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Traboulsi syndrome is a rare genetic disorder characterized by facial dysmorphism, lens subluxation, anterior segment anomalies, and spontaneous filtering blebs. The syndrome is due to mutations in the ASPH gene, which plays a crucial role in the development and maintenance of the lens. This case report describes the clinical and genetic findings in a Mexican male with Traboulsi syndrome, highlighting the identification of a novel ASPH variant. A 21-year-old male presented with trauma to the right eye while playing soccer. He had a history of lens subluxation and dysmorphic facial features. Ophthalmic examination revealed right eye lens subluxation into the anterior chamber (with signs of a previous episode of acute angle closure) and left eye posterior and inferior lens subluxation with sectorial iris atrophy. Genetic analysis identified a pathogenic ASPH variant (NM_004318.3:c.1892G>A, p.Trp631*) and a novel likely pathogenic variant (deletion of exons 20–21), confirming Traboulsi syndrome. This is the first instance of Traboulsi syndrome in the Mexican population. The absence of spontaneous filtering blebs in this patient supports previous reports of the wide phenotypic variability that could be related to the type of mutation. This novel ASPH variant expands the known genetic heterogeneity of Traboulsi syndrome. [ABSTRACT FROM AUTHOR]

Background: Traboulsi syndrome is a sporadic autosomal recessive disorder. Very few cases reported and no surgical treatment has been described. Purpose: The purpose of the study was to describe the surgical treatment of a case of Traboulsi syndrome with intercalary staphyloma. Synopsis: Traboulsi syndrome[1-3] is a type of spontaneous filtering bleb. The case was of a 31-year-old lady with a flat anterior chamber and large intercalary staphyloma, with a subluxated clear lens. Liberal peritomy was done. The staphyloma was cut and the displaced lens was delivered through it. It was closed with 7-0 vicryl continuous suture. A cross-linked cornea was used after removing the Descemet membrane. It was modified to match the crescentic shape of the limbus by using 11 and 6 mm trephine. Two wedge-shaped defects were created and tissue was excised between them, which were then sutured to increase the arc radius. A peripheral flange at the corneal edge was created. A pocket was created in the host cornea to accommodate the donor corneal flange. The donor cornea was tucked in and the graft was sutured. The sclera was used to suture another side prophylactically, making a 360-degree encirclage. The patient got ambulatory vision postsurgery. The use of the cornea as biological encirclage has not been described previously. Highlights: Using a cross-linked cornea. Creating wedge-shaped defects in crescentic corneal graft to increase arc radius. Use of cornea as encirclage. Link of video: https://youtu.be/T3b5rkvFmlc

Traboulsi syndrome is a rare disease clinically characterized by facial dysmorphism, abnormal spontaneous filtering blebs, ectopia lentis (EL) and multiple anterior segment abnormalities. An 18-year-old female was referred to the Emergency Service of Hospital São Geraldo (HSG) claiming decreased right eye (RE) visual acuity associated with ocular pain that was noticed approximately 2 months earlier. She underwent a complete ophthalmic and physical examination including hands, ankle, wrist and chest X-ray, abdominal ultrasound, echocardiogram and genetic analysis (whole-exome sequencing). The ophthalmic examination revealed a high myopia with spherical equivalent of − 9.50 D and best corrected visual acuity (BCVA) of 20/60 in RE and − 9.25 D with BCVA of 20/30 in the left eye (LE). Slit-lamp examination showed normal conjunctiva in both eyes (BE) and a superior-temporal cystic lesion in RE and nasal in LE; the flat anterior chamber in BE with the transparent crystalline lens touches the central corneal endothelium in the RE. Fundoscopy suggested glaucoma as the cup/disc ratio was 0.7, although the intraocular pressure (IOP) was 10 mmHg in BE without medication. Validation of data from whole exome demonstrated a novel splicing homozygous pathogenic variant (PV) (c.1765-1G>A) of the ASPH gene as well as a heterozygous variant of unknown significance (VUS) of the FBN1 gene (c.6832C>T). We here report a novel splice-affecting homozygous pathogenic variant in the ASPH gene that was detected in a Brazilian patient with clinical features of Traboulsi syndrome. [ABSTRACT FROM AUTHOR]

