, followed by improvement and few limitations in the 2nd and 3rd decades; from the 4th decade, mild weakness with distal predominance appears, especially in the anterior compartment of the leg, the finger extensors and the intrinsic hand muscles, with flat feet and without cardiac or respiratory involvement [14]. Mohassel and colleagues therefore proposed including dominant myopathic EDS in the differential diagnosis of adult distal myopathies and allowed that some patients classified as hypermobile EDS may have COL12A1 variants with unrecognised myopathy [14]. Brady and colleagues, with the nine patients known in 2017, already described improvement until young adulthood and some deterioration in the 4th decade [15]. In the three-generation Danish family of Witting and colleagues, the neonatal contractures resolved and motor performance was limited mainly by reduced exercise endurance; the oldest patient was 76 years old [4, 34]. In the families of Hicks and colleagues, with a picture similar to classic Bethlem, three patients from one family had onset in childhood or adolescence and CK between 824 and 1310 U/L [4, 19].

The two Italian families of Merlini and colleagues show the adult phenotype with objective strength measurement. A 29-year-old man and his 14-year-old sister, with skipping of exon 56, had 4/5 weakness in the neck and finger extensors, but, by myometry, neck flexion was at 50% of predicted, knee extension between 37% and 75% and elbow flexion at 40%; both had blue sclerae, atrophy of the sternocleidomastoid and recurrent dislocations (patella in the brother, knee and shoulders in the sister, from the age of 10) [4]. A 41-year-old woman with skipping of exon 55 walked after 18 months, W-sat, fell frequently in childhood and had, in adulthood, a Beighton score of 6 out of 9, grip at 56% and elbow flexion at 35% of predicted [4].

3.6. Musculoskeletal system and joints

Congenital contractures affect knees, hips, elbows, fingers (long flexors) and ankles; in the dominant and mild recessive forms they tend to regress, unlike in collagen VI disease [13, 15, 20]. The spine is frequently affected: congenital kyphosis, torticollis and progressive scoliosis, with spinal fusion between 8 and 10 years in severe cases and in adolescence in others [13, 15, 20, 21, 24]. Patellar instability is a recurrent feature: bilateral subluxation in early childhood with absent or hypoplastic trochlear groove in the recessive siblings, a small dislocated patella in a Pakistani patient, a flattened trochlear groove in a British dominant family, trochleoplasty at 27 years for recurrent dislocation with trochlear dysplasia in an Italian family and habitual patellar dislocation with limited knee mobility as the presentation in a 13-year-old Chinese adolescent [4, 28, 43]. In the same British family there were dislocations of the jaw and hip [28]. Congenital hip dislocation is common in both forms [13, 22]. Prominent calcanei, laxity of the wrists and ankles and flat feet are usual [12, 13]. In the severe forms, muscle atrophy is diffuse and imaging shows generalised fatty replacement; in the mild forms, the most characteristic muscle is the rectus femoris, atrophic and surrounded by thickened epimysium (see 5.4) [4, 13].

3.7. Face, oral cavity and teeth

The elongated face and very high-arched palate are features that help distinguish the disorder from collagen VI UCMD [12, 20]. In the recessive forms, McCarty and colleagues recorded high-arched palate in 7 of 8 patients (with a deep median groove or prominent lateral palatal ridges in two), gingival hypertrophy in 6, micrognathia in 4, myopathic facies in 4, dental anomalies (eruption cysts, malocclusion) in 3, bluish sclerae in 3, dolichocephaly or plagiocephaly in 4 and mild pterygium in 2; the gingival and dental changes are atypical in collagen VI disease [13]. Gingival hypertrophy is associated, in studies of gingival fibroblasts from a Chinese recessive patient, with hyperproliferation and reduced apoptosis [32]. Abnormal tooth eruption has also been recorded in the intermediate dominant form [21].

3.8. Skin

The skin is soft and doughy, especially on the palms and soles, without the hyperextensibility and fragility of the classical EDS [1, 24]. Brady and colleagues recorded hypertrophic scars in three patients, atrophic scars in two and keratosis pilaris in one [15]. In a review of 24 patients, skin hyperextensibility and slow healing were present in only one, and none had easy bruising [24]. Keratosis pilaris and keloids, common in collagen VI disease, have been described in some patients with COL12A1 [33, 41], but not in the eight of the recessive series of McCarty and colleagues [13]. Smith's Recognizable Patterns adds to the description of myopathic EDS frequent infections, hernias, marfanoid facies, acrogeria and prominent vasculature [46]; these features are not part of the mEDS criteria of the 2017 classification or of the published series and are not attributed to this disorder [1].

3.9. Respiratory system

Respiratory failure defines the prognosis of the severe recessive forms. In the 2025 review, three of ten patients with UCMD2 started NIV before 3 years, whereas in collagen VI UCMD the need for NIV usually arises at the end of the first decade; motor ability is similar, but respiratory function appears more compromised in collagen XII [4]. In the series of McCarty and colleagues, five of eight had respiratory failure, from mild to ventilator dependence via tracheostomy [13]. In the dominant form, recorded FVC ranged from 58% to 115% of predicted, with low values in two Danish patients and an FVC of 79% in a patient of Hicks and colleagues [4]; in the series of Mohassel and colleagues there was no respiratory involvement [14]. A female newborn with a de novo variant needed invasive ventilation from day 1, with no structural anomaly of the airways or lungs on imaging [42], and the Belgian boy with a de novo deletion had at 8 years a forced vital capacity of 1.36 L (73% of predicted) and total lung capacity of 2.37 L (90% of predicted), stable at the last assessment [23]. An Iranian boy homozygous for a variant of uncertain significance had recurrent pneumonia [38]. Neonatal laryngomalacia has been described in two dominant patients [21, 22].

3.10. Heart

Cardiac data are scarce and heterogeneous. In the recessive series of McCarty and colleagues, four of eight had abnormalities: thickened mitral leaflets with mild to moderate mitral regurgitation, dysplastic mitral and tricuspid valves with mild mitral regurgitation, trivial mitral regurgitation and, in one patient, hypertrophic cardiomyopathy, mitral prolapse and Wolff-Parkinson-White syndrome treated by ablation [13]. An Italian dominant girl had myxomatous mitral leaflets [4], and the Polish girl a patent foramen ovale without treatment [21]. The Belgian boy with a de novo deletion had at birth atrial and ventricular septal defects that closed spontaneously, and the authors did not establish whether they were coincidental or a consequence of collagen XII deficiency; in their review of the dominant cases published up to 2022, the heart was not affected in any [23]. The echocardiogram was normal in the Indian girl with biallelic variants [39]. In the adult dominant series the echocardiogram and electrocardiogram were normal [4, 14, 33].

