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Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 117-119

Weill–Marchesani syndrome: A rare cause of ectopia lentis and short stature

1 Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Pediatric Ophthalmology, Squint and Neuro-ophthalmology, Shroff Eye Centre, Viva Vision Eye Care, New Delhi, India

Date of Submission27-Mar-2021
Date of Decision06-May-2021
Date of Acceptance12-May-2021
Date of Web Publication31-May-2021

Correspondence Address:
Dr. Sunita Bijarnia-Mahay
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_102_21

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Background: Weill–Marchesani syndrome (WMS) is a rare heritable connective disorder characterized by short stature, brachydactyly, stiff joints and distinctive ocular manifestations of microspherophakia, myopia, ectopia lentis, and glaucoma. It is caused by either biallelic pathogenic variants in ADAMTS10, ADAMTS17, and LTBP2 or heterozygous pathogenic variants in FBN1 genes. Clinical Description: We describe a case of 6-year-old girl who had short stature, high myopia, and bilateral ectopia lentis. The visual acuity was 6/18 (−25.00/−3.00 × 35) in both the eyes with an intraocular pressure (IOP) 15 mmHg and 17 mmHg in right and left eye, respectively. The clinical exome sequencing identified a heterozygous pathogenic c.2413T>C in FBN1 gene confirming the diagnosis of WMS. Management: The proband was prescribed a trial of contact lenses and she is under regular follow-up. The patient is being regularly monitored for any signs of lens displacement, raised IOP. She has been planned for lens extraction, to prevent glaucoma, in case of any progression of symptoms or rise in IOP. Conclusion: WMS should be suspected in any child with short stature and high myopia. The rarity of this disorder often results in diagnostic delay and dreaded complications of secondary glaucoma and blindness.

Keywords: Brachydactyly, ectopia lentis, short stature

How to cite this article:
Sandal S, Shanker V, Pal S, Bijarnia-Mahay S. Weill–Marchesani syndrome: A rare cause of ectopia lentis and short stature. Indian Pediatr Case Rep 2021;1:117-9

How to cite this URL:
Sandal S, Shanker V, Pal S, Bijarnia-Mahay S. Weill–Marchesani syndrome: A rare cause of ectopia lentis and short stature. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 21];1:117-9. Available from: http://www.ipcares.org/text.asp?2021/1/2/117/317350

Weill–Marchesani syndrome (WMS) is rare genetic disorder with a reported prevalence of 1/100,000 population.[1] It was named after George Weill and Oswald Marchesani who first described this entity in 1932 and 1939, respectively.[2] WMS has now been classified under acromelic dysplasias for the last few years.[3] WMS can be inherited in an autosomal recessive (AR) or autosomal dominant (AD) manner due to pathogenic variations in ADAMTS10, ADAMTS17, LTBP2, or FBN1 gene, respectively.[1],[4],[5] In a large series of 128 patients, AD, AR, and sporadic causes accounted for 47%, 39%, and 16% cases, respectively.[6] As a number of hereditary and genetic conditions can result in ectopia lentis, identification of exact etiology is necessary to predict the prognosis and plan future management and surveillance. We describe a case of WMS in a girl with high myopia with progressive visual diminution and short stature.

  Clinical Description Top

A 6-year 5-month-old girl, first born to 3rd-degree consanguineous parents, was referred to the genetic clinic for the evaluation of short stature and visual problems. She was born preterm at 32 weeks, small for gestational age (birth weight: 1.3 kg) with an APGAR score of 8/9 at 1 and 5 min. She had respiratory distress syndrome requiring respiratory support in the form of continuous positive airway pressure for the first 3 days. The baby remained admitted in neonatal intensive care unit for the first 15 days of life for prematurity, low birth weight, and feeding issues. There was no history of neonatal jaundice, seizures, and apnea of prematurity. Her eye evaluation and BERA screening were normal on follow-up. However, subsequently, over the next few months, parents noticed delay in achieving gross motor and language milestones. She started neck holding at 7 months, sitting at 15 months, standing at 2 years, and walking at 2.5 years. Similarly, speech was also delayed. She started speaking one-word at 18 months and two-word sentences at 3 years. At the time of presentation, with an age of 6 years 5 months, she could climb up and downstairs, run, and jump, going to a school but with poor scholastic performance (borderline intelligence quotient of 74), could talk in sentences, recite rhymes, and recognized alphabets, numbers, colors.

