Weill-Marchesani syndrome

Mendelian MONDO:0018096 Pathograph 28 Show in embeddings browser syndromic disease connective tissue disease

Weill-Marchesani syndrome (WMS) is a rare heritable disorder of the fibrillin microfibril and one of the acromelic dysplasias, defined by short stature, brachydactyly and joint stiffness together with characteristic ocular abnormalities that can include microspherophakia, lenticular myopia, ectopia lentis and secondary glaucoma. WMS contrasts with Marfan syndrome in habitus: disruption of the same FBN1-microfibril system can instead produce a short, stiff, thick-skinned, muscular build with a small round lens. Four genes, all encoding secreted extracellular-matrix proteins that form or regulate fibrillin microfibrils, cause dominant or recessive forms of the disorder.

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Classifications

ISDS Skeletal Nosology

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Inheritance

Autosomal recessive inheritance HP:0000007

The recessive form, the more common of the two, is caused by biallelic variants in ADAMTS10 (WMS1), LTBP2 (WMS3) or ADAMTS17 (WMS4).

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"ADAMTS10-, ADAMTS17-, and LTPBP2-related WMS are inherited in an autosomal recessive manner."

GeneReviews assigns the three protease and binding-protein genes to autosomal recessive inheritance.

PMID:20301293 SUPPORT Human Clinical

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"

Gives the sibling recurrence risks used in counselling families with a recessive form.

Autosomal dominant inheritance HP:0000006

The dominant form (WMS2) is caused by heterozygous FBN1 variants, most clustering in the TB5 domain. Inheritance mode cannot be inferred from the clinical picture, only from the genotype.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:20301293 SUPPORT Human Clinical

"FBN1-related WMS is inherited in an autosomal dominant manner."

GeneReviews assigns FBN1-related WMS to autosomal dominant inheritance.

PMID:20301293 SUPPORT Human Clinical

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

Gives the transmission risk used in counselling families with the dominant form.

PMID:20301293 SUPPORT Human Clinical

"Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone."

Establishes that the two inheritance modes are clinically indistinguishable, which is why molecular testing rather than pedigree drives classification.

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Subtypes

Weill-Marchesani syndrome 1 (ADAMTS10-related, recessive) MONDO:0010194

ADAMTS10 hgnc:13201

The prototypic recessive form, caused by biallelic pathogenic ADAMTS10 variants. ADAMTS10 is a secreted metalloprotease that binds fibrillin-1 and accelerates microfibril biogenesis; patient fibroblasts deposit microfibrils sparsely. Cardiac anomalies are more frequent in the recessive forms.

Show evidence (1 reference)

PMID:15368195 SUPPORT Human Clinical

"Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs."

Original identification of ADAMTS10 as the recessive WMS gene.

Weill-Marchesani syndrome 2 (FBN1-related, dominant) MONDO:0012013

FBN1 hgnc:3603

The dominant form, caused by heterozygous FBN1 variants. Variants in the TB5 domain are associated with significantly shorter stature than variants elsewhere in the gene. The acronym GEMSS (glaucoma, ectopia, microspherophakia, stiff joints, short stature) was proposed for this form.

Show evidence (1 reference)

PMID:37734846 SUPPORT Human Clinical

"Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-β-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain"

Establishes the intragenic TB5 genotype-phenotype correlation within the dominant FBN1 arm.

Weill-Marchesani syndrome 3 (LTBP2-related, recessive) MONDO:0013899

LTBP2 hgnc:6715

A rare recessive form caused by biallelic LTBP2 variants. LTBP2 is a latent-TGF-beta-binding-protein-family member that associates with fibrillin-1 microfibrils; patient skin shows a disrupted microfibrillar network. Only two individuals were identified in a 61-patient series.

Show evidence (1 reference)

PMID:22539340 SUPPORT Human Clinical

"Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping."

Identifies the biallelic LTBP2 allele causing recessive WMS.

Weill-Marchesani syndrome 4 (ADAMTS17-related, recessive) MONDO:0013176

ADAMTS17 hgnc:17109

A recessive form caused by biallelic ADAMTS17 variants, and the most frequently identified genotype in a contemporary combined series. Classically described as having less severe cardiac involvement, presenting predominantly with musculoskeletal and ocular features, although valvular disease has since been reported.

Show evidence (2 references)

PMID:31726086 SUPPORT Human Clinical

"Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS."

Characterizes the comparatively cardiac-sparing phenotype classically attributed to the ADAMTS17 arm.

PMID:37506754 SUPPORT Human Clinical

"In particular, one child was detected with valvular heart disease, which has not previously been reported in patients with ADAMTS17 mutations."

Qualifies the cardiac-sparing characterization by documenting valvular disease in an ADAMTS17 patient.

Discussions and Knowledge Gaps

Why do FBN1 variants produce the short, stiff, thick-skinned Weill-Marchesani phenotype in some individuals and the tall, lax Marfan phenotype in others, when the same gene and the same microfibril system are involved?

KNOWLEDGE GAP OPEN gap_wms_fbn1_phenotypic_inversion

Attached to

pathophysiology#FBN1 WMS Microfibril-Scaffold Disruption pathophysiology#Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation

WMS2 and Marfan syndrome are allelic yet phenotypically opposite along nearly every systemic axis. Domain location clearly matters, since TB5 variants give the shortest stature within WMS, but domain location alone does not explain the sign reversal in growth, skin thickness and joint mobility. The mouse data point to reduced SMAD1/5/8 with increased p38 MAPK in the ADAMTS10 arm, which is not simply the inverse of the TGF-beta overactivation invoked for Marfan syndrome, so the two diseases may differ in which sequestered ligand class is released rather than in the direction of a single pathway. The inversion framing should not be over-tightened: domain location is associated with phenotype but is not established as a clean molecular switch between WMS and Marfan syndrome.

Proposed experiments

Domain-controlled FBN1 allelic series comparing WMS and Marfan signaling

exp_wms_fbn1_domain_swap_signalling

Build an isogenic FBN1 allelic series carrying WMS-associated and Marfan-associated variants, including same-domain pairs where available and variants inside and outside TB5, and measure microfibril architecture, BMP-family versus TGF-beta-family ligand activation, SMAD1/5/8, SMAD2/3 and p38 MAPK output in the same fibroblast and chondrocyte backgrounds.

Decision criterion

A consistent difference in which ligand class is liberated by WMS versus Marfan alleles, rather than a difference in overall signalling magnitude, would explain the phenotypic inversion.

Show evidence (1 reference)

PMID:22242013 SUPPORT Other

"Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues."

Establishes the mechanistic divergence while leaving the causal basis of the allelic phenotypic inversion unresolved.

Why is microspherophakia significantly more frequent in recessive WMS while ectopia lentis is significantly more frequent in dominant WMS, if both follow from the same zonular insufficiency?

KNOWLEDGE GAP OPEN gap_wms_lens_shape_versus_position

Attached to

pathophysiology#Zonular Insufficiency pathophysiology#Microspherophakia and Lenticular Myopia pathophysiology#Ectopia Lentis

Across 128 reviewed patients the two lens phenotypes dissociate in opposite directions by inheritance mode, with both differences statistically significant. That pattern is hard to reconcile with a single graded zonular defect, and suggests that shaping the lens during development and anchoring it thereafter may be separable functions of the zonule, differently sensitive to losing an assembly protease versus altering the fibrillin monomer itself.

Proposed experiments

Temporally resolved zonule phenotyping in ADAMTS10 versus Fbn1 WMS models

exp_wms_zonule_development_vs_maintenance

Compare zonular fibre architecture, tension and lens curvature at developmental and adult time points in the ADAMTS10 knock-in mouse against an Fbn1 WMS-allele model, testing whether the protease-loss model preferentially fails the developmental lens-shaping step while the fibrillin-variant model preferentially fails long-term anchorage.

Decision criterion

A temporal dissociation, with shape set early and anchorage failing late in the respective models, would account for the epidemiological pattern.

Show evidence (1 reference)

PMID:14598350 SUPPORT Human Clinical

"Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016)"

Documents the statistically significant opposite-direction dissociation of the two lens phenotypes by inheritance mode.

Can the Adamts10-null mouse be used to study the ocular and skeletal phenotype of Weill-Marchesani syndrome, when it fails to reproduce ectopia lentis, brachydactyly and cardiovascular defects?

HUMAN MODEL MISMATCH OPEN mismatch_wms_adamts10_null_mouse

Attached to

pathophysiology#Zonular Insufficiency pathophysiology#Microspherophakia and Lenticular Myopia pathophysiology#Ectopia Lentis pathophysiology#Acromelic Long-Bone Growth Restriction pathophysiology#Joint Limitation

Adamts10-null mice are slightly smaller with stiff skin but show no ectopia lentis, no brachydactyly and no cardiovascular defects, so three of the cardinal human features are simply absent. The authors attribute the ocular discrepancy to a species difference in zonular composition: the mouse zonule contains fibrillin-2 as well as fibrillin-1, so it can compensate where the human zonule cannot. This is a genuine translational limit rather than a weak model, and it means murine zonule findings cannot be read directly onto the human lens phenotype. Notably the separate CRISPR knock-in of a human truncation does reproduce growth and muscle changes, so the two ADAMTS10 mouse models are not interchangeable.

Proposed experiments

Fibrillin-2-depleted Adamts10-null zonule to test the compensation hypothesis

exp_wms_fbn2_humanized_zonule

Cross Adamts10-null mice onto a background with reduced ocular fibrillin-2 so that the zonule must rely on fibrillin-1, and test whether ectopia lentis and microspherophakia then appear. Compare zonular composition, lens shape and lens position against human WMS ocular tissue where available.

Decision criterion

Emergence of ectopia lentis and microspherophakia on the fibrillin-2-reduced background would confirm that species-specific zonular composition, not a different disease mechanism, explains the mismatch.

Show evidence (2 references)

PMID:30201140 SUPPORT Model Organism

"Ectopia lentis was not observed in Adamts10-/- mice, similar to Fbn1-/- mice, most likely because the mouse zonule contains fibrillin-2 in addition to fibrillin-1."

States the mismatch and the authors' species-composition explanation for it.

PMID:30201140 SUPPORT Model Organism

"although surviving mice were slightly smaller and had stiff skin, they lacked brachydactyly and cardiovascular defects"

Documents the additional skeletal and cardiac features that the null mouse fails to reproduce.

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Pathophysiology

ADAMTS10-Dependent Microfibril Assembly and Fibrillin-2 Remodeling

ADAMTS10 binds fibrillin-1 and accelerates fibrillin-1 microfibril biogenesis; WMS patient fibroblasts with ADAMTS10 variants deposit fibrillin-1 microfibrils sparsely. ADAMTS10 also cleaves fibrillin-2 in vitro, and its absence in mice prevents the normal postnatal shift toward a fibrillin-1-predominant ocular zonule. These assembly and remodeling activities are distinct from the secretion-loss mechanism demonstrated for ADAMTS17 variants.

ADAMTS10 hgnc:13201

extracellular matrix organization GO:0030198 ↓ DECREASED

Experimental models

ADAMTS10-WMS patient fibroblast microfibril-deposition model PRIMARY CELL CULTURE Compares endogenous fibrillin-1 microfibril deposition after loss of normal ADAMTS10 function.

Downstream

Deficient Fibrillin Microfibril Network Loss of the assembly-promoting protease leaves fibrillin-1 poorly deposited into microfibrils.

Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation The ADAMTS10 WMS knock-in mouse shows decreased SMAD1/5/8 signaling, restricting this experimentally observed signaling route to the ADAMTS10 arm rather than to every WMS genotype.

Altered Skeletal Myogenesis and Hypermuscularity Increased muscle mass, increased myofiber number and altered skeletal myogenesis were observed in the ADAMTS10 WMS knock-in mouse; this route is not generalized to the other genetic forms.

Zonular Insufficiency Failure of postnatal fibrillin-2 clearance perturbs maturation of the ADAMTS10-deficient ocular zonule.

Show evidence (3 references)

PMID:21402694 SUPPORT In Vitro

"Taken together, these findings suggest that ADAMTS10 participates in microfibril biogenesis rather than in fibrillin-1 turnover."

Establishes ADAMTS10 as a microfibril assembly factor rather than a degradative protease, which sets the direction of the disease mechanism.

PMID:21402694 SUPPORT In Vitro

"fibroblasts obtained from a Weill-Marchesani syndrome patient with ADAMTS10 mutations deposited fibrillin-1 microfibrils sparsely compared with unaffected control cells"

Direct patient-cell evidence that the ADAMTS10 lesion reduces fibrillin-1 microfibril deposition.

PMID:30201140 SUPPORT In Vitro

"ADAMTS10 was found to cleave fibrillin-2, providing an explanation for persistence of fibrillin-2 at these sites."

Identifies fibrillin-2 as an ADAMTS10 substrate; the cleavage assignment is IN_VITRO, while its ocular consequence is assessed separately in the mouse.

ADAMTS17 Secretion Loss and Microfibril Dysregulation

Pathogenic ADAMTS17 missense variants can markedly reduce secretion of the protein into the extracellular medium. Patient fibroblasts additionally show intracellular accumulation of fibrillin-1 and type I collagen with abnormal dermal extracellular matrix, consistent with loss of extracellular ADAMTS17 and disruption of early matrix-protein secretion or assembly.

ADAMTS17 hgnc:17109

extracellular matrix organization GO:0030198 ↓ DECREASED

Experimental models

ADAMTS17-WMS patient fibroblast secretion and matrix model PRIMARY CELL CULTURE Measures ADAMTS17 secretion and intracellular versus extracellular handling of fibrillin-1 and type I collagen.

Downstream

Deficient Fibrillin Microfibril Network Loss of extracellular ADAMTS17 perturbs fibrillin microfibril biogenesis or maturation.

Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation Adamts17 loss alters fibrillin-2 incorporation and reduces growth-plate BMP-SMAD signaling in vivo.

Show evidence (2 references)

PMID:32616716 SUPPORT In Vitro

"This variant caused severely reduced secretion of ADAMTS17 into the extracellular medium, suggesting functional loss of ADAMTS17 rather than impairment of a domain-specific function or interaction."

Functional expression data establish secretion loss as the effect of the p.Cys1023Tyr WMS4 allele.

PMID:31726086 SUPPORT In Vitro

"We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."

Patient-derived fibroblasts link impaired ADAMTS17 secretion to abnormal handling of two extracellular-matrix proteins.

FBN1 WMS Microfibril-Scaffold Disruption

Heterozygous FBN1 WMS variants alter the fibrillin-1 scaffold itself. A replicated human WMS deletion removes three fibrillin-1 domains and an ADAMTS-like-protein binding site; human and mouse ultrastructure shows altered microfibrils and a tissue-local microenvironmental response that differs from the broad TGF-beta activation associated with Marfan syndrome.

FBN1 hgnc:3603

Downstream

Deficient Fibrillin Microfibril Network Altering fibrillin-1 changes the structure and local organization of the microfibril scaffold.

Dermal Matrix Remodeling and Skin Thickening The allele-matched model links the altered scaffold to dermal collagen production and the thick-skin phenotype.

Show evidence (2 references)

PMID:22242013 SUPPORT Other

"The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin."

Identifies the structural deletion and lost binding interface in a human family whose allele was replicated in mice; OTHER reflects the combined human and model evidence in the same report.

PMID:22242013 SUPPORT Other

"Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production."

Directly supports the altered-scaffold and tissue-microenvironment claim using human tissue and the allele-matched mouse.

LTBP2-Dependent Microfibril-Bundle Assembly Failure

LTBP2 binds fibrillin-1 and is required for stable microfibril-bundle assembly, particularly in the ciliary zonule. WMS-associated mutant proteins can be retained intracellularly rather than secreted. Unlike other LTBPs, LTBP2 does not covalently bind latent TGF-beta; any effect on TGF-beta storage is therefore indirect, potentially through competition with LTBP1 for fibrillin-1 binding.

LTBP2 hgnc:6715

extracellular matrix organization GO:0030198 ↓ DECREASED

Experimental models

LTBP2-suppressed human ciliary epithelial microfibril model OTHER Tests whether LTBP2 suppression disrupts the ciliary-cell microfibril meshwork and whether extracellular LTBP2 restores it.

Downstream

Deficient Fibrillin Microfibril Network Loss of secreted LTBP2 disrupts formation of stable fibrillin-containing microfibril bundles.

Zonular Insufficiency The ciliary zonule is the tissue in which LTBP2-dependent bundle failure is directly demonstrated.

Show evidence (2 references)

PMID:24908666 SUPPORT Other

"The findings of this study suggest that LTBP-2 is an essential component for the formation of microfibril bundles in ciliary zonules."

Human ciliary-cell perturbation, rescue experiments and an Ltbp2-null mouse jointly establish the bundle-assembly role.

PMID:17293099 SUPPORT In Vitro

"LTBP-2 is a matrix protein of unknown function since, unlike other LTBPs, it does not form covalent complexes with latent TGF-beta."

Prevents conflation of LTBP2 with latent-TGF-beta-binding LTBPs and limits any signaling claim to an indirect mechanism.

Deficient Fibrillin Microfibril Network

The four genetic arms converge on abnormal assembly, composition or organization of fibrillin-containing extracellular microfibrils. Human ADAMTS10-mutant fibroblasts deposit fibrillin-1 sparsely, LTBP2-mutant skin has a disrupted microfibrillar network, and ADAMTS17-mutant cells mishandle matrix proteins. Microfibrils provide both structural support and local control of TGF-beta-superfamily growth-factor bioavailability, but the direction and ligand specificity of signaling changes are not uniform across WMS genotypes. The downstream edges from this shared node therefore capture only structural or phenotypic convergence, while experimentally resolved signaling and myogenesis routes remain attached to their specific gene arms.

fibroblast CL:0000057

extracellular matrix organization GO:0030198 ↓ DECREASED

Downstream

Zonular Insufficiency The ciliary zonule is a specialized fibrillin microfibril structure, so microfibril deficiency directly weakens lens suspension.

Acromelic Long-Bone Growth Restriction Abnormal growth-plate microfibrils and signaling restrict longitudinal bone growth.

Joint Limitation Matrix dysfunction in periarticular connective tissues is a plausible upstream contributor to the stiff-joint phenotype, although this edge has not been resolved experimentally in human tissue.

Dermal Matrix Remodeling and Skin Thickening Genotype-specific human and mouse studies connect altered microfibrils to dermal collagen or elastic-fiber abnormalities.

Show evidence (3 references)

PMID:30060141 SUPPORT Other

"Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily."

Establishes the dual structural and growth-factor-regulatory role of the microfibril that explains the breadth of the phenotype.

PMID:22539340 SUPPORT Human Clinical

"Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin."

Direct patient-tissue demonstration of the disrupted microfibrillar network.

PMID:25957949 SUPPORT Other

"Together, this strongly suggests that ADAMTS proteins are involved either in microfibril assembly, stability, and anchorage, or the formation of function-specific supramolecular networks having microfibrils as their foundation."

Review-level synthesis supports convergence of ADAMTS10 and ADAMTS17 on microfibril assembly, stability or function-specific matrix networks while leaving their gene-specific mechanisms distinct.

Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation

Adamts17-null growth plates show increased fibrillin-2 incorporation, reduced phospho-Smad1 and delayed terminal chondrocyte differentiation; BMP treatment prevents the differentiation delay. An independent ADAMTS10 WMS mouse also shows reduced SMAD1/5/8 signaling. These data support a reduced BMP-SMAD branch for the skeletal phenotype, not a generic claim that all WMS tissues have direct TGF-beta overactivation.

BMP signaling pathway GO:0030509 ↓ DECREASED

Downstream

Acromelic Long-Bone Growth Restriction Reduced BMP-SMAD output delays chondrocyte maturation and restricts long-bone growth in the mouse models.

Show evidence (4 references)

PMID:31201465 SUPPORT Model Organism

"Delayed terminal differentiation of Adamts17-/- chondrocytes, observed both in primary chondrocyte and primordial metatarsal cultures, and was prevented by BMP treatment."

The delayed differentiation and its BMP rescue provide functional evidence for reduced BMP signaling downstream of Adamts17 loss.

PMID:31201465 SUPPORT Model Organism

"Consistent with this, phospho-Smad1 levels were downregulated in the hypertrophic zone of the growth plate and in Adamts17-/- primary chondrocytes."

Directly localizes reduced BMP-SMAD output to the affected growth plate and Adamts17-null chondrocytes.

PMID:30060141 SUPPORT Model Organism

"Our data indicate that decreased SMAD1/5/8 and increased p38/MAPK signalling are associated with ADAMTS10-induced WMS."

Identifies the specific signalling shift downstream of the ADAMTS10 lesion in a CRISPR knock-in mouse model of the human truncation.

