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Classifications

ISDS Skeletal Nosology

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Inheritance

2

Autosomal dominant inheritance HP:0000006

The usual mode. A single heterozygous COL11A1 allele is sufficient because the mechanism is dominant negative: the shortened chain is made, is stable, and interferes with the heterotrimer that the normal allele also contributes to.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:10486316 SUPPORT Human Clinical

"Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit."

States the dominant mode of inheritance alongside the cardinal triad.

PMID:20301479 SUPPORT INDIRECT Human Clinical

"Each child of an individual with autosomal dominant Stickler syndrome has a 50% chance of inheriting the pathogenic variant."

The transmission risk that genetic counselling rests on. Indirect because GeneReviews covers COL11A1 inside its Stickler syndrome chapter rather than under the Marshall eponym; the 50 per cent figure follows from autosomal dominant transmission either way.

Autosomal recessive inheritance HP:0000007

A recessive form has been reported twice, both times from Saudi Arabia and both times with the same missense allele c.2702G>A (p.Gly901Glu) in homozygous form. It is recorded here because it is reproducible rather than anecdotal, but it is the exception; do not treat a negative parental examination as excluding the diagnosis in a consanguineous family.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:25073711 SUPPORT Human Clinical

"In this study, we describe the clinical presentations of seven patients with Marshall syndrome from three unrelated Saudi families, inherited as autosomal dominant (two families) and autosomal recessive (one family)."

Reports both modes segregating in one clinical series, with the recessive form in one of the three families.

PMID:25073711 SUPPORT Human Clinical

"Interestingly, the first report of autosomal recessive Marshall syndrome was from Saudi Arabia caused by the same mutation (c.2702G > A, p.Gly901Glu) as in one of our families."

Establishes that the recessive form has been seen twice with the same allele, which is why it is recorded as a mode rather than as a single unreplicated observation.

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Discussions and Knowledge Gaps

2

Are Marshall syndrome and Stickler syndrome type 2 two diseases or one, and does the 54-bp C-terminal splice correlation hold in a cohort large enough to counsel from?

KNOWLEDGE GAP OPEN gap_marshall_vs_stickler2_nosology

Attached to

disease#Marshall Syndrome genetic#COL11A1 pathophysiology#Heterozygous COL11A1 54-bp Exon Splice-Site Variant

dismech currently carries both as separate entries, and the evidence for that split is thinner than the separation implies. It rests on two cohorts: 23 novel COL11A1 variants across a mixed Marshall/Stickler/Stickler-like screen, and a series in which 4 of 10 COL11A1-positive patients were labelled Marshall - and in that second series the label was assigned on clinical grounds first and the genotype correlation observed afterwards, which is a weaker design than it looks. Against the split: patients with features of both syndromes are reported in both cohorts and within a single Tunisian family, and at least one group states outright that the two are one entity. What would settle it is a COL11A1 cohort large enough to test whether the 54-bp C-terminal splice class separates from other classes on prospectively collected audiological and facial measures, rather than on labels assigned before genotyping.

Every available animal model of Col11a1 is a loss-of-function null, while human Marshall syndrome is a dominant-negative disorder. Does the null phenotype tell us anything about what a shortened, co-assembling chain does?

HUMAN MODEL MISMATCH OPEN mismatch_marshall_dominant_negative_models

Attached to

pathophysiology#Dominant-Negative Poisoning of the Collagen XI Heterotrimer animal_models#cho/cho chondrodysplasia mouse animal_models#col11a1a morphant zebrafish

This is a mismatch rather than a gap: the model evidence exists and is good, but it is evidence about the wrong lesion. The cho/cho mouse and the col11a1a morphant both remove collagen XI. The human allele does something different and, on the face of it, worse - it supplies a defective chain that enters the heterotrimer and disrupts a fibril the normal allele is also trying to build. The entry's cartilage mechanism is therefore borrowed from a null phenotype, and the specifically dominant-negative step is supported only by the in-frame/in-register argument from collagen gene structure. The mouse is also neonatally lethal in the homozygote, so it cannot report on any of the progressive postnatal features. A knock-in carrying a 54-bp C-terminal splice variant on one allele would test the mechanism directly; none has been reported.

Proposed experiments

Heterozygous 54-bp exon splice knock-in mouse

exp_marshall_het_splice_knockin_mouse

Engineer the intron 50 donor-site change (or the equivalent murine 54-bp C-terminal exon) as a single heterozygous allele and phenotype the animals into adulthood, rather than using a null.

Would support

pathophysiology#Dominant-Negative Poisoning of the Collagen XI Heterotrimer

Supporting outcome

Heterozygotes show cartilage fibril disorganisation, vitreous abnormality and progressive cochlear hearing loss, with a phenotype more severe than Col11a1 heterozygous nulls examined in parallel.

Refuting outcome

Heterozygous knock-in animals are indistinguishable from heterozygous nulls, which would place the mechanism at reduced collagen XI dosage rather than at active interference by the shortened chain.

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Pathophysiology

7

Heterozygous COL11A1 54-bp Exon Splice-Site Variant

A splice-site change affecting one of the 54-bp exons in the C-terminal region of COL11A1. Intron 50 (c.3816+1G>A) is a recurrent hot spot. Other COL11A1 lesion classes exist - missense glycine substitutions and large intragenic deletions - but they correlate with the overlapping Marshall/Stickler end of the spectrum rather than with the Marshall phenotype proper.

COL11A1 hgnc:2186

Genetic context variant_origin: GERMLINE functional_impact_category: DOMINANT_NEGATIVE

Downstream

In-Frame Exon Skipping and a Shortened proalpha1(XI) Chain Loss of the splice donor causes the adjacent exon to be skipped.

Show evidence (2 references)

PMID:10486316 SUPPORT Human Clinical

"Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene."

The genotype-phenotype correlation that defines the Marshall-associated variant class.

PMID:17236192 SUPPORT Human Clinical

"In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50."

Independent replication of the correlation in a second cohort, and the source of the intron-50 hot spot.

In-Frame Exon Skipping and a Shortened proalpha1(XI) Chain

Because fibrillar collagen exons are sized in multiples of the 9-residue Gly-Xaa-Yaa unit, skipping one keeps the reading frame and the triple-helix register intact. The cell therefore produces a stable, shortened chain rather than degrading a truncated one - which is precisely why the allele is harmful rather than merely null.

Downstream

Dominant-Negative Poisoning of the Collagen XI Heterotrimer The shortened chain remains competent to enter the heterotrimer.

Show evidence (1 reference)

PMID:23621912 SUPPORT Other

"Because skipping of these exons leaves the message in-frame and the Gly-Xaa-Yaa repeating collagen motif in register, this results in mutant collagen α chains capable of co-assembly with α chains synthesized from the normal genes, resulting in a dominant negative effect"

States the in-frame/in-register argument and the co-assembly step it licenses.

Dominant-Negative Poisoning of the Collagen XI Heterotrimer

The shortened proalpha1(XI) chain co-assembles with normal chains, so a heterozygote's collagen XI pool is contaminated rather than halved. This is the step that makes the disease dominant and that separates it from a haploinsufficiency model.

extracellular matrix structural constituent conferring tensile strength GO:0030020 ⇓ LOSS OF FUNCTION

Downstream

Defective Heterotypic Collagen II/XI Fibril Assembly Collagen XI nucleates and limits the diameter of the collagen II fibril, so a poisoned heterotrimer is felt as a fibril-architecture defect.

Show evidence (2 references)

PMID:23621912 SUPPORT Other

"The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products."

The dominant-negative claim stated directly.

PMID:25073711 SUPPORT Human Clinical

"Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye."

Establishes where collagen XI acts, which is what makes the branch into cartilage and vitreous the expected one.

Defective Heterotypic Collagen II/XI Fibril Assembly

The shared upstream lesion for every organ branch below. Collagen XI is a minor component by mass but a controlling one by function: it templates fibril nucleation and diameter in the collagen II matrices of cartilage, vitreous and the membranous labyrinth.

collagen fibril organization GO:0030199 ↓ DECREASED

Animal models

cho/cho chondrodysplasia mouse Mouse recapitulates Cartilage collagen fibrils fail to form normally in the absence of collagen XI, which is the assertion this node makes.

Downstream

Growth Plate Chondrocyte Disorganization

Vitreoretinal Collagen Matrix Defect

Membranous Labyrinth Collagen Defect Recorded as indirect because the cochlear step is inferred from the clinical and imaging phenotype rather than from a demonstrated labyrinthine matrix abnormality.

Show evidence (1 reference)

PMID:7859283 SUPPORT Model Organism

"The data demonstrate that collagen XI is essential for normal formation of cartilage collagen fibrils and the cohesive properties of cartilage."

The fibril-assembly requirement, demonstrated by a naturally occurring Col11a1 null mouse.

Growth Plate Chondrocyte Disorganization

Loss of the fibril template disturbs the columnar organisation and differentiation of growth-plate chondrocytes. This is the branch behind the craniofacial and skeletal features, and it is the branch with the strongest animal-model support.

growth plate cartilage chondrocyte CL:1000217

cartilage development GO:0051216 ↓ DECREASED

Animal models

cho/cho chondrodysplasia mouse Mouse recapitulates Growth-plate chondrocyte differentiation and spatial organisation depend on collagen XI in the matrix.

col11a1a morphant zebrafish Zebrafish partially recapitulates Knockdown disorganises the chondrocytes of Meckel's cartilage and disturbs the adjacent bone formation.

Downstream

Midface retrusion

Short stature

Premature osteoarthritis

Show evidence (2 references)

PMID:7859283 SUPPORT Model Organism

"The results also suggest that the normal differentiation and spatial organization of growth plate chondrocytes is critially dependent on the presence of type XI collagen in cartilage extracellular matrix."

Names growth-plate chondrocyte organisation as the collagen XI-dependent process. Quoted verbatim including the source's typographical error in "critially", since a snippet reproduces its source rather than correcting it.

PMID:36278545 SUPPORT Model Organism

"Our results demonstrate that zebrafish col11a1a knockdown impairs the cellular organization of Meckel's cartilage in the developing jaw and alters the bone formation that occurs adjacent to the Meckel's cartilage."

Extends the cartilage-organisation defect specifically to the craniofacial cartilage that prefigures the midface phenotype.

Vitreoretinal Collagen Matrix Defect

The vitreous is a collagen II/XI gel, so the same fibril defect presents as an abnormal vitreous with progressive vitreoretinal degeneration. The clinical consequence that matters is a lifelong risk of retinal detachment; the myopia and the lens changes travel with it.

Downstream

High myopia

Retinal detachment

Cataract

Show evidence (2 references)

PMID:25073711 SUPPORT Human Clinical

"Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye."

Places collagen XI in the vitreous, which is what makes the ocular branch a consequence of the same lesion rather than a separate association.

