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Weill-Marchesani Syndrome

, MD, , MD, PhD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 10, 2020.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

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. 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. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Early detection and removal of an ectopic lens to decrease the possibility of pupillary block and glaucoma. Surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma; medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics. Consider physical therapy for joint issues. Careful evaluation prior to anesthesia because of stiff joints, poorly aligned teeth, and maxillary hypoplasia. Treatment of cardiac anomalies per cardiologist.

Surveillance: Annual ophthalmology examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma. Annual assessment of height and joint range of motion. Regular cardiac follow up with echocardiogram and electrocardiography.

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

Genetic counseling.

Autosomal dominant inheritance: FBN1-related WMS is inherited in an autosomal dominant manner. Most affected individuals have an affected parent. The proportion of individuals with autosomal dominant WMS caused by a de novo pathogenic variant is unknown. Each child of an individual with autosomal dominant WMS has a 50% chance of inheriting the pathogenic variant.

Autosomal recessive inheritance: ADAMTS10-, ADAMTS17-, and LTPBP2-related WMS are inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). If both parents are known to be heterozygous for a pathogenic variant, 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. Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family.

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

Diagnosis

No consensus clinical diagnostic criteria for Weill-Marchesani syndrome (WMS) have been published.

Suggestive Findings

WMS should be suspected in individuals with the following clinical and radiographic features.

Clinical features

  • Eye anomalies including microspherophakia and ectopia lentis
  • Short stature
  • Brachydactyly
  • Progressive joint stiffness
  • Thickened skin
  • Pseudomuscular build
  • Cardiovascular defects (e.g., patent ductus arteriosus, pulmonary stenosis, thoracic aortic aneurysm, cervical artery dissection, prolonged QTc)

Radiographic features

  • Shortened long tubular bones
  • Delayed bone age
  • Broad proximal phalanges

Establishing the Diagnosis

The diagnosis of WMS can be established in a proband with characteristic Suggestive Findings and/or by identification of biallelic pathogenic (or likely pathogenic) variants in ADAMTS10, ADAMTS17, or LTBP2 or of a heterozygous pathogenic (or likely pathogenic) variant in FBN1 by molecular genetic testing if clinical features are inconclusive (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with short stature, ocular anomalies, and/or cardiovascular anomalies are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Serial single-gene testing. In individuals suspected of having autosomal dominant WMS, perform sequence analysis of FBN1 first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no pathogenic variant is detected, the next step is to perform FBN1 deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A multigene panel that includes ADAMTS10, ADAMTS17, FBN1, LTBP2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of WMS, some panels may not include these genes. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue abnormalities, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is an option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Weill-Marchesani Syndrome (WMS)

Gene 1, 2Proportion of WMS
Attributed to Pathogenic
Variants in Gene
Proportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ADAMTS10 <10 probands reported 6, 77 probands reported 6See footnote 7.
ADAMTS17 6 probands reported 86 probands reported 8None reported
FBN1 9 probands reported 9, 106 probands reported 93 probands reported 10
LTBP2 1 family reported 111 reported 11None reported
1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein.

3.

See Molecular Genetics for information on variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

A whole-gene deletion has been reported as a founder variant in the Amish population [Strauss & Puffenberger 2009].

8.
9.
10.
11.

Clinical Characteristics

Clinical Description

Weill-Marchesani syndrome (WMS) is a connective tissue disorder that usually presents in childhood with short stature and/or ocular problems. The autosomal recessive and autosomal dominant forms of WMS share clinical manifestations in the following systems [Faivre et al 2003a].

Eyes. The mean age of recognition of an ocular problem is 7.5 years. Microspherophakia (small spherical lens) is the most important manifestation of WMS. Microspherophakia results in lenticular myopia (i.e., myopia primarily resulting from abnormal shape of the lens), ectopia lentis (abnormal position of the lens), and glaucoma (elevation of the intraocular pressure).

  • Lenticular myopia is usually the first ophthalmologic finding.
  • Ectopia lentis usually results in downward displacement of the lens.
  • Glaucoma is the most serious complication because it can lead to blindness. In most individuals glaucoma results from pupillary block resulting from forward movement of the lens or dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [Razeghinejad & Safavian 2006].