+ 1 more reference

Zonular Insufficiency

The ciliary zonule that suspends and tensions the lens is itself built from fibrillin-containing microfibril bundles. LTBP2 loss directly compromises zonule formation, while Adamts10-null mice retain fibrillin-2-rich, thick zonular fibers with reduced fibrillin-1. Failure of normal bundle assembly or maturation reduces zonular support and links the matrix lesion to both lens shape and position abnormalities.

extracellular matrix organization GO:0030198 ↓ DECREASED

Experimental models

LTBP2-suppressed human ciliary epithelial microfibril model OTHER Models the cell-derived microfibril network that contributes to ciliary zonule bundles.

Downstream

Microspherophakia and Lenticular Myopia Without zonular tension the lens relaxes into a small spherical shape.

Ectopia Lentis A deficient zonule also fails to anchor the lens, allowing it to displace.

Show evidence (4 references)

PMID:20301293 SUPPORT Human Clinical

"The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness."

Establishes that lens-shape and lens-position abnormalities coexist in the characteristic childhood ocular presentation; it directly supports only the lens-shape-to-myopia relation.

PMID:24908666 SUPPORT Model Organism

"Ltbp2(-/-) mice survived to adulthood but developed lens luxation caused by compromised ciliary zonule formation"

Directly links LTBP2 deficiency to compromised zonule formation and lens luxation in the knockout mouse.

PMID:30060141 SUPPORT Model Organism

"Furthermore, there are abnormalities in the ciliary apparatus of the eye with decreased ciliary processes and abundant fibrillin-2 microfibrils suggesting perturbation of a developmental expression switch."

Model-organism evidence of ciliary apparatus abnormality with a fibrillin-2-to-fibrillin-1 switch failure.

+ 1 more reference

Microspherophakia and Lenticular Myopia

Reduced zonular tension is the proposed mechanical basis for the small, steeply curved lens. The abnormal lens shape increases refractive power and produces lenticular rather than axial myopia. A longitudinal WMS4 case showed progressive childhood lens thickening with increasing lens power and myopic refractive error, but that single-patient observation should not be treated as a population-level trajectory.

Downstream

Pupillary Block and Angle Closure A small, thick, forward-sitting lens crowds the anterior chamber and obstructs aqueous flow through the pupil.

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens"

States that the myopia follows from the abnormal lens shape, establishing the lenticular mechanism.

PMID:36698805 SUPPORT Human Clinical

"During the 3 years of follow-up, the thickness of lenses increased significantly (right 4.49 mm, left 4.48 mm), but the equatorial diameter of the lenses had no significant change (right 7.32 mm, left 7.21 mm). As the equivalent lens power increased, the patient's myopia spherical refractive..."

Longitudinal biometric evidence in one child links progressive lens thickening and power to worsening lenticular myopia.

Ectopia Lentis

Failure of zonular anchorage allows the lens to subluxate or dislocate. A displaced lens is itself a mechanical cause of pupillary block, and it is the finding whose early detection and removal drives the whole management strategy.

Downstream

Pupillary Block and Angle Closure An anteriorly displaced lens obstructs the pupil directly.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"ectopia lentis (abnormal position of the lens)"

Defines ectopia lentis as the lens-position abnormality of WMS.

Pupillary Block and Angle Closure

In WMS the initiating glaucoma lesion is anatomical: a microspherophakic or displaced lens can block aqueous passage at the pupil and promote chronic angle closure. This is not equivalent to the trabecular-meshwork initiating lesion in the conserved glaucoma module, so conformance begins only at the downstream elevated-pressure node. The lens-driven anatomy also explains why GeneReviews warns that miotics and mydriatics can have paradoxical effects or induce pupillary block.

Downstream

Elevated Intraocular Pressure Obstructed aqueous egress raises intraocular pressure.

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"

Identifies pupillary block and chronic angle closure as the operative mechanism of glaucoma in WMS.

PMID:20301293 SUPPORT Human Clinical

"medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics"

Documents the paradoxical drug response that follows from the lens-driven rather than outflow-driven mechanism.

Elevated Intraocular Pressure

Aqueous outflow obstruction raises intraocular pressure. From this point onward WMS runs along the conserved glaucoma pathway, which is why the downstream nodes conform to the module without substitution.

Downstream

Retinal Ganglion Cell Apoptosis Sustained pressure elevation drives retinal ganglion cell death.

Show evidence (2 references)

PMID:32561029 SUPPORT Other

"Glaucoma is a blinding optic neuropathy, the main risk factor for which is increased intraocular pressure (IOP)."

Establishes increased IOP as the principal pressure-mediated risk factor in the conserved glaucoma pathway; this is general glaucoma review evidence.

PMID:25397784 SUPPORT Human Clinical

"Glaucoma developed in 16 eyes (44.4%). Half of them had high IOP at presentation."

A microspherophakia cohort directly documents high IOP in affected eyes, although the cohort was not restricted to molecularly confirmed WMS.

Retinal Ganglion Cell Apoptosis

Pressure-driven apoptotic loss of retinal ganglion cells, the cellular event that makes glaucomatous damage irreversible and therefore the reason WMS management is pre-emptive rather than reactive.

retinal ganglion cell CL:0000740

neuron apoptotic process GO:0051402 ↑ INCREASED

Downstream

Optic Nerve Degeneration and Neuroinflammation Ganglion-cell and axonal loss is accompanied by optic-nerve degeneration and a neuroinflammatory response.

Show evidence (1 reference)

PMID:25914734 SUPPORT Other

"This disease is a neurodegenerative disorder characterized by high intraocular pressure, loss of retinal ganglion cells (apoptosis)."

Supplies general-glaucoma evidence for the conserved retinal-ganglion-cell apoptosis step; WMS-specific evidence establishes the upstream glaucoma, not this cellular event.

Optic Nerve Degeneration and Neuroinflammation

Progressive retinal-ganglion-cell loss is accompanied by optic-nerve axon degeneration and neuroinflammation. This intermediate is conserved across glaucoma subtypes and is supported by general glaucoma evidence rather than WMS-specific tissue studies.

neuroinflammatory response GO:0150076 ↑ INCREASED

Downstream

Progressive Glaucomatous Optic Neuropathy and Vision Loss Cumulative neuronal and axonal injury produces progressive optic neuropathy.

Show evidence (1 reference)

PMID:33670885 SUPPORT Other

"oxidative DNA damage accumulates in this degenerating TM, accelerating a neuroinflammation process which drives the neurodegeneration in POAG pathology"

Supports the conserved neuroinflammatory amplification step using general glaucoma review evidence; it is not evidence for the WMS initiating lesion.

Progressive Glaucomatous Optic Neuropathy and Vision Loss

Optic nerve degeneration progressing to blindness if the lens problem is not corrected early. This endpoint is why the management priority is early lens removal rather than pressure-lowering drops.

Show evidence (2 references)

PMID:33670885 SUPPORT Other

"progressive degeneration of retinal ganglion cells (RGC) with a specific pattern of changes in the optic nerve head and retinal nerve fiber layer"

Supplies the conserved structural endpoint from a general glaucoma review.

PMID:20301293 SUPPORT Human Clinical

"glaucoma, which can lead to blindness"

Establishes progression to blindness as the ocular endpoint of untreated WMS glaucoma.

Acromelic Long-Bone Growth Restriction

Proportionate short stature and brachydactyly place WMS among the acromelic dysplasias. Adamts10 and Adamts17 mouse models map this outcome to shorter long bones, abnormal growth-plate zones, altered fibrillin-2 deposition and impaired chondrocyte maturation.

chondrocyte CL:0000138

Show evidence (3 references)

PMID:37734846 SUPPORT Human Clinical

"Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations."

Places WMS nosologically among the acromelic dysplasias by its systemic triad.

PMID:30060141 SUPPORT Model Organism

"Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation."

Model-organism evidence linking the matrix defect to growth plate disorganization and reduced long bone growth.

PMID:31201465 SUPPORT Model Organism

"Adamts17-/- mice recapitulated WMS, showing shorter long bones, brachydactyly, and thick skin."

Independently reproduces the acromelic skeletal outcome in an Adamts17-null model.

Joint Limitation

Joint stiffness and restricted mobility are common. Their tissue-level mechanism is less directly resolved than the growth-plate mechanism, so this node represents the systemic consequence without asserting a specific signaling pathway or universal trajectory.

Show evidence (1 reference)

PMID:14598350 SUPPORT Human Clinical

"joint limitations (49% in AR, 77% in AD, Fischer 0.010)"

Quantifies joint limitation and its difference between recessive and dominant WMS in a 128-patient literature review.

Dermal Matrix Remodeling and Skin Thickening

WMS can alter dermal microfibrils, elastic fibers and collagen homeostasis. The best resolved genotype-specific evidence comes from an allele-matched FBN1 WMS mouse and human tissue, while ADAMTS17 patient skin shows abnormal elastic fibers and collagen handling.

extracellular matrix organization GO:0030198 ↕ DYSREGULATED

Show evidence (2 references)

PMID:22242013 SUPPORT Other

"Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice."

Links a human WMS allele to thick skin in an allele-matched model; OTHER reflects the combined human and animal design.

PMID:31726086 SUPPORT Human Clinical

"transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband."

Direct patient-dermis evidence of matrix remodeling in ADAMTS17-related WMS.

Altered Skeletal Myogenesis and Hypermuscularity

Increased muscle mass is modeled in the ADAMTS10 WMS knock-in mouse, where more myofibers and altered myogenesis accompany the skeletal phenotype. This supports a developmental muscle-remodeling mechanism but does not establish that every WMS genotype shares the same pathway.

Show evidence (1 reference)

PMID:30060141 SUPPORT Model Organism

"WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis."

Provides model-organism evidence for altered myogenesis underlying the hypermuscular phenotype.

⬡

Pathograph

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

●

Phenotypes

Cardiovascular 1

Abnormal heart valve morphology OCCASIONAL HP:0001654

Show evidence (2 references)

PMID:37734846 SUPPORT Human Clinical

"10/61 individuals had valvulopathy"

Quantifies valvulopathy at 10 of 61 molecularly confirmed individuals, roughly 16%, supporting an OCCASIONAL band.

PMID:14598350 SUPPORT Human Clinical

"cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004)"

Documents the significantly higher cardiac burden of the recessive forms in the older literature review.

Eye 4

Ectopia lentis FREQUENT HP:0001083

Onset: CHILDHOOD

Show evidence (2 references)

PMID:14598350 SUPPORT Human Clinical

"ectopia lentis (64% in AR, 84% in AD, Fischer 0.016)"

Quantifies ectopia lentis at 64% recessive and 84% dominant, and documents the inverse gene-arm distribution relative to microspherophakia.

PMID:37734846 SUPPORT Human Clinical

"All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61)."

Confirms in a molecularly defined 61-patient series that eye anomalies are universal, with these two as the dominant findings.

High myopia HP:0011003

Onset: CHILDHOOD

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"myopia secondary to the abnormal shape of the lens"

Establishes the lenticular rather than axial origin of the myopia.

PMID:36698805 SUPPORT Human Clinical

"An 8-year-old boy presented to our ophthalmology department with progressive myopia for 1 year. He had high myopia in both eyes with normal funds, intraocular pressure, and axial length."

A longitudinal WMS4 case illustrates progressive childhood lenticular myopia without axial elongation; it does not establish population frequency.

Glaucoma HP:0000501

Course: PROGRESSIVE Onset: CHILDHOOD

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"and glaucoma, which can lead to blindness"

GeneReviews lists glaucoma among the cardinal ocular problems and its sight-threatening consequence.

Cataract HP:0000518

Show evidence (1 reference)

PMID:32616716 SUPPORT Other

"Patients may also have microspherophakia, severe myopia, ectopia lentis, glaucoma and cataracts."

Contemporary review background recognizes cataract as part of the ocular spectrum; it does not quantify frequency.

Integument 1

Thickened skin HP:0001072

Show evidence (1 reference)

PMID:30060141 SUPPORT Human Clinical

"Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin."

Lists thickened skin and hypermuscularity among the defining features of WMS.

Limbs 1

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:37734846 SUPPORT Human Clinical

"Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations."

Brachydactyly is one of the three defining features of the acromelic dysplasia group to which WMS belongs.

Musculoskeletal 1

Joint stiffness FREQUENT HP:0001387

Show evidence (1 reference)

PMID:14598350 SUPPORT Human Clinical

"joint limitations (49% in AR, 77% in AD, Fischer 0.010)"

Quantifies joint limitation at 49% recessive and 77% dominant, supporting a FREQUENT band.

Growth 1

Short stature FREQUENT HP:0004322

Show evidence (2 references)

PMID:37734846 SUPPORT Human Clinical

"Short stature was present in 73% (from -2.2 to -5.5 SD)"

Quantifies frequency at 73% with the severity range, supporting a FREQUENT band.

PMID:20301293 SUPPORT Human Clinical

"Height of adult males is 142-169 cm; height of adult females is 130-157 cm."

Provides the adult height ranges that define the degree of short stature.

Other 3

Microspherophakia FREQUENT HP:0030961

Onset: CHILDHOOD

Show evidence (3 references)

PMID:14598350 SUPPORT Human Clinical

"Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007)"

Quantifies microspherophakia at 94% in recessive and 74% in dominant WMS; the dominant estimate and the 42/61 contemporary combined-cohort count support the conservative FREQUENT band for WMS overall.

PMID:37734846 SUPPORT Human Clinical

"All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61)."

The contemporary molecular series finds spherophakia in 42 of 61 individuals, supporting a FREQUENT rather than VERY_FREQUENT overall band.

PMID:20301293 SUPPORT Human Clinical

Supports childhood recognition of the characteristic ocular phenotype.

Angle closure glaucoma HP:0012109

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"trabeculectomy in advanced chronic angle closure glaucoma"

GeneReviews identifies chronic angle closure as the glaucoma subtype requiring surgical management in WMS.

Generalized muscle hypertrophy HP:0003720

Show evidence (2 references)

PMID:30060141 SUPPORT Human Clinical

"Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin."

Lists hypermuscularity among the defining features of WMS.

PMID:30060141 SUPPORT Model Organism

"WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis."

Model-organism correlate of the human hypermuscularity, attributing it to altered myogenesis rather than training.

🧬

Genetic Associations

ADAMTS10 (Pathogenic Variants)

Gene: ADAMTS10 hgnc:13201 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:15368195 SUPPORT Human Clinical

"We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans."

Establishes the causal role of ADAMTS10 across the exact organ set affected in WMS.

PMID:15368195 SUPPORT In Vitro

"ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart."

Expression data matching the affected tissues, supporting tissue specificity of the phenotype.

ADAMTS17 (Pathogenic Variants)

Gene: ADAMTS17 hgnc:17109 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:37734846 SUPPORT Human Clinical

"21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."

Gives the relative genetic contribution of each WMS gene in a combined cohort and literature series.

PMID:31726086 SUPPORT In Vitro

"We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."

Functional mechanism of the ADAMTS17 allele: blocked secretion with intracellular retention of matrix components.

FBN1 (Pathogenic Variants)

Gene: FBN1 hgnc:3603 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37734846 SUPPORT Human Clinical

"Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10, ADAMTS17 and LTBP2 are responsible for a recessive form of WMS."

States the gene-to-inheritance-mode mapping across the four WMS genes.

LTBP2 (Pathogenic Variants)

Gene: LTBP2 hgnc:6715 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:22539340 SUPPORT Human Clinical

"Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils."

Establishes LTBP2 as a fibrillin-1 microfibril-associated protein, placing it in the same molecular system as the other three genes.

PMID:17293099 SUPPORT In Vitro

"LTBP-2 is a matrix protein of unknown function since, unlike other LTBPs, it does not form covalent complexes with latent TGF-beta."

Clarifies that LTBP2 is not a direct latent-TGF-beta carrier despite its family name.

💊

Medical Actions

Early lens extraction

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Early detection and removal of an ectopic lens is the central preventive intervention, taken to reduce the chance of pupillary block and consequent glaucoma. Because the lens is the upstream cause of the pressure rise, lens surgery is mechanistically prior to any pressure-lowering measure.

Mechanism Target:

INHIBITS Pupillary Block and Angle Closure — Removing the microspherophakic or subluxated lens eliminates the anatomical cause of pupillary block before pressure rises.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Early detection and removal of an ectopic lens to decrease the possibility of pupillary block and glaucoma."

GeneReviews names early lens removal as the treatment directed at the pupillary block mechanism.

Peripheral iridectomy

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Peripheral iridectomy can prevent or relieve pupillary block by creating an alternative route for aqueous humor around the obstructed pupil.

Mechanism Target:

INHIBITS Pupillary Block and Angle Closure — Iridectomy bypasses the blocked pupil and directly addresses the lens-driven initiating lesion.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"

Specifically supports peripheral iridectomy for prevention or relief of pupillary block.

Trabeculectomy for advanced chronic angle-closure glaucoma

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Trabeculectomy is considered when chronic angle closure is advanced and pressure remains inadequately controlled, creating a new aqueous outflow pathway downstream of the lens-driven block.

Mechanism Target:

INHIBITS Elevated Intraocular Pressure — The filtering procedure lowers pressure after chronic angle closure has established persistent outflow impairment.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"

Specifically supports trabeculectomy in advanced chronic angle-closure glaucoma.

Avoidance of ophthalmic miotics and mydriatics

Action: supportive care Ontology label: Supportive Care NCIT:C15747

A drug-safety measure rather than a therapy. Ophthalmic miotics and mydriatics must be avoided because they can induce pupillary block: this is the paradoxical response that makes medical glaucoma management difficult in WMS, and it inverts the usual pharmacological reflex for angle closure. Activities carrying a risk of eye injury should also be avoided.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Agents/circumstances to avoid: Ophthalmic miotics and mydriatics because they can induce pupillary block; activities that increase risk of eye injury."

GeneReviews Agents/Circumstances to Avoid section, the drug-safety warning specific to this disorder.

Annual ophthalmologic surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Annual ophthalmology examinations, aimed at detecting an ectopic lens early enough to remove it before pupillary block and glaucoma develop.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Annual ophthalmology examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma."

Establishes the surveillance interval and its explicit preventive rationale.

Cardiac surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Regular cardiac follow-up with echocardiography and electrocardiography, warranted by the valvular disease burden, with treatment of cardiac anomalies directed by a cardiologist.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Regular cardiac follow up with echocardiogram and electrocardiography."

Specifies the cardiac surveillance modality recommended in WMS.

Physical therapy for joint limitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical therapy is considered for joint stiffness and reduced mobility.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Consider physical therapy for joint issues."

GeneReviews recommends considering physical therapy for the joint manifestations.

Annual growth and joint-range surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Height and joint range of motion should be assessed annually to document growth restriction and joint limitation and to guide timely rehabilitation.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Annual assessment of height and joint range of motion."

Provides the explicit surveillance interval and outcomes.

Pre-anaesthetic airway evaluation

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Careful evaluation before anaesthesia is required because stiff joints, poorly aligned teeth and maxillary hypoplasia together predict a difficult airway. This is a procedural safety consideration that follows directly from the connective tissue and craniofacial phenotype.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Careful evaluation prior to anesthesia because of stiff joints, poorly aligned teeth, and maxillary hypoplasia."

Documents the anaesthetic risk and the anatomical features that create it.

Genetic counseling and family-specific reproductive testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Molecular assignment of the dominant FBN1 form versus a recessive ADAMTS10, ADAMTS17 or LTBP2 form determines recurrence counseling. Once the familial variant or variants are known, carrier testing is available for relatives at risk of a recessive form, and prenatal or preimplantation testing is possible.

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family."

Supports family-specific carrier testing for the recessive forms.

PMID:20301293 SUPPORT Human Clinical

"Prenatal and preimplantation genetic testing are possible once the WMS-related pathogenic variant(s) have been identified in an affected family member."

Supports reproductive testing after identification of the familial pathogenic variant or variants.

🔬

Diagnosis

Clinical diagnosis

The diagnosis is established clinically in a proband with the characteristic combination of ocular, skeletal and joint findings. The ophthalmological findings are mandatory for the diagnosis; the systemic phenotype is more variable than originally described.

physical examination NCIT:C20989

Show evidence (2 references)

PMID:20301293 SUPPORT Human Clinical

"The diagnosis WMS is established in a proband with characteristic clinical features."

GeneReviews states that the diagnosis rests on characteristic clinical features.

PMID:37734846 SUPPORT Human Clinical

"Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described"

Establishes the ocular findings as the obligate diagnostic anchor and warns that the systemic phenotype is variable.

Anterior-segment eye examination and ocular biometry

Detailed ophthalmic assessment should evaluate lens shape and thickness, refraction, axial length, lens position, anterior-chamber angle and intraocular pressure. In children, progressive lens-induced myopia with a normal axial length can be an early clue before the full systemic phenotype is recognized.

eye examination NCIT:C38060

Results: Microspherophakia or progressive lens thickening, lenticular myopia, ectopia lentis or iridodonesis, angle narrowing and/or elevated intraocular pressure.

Show evidence (2 references)

PMID:36698805 SUPPORT Human Clinical

"Comprehensive clinical examinations and genetic testing may improve diagnosis, which allows early therapeutic interventions for complications and better visual outcomes for the patient."