3.11. Other manifestations

Isolated cases have been described of Chiari I malformation with asymptomatic hydrocephalus and bilateral sensorineural hearing loss [33], of multiple fractures at birth [13], of undescended testes and inguinal hernia [4, 24], of diastasis recti with fibroadipose replacement of the abdominal wall [4] and of mild ventricular enlargement [21]. Cognition was normal in all patients in whom it was assessed, with isolated speech delay in one case of complicated pregnancy [20, 21, 24]. The exceptions are two newborns with seizures in the first days, a de novo heterozygous girl with respiratory failure and a boy homozygous for a variant of uncertain significance who later had spasticity, mild microcephaly and absence of speech; in neither do the authors describe studies linking these signs to COL12A1 [38, 42]. The mother of a Japanese patient died suddenly at 69 years and the father had aortic dissection at 76, without genetic study relating them to the variant [24].

3.12. Natural history and treated disease

The most consistent natural history feature is the absence of regression: the severe forms remain stable from birth, the mild forms improve during childhood and weakness returns, mildly and distally, from the 4th decade in the dominant forms [13–15, 28]. In the patient with COL6A1 variants from the Belgian cohort, the picture at 2 years was indistinguishable from that of children with COL12A1 and later evolved into classic UCMD, whereas the patients with COL12A1 appeared to improve; the authors stress that this difference requires long natural history studies [22]. The available data come from reports and small series, with patients already treated (gastrostomy, NIV, spinal fusion), and no study describes the course without supportive care. Most of the published dominant patients are still paediatric, which limits the description of the adult [4].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

In the prenatal and neonatal period, suspicion arises in the presence of fetal hypokinesia, oligohydramnios or growth restriction, followed by a hypotonic newborn with arthrogryposis or proximal contractures, hip dysplasia or dislocation, clubfeet, marked distal hypermobility, prominent calcanei, high-arched palate and, in the severe forms, feeding difficulty and respiratory failure [13, 21, 23, 42]. In the infant and young child, the combination of motor delay with hypotonia, laxity of the hands and feet, flat feet, frequent falls and inability to run, with contractures that regress rather than progress, is the most frequent pattern [20, 22, 41]. In the older child and adolescent, the disorder may present with recurrent dislocations (patella, shoulder, clavicle), with scoliosis, or with mild weakness of the upper limbs noticed during sport, as in the 14-year-old Portuguese girl with recurrent dislocations of the clavicle when throwing a ball [4, 37, 43]. In adults, it should be considered in the presence of mild distal weakness with hypermobility and a history of hypotonia in childhood, and in hypermobility diagnosed as hypermobile EDS when there is muscle weakness or atrophy [14].

4.2. Situations pointing to collagen XII

In a patient with an Ullrich or Bethlem phenotype, the following point to COL12A1 rather than COL6: pronounced, generalised joint laxity with dislocations, elongated face, very high-arched palate, earlier respiratory failure in the severe form, predominantly distal weakness in the mild form and a merely myopathic biopsy [12]. Gingival hypertrophy and dental changes, less marked and non-progressive contractures, motor improvement over time, absence of the «central cloud» sign of the rectus femoris on imaging and isolated atrophy of this muscle also contribute [13, 14, 34]. Conversely, torticollis, kyphoscoliosis and abnormal positioning of the hands and feet at birth, progressive proximal contractures with distal hyperlaxity and the «central cloud» and «outside-in» imaging pattern are more typical of collagen VI disease [12]. The presence of clinical criteria for myopathic EDS with negative COL6 testing is, on its own, an indication to study COL12A1 [1].

4.3. Warning and emergency signs

Respiratory warning signs are disturbed sleep, the need to turn over often during the night, tiredness on waking, morning headaches, nausea, use of accessory muscles, recurrent respiratory infections and poor weight gain, which reflect nocturnal hypoventilation and require immediate respiratory assessment [47]. In the recessive forms, hypoventilation may arise before 3 years [4]. Swallowing difficulty and aspiration are emergency signs in the severely affected infant [13, 47]. Rapid progression of scoliosis and acute joint dislocation require orthopaedic assessment [21, 28].

4.4. Newborn screening

There is no newborn screening for this disorder, nor any biochemical marker that would allow it; CK is normal or slightly elevated [4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria of the 2017 classification

The 2017 international EDS classification proposes for myopathic EDS three major criteria, four minor criteria and a minimal threshold of suspicion, but requires molecular confirmation for the final diagnosis (Table 5.1) [1]. These criteria were written when only five families had been published; the Belgian cohort showed that they are broad, because 72 of 78 patients who met them remained without a molecular diagnosis [1, 22].

Table 5.1. Clinical criteria for myopathic EDS according to the 2017 international classification [1].

The classification recommends a targeted panel including COL12A1 and the genes of overlapping phenotypes (COL6A1, COL6A2, COL6A3), or exome; if no variant, or only one, is found, a copy-number variation (CNV) detection strategy should be added. The absence of findings does not exclude the diagnosis, because deep intronic variants may escape the usual techniques and other genes may exist; without COL12A1 variants, collagen VI UCMD and Bethlem myopathy should be considered [1]. The criteria for hypermobile EDS include the exclusion of neuromuscular disorders such as myopathic EDS and Bethlem myopathy [1].

The practice guideline of the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) for congenital muscular dystrophies (CMD), which predates the description of COL12A1 disease, recommends using the patterns of weakness and contractures, involvement of other organs and CK to guide diagnosis in the collagenopathies (level B), considering lower-limb muscle imaging by ultrasound or magnetic resonance imaging (MRI) in suspected collagenopathies (level C), performing a biopsy with immunohistochemistry when the subtype is not apparent and the anaesthetic risk is acceptable (level C), in experienced centres (level B), and using exome or genome when the usual genes are negative (level C) [16].

5.2. Creatine kinase and neurophysiological studies

CK is normal in most; it was mildly elevated in four dominant patients of Hicks and colleagues (between 747 and 1310 U/L), between 73 and 258 U/L in the Belgian cohort and about 500 U/L in two recessive patients, and was normal in the severely affected recessive siblings and in an Indian girl with biallelic variants (90 U/L) [4, 13, 15, 22, 39]. In a female newborn with a de novo variant and respiratory failure it was 380 U/L [42]. A normal CK does not exclude the disorder. Electromyography shows myopathic motor unit potentials in most adults, with occasional isolated neurogenic findings, mild reduction of distal motor amplitudes and, in one patient, non-sustained myotonic discharges that led to the exclusion of myotonic dystrophy; in children, electromyography and nerve conduction are often normal [14, 20, 21, 33, 39].