Loss of vision occurs earlier in WMS and is more severe than in other lens dislocation syndromes. In some individuals, lens dislocation and pupillary block appear after blunt trauma to the eye weakens the zonular fibers.

Presenile vitreous liquefaction has been described in a large family with autosomal dominant WMS [Evereklioglu et al 1999].

Retinal vascular tortuosity in the absence of congenital heart disease has been described in one affected individual [Gallagher et al 2011].

Retinitis pigmentosa has been reported in an affected female age 14 years [Jethani et al 2007].

Advanced glaucoma and corneal endothelial dysfunction have recently been reported in an affected female age 30 years [Guo et al 2015].

Growth. Short stature is reported in all affected individuals. The growth rate falls below the standard growth curve in the first years of life. An adult male with WMS is expected to achieve a height of 142-169 cm and an adult female a height of 130-157 cm. No information is available about growth hormone efficacy in individuals with WMS.

Musculoskeletal. The skeletal features include brachydactyly and short metacarpals. The metacarpophalangeal and interphalangeal joints may be prominent. Joint stiffness of the digits, wrists, shoulders, hips, knees, and ankles may be progressive.

Heart abnormalities are frequently seen and include patent ductus arteriosus, pulmonary stenosis, aortic stenosis, and mitral valve prolapse [Haji-Seyed-Javadi et al 2012]. Thoracic aortic aneurysm and cervical artery dissection was recently reported in a three-generation family with FBN1-related WMS [Cecchi et al 2013, Newell et al 2017]. Systematic electrocardiogram revealed prolonged QT in individuals with WMS [Kojuri et al 2007].

Skin. Taut skin with thickened skin folds is seen.

Intellectual disability has been reported in 11%-17% of individuals and is always mild.

Phenotype Correlations by Gene

Table 2.

Weill-Marchesani Syndrome Phenotype Correlations by Gene

GenePhenotypic Feature
Eye anomaliesShort statureBrachydactylyJoint stiffnessOther
ADAMTS10 ++++Heart defects, mild ID
ADAMTS17 ++±+Heart defects
FBN1 ++++Heart defects
LTBP2 ++++Heart defects

ID = intellectual disability

Genotype-Phenotype Correlations

Given the limited number of individuals with WMS in the literature, no genotype-phenotype correlations for ADAMTS10, ADAMTS17, FBN1, or LTBP2 have been identified.

Penetrance

The penetrance in those with autosomal recessive and dominant WMS is thought to be 100%. Intrafamilial and interfamilial variable expressivity is observed in WMS.

Nomenclature

Other terms previously used to refer to Weill-Marchesani syndrome:

  • Spherophakia-brachymorphia syndrome
  • Mesodermal dysmorphodystrophy, congenital

Prevalence

WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population.

Differential Diagnosis

Ectopia Lentis

Ectopia lentis may occur in the conditions listed in Table 4. All, however, are clinically distinct from Weill-Marchesani syndrome (WMS).

Table 4.

Other Genes and Disorders Associated with Ectopia Lentis

Gene(s)DisorderMOIClinically Distinctive Features
AASS Hyperlysinemia type I (OMIM 238700)ARMild ID
ADAMTSL4 Ectopia lentis et pupilae (OMIM 225200)AREctopic pupil, flat-appearing iris, cataracts
CBS Classic homocystinuria 1AR
  • DD/ID
  • Tall & slender w/asthenic habitus ("marfanoid")
  • Biochemical features 1
  • Thromboembolism
FBN1 Marfan syndrome AD
  • Skeletal manifestations: bone overgrowth & joint laxity; extremities disproportionately long for trunk size (dolichostenomelia)
  • Cardiovascular manifestations: dilatation of aorta at the level of sinuses of Valsalva, predisposition for aortic tear & rupture, mitral valve prolapse w/or w/o regurgitation, tricuspid valve prolapse, & enlargement of proximal pulmonary artery
SUOX Isolated sulfite oxidase deficiency 2ARSevere neurologic symptoms: untreatable seizures, opisthotonus, attenuated growth of the brain, & ID 2

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance

1.

