Sclerocornea in a patient with van den Ende–Gupta syndrome homozygous for a SCARF2 microdeletion

Abstract

Van den Ende–Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553–559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2011] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge-velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year-old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2.

New Tools for Mendelian Disease Gene Identification: PhenoDB Variant Analysis Module; and GeneMatcher, a Web-Based Tool for Linking Investigators with an Interest in the Same Gene

“…Autosomal-recessive homozygous identifies homozygous variants that are shared by all affected individuals and excludes variants that are homozygous in an unaffected individual [Hoover-Fong et al, 2014;Migliavacca et al, 2014;Moldenhauer Minillo et al, 2014];…”

Diagnosis of Van den Ende–Gupta syndrome: Approach to the Marden–Walker‐like spectrum of disorders

“…MWS is a rare multisystem disorder that is not well characterized and shows marked phenotypic overlap with several other syndromes, making this group of conditions a difficult area to navigate for clinicians and radiologists alike. Here, we describe the 26th patient with VDEGS [van den Ende et al, ; Bistritzer et al, ; Gupta et al, ; Phadke et al, ; Schweitzer et al, ; Guerra et al, ; Carr et al, ; Leal and Silva., ; Ali et al, ; Anastasio et al, ; Bedeschi et al, ; Patel et al, ; Migliavacca et al, ], the 10th confirmed molecularly [Anastasio et al, ; Bedeschi et al, ; Patel et al, ; Migliavacca et al, ], and characterize in detail the radiologic findings associated with this rare condition. We also take this opportunity to illustrate a parsimonious diagnostic approach to patients presenting with MWS‐like features.…”

“…Recently, recessive mutations in SCARF2 were identified as a cause of VDEGS among a cohort of Qatari affected individuals [Anastasio et al, ] and subsequently identified in an individual in whom a single mutation was unmasked by deletion of the trans locus [Bedeschi et al, ], in a (presumed) Saudi‐Arabian sib pair [Patel et al, ], and in a Brazilian individual [Migliavacca et al, ], illustrating the pan‐ethnic nature of this condition. SCARF2 is a transmembrane protein primarily found on endothelial cells; its extracellular domain interacts with SCARF1 more strongly than it interacts with itself and this binding can be disrupted by acetylated low‐density lipoprotein.…”

“…Key features of VDEGS include craniofacial findings of blepharophimosis, underdeveloped malar and maxillary regions, a distinctive nose, arachno‐camptodactyly, and skeletal abnormalities of the limbs, hands, and feet [Van den Ende et al, ; Gupta et al, ]. Mutations in SCARF2 , a member of the scavenger receptor type F family involved in LDL scavenging [Ishii et al, ], have recently been identified in nine individuals with a clinical diagnosis of VDEGS [Anastasio et al, ; Bedeschi et al, ; Patel et al, ; Migliavacca et al, ]. Allelic heterogeneity seems probable, as 16 additional individuals suspected of having this diagnosis were not found to have mutations in SCARF2 [LA Jerome‐Majewska, unpublished results].…”

Pediatric genetic disease of the cornea

“…Other ocular malformations that have been found in association with 22q11.2 deletion include posterior embryotoxon, retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. Sclerocornea has also been reported in association with Van den Ende-Gupta syndrome (syndrome, which is AR and is characterized by blepharophimosis, hypoplastic maxilla, skeletal abnormalities, joint contractures, arachnodactyly, and a distinctive nose [56,57]. Children with sclerocornea and findings suggestive of these syndromes should be referred for appropriate genetic workup.…”