5.3. Muscle biopsy

The biopsy shows a mild myopathic process: subtle variation in fibre size, sometimes internalised nuclei, type 1 fibre predominance or hypotrophy, without degeneration, regeneration or prominent interstitial fibrosis [4, 13, 20]. In one review, 6 of 7 patients with a biopsy had myopathic changes [24]. In the Belgian boy with a de novo deletion, the biopsy at 8 years showed only very mild variation in fibre size [23]. A dominant adult had numerous ring fibres in the tibialis anterior, and a biopsy of a clinically spared proximal muscle was normal [14]. In collagen VI UCMD, by contrast, interstitial fibrosis is disproportionate to the scarcity of necrosis and regeneration [4]. Immunohistochemistry shows collagen XII absent from muscle in the null recessive forms, reduced in the endomysium in the dominant forms and greatly reduced in the sarcolemma and interstitium in a mild recessive form, with collagen VI and laminin γ1 preserved in all [20, 33]. The 2017 classification considers the myopathic pattern suggestive, but not diagnostic [1].

5.4. Muscle imaging

Imaging is the most useful non-invasive test for separating COL12A1 disease from collagen VI disease. In COL6-RD, the rectus femoris has a «central cloud» of abnormal signal around the central fascia and the vastus lateralis an «outside-in» pattern, with the periphery replaced by fat; in COL6 Bethlem a rim of fatty infiltration between the soleus and the gastrocnemius appears early [2, 12]. In dominant COL12A1 disease, ultrasound shows mild to moderate, granular and striated echogenicity, without a central cloud; adult MRI shows normal or slightly altered T1, with atrophy and increased epimysial fat in the rectus femoris, peroneus longus and medial gastrocnemius [14]. Selective, rounded atrophy of the rectus femoris was the only T1 finding in a family of Hicks and colleagues, the central finding in the Danish family and the finding common to the two Italian families; in the latter, computed tomography (CT) and MRI also showed atrophy of the neck muscles with fibroadipose tissue, fibroadipose replacement of the lumbar paravertebral muscles and abdominal wall, and diastasis recti [2, 4, 34]. Merlini and colleagues describe the muscle as reduced in size and surrounded by thickened epimysium, «strangled» by connective tissue [4]. Atrophy of the rectus femoris is not constant: in the Belgian boy with deletion of exons 45 to 54, T1 MRI showed only increased signal in the distal part of the vastus intermedius and around the posterior part of the flexor digitorum longus and the anterior part of the soleus, similar to that described in a family of Mohassel and colleagues [23]. In the recessive forms, MRI may be normal in the mild ones and show diffuse atrophy in the severe ones; in the intermediate ones the posterior compartment of the thigh predominates, with the rectus femoris as the most affected muscle of the anterior compartment and lesser involvement of the vastus lateralis [13]. The 2017 classification considers MRI insufficiently specific to confirm the diagnosis [1].

5.5. Fibroblast studies

Dermal fibroblast culture allows collagen XII to be studied by immunocytochemistry, with and without cell permeabilisation, and by western blot. The patterns described depend on the mechanism: total absence, intra- and extracellular, in the null recessive forms; matrix reduction with intracellular retention in the dominant forms with glycine substitution, in-frame deletions and some splicing variants; mild reduction or apparently normal matrix in the recessive forms affecting only the long isoform and in some dominant ones; and altered migration or network organisation in others [4, 13, 14, 20, 22]. Collagen VI is normal in the fibroblasts of patients with COL12A1, which separates the two disorders [20, 21, 23]. In the in-frame deletion of exons 45 to 54, collagen XII was absent from the extracellular matrix and retained within the cells, with normal tenascin-X [23]. The technique has limits: Delbaere and colleagues found a normal extracellular matrix in all their patients and attributed the discordance with earlier reports to differences in seeding density and protocol [22]. In practice, the fibroblast study serves as functional support for the pathogenicity of a novel variant and was decisive in finding the exon 52 deletion after a negative exome, but it does not replace molecular diagnosis [14, 27]. The 2014 international consensus for the diagnosis of CMD already noted that fibroblasts allow splicing variants to be confirmed in complementary DNA and that these analyses were mainly available in research laboratories [48].

5.6. Genetic testing and its limits

The first line is a panel of myopathy and connective tissue disease genes including COL12A1 and the three collagen VI genes, or an exome with targeted analysis, followed by CNV analysis when the result is negative or there is only one variant [1]. Sequencing detects glycine substitutions and canonical splicing variants well, but not large deletions, duplications, inversions and deep intronic variants: the 1771 base-pair deletion spanning exon 52 escaped the diagnostic exome and was found only in fibroblast complementary DNA, and the deletion of exons 45 to 54 was found only with a CNV tool applied to an initially negative trio exome [14, 23]. Mohassel and colleagues recommend adding high-resolution microarray and RNA sequencing of fibroblasts or muscle when clinical suspicion persists [14]. Genome sequencing and muscle RNA sequencing were used in the case of Shinmi and colleagues, the latter to measure the expression of each isoform [33]. In a homozygous patient, copy-number analysis excluded hemizygosity due to deletion of the other allele [24]. A negative result does not exclude the disorder; in the Belgian cohort, only 6 of 78 patients with clinical criteria received a molecular diagnosis (5 with COL12A1 and 1 with COL6A1), which suggests genetic heterogeneity and leaves open undetected variants [22].

5.7. Variant interpretation and report content

The report should state the gene, the transcript with version (NM_004370.6), the description according to Human Genome Variation Society (HGVS) nomenclature at DNA and protein level, the zygosity, the phase of the variants in biallelic cases (by parental testing), de novo origin when confirmed and the class according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP), with the criteria used, as in the Japanese patient classified as pathogenic with PS3, PVS1_Strong, PM2_Supporting and PM3_Supporting [24]. Conversion of published variants with historical numbering requires confirmation in VariantValidator or ClinVar (see 2.7) [6]. Interpretation has four pitfalls: the historical 2014 numbering, which differs by 166 nucleotides; arginine-to-cysteine substitutions, with non-negligible population frequencies and conflicting classifications; missense variants in homozygosity or compound heterozygosity without functional proof, such as p.(Pro2968Leu), p.(Pro2943Leu) and the pair p.(Asp2514Gly) and p.(Pro2790Leu), classified as VUS or with conflicting classifications; and the fact that heterozygosity for a null variant does not cause the dominant form, because haploinsufficiency is practically silent [14, 22, 24, 35, 38, 39, 41]. Family segregation, demonstration of de novo origin, RNA study for splicing variants and fibroblast immunocytochemistry are the tools for reclassifying a VUS [4, 14, 22].

5.8. Practical algorithm

Table 5.2. Proposed diagnostic sequence based on the sources consulted.

5.9. Assessment after diagnosis

After confirmation, the initial assessment should include spirometry sitting and supine (or crying vital capacity in young children), oximetry and, when there are symptoms or a postural difference in vital capacity, a sleep study; baseline cardiac assessment with echocardiogram and electrocardiogram, given the valvulopathies described in the recessive forms; nutritional and swallowing assessment; spinal radiograph and assessment of the hips, knees and feet; strength assessment with myometry, which detects deficits that the manual scale underestimates; and referral to a genetics clinic [4, 13, 16, 47]. Hearing assessment and brain MRI are not routine, but the case with hearing loss and Chiari I suggests attention to compatible symptoms [33].