The longitudinal WMS4 report demonstrates how multimodal ocular biometry can distinguish progressive lens-induced myopia from ordinary axial myopia.

PMID:20301293 SUPPORT Human Clinical

Defines the childhood ocular abnormalities the examination is intended to detect.

Molecular genetic testing

Molecular testing confirms the diagnosis when clinical features are inconclusive, and is the only way to assign inheritance mode, since the recessive and dominant forms cannot be told apart clinically.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

"Identification of biallelic pathogenic variants in ADAMTS10, ADAMTS17, or LTBP2 or of a heterozygous pathogenic variant in FBN1 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive."

Specifies the four-gene molecular testing strategy and its role relative to clinical diagnosis.

📈

Progression

Childhood ocular recognition

Age: Childhood

Lens-shape and lens-position abnormalities, lenticular myopia and glaucoma are typically recognized in childhood, although the exact combination and timing vary between individuals.

Show evidence (1 reference)

PMID:20301293 SUPPORT Human Clinical

Establishes childhood as the typical recognition period for the ocular phenotype without implying that every listed abnormality is present.

📊

Prevalence

Worldwide

Unknown 1.0 per 100,000 1–9 per 100,000

A contemporary WMS family study reports a prevalence estimate of one per 100,000; because ascertainment for this rare, genetically heterogeneous disorder is incomplete, this should be treated as an approximate estimate.

Show evidence (1 reference)

PMID:32616716 SUPPORT Other

"Weill-Marchesani syndrome (WMS) is a rare heritable connective tissue disorder (prevalence 1 in 100,000)"

Provides the published worldwide prevalence estimate; evidence source is OTHER because the value is background synthesis rather than a new population ascertainment study.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Weill-Marchesani syndrome:

Marfan syndrome

Overlapping Features The instructive contrast rather than a close mimic. Both are FBN1 microfibril disorders with ectopia lentis, but the habitus is inverted: Marfan syndrome gives tall stature, arachnodactyly, joint laxity and aortic root dilation, while WMS gives short stature, brachydactyly, joint stiffness and thickened skin. Lens shape separates them, since microspherophakia is characteristic of WMS.

Distinguishing Features

Tall stature with arachnodactyly and joint laxity, versus short stature with brachydactyly and joint stiffness
Aortic root dilation and dissection risk, versus valvular disease without characteristic aortopathy
Microspherophakia strongly favors WMS in an ectopia-lentis presentation

Show evidence (3 references)

PMID:22242013 SUPPORT Other

"Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis."

Directly supports the Marfan side of the phenotypic contrast from a fibrillin-1 mechanistic study.

PMID:22242013 SUPPORT Other

"Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice."

Supports the contrasting WMS habitus in a human-family/allele-matched-mouse study.

PMID:30201140 SUPPORT Other

"Unlike MFS, WMS does not typically predispose to aortic aneurysm."

Supports the cardiovascular discriminator while appropriately retaining "typically" rather than treating aortopathy as impossible in WMS.

Isolated ectopia lentis, especially ADAMTSL4-related disease

Overlapping Features An ocular-first presentation with progressive lens dislocation can be a nonsyndromic zonular disorder rather than WMS. Familial isolated ectopia lentis can have dominant or recessive inheritance, and biallelic ADAMTSL4 variants are an established cause of the autosomal recessive form. Absence of the characteristic WMS combination of short stature, brachydactyly, joint stiffness and cardiovascular findings favors the isolated diagnosis, while molecular testing distinguishes ADAMTSL4-related disease from the four WMS gene forms. The word "isolated" should be applied only after a systemic assessment rather than inferred from an ocular presentation alone.

Distinguishing Features

Ectopia lentis is the principal finding without the characteristic multisystem WMS habitus
Biallelic ADAMTSL4 variants support autosomal recessive isolated ectopia lentis rather than WMS
Progressive lens dislocation can occur in isolated disease, so progression alone does not establish WMS

Show evidence (4 references)

PMID:20141359 SUPPORT Human Clinical

"Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation."

Defines the shared ocular presentation and cautions that progressive lens dislocation is not by itself specific for WMS.

PMID:20141359 SUPPORT Human Clinical

"Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive."

Keeps the differential broader than ADAMTSL4 by documenting both dominant and recessive familial isolated ectopia lentis.

PMID:20141359 SUPPORT Human Clinical

"Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular..."

Provides family-based molecular evidence for ADAMTSL4-related isolated autosomal recessive ectopia lentis.

+ 1 more reference

Isolated microspherophakia

Overlapping Features A small spherical lens can occur as a familial isolated ocular disorder, so microspherophakia alone does not establish WMS. A reported consanguineous family had bilateral isolated microspherophakia with likely recessive inheritance, and linkage to ADAMTS10 was excluded in that family. That family-specific genetic result is not evidence that every isolated case has the same cause. Lenticular myopia, lens subluxation and glaucoma can follow microspherophakia in either setting; systemic examination and WMS molecular testing are therefore the useful separators when the presentation is ocular-first.

Distinguishing Features

Bilateral microspherophakia without short stature, brachydactyly, joint stiffness or cardiovascular disease favors an isolated ocular diagnosis
Lenticular myopia, lens subluxation and glaucoma are complications of lens shape and do not by themselves distinguish isolated disease from WMS
Exclusion of ADAMTS10 linkage was specific to the cited family; inconclusive patients still warrant testing of the established WMS genes

Show evidence (4 references)

PMID:19696795 SUPPORT Human Clinical

"A consanguineous family (MSP-M), including six family members and two patients, presented with decreased vision secondary to bilateral isolated microspherophakia."

Establishes that bilateral microspherophakia can present as a familial isolated ocular phenotype.

PMID:19696795 SUPPORT Human Clinical

"Using a homozygosity-mapping strategy, haplotypic analysis using four STRs showed an exclusion of linkage between the ADAMTS10 gene and the disease locus in this family."

Supports a genetic distinction from ADAMTS10-related WMS only for the family studied, without extrapolating an unknown universal cause.

PMID:25397784 SUPPORT Human Clinical

"Microspherophakia is associated with a high incidence of lenticular myopia, subluxation of the crystalline lens and glaucoma."

Shows why common ocular complications reflect microspherophakia itself and cannot serve as reliable WMS-specific discriminators.

+ 1 more reference

Geleophysic dysplasia and acromicric dysplasia

Overlapping Features These other acromelic dysplasias share short stature, small hands and feet, thick skin and stiff joints. Microspherophakia and ectopia lentis favor WMS. Progressive cardiac-valve thickening, tracheal stenosis and bronchopulmonary insufficiency strongly favor geleophysic dysplasia; ocular findings can occasionally overlap, so molecular testing may be necessary.

Distinguishing Features

Microspherophakia and ectopia lentis are characteristic diagnostic anchors for WMS
Progressive valvular thickening, tracheal stenosis or bronchopulmonary insufficiency favor geleophysic dysplasia
Molecular testing separates overlapping FBN1-associated acromelic phenotypes and identifies ADAMTSL2-related geleophysic dysplasia

Show evidence (1 reference)

PMID:24214363 SUPPORT Human Clinical

"Weill-Marchesani syndrome, on the basis of microspherophakia and ectopia lentis; geleophysic dysplasia by progressive cardiac valvular thickening, tracheal stenosis, and/or bronchopulmonary insufficiency, often leading to early death."

Gives the principal clinical discriminators within the acromelic-dysplasia differential while the reported overlapping case cautions that they are not absolute.

Homocystinuria due to cystathionine beta-synthase deficiency

Overlapping Features Homocystinuria can present with severe myopia and ectopia lentis and should be excluded when the ocular phenotype is prominent. Excessive height, long limbs, osteoporosis, arachnodactyly, thromboembolism and neurodevelopmental manifestations contrast with the short, brachydactylous WMS habitus; plasma total homocysteine and amino-acid testing provides a rapid biochemical discriminator.

Distinguishing Features

Excessive height and arachnodactyly rather than short stature and brachydactyly
Thromboembolic risk and possible neurodevelopmental manifestations
Markedly elevated plasma total homocysteine and characteristic amino-acid abnormalities

Show evidence (2 references)

PMID:20301697 SUPPORT Human Clinical

"Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is characterized by involvement of four major systems: the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, osteoporosis, scoliosis, arachnodactyly, pes cavus,..."

Supports both the ocular overlap and the systemic findings that distinguish homocystinuria from WMS.

PMID:20301697 SUPPORT Human Clinical

"Plasma concentrations of total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment."

Supports plasma total-homocysteine and amino-acid analysis as the biochemical route to early recognition.

🧫

Experimental Models

ADAMTS10-WMS patient fibroblast microfibril-deposition model PRIMARY_CELL_CULTURE

Organism

human NCBITaxon:9606

Cell source

Primary fibroblasts from a person with ADAMTS10-related WMS and unaffected control fibroblasts

Culture

Two-dimensional fibroblast culture with fibrillin-1 microfibril-deposition imaging

Publication

PMID:21402694

Pathograph links

ADAMTS10-Dependent Microfibril Assembly and Fibrillin-2 Remodeling Compares endogenous fibrillin-1 microfibril deposition after loss of normal ADAMTS10 function.

Show evidence (1 reference)

PMID:21402694 SUPPORT In Vitro

"fibroblasts obtained from a Weill-Marchesani syndrome patient with ADAMTS10 mutations deposited fibrillin-1 microfibrils sparsely compared with unaffected control cells"

Directly establishes the patient-cell model and its disease-relevant matrix readout.

ADAMTS17-WMS patient fibroblast secretion and matrix model PRIMARY_CELL_CULTURE

Organism

human NCBITaxon:9606

Cell source

Patient-derived primary skin fibroblasts carrying a pathogenic ADAMTS17 variant

Culture

Two-dimensional fibroblast culture with secretion and matrix-deposition assays

Publication

PMID:31726086

Pathograph links

ADAMTS17 Secretion Loss and Microfibril Dysregulation Measures ADAMTS17 secretion and intracellular versus extracellular handling of fibrillin-1 and type I collagen.

Show evidence (1 reference)

PMID:31726086 SUPPORT In Vitro

"We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."

Directly supports the patient-derived culture and its secretion/matrix readouts.

LTBP2-suppressed human ciliary epithelial microfibril model OTHER

Organism

human NCBITaxon:9606

Cell source

Cultured human ciliary epithelial cells with siRNA-mediated LTBP2 suppression

Culture

Two-dimensional culture with microfibril-meshwork imaging and recombinant-LTBP2 rescue

Publication

PMID:24908666

Pathograph links

LTBP2-Dependent Microfibril-Bundle Assembly Failure Tests whether LTBP2 suppression disrupts the ciliary-cell microfibril meshwork and whether extracellular LTBP2 restores it.

Zonular Insufficiency Models the cell-derived microfibril network that contributes to ciliary zonule bundles.

Show evidence (2 references)

PMID:24908666 SUPPORT In Vitro

"The suppression of LTBP2 expression in cultured human ciliary epithelial cells by siRNA disrupted the formation of the microfibril meshwork by the cells."

Establishes the human-cell loss-of-function model and matrix-assembly phenotype.

PMID:24908666 SUPPORT In Vitro

"Supplementation of recombinant LTBP-2 in culture medium not only rescued the microfibril meshwork formation in LTBP2-suppressed ciliary epithelial cells"

Provides a target-specific extracellular rescue of the modeled defect.