PMID:9235398 SUPPORT Human Clinical

"We are reporting on a female patient with typical ocular and systemic manifestations of both syndromes: high myopia, glaucoma and goniodysgenesis, submucosal cleft palate, sensorineural hearing loss, and "flat" mid-face."

Documents the ocular spectrum, including the anterior-segment features that are less often listed.

Membranous Labyrinth Collagen Defect

The hearing loss is cochlear, and imaging shows the bony labyrinth is normally formed - so the lesion is in the membranous labyrinth rather than in osseous morphogenesis. This node records that inference, which is what the audiovestibular study concluded rather than what it directly observed; no labyrinthine matrix has been examined histologically in a Marshall patient.

cochlea UBERON:0001844

Downstream

Progressive sensorineural hearing impairment

Show evidence (2 references)

PMID:10889003 SUPPORT Human Clinical

"The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system."

The authors' localisation of the lesion, which this node restates.

PMID:10889003 SUPPORT INDIRECT Human Clinical

"Computed tomography detected no malformations of temporal bone structures."

The negative imaging finding the localisation rests on. Indirect because a normal bony labyrinth excludes one explanation rather than demonstrating a membranous one.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Ear 1

Progressive sensorineural hearing impairment HP:0000408

Course: PROGRESSIVE

Show evidence (3 references)

PMID:20301479 SUPPORT INDIRECT Human Clinical

"hearing loss that is both conductive and sensorineural"

GeneReviews names sensorineural hearing loss as a defining clinical characteristic of the disorder group this entry belongs to. Note the chapter reports the hearing loss as both conductive and sensorineural, while this phenotype node is the sensorineural component specifically; the conductive element is secondary to the cleft palate and otitis media rather than to the labyrinthine collagen defect modeled here. Indirect: written for Stickler syndrome rather than the Marshall eponym.

PMID:10889003 SUPPORT Human Clinical

"The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems."

Characterises the hearing loss as progressive and cochlear, and notes the subclinical vestibular involvement that accompanies it.

PMID:11556853 SUPPORT INDIRECT Human Clinical

"The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely..."

Supports the severity claim by contrast. Indirect because the cohort studied was Stickler syndrome and the statement about Marshall syndrome is a comparison the authors draw rather than a measurement they made.

Eye 5

High myopia HP:0011003

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:25073711 SUPPORT Human Clinical

"Characteristic features of Marshall syndrome include midfacial hypoplasia, high myopia, and sensorineural-hearing deficit."

States high myopia as one of the three characteristic features.

Cataract HP:0000518

Show evidence (1 reference)

PMID:10889003 SUPPORT Human Clinical

"Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1."

Lists cataract among the defining features.

Retinal detachment HP:0000541

Show evidence (1 reference)

PMID:21466760 SUPPORT INDIRECT Human Clinical

"It is the most commonly identified inherited cause of retinal detachment in childhood."

Establishes the magnitude of the childhood retinal-detachment risk in this collagenopathy spectrum. Indirect because the systematic review is framed around Stickler syndrome; Marshall syndrome is the allelic COL11A1 neighbour rather than the population studied.

Glaucoma HP:0000501

Show evidence (1 reference)

PMID:9235398 SUPPORT Human Clinical

"We are reporting on a female patient with typical ocular and systemic manifestations of both syndromes: high myopia, glaucoma and goniodysgenesis, submucosal cleft palate, sensorineural hearing loss, and "flat" mid-face."

Documents glaucoma with goniodysgenesis in a patient with the syndrome.

Ectopia lentis HP:0001083

Show evidence (1 reference)

PMID:9235398 SUPPORT Human Clinical

"Coloboma and subluxation of the lens have to be regarded as possible manifestations of the Stickler (Marshall) syndrome. The syndrome(s) should be included in the differential diagnosis of ectopia lentis-associated systemic diseases."

The authors' conclusion that lens subluxation belongs in the phenotype and that the syndrome belongs on the ectopia lentis differential.

Head and Neck 3

Midface retrusion HP:0011800

Show evidence (2 references)

PMID:10486316 SUPPORT Human Clinical

"Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit."

Names midfacial hypoplasia as a cardinal feature.

PMID:17236192 SUPPORT Human Clinical

"In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features."

Records that the facial features are one of the two criteria used in practice to assign the Marshall label.

Depressed nasal bridge HP:0005280

Show evidence (1 reference)

PMID:10486316 SUPPORT Human Clinical

"It has been suggested that Marshall syndrome differs from Stickler syndrome in that patients with Marshall syndrome more often have short stature, deafness, and abnormalities in cranial ossification and more-pronounced dysmorphic features, including a retracted midface with flat nasal bridge,..."

Describes the facial phenotype and states it as a proposed discriminator from Stickler syndrome.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:9235398 SUPPORT Human Clinical

"In both children of the patient manifestations of the syndrome were present (high myopia, cleft palate, sensorineural hearing loss)."

Documents cleft palate in affected family members.

Musculoskeletal 1

Premature osteoarthritis HP:0003088

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:9188673 SUPPORT INDIRECT Human Clinical

"Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood."

Documents the early severe arthropathy of collagen XI disease and its surgical consequence. Indirect because the patients studied carried COL11A2 variants (OSMED); the same paper argues on phenotypic grounds that Marshall syndrome is the COL11A1 counterpart.

Growth 1

Short stature HP:0004322

Show evidence (1 reference)

PMID:10486316 SUPPORT Human Clinical

"It has been suggested that Marshall syndrome differs from Stickler syndrome in that patients with Marshall syndrome more often have short stature, deafness, and abnormalities in cranial ossification and more-pronounced dysmorphic features"

Names short stature as one of the features proposed to distinguish the two syndromes.

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Genetic Associations

1

COL11A1 (Causal heterozygous variant)

Gene: COL11A1 hgnc:2186

Show evidence (3 references)

PMID:17236192 SUPPORT Human Clinical

"A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1..."

Gives both the causal gene and the yield in a clinically selected, COL2A1-negative series - 10 of 44.

PMID:17236192 SUPPORT Human Clinical

"The remaining 6/10 patients had an overlapping Marshall-Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50."

The other half of the genotype-phenotype correlation: the overlapping phenotypes lacked the hot-spot variant.

PMID:23621912 SUPPORT Human Clinical

"Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing."

The basis for including a deletion assay in testing rather than relying on exon sequencing.

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External Assertions

2

OMIM Marshall syndrome record

OMIM disease record OMIM:154780

The OMIM phenotype entry for Marshall syndrome, and the identifier the genotype-phenotype literature keys on. It is also the xref MONDO:0007949 carries, so it is the join between this entry and OMIM-keyed tooling.

OMIM COL11A1 gene record

OMIM gene record OMIM:120280

The OMIM gene entry for COL11A1. Worth recording separately from the phenotype entry because the same gene entry is the locus for Stickler syndrome type 2 and for fibrochondrogenesis, which is the allelic relationship this entry's differentials describe.

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Medical Actions

5

Retinal surveillance and prophylactic retinal intervention

Action: prophylactic retinal laser therapy Ontology label: Laser Therapy NCIT:C15466

Platform: Surgery

Regular dilated retinal examination from childhood, with prophylactic laser or cryotherapy to reduce detachment risk in selected eyes. This is the intervention with the most to gain and the least settled evidence: the systematic review that covers it found no consensus and no guidelines, so the practice is reasonable extrapolation rather than demonstrated benefit.

Target Phenotypes: Retinal detachment HP:0000541

Show evidence (2 references)

PMID:21466760 SUPPORT INDIRECT Human Clinical

"However, there is no consensus regarding best practice and no current guidelines on prophylactic interventions for this population."

Records the state of the evidence honestly: the intervention is offered, and it is not standardised. Indirect because the review addresses Stickler syndrome, from which practice in Marshall syndrome is extrapolated.

PMID:20301479 SUPPORT INDIRECT Human Clinical

"laser therapy for prevention of retinal detachment; education on risks and symptoms of retinal detachment"

The authoritative management recommendation, which the systematic review above says is not standardised - the two are cited together because the disagreement is the point. Indirect: GeneReviews covers COL11A1 within its Stickler syndrome chapter.

Hearing amplification and cochlear implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

Amplification early, to protect language acquisition, and cochlear implantation as the loss progresses. The cochlear localisation of the deficit is what makes implantation a rational option rather than a hopeful one.

Target Phenotypes: Progressive sensorineural hearing impairment HP:0000408

Show evidence (2 references)

PMID:10889003 SUPPORT INDIRECT Human Clinical

"The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin"

Establishes the cochlear site of the lesion, which is the premise for amplification and implantation. Indirect because the study characterises the deficit rather than reporting an intervention outcome.

PMID:20301479 SUPPORT INDIRECT Human Clinical

"standard treatment of sensorineural and conductive hearing loss"

The management recommendation itself, rather than an inference from where the lesion sits. Indirect: the GeneReviews chapter is written for Stickler syndrome and includes COL11A1.

Joint replacement for degenerative arthropathy

Action: joint arthroplasty Ontology label: Arthroplasty NCIT:C51691

Platform: Surgery

Arthroplasty for the early-onset osteoarthritis, which in the related COL11A2 disorder has been needed as early as young adulthood.

Target Phenotypes: Premature osteoarthritis HP:0003088

Show evidence (2 references)

PMID:9188673 SUPPORT INDIRECT Human Clinical

"Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood."

The basis for anticipating arthroplasty. Indirect: the observation is from COL11A2 OSMED patients, and is applied here on the argument of collagen XI mechanism shared between the two genes.

PMID:20301479 SUPPORT INDIRECT Human Clinical

"symptomatic treatment for arthropathy; treatment of osteoarticular manifestations per orthopedist"

The orthopaedic management recommendation. Indirect: GeneReviews covers COL11A1 within its Stickler syndrome chapter.

Cataract surgery

Action: Cataract Surgery NCIT:C157809

Platform: Surgery

Surgical extraction for the congenital or juvenile cataract. It is the one intervention in this entry that restores function rather than preventing deterioration, which is why the cataract phenotype is described as having a clean intervention. Timing has to be coordinated with the vitreoretinal surveillance, since the same eye carries a lifelong detachment risk.

Target Phenotypes: Cataract HP:0000518

Show evidence (2 references)

PMID:20301479 SUPPORT INDIRECT Human Clinical

"Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment"

Establishes cataract as a managed ocular manifestation of the collagenopathy that GeneReviews covers, which is the indication for extraction. Indirect: GeneReviews addresses the Stickler chapter including COL11A1, and states the manifestation rather than evaluating surgery.

PMID:10889003 SUPPORT INDIRECT Human Clinical

"Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1."

Confirms cataract as a feature of Marshall syndrome specifically, which is what makes the borrowed management recommendation applicable. Indirect: a phenotype description, not a surgical outcome.