5.10. Prenatal and preimplantation diagnosis

In EDS in general, prenatal diagnosis is technically possible when the familial variant is known, although rarely requested outside the vascular form [25]; the same knowledge of the variant allows, in principle, preimplantation genetic testing. The sources consulted do not describe prenatal or preimplantation diagnoses in COL12A1 disease. There are no specific ultrasound markers; fetal hypokinesia, oligohydramnios, growth restriction and breech presentation have been described in the pregnancies of patients [15, 21, 23, 38].

6. Differential Diagnosis

6.1. Principles

The differential is made along two axes. On the neuromuscular axis, COL12A1 disease is confused mainly with collagen VI-related disease and, less so, with other congenital muscular dystrophies with contractures or rigid spine and, in adults, with the distal myopathies [12, 14, 48]. On the connective tissue axis, the differentials are the EDS that combine hypotonia and hypermobility with contractures or kyphoscoliosis: kyphoscoliotic EDS (PLOD1, FKBP14), classical-like EDS due to tenascin-X deficiency, musculocontractural EDS and spondylodysplastic EDS, and also hypermobile EDS, whose criteria require the exclusion of myopathic EDS [1, 15]. In all cases, the discriminating test is molecular, supported by muscle imaging and fibroblast studies.

6.2. Differential table

Table 6.1. Differential diagnosis of collagen XII-related disorder.

6.3. Collagen VI-related disease

This is the main and most difficult differential, especially in the first years. In the Belgian cohort, a boy with biallelic COL6A1 variants had at 2 years a picture overlapping that of the children with COL12A1 and only the evolution to classic UCMD separated him [22]. The features favouring collagen XII are more generalised hypermobility (including large joints), less prominent contractures that regress, non-progressive weakness with motor improvement, gingival and dental changes, an elongated face with a very high-arched palate, earlier respiratory failure in the severe forms and, in the adult dominant form, distal weakness [4, 12–14]. The two disorders share velvety skin of the palms and soles, early kyphosis and scoliosis, and keratosis pilaris and keloids, more typical of collagen VI, have also been described in some patients with COL12A1 [13, 33, 41]. Muscle imaging and fibroblast studies are the tests that best separate the two: in collagen XII disease there is no central cloud or «outside-in» pattern, and fibroblast collagen VI is normal [14, 20, 34]. Shinmi and colleagues proposed Chiari I malformation as a feature favouring myopathic EDS, as it is described in EDS and not in collagen VI disease, on the basis of a single patient [33].

6.4. EDS with hypotonia and kyphoscoliosis

Kyphoscoliotic EDS shares with COL12A1 disease congenital hypotonia, kyphoscoliosis and hypermobility with dislocations. The FKBP14 form combines myopathy, congenital hearing loss and, on imaging, relative involvement of the rectus femoris, like collagen XII disease; deafness and bladder diverticula point to FKBP14 [1, 13, 15]. The PLOD1 form is distinguished by skin and ocular fragility and by an elevated urinary deoxypyridinoline/pyridinoline ratio [1]. Classical-like EDS due to tenascin-X deficiency has muscle weakness, myalgia and fatigability, with axonal polyneuropathy in 40% and a mildly myopathic biopsy in 20% in a series of 10 patients, but the skin is hyperextensible and bruising is frequent, unlike myopathic EDS [15]. Tenascin-X binds to the NC3 of collagen XII; in the tenascin-X-null mouse collagen XII is reduced by 70% in muscle and skin, but in biopsies from two patients with tenascin-X deficiency collagen XII was normal [20]. Hernia, marfanoid habitus and equinovarus foot are minor criteria of kyphoscoliotic EDS and not of myopathic EDS [1].

6.5. Other neuromuscular disorders

Among CMD with contractures and rigid spine, Emery-Dreifuss dystrophy and the laminopathies are distinguished by cardiac involvement, absent in collagen VI disease and of little significance in collagen XII disease [13, 48]. In adults, mild distal weakness with flat feet and hypermobility should lead to the inclusion of COL12A1 in distal myopathy panels [14]. A COL12A1 VUS was found in a Pakistani cohort of patients with a limb-girdle dystrophy phenotype and elevated CK, which, without confirmation, does not broaden the phenotype [45]. Arthrogryposes of other causes enter the differential of the recessive forms with congenital contractures [13].

7. Treatments and Risk Management Strategies

7.1. Principles and reference documents

There is no disease-modifying treatment, nor any guideline dedicated to collagen XII-related disorder. Brady and colleagues, in the 2017 review of the rare EDS types, summarised management as anticipatory guidance to prevent complications and treat symptoms: physiotherapy for the contractures, which tend to resolve, and surveillance of feeding and respiratory difficulties, especially nocturnal hypoventilation, with nocturnal non-invasive ventilation when present [15]. The 2025 series describe the same care (physiotherapy and stretching, orthopaedic management of scoliosis, feet and joint instability, mobility aids, NIV, nutritional support) and stress that the limited number of patients and incomplete follow-up of strength, motor function and respiratory function have hampered rehabilitative, orthopaedic and ventilatory care [4, 27]. The EDS working group of ERN ReCONNET found, in a systematic review, no good-quality clinical practice guidelines for any EDS [49].

Therefore, the following recommendations apply by extrapolation the documents for the congenital muscular dystrophies, the group to which UCMD2 and BTHLM2 belong: the 2015 AAN/AANEM evidence-based guideline and the 2010 international consensus on care, both predating the description of COL12A1 disease [16, 47]. The international EDS consortium announced for December 2026 the publication of assessment and treatment guidance for the monogenic types, which should be consulted as soon as published [26].

Table 7.1. Reference documents for management and their scope.

7.2. Organisation of care

The AAN/AANEM guideline recommends that children with CMD be assessed by a paediatric neuromuscular specialist, who coordinates a multidisciplinary team, and that families have access to genetic counselling (level B) [16]. The 2010 consensus proposes visits at least every 3 to 4 months in infants under 12 months and in children with severe or worsening problems (severe hypotonia, respiratory or nutritional problems), and every 4 to 6 months in stable children over 12 months, with recording of blood pressure, heart and respiratory rates, weight, height or arm span and head circumference [47]. In the mild adult dominant forms, the sources do not propose intervals; neuromuscular follow-up should be maintained because of the possibility of distal weakness from the 4th decade [14]. In Europe, the disorder falls within ERN EURO-NMD (neuromuscular) and ERN ReCONNET (connective tissue) [17, 18].