Traboulsi syndrome is a multi-organ disorder typically characterized by pleiotropic manifestations including facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs (FDLAB). It is caused by mutations in the candidate gene ASPH, which encodes an enzyme aspartyl/asparaginyl beta-hydroxylase involved in the hydroxylation of the epidermal growth factor domain (EGFD). It is a rare monogenic disorder, inherited in an autosomal recessive manner. In recent years, many rare genetic disorders have been identified without established registries, which poses a major public health challenge. Consequently, diagnosing and treating rare disorders requires a thorough understanding of their predisposition factors. This review provides an in-depth understanding of genetic aetiology, pathophysiology, and possible disease management approaches contributing to Traboulsi syndrome.

• We identified a novel missense variant c.2075G > A and a recurrent nonsense variant c.1126C > G of ASPH in two pedigrees. • The single-cell expression atlas demonstrated coexpression of ASPH with FBN1, FBN2, and LTBP2 in non-pigmented ciliary epithelial cells. • Molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and destabilization of the calcium-binding motif. • Genotype-phenotype analysis revealed that patients with cardiac involvement all harbored biallelic truncation variants. Traboulsi syndrome is an under-recognized syndromic form of ectopia lentis (EL) caused by the aspartate beta-Hydroxylase (ASPH) variant. The genotype-phenotype profile of ASPH-associated disease is poorly understood due to the rarity of the condition. We conducted targeted next-generation sequencing and bioinformatics analysis to identify potentially pathogenic ASPH variants in the cohort. Furthermore, we characterized the expression pattern of ASPH and major components of the zonules using single-cell RNA-sequencing (scRNA-seq) and evaluated the genotype-phenotype correlations by combining our data and those from the literature. We identified a novel missense variant c.2075G > A (p.G692D) and a recurrent nonsense variant c.1126C > G (p.R376*) of ASPH in two pedigrees from a Chinese cohort of EL. Both probands were 5-year-old boys with canonical facial dysmorphisms and bilateral anteriorly-dislocated lenses. Other ocular comorbidities included microspherophakia, shallow anterior chamber, and narrow chamber angel. No cardiac involvements or filtering blebs were identified. The single-cell expression atlas of ciliary epithelium demonstrated the coexpression of ASPH with FBN1 , FBN2 , and LTBP2 in the non-pigmented ciliary epithelium cells. Furthermore, molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and a subsequent destabilized calcium-binding motif. The genotype-phenotype analysis demonstrated that patients with cardiac involvements all harbored biallelic truncation variants. The data from this study provide new insights into the genotype-phenotype profile of ASPH -associated disease and implicate the potential role of ASPH in the pathogenesis of EL. [ABSTRACT FROM AUTHOR]

Background: Traboulsi syndrome is a sporadic autosomal recessive disorder. Very few cases reported and no surgical treatment has been described. Purpose: The purpose of the study was to describe the surgical treatment of a case of Traboulsi syndrome with intercalary staphyloma. Synopsis: Traboulsi syndrome[1‑3] is a type of spontaneous filtering bleb. The case was of a 31‑year‑old lady with a flat anterior chamber and large intercalary staphyloma, with a subluxated clear lens. Liberal peritomy was done. The staphyloma was cut and the displaced lens was delivered through it. It was closed with 7‑0 vicryl continuous suture. A cross‑linked cornea was used after removing the Descemet membrane. It was modified to match the crescentic shape of the limbus by using 11 and 6 mm trephine. Two wedge‑shaped defects were created and tissue was excised between them, which were then sutured to increase the arc radius. A peripheral flange at the corneal edge was created. A pocket was created in the host cornea to accommodate the donor corneal flange. The donor cornea was tucked in and the graft was sutured. The sclera was used to suture another side prophylactically, making a 360‑degree encirclage. The patient got ambulatory vision postsurgery. The use of the cornea as biological encirclage has not been described previously. Highlights: Using a cross‑linked cornea. Creating wedge‑shaped defects in crescentic corneal graft to increase arc radius. Use of cornea as encirclage. [ABSTRACT FROM AUTHOR]