Genetic counselling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Fifty per cent recurrence risk for the offspring of an affected parent in the usual dominant form, and 25 per cent in the reported recessive families once the biallelic variant is known. Counselling also has to cover the variable expressivity, which is wide enough within one family that a mildly affected parent is not a guide to how a child will be affected.

Show evidence (1 reference)

PMID:26367406 SUPPORT Human Clinical

"There is a variability of the clinical expression among the affected members of the study's family."

Documents the within-family variability that counselling has to convey.

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Environmental Factors

1

Ocular or head trauma, including contact sports

Left without an `exposure_term`. ECTO was searched for trauma, injury, mechanical and physical exposure terms and for sport; it has `ECTO:6000002` exposure to exercise and `ECTO:6000031` exposure to strenuous exercise, neither of which means blunt ocular or head trauma. No term beats a wrong one, so none is bound. Recorded so the next curator does not repeat the search; Stickler_Syndrome_Type_2 records the same result for the same exposure.

Trauma does not cause Marshall syndrome - the disorder is monogenic - but it is what converts an already abnormal vitreoretinal interface into a detachment. This is the entry's one activity restriction, and it is the kind of advice that is easy to omit from a genetics consultation and materially changes outcome in a disorder whose defining ocular risk is retinal detachment.

Show evidence (1 reference)

PMID:20301479 SUPPORT INDIRECT Human Clinical

"Agents/circumstances to avoid: Activities such as contact sports that may lead to traumatic retinal detachment."

The recommendation stated as an avoidance, which is how it reaches a patient. Indirect for the same reason as the link evidence above.

Mechanism Target:

TRIGGERS Retinal detachment — Impact transmitted to an abnormal vitreous gel produces the tractional tear, and the detachment follows. The exposure is attached to the detachment rather than to the collagen matrix defect upstream of it, because the matrix defect is what the COL11A1 allele made it and trauma cannot worsen it. Against the detachment the exposure genuinely initiates the event, so the predicate is TRIGGERS.

Show evidence (1 reference)

PMID:20301479 SUPPORT INDIRECT Human Clinical

"Activities such as contact sports that may lead to traumatic retinal detachment."

GeneReviews names contact sports as the activity that may lead to traumatic retinal detachment, which is the exposure-to-mechanism link asserted here. Indirect: the chapter covers COL11A1 within Stickler syndrome rather than under the Marshall eponym.

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Diagnosis

4

COL11A1 sequencing with a deletion/duplication assay

Sequence COL11A1, and pair it with a dosage assay. In practice this is done within a type II/IX/XI collagenopathy panel, since the clinical picture does not reliably separate COL11A1 from COL2A1 or COL11A2 before testing.

Results: A heterozygous COL11A1 splice-site variant, most often at a 54-bp C-terminal exon; alternatively a glycine missense variant or a multi-exon deletion.

Show evidence (3 references)

PMID:23621912 SUPPORT Human Clinical

"We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone."

Demonstrates the deletions that sequencing alone misses, which is why the dosage assay is part of the recommended workup rather than a reflex test.

PMID:20301479 SUPPORT INDIRECT Human Clinical

"The diagnosis of Stickler syndrome can be established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 identified by molecular genetic testing."

The authoritative statement that molecular testing establishes the diagnosis, and that COL11A1 is one of the genes on which it is established. This is what the entry's testing recommendation rests on. Indirect: the chapter is written for Stickler syndrome, within which COL11A1 disease sits, rather than under the Marshall eponym.

PMID:41856555 SUPPORT INDIRECT Human Clinical

"The diagnostic yield of Stickler syndrome panels was 50%, with a higher rate among cases reporting a family history (OR: 2.6 (95% CI 1.3 to 5.4); p=0.005) or presenting with ocular signs (OR: 2.2 (95% CI 1.1 to 4.5), p=0.03)."

Sets the expectation for a negative result: half of clinically suspected cases have no pathogenic variant on a six-gene collagenopathy panel, so a negative panel does not exclude the clinical diagnosis. Indirect: a laboratory case series across the whole type II/IX/XI collagenopathy spectrum rather than a Marshall syndrome cohort.

Audiometry with temporal bone imaging

Pure-tone audiometry to document the degree and progression of the sensorineural loss, with temporal bone CT. The expected imaging result is a normal osseous labyrinth; that normality is informative, because it places the lesion in the membranous labyrinth and argues against a malformation syndrome.

Results: Progressive, predominantly cochlear sensorineural hearing loss with normally formed temporal bone structures.

Show evidence (1 reference)

PMID:10889003 SUPPORT Human Clinical

"Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems."

The assessment battery this recommendation is drawn from.

Skeletal radiography

Plain radiographs for the characteristic skeletal signs. Worth doing in a patient whose ocular and auditory features already suggest a collagenopathy, because the skeletal findings are part of what separates the Marshall end of the spectrum from a purely ocular Stickler phenotype.

Results: Radiological signs described as characteristic of Marshall syndrome, alongside the abnormalities of cranial ossification reported in the older literature.

Show evidence (1 reference)

PMID:26367406 SUPPORT Human Clinical

"Marshall syndrome's specific radiological signs were found."

Records that the radiographic signs were identified in this family and described as specific to the syndrome. The paper does not enumerate them in the abstract, so the entry names the test rather than a finding list.

Ophthalmologic assessment

Refraction, slit-lamp examination for cataract and lens position, gonioscopy and tonometry, and dilated fundoscopy for vitreoretinal degeneration. The anterior-segment elements are easy to omit and have both been reported.

Results: High myopia, congenital or juvenile cataract, vitreoretinal degeneration, and in some patients goniodysgenesis with glaucoma or lens subluxation.

Show evidence (1 reference)

PMID:9235398 SUPPORT Human Clinical

"Additionally, we observed subluxation of the ocular lens in one eye which was previously described in only a few cases."

The rare anterior-segment finding that justifies examining lens position rather than stopping at refraction and fundoscopy.

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Prevalence

1

Worldwide

Point Prevalence <1 in 1,000,000

The only figure in the literature, and it is a statement in a single case report rather than a population study. Treat it as an order-of-magnitude claim about rarity, not a measured rate. Case ascertainment is further confounded by the Marshall/Stickler boundary - a patient counted as Stickler type 2 in one centre may be counted as Marshall in another.

Show evidence (1 reference)

PMID:38062645 SUPPORT Human Clinical

"Marshall syndrome is an extremely rare genetic disorder usually diagnosed in infancy with a prevalence of <1 in 1 million."

The prevalence statement itself, together with the infancy onset.

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Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Marshall Syndrome:

Stickler syndrome type 2 MONDO:0011493

Overlapping Features The allelic neighbour, and the one that matters. Both are COL11A1. The working discriminators are the variant class (54-bp C-terminal splice variants track Marshall) and the audiological phenotype (earlier and more severe in Marshall), together with the facial gestalt. Neither is absolute, and patients with both phenotypes are reported.

Distinguishing Features

Splice variants of the 54-bp C-terminal COL11A1 exons, the intron 50 hot spot in particular
Earlier-onset and more severe sensorineural hearing loss
More pronounced midfacial hypoplasia and a more distinctive facial gestalt
Short stature reported more often

Show evidence (2 references)

PMID:17236192 SUPPORT Human Clinical

"In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50."

Shows the clinical criteria actually used to split the two, and the genotype that accompanied the split in this cohort.

PMID:9235398 REFUTE Human Clinical

"Probably, both syndromes represent the same entity with occasional partially different clinical manifestations."

Recorded as a refutation of the separate-entity claim, not as a hedge. These authors, reporting a patient with features of both, take the view that Marshall and Stickler are one disorder. Curating the split without this dissent would overstate how settled the question is.

Stickler syndrome type 1 MONDO:0007160

Overlapping Features The COL2A1 form, and the most common. Distinguished by its hearing loss more than by anything else: mild, high-frequency, and no more progressive than presbycusis, against the early severe loss of Marshall syndrome. Retinal detachment risk is at least as high, so the distinction does not change ophthalmic surveillance.

Distinguishing Features

COL2A1 rather than COL11A1
Mild, non-progressive high-frequency sensorineural hearing loss
Hypermobile middle ear systems reported as a diagnostic feature

Show evidence (1 reference)

PMID:11556853 SUPPORT Human Clinical

"The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely..."

The audiological contrast, drawn from 46 affected individuals in 29 families, that makes hearing the most useful discriminator.

Otospondylomegaepiphyseal dysplasia Not Yet Curated MONDO:0044206

Overlapping Features The COL11A2 disorder. It shares midface hypoplasia, deafness and epiphyseal dysplasia, and its recessive form is severe. The clean separator is ocular: COL11A2 is not expressed in vitreous, so OSMED has no myopia and no vitreoretinopathy, while the ocular features are central to Marshall syndrome.

Distinguishing Features

COL11A2 rather than COL11A1
No high myopia and no vitreoretinal degeneration
Megaepiphyses with severe epiphyseal dysplasia

Show evidence (2 references)

PMID:9188673 SUPPORT Human Clinical

"We describe a syndrome of midface hypoplasia, non-progressive sensorineural deafness and epiphyseal dysplasia in 3 sibs born to consanguineous parents."

Describes the overlapping OSMED phenotype in the three siblings this differential is drawn from.

PMID:9188673 SUPPORT Human Clinical

"Of these, Marshall syndrome is very similar to OSMED. Considering these phenotypic similarities and the close association between the COL11A1 and COL11A2 gene products, we propose that Marshall syndrome may be caused by a mutation in COL11A1."

The phenotypic similarity is strong enough that it was the argument by which COL11A1 was first predicted as the Marshall gene - which is also why OSMED is the differential most likely to be confused with it.

Fibrochondrogenesis MONDO:0016068

Overlapping Features The severe recessive end of the same gene, and the most informative contrast in this entry. Biallelic COL11A1 variants produce a neonatally severe skeletal dysplasia, while the heterozygous dominant-negative alleles produce Marshall syndrome. The comparison is what shows that the disorder curated here is not simply "less collagen XI": losing both alleles gives a different and far worse disease than contaminating the heterotrimer does.

Distinguishing Features

Biallelic COL11A1 rather than a single dominant-negative allele
Neonatally severe skeletal dysplasia rather than a survivable multisystem disorder
Not a differential in practice; a mechanistic contrast

Show evidence (1 reference)

PMID:23621912 SUPPORT Human Clinical

"Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis."

States the three-way allelic relationship at COL11A1 that makes fibrochondrogenesis the recessive counterpart of this disorder.

Autosomal recessive Stickler syndrome MONDO:0031047

Overlapping Features The type IX collagen forms, caused by biallelic COL9A1, COL9A2 or COL9A3 variants. Included because the inheritance pattern is the discriminator a clinician is most likely to get wrong: a consanguineous family with an apparently Stickler-like phenotype is more likely to be type IX collagen than to be the rare recessive Marshall families reported from Saudi Arabia.