7.3. Respiratory care

Respiratory failure may be inapparent at onset, so the AAN/AANEM guideline recommends informing families, monitoring spirometry and oximetry during wakefulness and sleep at intervals adjusted to the clinical state, and referring to experienced pulmonary or aerodigestive teams (level B) [16]. The 2010 consensus describes the tools and thresholds: spirometry sitting and supine, in which a difference of more than 20% in vital capacity indicates diaphragmatic weakness and predicts nocturnal hypoventilation; vital capacity below 60% of predicted as a predictor of sleep-disordered breathing and below 40% as a predictor of nocturnal hypoventilation; maximal inspiratory and expiratory pressures (normal between 80 and 120 cmH2O); peak cough flow, with 160 to 270 L/min as the threshold for clearing secretions; and polysomnography and blood gases when indicated [47]. In disorders with axial weakness and rigid spine, such as the collagen VI myopathies, respiratory failure may arise while the patient is still walking, and the same surveillance applies to collagen XII disease, in which NIV may be needed before 3 years in the recessive forms [4, 47].

Cough assistance by mechanical insufflation-exsufflation is the standard when peak cough flow is below 270 L/min; breath stacking with a manual resuscitation bag and intrapulmonary percussive ventilation help maintain chest wall compliance and clear secretions [47]. NIV is started when there is alveolar hypoventilation with nocturnal or daytime hypercapnia and may also be justified in recurrent respiratory infections or poor weight gain, with nocturnal monitoring of oxygenation and carbon dioxide after initiation [47]. In the siblings of Zou and colleagues, nocturnal NIV began before 3 years and continued into adulthood [20, 28]. In acute infections, assessment includes cough effectiveness and oximetry; in the presence of low saturation, supplemental oxygen should be accompanied by measurement of carbon dioxide, because oxygen alone may reduce respiratory drive in some patients [47]. The 2010 consensus suggests pneumococcal and influenza vaccines in all CMD and, at the time, recommended respiratory syncytial virus (RSV) prophylaxis with palivizumab (Synagis®) in children under 2 years [47]. Nirsevimab (Beyfortus®) has been authorised in the EU since 31 October 2022 for newborns and infants in their first RSV season (50 mg below 5 kg and 100 mg from 5 kg, as a single IM dose); since 1 August 2024 it also covers children up to 24 months who remain vulnerable to severe disease in their second season, with 200 mg [50]. Clesrovimab (Enflonsia®), at a fixed dose of 105 mg IM, was approved by the FDA on 9 June 2025 and authorised in the EU on 15 April 2026, for the first season only [51, 52]. Palivizumab, 15 mg/kg monthly during the season, remains authorised for prematurity of 35 weeks or less, bronchopulmonary dysplasia and haemodynamically significant congenital heart disease, and the eligibility of each child follows the national recommendations in force [53].

7.4. Nutrition, swallowing and gastrointestinal tract

Neonatal feeding difficulties are frequent in the recessive forms and required a nasogastric tube or gastrostomy in seven of eight patients in the series of McCarty and colleagues [13]. The AAN/AANEM guideline recommends monitoring growth with primary care, requesting multidisciplinary assessment (swallowing therapy, gastroenterology, radiology) in the presence of poor weight gain or respiratory symptoms and deciding on gastrostomy, with or without fundoplication, as a team (level B) [16]. The 2010 consensus reserves the nasogastric tube for short periods, considers gastrostomy or jejunostomy the option for prolonged enteral nutrition, records the absence of consensus on Nissen fundoplication and recommends treating reflux and slow gastric emptying with an H2 antagonist or proton pump inhibitor, with or without a prokinetic, when indicated [47].

7.5. Spine, joints and orthopaedics

Scoliosis is the main surgical indication: spinal fusion at 9 years and in adolescence in the recessive siblings, at 10 years in a patient in the series of McCarty and colleagues, at 8 years in the Polish girl (correction of Cobb angles of 52° and 43° to 17° and 25°) and in the 3rd cycle of basic education (lower secondary school) in the 47-year-old Japanese patient [13, 20, 21, 24, 28]. The 2010 consensus recommends a trunk orthosis to maintain sitting posture and delay progression until the appropriate age for surgery, without compressing the chest in patients with respiratory failure, spirometry with and without the orthosis, growing rods in young children and, in spinal fusion, sparing the lumbosacral junction in patients who walk and including the pelvis in those who do not, with fusion up to C3 when there is fixed cervical hyperextension [47]. Surgery requires respiratory and nutritional preparation and intensive respiratory physiotherapy for up to six months afterwards [47].

The contractures of collagen XII disease tend to regress, which reinforces the role of physiotherapy and advises against early release surgery without reassessment [15, 20]. The 2010 consensus recommends daily stretching from the onset of symptoms (limbs, iliotibial bands, neck, spine and jaw), night-time positioning, splints, serial casting and standing programmes, and the AAN/AANEM guideline allows range-of-motion exercises, orthoses and Achilles tendon lengthening in selected circumstances (level B), advising against botulinum toxin unless the contracture is more disabling than the foreseeable worsening of weakness (level C) [16, 47]. In generalised hypermobility, the goal is joint stabilisation: recurrent dislocations of the patella, shoulder and clavicle were treated individually, including a trochleoplasty for recurrent patellar dislocation with trochlear dysplasia and surgery for recurrent knee subluxation at 8 years [4, 33, 37]. Hip dysplasia and congenital clubfoot follow the usual orthopaedic care [13, 22].

7.6. Rehabilitation and activity

The AAN/AANEM guideline recommends referral to physiotherapy, occupational therapy, speech therapy, seating and mobility specialists, physical medicine and rehabilitation and orthopaedics (level B) [16]. Mobility aids range from the powered wheelchair in the severe recessive forms to orthoses and adapted footwear for flat feet in the mild forms [14, 20, 47]. Myometry, which in the Italian families revealed strength between 35% and 75% of predicted in muscles graded 4/5, is useful for following strength and guiding rehabilitation [4]. The sources consulted do not describe trials of exercise programmes in this disorder.

7.7. Heart

The AAN/AANEM guideline recommends baseline cardiac assessment in all children with CMD, with subsequent intervals defined by the result and by the subtype (level B) [16], and the 2010 consensus proposes, in CMD that are neither laminopathies nor dystroglycanopathies, reassessment at least every 2 years in the asymptomatic and annually in those with symptoms [47]. In collagen XII disease, the mitral and tricuspid valvulopathies, hypertrophic cardiomyopathy and pre-excitation described in the recessive forms justify echocardiogram and electrocardiogram at diagnosis [13]. The sources do not define a specific interval for this disorder; the two documents differ in wording (interval by subtype versus a fixed 2-year interval) and have no data of their own for collagen XII.