{ }

Source YAML

click to show

name: Weill-Marchesani syndrome
creation_date: "2026-08-01T04:23:04Z"
description: >-
  Weill-Marchesani syndrome (WMS) is a rare heritable disorder of the fibrillin
  microfibril and one of the acromelic dysplasias, defined by short stature,
  brachydactyly and joint stiffness together with characteristic ocular
  abnormalities that can include microspherophakia, lenticular myopia, ectopia
  lentis and secondary glaucoma. WMS contrasts with Marfan syndrome in habitus:
  disruption of the same FBN1-microfibril system can instead produce a short,
  stiff, thick-skinned, muscular build with a small round lens. Four genes, all
  encoding secreted extracellular-matrix proteins that form or regulate fibrillin
  microfibrils, cause dominant or recessive forms of the disorder.
category: Mendelian
parents:
- syndromic disease
- connective tissue disease
synonyms:
- WMS
- spherophakia-brachymorphia syndrome
- GEMSS syndrome
disease_term:
  preferred_term: Weill-Marchesani syndrome
  term:
    id: MONDO:0018096
    label: Weill-Marchesani syndrome
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  percentage: 1 in 100,000
  notes: >-
    A contemporary WMS family study reports a prevalence estimate of one per
    100,000; because ascertainment for this rare, genetically heterogeneous
    disorder is incomplete, this should be treated as an approximate estimate.
  evidence:
  - reference: PMID:32616716
    reference_title: "A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Weill-Marchesani syndrome (WMS) is a rare heritable connective tissue disorder (prevalence 1 in 100,000)"
    explanation: >-
      Provides the published worldwide prevalence estimate; evidence source is
      OTHER because the value is background synthesis rather than a new
      population ascertainment study.
progression:
- phase: Childhood ocular recognition
  age_range: Childhood
  notes: >-
    Lens-shape and lens-position abnormalities, lenticular myopia and glaucoma
    are typically recognized in childhood, although the exact combination and
    timing vary between individuals.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness."
    explanation: >-
      Establishes childhood as the typical recognition period for the ocular
      phenotype without implying that every listed abnormality is present.
- phase: Progressive lens-related and glaucomatous complications
  age_range: Childhood onward
  notes: >-
    Lens thickening and lenticular myopia can progress during childhood in WMS4;
    ectopic or microspherophakic lenses can later produce pupillary block,
    chronic angle closure and sight-threatening glaucoma. The longitudinal lens
    trajectory is documented in a single child and may not generalize to every
    genotype.
  evidence:
  - reference: PMID:36698805
    reference_title: "Abnormal lens thickening in a child with Weill-Marchesani syndrome 4: A 3-year follow-up case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the 3 years of follow-up, the thickness of lenses increased significantly (right 4.49 mm, left 4.48 mm), but the equatorial diameter of the lenses had no significant change (right 7.32 mm, left 7.21 mm). As the equivalent lens power increased, the patient's myopia spherical refractive error rose accordingly."
    explanation: >-
      Provides longitudinal evidence for progressive childhood lens thickening
      and lenticular myopia in one molecularly diagnosed WMS4 patient.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and glaucoma, which can lead to blindness"
    explanation: >-
      Establishes the sight-threatening endpoint of the ocular course.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    The recessive form, the more common of the two, is caused by biallelic
    variants in ADAMTS10 (WMS1), LTBP2 (WMS3) or ADAMTS17 (WMS4).
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADAMTS10-, ADAMTS17-, and LTPBP2-related WMS are inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews assigns the three protease and binding-protein genes to
      autosomal recessive inheritance.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
    explanation: >-
      Gives the sibling recurrence risks used in counselling families with a
      recessive form.
- name: Autosomal dominant inheritance
  description: >-
    The dominant form (WMS2) is caused by heterozygous FBN1 variants, most
    clustering in the TB5 domain. Inheritance mode cannot be inferred from the
    clinical picture, only from the genotype.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FBN1-related WMS is inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews assigns FBN1-related WMS to autosomal dominant inheritance.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with autosomal dominant WMS has a 50% chance of inheriting the pathogenic variant."
    explanation: >-
      Gives the transmission risk used in counselling families with the dominant
      form.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone."
    explanation: >-
      Establishes that the two inheritance modes are clinically indistinguishable,
      which is why molecular testing rather than pedigree drives classification.
has_subtypes:
- name: WMS1
  display_name: Weill-Marchesani syndrome 1 (ADAMTS10-related, recessive)
  subtype_term:
    preferred_term: Weill-Marchesani syndrome 1
    term:
      id: MONDO:0010194
      label: Weill-Marchesani syndrome 1
  description: >-
    The prototypic recessive form, caused by biallelic pathogenic ADAMTS10
    variants. ADAMTS10 is a secreted metalloprotease that binds fibrillin-1 and
    accelerates microfibril biogenesis; patient fibroblasts deposit microfibrils
    sparsely. Cardiac anomalies are more frequent in the recessive forms.
  genes:
  - preferred_term: ADAMTS10
    term:
      id: hgnc:13201
      label: ADAMTS10
  evidence:
  - reference: PMID:15368195
    reference_title: "ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs."
    explanation: >-
      Original identification of ADAMTS10 as the recessive WMS gene.
- name: WMS2
  display_name: Weill-Marchesani syndrome 2 (FBN1-related, dominant)
  subtype_term:
    preferred_term: Weill-Marchesani syndrome 2, dominant
    term:
      id: MONDO:0012013
      label: Weill-Marchesani syndrome 2, dominant
  description: >-
    The dominant form, caused by heterozygous FBN1 variants. Variants in the TB5
    domain are associated with significantly shorter stature than variants
    elsewhere in the gene. The acronym GEMSS (glaucoma, ectopia,
    microspherophakia, stiff joints, short stature) was proposed for this form.
  genes:
  - preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-β-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain"
    explanation: >-
      Establishes the intragenic TB5 genotype-phenotype correlation within the
      dominant FBN1 arm.
- name: WMS3
  display_name: Weill-Marchesani syndrome 3 (LTBP2-related, recessive)
  subtype_term:
    preferred_term: Weill-Marchesani syndrome 3
    term:
      id: MONDO:0013899
      label: Weill-Marchesani syndrome 3
  description: >-
    A rare recessive form caused by biallelic LTBP2 variants. LTBP2 is a
    latent-TGF-beta-binding-protein-family member that associates with
    fibrillin-1 microfibrils; patient skin shows a disrupted microfibrillar
    network. Only two individuals were identified in a 61-patient series.
  genes:
  - preferred_term: LTBP2
    term:
      id: hgnc:6715
      label: LTBP2
  evidence:
  - reference: PMID:22539340
    reference_title: "LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping."
    explanation: >-
      Identifies the biallelic LTBP2 allele causing recessive WMS.
- name: WMS4
  display_name: Weill-Marchesani syndrome 4 (ADAMTS17-related, recessive)
  subtype_term:
    preferred_term: Weill-Marchesani 4 syndrome, recessive
    term:
      id: MONDO:0013176
      label: Weill-Marchesani 4 syndrome, recessive
  description: >-
    A recessive form caused by biallelic ADAMTS17 variants, and the most
    frequently identified genotype in a contemporary combined series. Classically
    described as having less severe cardiac involvement, presenting predominantly
    with musculoskeletal and ocular features, although valvular disease has since
    been reported.
  genes:
  - preferred_term: ADAMTS17
    term:
      id: hgnc:17109
      label: ADAMTS17
  evidence:
  - reference: PMID:31726086
    reference_title: "A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS."
    explanation: >-
      Characterizes the comparatively cardiac-sparing phenotype classically
      attributed to the ADAMTS17 arm.
  - reference: PMID:37506754
    reference_title: "Characteristics and genotype-phenotype correlations in ADAMTS17 mutation-related Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, one child was detected with valvular heart disease, which has not previously been reported in patients with ADAMTS17 mutations."
    explanation: >-
      Qualifies the cardiac-sparing characterization by documenting valvular
      disease in an ADAMTS17 patient.
classifications:
  isds_skeletal_category:
  - classification_value: acromelic_dysplasias
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 15 "Acromelic
      dysplasias"; listed as "Weill-Marchesani syndrome".
pathophysiology:
- name: ADAMTS10-Dependent Microfibril Assembly and Fibrillin-2 Remodeling
  biological_scale: MOLECULAR
  description: >-
    ADAMTS10 binds fibrillin-1 and accelerates fibrillin-1 microfibril biogenesis;
    WMS patient fibroblasts with ADAMTS10 variants deposit fibrillin-1
    microfibrils sparsely. ADAMTS10 also cleaves fibrillin-2 in vitro, and its
    absence in mice prevents the normal postnatal shift toward a
    fibrillin-1-predominant ocular zonule. These assembly and remodeling
    activities are distinct from the secretion-loss mechanism demonstrated for
    ADAMTS17 variants.
  genes:
  - preferred_term: ADAMTS10
    term:
      id: hgnc:13201
      label: ADAMTS10
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  evidence:
  - reference: PMID:21402694
    reference_title: "ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Taken together, these findings suggest that ADAMTS10 participates in microfibril biogenesis rather than in fibrillin-1 turnover."
    explanation: >-
      Establishes ADAMTS10 as a microfibril assembly factor rather than a
      degradative protease, which sets the direction of the disease mechanism.
  - reference: PMID:21402694
    reference_title: "ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "fibroblasts obtained from a Weill-Marchesani syndrome patient with ADAMTS10 mutations deposited fibrillin-1 microfibrils sparsely compared with unaffected control cells"
    explanation: >-
      Direct patient-cell evidence that the ADAMTS10 lesion reduces fibrillin-1
      microfibril deposition.
  - reference: PMID:30201140
    reference_title: "Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ADAMTS10 was found to cleave fibrillin-2, providing an explanation for persistence of fibrillin-2 at these sites."
    explanation: >-
      Identifies fibrillin-2 as an ADAMTS10 substrate; the cleavage assignment is
      IN_VITRO, while its ocular consequence is assessed separately in the mouse.
  downstream:
  - target: Deficient Fibrillin Microfibril Network
    description: >-
      Loss of the assembly-promoting protease leaves fibrillin-1 poorly deposited
      into microfibrils.
  - target: Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation
    description: >-
      The ADAMTS10 WMS knock-in mouse shows decreased SMAD1/5/8 signaling,
      restricting this experimentally observed signaling route to the ADAMTS10
      arm rather than to every WMS genotype.
  - target: Altered Skeletal Myogenesis and Hypermuscularity
    description: >-
      Increased muscle mass, increased myofiber number and altered skeletal
      myogenesis were observed in the ADAMTS10 WMS knock-in mouse; this route is
      not generalized to the other genetic forms.
  - target: Zonular Insufficiency
    description: >-
      Failure of postnatal fibrillin-2 clearance perturbs maturation of the
      ADAMTS10-deficient ocular zonule.
- name: ADAMTS17 Secretion Loss and Microfibril Dysregulation
  biological_scale: MOLECULAR
  description: >-
    Pathogenic ADAMTS17 missense variants can markedly reduce secretion of the
    protein into the extracellular medium. Patient fibroblasts additionally show
    intracellular accumulation of fibrillin-1 and type I collagen with abnormal
    dermal extracellular matrix, consistent with loss of extracellular ADAMTS17
    and disruption of early matrix-protein secretion or assembly.
  genes:
  - preferred_term: ADAMTS17
    term:
      id: hgnc:17109
      label: ADAMTS17
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  evidence:
  - reference: PMID:32616716
    reference_title: "A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This variant caused severely reduced secretion of ADAMTS17 into the extracellular medium, suggesting functional loss of ADAMTS17 rather than impairment of a domain-specific function or interaction."
    explanation: >-
      Functional expression data establish secretion loss as the effect of the
      p.Cys1023Tyr WMS4 allele.
  - reference: PMID:31726086
    reference_title: "A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."
    explanation: >-
      Patient-derived fibroblasts link impaired ADAMTS17 secretion to abnormal
      handling of two extracellular-matrix proteins.
  downstream:
  - target: Deficient Fibrillin Microfibril Network
    description: >-
      Loss of extracellular ADAMTS17 perturbs fibrillin microfibril biogenesis or
      maturation.
  - target: Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation
    description: >-
      Adamts17 loss alters fibrillin-2 incorporation and reduces growth-plate
      BMP-SMAD signaling in vivo.
- name: FBN1 WMS Microfibril-Scaffold Disruption
  biological_scale: MOLECULAR
  description: >-
    Heterozygous FBN1 WMS variants alter the fibrillin-1 scaffold itself. A
    replicated human WMS deletion removes three fibrillin-1 domains and an
    ADAMTS-like-protein binding site; human and mouse ultrastructure shows altered
    microfibrils and a tissue-local microenvironmental response that differs from
    the broad TGF-beta activation associated with Marfan syndrome.
  genes:
  - preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  evidence:
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin."
    explanation: >-
      Identifies the structural deletion and lost binding interface in a human
      family whose allele was replicated in mice; OTHER reflects the combined
      human and model evidence in the same report.
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production."
    explanation: >-
      Directly supports the altered-scaffold and tissue-microenvironment claim
      using human tissue and the allele-matched mouse.
  downstream:
  - target: Deficient Fibrillin Microfibril Network
    description: >-
      Altering fibrillin-1 changes the structure and local organization of the
      microfibril scaffold.
  - target: Dermal Matrix Remodeling and Skin Thickening
    description: >-
      The allele-matched model links the altered scaffold to dermal collagen
      production and the thick-skin phenotype.
- name: LTBP2-Dependent Microfibril-Bundle Assembly Failure
  biological_scale: MOLECULAR
  description: >-
    LTBP2 binds fibrillin-1 and is required for stable microfibril-bundle
    assembly, particularly in the ciliary zonule. WMS-associated mutant proteins
    can be retained intracellularly rather than secreted. Unlike other LTBPs,
    LTBP2 does not covalently bind latent TGF-beta; any effect on TGF-beta storage
    is therefore indirect, potentially through competition with LTBP1 for
    fibrillin-1 binding.
  genes:
  - preferred_term: LTBP2
    term:
      id: hgnc:6715
      label: LTBP2
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  evidence:
  - reference: PMID:24908666
    reference_title: "Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The findings of this study suggest that LTBP-2 is an essential component for the formation of microfibril bundles in ciliary zonules."
    explanation: >-
      Human ciliary-cell perturbation, rescue experiments and an Ltbp2-null mouse
      jointly establish the bundle-assembly role.
  - reference: PMID:17293099
    reference_title: "LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LTBP-2 is a matrix protein of unknown function since, unlike other LTBPs, it does not form covalent complexes with latent TGF-beta."
    explanation: >-
      Prevents conflation of LTBP2 with latent-TGF-beta-binding LTBPs and limits
      any signaling claim to an indirect mechanism.
  downstream:
  - target: Deficient Fibrillin Microfibril Network
    description: >-
      Loss of secreted LTBP2 disrupts formation of stable fibrillin-containing
      microfibril bundles.
  - target: Zonular Insufficiency
    description: >-
      The ciliary zonule is the tissue in which LTBP2-dependent bundle failure is
      directly demonstrated.
- name: Deficient Fibrillin Microfibril Network
  biological_scale: TISSUE
  description: >-
    The four genetic arms converge on abnormal assembly, composition or
    organization of fibrillin-containing extracellular microfibrils. Human
    ADAMTS10-mutant fibroblasts deposit fibrillin-1 sparsely, LTBP2-mutant skin
    has a disrupted microfibrillar network, and ADAMTS17-mutant cells mishandle
    matrix proteins. Microfibrils provide both structural support and local
    control of TGF-beta-superfamily growth-factor bioavailability, but the
    direction and ligand specificity of signaling changes are not uniform across
    WMS genotypes. The downstream edges from this shared node therefore capture
    only structural or phenotypic convergence, while experimentally resolved
    signaling and myogenesis routes remain attached to their specific gene arms.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily."
    explanation: >-
      Establishes the dual structural and growth-factor-regulatory role of the
      microfibril that explains the breadth of the phenotype.
  - reference: PMID:22539340
    reference_title: "LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin."
    explanation: >-
      Direct patient-tissue demonstration of the disrupted microfibrillar network.
  - reference: PMID:25957949
    reference_title: "ADAMTS proteins as modulators of microfibril formation and function."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Together, this strongly suggests that ADAMTS proteins are involved either in microfibril assembly, stability, and anchorage, or the formation of function-specific supramolecular networks having microfibrils as their foundation."
    explanation: >-
      Review-level synthesis supports convergence of ADAMTS10 and ADAMTS17 on
      microfibril assembly, stability or function-specific matrix networks while
      leaving their gene-specific mechanisms distinct.
  downstream:
  - target: Zonular Insufficiency
    description: >-
      The ciliary zonule is a specialized fibrillin microfibril structure, so
      microfibril deficiency directly weakens lens suspension.
  - target: Acromelic Long-Bone Growth Restriction
    description: >-
      Abnormal growth-plate microfibrils and signaling restrict longitudinal bone
      growth.
  - target: Joint Limitation
    description: >-
      Matrix dysfunction in periarticular connective tissues is a plausible
      upstream contributor to the stiff-joint phenotype, although this edge has
      not been resolved experimentally in human tissue.
  - target: Dermal Matrix Remodeling and Skin Thickening
    description: >-
      Genotype-specific human and mouse studies connect altered microfibrils to
      dermal collagen or elastic-fiber abnormalities.
- name: Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation
  biological_scale: MOLECULAR
  description: >-
    Adamts17-null growth plates show increased fibrillin-2 incorporation,
    reduced phospho-Smad1 and delayed terminal chondrocyte differentiation; BMP
    treatment prevents the differentiation delay. An independent ADAMTS10 WMS
    mouse also shows reduced SMAD1/5/8 signaling. These data support a reduced
    BMP-SMAD branch for the skeletal phenotype, not a generic claim that all WMS
    tissues have direct TGF-beta overactivation.
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:31201465
    reference_title: "Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Delayed terminal differentiation of Adamts17-/- chondrocytes, observed both in primary chondrocyte and primordial metatarsal cultures, and was prevented by BMP treatment."
    explanation: >-
      The delayed differentiation and its BMP rescue provide functional evidence
      for reduced BMP signaling downstream of Adamts17 loss.
  - reference: PMID:31201465
    reference_title: "Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with this, phospho-Smad1 levels were downregulated in the hypertrophic zone of the growth plate and in Adamts17-/- primary chondrocytes."
    explanation: >-
      Directly localizes reduced BMP-SMAD output to the affected growth plate and
      Adamts17-null chondrocytes.
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data indicate that decreased SMAD1/5/8 and increased p38/MAPK signalling are associated with ADAMTS10-induced WMS."
    explanation: >-
      Identifies the specific signalling shift downstream of the ADAMTS10 lesion
      in a CRISPR knock-in mouse model of the human truncation.
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results correlated with expression data showing down regulation of Growth differentiation factor (GDF8) and Bone Morphogenetic Protein (BMP) growth factor genes."
    explanation: >-
      Links the growth and skeletal muscle phenotypes to reduced GDF8 and BMP
      family expression.
  downstream:
  - target: Acromelic Long-Bone Growth Restriction
    description: >-
      Reduced BMP-SMAD output delays chondrocyte maturation and restricts long-bone
      growth in the mouse models.
- name: Zonular Insufficiency
  biological_scale: TISSUE
  description: >-
    The ciliary zonule that suspends and tensions the lens is itself built from
    fibrillin-containing microfibril bundles. LTBP2 loss directly compromises
    zonule formation, while Adamts10-null mice retain fibrillin-2-rich, thick
    zonular fibers with reduced fibrillin-1. Failure of normal bundle assembly or
    maturation reduces zonular support and links the matrix lesion to both lens
    shape and position abnormalities.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness."
    explanation: >-
      Establishes that lens-shape and lens-position abnormalities coexist in the
      characteristic childhood ocular presentation; it directly supports only
      the lens-shape-to-myopia relation.
  - reference: PMID:24908666
    reference_title: "Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ltbp2(-/-) mice survived to adulthood but developed lens luxation caused by compromised ciliary zonule formation"
    explanation: >-
      Directly links LTBP2 deficiency to compromised zonule formation and lens
      luxation in the knockout mouse.
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, there are abnormalities in the ciliary apparatus of the eye with decreased ciliary processes and abundant fibrillin-2 microfibrils suggesting perturbation of a developmental expression switch."
    explanation: >-
      Model-organism evidence of ciliary apparatus abnormality with a
      fibrillin-2-to-fibrillin-1 switch failure.
  - reference: PMID:30201140
    reference_title: "Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in contrast to wild-type eyes, Adamts10-/- zonule fibers were thicker and immunostained strongly with fibrillin-2 antibodies into adulthood, whereas fibrillin-1 staining was reduced"
    explanation: >-
      Shows the zonule retains immature fibrillin-2 composition when ADAMTS10 is
      absent, a compositional rather than purely quantitative defect.
  downstream:
  - target: Microspherophakia and Lenticular Myopia
    description: >-
      Without zonular tension the lens relaxes into a small spherical shape.
  - target: Ectopia Lentis
    description: >-
      A deficient zonule also fails to anchor the lens, allowing it to displace.
- name: Microspherophakia and Lenticular Myopia
  biological_scale: TISSUE
  description: >-
    Reduced zonular tension is the proposed mechanical basis for the small,
    steeply curved lens. The abnormal lens shape increases refractive power and
    produces lenticular rather than axial myopia. A longitudinal WMS4 case showed
    progressive childhood lens thickening with increasing lens power and myopic
    refractive error, but that single-patient observation should not be treated as
    a population-level trajectory.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens"
    explanation: >-
      States that the myopia follows from the abnormal lens shape, establishing
      the lenticular mechanism.
  - reference: PMID:36698805
    reference_title: "Abnormal lens thickening in a child with Weill-Marchesani syndrome 4: A 3-year follow-up case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the 3 years of follow-up, the thickness of lenses increased significantly (right 4.49 mm, left 4.48 mm), but the equatorial diameter of the lenses had no significant change (right 7.32 mm, left 7.21 mm). As the equivalent lens power increased, the patient's myopia spherical refractive error rose accordingly."
    explanation: >-
      Longitudinal biometric evidence in one child links progressive lens
      thickening and power to worsening lenticular myopia.
  downstream:
  - target: Pupillary Block and Angle Closure
    description: >-
      A small, thick, forward-sitting lens crowds the anterior chamber and
      obstructs aqueous flow through the pupil.
- name: Ectopia Lentis
  biological_scale: TISSUE
  description: >-
    Failure of zonular anchorage allows the lens to subluxate or dislocate. A
    displaced lens is itself a mechanical cause of pupillary block, and it is the
    finding whose early detection and removal drives the whole management
    strategy.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ectopia lentis (abnormal position of the lens)"
    explanation: >-
      Defines ectopia lentis as the lens-position abnormality of WMS.
  downstream:
  - target: Pupillary Block and Angle Closure
    description: >-
      An anteriorly displaced lens obstructs the pupil directly.
- name: Pupillary Block and Angle Closure
  biological_scale: TISSUE
  description: >-
    In WMS the initiating glaucoma lesion is anatomical: a microspherophakic or
    displaced lens can block aqueous passage at the pupil and promote chronic
    angle closure. This is not equivalent to the trabecular-meshwork initiating
    lesion in the conserved glaucoma module, so conformance begins only at the
    downstream elevated-pressure node. The lens-driven anatomy also explains why
    GeneReviews warns that miotics and mydriatics can have paradoxical effects or
    induce pupillary block.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"
    explanation: >-
      Identifies pupillary block and chronic angle closure as the operative
      mechanism of glaucoma in WMS.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics"
    explanation: >-
      Documents the paradoxical drug response that follows from the lens-driven
      rather than outflow-driven mechanism.
  downstream:
  - target: Elevated Intraocular Pressure
    description: >-
      Obstructed aqueous egress raises intraocular pressure.
- name: Elevated Intraocular Pressure
  biological_scale: ORGANISM
  conforms_to: "glaucoma_optic_neuropathy#Elevated Intraocular Pressure"
  description: >-
    Aqueous outflow obstruction raises intraocular pressure. From this point
    onward WMS runs along the conserved glaucoma pathway, which is why the
    downstream nodes conform to the module without substitution.
  evidence:
  - reference: PMID:32561029
    reference_title: "The trabecular meshwork: Structure, function and clinical implications. A review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glaucoma is a blinding optic neuropathy, the main risk factor for which is increased intraocular pressure (IOP)."
    explanation: >-
      Establishes increased IOP as the principal pressure-mediated risk factor in
      the conserved glaucoma pathway; this is general glaucoma review evidence.
  - reference: PMID:25397784
    reference_title: "Visual outcome and incidence of glaucoma in patients with microspherophakia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glaucoma developed in 16 eyes (44.4%). Half of them had high IOP at presentation."
    explanation: >-
      A microspherophakia cohort directly documents high IOP in affected eyes,
      although the cohort was not restricted to molecularly confirmed WMS.
  downstream:
  - target: Retinal Ganglion Cell Apoptosis
    description: >-
      Sustained pressure elevation drives retinal ganglion cell death.
- name: Retinal Ganglion Cell Apoptosis
  biological_scale: CELLULAR
  conforms_to: "glaucoma_optic_neuropathy#Retinal Ganglion Cell Apoptosis"
  description: >-
    Pressure-driven apoptotic loss of retinal ganglion cells, the cellular event
    that makes glaucomatous damage irreversible and therefore the reason WMS
    management is pre-emptive rather than reactive.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:25914734
    reference_title: "Biochemical changes and treatment in glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This disease is a neurodegenerative disorder characterized by high intraocular pressure, loss of retinal ganglion cells (apoptosis)."
    explanation: >-
      Supplies general-glaucoma evidence for the conserved retinal-ganglion-cell
      apoptosis step; WMS-specific evidence establishes the upstream glaucoma,
      not this cellular event.
  downstream:
  - target: Optic Nerve Degeneration and Neuroinflammation
    description: >-
      Ganglion-cell and axonal loss is accompanied by optic-nerve degeneration
      and a neuroinflammatory response.
- name: Optic Nerve Degeneration and Neuroinflammation
  biological_scale: TISSUE
  conforms_to: "glaucoma_optic_neuropathy#Optic Nerve Degeneration and Neuroinflammation"
  description: >-
    Progressive retinal-ganglion-cell loss is accompanied by optic-nerve axon
    degeneration and neuroinflammation. This intermediate is conserved across
    glaucoma subtypes and is supported by general glaucoma evidence rather than
    WMS-specific tissue studies.
  biological_processes:
  - preferred_term: neuroinflammatory response
    term:
      id: GO:0150076
      label: neuroinflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:33670885
    reference_title: "Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oxidative DNA damage accumulates in this degenerating TM, accelerating a neuroinflammation process which drives the neurodegeneration in POAG pathology"
    explanation: >-
      Supports the conserved neuroinflammatory amplification step using general
      glaucoma review evidence; it is not evidence for the WMS initiating lesion.
  downstream:
  - target: Progressive Glaucomatous Optic Neuropathy and Vision Loss
    description: >-
      Cumulative neuronal and axonal injury produces progressive optic neuropathy.
- name: Progressive Glaucomatous Optic Neuropathy and Vision Loss
  biological_scale: ORGANISM
  conforms_to: "glaucoma_optic_neuropathy#Progressive Glaucomatous Optic Neuropathy"
  description: >-
    Optic nerve degeneration progressing to blindness if the lens problem is not
    corrected early. This endpoint is why the management priority is early lens
    removal rather than pressure-lowering drops.
  evidence:
  - reference: PMID:33670885
    reference_title: "Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive degeneration of retinal ganglion cells (RGC) with a specific pattern of changes in the optic nerve head and retinal nerve fiber layer"
    explanation: >-
      Supplies the conserved structural endpoint from a general glaucoma review.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glaucoma, which can lead to blindness"
    explanation: >-
      Establishes progression to blindness as the ocular endpoint of untreated
      WMS glaucoma.
- name: Acromelic Long-Bone Growth Restriction
  biological_scale: ORGANISM
  description: >-
    Proportionate short stature and brachydactyly place WMS among the acromelic
    dysplasias. Adamts10 and Adamts17 mouse models map this outcome to shorter
    long bones, abnormal growth-plate zones, altered fibrillin-2 deposition and
    impaired chondrocyte maturation.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations."
    explanation: >-
      Places WMS nosologically among the acromelic dysplasias by its systemic
      triad.
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation."
    explanation: >-
      Model-organism evidence linking the matrix defect to growth plate
      disorganization and reduced long bone growth.
  - reference: PMID:31201465
    reference_title: "Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adamts17-/- mice recapitulated WMS, showing shorter long bones, brachydactyly, and thick skin."
    explanation: >-
      Independently reproduces the acromelic skeletal outcome in an Adamts17-null
      model.
- name: Joint Limitation
  biological_scale: ORGANISM
  description: >-
    Joint stiffness and restricted mobility are common. Their tissue-level
    mechanism is less directly resolved than the growth-plate mechanism, so this
    node represents the systemic consequence without asserting a specific
    signaling pathway or universal trajectory.
  evidence:
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joint limitations (49% in AR, 77% in AD, Fischer 0.010)"
    explanation: >-
      Quantifies joint limitation and its difference between recessive and
      dominant WMS in a 128-patient literature review.
- name: Dermal Matrix Remodeling and Skin Thickening
  biological_scale: TISSUE
  description: >-
    WMS can alter dermal microfibrils, elastic fibers and collagen homeostasis.
    The best resolved genotype-specific evidence comes from an allele-matched
    FBN1 WMS mouse and human tissue, while ADAMTS17 patient skin shows abnormal
    elastic fibers and collagen handling.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice."
    explanation: >-
      Links a human WMS allele to thick skin in an allele-matched model; OTHER
      reflects the combined human and animal design.
  - reference: PMID:31726086
    reference_title: "A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband."
    explanation: >-
      Direct patient-dermis evidence of matrix remodeling in ADAMTS17-related WMS.
- name: Altered Skeletal Myogenesis and Hypermuscularity
  biological_scale: TISSUE
  description: >-
    Increased muscle mass is modeled in the ADAMTS10 WMS knock-in mouse, where
    more myofibers and altered myogenesis accompany the skeletal phenotype. This
    supports a developmental muscle-remodeling mechanism but does not establish
    that every WMS genotype shares the same pathway.
  evidence:
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis."
    explanation: >-
      Provides model-organism evidence for altered myogenesis underlying the
      hypermuscular phenotype.
phenotypes:
- name: Microspherophakia
  category: Ophthalmologic
  description: >-
    A small, spherical lens is the cardinal ocular feature. It causes high
    lenticular myopia directly and predisposes to pupillary block. It is
    significantly more frequent in the recessive than the dominant form.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microspherophakia
    term:
      id: HP:0030961
      label: Microspherophakia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007)"
    explanation: >-
      Quantifies microspherophakia at 94% in recessive and 74% in dominant WMS;
      the dominant estimate and the 42/61 contemporary combined-cohort count
      support the conservative FREQUENT band for WMS overall.
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61)."
    explanation: >-
      The contemporary molecular series finds spherophakia in 42 of 61
      individuals, supporting a FREQUENT rather than VERY_FREQUENT overall band.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness."
    explanation: >-
      Supports childhood recognition of the characteristic ocular phenotype.
- name: Ectopia lentis
  category: Ophthalmologic
  description: >-
    Displacement of the lens from its normal position, following from zonular
    insufficiency. Significantly more frequent in the dominant form, the mirror
    image of the microspherophakia distribution.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ectopia lentis
    term:
      id: HP:0001083
      label: Ectopia lentis
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ectopia lentis (64% in AR, 84% in AD, Fischer 0.016)"
    explanation: >-
      Quantifies ectopia lentis at 64% recessive and 84% dominant, and documents
      the inverse gene-arm distribution relative to microspherophakia.
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61)."
    explanation: >-
      Confirms in a molecularly defined 61-patient series that eye anomalies are
      universal, with these two as the dominant findings.
- name: High myopia
  category: Ophthalmologic
  description: >-
    Severe myopia arises secondarily from the abnormally steep, spherical lens
    rather than from axial elongation, so it is lenticular in origin.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myopia secondary to the abnormal shape of the lens"
    explanation: >-
      Establishes the lenticular rather than axial origin of the myopia.
  - reference: PMID:36698805
    reference_title: "Abnormal lens thickening in a child with Weill-Marchesani syndrome 4: A 3-year follow-up case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 8-year-old boy presented to our ophthalmology department with progressive myopia for 1 year. He had high myopia in both eyes with normal funds, intraocular pressure, and axial length."
    explanation: >-
      A longitudinal WMS4 case illustrates progressive childhood lenticular
      myopia without axial elongation; it does not establish population frequency.
- name: Glaucoma
  category: Ophthalmologic
  description: >-
    Secondary glaucoma, typically by pupillary block and angle closure, and the
    manifestation that threatens sight. It is the reason ophthalmologic
    surveillance is annual and lens removal is pre-emptive.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
    onset:
      onset_category: CHILDHOOD
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and glaucoma, which can lead to blindness"
    explanation: >-
      GeneReviews lists glaucoma among the cardinal ocular problems and its
      sight-threatening consequence.
- name: Angle closure glaucoma
  category: Ophthalmologic
  description: >-
    The specific glaucoma mechanism in WMS: the small spherical or subluxated
    lens crowds the anterior chamber and blocks the pupil, closing the angle.
    This is what makes the pharmacology paradoxical and lens removal the
    definitive intervention.
  phenotype_term:
    preferred_term: Angle closure glaucoma
    term:
      id: HP:0012109
      label: Angle closure glaucoma
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "trabeculectomy in advanced chronic angle closure glaucoma"
    explanation: >-
      GeneReviews identifies chronic angle closure as the glaucoma subtype
      requiring surgical management in WMS.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Lens opacity is a reported ocular complication of WMS, but available sources
    do not support a reliable syndrome-wide frequency estimate.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:32616716
    reference_title: "A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients may also have microspherophakia, severe myopia, ectopia lentis, glaucoma and cataracts."
    explanation: >-
      Contemporary review background recognizes cataract as part of the ocular
      spectrum; it does not quantify frequency.
- name: Short stature
  category: Growth
  description: >-
    Proportionate short stature is present in about three quarters of
    molecularly confirmed individuals, ranging from roughly two to five and a
    half standard deviations below the mean.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature was present in 73% (from -2.2 to -5.5 SD)"
    explanation: >-
      Quantifies frequency at 73% with the severity range, supporting a FREQUENT
      band.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Height of adult males is 142-169 cm; height of adult females is 130-157 cm."
    explanation: >-
      Provides the adult height ranges that define the degree of short stature.
- name: Brachydactyly
  category: Skeletal
  description: >-
    Short digits, part of the acromelic triad that defines the systemic
    phenotype alongside short stature and joint limitation.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations."
    explanation: >-
      Brachydactyly is one of the three defining features of the acromelic
      dysplasia group to which WMS belongs.
- name: Joint stiffness
  category: Skeletal
  description: >-
    Joint limitation is significantly more frequent in the dominant form. It
    also carries an anaesthetic implication, since stiff joints complicate
    airway positioning.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joint limitations (49% in AR, 77% in AD, Fischer 0.010)"
    explanation: >-
      Quantifies joint limitation at 49% recessive and 77% dominant, supporting a
      FREQUENT band.
- name: Abnormal heart valve morphology
  category: Cardiovascular
  description: >-
    Valvular heart disease is the principal cardiovascular manifestation and is
    significantly more frequent in the recessive than the dominant form. It is
    the reason cardiac surveillance is part of routine care.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart valve morphology
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "10/61 individuals had valvulopathy"
    explanation: >-
      Quantifies valvulopathy at 10 of 61 molecularly confirmed individuals,
      roughly 16%, supporting an OCCASIONAL band.
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004)"
    explanation: >-
      Documents the significantly higher cardiac burden of the recessive forms in
      the older literature review.
- name: Generalized muscle hypertrophy
  category: Musculoskeletal
  description: >-
    A pseudo-athletic, unusually muscular build is characteristic and, with the
    thick skin and short stature, produces the stocky habitus that is the visual
    opposite of the Marfan phenotype.
  phenotype_term:
    preferred_term: Generalized muscle hypertrophy
    term:
      id: HP:0003720
      label: Generalized muscle hypertrophy
  evidence:
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin."
    explanation: >-
      Lists hypermuscularity among the defining features of WMS.
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis."
    explanation: >-
      Model-organism correlate of the human hypermuscularity, attributing it to
      altered myogenesis rather than training.
- name: Thickened skin
  category: Integumentary
  description: >-
    Thick skin, together with an unusually muscular build, contributes to the
    stocky habitus that contrasts so sharply with Marfan syndrome.
  phenotype_term:
    preferred_term: Thickened skin
    term:
      id: HP:0001072
      label: Thickened skin
  evidence:
  - reference: PMID:30060141
    reference_title: "ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin."
    explanation: >-
      Lists thickened skin and hypermuscularity among the defining features of
      WMS.
genetic:
- name: ADAMTS10
  gene_term:
    preferred_term: ADAMTS10
    term:
      id: hgnc:13201
      label: ADAMTS10
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    Secreted metalloprotease that binds fibrillin-1 at two sites and promotes
    microfibril deposition. Expressed in skin, fetal chondrocytes, and fetal and
    adult heart, matching the tissue distribution of the phenotype. Its zymogen
    resists furin activation, so it acts as an assembly factor rather than an
    efficient fibrillinase.
  evidence:
  - reference: PMID:15368195
    reference_title: "ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans."
    explanation: >-
      Establishes the causal role of ADAMTS10 across the exact organ set affected
      in WMS.
  - reference: PMID:15368195
    reference_title: "ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart."
    explanation: >-
      Expression data matching the affected tissues, supporting tissue specificity
      of the phenotype.
  case_fractions:
  - population: 61 molecularly confirmed individuals (18-person cohort plus 43 literature cases)
    case_fraction_percent: 31.1
    cohort_size: 61
    notes: ADAMTS10 variants were present in 19 of 61 individuals.
    evidence:
    - reference: PMID:37734846
      reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."
      explanation: >-
        Supports the 19/61 ADAMTS10 case fraction in the combined molecular series.
- name: ADAMTS17
  gene_term:
    preferred_term: ADAMTS17
    term:
      id: hgnc:17109
      label: ADAMTS17
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    The most frequently identified WMS gene in a contemporary combined series
    (21 of 61 patients). The studied variant blocks ADAMTS17 secretion, with
    intracellular accumulation of both fibrillin-1 and type I collagen in patient
    fibroblasts, suggesting a broader secretory or early-assembly role.
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."
    explanation: >-
      Gives the relative genetic contribution of each WMS gene in a combined
      cohort and literature series.
  - reference: PMID:31726086
    reference_title: "A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."
    explanation: >-
      Functional mechanism of the ADAMTS17 allele: blocked secretion with
      intracellular retention of matrix components.
  case_fractions:
  - population: 61 molecularly confirmed individuals (18-person cohort plus 43 literature cases)
    case_fraction_percent: 34.4
    cohort_size: 61
    notes: ADAMTS17 variants were present in 21 of 61 individuals.
    evidence:
    - reference: PMID:37734846
      reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."
      explanation: >-
        Supports the 21/61 ADAMTS17 case fraction in the combined molecular series.
- name: FBN1
  gene_term:
    preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous variants cause the dominant form. The same gene causes Marfan
    syndrome, with an essentially opposite habitus. Variant context and domain
    can modify phenotype, but they are not a deterministic switch; within WMS,
    TB5-domain variants were associated with shorter stature than variants
    outside TB5.
  evidence:
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10, ADAMTS17 and LTBP2 are responsible for a recessive form of WMS."
    explanation: >-
      States the gene-to-inheritance-mode mapping across the four WMS genes.
  case_fractions:
  - population: 61 molecularly confirmed individuals (18-person cohort plus 43 literature cases)
    case_fraction_percent: 31.1
    cohort_size: 61
    notes: FBN1 variants were present in 19 of 61 individuals.
    evidence:
    - reference: PMID:37734846
      reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."
      explanation: >-
        Supports the 19/61 FBN1 case fraction in the combined molecular series.
- name: LTBP2
  gene_term:
    preferred_term: LTBP2
    term:
      id: hgnc:6715
      label: LTBP2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    LTBP2 is an extracellular-matrix protein that associates with
    fibrillin-1-containing microfibrils. Despite its family name, it does not
    form covalent complexes with latent TGF-beta. It was the rarest WMS gene in a
    combined series, accounting for 2 of 61 individuals.
  evidence:
  - reference: PMID:22539340
    reference_title: "LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils."
    explanation: >-
      Establishes LTBP2 as a fibrillin-1 microfibril-associated protein, placing
      it in the same molecular system as the other three genes.
  - reference: PMID:17293099
    reference_title: "LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LTBP-2 is a matrix protein of unknown function since, unlike other LTBPs, it does not form covalent complexes with latent TGF-beta."
    explanation: >-
      Clarifies that LTBP2 is not a direct latent-TGF-beta carrier despite its
      family name.
  case_fractions:
  - population: 61 molecularly confirmed individuals (18-person cohort plus 43 literature cases)
    case_fraction_percent: 3.3
    cohort_size: 61
    notes: LTBP2 variants were present in 2 of 61 individuals.
    evidence:
    - reference: PMID:37734846
      reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2."
      explanation: >-
        Supports the 2/61 LTBP2 case fraction in the combined molecular series.
diagnosis:
- name: Clinical diagnosis
  description: >-
    The diagnosis is established clinically in a proband with the characteristic
    combination of ocular, skeletal and joint findings. The ophthalmological
    findings are mandatory for the diagnosis; the systemic phenotype is more
    variable than originally described.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis WMS is established in a proband with characteristic clinical features."
    explanation: >-
      GeneReviews states that the diagnosis rests on characteristic clinical
      features.
  - reference: PMID:37734846
    reference_title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described"
    explanation: >-
      Establishes the ocular findings as the obligate diagnostic anchor and warns
      that the systemic phenotype is variable.
- name: Anterior-segment eye examination and ocular biometry
  description: >-
    Detailed ophthalmic assessment should evaluate lens shape and thickness,
    refraction, axial length, lens position, anterior-chamber angle and
    intraocular pressure. In children, progressive lens-induced myopia with a
    normal axial length can be an early clue before the full systemic phenotype
    is recognized.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  results: >-
    Microspherophakia or progressive lens thickening, lenticular myopia, ectopia
    lentis or iridodonesis, angle narrowing and/or elevated intraocular pressure.
  evidence:
  - reference: PMID:36698805
    reference_title: "Abnormal lens thickening in a child with Weill-Marchesani syndrome 4: A 3-year follow-up case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive clinical examinations and genetic testing may improve diagnosis, which allows early therapeutic interventions for complications and better visual outcomes for the patient."
    explanation: >-
      The longitudinal WMS4 report demonstrates how multimodal ocular biometry
      can distinguish progressive lens-induced myopia from ordinary axial myopia.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness."
    explanation: >-
      Defines the childhood ocular abnormalities the examination is intended to
      detect.
- name: Molecular genetic testing
  description: >-
    Molecular testing confirms the diagnosis when clinical features are
    inconclusive, and is the only way to assign inheritance mode, since the
    recessive and dominant forms cannot be told apart clinically.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in ADAMTS10, ADAMTS17, or LTBP2 or of a heterozygous pathogenic variant in FBN1 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive."
    explanation: >-
      Specifies the four-gene molecular testing strategy and its role relative to
      clinical diagnosis.
treatments:
- name: Early lens extraction
  description: >-
    Early detection and removal of an ectopic lens is the central preventive
    intervention, taken to reduce the chance of pupillary block and consequent
    glaucoma. Because the lens is the upstream cause of the pressure rise, lens
    surgery is mechanistically prior to any pressure-lowering measure.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Pupillary Block and Angle Closure
    treatment_effect: INHIBITS
    description: >-
      Removing the microspherophakic or subluxated lens eliminates the anatomical
      cause of pupillary block before pressure rises.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early detection and removal of an ectopic lens to decrease the possibility of pupillary block and glaucoma."
    explanation: >-
      GeneReviews names early lens removal as the treatment directed at the
      pupillary block mechanism.
- name: Peripheral iridectomy
  description: >-
    Peripheral iridectomy can prevent or relieve pupillary block by creating an
    alternative route for aqueous humor around the obstructed pupil.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Pupillary Block and Angle Closure
    treatment_effect: INHIBITS
    description: >-
      Iridectomy bypasses the blocked pupil and directly addresses the
      lens-driven initiating lesion.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"
    explanation: >-
      Specifically supports peripheral iridectomy for prevention or relief of
      pupillary block.
- name: Trabeculectomy for advanced chronic angle-closure glaucoma
  description: >-
    Trabeculectomy is considered when chronic angle closure is advanced and
    pressure remains inadequately controlled, creating a new aqueous outflow
    pathway downstream of the lens-driven block.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Elevated Intraocular Pressure
    treatment_effect: INHIBITS
    description: >-
      The filtering procedure lowers pressure after chronic angle closure has
      established persistent outflow impairment.
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma"
    explanation: >-
      Specifically supports trabeculectomy in advanced chronic angle-closure
      glaucoma.
- name: Avoidance of ophthalmic miotics and mydriatics
  description: >-
    A drug-safety measure rather than a therapy. Ophthalmic miotics and
    mydriatics must be avoided because they can induce pupillary block: this is
    the paradoxical response that makes medical glaucoma management difficult in
    WMS, and it inverts the usual pharmacological reflex for angle closure.
    Activities carrying a risk of eye injury should also be avoided.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Ophthalmic miotics and mydriatics because they can induce pupillary block; activities that increase risk of eye injury."
    explanation: >-
      GeneReviews Agents/Circumstances to Avoid section, the drug-safety warning
      specific to this disorder.
- name: Annual ophthalmologic surveillance
  description: >-
    Annual ophthalmology examinations, aimed at detecting an ectopic lens early
    enough to remove it before pupillary block and glaucoma develop.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual ophthalmology examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma."
    explanation: >-
      Establishes the surveillance interval and its explicit preventive rationale.
- name: Cardiac surveillance
  description: >-
    Regular cardiac follow-up with echocardiography and electrocardiography,
    warranted by the valvular disease burden, with treatment of cardiac anomalies
    directed by a cardiologist.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular cardiac follow up with echocardiogram and electrocardiography."
    explanation: >-
      Specifies the cardiac surveillance modality recommended in WMS.
- name: Physical therapy for joint limitation
  description: >-
    Physical therapy is considered for joint stiffness and reduced mobility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consider physical therapy for joint issues."
    explanation: >-
      GeneReviews recommends considering physical therapy for the joint
      manifestations.
- name: Annual growth and joint-range surveillance
  description: >-
    Height and joint range of motion should be assessed annually to document
    growth restriction and joint limitation and to guide timely rehabilitation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual assessment of height and joint range of motion."
    explanation: >-
      Provides the explicit surveillance interval and outcomes.
- name: Pre-anaesthetic airway evaluation
  description: >-
    Careful evaluation before anaesthesia is required because stiff joints,
    poorly aligned teeth and maxillary hypoplasia together predict a difficult
    airway. This is a procedural safety consideration that follows directly from
    the connective tissue and craniofacial phenotype.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Careful evaluation prior to anesthesia because of stiff joints, poorly aligned teeth, and maxillary hypoplasia."
    explanation: >-
      Documents the anaesthetic risk and the anatomical features that create it.
- name: Genetic counseling and family-specific reproductive testing
  description: >-
    Molecular assignment of the dominant FBN1 form versus a recessive ADAMTS10,
    ADAMTS17 or LTBP2 form determines recurrence counseling. Once the familial
    variant or variants are known, carrier testing is available for relatives at
    risk of a recessive form, and prenatal or preimplantation testing is possible.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family."
    explanation: >-
      Supports family-specific carrier testing for the recessive forms.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal and preimplantation genetic testing are possible once the WMS-related pathogenic variant(s) have been identified in an affected family member."
    explanation: >-
      Supports reproductive testing after identification of the familial
      pathogenic variant or variants.
differential_diagnoses:
- name: Marfan syndrome
  description: >-
    The instructive contrast rather than a close mimic. Both are FBN1 microfibril
    disorders with ectopia lentis, but the habitus is inverted: Marfan syndrome
    gives tall stature, arachnodactyly, joint laxity and aortic root dilation,
    while WMS gives short stature, brachydactyly, joint stiffness and thickened
    skin. Lens shape separates them, since microspherophakia is characteristic of
    WMS.
  distinguishing_features:
  - Tall stature with arachnodactyly and joint laxity, versus short stature with brachydactyly and joint stiffness
  - Aortic root dilation and dissection risk, versus valvular disease without characteristic aortopathy
  - Microspherophakia strongly favors WMS in an ectopia-lentis presentation
  evidence:
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis."
    explanation: >-
      Directly supports the Marfan side of the phenotypic contrast from a
      fibrillin-1 mechanistic study.
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice."
    explanation: >-
      Supports the contrasting WMS habitus in a human-family/allele-matched-mouse
      study.
  - reference: PMID:30201140
    reference_title: "Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unlike MFS, WMS does not typically predispose to aortic aneurysm."
    explanation: >-
      Supports the cardiovascular discriminator while appropriately retaining
      "typically" rather than treating aortopathy as impossible in WMS.
- name: Isolated ectopia lentis, especially ADAMTSL4-related disease
  description: >-
    An ocular-first presentation with progressive lens dislocation can be a
    nonsyndromic zonular disorder rather than WMS. Familial isolated ectopia
    lentis can have dominant or recessive inheritance, and biallelic ADAMTSL4
    variants are an established cause of the autosomal recessive form. Absence
    of the characteristic WMS combination of short stature, brachydactyly, joint
    stiffness and cardiovascular findings favors the isolated diagnosis, while
    molecular testing distinguishes ADAMTSL4-related disease from the four WMS
    gene forms. The word "isolated" should be applied only after a systemic
    assessment rather than inferred from an ocular presentation alone.
  distinguishing_features:
  - Ectopia lentis is the principal finding without the characteristic multisystem WMS habitus
  - Biallelic ADAMTSL4 variants support autosomal recessive isolated ectopia lentis rather than WMS
  - Progressive lens dislocation can occur in isolated disease, so progression alone does not establish WMS
  evidence:
  - reference: PMID:20141359
    reference_title: "Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation."
    explanation: >-
      Defines the shared ocular presentation and cautions that progressive lens
      dislocation is not by itself specific for WMS.
  - reference: PMID:20141359
    reference_title: "Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive."
    explanation: >-
      Keeps the differential broader than ADAMTSL4 by documenting both dominant
      and recessive familial isolated ectopia lentis.
  - reference: PMID:20141359
    reference_title: "Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis."
    explanation: >-
      Provides family-based molecular evidence for ADAMTSL4-related isolated
      autosomal recessive ectopia lentis.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects."
    explanation: >-
      Supplies the multisystem WMS features whose presence argues against a
      genuinely isolated ectopia-lentis diagnosis.
- name: Isolated microspherophakia
  description: >-
    A small spherical lens can occur as a familial isolated ocular disorder, so
    microspherophakia alone does not establish WMS. A reported consanguineous
    family had bilateral isolated microspherophakia with likely recessive
    inheritance, and linkage to ADAMTS10 was excluded in that family. That
    family-specific genetic result is not evidence that every isolated case has
    the same cause. Lenticular myopia, lens subluxation and glaucoma can follow
    microspherophakia in either setting; systemic examination and WMS molecular
    testing are therefore the useful separators when the presentation is
    ocular-first.
  distinguishing_features:
  - Bilateral microspherophakia without short stature, brachydactyly, joint stiffness or cardiovascular disease favors an isolated ocular diagnosis
  - Lenticular myopia, lens subluxation and glaucoma are complications of lens shape and do not by themselves distinguish isolated disease from WMS
  - Exclusion of ADAMTS10 linkage was specific to the cited family; inconclusive patients still warrant testing of the established WMS genes
  evidence:
  - reference: PMID:19696795
    reference_title: "Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A consanguineous family (MSP-M), including six family members and two patients, presented with decreased vision secondary to bilateral isolated microspherophakia."
    explanation: >-
      Establishes that bilateral microspherophakia can present as a familial
      isolated ocular phenotype.
  - reference: PMID:19696795
    reference_title: "Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a homozygosity-mapping strategy, haplotypic analysis using four STRs showed an exclusion of linkage between the ADAMTS10 gene and the disease locus in this family."
    explanation: >-
      Supports a genetic distinction from ADAMTS10-related WMS only for the
      family studied, without extrapolating an unknown universal cause.
  - reference: PMID:25397784
    reference_title: "Visual outcome and incidence of glaucoma in patients with microspherophakia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microspherophakia is associated with a high incidence of lenticular myopia, subluxation of the crystalline lens and glaucoma."
    explanation: >-
      Shows why common ocular complications reflect microspherophakia itself and
      cannot serve as reliable WMS-specific discriminators.
  - reference: PMID:20301293
    reference_title: "Weill-Marchesani Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in ADAMTS10, ADAMTS17, or LTBP2 or of a heterozygous pathogenic variant in FBN1 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive."
    explanation: >-
      Supports WMS-gene testing when an ocular-first presentation remains
      clinically ambiguous after systemic assessment.
- name: Geleophysic dysplasia and acromicric dysplasia
  description: >-
    These other acromelic dysplasias share short stature, small hands and feet,
    thick skin and stiff joints. Microspherophakia and ectopia lentis favor WMS.
    Progressive cardiac-valve thickening, tracheal stenosis and
    bronchopulmonary insufficiency strongly favor geleophysic dysplasia; ocular
    findings can occasionally overlap, so molecular testing may be necessary.
  distinguishing_features:
  - Microspherophakia and ectopia lentis are characteristic diagnostic anchors for WMS
  - Progressive valvular thickening, tracheal stenosis or bronchopulmonary insufficiency favor geleophysic dysplasia
  - Molecular testing separates overlapping FBN1-associated acromelic phenotypes and identifies ADAMTSL2-related geleophysic dysplasia
  evidence:
  - reference: PMID:24214363
    reference_title: "Similarity of geleophysic dysplasia and Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weill-Marchesani syndrome, on the basis of microspherophakia and ectopia lentis; geleophysic dysplasia by progressive cardiac valvular thickening, tracheal stenosis, and/or bronchopulmonary insufficiency, often leading to early death."
    explanation: >-
      Gives the principal clinical discriminators within the acromelic-dysplasia
      differential while the reported overlapping case cautions that they are not
      absolute.
- name: Homocystinuria due to cystathionine beta-synthase deficiency
  description: >-
    Homocystinuria can present with severe myopia and ectopia lentis and should be
    excluded when the ocular phenotype is prominent. Excessive height, long
    limbs, osteoporosis, arachnodactyly, thromboembolism and neurodevelopmental
    manifestations contrast with the short, brachydactylous WMS habitus; plasma
    total homocysteine and amino-acid testing provides a rapid biochemical
    discriminator.
  distinguishing_features:
  - Excessive height and arachnodactyly rather than short stature and brachydactyly
  - Thromboembolic risk and possible neurodevelopmental manifestations
  - Markedly elevated plasma total homocysteine and characteristic amino-acid abnormalities
  evidence:
  - reference: PMID:20301697
    reference_title: "Homocystinuria due to Cystathionine Beta-Synthase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is characterized by involvement of four major systems: the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, osteoporosis, scoliosis, arachnodactyly, pes cavus, pectus excavatum or carinatum, and genu valgum), vascular system (thromboembolism), and central nervous system (developmental delay, intellectual disability, seizures, psychiatric and behavioral manifestations, and dystonia)."
    explanation: >-
      Supports both the ocular overlap and the systemic findings that distinguish
      homocystinuria from WMS.
  - reference: PMID:20301697
    reference_title: "Homocystinuria due to Cystathionine Beta-Synthase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma concentrations of total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment."
    explanation: >-
      Supports plasma total-homocysteine and amino-acid analysis as the
      biochemical route to early recognition.
experimental_models:
- name: ADAMTS10-WMS patient fibroblast microfibril-deposition model
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Primary fibroblasts from a person with ADAMTS10-related WMS and unaffected control fibroblasts
  culture_system: Two-dimensional fibroblast culture with fibrillin-1 microfibril-deposition imaging
  conditions:
  - ADAMTS10-related WMS fibroblasts
  - Unaffected control fibroblasts
  publication: PMID:21402694
  modeled_mechanisms:
  - target: ADAMTS10-Dependent Microfibril Assembly and Fibrillin-2 Remodeling
    description: >-
      Compares endogenous fibrillin-1 microfibril deposition after loss of normal
      ADAMTS10 function.
  evidence:
  - reference: PMID:21402694
    reference_title: "ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "fibroblasts obtained from a Weill-Marchesani syndrome patient with ADAMTS10 mutations deposited fibrillin-1 microfibrils sparsely compared with unaffected control cells"
    explanation: >-
      Directly establishes the patient-cell model and its disease-relevant matrix
      readout.
- name: ADAMTS17-WMS patient fibroblast secretion and matrix model
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Patient-derived primary skin fibroblasts carrying a pathogenic ADAMTS17 variant
  culture_system: Two-dimensional fibroblast culture with secretion and matrix-deposition assays
  conditions:
  - ADAMTS17-related WMS fibroblasts
  - Unaffected control fibroblasts
  publication: PMID:31726086
  modeled_mechanisms:
  - target: ADAMTS17 Secretion Loss and Microfibril Dysregulation
    description: >-
      Measures ADAMTS17 secretion and intracellular versus extracellular handling
      of fibrillin-1 and type I collagen.
  evidence:
  - reference: PMID:31726086
    reference_title: "A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts."
    explanation: >-
      Directly supports the patient-derived culture and its secretion/matrix
      readouts.
- name: LTBP2-suppressed human ciliary epithelial microfibril model
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Cultured human ciliary epithelial cells with siRNA-mediated LTBP2 suppression
  culture_system: Two-dimensional culture with microfibril-meshwork imaging and recombinant-LTBP2 rescue
  conditions:
  - LTBP2 siRNA suppression
  - Recombinant LTBP2 rescue
  - Control ciliary epithelial cells
  publication: PMID:24908666
  modeled_mechanisms:
  - target: LTBP2-Dependent Microfibril-Bundle Assembly Failure
    description: >-
      Tests whether LTBP2 suppression disrupts the ciliary-cell microfibril
      meshwork and whether extracellular LTBP2 restores it.
  - target: Zonular Insufficiency
    description: >-
      Models the cell-derived microfibril network that contributes to ciliary
      zonule bundles.
  evidence:
  - reference: PMID:24908666
    reference_title: "Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The suppression of LTBP2 expression in cultured human ciliary epithelial cells by siRNA disrupted the formation of the microfibril meshwork by the cells."
    explanation: >-
      Establishes the human-cell loss-of-function model and matrix-assembly
      phenotype.
  - reference: PMID:24908666
    reference_title: "Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Supplementation of recombinant LTBP-2 in culture medium not only rescued the microfibril meshwork formation in LTBP2-suppressed ciliary epithelial cells"
    explanation: >-
      Provides a target-specific extracellular rescue of the modeled defect.
discussions:
- discussion_id: gap_wms_fbn1_phenotypic_inversion
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do FBN1 variants produce the short, stiff, thick-skinned Weill-Marchesani
    phenotype in some individuals and the tall, lax Marfan phenotype in others,
    when the same gene and the same microfibril system are involved?
  attaches_to:
  - pathophysiology#FBN1 WMS Microfibril-Scaffold Disruption
  - pathophysiology#Reduced BMP-SMAD1/5/8 Signaling and Delayed Chondrocyte Differentiation
  rationale: >-
    WMS2 and Marfan syndrome are allelic yet phenotypically opposite along nearly
    every systemic axis. Domain location clearly matters, since TB5 variants give
    the shortest stature within WMS, but domain location alone does not explain
    the sign reversal in growth, skin thickness and joint mobility. The mouse
    data point to reduced SMAD1/5/8 with increased p38 MAPK in the ADAMTS10 arm,
    which is not simply the inverse of the TGF-beta overactivation invoked for
    Marfan syndrome, so the two diseases may differ in which sequestered ligand
    class is released rather than in the direction of a single pathway. The
    inversion framing should not be over-tightened: domain location is associated
    with phenotype but is not established as a clean molecular switch between
    WMS and Marfan syndrome.
  proposed_experiments:
  - experiment_id: exp_wms_fbn1_domain_swap_signalling
    name: Domain-controlled FBN1 allelic series comparing WMS and Marfan signaling
    description: >-
      Build an isogenic FBN1 allelic series carrying WMS-associated and
      Marfan-associated variants, including same-domain pairs where available and
      variants inside and outside TB5, and measure microfibril architecture,
      BMP-family versus TGF-beta-family ligand activation, SMAD1/5/8, SMAD2/3 and
      p38 MAPK output in the same fibroblast and chondrocyte backgrounds.
    decision_criterion: >-
      A consistent difference in which ligand class is liberated by WMS versus
      Marfan alleles, rather than a difference in overall signalling magnitude,
      would explain the phenotypic inversion.
  evidence:
  - reference: PMID:22242013
    reference_title: "Microenvironmental regulation by fibrillin-1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues."
    explanation: >-
      Establishes the mechanistic divergence while leaving the causal basis of
      the allelic phenotypic inversion unresolved.
- discussion_id: gap_wms_lens_shape_versus_position
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is microspherophakia significantly more frequent in recessive WMS while
    ectopia lentis is significantly more frequent in dominant WMS, if both follow
    from the same zonular insufficiency?
  attaches_to:
  - pathophysiology#Zonular Insufficiency
  - pathophysiology#Microspherophakia and Lenticular Myopia
  - pathophysiology#Ectopia Lentis
  rationale: >-
    Across 128 reviewed patients the two lens phenotypes dissociate in opposite
    directions by inheritance mode, with both differences statistically
    significant. That pattern is hard to reconcile with a single graded zonular
    defect, and suggests that shaping the lens during development and anchoring it
    thereafter may be separable functions of the zonule, differently sensitive to
    losing an assembly protease versus altering the fibrillin monomer itself.
  proposed_experiments:
  - experiment_id: exp_wms_zonule_development_vs_maintenance
    name: Temporally resolved zonule phenotyping in ADAMTS10 versus Fbn1 WMS models
    description: >-
      Compare zonular fibre architecture, tension and lens curvature at
      developmental and adult time points in the ADAMTS10 knock-in mouse against
      an Fbn1 WMS-allele model, testing whether the protease-loss model
      preferentially fails the developmental lens-shaping step while the
      fibrillin-variant model preferentially fails long-term anchorage.
    decision_criterion: >-
      A temporal dissociation, with shape set early and anchorage failing late in
      the respective models, would account for the epidemiological pattern.
  evidence:
  - reference: PMID:14598350
    reference_title: "Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016)"
    explanation: >-
      Documents the statistically significant opposite-direction dissociation of
      the two lens phenotypes by inheritance mode.
- discussion_id: mismatch_wms_adamts10_null_mouse
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Can the Adamts10-null mouse be used to study the ocular and skeletal
    phenotype of Weill-Marchesani syndrome, when it fails to reproduce ectopia
    lentis, brachydactyly and cardiovascular defects?
  attaches_to:
  - pathophysiology#Zonular Insufficiency
  - pathophysiology#Microspherophakia and Lenticular Myopia
  - pathophysiology#Ectopia Lentis
  - pathophysiology#Acromelic Long-Bone Growth Restriction
  - pathophysiology#Joint Limitation
  rationale: >-
    Adamts10-null mice are slightly smaller with stiff skin but show no ectopia
    lentis, no brachydactyly and no cardiovascular defects, so three of the
    cardinal human features are simply absent. The authors attribute the ocular
    discrepancy to a species difference in zonular composition: the mouse zonule
    contains fibrillin-2 as well as fibrillin-1, so it can compensate where the
    human zonule cannot. This is a genuine translational limit rather than a
    weak model, and it means murine zonule findings cannot be read directly onto
    the human lens phenotype. Notably the separate CRISPR knock-in of a human
    truncation does reproduce growth and muscle changes, so the two ADAMTS10
    mouse models are not interchangeable.
  proposed_experiments:
  - experiment_id: exp_wms_fbn2_humanized_zonule
    name: Fibrillin-2-depleted Adamts10-null zonule to test the compensation hypothesis
    description: >-
      Cross Adamts10-null mice onto a background with reduced ocular fibrillin-2
      so that the zonule must rely on fibrillin-1, and test whether ectopia
      lentis and microspherophakia then appear. Compare zonular composition,
      lens shape and lens position against human WMS ocular tissue where
      available.
    decision_criterion: >-
      Emergence of ectopia lentis and microspherophakia on the
      fibrillin-2-reduced background would confirm that species-specific zonular
      composition, not a different disease mechanism, explains the mismatch.
  evidence:
  - reference: PMID:30201140
    reference_title: "Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ectopia lentis was not observed in Adamts10-/- mice, similar to Fbn1-/- mice, most likely because the mouse zonule contains fibrillin-2 in addition to fibrillin-1."
    explanation: >-
      States the mismatch and the authors' species-composition explanation for
      it.
  - reference: PMID:30201140
    reference_title: "Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "although surviving mice were slightly smaller and had stiff skin, they lacked brachydactyly and cardiovascular defects"
    explanation: >-
      Documents the additional skeletal and cardiac features that the null mouse
      fails to reproduce.
references:
- reference: PMID:20301293
  title: "Weill-Marchesani Syndrome"
  tags:
  - GeneReviews
- reference: PMID:37734846
  title: "Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature"

