Facial Dysmorphism, Lens Dislocation, Anterior Segment Abnormalities, And Spontaneous Filtering Blebs

A number sign (#) is used with this entry because of evidence that facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs (FDLAB) is caused by homozygous mutation in the ASPH gene (600582) on chromosome 8q12.

Description

Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (Patel et al., 2014).

Clinical Features

Shawaf et al. (1995) noted an association of craniofacial dysmorphism (downward slanting palpebral fissures, large beaked nose, triangular retracted chin, dental malocclusion), ectopia lentis, variable degree of angle closure secondary to iridocorneal adhesions, patchy areas of atrophy in both irides, and avascular elevations of the bulbar conjunctiva in 6 members of a consanguineous Lebanese family, including a man, his 2 daughters, 2 of his sibs, and his maternal aunt. All affected persons were of average height and had normal body proportions and normal joint mobility. Shawaf et al. (1995) proposed that this is a new syndrome.

Haddad et al. (2001) reported the same constellation of features in 4 sisters of a presumably unrelated Lebanese-Druze family.

That this syndrome is distinct was apparently corroborated by the identification of a third presumably unrelated family. Among 8 Druze-Lebanese sibs of consanguineous parents, 2 sisters were affected (Traboulsi, 2002).

Mansour et al. (2013) reported a 16-year-old Lebanese female orphan who presented with loss of vision to 20/200 bilaterally. She had an elongated face with a prominent, broad, and beaked nose. Ocular examination revealed central superficial corneal opacification as well as central retrocorneal nodular thickening bilaterally. There was iridocorneal touch on slit-lamp view, with a diffusely flat anterior chamber. The pupil failed to dilate due to diffuse posterior synechiae. Conjunctival blebs were present superiorly and nasally in both eyes with a low intraocular pressure of 8 mm Hg. The patient had decreased axial lengths, measuring 19.41 and 20.12 mm on the right and left, respectively, by ultrasonography. Optical coherence tomography (OCT) demonstrated central retrocorneal fibrosis and near-apposition of the cornea to the iris, with angle closure.

Patel et al. (2014) described a 19-year-old Saudi woman, born of consanguineous parents, who first noticed visual difficulties at 10 years of age. Her facial features were consistent with FDLAB and included a beaked nose, flat cheeks, and retrognathia. At 18 years of age, she underwent implantation of scleral-fixated intraocular lenses bilaterally due to anterior dislocation of the right lens and spherophakia on the left. Best-corrected visual acuity was 20/25 in both eyes. Slit-lamp examination showed stable intraocular implants, with filtering blebs and patchy iris atrophy bilaterally. She had no other health issues, and her 3 sibs were unaffected.

Abarca Barriga et al. (2018) reported a boy, born to consanguineous Peruvian parents, with bilateral lens dislocation, developmental delay, and inguinal hernias. His height was within normal limits, but his weight at age 11 years was -2.71 SD and his body mass index was 12.7 (-3.74 SD). He had a long and slender body build, dolichocephaly, long and somewhat asymmetric face, mild strabismus, downslanting palpebral fissures, malar hypoplasia, high nasal ridge, high-arched palate, bifid uvula, irregularly placed teeth, and small chin. He also had pectus excavatum, cubiti valgi, long and thin fingers, and joint hypermobility. Echocardiogram was normal. Abarca Barriga et al. (2018) compared the findings in their patient with the 12 previously reported patients, and noted that multiple ocular abnormalities were seen, with ectopia lentis being seen in all 13 and conjunctival blebs in 7. Typical facial appearance included a long face, downslanting palpebral fissures, a convex nasal ridge, malar hypoplasia, crowded teeth/malocclusion, and retrognathia. Novel findings in their patient included bifid uvula, pectus excavatum, cubitus valgus, flat feet, and lax joints.

Inheritance

Shawaf et al. (1995) suggested that the syndrome they reported in a Lebanese family was most compatible with autosomal recessive inheritance with pseudodominance. Haddad et al. (2001) also suggested autosomal recessive inheritance of the disorder.

Molecular Genetics

In a Saudi woman with facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs, Patel et al. (2014) performed autozygosity mapping followed by whole-exome sequencing and identified homozygosity for a 5-bp deletion/3-bp insertion mutation in the ASPH gene (600582.0001). The mutation, which segregated with disease in the family, was not found in 425 in-house Saudi exomes, 100 Saudi controls by Sanger sequencing, or any publicly available variant databases. Sequencing of ASPH in 2 Lebanese patients, including the 16-year-old girl reported by Mansour et al. (2013) and 1 of the 4 affected Lebanese Druze sisters reported by Haddad et al. (2001), revealed that they were both homozygous for the same missense mutation (R735W; 600582.0002), which was not found in 208 Lebanese Druze control chromosomes.

In a boy with FDLAB, who was born to consanguineous Peruvian parents, Abarca Barriga et al. (2018) identified homozygosity for a nonsense mutation in the ASPH gene (W57X; 600582.0003). The mutation was identified by whole-exome sequencing. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes Project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes.