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.

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).

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

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.

Ectopia Lentis

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

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.

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.

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].

Surveillance

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.

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.

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.

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.

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

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