7.8. Investigational therapies

The only published targeted approach is preclinical. Mohassel and colleagues designed small interfering RNAs (siRNA) targeting the junction of exons 51 and 53, present only in the messenger RNA of the allele with deletion of exon 52, and showed, in the patient's fibroblasts, dose-dependent reduction of the mutant RNA and restoration of the fibrillar pattern of collagen XII, with maximum effect at 0.1 nmol/L and no effect on the normal allele up to 100 nmol/L [14]. The rationale is that haploinsufficiency is practically silent, so silencing the dominant-negative allele should convert the disorder into a mild clinical state; the authors presented it as proof of concept, without study in animals or patients [14]. No interventional clinical trials were found on ClinicalTrials.gov; the only registered study that includes the disorder is the international observational registry of congenital muscle diseases of Cure CMD (NCT01403402), recruiting since 2009 with 4000 planned participants [54]. This negative search does not prove the non-existence of unregistered studies.

Table 7.2. Regulatory status in the United States and the European Union.

Table 7.3. Studies with intervention or prospective data collection.

None of these studies measures clinical efficacy: the first is a single cell experiment and the second a registry without a comparison group. There is therefore no basis for comparing interventions or estimating effects.

7.9. Developments in the last 12 months

Between October 2025 and October 2026, the literature on the disorder added case reports, an association study and preclinical research, without clinical trials or regulatory decisions. The levels of evidence are those indicated in Table 7.4.

Table 7.4. Publications and announcements between October 2025 and October 2026.

7.10. Anaesthesia and surgery

The AAN/AANEM guideline recommends discussing with families the increased risk of complications before elective surgery and general anaesthesia and prolonging postoperative surveillance for respiratory, nutritional, mobility and gastrointestinal motility complications (level B) [16]. The 2010 consensus recommends proactive multidisciplinary preparation (pulmonology, anaesthesia, nutrition, cardiology) before any procedure with anaesthesia, sedation or prolonged recumbency, such as spinal surgery, contracture release or dental treatment [47]. The sources consulted do not describe specific anaesthetic reactions or an association with malignant hyperthermia in COL12A1 disease. Cervical hypermobility should be considered in positioning, especially if there is a Chiari I malformation, which in one patient coexisted with hydrocephalus [33].

7.11. Pregnancy, delivery and lactation

The sources consulted do not describe pregnancies in women with myopathic EDS. In EDS in general, the Oxford Desk Reference reports an increased risk of preterm delivery in classical EDS and, in a Dutch study, postpartum haemorrhage in 19% of women with EDS versus 7% without EDS and perineal wound complications in 8% versus less than 1%, recommending referral to a high-risk pregnancy clinic, preferably before conception [25]. These figures are not specific to myopathic EDS. In pregnancies with affected fetuses, oligohydramnios, growth restriction, breech presentation and fetal hypokinesia have been described [15, 21, 23]. In women with axial weakness or respiratory failure, the respiratory and anaesthetic precautions of section 7.10 apply. There are no targeted drugs with implications for lactation.

7.12. Oral health

The 2010 consensus recommends a paediatric dentistry visit before 2 years or at diagnosis, reviews at least every six months, sealants on molars with deep fissures, orthodontic assessment at around 6 years and maintenance of oral hygiene in adults [47]. In collagen XII disease, the gingival hypertrophy, eruption cysts, abnormal eruption and malocclusion of the recessive forms, and the very high-arched palate in almost all, make this follow-up particularly relevant [13, 21, 32].

7.13. Transition to adulthood and agents to avoid

Patients with severe recessive forms reach adulthood with stable needs (wheelchair, nocturnal NIV, previous spinal fusion), and the dominant ones with motor improvement but a risk of distal weakness from the 4th decade, which requires transferring neuromuscular and respiratory follow-up to adult teams [14, 28]. The 2010 consensus recommends referral to educational and developmental support, and the AAN/AANEM guideline asks that, from diagnosis, families be informed of the prognostic uncertainties and multisystem implications (level B) [16, 47]. There are no drugs contraindicated by evidence specific to this disorder; the AAN/AANEM guideline advises caution with neuromuscular blocking agents such as botulinum toxin (level C), and the 2010 consensus calls for multidisciplinary preparation before any sedation [16, 47].

8. Reproductive Options and Family Counselling

8.1. Determining the mode of inheritance in each family

Counselling depends on knowing, in each family, which of the two mechanisms is acting, and this requires characterising the variant and studying the parents. A missense variant substituting a glycine of the triple-helical domain, in-frame skipping or an in-frame deletion, in heterozygosity, point to the dominant form; two loss-of-function variants, in homozygosity or in compound heterozygosity confirmed in trans, point to the recessive form [13, 14, 22]. Heterozygosity for a null variant is not enough to explain a dominant phenotype, because haploinsufficiency is clinically mild or silent [14, 20]. The AAN/AANEM guideline recommends facilitating access to genetic counselling for the interpretation of results and reproductive decisions (level B) [16].

8.2. Dominant form

An affected parent has a 50% probability of transmitting the variant in each pregnancy. Expressivity varies greatly within the same family: in the Belgian family with skipping of exon 53, the father and a sister had milder pictures than the proband; in the Danish family, the patients from three generations had FVC between 58% and 105% and different degrees of weakness; in the North American family with deletion of exon 52, the 37-year-old mother, the 5-year-old son and a 33-year-old maternal uncle had distinct pictures [4, 14, 22]. There are no documented cases of non-penetrance, but formal penetrance is unknown, and there are adults with a history that is only identified by targeted questioning (hypotonia and motor delay in childhood) [14, 15]. Therefore, the parents of a child with an apparently de novo variant should be examined and tested. Many published dominant variants arose de novo [14, 20, 22, 23]; in these cases, the recurrence risk for siblings is low, but not zero, because of the possibility of germline mosaicism, which the sources consulted do not quantify in this disorder. In the Polish girl, the variant was absent in the mother, the father was not tested and somatic mosaicism was excluded in three tissues [21].

8.3. Recessive form

The parents of an affected child are, as a rule, heterozygous, and the recurrence risk for each sibling is 25%; consanguinity was present in several families (of Turkish, Palestinian, Afghan, Pakistani, Japanese and Chinese origin) [13, 20, 24, 32, 41]. Confirmation of phase by parental testing is indispensable in compound heterozygotes [13, 33]. In the recessive forms, severity depends on the isoforms affected, but the correlation rests on few patients and does not allow the phenotype of a fetus to be predicted reliably [13, 24]. As for carriers, the parents of the siblings of Zou and colleagues walked after 2 years and had normal strength as adults, and the heterozygous parents of the other families were described as unaffected; Brady and colleagues interpreted the late walking of those parents as a mild carrier phenotype [13, 15, 20]. In the family with p.(Ala1110Asp) and p.(Ile1393PhefsTer11), collagen XII secretion by the heterozygous parents was normal [13].

8.4. Cascade testing, prenatal and preimplantation diagnosis

Once the familial variant has been identified, cascade testing allows the status of siblings and other at-risk relatives to be clarified. In the recessive form, testing the siblings of a patient may identify mild forms not yet diagnosed, as in family 5 of McCarty and colleagues, in which a sister and a brother had disease of similar severity [13]. When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are technically possible, as in the other EDS, although the sources consulted do not describe their use in this disorder [25]. Fetal ultrasound has no specific markers; hypokinesia, oligohydramnios and growth restriction have been described in pregnancies with affected fetuses [21, 23].