At 3.5 years of age, when she started going to school, parents also noticed that she was not growing well and looked small compared to other children of her age. Furthermore, she used to hold books close to her eyes while reading for which she was prescribed high-powered glasses at 4 years of age. For the past 3 months before presenting to us, she had painless decline in vision for which she was evaluated and detected to have bilateral ectopia lentis. There was no history of ectopia lentis or early vision loss and short stature in any of the family members.

Examination at 6 years 5 months demonstrated a proportionate short stature with a height of 101 cm (−3.2 z), arm span of 104 cm, upper segment:lower segment ratio: 1:1, and a mid-parenteral height of 168 ± 8 cm. She weighed 14.2 kg (−2.76 z) and had a head circumference of 48 cm (<−2 SD) with brachycephaly. She was noted to have a synophrys, hypertrichosis over the face with low anterior and posterior hairline, downslanted palpebral fissures, and use of high-powered refractive glasses. There was mild brachydactyly [Figure 1]. Examination of her joints was normal with no stiffness though the skin had a thick texture. Rest of systemic examination was unremarkable. Two-dimensional echocardiography performed for the evaluation of valvular and vascular pathology was normal. This was performed to look for any congenital cardiac defect as may be present in any syndromic diagnosis and especially for aortic root dilatation to rule out possibility of Marfan syndrome and other collagenopathy.
Figure 1: Showing brachydactyly

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On ophthalmological evaluation, she had bilateral high myopia with best-corrected visual acuity in right eye: 6/18 (−25.00/−3.00 × 35) and left eye: 6/18 (−25.00/−3.00 × 35). Intraocular pressure (IOP) using an Icare tonometer in right eye was 15 mmHg and left eye was 17 mmHg. Anterior segment evaluation showed bilateral deep anterior chamber, iridodonesis, and mild nasal subluxation of a spherical and clear lens in both eyes. Fundus evaluation showed normal-sized discs with cup-to-disc of 0.6, normal foveal reflex, tessellated retina with peripheral areas of lattice degeneration. These findings were suggestive of high myopia, bilateral mild lens subluxation (ectopia lentis), and early changes of retinal degeneration. In view of short stature and high myopia with bilateral ectopia lentis, she was suspected to have WMS and was evaluated for the same.

Management and outcome

Clinical exome sequencing study identified a heterozygous variant in exon 20 of FBN1 gene (c.2413T > C; p.C805R; NM_000138.4) confirming the diagnosis of AD, WMS 2. This variant has been previously reported in a patient with congenital ectopia lentis.[7] It is classified as likely pathogenic by revised ACMG criteria (PM1+PM2+PM5+PP2+PP3). The proband has been prescribed a trial of contact lenses. The child is under follow-up to watch for further signs of lens displacement, to monitor IOP and do lens removal to prevent glaucoma, in case of any progression of symptoms. WMS is a multisystem disorder where, apart from short stature (100%), intellectual disability (11%–17%), and brachydactyly which were present in index case; cardiac anomalies are an important feature. The spectrum of cardiac anomalies includes patent ductus arteriosus, mitral valve prolapse, pulmonary, and aortic stenosis. These were ruled out by normal echocardiography.

  Discussion Top

Bilateral ectopia lentis has been associated with genetic conditions such as Marfan syndrome, WMS, homocystinuria, Ehler-Danlos syndrome (EDS), hyperlysinemia, and sulfite oxidase deficiency.[8] Marfan syndrome and homocystinuria are usually associated with a thin tall stature and arachnodactyly, whereas EDS usually has joint laxity as a characteristic feature. Hyperlysinemia and sulfite oxidase deficiency present with intellectual disability and seizures as main manifestations. The presence of cardinal features of short stature, brachydactyly, high myopia, and bilateral ectopia lentis narrowed the diagnosis to WMS in the index case which was later confirmed by genetic testing.

