Weill-Marchesani Syndrome
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 variants in ADAMTS10, ADAMTS17, or LTBP2 or of a heterozygous pathogenic variant in FBN1 by molecular genetic testing if clinical features are inconclusive (see Table 1).
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 at the most reasonable cost 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, 2 | Proportion of WMS Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| ADAMTS10 | <10 probands reported 6, 7 | 7 probands reported 6 | See footnote 7. |
| ADAMTS17 | 6 probands reported 8 | 6 probands reported 8 | None reported |
| FBN1 | 9 probands reported 9, 10 | 6 probands reported 9 | 3 probands reported 10 |
| LTBP2 | 1 family reported 11 | 1 reported 11 | None 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 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.
Dagoneau et al [2004], Morales et al [2009], Kutz et al [2011], Pimienta et al [2013], Li et al [2014]
- 7.
A whole-gene deletion has been reported as a founder variant in the Amish population [Strauss & Puffenberger 2009].
- 8.
Morales et al [2009], Shah et al [2014], Yi et al [2019], Karoulias et al [2020]
- 9.
Faivre et al [2003b], De Backer et al [2007], Sengle et al [2012], Cecchi et al [2013], Lerner-Ellis et al [2014], Wang et al [2014], Newell et al [2017], Groth et al [2017]
- 10.
De Backer et al [2007], Groth et al [2017]
- 11.
Haji-Seyed-Javadi et al [2012]
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
| Gene | Phenotypic Feature | ||||
|---|---|---|---|---|---|
| Eye anomalies | Short stature | Brachydactyly | Joint stiffness | Other | |
| 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) | Disorder | MOI | Clinically Distinctive Features |
|---|---|---|---|
| AASS | Hyperlysinemia type I (OMIM 238700) | AR | Mild ID |
| ADAMTSL4 | Ectopia lentis et pupilae (OMIM 225200) | AR | Ectopic pupil, flat-appearing iris, cataracts |
| CBS | Classic homocystinuria 1 | AR |
|
| FBN1 | Marfan syndrome | AD |
|
| SUOX | Isolated sulfite oxidase deficiency 2 | AR | Severe 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 as 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 Disorder | MOI | Clinical Features of DiffDx Disorder | |
|---|---|---|---|---|
| Overlapping w/WMS | Distinguishing from WMS | |||
| ADAMTSL2 FBN1 LTBP3 | Geleophysic dysplasia | AD AR |
|
|
| FBN1 LTBP3 1 | Acromicric dysplasia (OMIM 102370) | AD | Absence of lens abnormalities | |
| SMAD4 | Myhre syndrome | AD 2 |
|
|
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance
- 1.
McInerney-Leo et al [2016]
- 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/Concern | Evaluation | Comment |
|---|---|---|
| Ophthalmology | Complete ophthalmologic exam | |
| Musculoskeletal |
| |
| Cardiology |
| To evaluate for:
|
| Genetic counseling | By genetics professionals 1 | To inform patients & their families re nature, MOI, & implications of WMS to facilitate medical & personal decision making |
MOI = mode of inheritance
- 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/Concern | Treatment | Considerations/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 anesthesia | Anesthesia 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/Concern | Evaluation | Frequency |
|---|---|---|
| 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 |