8.5. Testing of minors and special situations

In symptomatic children, testing is diagnostic and guides respiratory, orthopaedic and cardiac surveillance [16]. In asymptomatic children from families with the dominant form, the decision to test weighs the usefulness of anticipating surveillance against the absence of disease-modifying treatment; the sources consulted do not issue a specific recommendation. The interpretation of arginine-to-cysteine variants, of homozygous missense variants classified as VUS and of the historical numbering should be reviewed before any reproductive decision (see 5.7) [22, 24, 41].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

No population prevalence estimate has been published. Orphanet places myopathic EDS in the prevalence class of less than 1 per 1 000 000, based on the 2017 review by Brady and colleagues, which counted eight to nine patients; this is a class assigned from published cases, not a measurement [9, 15]. The cumulative count grew from five families in 2017 to 19 patients with pathogenic variants in 2020, 24 patients from 15 families by 2022 and 31 families published by 2025 (18 dominant and 13 recessive), to which Merlini and colleagues added two and to which were later added at least one Japanese recessive patient, a Chinese recessive family with gingival hyperplasia and a Chinese adolescent with patellar dislocation [1, 4, 22, 24, 32, 33, 43]. These counts measure published patients, not frequency, and cannot be converted into a rate per 100 000 [27]. The Orphanet prevalences for Bethlem dystrophy (0.77 per 100 000) and UCMD (0.13 per 100 000), measured in the north of England, refer mainly to collagen VI disease and do not apply to collagen XII [10, 11].

9.2. Diagnostic yield in selected cohorts

Two European cohorts give an idea of the proportion of COL12A1 among patients with a compatible phenotype. In Newcastle, among about 24 patients with a Bethlem-like phenotype and without COL6 variants, the exome found COL12A1 in two families [19]. In Ghent, among 78 patients who met the clinical criteria for myopathic EDS and were undiagnosed, the panel found pathogenic COL12A1 variants in four, a variant of uncertain significance in one and COL6A1 variants in one; 72 remained undiagnosed [22]. These figures refer to cohorts from reference centres, already preselected, and do not represent the general population.

9.3. Geographical distribution and populations

The published patients come from Europe (Germany, in a family of Turkish origin; United Kingdom; Poland; Denmark; Belgium and France; Italy; Portugal), the United States, the Middle East and Asia (Turkey, Iran, Palestine, Pakistan, Afghanistan, India, China, Japan) and Africa (Egypt) [4, 13, 14, 19–22, 24, 34, 36–42]. The recessive forms are concentrated in consanguineous families, but no founder variants have been described: each family has its own variant [4, 13]. The relevant population data are the constraint of COL12A1 for loss-of-function variants in gnomAD and the non-negligible frequency of some arginine-to-cysteine substitutions, such as p.Arg1965Cys, present in 0.016% of African Americans in the Exome Sequencing Project and with a frequency of about 1 in 4009 in gnomAD, or p.Arg1863Cys, with about 1 in 2095 in a Japanese panel [5, 13, 24].

In Portugal, the only case published in the sources consulted is that of a 14-year-old Caucasian girl followed at the Hospital de Braga, daughter of non-consanguineous parents and also followed for autoimmune hepatitis, with joint hypermobility, recurrent dislocations of the clavicle, mild reduction of upper-limb strength, without contractures, kyphosis or scoliosis, and the heterozygous variant c.8336G>A p.(Arg2779His), identified by targeted sequencing, whose impact the prediction algorithms did not establish concordantly and which currently has conflicting classifications in ClinVar [35, 37]. No published cases from Brazil were found in the sources consulted, which does not demonstrate their absence.

9.4. Special populations

In children with severe recessive forms, needs are concentrated on ventilation, nutrition and the spine; in adults with dominant forms, on distal weakness and joint instability [13, 14]. Women of childbearing age should have pregnancy planning with respiratory assessment when there is axial weakness, without data specific to this disorder (see 7.11). People with a diagnosis of hypermobile EDS and muscle weakness constitute a population in which the disorder may be underdiagnosed [14].

9.5. Reference networks and patient associations

In the European Union, the disorder falls within ERN EURO-NMD, for rare neuromuscular diseases, which maintains a registry portal, and ERN ReCONNET, for rare connective tissue diseases, which includes EDS [17, 18]. The Ehlers-Danlos Society (https://www.ehlers-danlos.com/), with a dedicated page for myopathic EDS, and Ehlers-Danlos Support UK (https://www.ehlers-danlos.org/) support patients with EDS [25, 26]. Cure CMD (https://www.curecmd.org/) maintains the international registry of congenital muscle diseases (https://www.cmdir.org/), which includes collagen XII-related disorders [54]. In Portugal, APN — Associação Portuguesa de Neuromusculares (https://www.apn.pt/) and, in Brazil, the Associação Brasileira de Distrofia Muscular (ABDIM, https://www.abdim.org.br/) support neuromuscular patients in general, without a specific programme for this disorder [55, 56].

10. Illustrative Clinical Case

10.1. Dominant form: two Italian siblings with skipping of exon 56

Merlini and colleagues, at the Istituto Ortopedico Rizzoli in Bologna, described a family of non-consanguineous parents with two affected children [4]. The boy was born at term by caesarean section, with mild hypotonia, marked joint hypermobility, talipes calcaneus and inguinal hernia. He walked at 17 months and, from childhood, could not run like his peers. At 18 years, at another hospital, a needle muscle biopsy showed a myopathic pattern, with increased endomysial connective tissue and variation in fibre size, without necrosis. At 27 years he underwent surgery (trochleoplasty) for recurrent dislocation of the left patella, with trochlear dysplasia and a discoid lateral meniscus [4].

At 29 years he walked on tiptoe and on his heels and climbed stairs, but did not run, mainly because of pain in the left knee. He had blue sclerae, mild diffuse muscle hypotrophy, more distal and on the left, and atrophy of the right sternocleidomastoid; the strength of the neck flexors and finger extensors was 4/5 on the Medical Research Council (MRC) scale, but myometry showed neck flexion of 71 N (50% of predicted for age and sex) and right knee extension of 209 N (75%). The Beighton score was 5 out of 9, with a mild contracture of the fingers. FVC was 90% of predicted (the patient smoked), and the electrocardiogram, echocardiogram and CK were normal. Muscle CT showed atrophy of the right sternocleidomastoid and hypotrophy of the left, diffuse hypotrophy of the left leg, marked rounded atrophy of the rectus femoris, mild diastasis recti and partial fibroadipose replacement of the abdominal and lumbar paravertebral muscles [4]. Figure 1 of the article shows the hypermobility of the hands, the hypotrophy of the sternocleidomastoid, the bilateral rounded hypotrophy of the rectus femoris and the abdominal diastasis (https://pmc.ncbi.nlm.nih.gov/articles/PMC12154473/figure/ijms-26-05387-f001/).