Distinguishing Features

Biallelic COL9A1, COL9A2 or COL9A3 rather than COL11A1
Autosomal recessive with unaffected heterozygous parents
Very rare, with fewer than twenty reported patients at the time of the cited report

Show evidence (2 references)

PMID:33570243 SUPPORT Human Clinical

"However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3."

Names the three recessive genes and the size of the reported experience, which is what makes this a real but uncommon differential.

PMID:33570243 SUPPORT Human Clinical

"STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare."

Sets the base rate that makes inheritance pattern the useful discriminator here.

🐁

Animal Models

2

cho/cho chondrodysplasia mouse

A spontaneous Col11a1 null that mapped the gene and established what collagen XI does. It is the source of the cartilage mechanism in this entry and it is not a model of the human disease: it is recessive and null where the human disorder is dominant and dominant-negative, and it dies at birth.

Species

Mouse

Genotype

Col11a1 cho allele, homozygous (single-cytidine deletion causing a frameshift and premature stop)

Publication

PMID:7859283

Pathograph links

Defective Heterotypic Collagen II/XI Fibril Assembly recapitulates fidelity: moderate Cartilage collagen fibrils fail to form normally in the absence of collagen XI, which is the assertion this node makes.

Limitations: Complete loss of function, in the homozygote, of a gene that in humans causes disease in the heterozygous dominant-negative state. The null removes collagen XI; the human allele contaminates it. The two are not the same lesion and the mouse cannot show that a shortened chain is worse than no chain.

Show evidence (1 reference)

PMID:7859283 SUPPORT Model Organism

"The data demonstrate that collagen XI is essential for normal formation of cartilage collagen fibrils and the cohesive properties of cartilage."

The fibril-assembly conclusion the model supports.

Growth Plate Chondrocyte Disorganization recapitulates fidelity: moderate Growth-plate chondrocyte differentiation and spatial organisation depend on collagen XI in the matrix.

Limitations: Neonatally lethal, so it reports on skeletal morphogenesis only and can say nothing about the progressive postnatal features - the myopia, the vitreoretinal degeneration, the progressive deafness, the adult osteoarthritis - that make up most of the human disease burden.

Readouts

Long bone length and metaphyseal width

Direction: DECREASED

Interpretation: Shortened, metaphyseally widened limb bones as the structural readout of disorganised growth-plate cartilage.

Show evidence (1 reference)

PMID:7859283 SUPPORT Model Organism

"Limb bones of newborn cho/cho mice are wider at the metaphyses than normal bones and only about half the normal length."

The measurement behind this readout.

Show evidence (1 reference)

PMID:7859283 SUPPORT Model Organism

"The results also suggest that the normal differentiation and spatial organization of growth plate chondrocytes is critially dependent on the presence of type XI collagen in cartilage extracellular matrix."

Links collagen XI loss to growth-plate chondrocyte organisation. Reproduces the source's spelling of "critially".

Show evidence (1 reference)

PMID:7859283 SUPPORT Model Organism

"Mice that are homozygous for the autosomal recessive chondrodysplasia (cho) mutation die at birth with abnormalities in cartilage of limbs, ribs, mandible, and trachea."

Describes the model and its neonatal lethality, which is the limit on what it can be used for.

col11a1a morphant zebrafish

A craniofacial knockdown model. Its value here is specificity: it shows the cartilage-organisation defect in Meckel's cartilage, the first pharyngeal arch cartilage that prefigures the lower jaw, which is the closest available experimental correlate of the human midface phenotype.

Species

Zebrafish

Genotype

col11a1a antisense morpholino knockdown

Publication

PMID:36278545

Pathograph links

Growth Plate Chondrocyte Disorganization partially recapitulates fidelity: low Knockdown disorganises the chondrocytes of Meckel's cartilage and disturbs the adjacent bone formation.

Limitations: Morpholino knockdown rather than a genetic allele, so off-target and transient-knockdown caveats apply and no stable line is characterised. Zebrafish craniofacial cartilage is not a mammalian growth plate, and the human lesion is a dominant-negative chain rather than reduced gene product, so this supports the general requirement for col11a1a in cartilage organisation rather than the specific human mechanism.

Show evidence (1 reference)

PMID:36278545 SUPPORT Model Organism

"Our results demonstrate that zebrafish col11a1a knockdown impairs the cellular organization of Meckel's cartilage in the developing jaw and alters the bone formation that occurs adjacent to the Meckel's cartilage."

The craniofacial cartilage result this link rests on.

{ }

Source YAML

click to show

name: Marshall Syndrome
creation_date: "2026-09-11T11:40:00Z"
category: Mendelian
synonyms:
- MRSHS
- deafness, myopia, cataract, saddle nose-Marshall type
- Marshall syndrome (COL11A1)
description: >-
  Marshall syndrome is a dominantly inherited type XI collagenopathy caused by
  heterozygous COL11A1 variants, presenting from infancy with midfacial
  hypoplasia and a depressed nasal bridge, high myopia with congenital or
  juvenile cataract and vitreoretinal degeneration, and an early, severe,
  progressive sensorineural hearing loss that is predominantly cochlear. Short
  stature, cleft palate and early-onset osteoarthritis complete the picture.

  The mechanism is dominant negative rather than haploinsufficient, and that
  distinction is what organises the rest of the entry. The characteristic
  variant class is a splice-site change at one of the 54-bp exons in the
  C-terminal region of COL11A1. Because collagen exons are sized to keep the
  Gly-Xaa-Yaa repeat in register, skipping one leaves the message in frame, so
  the cell makes a shortened but stable proalpha1(XI) chain that still
  co-assembles into the collagen XI heterotrimer and poisons it. Collagen XI
  templates the diameter of heterotypic collagen II/XI fibrils, so the
  consequences fall on the three tissues that depend most on precisely
  organised fibrils: growth-plate cartilage, the ocular vitreous, and the
  membranous labyrinth.

  Whether Marshall syndrome is a disease distinct from Stickler syndrome type 2
  has been argued since the 1970s, and dismech does not treat the question as
  closed. The two are allelic - both are COL11A1 - and individual patients with
  features of both are reported repeatedly, including within a single family.
  What supports separating them is a genotype-phenotype correlation (the 54-bp
  C-terminal splice class tracks the Marshall end) and an audiological one (the
  hearing loss is earlier and more severe than in Stickler type 1). The entry
  records the correlation, the overlap, and a published argument that the two
  are one entity, rather than asserting the split and leaving the dissent out.