WMS is a disorder with distinctive skeletal and ocular manifestations. Ocular complications such as high myopia, ectopia lentis, glaucoma, and optic neuropathy due to chronic elevation of IOP are the cause of main morbidity associated with this disorder.[2] Weakened zonular fibers and microspherophakia predispose to lens displacement, more commonly in nasal and downward direction as in index case. Glaucoma occurs secondary to displacement of lens into the anterior chamber of the eye and resultant pupillary block and angle closure.[1],[5] Furthermore, these patients develop central corneal thickness with age which can further increase the IOP.[2] Retinal degenerative changes as in our case can be seen secondary to high myopia.[2],[5]

Most of the patients with WMS have high myopia for many years and present late with complications because of unawareness about this condition among the physicians. The rate of legal blindness, defined as a visual acuity of 20/200 or less in the better eye with best correction, is approximately 30%.[9] Glaucoma is seen in nearly all the patients by the fourth decade[9] which underscores the importance of early diagnosis and genetic testing in these patients.

There are no universally accepted treatment guidelines for the treatment of ectopia lentis and glaucoma in WMS. Regular surveillance is recommended and can be individualized for each patient depending on his clinical features. Removal of abnormally small lens is usually required to control the IOP. In cases of advanced glaucoma, combined lens extraction and trabeculectomy may be required.[9] The index case has been prescribed contact lenses. She is under regular follow-up for increase in IOP and signs of lens displacement. We plan a surgical intervention in case of any further progression of symptoms. Important thing to note in these patients is that miotic and mydriatics should be avoided as they can precipitate glaucoma due to induction of pupillary block.[5]

Short stature is a consistent finding seen in nearly all the affected individuals with a reported average height of 130–157 cm in females with WMS.[1] The other important musculoskeletal features which aid in the early diagnosis are brachydactyly with short metacarpals which was seen in index case.

Intellectual disability has been reported in 11%–17% cases with WMS and is always mild in nature.[1] The index child had borderline intelligence with poor scholastic performance.

Although many cases of WMS have been reported from India, but without confirmed molecular diagnosis. This case also highlights the variable clinical expressivity of FBN1-related disorders. In a previously reported patient with this pathogenic variation in FBN1 gene, the clinical phenotype was of congenital ectopia lentis in contrast to complete clinical phenotype of WMS as seen in our case.[7] Furthermore, in our case, as there was consanguinity, we suspected AR WMS but genetic analysis showed an inheritance of AD variety of WMS. Clinical distinction between AR and AD forms of this disease has not been possible till now.[6] In familial cases, AD WMS shows complete penetrance with variable expression.[1] The need of further genetic studies has been counseled and emphasized to the parents.

WMS is a multisystemic disease affecting predominantly eyes, bone and joints, height, and skin. The combination of short stature and myopia should prompt for an early evaluation. Early suspicion and surgical intervention scan avoid complications of glaucoma and blindness. Molecular genetic testing is important for proper patient management and counseling as well as screening of other family members to avoid recurrence.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Marzin P, Cormier-Daire V, Tsilou E. Weill-Marchesani Syndrome. 2007 [Updated 2020 Dec 10]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews®. Seattle (WA): University of Washington, Seattle; 1993. p. 2020.  Back to cited text no. 1
Guo H, Wu X, Cai K, et al. Weill-Marchesani syndrome with advanced glaucoma and corneal endothelial dysfunction: A case report and literature review. BMC Ophthalmol 2015;15:3.  Back to cited text no. 2
Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A 2019;179:2393-419.  Back to cited text no. 3
Khan AO, Aldahmesh MA, Al-Ghadeer H, et al. Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. Ophthalmic Genet 2012;33:235-9.  Back to cited text no. 4
Lopez CR, González GM, García GJ. Weil–Marchesani syndrome: A case report and literature review. Pan-Am J Ophthalmol 2020;2:10.  Back to cited text no. 5
Faivre L, Dollfus H, Lyonnet S, et al. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A 2003;123A:204-7.  Back to cited text no. 6
Li J, Jia X, Li S, et al. Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis. Mol Vis 2014;20:1017-24.  Back to cited text no. 7
Sadiq MA, Vanderveen D. Genetics of ectopia lentis. Semin Ophthalmol 2013;28:313-20.  Back to cited text no. 8
Senthil S, Rao HL, Hoang NT, et al. Glaucoma in microspherophakia: Presenting features and treatment outcomes. J Glaucoma 2014;23:262-7.  Back to cited text no. 9


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