Homocystinuria 1 is a metabolic disorder caused by cystathionine β-synthase deficiency. The cardinal biochemical features of homocystinuria are markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity.

2.

Sulfite oxidase deficiency results from an isolated deficiency in the enzyme sulfite oxidase (which is responsible for the oxidation of sulfite to sulfate) or from molybdenum cofactor deficiency.

Acromelic Dysplasia

The acromelic dysplasia group includes four rare disorders: Weill-Marchesani syndrome, geleophysic dysplasia, acromicric dysplasia, and Myhre syndrome. The clinical overlap between the four disorders is striking. Overlapping and distinguishing clinical features are summarized in Table 5.

Table 5.

Other Acromelic Dysplasias to Consider in the Differential Diagnosis of Weill-Marchesani Syndrome (WMS)

Gene(s)DiffDx DisorderMOIClinical Features of DiffDx Disorder
Overlapping w/WMSDistinguishing from WMS
ADAMTSL2
FBN1
LTBP3
Geleophysic dysplasia AD
AR
Short stature; brachydactyly; stiff joints; delayed bone age; cone-shaped phalangeal epiphyses; thickened skin; heart diseaseHepatomegaly; no lens abnormalities
FBN1
LTBP3 1
Acromicric dysplasia (OMIM 102370)ADNo lens abnormalities
SMAD4 Myhre syndrome AD 2IUGR; short stature; brachydactyly; joint stiffness; thickened skin; heart diseaseHearing loss; characteristic facial features; variable degree of cognitive impairment; no lens abnormalities

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance

1.
2.

All probands with Myhre syndrome reported to date have had a de novo SMAD4 pathogenic variant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Weill-Marchesani syndrome (WMS), the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Weill-Marchesani Syndrome

System/ConcernEvaluationComment
Ophthalmology Complete ophthalmologic exam
Musculoskeletal
  • Growth assessment
  • Assessment of joint range of motion by orthopedist/PT
Cardiology
  • Echocardiography
  • Electrocardiogram
To evaluate for:
  • Patent ductus arteriosus, valvular stenosis, &/or arterial narrowing
  • Prolonged QT
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of WMS to facilitate medical & personal decision making

MOI = mode of inheritance; PT = physical therapist

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Ocular complications. It is not possible to generalize the management of the ocular complications of WMS.

  • The medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics.
  • A peripheral iridectomy should be performed to prevent or relieve pupillary block [Chang et al 2002, Ritch et al 2003].
  • Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [Harasymowycz & Wilson 2004].
  • Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [Razeghinejad & Safavian 2006].

Table 7.

Treatment of Manifestations in Individuals with Weill-Marchesani Syndrome (WMS)

Manifestation/ConcernTreatmentConsiderations/Other
Ocular complications See above.
Joint stiffness Consider PT to maintain joint mobility.No study has been done on efficacy of passive range-of-motion exercises to help maintain flexibility.
Airway management during anesthesia Careful eval prior to anesthesiaAnesthesia can be difficult in persons w/WMS because of stiff joints, poorly aligned teeth, & maxillary hypoplasia [Dal et al 2003, Karabiyik 2003, Riad et al 2006].
Cardiac anomalies Treatment per cardiologist

PT = physical therapy

Surveillance

Table 8.

Recommended Surveillance for Individuals with Weill-Marchesani Syndrome

System/ConcernEvaluationFrequency
Ophthalmology Ophthalmology exams for early detection & removal of ectopic lens can help ↓ possibility of pupillary block & glaucoma.Annually
Growth Assessment of height
Joint stiffness Assessment of joint range of motion by orthopedist/physiotherapist
Cardiac
anomalies
  • Echocardiogram for evidence of valvular stenosis, arterial narrowing, &/or aneurysm
  • Electrocardiography to evaluate QT interval
Periodic if normal; otherwise, specific follow up according to cardiac defect

Agents/Circumstances to Avoid

Use of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.