  A practical warning, because it is a live source of error rather than a
  curiosity: the eponym "Marshall syndrome" is also used for PFAPA (periodic
  fever, aphthous stomatitis, pharyngitis, adenitis) and for acquired cutis
  laxa type II. Neither has anything to do with COL11A1. A literature search on
  the name alone returns all three.
disease_term:
  preferred_term: Marshall syndrome
  term:
    id: MONDO:0007949
    label: Marshall syndrome
parents:
- Type XI collagenopathy
- Hereditary connective tissue disorder
- Skeletal dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: type_11_collagen
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, group 3
      "Type 11 collagen group" (2019 revision, Mortier et al., PMID:31633310).
      The group covers the COL11A1 and COL11A2 disorders and names Marshall
      syndrome explicitly alongside Stickler syndrome types 2 and 3,
      fibrochondrogenesis and OSMED. Note that dismech's Stickler_Syndrome_Type_1
      sits in group 2 (type 2 collagen), which is the nosological expression of
      the same COL2A1-versus-COL11A1 split this entry's differential describes.
    evidence:
    - reference: PMID:31633310
      reference_title: "Nosology and classification of genetic skeletal disorders: 2019 revision."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes.
      explanation: >-
        Establishes the classification system this assignment is made under, and
        that its groups are defined on clinical, radiographic and molecular
        phenotype. Marked INDIRECT deliberately: the abstract does not name the
        type 11 collagen group or place Marshall syndrome in it. That assignment
        comes from the nosology's own group table in the full text, which is not
        in the cached record, so this snippet is cited for the framework rather
        than for the group membership stated in the notes above.
references:
- reference: PMID:10486316
  title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
- reference: PMID:10889003
  title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
- reference: PMID:17236192
  title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
- reference: PMID:23621912
  title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
- reference: PMID:25073711
  title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
- reference: PMID:26367406
  title: "[Marshall syndrome: Clinical, radiological and genetical features of a Tunisian family]."
- reference: PMID:38062645
  title: "Growing up with Marshall syndrome: A case report from infancy to age 12.5 years."
- reference: PMID:9235398
  title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
- reference: PMID:9188673
  title: "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene."
- reference: PMID:11556853
  title: Auditory dysfunction in Stickler syndrome.
- reference: PMID:7859283
  title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
- reference: PMID:36278545
  title: "The Shape of the Jaw-Zebrafish Col11a1a Regulates Meckel's Cartilage Morphogenesis and Mineralization."
- reference: PMID:21466760
  title: "The clinical effectiveness and safety of prophylactic retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults and children with Stickler syndrome: a systematic review."
- reference: PMID:20301479
  title: "Stickler Syndrome."
  tags:
  - GeneReviews
- reference: PMID:31633310
  title: "Nosology and classification of genetic skeletal disorders: 2019 revision."
- reference: PMID:41856555
  title: "Diagnostic genetic testing indications and findings in type II, IX and XI collagenopathies."
- reference: PMID:33570243
  title: Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene.
external_assertions:
- name: OMIM Marshall syndrome record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:154780
  url: https://omim.org/entry/154780
  description: >-
    The OMIM phenotype entry for Marshall syndrome, and the identifier the
    genotype-phenotype literature keys on. It is also the xref MONDO:0007949
    carries, so it is the join between this entry and OMIM-keyed tooling.
- name: OMIM COL11A1 gene record
  source: OMIM
  assertion_type: gene_record
  external_id: OMIM:120280
  url: https://omim.org/entry/120280
  description: >-
    The OMIM gene entry for COL11A1. Worth recording separately from the
    phenotype entry because the same gene entry is the locus for Stickler
    syndrome type 2 and for fibrochondrogenesis, which is the allelic
    relationship this entry's differentials describe.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The usual mode. A single heterozygous COL11A1 allele is sufficient because
    the mechanism is dominant negative: the shortened chain is made, is stable,
    and interferes with the heterotrimer that the normal allele also
    contributes to.
  evidence:
  - reference: PMID:10486316
    reference_title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit.
    explanation: >-
      States the dominant mode of inheritance alongside the cardinal triad.
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with autosomal dominant Stickler syndrome has a 50% chance of inheriting the pathogenic variant.
    explanation: >-
      The transmission risk that genetic counselling rests on. Indirect because
      GeneReviews covers COL11A1 inside its Stickler syndrome chapter rather
      than under the Marshall eponym; the 50 per cent figure follows from
      autosomal dominant transmission either way.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A recessive form has been reported twice, both times from Saudi Arabia and
    both times with the same missense allele c.2702G>A (p.Gly901Glu) in
    homozygous form. It is recorded here because it is reproducible rather than
    anecdotal, but it is the exception; do not treat a negative parental
    examination as excluding the diagnosis in a consanguineous family.
  evidence:
  - reference: PMID:25073711
    reference_title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we describe the clinical presentations of seven patients with Marshall syndrome from three unrelated Saudi families, inherited as autosomal dominant (two families) and autosomal recessive (one family).
    explanation: >-
      Reports both modes segregating in one clinical series, with the recessive
      form in one of the three families.
  - reference: PMID:25073711
    reference_title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, the first report of autosomal recessive Marshall syndrome was from Saudi Arabia caused by the same mutation (c.2702G > A, p.Gly901Glu) as in one of our families.
    explanation: >-
      Establishes that the recessive form has been seen twice with the same
      allele, which is why it is recorded as a mode rather than as a single
      unreplicated observation.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    The only figure in the literature, and it is a statement in a single case
    report rather than a population study. Treat it as an order-of-magnitude
    claim about rarity, not a measured rate. Case ascertainment is further
    confounded by the Marshall/Stickler boundary - a patient counted as
    Stickler type 2 in one centre may be counted as Marshall in another.
  evidence:
  - reference: PMID:38062645
    reference_title: "Growing up with Marshall syndrome: A case report from infancy to age 12.5 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marshall syndrome is an extremely rare genetic disorder usually diagnosed in infancy with a prevalence of <1 in 1 million.
    explanation: >-
      The prevalence statement itself, together with the infancy onset.
pathophysiology:
- name: Heterozygous COL11A1 54-bp Exon Splice-Site Variant
  biological_scale: MOLECULAR
  description: >-
    A splice-site change affecting one of the 54-bp exons in the C-terminal
    region of COL11A1. Intron 50 (c.3816+1G>A) is a recurrent hot spot. Other
    COL11A1 lesion classes exist - missense glycine substitutions and large
    intragenic deletions - but they correlate with the overlapping
    Marshall/Stickler end of the spectrum rather than with the Marshall
    phenotype proper.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: DOMINANT_NEGATIVE
  genes:
  - preferred_term: COL11A1
    term:
      id: hgnc:2186
      label: COL11A1
  downstream:
  - target: In-Frame Exon Skipping and a Shortened proalpha1(XI) Chain
    causal_link_type: DIRECT
    description: >-
      Loss of the splice donor causes the adjacent exon to be skipped.
    evidence:
    - reference: PMID:23621912
      reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame.
      explanation: >-
        The authors' statement of the established splice-to-skip step. Graded
        OTHER because it is a background assertion in the paper's framing
        rather than a result the paper reports.
  evidence:
  - reference: PMID:10486316
    reference_title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene.
    explanation: >-
      The genotype-phenotype correlation that defines the Marshall-associated
      variant class.
  - reference: PMID:17236192
    reference_title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50.
    explanation: >-
      Independent replication of the correlation in a second cohort, and the
      source of the intron-50 hot spot.
- name: In-Frame Exon Skipping and a Shortened proalpha1(XI) Chain
  biological_scale: MOLECULAR
  description: >-
    Because fibrillar collagen exons are sized in multiples of the 9-residue
    Gly-Xaa-Yaa unit, skipping one keeps the reading frame and the triple-helix
    register intact. The cell therefore produces a stable, shortened chain
    rather than degrading a truncated one - which is precisely why the allele is
    harmful rather than merely null.
  downstream:
  - target: Dominant-Negative Poisoning of the Collagen XI Heterotrimer
    causal_link_type: DIRECT
    description: >-
      The shortened chain remains competent to enter the heterotrimer.
  evidence:
  - reference: PMID:23621912
    reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Because skipping of these exons leaves the message in-frame and the Gly-Xaa-Yaa repeating collagen motif in register, this results in mutant collagen α chains capable of co-assembly with α chains synthesized from the normal genes, resulting in a dominant negative effect
    explanation: >-
      States the in-frame/in-register argument and the co-assembly step it
      licenses.
- name: Dominant-Negative Poisoning of the Collagen XI Heterotrimer
  biological_scale: MOLECULAR
  description: >-
    The shortened proalpha1(XI) chain co-assembles with normal chains, so a
    heterozygote's collagen XI pool is contaminated rather than halved. This is
    the step that makes the disease dominant and that separates it from a
    haploinsufficiency model.
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent conferring tensile strength
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0030020
      label: extracellular matrix structural constituent conferring tensile strength
  downstream:
  - target: Defective Heterotypic Collagen II/XI Fibril Assembly
    causal_link_type: DIRECT
    description: >-
      Collagen XI nucleates and limits the diameter of the collagen II fibril,
      so a poisoned heterotrimer is felt as a fibril-architecture defect.
  evidence:
  - reference: PMID:23621912
    reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products.
    explanation: >-
      The dominant-negative claim stated directly.
  - reference: PMID:25073711
    reference_title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye.
    explanation: >-
      Establishes where collagen XI acts, which is what makes the branch into
      cartilage and vitreous the expected one.
- name: Defective Heterotypic Collagen II/XI Fibril Assembly
  biological_scale: TISSUE
  description: >-
    The shared upstream lesion for every organ branch below. Collagen XI is a
    minor component by mass but a controlling one by function: it templates
    fibril nucleation and diameter in the collagen II matrices of cartilage,
    vitreous and the membranous labyrinth.
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  downstream:
  - target: Growth Plate Chondrocyte Disorganization
    causal_link_type: DIRECT
  - target: Vitreoretinal Collagen Matrix Defect
    causal_link_type: DIRECT
  - target: Membranous Labyrinth Collagen Defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recorded as indirect because the cochlear step is inferred from the
      clinical and imaging phenotype rather than from a demonstrated
      labyrinthine matrix abnormality.
  evidence:
  - reference: PMID:7859283
    reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The data demonstrate that collagen XI is essential for normal formation of cartilage collagen fibrils and the cohesive properties of cartilage.
    explanation: >-
      The fibril-assembly requirement, demonstrated by a naturally occurring
      Col11a1 null mouse.
- name: Growth Plate Chondrocyte Disorganization
  biological_scale: TISSUE
  description: >-
    Loss of the fibril template disturbs the columnar organisation and
    differentiation of growth-plate chondrocytes. This is the branch behind the
    craniofacial and skeletal features, and it is the branch with the strongest
    animal-model support.
  cell_types:
  - preferred_term: growth plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: cartilage development
    modifier: DECREASED
    term:
      id: GO:0051216
      label: cartilage development
  downstream:
  - target: Midface retrusion
    causal_link_type: DIRECT
  - target: Short stature
    causal_link_type: DIRECT
  - target: Premature osteoarthritis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:7859283
    reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The results also suggest that the normal differentiation and spatial organization of growth plate chondrocytes is critially dependent on the presence of type XI collagen in cartilage extracellular matrix.
    explanation: >-
      Names growth-plate chondrocyte organisation as the collagen XI-dependent
      process. Quoted verbatim including the source's typographical error in
      "critially", since a snippet reproduces its source rather than correcting
      it.
  - reference: PMID:36278545
    reference_title: "The Shape of the Jaw-Zebrafish Col11a1a Regulates Meckel's Cartilage Morphogenesis and Mineralization."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results demonstrate that zebrafish col11a1a knockdown impairs the cellular organization of Meckel's cartilage in the developing jaw and alters the bone formation that occurs adjacent to the Meckel's cartilage.
    explanation: >-
      Extends the cartilage-organisation defect specifically to the craniofacial
      cartilage that prefigures the midface phenotype.
- name: Vitreoretinal Collagen Matrix Defect
  biological_scale: TISSUE
  description: >-
    The vitreous is a collagen II/XI gel, so the same fibril defect presents as
    an abnormal vitreous with progressive vitreoretinal degeneration. The
    clinical consequence that matters is a lifelong risk of retinal detachment;
    the myopia and the lens changes travel with it.
  downstream:
  - target: High myopia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Retinal detachment
    causal_link_type: DIRECT
  - target: Cataract
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:25073711
    reference_title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye.
    explanation: >-
      Places collagen XI in the vitreous, which is what makes the ocular branch
      a consequence of the same lesion rather than a separate association.
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We are reporting on a female patient with typical ocular and systemic manifestations of both syndromes: high myopia, glaucoma and goniodysgenesis, submucosal cleft palate, sensorineural hearing loss, and "flat" mid-face.
    explanation: >-
      Documents the ocular spectrum, including the anterior-segment features
      that are less often listed.
- name: Membranous Labyrinth Collagen Defect
  biological_scale: TISSUE
  description: >-
    The hearing loss is cochlear, and imaging shows the bony labyrinth is
    normally formed - so the lesion is in the membranous labyrinth rather than
    in osseous morphogenesis. This node records that inference, which is what
    the audiovestibular study concluded rather than what it directly observed;
    no labyrinthine matrix has been examined histologically in a Marshall
    patient.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  downstream:
  - target: Progressive sensorineural hearing impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system.
    explanation: >-
      The authors' localisation of the lesion, which this node restates.
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Computed tomography detected no malformations of temporal bone structures.
    explanation: >-
      The negative imaging finding the localisation rests on. Indirect because
      a normal bony labyrinth excludes one explanation rather than
      demonstrating a membranous one.
phenotypes:
- name: Midface retrusion
  category: Craniofacial
  diagnostic: true
  description: >-
    Midfacial hypoplasia with a flat, retracted midface. With the depressed
    nasal bridge it forms the facial gestalt that, together with early severe
    deafness, is what makes a clinician call a COL11A1 patient "Marshall"
    rather than "Stickler type 2".
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:10486316
    reference_title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit.
    explanation: >-
      Names midfacial hypoplasia as a cardinal feature.
  - reference: PMID:17236192
    reference_title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features.
    explanation: >-
      Records that the facial features are one of the two criteria used in
      practice to assign the Marshall label.
- name: Depressed nasal bridge
  category: Craniofacial
  description: >-
    The flat or saddle nasal bridge, with a short nose, anteverted nostrils and
    a long philtrum. It is present from birth and does not progress.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:10486316
    reference_title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has been suggested that Marshall syndrome differs from Stickler syndrome in that patients with Marshall syndrome more often have short stature, deafness, and abnormalities in cranial ossification and more-pronounced dysmorphic features, including a retracted midface with flat nasal bridge, short nose, anteverted nostrils, and a long philtrum.