Traboulsi syndrome is a very rare, syndromic form of ectopia lentis that is potentially sight-threatening at a young age. It is characterized by typical facial, skeletal and ocular signs. Two siblings, born to consanguineous parents, with a clinical phenotype consistent with Traboulsi syndrome, underwent extensive ophthalmic imaging and exome-based genetic testing. Both were treated with unilateral clear lens extraction via a limbal approach. Two siblings, one male and one female, presented with systemic and ocular features consistent with Traboulsi syndrome. Lens subluxation was present in all 4fouraffected eyes, and spontaneous subconjunctival bleb formation was detected in one eye. This eye also showed evidence of keratoconus-related corneal thinning. The clinical diagnosis of Traboulsi syndrome was confirmed molecularly. A homozygous, novel, pathogenic nonsense variant was identified in exon 25 of the ASPH gene: c.2181_2183dup, p.(Val727_Trp728insTer). Excellent visual outcomes following clear lens extraction and postoperative rigid gas-permeable contact lens fitting were obtained. We expanded the genetic spectrum of Traboulsi syndrome with a novel frameshift variant in the ASPH gene. We showed that lensectomy followed by gas-permeable contact lenses is an efficient therapeutic approach to treat lens subluxation in Traboulsi syndrome. However, lifelong follow-up is crucial to avoid (late) postoperative complications. [ABSTRACT FROM AUTHOR]

A lady who underwent lensectomy for microspherophakia and pars plana vitrectomy for retinal detachment in her left eye developed recurrent filtering blebs at the site of sclerotomies. Filtering blebs were managed by suturing the sclerotomies. Targeted gene sequencing identified a variant of ASPH gene (p.Arg688Gln) which is not known to be associated with Traboulsi syndrome. But considering the paucity of cases with genetic analysis, it would be possible that p.Arg688Gln is a pathogenic variant. This is the first case report of Traboulsi syndrome due to an ASPH variant not reported earlier that can lead to recurrent filtering blebs.

Abstract Background Traboulsi syndrome is a rare disorder characterized by ectopia lentis and facial dysmorphism (large beaked nose), which was only reported in 18 individuals to date. It is caused by homozygous/compound heterozygous variants in the aspartate/asparagine‐β‐hydroxylase (ASPH) gene, which hydroxylates the aspartic acid and asparagine in epidermal growth factor‐like domains of various proteins. Methods Whole‐exome and Sanger sequencing were used to identify the disease‐causing gene of the patient in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ASPH protein. Results Through exome and Sanger sequencing, we identified a novel homozygous ASPH variant (NM_004318.4:c.1910del/NP_004309.2: p.(Asn637MetfsTer15)) in the patient, which may lead to blockage of the ASPH function through truncating the AspH oxygenase domain of the ASPH protein and/or nonsense‐mediated decay of the ASPH transcript. This is the first report of Traboulsi syndrome in a Chinese patient who was combined with ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax. Conclusion Our results revealed the clinical characteristics of the first Chinese patient with Traboulsi syndrome. Additionally, our study expands the mutational spectrum of Traboulsi syndrome and provides information for clinical genetic counseling to this family.

Background: Traboulsi syndrome is a rare disorder characterized by ectopia lentis and facial dysmorphism (large beaked nose), which was only reported in 18 individuals to date. It is caused by homozygous/compound heterozygous variants in the aspartate/asparagine‐β‐hydroxylase (ASPH) gene, which hydroxylates the aspartic acid and asparagine in epidermal growth factor‐like domains of various proteins. Methods: Whole‐exome and Sanger sequencing were used to identify the disease‐causing gene of the patient in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ASPH protein. Results: Through exome and Sanger sequencing, we identified a novel homozygous ASPH variant (NM_004318.4:c.1910del/NP_004309.2: p.(Asn637MetfsTer15)) in the patient, which may lead to blockage of the ASPH function through truncating the AspH oxygenase domain of the ASPH protein and/or nonsense‐mediated decay of the ASPH transcript. This is the first report of Traboulsi syndrome in a Chinese patient who was combined with ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax. Conclusion: Our results revealed the clinical characteristics of the first Chinese patient with Traboulsi syndrome. Additionally, our study expands the mutational spectrum of Traboulsi syndrome and provides information for clinical genetic counseling to this family. [ABSTRACT FROM AUTHOR]