Potential increased risk of WMS-related ocular complications associated with contact sports should be discussed with the ophthalmologist.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from ophthalmology and cardiology evaluations. Evaluations can include:

  • Molecular genetic testing if the pathogenic variant(s) in the family are known;
  • Ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Weill-Marchesani syndrome (WMS) caused by pathogenic variants in FBN1 is inherited in an autosomal dominant manner.

WMS caused by pathogenic variants ADAMTS10, ADAMTS17, or LTPBP2 is inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance ‒ Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with autosomal dominant WMS have an affected parent.
  • A proband with autosomal dominant WMS may have the disorder as the result of a de novo FBN1 pathogenic variant. The proportion of individuals with autosomal dominant WMS caused by a de novo pathogenic variant is unknown.
  • If the proband appears to be the only affected family member, molecular genetic testing (if a molecular diagnosis has been established in the proband) is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. Recommendations may also include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist.
  • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
      * A parent with somatic and germline mosaicism for a FBN1 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the FBN1 pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial variable expressivity is observed in WMS.
  • If the proband has a known WMS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the FBN1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for WMS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance ‒ Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one ADAMTS10, ADAMTS17, or LTPBP2 pathogenic variant based on family history).
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents to confirm that both parents are heterozygous for an ADAMTS10, ADAMTS17, or LTPBP2 pathogenic variant and to allow reliable recurrence risk assessment. (In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred de novo in the proband or (2) uniparental isodisomy and consequent homozygosity for the pathogenic variant transmitted by a heterozygous parent [Jónsson et al 2017].)
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ADAMTS10, ADAMTS17, or LTPBP2 pathogenic variant, 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.
  • Intrafamilial variable expressivity is observed in WMS.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive WMS are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WMS-related pathogenic variant.

Carrier Detection

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Weill-Marchesani Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Weill-Marchesani Syndrome (View All in OMIM)

134797FIBRILLIN 1; FBN1
277600WEILL-MARCHESANI SYNDROME 1; WMS1
602091LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 2; LTBP2
607511A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 17; ADAMTS17
608328WEILL-MARCHESANI SYNDROME 2; WMS2
608990A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 10; ADAMTS10
613195WEILL-MARCHESANI SYNDROME 4; WMS4
614819WEILL-MARCHESANI SYNDROME 3; WMS3

Molecular Pathogenesis

Weill-Marchesani syndrome (WMS) is a genetic disorder of the connective tissue caused by pathogenic variants in four genes, ADAMTS10, ADAMTS17, LTBP2, and FBN1, which encode extracellular matrix components.

ADAMS10 and ADAMTS17 belong to the ADAMTS (disintegrin-like and metalloprotease with thrombospondin type 1 motif) gene superfamily which codes for proteases. These zinc metalloendopeptidases have diverse roles in the formation, remodeling, and destruction of the extracellular matrix [Yi et al 2019].

A direct interaction between the protein products encoded by ADAMTS10 and FBN1 has been demonstrated; the ADAMTS10 protein promotes fibrillin-1 deposition in the extracellular matrix of cultured fibroblasts [Kutz et al 2011].

Latent transforming growth factor beta-binding protein 2 (LTBP2) is an extracellular matrix protein that associates with fibrillin-1 containing microfibrils. LTBP2 pathogenic variants are responsible for disruptions of the microfibrillar network in the extracellular matrix in fibroblasts of individuals with WMS [Haji-Seyed-Javadi et al 2012].

Mechanism of disease causation. The precise mechanism of WMS-related pathogenic variants remains unclear.

Chapter Notes

Author History

Valérie Cormier-Daire, MD, PhD (2020-present)
Ian M MacDonald, MDCM; University of Alberta (2007-2020)
Pauline Marzin, MD (2020-present)
Ekaterini Tsilou, MD (2007-present)

Revision History

  • 10 December 2020 (sw) Comprehensive update posted live
  • 14 February 2013 (me) Comprehensive update posted live
  • 1 November 2007 (me) Review posted live
  • 3 August 2007 (et) Original submission

References

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