    explanation: >-
      Describes the facial phenotype and states it as a proposed discriminator
      from Stickler syndrome.
- name: High myopia
  category: Ophthalmologic
  diagnostic: true
  description: >-
    High myopia is one of the cardinal triad and is typically established in
    childhood. It travels with the vitreous abnormality rather than being an
    independent refractive finding.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25073711
    reference_title: "Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic features of Marshall syndrome include midfacial hypoplasia, high myopia, and sensorineural-hearing deficit.
    explanation: >-
      States high myopia as one of the three characteristic features.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Congenital or juvenile cataract. It is surgically treatable and is one of
    the few features of the disorder with a clean intervention.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1.
    explanation: >-
      Lists cataract among the defining features.
- name: Retinal detachment
  category: Ophthalmologic
  description: >-
    The complication that drives ophthalmic management. Risk is lifelong and
    begins in childhood, which is why surveillance rather than reactive
    treatment is the standard approach across the collagenopathy spectrum.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:21466760
    reference_title: "The clinical effectiveness and safety of prophylactic retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults and children with Stickler syndrome: a systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is the most commonly identified inherited cause of retinal detachment in childhood.
    explanation: >-
      Establishes the magnitude of the childhood retinal-detachment risk in this
      collagenopathy spectrum. Indirect because the systematic review is framed
      around Stickler syndrome; Marshall syndrome is the allelic COL11A1
      neighbour rather than the population studied.
- name: Progressive sensorineural hearing impairment
  category: Otologic
  diagnostic: true
  description: >-
    Early-onset, severe, progressive and predominantly cochlear. Its severity
    and early onset are the single most useful clinical discriminator from
    Stickler type 1, where the hearing loss is mild and largely
    non-progressive.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing loss that is both conductive and sensorineural
    explanation: >-
      GeneReviews names sensorineural hearing loss as a defining clinical
      characteristic of the disorder group this entry belongs to. Note the
      chapter reports the hearing loss as both conductive and sensorineural,
      while this phenotype node is the sensorineural component specifically;
      the conductive element is secondary to the cleft palate and otitis
      media rather than to the labyrinthine collagen defect modeled here.
      Indirect: written for Stickler syndrome rather than the Marshall eponym.
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems.
    explanation: >-
      Characterises the hearing loss as progressive and cochlear, and notes the
      subclinical vestibular involvement that accompanies it.
  - reference: PMID:11556853
    reference_title: Auditory dysfunction in Stickler syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome.
    explanation: >-
      Supports the severity claim by contrast. Indirect because the cohort
      studied was Stickler syndrome and the statement about Marshall syndrome is
      a comparison the authors draw rather than a measurement they made.
- name: Cleft palate
  category: Craniofacial
  description: >-
    Cleft or submucosal cleft palate, part of the shared Stickler/Marshall
    craniofacial phenotype.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both children of the patient manifestations of the syndrome were present (high myopia, cleft palate, sensorineural hearing loss).
    explanation: >-
      Documents cleft palate in affected family members.
- name: Short stature
  category: Growth
  description: >-
    Reported more often in Marshall syndrome than in Stickler syndrome, and one
    of the features originally used to argue that they are separate entities.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:10486316
    reference_title: Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has been suggested that Marshall syndrome differs from Stickler syndrome in that patients with Marshall syndrome more often have short stature, deafness, and abnormalities in cranial ossification and more-pronounced dysmorphic features
    explanation: >-
      Names short stature as one of the features proposed to distinguish the two
      syndromes.
- name: Premature osteoarthritis
  category: Musculoskeletal
  description: >-
    Early-onset degenerative arthropathy, the long-term cost of a defective
    cartilage collagen matrix. It is the feature most likely to require surgery
    in adult life.
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:9188673
    reference_title: "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood.
    explanation: >-
      Documents the early severe arthropathy of collagen XI disease and its
      surgical consequence. Indirect because the patients studied carried
      COL11A2 variants (OSMED); the same paper argues on phenotypic grounds that
      Marshall syndrome is the COL11A1 counterpart.
- name: Glaucoma
  category: Ophthalmologic
  description: >-
    Reported with goniodysgenesis, so anterior-segment involvement belongs in
    the ophthalmic assessment alongside the vitreoretinal work.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We are reporting on a female patient with typical ocular and systemic manifestations of both syndromes: high myopia, glaucoma and goniodysgenesis, submucosal cleft palate, sensorineural hearing loss, and "flat" mid-face.
    explanation: >-
      Documents glaucoma with goniodysgenesis in a patient with the syndrome.
- name: Ectopia lentis
  category: Ophthalmologic
  description: >-
    Lens subluxation, reported rarely and in one case with a lens coloboma. It
    matters chiefly because it puts this disorder on the differential for
    inherited ectopia lentis, where it is not usually considered.
  phenotype_term:
    preferred_term: Ectopia lentis
    term:
      id: HP:0001083
      label: Ectopia lentis
  evidence:
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coloboma and subluxation of the lens have to be regarded as possible manifestations of the Stickler (Marshall) syndrome. The syndrome(s) should be included in the differential diagnosis of ectopia lentis-associated systemic diseases.
    explanation: >-
      The authors' conclusion that lens subluxation belongs in the phenotype and
      that the syndrome belongs on the ectopia lentis differential.
genetic:
- name: COL11A1
  association: Causal heterozygous variant
  gene_term:
    preferred_term: COL11A1
    term:
      id: hgnc:2186
      label: COL11A1
  frequency: The only gene associated with Marshall syndrome.
  notes: >-
    Two practical points about testing. First, the gene is around 250 kb with 68
    exons, and large intragenic deletions are a real and previously
    underestimated share of COL11A1 disease; exon sequencing alone will miss
    them, so a dosage assay belongs in the workup. Second, the variant class
    carries prognostic weight: a 54-bp C-terminal splice variant, and the intron
    50 hot spot in particular, predicts the Marshall end of the spectrum with
    its early severe deafness, while other lesion classes predict the
    overlapping Marshall/Stickler picture. That correlation is a tendency drawn
    from two modest cohorts, not a rule to counsel from.
  evidence:
  - reference: PMID:17236192
    reference_title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals.
    explanation: >-
      Gives both the causal gene and the yield in a clinically selected,
      COL2A1-negative series - 10 of 44.
  - reference: PMID:17236192
    reference_title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remaining 6/10 patients had an overlapping Marshall-Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50.
    explanation: >-
      The other half of the genotype-phenotype correlation: the overlapping
      phenotypes lacked the hot-spot variant.
  - reference: PMID:23621912
    reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.
    explanation: >-
      The basis for including a deletion assay in testing rather than relying on
      exon sequencing.
environmental:
- name: Ocular or head trauma, including contact sports
  description: >-
    Trauma does not cause Marshall syndrome - the disorder is monogenic - but it
    is what converts an already abnormal vitreoretinal interface into a
    detachment. This is the entry's one activity restriction, and it is the kind
    of advice that is easy to omit from a genetics consultation and materially
    changes outcome in a disorder whose defining ocular risk is retinal
    detachment.
  effect: Precipitates retinal tear and detachment in an eye already at risk
  influences_mechanisms:
  - target: Retinal detachment
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Impact transmitted to an abnormal vitreous gel produces the tractional
      tear, and the detachment follows. The exposure is attached to the
      detachment rather than to the collagen matrix defect upstream of it,
      because the matrix defect is what the COL11A1 allele made it and trauma
      cannot worsen it. Against the detachment the exposure genuinely initiates
      the event, so the predicate is TRIGGERS.
    evidence:
    - reference: PMID:20301479
      reference_title: "Stickler Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Activities such as contact sports that may lead to traumatic retinal detachment.
      explanation: >-
        GeneReviews names contact sports as the activity that may lead to
        traumatic retinal detachment, which is the exposure-to-mechanism link
        asserted here. Indirect: the chapter covers COL11A1 within Stickler
        syndrome rather than under the Marshall eponym.
  evidence:
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Activities such as contact sports that may lead to traumatic retinal detachment.
    explanation: >-
      The recommendation stated as an avoidance, which is how it reaches a
      patient. Indirect for the same reason as the link evidence above.
  notes: >-
    Left without an `exposure_term`. ECTO was searched for trauma, injury,
    mechanical and physical exposure terms and for sport; it has
    `ECTO:6000002` exposure to exercise and `ECTO:6000031` exposure to
    strenuous exercise, neither of which means blunt ocular or head trauma.
    No term beats a wrong one, so none is bound. Recorded so the next curator
    does not repeat the search; Stickler_Syndrome_Type_2 records the same
    result for the same exposure.
treatments:
- name: Retinal surveillance and prophylactic retinal intervention
  description: >-
    Regular dilated retinal examination from childhood, with prophylactic laser
    or cryotherapy to reduce detachment risk in selected eyes. This is the
    intervention with the most to gain and the least settled evidence: the
    systematic review that covers it found no consensus and no guidelines, so
    the practice is reasonable extrapolation rather than demonstrated benefit.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: prophylactic retinal laser therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  target_phenotypes:
  - preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:21466760
    reference_title: "The clinical effectiveness and safety of prophylactic retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults and children with Stickler syndrome: a systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, there is no consensus regarding best practice and no current guidelines on prophylactic interventions for this population.
    explanation: >-
      Records the state of the evidence honestly: the intervention is offered,
      and it is not standardised. Indirect because the review addresses Stickler
      syndrome, from which practice in Marshall syndrome is extrapolated.
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      laser therapy for prevention of retinal detachment; education on risks and symptoms of retinal detachment
    explanation: >-
      The authoritative management recommendation, which the systematic review
      above says is not standardised - the two are cited together because the
      disagreement is the point. Indirect: GeneReviews covers COL11A1 within its
      Stickler syndrome chapter.
- name: Hearing amplification and cochlear implantation
  description: >-
    Amplification early, to protect language acquisition, and cochlear
    implantation as the loss progresses. The cochlear localisation of the
    deficit is what makes implantation a rational option rather than a hopeful
    one.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_phenotypes:
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin
    explanation: >-
      Establishes the cochlear site of the lesion, which is the premise for
      amplification and implantation. Indirect because the study characterises
      the deficit rather than reporting an intervention outcome.
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment of sensorineural and conductive hearing loss
    explanation: >-
      The management recommendation itself, rather than an inference from where
      the lesion sits. Indirect: the GeneReviews chapter is written for Stickler
      syndrome and includes COL11A1.
- name: Joint replacement for degenerative arthropathy
  description: >-
    Arthroplasty for the early-onset osteoarthritis, which in the related
    COL11A2 disorder has been needed as early as young adulthood.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: joint arthroplasty
    term:
      id: NCIT:C51691
      label: Arthroplasty
  target_phenotypes:
  - preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  evidence:
  - reference: PMID:9188673
    reference_title: "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood.
    explanation: >-
      The basis for anticipating arthroplasty. Indirect: the observation is from
      COL11A2 OSMED patients, and is applied here on the argument of collagen XI
      mechanism shared between the two genes.
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      symptomatic treatment for arthropathy; treatment of osteoarticular manifestations per orthopedist
    explanation: >-
      The orthopaedic management recommendation. Indirect: GeneReviews covers
      COL11A1 within its Stickler syndrome chapter.
- name: Cataract surgery
  description: >-
    Surgical extraction for the congenital or juvenile cataract. It is the one
    intervention in this entry that restores function rather than preventing
    deterioration, which is why the cataract phenotype is described as having a
    clean intervention. Timing has to be coordinated with the vitreoretinal
    surveillance, since the same eye carries a lifelong detachment risk.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cataract Surgery
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  target_phenotypes:
  - preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment
    explanation: >-
      Establishes cataract as a managed ocular manifestation of the
      collagenopathy that GeneReviews covers, which is the indication for
      extraction. Indirect: GeneReviews addresses the Stickler chapter including
      COL11A1, and states the manifestation rather than evaluating surgery.
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1.
    explanation: >-
      Confirms cataract as a feature of Marshall syndrome specifically, which is
      what makes the borrowed management recommendation applicable. Indirect: a
      phenotype description, not a surgical outcome.
- name: Genetic counselling
  description: >-
    Fifty per cent recurrence risk for the offspring of an affected parent in
    the usual dominant form, and 25 per cent in the reported recessive families
    once the biallelic variant is known. Counselling also has to cover the
    variable expressivity, which is wide enough within one family that a mildly
    affected parent is not a guide to how a child will be affected.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26367406
    reference_title: "[Marshall syndrome: Clinical, radiological and genetical features of a Tunisian family]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a variability of the clinical expression among the affected members of the study's family.
    explanation: >-
      Documents the within-family variability that counselling has to convey.
diagnosis:
- name: COL11A1 sequencing with a deletion/duplication assay
  description: >-
    Sequence COL11A1, and pair it with a dosage assay. In practice this is done
    within a type II/IX/XI collagenopathy panel, since the clinical picture does
    not reliably separate COL11A1 from COL2A1 or COL11A2 before testing.
  results: >-
    A heterozygous COL11A1 splice-site variant, most often at a 54-bp C-terminal
    exon; alternatively a glycine missense variant or a multi-exon deletion.
  evidence:
  - reference: PMID:23621912
    reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone.
    explanation: >-
      Demonstrates the deletions that sequencing alone misses, which is why the
      dosage assay is part of the recommended workup rather than a reflex test.
  - reference: PMID:20301479
    reference_title: "Stickler Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Stickler syndrome can be established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 identified by molecular genetic testing.
    explanation: >-
      The authoritative statement that molecular testing establishes the
      diagnosis, and that COL11A1 is one of the genes on which it is
      established. This is what the entry's testing recommendation rests on.
      Indirect: the chapter is written for Stickler syndrome, within which
      COL11A1 disease sits, rather than under the Marshall eponym.
  - reference: PMID:41856555
    reference_title: "Diagnostic genetic testing indications and findings in type II, IX and XI collagenopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnostic yield of Stickler syndrome panels was 50%, with a higher rate among cases reporting a family history (OR: 2.6 (95% CI 1.3 to 5.4); p=0.005) or presenting with ocular signs (OR: 2.2 (95% CI 1.1 to 4.5), p=0.03).
    explanation: >-