📚

References & Deep Research

References

PMID:20301293

Weill-Marchesani Syndrome

No top-level findings curated for this source.

PMID:37734846

Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature

No top-level findings curated for this source.

Deep Research

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 24 citations 2026-08-01T00:34:21.212653

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Weill-Marchesani syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Weill-Marchesani syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

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Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

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Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

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Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Weill–Marchesani syndrome: comprehensive disease-characteristics report

Executive summary

Weill–Marchesani syndrome (WMS) is a rare, congenital, Mendelian extracellular-matrix disorder in the acromelic-dysplasia spectrum. Its defining combination is microspherophakia/lenticular myopia, ectopia lentis and secondary glaucoma together with short stature, brachydactyly and joint stiffness. Thick skin, a pseudomuscular habitus and cardiovascular abnormalities occur variably. Estimated prevalence is approximately 1 in 100,000, but this is based on rare-disease summaries rather than population surveillance. Both autosomal-dominant and autosomal-recessive forms exist: dominant disease is principally associated with heterozygous FBN1 variants, whereas recessive disease results from biallelic ADAMTS10, ADAMTS17, or LTBP2 variants. The common biological theme is defective fibrillin-rich extracellular microfibrils and altered tissue-specific growth-factor microenvironments. (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2)

The most important preventable morbidity is visual loss from lens-induced angle closure and glaucoma. There is no disease-modifying drug, gene therapy, or validated molecular prognostic biomarker; current care combines early molecular diagnosis, detailed anterior-segment assessment, lifelong glaucoma surveillance, complication-directed lens/glaucoma surgery, cardiac monitoring, orthopedic/rehabilitative care and genetic counseling. (protasiuk2025weillmarchesanisyndromea pages 3-5, protasiuk2025weillmarchesanisyndromea pages 1-2)

The following compact curation table summarizes disease, phenotype, mechanism, anatomy, diagnostic and intervention mappings.

