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.