      Sets the expectation for a negative result: half of clinically suspected
      cases have no pathogenic variant on a six-gene collagenopathy panel, so a
      negative panel does not exclude the clinical diagnosis. Indirect: a
      laboratory case series across the whole type II/IX/XI collagenopathy
      spectrum rather than a Marshall syndrome cohort.
- name: Audiometry with temporal bone imaging
  description: >-
    Pure-tone audiometry to document the degree and progression of the
    sensorineural loss, with temporal bone CT. The expected imaging result is a
    normal osseous labyrinth; that normality is informative, because it places
    the lesion in the membranous labyrinth and argues against a malformation
    syndrome.
  results: >-
    Progressive, predominantly cochlear sensorineural hearing loss with normally
    formed temporal bone structures.
  evidence:
  - reference: PMID:10889003
    reference_title: Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems.
    explanation: >-
      The assessment battery this recommendation is drawn from.
- name: Skeletal radiography
  description: >-
    Plain radiographs for the characteristic skeletal signs. Worth doing in a
    patient whose ocular and auditory features already suggest a
    collagenopathy, because the skeletal findings are part of what separates
    the Marshall end of the spectrum from a purely ocular Stickler phenotype.
  results: >-
    Radiological signs described as characteristic of Marshall syndrome,
    alongside the abnormalities of cranial ossification reported in the older
    literature.
  evidence:
  - reference: PMID:26367406
    reference_title: "[Marshall syndrome: Clinical, radiological and genetical features of a Tunisian family]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marshall syndrome's specific radiological signs were found.
    explanation: >-
      Records that the radiographic signs were identified in this family and
      described as specific to the syndrome. The paper does not enumerate them
      in the abstract, so the entry names the test rather than a finding list.
- name: Ophthalmologic assessment
  description: >-
    Refraction, slit-lamp examination for cataract and lens position, gonioscopy
    and tonometry, and dilated fundoscopy for vitreoretinal degeneration. The
    anterior-segment elements are easy to omit and have both been reported.
  results: >-
    High myopia, congenital or juvenile cataract, vitreoretinal degeneration,
    and in some patients goniodysgenesis with glaucoma or lens subluxation.
  evidence:
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, we observed subluxation of the ocular lens in one eye which was previously described in only a few cases.
    explanation: >-
      The rare anterior-segment finding that justifies examining lens position
      rather than stopping at refraction and fundoscopy.
differential_diagnoses:
- name: Stickler syndrome type 2
  description: >-
    The allelic neighbour, and the one that matters. Both are COL11A1. The
    working discriminators are the variant class (54-bp C-terminal splice
    variants track Marshall) and the audiological phenotype (earlier and more
    severe in Marshall), together with the facial gestalt. Neither is
    absolute, and patients with both phenotypes are reported.
  disease_term:
    preferred_term: Stickler syndrome type 2
    term:
      id: MONDO:0011493
      label: Stickler syndrome type 2
  distinguishing_features:
  - Splice variants of the 54-bp C-terminal COL11A1 exons, the intron 50 hot spot in particular
  - Earlier-onset and more severe sensorineural hearing loss
  - More pronounced midfacial hypoplasia and a more distinctive facial gestalt
  - Short stature reported more often
  evidence:
  - reference: PMID:17236192
    reference_title: A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50.
    explanation: >-
      Shows the clinical criteria actually used to split the two, and the
      genotype that accompanied the split in this cohort.
  - reference: PMID:9235398
    reference_title: "[Lens coloboma and lens dislocation in Stickler (Marshall) syndrome]."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probably, both syndromes represent the same entity with occasional partially different clinical manifestations.
    explanation: >-
      Recorded as a refutation of the separate-entity claim, not as a hedge.
      These authors, reporting a patient with features of both, take the view
      that Marshall and Stickler are one disorder. Curating the split without
      this dissent would overstate how settled the question is.
- name: Stickler syndrome type 1
  description: >-
    The COL2A1 form, and the most common. Distinguished by its hearing loss more
    than by anything else: mild, high-frequency, and no more progressive than
    presbycusis, against the early severe loss of Marshall syndrome. Retinal
    detachment risk is at least as high, so the distinction does not change
    ophthalmic surveillance.
  disease_term:
    preferred_term: Stickler syndrome type 1
    term:
      id: MONDO:0007160
      label: Stickler syndrome type 1
  distinguishing_features:
  - COL2A1 rather than COL11A1
  - Mild, non-progressive high-frequency sensorineural hearing loss
  - Hypermobile middle ear systems reported as a diagnostic feature
  evidence:
  - reference: PMID:11556853
    reference_title: Auditory dysfunction in Stickler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome.
    explanation: >-
      The audiological contrast, drawn from 46 affected individuals in 29
      families, that makes hearing the most useful discriminator.
- name: Otospondylomegaepiphyseal dysplasia
  description: >-
    The COL11A2 disorder. It shares midface hypoplasia, deafness and epiphyseal
    dysplasia, and its recessive form is severe. The clean separator is ocular:
    COL11A2 is not expressed in vitreous, so OSMED has no myopia and no
    vitreoretinopathy, while the ocular features are central to Marshall
    syndrome.
  disease_term:
    preferred_term: otospondylomegaepiphyseal dysplasia, autosomal recessive
    term:
      id: MONDO:0044206
      label: otospondylomegaepiphyseal dysplasia, autosomal recessive
  distinguishing_features:
  - COL11A2 rather than COL11A1
  - No high myopia and no vitreoretinal degeneration
  - Megaepiphyses with severe epiphyseal dysplasia
  evidence:
  - reference: PMID:9188673
    reference_title: "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a syndrome of midface hypoplasia, non-progressive sensorineural deafness and epiphyseal dysplasia in 3 sibs born to consanguineous parents.
    explanation: >-
      Describes the overlapping OSMED phenotype in the three siblings this
      differential is drawn from.
  - reference: PMID:9188673
    reference_title: "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, Marshall syndrome is very similar to OSMED. Considering these phenotypic similarities and the close association between the COL11A1 and COL11A2 gene products, we propose that Marshall syndrome may be caused by a mutation in COL11A1.
    explanation: >-
      The phenotypic similarity is strong enough that it was the argument by
      which COL11A1 was first predicted as the Marshall gene - which is also why
      OSMED is the differential most likely to be confused with it.
- name: Fibrochondrogenesis
  description: >-
    The severe recessive end of the same gene, and the most informative contrast
    in this entry. Biallelic COL11A1 variants produce a neonatally severe
    skeletal dysplasia, while the heterozygous dominant-negative alleles produce
    Marshall syndrome. The comparison is what shows that the disorder curated
    here is not simply "less collagen XI": losing both alleles gives a different
    and far worse disease than contaminating the heterotrimer does.
  disease_term:
    preferred_term: fibrochondrogenesis
    term:
      id: MONDO:0016068
      label: fibrochondrogenesis
  distinguishing_features:
  - Biallelic COL11A1 rather than a single dominant-negative allele
  - Neonatally severe skeletal dysplasia rather than a survivable multisystem disorder
  - Not a differential in practice; a mechanistic contrast
  evidence:
  - reference: PMID:23621912
    reference_title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis.
    explanation: >-
      States the three-way allelic relationship at COL11A1 that makes
      fibrochondrogenesis the recessive counterpart of this disorder.
- name: Autosomal recessive Stickler syndrome
  description: >-
    The type IX collagen forms, caused by biallelic COL9A1, COL9A2 or COL9A3
    variants. Included because the inheritance pattern is the discriminator a
    clinician is most likely to get wrong: a consanguineous family with an
    apparently Stickler-like phenotype is more likely to be type IX collagen
    than to be the rare recessive Marshall families reported from Saudi Arabia.
  disease_term:
    preferred_term: Stickler syndrome, type 6
    term:
      id: MONDO:0031047
      label: Stickler syndrome, type 6
  distinguishing_features:
  - Biallelic COL9A1, COL9A2 or COL9A3 rather than COL11A1
  - Autosomal recessive with unaffected heterozygous parents
  - Very rare, with fewer than twenty reported patients at the time of the cited report
  evidence:
  - reference: PMID:33570243
    reference_title: Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3.
    explanation: >-
      Names the three recessive genes and the size of the reported experience,
      which is what makes this a real but uncommon differential.
  - reference: PMID:33570243
    reference_title: Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare.
    explanation: >-
      Sets the base rate that makes inheritance pattern the useful
      discriminator here.
animal_models:
- name: cho/cho chondrodysplasia mouse
  species: Mouse
  genotype: Col11a1 cho allele, homozygous (single-cytidine deletion causing a frameshift and premature stop)
  publication: PMID:7859283
  description: >-
    A spontaneous Col11a1 null that mapped the gene and established what
    collagen XI does. It is the source of the cartilage mechanism in this entry
    and it is not a model of the human disease: it is recessive and null where
    the human disorder is dominant and dominant-negative, and it dies at birth.
  modeled_mechanisms:
  - target: Defective Heterotypic Collagen II/XI Fibril Assembly
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Cartilage collagen fibrils fail to form normally in the absence of
      collagen XI, which is the assertion this node makes.
    limitations: >-
      Complete loss of function, in the homozygote, of a gene that in humans
      causes disease in the heterozygous dominant-negative state. The null
      removes collagen XI; the human allele contaminates it. The two are not the
      same lesion and the mouse cannot show that a shortened chain is worse than
      no chain.
    evidence:
    - reference: PMID:7859283
      reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The data demonstrate that collagen XI is essential for normal formation of cartilage collagen fibrils and the cohesive properties of cartilage.
      explanation: >-
        The fibril-assembly conclusion the model supports.
  - target: Growth Plate Chondrocyte Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Growth-plate chondrocyte differentiation and spatial organisation depend
      on collagen XI in the matrix.
    limitations: >-
      Neonatally lethal, so it reports on skeletal morphogenesis only and can say
      nothing about the progressive postnatal features - the myopia, the
      vitreoretinal degeneration, the progressive deafness, the adult
      osteoarthritis - that make up most of the human disease burden.
    readouts:
    - name: Long bone length and metaphyseal width
      target: Growth Plate Chondrocyte Disorganization
      direction: DECREASED
      interpretation: >-
        Shortened, metaphyseally widened limb bones as the structural readout of
        disorganised growth-plate cartilage.
      evidence:
      - reference: PMID:7859283
        reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Limb bones of newborn cho/cho mice are wider at the metaphyses than normal bones and only about half the normal length.
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:7859283
      reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The results also suggest that the normal differentiation and spatial organization of growth plate chondrocytes is critially dependent on the presence of type XI collagen in cartilage extracellular matrix.
      explanation: >-
        Links collagen XI loss to growth-plate chondrocyte organisation.
        Reproduces the source's spelling of "critially".
  evidence:
  - reference: PMID:7859283
    reference_title: "A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice that are homozygous for the autosomal recessive chondrodysplasia (cho) mutation die at birth with abnormalities in cartilage of limbs, ribs, mandible, and trachea.
    explanation: >-
      Describes the model and its neonatal lethality, which is the limit on what
      it can be used for.
- name: col11a1a morphant zebrafish
  species: Zebrafish
  genotype: col11a1a antisense morpholino knockdown
  publication: PMID:36278545
  description: >-
    A craniofacial knockdown model. Its value here is specificity: it shows the
    cartilage-organisation defect in Meckel's cartilage, the first pharyngeal
    arch cartilage that prefigures the lower jaw, which is the closest available
    experimental correlate of the human midface phenotype.
  modeled_mechanisms:
  - target: Growth Plate Chondrocyte Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Knockdown disorganises the chondrocytes of Meckel's cartilage and disturbs
      the adjacent bone formation.
    limitations: >-
      Morpholino knockdown rather than a genetic allele, so off-target and
      transient-knockdown caveats apply and no stable line is characterised.
      Zebrafish craniofacial cartilage is not a mammalian growth plate, and the
      human lesion is a dominant-negative chain rather than reduced gene
      product, so this supports the general requirement for col11a1a in
      cartilage organisation rather than the specific human mechanism.
    evidence:
    - reference: PMID:36278545
      reference_title: "The Shape of the Jaw-Zebrafish Col11a1a Regulates Meckel's Cartilage Morphogenesis and Mineralization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results demonstrate that zebrafish col11a1a knockdown impairs the cellular organization of Meckel's cartilage in the developing jaw and alters the bone formation that occurs adjacent to the Meckel's cartilage.
      explanation: >-
        The craniofacial cartilage result this link rests on.
discussions:
- discussion_id: gap_marshall_vs_stickler2_nosology
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are Marshall syndrome and Stickler syndrome type 2 two diseases or one, and
    does the 54-bp C-terminal splice correlation hold in a cohort large enough
    to counsel from?
  attaches_to:
  - disease#Marshall Syndrome
  - genetic#COL11A1
  - pathophysiology#Heterozygous COL11A1 54-bp Exon Splice-Site Variant
  rationale: >-
    dismech currently carries both as separate entries, and the evidence for
    that split is thinner than the separation implies. It rests on two cohorts:
    23 novel COL11A1 variants across a mixed Marshall/Stickler/Stickler-like
    screen, and a series in which 4 of 10 COL11A1-positive patients were
    labelled Marshall - and in that second series the label was assigned on
    clinical grounds first and the genotype correlation observed afterwards,
    which is a weaker design than it looks. Against the split: patients with
    features of both syndromes are reported in both cohorts and within a single
    Tunisian family, and at least one group states outright that the two are
    one entity. What would settle it is a COL11A1 cohort large enough to test
    whether the 54-bp C-terminal splice class separates from other classes on
    prospectively collected audiological and facial measures, rather than on
    labels assigned before genotyping.
- discussion_id: mismatch_marshall_dominant_negative_models
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Every available animal model of Col11a1 is a loss-of-function null, while
    human Marshall syndrome is a dominant-negative disorder. Does the null
    phenotype tell us anything about what a shortened, co-assembling chain does?
  attaches_to:
  - pathophysiology#Dominant-Negative Poisoning of the Collagen XI Heterotrimer
  - animal_models#cho/cho chondrodysplasia mouse
  - animal_models#col11a1a morphant zebrafish
  rationale: >-
    This is a mismatch rather than a gap: the model evidence exists and is good,
    but it is evidence about the wrong lesion. The cho/cho mouse and the
    col11a1a morphant both remove collagen XI. The human allele does something
    different and, on the face of it, worse - it supplies a defective chain that
    enters the heterotrimer and disrupts a fibril the normal allele is also
    trying to build. The entry's cartilage mechanism is therefore borrowed from
    a null phenotype, and the specifically dominant-negative step is supported
    only by the in-frame/in-register argument from collagen gene structure. The
    mouse is also neonatally lethal in the homozygote, so it cannot report on any
    of the progressive postnatal features. A knock-in carrying a 54-bp
    C-terminal splice variant on one allele would test the mechanism directly;
    none has been reported.
  proposed_experiments:
  - experiment_id: exp_marshall_het_splice_knockin_mouse
    name: Heterozygous 54-bp exon splice knock-in mouse
    description: >-
      Engineer the intron 50 donor-site change (or the equivalent murine 54-bp
      C-terminal exon) as a single heterozygous allele and phenotype the animals
      into adulthood, rather than using a null.
    would_support:
    - pathophysiology#Dominant-Negative Poisoning of the Collagen XI Heterotrimer
    supporting_outcome:
    - >-
      Heterozygotes show cartilage fibril disorganisation, vitreous abnormality
      and progressive cochlear hearing loss, with a phenotype more severe than
      Col11a1 heterozygous nulls examined in parallel.
    refuting_outcome:
    - >-
      Heterozygous knock-in animals are indistinguishable from heterozygous
      nulls, which would place the mechanism at reduced collagen XI dosage
      rather than at active interference by the shortened chain.
notes: >-
  Three things a curator or reader should carry away from this entry.