Purpose: Stability of the crystalline lens requires formation of microfibril bundles and their higher-order structures of ciliary zonules. Trauma, malformation, or degeneration of the ciliary zonules can lead to dislocation or displacement of the lens, which in turn can cause transient or permanent loss of visual acuity. The purpose of this study was to identify the predicted substrates of aspartyl/asparaginyl hydroxylase (ASPH), a 2-oxoglutarate- and Fe2+-dependent hydroxylase, which may account for the lens instability phenotype of ASPH-associated syndromes. Methods: A single proband of European ancestry with spherophakia and high myopia was subjected to exome sequencing. Proteins containing the ASPH hydroxylation motif were identified within the SwissProt protein database. Results: We identified 105 putative substrates of ASPH-mediated hydroxylation in the human proteome, of which two (fibrillin-1 and latent transforming growth factor beta binding protein-2) are associated with inherited ectopia lentis syndromes, and are essential for microfibril and ciliary zonule development. Conclusion: Our results implicate ASPH-mediated hydroxylation in the formation of FBN1/LTBP2 microfibril bundles and competent ciliary zonules. [ABSTRACT FROM AUTHOR]

A lady who underwent lensectomy for microspherophakia and pars plana vitrectomy for retinal detachment in her left eye developed recurrent filtering blebs at the site of sclerotomies. Filtering blebs were managed by suturing the sclerotomies. Targeted gene sequencing identified a variant of ASPH gene (p.Arg688Gln) which is not known to be associated with Traboulsi syndrome. But considering the paucity of cases with genetic analysis, it would be possible that p.Arg688Gln is a pathogenic variant. This is the first case report of Traboulsi syndrome due to an ASPH variant not reported earlier that can lead to recurrent filtering blebs. [ABSTRACT FROM AUTHOR]

Shawaf‐Traboulsi syndrome (or Traboulsi syndrome; MIM 601552) is an infrequently reported entity characterized by a typical face (long face, large nose, convex nasal ridge, underdeveloped malae, crowded teeth, retrognathia), skeletal signs (long and slender fingers, sometimes pectus deformation and hypermobile joints), and ectopia lentis with conjunctival blebs, shallow anterior chamber and iridocorneal adhesions. The entity is caused by homozygous variants in ASPH. Here, we report on a boy with the clinical diagnosis of Shawaf‐Traboulsi syndrome, in whom exome sequencing allowed identification of a novel variant in ASPH. We compare the findings in the present patient to those of earlier reported patients; furthermore add new signs for this entity. [ABSTRACT FROM AUTHOR]

Traboulsi syndrome, otherwise known as facial dysmorphism, lens dislocation, anterior-segment abnormalities and spontaneous filtering blebs, is an autosomal recessive condition associated with characteristic ocular features including dislocated crystalline lenses, anterior segment abnormalities and in some individuals, non-traumatic conjunctival cysts. There is a distinctive facial appearance which includes flattened malar region with convex nasal ridge. Alterations in the aspartate beta-hydroxylase (ASPH) gene are known to be the cause of the condition. We report seven further individuals from six unrelated families with characteristic ocular and facial features. Five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Interestingly, inguinal hernias were commonly reported. Although some skeletal features were seen, these were not consistent. One of the patients had mild deficiency of factor VII on clotting studies. The ASPH protein hydroxylates specific asparagine- and aspartate-residues in epidermal growth factor (EGF)-domain containing proteins including coagulation factors and associated genes including FBN1. We propose this as an explanation for the overlap in clinical features with Marfan syndrome and conclude that Traboulsi syndrome is an important differential diagnosis. We strongly recommend echocardiography surveillance for patients with Traboulsi syndrome. [ABSTRACT FROM AUTHOR]