The sister had normal motor development. At 10 years she began to have recurrent dislocations of the right knee, then of the shoulders, with myalgia after exertion and frequent cramps. At 14 years she walked on tiptoe but had difficulty walking on her heels; she had blue sclerae, mild diffuse hypotrophy, mild atrophy of the sternocleidomastoid and pectorals, strength of 4/5 in neck flexion and finger extension and a Beighton score of 6 out of 9. On myometry, neck flexion was at 50%, elbow flexion at 40% and knee extension at 37% and 45% of predicted, with normal grip (30 kg). FVC and CK were normal, the echocardiogram showed myxomatous mitral leaflets and thigh MRI only mild hypotrophy [4].

The exome identified in both siblings the variant NM_004370.6:c.8415+1G>A, absent from gnomAD v4.0 and classified as likely pathogenic (PVS1, PM2); muscle RNA sequencing confirmed skipping of exon 56, with an in-frame deletion in the COL2 domain. The mother had a normal examination and the father could not be examined. In the brother's skin fibroblasts, collagen XII was not retained in the cells, but formed a filamentous extracellular network with punctate aggregates, with coarse organisation of collagens I and VI, and western blot showed more collagen XII, with altered migration of the long isoform [4]. The variant is listed in ClinVar as likely pathogenic (VCV003256738) [35].

The case brings together the features that separate the dominant form from collagen VI disease: mild hypotonia and early walking, persistent difficulty running, recurrent dislocations as the main orthopaedic problem, cervical and axial weakness that the manual scale underestimates, rounded atrophy of the rectus femoris and a biopsy without a dystrophic pattern. It also shows intrafamilial variability, with onset at birth in the brother and in adolescence in the sister. The trochleoplasty was an individual decision for patellar instability with trochlear dysplasia, a change described in other families and in the mouse model, and does not represent a standardised approach [4, 28].

10.2. Contrast: the severe recessive form

The siblings of Zou and colleagues, homozygous for NM_004370.6:c.7840+1G>A (described in the article as c.8006+1G>A), show the other extreme: profound weakness at birth, gastrostomy before 2 years, nocturnal NIV before 3, spinal fusion at 9 and absence of walking, without regression into adulthood; Figure 1 of the article shows the distal hyperlaxity with knee contractures and the kyphoscoliosis of the two siblings and the posture of the boy with the dominant form at 2 and 3 years (https://pmc.ncbi.nlm.nih.gov/articles/PMC3976332/figure/DDT627F1/) [6, 20, 28].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends on the form. In the dominant form, most walk: 31 of 33 patients published by 2025, with the oldest patient recorded at 76 years and respiratory function generally preserved (FVC between 58% and 115% of predicted in the records) [4]. The typical course is improvement in childhood, few limitations in the 2nd and 3rd decades and mild distal weakness from the 4th decade, without cardiac or respiratory involvement in the series of Mohassel and colleagues [14, 15]. The dominant functional problem in many adults is joint instability, with recurrent dislocations and orthopaedic surgery [4, 23]. In the severe recessive form, absence of walking, NIV from the first years, gastrostomy and spinal fusion are the rule, but the myopathy does not progress and the siblings of Zou and colleagues reached adulthood in a stable condition [4, 20, 28]. The recessive forms that spare the short isoform allow an active adult life, as in the 47-year-old man who worked without limitations and the 30-year-old patient who completed technical secondary school [24, 33]. The only death described in a patient with a molecular diagnosis is that of an Iranian boy homozygous for a variant of uncertain significance, at 10 years, with no cause given and with central nervous system signs that do not belong to the known spectrum [38]; the deaths in early childhood in the extended family of Zou and colleagues were not studied genetically [20]. The long-term prognosis of the paediatric dominant forms remains uncertain, because fewer than half of the published patients were adults [4].

11.2. Surveillance

There is no surveillance protocol specific to this disorder. Table 11.1 adapts the intervals of the CMD documents to the findings of the COL12A1 series; the intervals are the same as in section 7.

Table 11.1. Proposed surveillance, by extrapolation from the documents for the congenital muscular dystrophies.

11.3. Transition and adult follow-up

Transition should transfer neuromuscular, respiratory (NIV), orthopaedic and cardiac follow-up to adult teams, with the information that the dominant forms may develop distal weakness in middle age and that the severe recessive forms remain stable [14, 28]. Adult follow-up should include distal strength, respiratory function when there was involvement in childhood, joint instability and pain [4, 14].

12. Summary and Final Considerations

Collagen XII-related disorder is an overlap disorder of muscle and connective tissue, described in 2014, which has three designations: myopathic EDS in the 2017 EDS classification, Bethlem myopathy 2 and Ullrich congenital muscular dystrophy 2 in OMIM [1–3]. The COL12A1 gene encodes the collagen XII chain, a FACIT collagen that links collagen I fibrils to tenascin-X, decorin and other matrix molecules; the deficiency makes the matrix more compliant, reduces force transmission in muscle and weakens tendons, ligaments and bone [7, 8, 20]. Dominant variants (glycine substitutions, in-frame skipping, in-frame deletions) act through a dominant-negative effect and give, on average, mild pictures, with walking and distal weakness in adults; recessive loss-of-function variants give, when they affect both isoforms, a severe congenital picture with early respiratory failure, and, when they spare the short isoform, mild pictures [13, 14, 24, 33].

Recognition rests on the combination of congenital hypotonia that improves, proximal contractures that regress and distal or generalised hypermobility with dislocations, together with an elongated face, very high-arched palate, gingival changes in the recessive forms and selective atrophy of the rectus femoris [1, 4, 13]. The distinction from collagen VI disease, the main differential diagnosis, relies on the non-progressive course, muscle imaging without a central cloud, a merely myopathic biopsy and normal collagen VI in fibroblasts [12, 14, 20]. Diagnosis is molecular and requires copy-number analysis and, at times, RNA studies, because intragenic deletions have escaped the exome; interpretation must correct the historical numbering of the first variants and take into account the arginine-to-cysteine substitutions of debated significance [1, 6, 14, 22, 23].

Treatment is supportive and follows, by extrapolation, the documents for the congenital muscular dystrophies: respiratory surveillance with NIV when there is hypoventilation, nutrition, physiotherapy, orthopaedic management of the spine and unstable joints, baseline cardiac assessment and oral health [15, 16, 47]. Allele-specific silencing of the dominant allele by siRNA remains an in vitro proof of concept [14]. With about three dozen families published, the natural history in adults, the correlation with the isoforms and the population frequency remain to be defined, and the new EDS classification, announced for December 2026, may revise the criteria for myopathic EDS [4, 26].

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