  The eponym is ambiguous and the ambiguity is dangerous for automated
  literature work. "Marshall syndrome" also names PFAPA - periodic fever,
  aphthous stomatitis, pharyngitis and adenitis, a common paediatric
  autoinflammatory disease - and acquired cutis laxa type II. A keyword search
  on the name returns all three, and the PFAPA literature is by far the largest
  of the three. Every reference in this entry was checked to be about the
  COL11A1 disorder.

  The Marshall/Stickler type 2 split is recorded, not asserted. See the
  knowledge-gap discussion. The entry deliberately includes a published
  statement that the two are a single entity, graded REFUTE against the
  separate-entity claim, rather than only citing the sources that support the
  split.

  Much of the evidence is marked directness INDIRECT because the study
  populations are neighbouring collagenopathies rather than Marshall syndrome
  itself - the retinal-detachment prophylaxis review and the auditory natural
  history study are Stickler cohorts, the arthropathy and joint-replacement
  observations come from COL11A2 OSMED patients, and the GeneReviews management
  and counselling recommendations come from the Stickler syndrome chapter, which
  covers COL11A1 but is not written under the Marshall eponym. There is no
  Marshall-specific GeneReviews chapter. That is the real evidence base for this
  ultra-rare disorder, and marking it is more useful than either omitting the
  claims or presenting borrowed evidence as direct.

  Two management points are worth not losing in the list. The activity
  restriction - avoiding contact sports - is modeled as an environmental
  exposure acting on the vitreoretinal node rather than buried in a treatment
  description, because it is advice that changes outcome and is easy to omit
  from a genetics consultation. And the reported diagnostic yield of a six-gene
  collagenopathy panel is about half, so a negative panel does not exclude the
  clinical diagnosis.

  OMIM identifiers are recorded in external_assertions, not in mappings.
  DiseaseMappings does carry only icd10cm, icd11f, mondo and ncit slots, and
  that is a real limit - but it is the wrong class to look in. external_assertions
  is the established convention for OMIM and ORPHA, with 89 disorder entries
  already using it, and issue #9922 withdrew a proposal to add omim_mappings on
  exactly that ground. Recorded here because this entry initially made the same
  mistake: absent from the class I checked is not absent from the schema.

📚

References & Deep Research

References

17

PMID:10486316

Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.