Domain	Finding	Suggested ontology/identifier	Evidence/notes
Disease	Weill-Marchesani syndrome (rare hereditary connective-tissue / acromelic dysplasia syndrome with ocular, skeletal, and sometimes cardiac involvement)	ORPHA:3447; MONDO:0018097 (verification recommended); Mendelian disease	Estimated prevalence about 1 in 100,000; phenotype and gene evidence are disease-level aggregated from published case reports/reviews, not EHR-derived (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2)
Disease subtypes	Historically subdivided by gene/inheritance into AD and AR forms; “WMS4” used for ADAMTS17-related disease in recent literature	OMIM subtype labels verification needed	Recent sources explicitly distinguish AD FBN1-associated disease from AR ADAMTS10/ADAMTS17/LTBP2-associated disease; exact OMIM subtype mapping should be checked directly in OMIM before database load (li2026anovelhomozygous pages 1-2, huang2023abnormallensthickening pages 1-2)
Synonym/related label	Weill-Marchesani-like syndrome	Disease synonym/related concept (verification needed)	Used especially for some LTBP2-associated families and overlapping phenotypes; may not always be nosologically identical to classic WMS (chen2024autosomaldominantweillmarchesanilike pages 7-8)
Gene / inheritance	FBN1: autosomal dominant WMS	HGNC: FBN1	Dominant WMS linked to heterozygous FBN1 variants; often associated with ectopia lentis/joint stiffness and acromelic dysplasia overlap (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2, arnaud2024pathogenicvariantsaffecting pages 8-8)
Gene / inheritance	ADAMTS10: autosomal recessive WMS	HGNC: ADAMTS10	Established AR cause; recent quantitative review of 19 ADAMTS10 cases found universal microspherophakia, high myopia, short stature, brachydactyly, and joint stiffness (li2026anovelhomozygous pages 1-2, li2026anovelhomozygous pages 4-6)
Gene / inheritance	ADAMTS17: autosomal recessive WMS / WMS4	HGNC: ADAMTS17	ADAMTS17-related disease shows ocular-predominant presentation and may lack heart defects/joint stiffness compared with other forms (huang2023abnormallensthickening pages 1-2)
Gene / inheritance	LTBP2: autosomal recessive WMS; atypical dominant WMS-like families also reported	HGNC: LTBP2	Classic teaching supports AR disease; a 2024 Chinese family report proposed dominant WMS-like inheritance from haplotypic LTBP2 variants, requiring cautious interpretation (li2026anovelhomozygous pages 1-2, chen2024autosomaldominantweillmarchesanilike pages 7-8)
Variant class	Germline pathogenic variants include missense, nonsense, frameshift, splice-site, exon deletions, and in-frame/deletion events depending on gene	ACMG/AMP classification framework	Somatic origin is not implicated; reported disease variants are germline. ADAMTS10 frameshift c.1560_1575dup p.Ile526Valfs*51 classified pathogenic in 2026 report (li2026anovelhomozygous pages 1-2, li2026anovelhomozygous pages 4-6)
Phenotype	Microspherophakia / spherophakia	HPO term suggestion: Microspherophakia	Core ocular trait; 100% in ADAMTS10 literature synthesis cited in recent report (19/19) (li2026anovelhomozygous pages 4-6)
Phenotype	High myopia / lenticular myopia	HPO term suggestion: High myopia; Lenticular myopia	Universal in ADAMTS10 synthesis (19/19); in WMS4 child, progressive myopia tracked with lens thickening despite normal axial length (li2026anovelhomozygous pages 4-6, huang2023abnormallensthickening pages 1-2)
Phenotype	Ectopia lentis / lens subluxation	HPO term suggestion: Ectopia lentis	Frequently reported across genetic subtypes; especially emphasized in dominant FBN1 disease and WMS-like families (protasiuk2025weillmarchesanisyndromea pages 1-2, chen2024autosomaldominantweillmarchesanilike pages 7-8)
Phenotype	Glaucoma, often secondary angle closure / phacomorphic mechanism	HPO term suggestion: Glaucoma; Angle-closure glaucoma	Glaucoma in 47.4% (9/19) in ADAMTS10 synthesis; literature range 44.4%–51%; mean onset in one cited series ~20 ± 13 years, but childhood acute attacks can occur (li2026anovelhomozygous pages 4-6, li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 9-10)
Phenotype	Short stature	HPO term suggestion: Short stature	Universal in recent ADAMTS10 synthesis; common across WMS spectrum (protasiuk2025weillmarchesanisyndromea pages 1-2, li2026anovelhomozygous pages 4-6)
Phenotype	Brachydactyly	HPO term suggestion: Brachydactyly	Universal in recent ADAMTS10 synthesis; useful for syndromic recognition in ophthalmology settings (li2026anovelhomozygous pages 4-6, huang2023abnormallensthickening pages 1-2)
Phenotype	Joint stiffness / contractures	HPO term suggestion: Joint stiffness	Universal in ADAMTS10 synthesis; may be absent or less conspicuous in ADAMTS17-related WMS4 (li2026anovelhomozygous pages 4-6, huang2023abnormallensthickening pages 1-2)
Phenotype	Thick skin / muscular habitus	HPO term suggestion: Thickened skin; Muscular hypertrophy/pseudomuscular build	Recurrently described in reviews and classic WMS descriptions; frequency not well quantified in retrieved recent primary evidence (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2)
Phenotype	Cardiac abnormalities (valves/other cardiovascular findings)	HPO term suggestion: Abnormality of the cardiovascular system; Heart valve abnormality	Cardiac abnormalities in 55.6% (10/18) of literature cases in one ADAMTS10 review; ADAMTS17-related WMS4 may have fewer/no heart defects (li2026anovelhomozygous pages 4-6, huang2023abnormallensthickening pages 1-2)
Onset/course	Usually congenital or childhood-onset, chronic lifelong condition	Temporal descriptor: congenital/childhood onset	Ocular findings often first recognized in childhood; WMS4 can present insidiously as “high myopia” before glaucoma or overt ectopia lentis (li2026anovelhomozygous pages 1-2, huang2023abnormallensthickening pages 1-2)
Anatomy affected	Crystalline lens, zonule/ciliary zonule, anterior chamber angle	UBERON term suggestions: lens of eye; suspensory ligament of lens / ciliary zonule; anterior chamber angle of eye	Ocular biometry/imaging shows thick, small-diameter lenses, shallow anterior chambers, and zonular pathology driving glaucoma risk (li2026anovelhomozygous pages 9-10, huang2023abnormallensthickening pages 1-2, wang2019adamts10inactivationin pages 24-29)
Anatomy affected	Cornea / anterior segment	UBERON term suggestions: cornea; anterior segment of eyeball	Increased corneal thickness reported in WMS; anterior segment crowding is clinically important for angle-closure risk (li2026anovelhomozygous pages 9-10)
Anatomy affected	Growth plate, long bone skeleton, digits, joints	UBERON term suggestions: epiphyseal growth plate; long bone; digit; synovial joint	Short stature/brachydactyly implicate disturbed skeletogenesis and endochondral growth (mead2022proteolysisoffibrillin2 pages 32-34)
Anatomy affected	Heart valves / cardiovascular connective tissue	UBERON term suggestions: heart valve; cardiovascular system	Cardiovascular manifestations are less consistent than ocular/skeletal features but important for surveillance (protasiuk2025weillmarchesanisyndromea pages 1-2, li2026anovelhomozygous pages 4-6)
Cell/tissue context	Connective tissue fibroblasts, chondrocytes, ocular microfibril-rich tissues	CL term suggestions: fibroblast; chondrocyte	Mechanistic studies and models implicate ECM-producing stromal cells and growth-plate chondrocytes; exact cell ontology IDs should be verified during curation (mead2022proteolysisoffibrillin2 pages 32-34, wang2019adamts10inactivationin pages 24-29)
Mechanism	Extracellular matrix and fibrillin microfibril assembly disorder	GO term suggestion: extracellular matrix organization; microfibril assembly	Strong convergence across FBN1, ADAMTS10, ADAMTS17, and LTBP2 supports a shared microfibril/ECM pathway (protasiuk2025weillmarchesanisyndromea pages 1-2, mead2022proteolysisoffibrillin2 pages 32-34, hubmacher2015adamtsproteinsas pages 10-10)
Mechanism	ADAMTS10 proteolytic regulation of fibrillin-2 in ocular tissues	GO term suggestion: proteolysis; extracellular matrix disassembly	Mouse/in vitro work showed reduced fibrillin-2 cleavage and persistence of ocular microfibrils after Adamts10 inactivation (wang2019adamts10inactivationin pages 24-29)
Mechanism	Local tissue-microenvironment dysregulation rather than classic Marfan-like generalized TGF-β activation	GO term suggestion: regulation of signaling receptor activity; extracellular structure organization	FBN1 WMS models suggest altered local microenvironments and collagen regulation; mechanism diverges from canonical Marfan pathogenesis (mead2022proteolysisoffibrillin2 pages 32-34)
Mechanism	BMP-Smad pathway involvement in skeletogenesis (especially ADAMTS17 biology)	GO term suggestion: BMP signaling pathway; endochondral bone morphogenesis	Experimental data in Adamts17 biology support BMP-Smad1/5/8 modulation during skeletogenesis; relevance to human WMS is plausible but still mechanistically incomplete (mead2022proteolysisoffibrillin2 pages 32-34)
Mechanism	LTBP2-related zonule/microfibril and elastic-fiber biology	GO term suggestion: elastic fiber assembly; ciliary zonule development	LTBP2 is implicated in microfibril formation and ocular connective tissue integrity; precise causal chain to all WMS manifestations remains incompletely resolved (chen2024autosomaldominantweillmarchesanilike pages 7-8, hubmacher2015adamtsproteinsas pages 10-10)
Diagnostics	Clinical recognition based on syndromic combination of microspherophakia/high myopia/ectopia lentis plus short stature and brachydactyly	Clinical feature set (no single universal formal criteria retrieved)	No universally adopted formal diagnostic criteria were retrieved; diagnosis is phenotype-led and then molecularly confirmed (protasiuk2025weillmarchesanisyndromea pages 1-2, huang2023abnormallensthickening pages 1-2)
Diagnostics	Ophthalmic biometry and imaging	Test suggestions: slit-lamp exam; ocular biometry; Pentacam; ultrasound biomicroscopy; IOLMaster	2023 WMS4 case used multiple imaging modalities to document lens thickening and reduced equatorial diameter over 3 years (huang2023abnormallensthickening pages 1-2)
Diagnostics	Intraocular pressure assessment / gonioscopy for glaucoma surveillance	Test suggestions: tonometry; gonioscopy	Essential because glaucoma is common and may arise acutely in anatomically crowded eyes (li2026anovelhomozygous pages 9-10, li2026anovelhomozygous pages 7-9)
Diagnostics	Echocardiography / cardiovascular evaluation	Test suggestion: echocardiography	Recommended because cardiac involvement occurs in a substantial subset, especially some AR forms (protasiuk2025weillmarchesanisyndromea pages 1-2, li2026anovelhomozygous pages 4-6)
Diagnostics	Molecular testing	WES/WGS/gene panel; confirmatory Sanger sequencing	WES plus Sanger was used in recent ADAMTS10 and ADAMTS17 cases; gene panels for ectopia lentis/anterior segment dysgenesis/connective-tissue disease are reasonable (li2026anovelhomozygous pages 1-2, huang2023abnormallensthickening pages 1-2)
Differential diagnosis	Marfan syndrome, isolated ectopia lentis, acromicric dysplasia, geleophysic dysplasia, other microspherophakia syndromes	Related disease term suggestions	Distinguishing clues include short stature/brachydactyly/joint stiffness rather than tall stature; acromelic dysplasia spectrum overlaps at FBN1 TB5 domain (protasiuk2025weillmarchesanisyndromea pages 1-2, arnaud2024pathogenicvariantsaffecting pages 8-8)
Intervention	Peripheral iridotomy / laser iridotomy	NCIT-style term suggestion: Peripheral Iridotomy	Used prophylactically or therapeutically for pupillary block/angle closure risk in WMS (protasiuk2025weillmarchesanisyndromea pages 3-5, protasiuk2025weillmarchesanisyndromea pages 1-2)
Intervention	Lensectomy / lens extraction	NCIT-style term suggestion: Lensectomy	Key intervention for microspherophakia-related glaucoma or lens-induced crowding; recent pediatric case used staged bilateral lens extraction (protasiuk2025weillmarchesanisyndromea pages 3-5, li2026anovelhomozygous pages 9-10)
Intervention	Anterior vitrectomy	NCIT-style term suggestion: Anterior Vitrectomy	Used in advanced ocular surgical management alongside lensectomy in reviews/case-based practice (protasiuk2025weillmarchesanisyndromea pages 3-5)
Intervention	Intraocular lens implantation	NCIT-style term suggestion: Intraocular Lens Implantation	May be deferred initially in high-risk eyes; individualized surgical planning is emphasized (protasiuk2025weillmarchesanisyndromea pages 3-5, li2026anovelhomozygous pages 9-10)
Intervention	Glaucoma drainage or filtering procedures	NCIT-style term suggestions: Glaucoma Surgery; Molteno Implantation; ExPRESS Shunt Placement	Described for refractory glaucoma in review literature (protasiuk2025weillmarchesanisyndromea pages 3-5)
Intervention	Multidisciplinary supportive care	NCIT-style term suggestions: Ophthalmologic Monitoring; Cardiology Follow-Up; Orthopedic Care; Physical Therapy	No disease-modifying pharmacotherapy identified; management is complication-directed and longitudinal (protasiuk2025weillmarchesanisyndromea pages 3-5, protasiuk2025weillmarchesanisyndromea pages 1-2)
Prevention	Genetic counseling, cascade testing, reproductive counseling	Clinical service term suggestion: Genetic Counseling	Most actionable prevention relates to family-risk assessment for AD or AR inheritance and early ophthalmic surveillance of at-risk relatives (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2)
Prognosis	Morbidity driven mainly by progressive refractive error, ectopia lentis, and glaucoma; vision can be preserved with early detection/intervention	Outcome descriptor (no validated prognostic biomarker retrieved)	Acute glaucoma can occur in childhood, but mean glaucoma onset in one cited literature set was ~20 years; survival/life-expectancy data were not retrieved (li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 9-10)
Model organisms	Adamts10-null mouse	Model suggestion: Mus musculus Adamts10 loss-of-function	Recapitulates ocular microfibril persistence and supports ADAMTS10-mediated fibrillin-2 cleavage mechanism; limited for full human multisystem spectrum (wang2019adamts10inactivationin pages 24-29)
Model organisms	Fbn1 WMS mouse model	Model suggestion: Mus musculus Fbn1 WMS-associated deletion model	Replicates thick skin, short stature, and brachydactyly, supporting tissue-microenvironment mechanism distinct from Marfan syndrome (mead2022proteolysisoffibrillin2 pages 32-34)
Evidence limitations	Most evidence comes from small case reports/series and mechanistic mouse studies; phenotype frequencies differ by gene and publication bias is likely	Evidence-quality note	No randomized trials retrieved; no disease-specific interventional ClinicalTrials.gov evidence found in the search set; several detailed 2024 papers were cited in references but not fully available in retrieved text (protasiuk2025weillmarchesanisyndromea pages 1-2, li2026anovelhomozygous pages 10-10, li2026anovelhomozygous pages 9-10)

Table: This table summarizes key disease, gene, phenotype, anatomy, mechanism, diagnostic, and management mappings for Weill-Marchesani syndrome. It is designed as a compact curation aid and flags ontology identifiers or claims that should be verified before formal database ingestion.

1. Disease information

Definition and identifiers

WMS is a hereditary connective-tissue disorder and acromelic skeletal dysplasia involving the eye, skeleton, joints, skin and, inconsistently, cardiovascular system. Suggested identifiers are ORPHA:3447, MONDO:0018097 and OMIM 277600 for the classic/recessive disease concept; subtype-level OMIM assignments should be checked directly in OMIM before database ingestion because nomenclature varies by gene and “WMS-like” versus classic WMS. The disorder does not appear to have a uniquely specific ICD-10 code and will generally require a broader congenital connective-tissue or ocular diagnosis code. MeSH indexing is usually through the disease name and related terms such as microspherophakia or ectopia lentis. (li2026anovelhomozygous pages 1-2)

Synonyms include Weill-Marchesani syndrome, Weill–Marchesani syndrome, brachymorphia–ectopia lentis syndrome, and, for overlapping presentations, Weill-Marchesani-like syndrome. “WMS4” is used for ADAMTS17-related disease. WMS-like should not automatically be treated as exactly equivalent to classic WMS, particularly in atypical LTBP2 families. (huang2023abnormallensthickening pages 1-2, chen2024autosomaldominantweillmarchesanilike pages 7-8)

The evidence summarized here is aggregated disease-level evidence from published families, case reports, small cohorts, reviews and experimental models—not individual EHR-derived data. The rarity of WMS and gene-specific ascertainment produce substantial publication and referral bias.

2. Etiology, risk and protective factors

Causal factors

WMS is primarily genetic. Established causes are germline pathogenic variants in:

FBN1—usually heterozygous, autosomal dominant;
ADAMTS10—biallelic, autosomal recessive;
ADAMTS17—biallelic, autosomal recessive;
LTBP2—classically biallelic and recessive, although a 2024 four-generation family suggested an unusual dominant WMS-like mechanism from two variants in cis. (li2026anovelhomozygous pages 1-2, chen2024autosomaldominantweillmarchesanilike pages 7-8)

The 2024 LTBP2 family contained 25 examined relatives, nine clinically affected individuals and seven children of uncertain status. The reported haplotype combined c.2657C>A (p.Thr886Lys) with deletion of exons 25–36 and segregated with ectopia lentis, short stature and obesity. This expands the proposed inheritance spectrum but should be regarded as family-level evidence requiring replication. Publication: May 2024; DOI: https://doi.org/10.1159/000538844. (chen2024autosomaldominantweillmarchesanilike pages 7-8)

Risk factors

The principal risks are inheritance of a causal allele, an affected parent in dominant WMS, two carrier parents in recessive WMS, consanguinity and family history. For each pregnancy, a heterozygous affected parent generally confers a 50% transmission probability; two carriers of the same recessive condition confer 25% affected, 50% carrier and 25% unaffected probabilities, assuming full Mendelian segregation.

No reproducible environmental, infectious, occupational, dietary, sex-specific or lifestyle risk factors are established. Atropine did not cause WMS, but pharmacologic pupillary dilation precipitated acute angle closure in one anatomically predisposed child, illustrating that environmental or iatrogenic exposures may trigger complications rather than disease initiation. (li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 9-10)

Protective factors and gene–environment interaction

No validated protective allele, diet, drug or lifestyle exposure prevents WMS. Early diagnosis, avoidance of unsupervised mydriatic/anticholinergic exposure in narrow-angle eyes, and surveillance are best considered complication prevention rather than etiologic protection. Formal gene–environment interaction studies are unavailable.

3. Phenotypes

Ocular phenotype

Microspherophakia/spherophakia (suggested HPO: Microspherophakia) is a small-equatorial-diameter, abnormally thick and spherical lens. It causes increased lenticular power, high myopia, zonular instability, pupillary block and anterior-segment crowding.
High or lenticular myopia (HPO: High myopia) often appears in childhood and may be mistaken for ordinary axial myopia.
Ectopia lentis/lens subluxation (HPO: Ectopia lentis), iridodonesis and shallow anterior chamber are common.
Secondary glaucoma, especially angle-closure/phacomorphic or pupillary-block glaucoma (HPO: Glaucoma; Angle-closure glaucoma), is the major vision-threatening complication.

A recent synthesis of 19 ADAMTS10-associated patients reported microspherophakia and high myopia in 19/19, and glaucoma in 9/19 (47.4%). The wider published glaucoma range was 44.4–51%; a cited ocular series reported glaucoma in 81/159 eyes with mean onset 20 ± 13 years. These estimates are not population frequencies and are vulnerable to ascertainment bias. (li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 4-6)

A 2023 three-year longitudinal WMS4 case provides direct evidence of progression. At age eight, lens thickness was 4.38/4.31 mm and equatorial diameter 7.33/7.17 mm; three years later thickness increased to 4.49/4.48 mm while diameter remained approximately 7.32/7.21 mm. Myopia progressed despite normal axial length. The authors’ abstract states that the report “highlights the abnormal thickening of the lens in WMS4 compared to the physiological thinning process during childhood.” Publication: January 2023; DOI: https://doi.org/10.3389/fmed.2022.1021489. (huang2023abnormallensthickening pages 1-2)

Skeletal, joint and integumentary phenotype

Short stature (HPO: Short stature), brachydactyly (HPO: Brachydactyly), short hands/feet, joint stiffness or contractures (HPO: Joint stiffness), thickened skin and a muscular or pseudomuscular build are characteristic. A 19-person ADAMTS10 synthesis reported short stature, brachydactyly and joint stiffness in 100%, but this is a selected genotype-specific literature sample rather than a universal WMS estimate. ADAMTS17-related WMS4 may be more ocular-predominant and can lack conspicuous joint stiffness. (huang2023abnormallensthickening pages 1-2, li2026anovelhomozygous pages 4-6)

Cardiovascular and other manifestations

Heart-valve abnormalities and other cardiovascular findings are variably described. In the recent ADAMTS10 literature synthesis, cardiac abnormalities occurred in 10/18 (55.6%) previously reported cases. Apparent rates differed by variant category, including 2/2 compound-heterozygous splice cases and 6/9 homozygous missense cases, but numbers are far too small for clinical prediction. Hearing impairment and intellectual disability have occasionally been reported; neither is a defining or well-quantified phenotype. (li2026anovelhomozygous pages 4-6, li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 1-2)

Functional and quality-of-life effect

Visual blur, repeated examinations, glaucoma, surgery and possible irreversible visual-field loss can impair schooling, mobility, work and independence. Short stature and joint limitation can restrict reach, dexterity and physical activity. No WMS-specific EQ-5D, SF-36, PROMIS or validated quality-of-life dataset was identified.

4. Genetic and molecular information

All established WMS variants are germline; a somatic disease mechanism is not recognized. Reported classes include missense, nonsense, frameshift, splice-altering and in-frame variants, plus exon-level deletions. Variant interpretation should follow ACMG/AMP criteria and incorporate segregation, population frequency, predicted loss of function, phenotype specificity and functional evidence.

A recent ADAMTS10 example is NM_030957.4:c.1560_1575dup; p.Ile526Valfs*51, a homozygous 16-bp duplication predicted to truncate the protein before thrombospondin type-1 and cysteine-rich regions and/or undergo nonsense-mediated decay. It was classified pathogenic using PVS1+PM3+PM2; both unaffected parents were heterozygous carriers. (li2026anovelhomozygous pages 7-9, li2026anovelhomozygous pages 4-6)

A 2023 ADAMTS17 case carried compound-heterozygous missense variants c.2984G>A (p.Arg995Gln) and c.2254A>G (p.Ile752Val). Their reported association with WMS4 is clinically informative, although individual missense classifications should always be rechecked in current ClinVar/gnomAD and against updated segregation/functional evidence. (huang2023abnormallensthickening pages 1-2)

FBN1-related acromelic dysplasias cluster around functionally important fibrillin-1 regions, particularly the fifth TGF-β-binding-protein-like domain (TB5). However, 2024 data showed that TB5 variants can also produce classic Marfan syndrome, demonstrating that domain location alone does not establish phenotype. Publication: March 2024; DOI: https://doi.org/10.1136/jmg-2023-109646. (arnaud2024pathogenicvariantsaffecting pages 8-8)

No validated modifier genes, WMS-specific epigenetic signature, recurrent chromosomal rearrangement, anticipation phenomenon or established germline-mosaicism rate is known. Large deletions can occur within a causal gene, but WMS is not primarily an aneuploidy or contiguous-gene disorder. Population allele frequencies should be retrieved variant-by-variant from current gnomAD; pathogenic alleles are expected to be absent or extremely rare.

5. Environmental information

No toxin, radiation exposure, pollutant, dietary pattern, smoking behavior, alcohol exposure or infectious agent is known to cause WMS. Environmental and lifestyle variables may influence general cardiovascular, musculoskeletal and ocular health but have not been shown to modify penetrance. Mydriasis can provoke angle closure in predisposed eyes and therefore warrants ophthalmic caution. (li2026anovelhomozygous pages 7-9)

6. Mechanism and pathophysiology

Upstream molecular defect

FBN1 encodes fibrillin-1, the principal structural component of 10–12-nm extracellular microfibrils. ADAMTS10 and ADAMTS17 are secreted metalloproteases that interact functionally with fibrillin-rich matrices. LTBP2 is an extracellular microfibril-associated latent-TGF-β-binding-protein-family member important to the ciliary zonule and elastic-fiber organization. Human genetics therefore converges on defective extracellular-matrix organization and microfibril assembly/homeostasis. Suggested GO terms include extracellular matrix organization, microfibril assembly, proteolysis, elastic-fiber assembly, BMP signaling and endochondral ossification. (chen2024autosomaldominantweillmarchesanilike pages 7-8, hubmacher2015adamtsproteinsas pages 10-10)

Ocular causal chain

ADAMTS10 deficiency reduces fibrillin-2 processing. In Adamts10-null mice, fibrillin-2 accumulates in the zonule and vitreous. In vitro, active ADAMTS10 cleaved a 185-kDa fibrillin-2 construct and generated an approximately 100-kDa fragment, whereas catalytically inactive ADAMTS10 did not. The supported chain is: ADAMTS10 loss → reduced fibrillin-2 proteolysis/persistent ocular microfibrils → abnormal zonular/lens development → microspherophakia and lens instability → lenticular myopia, anterior chamber crowding and secondary angle closure/glaucoma. This is strong model/in-vitro evidence, though direct confirmation of every intermediate in human eyes remains incomplete. PMID 30201140; DOI: https://doi.org/10.1016/j.matbio.2018.09.004. (mead2022proteolysisoffibrillin2 pages 32-34, wang2019adamts10inactivationin pages 24-29)

Skeletal and connective-tissue causal chain

Disrupted fibrillin/ADAMTS matrix organization alters local growth-factor presentation and growth-plate extracellular matrix. Fibrillin-1 WMS models support tissue-specific microenvironmental disturbance and altered dermal collagen production rather than the broad TGF-β activation emphasized in Marfan syndrome. ADAMTS17 experimental work also implicates BMP–SMAD1/5/8 regulation during skeletogenesis. The likely chain is microfibril dysfunction → altered chondrocyte matrix/signaling and endochondral growth → short long bones, short digits and joint limitation. Relevant cells include fibroblasts (CL: fibroblast), growth-plate chondrocytes (CL: chondrocyte) and ocular stromal/zonular matrix-producing cells. (mead2022proteolysisoffibrillin2 pages 32-34)

No disease-specific metabolomic, lipidomic, proteomic, single-cell, spatial-transcriptomic or integrated multi-omic signature is validated. Immune activation, autoimmunity, infection, mitochondrial dysfunction and primary metabolic enzyme deficiency are not established central mechanisms.

7. Anatomical structures affected

Primary sites are bilateral crystalline lenses, ciliary zonules, iris–lens/anterior-chamber-angle anatomy and other anterior-segment tissues; long bones, epiphyseal growth plates, digits and joints; skin/dermal connective tissue; and, variably, heart valves and cardiovascular connective tissue. Suggested UBERON mappings include lens of eye, ciliary zonule/suspensory ligament of lens, anterior chamber of eye, cornea, epiphyseal growth plate, long bone, digit, synovial joint, skin and heart valve.

In one recent child, corneal thickness was 714/724 μm versus a reported control mean of 549.97 ± 25.78 μm; anterior chambers measured 1.70/1.80 mm and axial lengths 21.75/21.18 mm. These findings illustrate anterior-segment crowding but should not be treated as diagnostic cutoffs. Ocular disease is usually bilateral, although severity and glaucoma damage may be asymmetric. (li2026anovelhomozygous pages 9-10)

At subcellular level, the relevant compartment is predominantly extracellular: fibrillin microfibrils, elastic-fiber-associated matrix and pericellular matrix. Suggested GO cellular-component terms are extracellular matrix and proteinaceous extracellular matrix.

8. Temporal development and natural history

WMS is congenital and lifelong, but recognition is often delayed until childhood myopia, lens displacement or glaucoma. Skeletal proportions and brachydactyly emerge during growth; joint stiffness is chronic. The ocular course may be insidious and progressive: increasing lens thickness/power, zonular instability, shallow angles and glaucoma risk. The 2023 WMS4 follow-up directly documented progressive lens thickening over three years. (huang2023abnormallensthickening pages 1-2)

A 2024 Journal of Medical Genetics study reported natural history and genotype–phenotype correlations in 18 new cases plus literature review (Marzin et al., volume 61, pages 109–116; DOI: https://doi.org/10.1136/jmg-2023-109288). Retrieved text confirmed the study’s existence and scope but did not expose its complete tables; exact subtype frequencies should therefore be taken from the original paper before database loading. (li2026anovelhomozygous pages 10-10)

There is no accepted stage classification, remission pattern or end-stage definition. The disease does not spontaneously remit. The critical intervention window is before irreversible glaucomatous optic neuropathy or amblyopia develops.

9. Inheritance and population

Prevalence is commonly cited as approximately 1/100,000; robust incidence, sex-ratio, carrier-frequency and mortality estimates are unavailable. WMS occurs across ancestries, with no established ethnic restriction. Consanguinity increases the probability of recessive disease, while family clustering occurs in both inheritance modes. (li2026anovelhomozygous pages 1-2, protasiuk2025weillmarchesanisyndromea pages 1-2)

Penetrance and expressivity are incompletely quantified and vary by gene and variant. The 2024 dominant LTBP2 family included young carriers of uncertain status, consistent with age-dependent ascertainment or possible reduced penetrance. No established anticipation exists. Founder effects may occur in individual populations, but no globally dominant founder allele was identified in the retrieved evidence. (chen2024autosomaldominantweillmarchesanilike pages 7-8)

10. Diagnostics

Clinical and ophthalmic evaluation

Suspect WMS when childhood high myopia or ectopia lentis co-occurs with microspherophakia, short stature, brachydactyly or stiff joints. Recommended evaluation includes refraction, slit-lamp examination after careful angle assessment, tonometry, gonioscopy, optic-nerve/visual-field assessment when age appropriate, axial-length and lens biometry, anterior-segment OCT or ultrasound biomicroscopy, corneal tomography/pachymetry, and dilated retinal examination when safe. The 2023 case used IOLMaster 700, Pentacam and ultrasound biomicroscopy to distinguish lenticular from axial myopia. (huang2023abnormallensthickening pages 1-2)

Systemic assessment should include height and proportions, hands/feet, range of motion, skin and muscular habitus, blood pressure, cardiac examination and baseline echocardiography. Routine blood/urine chemistry, biopsy, EEG, EMG or metabolic assays are not diagnostic.

Genetic testing

A practical strategy is an ectopia-lentis/microspherophakia or connective-tissue panel containing FBN1, ADAMTS10, ADAMTS17 and LTBP2, with deletion/duplication analysis. Phenotype-guided single-gene testing is reasonable in a strongly suggestive family. Trio or family WES is useful for atypical or panel-negative cases and was diagnostic in recent ADAMTS10/ADAMTS17 reports; WGS can identify noncoding and structural variants missed by WES. Candidate variants require orthogonal confirmation and segregation analysis. (li2026anovelhomozygous pages 1-2, huang2023abnormallensthickening pages 1-2)

CMA, karyotyping, FISH, mitochondrial sequencing and repeat-expansion testing are not first-line unless additional findings suggest another diagnosis. RNA sequencing may help resolve a suspected splice variant but is not validated as routine WMS testing.

Differential diagnosis

Major alternatives are Marfan syndrome, isolated ectopia lentis from ADAMTSL4, homocystinuria, sulfite oxidase/molybdenum-cofactor deficiency, isolated microspherophakia, geleophysic dysplasia, acromicric dysplasia, congenital contractural arachnodactyly and other anterior-segment dysgeneses. Short stature, brachydactyly, stiff joints and a spherical lens favor WMS; tall stature, arachnodactyly and aortic-root disease favor Marfan syndrome. Homocystinuria requires urgent biochemical exclusion when clinically plausible.

No universally accepted scoring criteria or population/newborn-screening program exists. Cascade molecular testing is appropriate after a familial variant is established.

11. Outcome and prognosis

Life-expectancy, five- or ten-year survival and disease-specific mortality have not been quantified. Most morbidity is ophthalmic and musculoskeletal rather than fatal. Untreated angle closure can cause irreversible optic-nerve damage and blindness; early recognition and appropriate surgery can preserve useful vision. Refractive error and joint limitations are chronic, and surgery does not correct the underlying matrix disorder.

Prognosis depends on age at recognition, angle anatomy, intraocular pressure, optic-nerve damage, lens position, amblyopia, surgical complexity and cardiac involvement. No validated molecular prognostic biomarker exists. In a selected ADAMTS10 dataset, loss-of-function groups appeared to have more glaucoma, but sample sizes—e.g., two nonsense and one frameshift case—are insufficient for clinical genotype-based prediction. (li2026anovelhomozygous pages 4-6)

12. Treatment and current implementation

There is no approved disease-modifying pharmacotherapy. Refractive correction and amblyopia treatment are appropriate early measures. Pressure-lowering drops may be used, but lens-induced pupillary block or crowded-angle anatomy often requires intervention.

Ocular procedures include peripheral laser iridotomy for pupillary block risk, lensectomy/lens extraction for microspherophakia-related crowding or uncontrolled glaucoma, anterior vitrectomy when indicated, individualized intraocular-lens implantation, and filtering or drainage surgery for refractory glaucoma. Reported procedures include Molteno and ExPRESS shunts. Suggested NCIT intervention concepts are Peripheral Iridotomy, Lensectomy, Anterior Vitrectomy, Intraocular Lens Implantation and Glaucoma Surgery. (protasiuk2025weillmarchesanisyndromea pages 3-5)

A recent eight-year-old underwent bilateral lens extraction; IOL placement was initially deferred in one eye because of malignant-glaucoma risk and subsequently individualized after anterior-chamber reformation and pressure control. This is useful real-world evidence but not a comparative trial. (li2026anovelhomozygous pages 9-10)

Systemic care includes periodic cardiology review/echocardiography, orthopedic assessment, physiotherapy or occupational therapy for joint limitation, hearing evaluation if symptomatic and educational support. No WMS-specific pharmacogenomic guidance exists. Growth-hormone efficacy is unproven and should not be extrapolated from isolated reports in overlapping acromelic dysplasias.

No disease-specific interventional ClinicalTrials.gov study, gene therapy, CRISPR therapy, cell therapy, RNA therapy or targeted biologic was identified. Management recommendations are therefore based on rare-disease reviews, case series and extrapolation from glaucoma/ectopia-lentis practice rather than randomized trials. (protasiuk2025weillmarchesanisyndromea pages 3-5, protasiuk2025weillmarchesanisyndromea pages 1-2)

13. Prevention

Primary prevention through lifestyle change or vaccination is not applicable. Genetic counseling is the central preventive strategy. Once the familial pathogenic variant is known, options include cascade testing, prenatal diagnosis and preimplantation genetic testing, subject to local regulations and informed patient choice.

Secondary prevention consists of early ophthalmic examination of affected or at-risk relatives, careful assessment before pharmacologic dilation, periodic intraocular-pressure/angle/optic-nerve monitoring and cardiac surveillance. Tertiary prevention includes timely iridotomy or lens/glaucoma surgery, amblyopia management, rehabilitation and adaptation for joint or visual disability. No vaccine, chemoprophylaxis or population screening program is indicated.

14. Other species and natural disease

No well-established naturally occurring veterinary disorder identical to human WMS was identified. Related fibrillin/ADAMTS-family diseases occur in animals, but they should not be labeled WMS without equivalent genotype and phenotype. Musladin–Lueke syndrome in Beagles is an ADAMTSL2 founder disorder with stiff skin and joint contractures and is a model of geleophysic-dysplasia biology, not WMS itself. WMS is noninfectious and has no zoonotic or cross-species transmission potential.

Orthologues of FBN1, ADAMTS10, ADAMTS17 and LTBP2 are evolutionarily conserved in vertebrates, supporting comparative analysis of microfibrils, ocular zonules and skeletal development.

15. Model organisms

The strongest WMS-relevant models are genetically engineered mice:

Adamts10-null mouse: persistence of fibrillin-2-rich ocular microfibrils in the zonule/vitreous, directly supporting defective fibrillin-2 clearance. It is valuable for ocular microfibril biology but does not reproduce every human systemic feature. (wang2019adamts10inactivationin pages 24-29)
Fbn1 WMS-associated deletion mouse: recapitulates thick skin, short stature and brachydactyly and supports altered local microenvironments/collagen regulation rather than a Marfan phenotype. (mead2022proteolysisoffibrillin2 pages 32-34)
Adamts17-related experimental models: support a role in skeletogenesis and BMP–SMAD1/5/8 modulation, but translation to the complete human WMS4 phenotype remains incomplete. (mead2022proteolysisoffibrillin2 pages 32-34)

Cellular approaches include patient or engineered fibroblasts for fibrillin/collagen deposition and microfibril assembly, plus recombinant-protein cleavage assays. No validated WMS organoid, iPSC disease platform, zebrafish therapeutic screen or humanized model was identified in the retrieved literature.

Recent developments and expert assessment

The important 2023–2024 developments are: longitudinal recognition of abnormal childhood lens thickening in ADAMTS17-associated WMS4; publication of an 18-case natural-history/genotype–phenotype cohort; an atypical dominant LTBP2 WMS-like family; and evidence that FBN1 TB5-domain location alone does not uniquely predict an acromelic phenotype. Together, these findings reinforce three expert conclusions: WMS is genetically and phenotypically heterogeneous; quantitative ocular biometry can reveal disease before overt glaucoma; and genotype–phenotype rules remain provisional because cohorts are small. (huang2023abnormallensthickening pages 1-2, chen2024autosomaldominantweillmarchesanilike pages 7-8, li2026anovelhomozygous pages 10-10, arnaud2024pathogenicvariantsaffecting pages 8-8)

A later 2026 ADAMTS10 synthesis supplies useful numerical estimates—19/19 core ocular and skeletal features, 9/19 glaucoma and 10/18 cardiac abnormalities—but postdates the requested 2023–2024 priority window and combines highly selected published cases. It should be used as supportive rather than definitive epidemiologic evidence. (li2026anovelhomozygous pages 4-6)

Evidence limitations

WMS lacks large registries, population-based epidemiology, standardized diagnostic criteria, controlled treatment trials, validated patient-reported outcomes and robust genotype-specific penetrance estimates. Several claims derive from individual families or literature-assembled cohorts. Exact HPO, UBERON, GO, NCIT, MONDO and subtype OMIM identifiers should be validated against current ontology releases before production ingestion. The retrieved evidence supported selected exact abstract statements and PMIDs, but not every paper exposed a PubMed identifier or complete abstract; DOI URLs and publication dates are therefore supplied where available.

References

(li2026anovelhomozygous pages 1-2): Mengyang Li, Rong Bai, Yuanyuan Lian, Can Shu, Huiping Li, and Xun-Lun Sheng. A novel homozygous adamts10 frameshift variant in weill-marchesani syndrome in a chinese family. BMC Medical Genomics, Feb 2026. URL: https://doi.org/10.1186/s12920-026-02308-7, doi:10.1186/s12920-026-02308-7. This article has 1 citations and is from a peer-reviewed journal.
(protasiuk2025weillmarchesanisyndromea pages 1-2): Agnieszka Protasiuk, Agata Żak-Gontarz, Rafał Sierzpowski, Patrycja Tymoszuk, Bartosz Kasperek, Katarzyna Augustowska, Kamila Budzyńska, Klaudia Klimczak, and Laura Loryś. Weill-marchesani syndrome: a comprehensive review of pathogenesis, clinical features, and management. Lekarz Wojskowy, 103:206-210, Sep 2025. URL: https://doi.org/10.53301/lw/204988, doi:10.53301/lw/204988. This article has 0 citations.
(protasiuk2025weillmarchesanisyndromea pages 3-5): Agnieszka Protasiuk, Agata Żak-Gontarz, Rafał Sierzpowski, Patrycja Tymoszuk, Bartosz Kasperek, Katarzyna Augustowska, Kamila Budzyńska, Klaudia Klimczak, and Laura Loryś. Weill-marchesani syndrome: a comprehensive review of pathogenesis, clinical features, and management. Lekarz Wojskowy, 103:206-210, Sep 2025. URL: https://doi.org/10.53301/lw/204988, doi:10.53301/lw/204988. This article has 0 citations.
(huang2023abnormallensthickening pages 1-2): Junting Huang, Kailai Nie, Xinpin Lv, Yuting Liu, Guiqi Yang, Junjiang Fu, Longqian Liu, and Hongbin Lv. Abnormal lens thickening in a child with weill–marchesani syndrome 4: a 3-year follow-up case report. Frontiers in Medicine, Jan 2023. URL: https://doi.org/10.3389/fmed.2022.1021489, doi:10.3389/fmed.2022.1021489. This article has 2 citations.
(chen2024autosomaldominantweillmarchesanilike pages 7-8): Juan Chen, Jifeng Wan, Jiayi Jin, Guangming Jin, Yongxin Zheng, Danying Zheng, and Liuxueying Zhong. Autosomal dominant weill-marchesani-like syndrome in a chinese family due to novel haplotypic mutations in ltbp2. Ophthalmic research, May 2024. URL: https://doi.org/10.1159/000538844, doi:10.1159/000538844. This article has 6 citations and is from a peer-reviewed journal.
(arnaud2024pathogenicvariantsaffecting pages 8-8): Pauline Arnaud, Zakaria Mougin, Genevieve Baujat, Valérie Drouin-Garraud, Salima El Chehadeh, Laurent Gouya, Sylvie Odent, Guillaume Jondeau, Catherine Boileau, Nadine Hanna, and Carine Le Goff. Pathogenic variants affecting the tb5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in marfan syndrome. Journal of Medical Genetics, 61:469-476, Mar 2024. URL: https://doi.org/10.1136/jmg-2023-109646, doi:10.1136/jmg-2023-109646. This article has 2 citations and is from a domain leading peer-reviewed journal.
(li2026anovelhomozygous pages 4-6): Mengyang Li, Rong Bai, Yuanyuan Lian, Can Shu, Huiping Li, and Xun-Lun Sheng. A novel homozygous adamts10 frameshift variant in weill-marchesani syndrome in a chinese family. BMC Medical Genomics, Feb 2026. URL: https://doi.org/10.1186/s12920-026-02308-7, doi:10.1186/s12920-026-02308-7. This article has 1 citations and is from a peer-reviewed journal.
(li2026anovelhomozygous pages 7-9): Mengyang Li, Rong Bai, Yuanyuan Lian, Can Shu, Huiping Li, and Xun-Lun Sheng. A novel homozygous adamts10 frameshift variant in weill-marchesani syndrome in a chinese family. BMC Medical Genomics, Feb 2026. URL: https://doi.org/10.1186/s12920-026-02308-7, doi:10.1186/s12920-026-02308-7. This article has 1 citations and is from a peer-reviewed journal.
(li2026anovelhomozygous pages 9-10): Mengyang Li, Rong Bai, Yuanyuan Lian, Can Shu, Huiping Li, and Xun-Lun Sheng. A novel homozygous adamts10 frameshift variant in weill-marchesani syndrome in a chinese family. BMC Medical Genomics, Feb 2026. URL: https://doi.org/10.1186/s12920-026-02308-7, doi:10.1186/s12920-026-02308-7. This article has 1 citations and is from a peer-reviewed journal.
(wang2019adamts10inactivationin pages 24-29): Lauren W. Wang, Wendy E. Kutz, Timothy J. Mead, Lauren C. Beene, Shweta Singh, Michael W. Jenkins, Dieter P. Reinhardt, and Suneel S. Apte. Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage. Matrix biology : journal of the International Society for Matrix Biology, 77:117-128, Apr 2019. URL: https://doi.org/10.1016/j.matbio.2018.09.004, doi:10.1016/j.matbio.2018.09.004. This article has 61 citations.
(mead2022proteolysisoffibrillin2 pages 32-34): Timothy J. Mead, Daniel R. Martin, Lauren W. Wang, Stuart A. Cain, Cagri Gulec, Elisabeth Cahill, Joseph Mauch, Dieter P. Reinhardt, Cecilia W. Lo, Clair Baldock, and Suneel S. Apte. Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development. eLife, Feb 2021. URL: https://doi.org/10.1101/2021.02.03.429587, doi:10.1101/2021.02.03.429587. This article has 40 citations and is from a domain leading peer-reviewed journal.
(hubmacher2015adamtsproteinsas pages 10-10): Dirk Hubmacher and Suneel S. Apte. Adamts proteins as modulators of microfibril formation and function. Matrix biology : journal of the International Society for Matrix Biology, 47:34-43, Sep 2015. URL: https://doi.org/10.1016/j.matbio.2015.05.004, doi:10.1016/j.matbio.2015.05.004. This article has 196 citations.
(li2026anovelhomozygous pages 10-10): Mengyang Li, Rong Bai, Yuanyuan Lian, Can Shu, Huiping Li, and Xun-Lun Sheng. A novel homozygous adamts10 frameshift variant in weill-marchesani syndrome in a chinese family. BMC Medical Genomics, Feb 2026. URL: https://doi.org/10.1186/s12920-026-02308-7, doi:10.1186/s12920-026-02308-7. This article has 1 citations and is from a peer-reviewed journal.

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

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Weill–Marchesani syndrome: comprehensive disease-characteristics report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk and protective factors

Causal factors

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

Ocular phenotype

Skeletal, joint and integumentary phenotype

Cardiovascular and other manifestations

Functional and quality-of-life effect

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Upstream molecular defect

Ocular causal chain

Skeletal and connective-tissue causal chain

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population

10. Diagnostics

Clinical and ophthalmic evaluation

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current implementation

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments and expert assessment

Evidence limitations

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