Traboulsi syndrome (Shawaf-Traboulsi syndrome, FDLAB syndrome) is an extremely rare autosomal recessive disorder caused by mutations in the ASPH gene. It was first reported in 1995 in a consanguineous Druze family from Lebanon. It is characterized by four major findings represented by the acronym FDLAB (Facial Dysmorphism, Lens subluxation, Anterior segment anomalies, spontaneous filtering Blebs).
The prevalence is estimated to be less than 1 in 1,000,000. More than 28 cases have been reported, identified in diverse ethnic groups including Lebanon, India, Saudi Arabia, Peru, China, Pakistan, the United Kingdom, and Mexico 1)3). It often occurs in consanguineous families.
| Item | Content |
|---|---|
| Inheritance pattern | Autosomal recessive |
| Causative gene | ASPH (8q12.1) |
| Prevalence | Less than 1 in 1,000,000 |
Both conditions share ectopia lentis, but they differ in inheritance pattern and causative gene. Traboulsi syndrome is autosomal recessive and caused by mutations in the ASPH gene, while Marfan syndrome is autosomal dominant and caused by mutations in the FBN1 gene. Traboulsi syndrome is characterized by spontaneous filtering blebs and scleral thinning, and does not involve aortic root dilation seen in Marfan syndrome. The Chinese case reported by Lei et al. was initially misdiagnosed as Marfan syndrome, but was confirmed as Traboulsi syndrome based on a family history of consanguineous marriage and genetic testing 3). Genetic testing is useful for differentiation.
The ASPH gene (chromosome 8q12.1) encodes aspartyl/asparaginyl beta-hydroxylase (ASPH). ASPH has a C-terminal catalytic domain that catalyzes the post-translational hydroxylation of aspartate and asparagine residues within EGF-like domains of various proteins.
Almost all genes involved in lens dislocation (FBN1, ADAMTSL4, ADAMTS10, ADAMTS17) encode proteins that interact with EGF domains1). ASPH mutations impair hydroxylation of these proteins, leading to abnormalities in the formation and maintenance of the zonules.
In a literature review by Ibarra-Ramírez et al., 17 different genetic mutations were reported from 28 cases: 5 missense mutations, 8 nonsense mutations, 2 splice site mutations, 1 large deletion, and 1 synonymous mutation1). Most mutations are located in exons 21–25, affecting the AspH oxygenase domain1).
Bleb formation occurs in 85.7% of patients with missense mutations, compared to only 33% with nonsense mutations1). This correlation may be useful for predicting bleb formation risk, but further validation is needed due to the limited number of cases1).
In a literature review by Ibarra-Ramírez et al., 85.7% of patients with missense mutations developed spontaneous filtering blebs, compared to only 33% with nonsense mutations 1). Additionally, Senthil et al. reported that patients sharing a specific mutation had cardiac abnormalities, while another mutation showed no cardiac involvement. These findings suggest that specific ASPH mutations may cause varying degrees of EGF hydroxylation impairment, leading to diverse phenotypes, but definitive conclusions cannot be drawn due to the limited number of cases 1).
Clinical Diagnosis
Slit-lamp examination: Check for lens subluxation, iris atrophy, shallow anterior chamber, corneal opacity, and spontaneous filtering blebs.
Tonometry: Evaluate for angle closure and glaucoma. In the case by Ibarra-Ramírez et al., intraocular pressure was normal at 10 mmHg in both eyes 1).
Ultrasound biomicroscopy (UBM): Useful for detailed evaluation of anterior segment structures.
Genetic Testing
Whole-exome sequencing: Used to identify ASPH gene mutations. Lei et al. identified a novel homozygous frameshift mutation by whole-exome and Sanger sequencing 3).
Sanger sequencing: Used to confirm candidate mutations and perform segregation analysis within families 3).
Imaging studies: Echocardiography and chest CT to evaluate systemic complications 3).
| Differential Diagnosis | Distinguishing Features from Traboulsi Syndrome |
|---|---|
| Marfan Syndrome | Autosomal dominant, aortic root dilation |
| Homocystinuria | Elevated blood methionine |
| Isolated ectopia lentis | No systemic symptoms |
The case reported by Lei et al. was clinically diagnosed as Marfan syndrome based on lens dislocation, tall stature, and lean body type, but an autosomal recessive inheritance was suspected due to a family history of consanguineous marriage, and genetic testing confirmed Traboulsi syndrome 3).
Lensectomy: This is the main treatment for lens subluxation. Early surgery is recommended as soon as subluxation is detected to avoid irreversible corneal and trabecular meshwork damage due to chronic angle closure. In the case reported by Ibarra-Ramírez et al., extracapsular lens extraction was performed without complications 1).
Repair of intercalary staphyloma: Beniwal et al. reported a new surgical technique called biological encirclage using cross-linked cornea 2). A crescent-shaped corneal graft is transplanted into the thinned scleral area and sutured as a 360-degree encirclage 2).
After lensectomy, refractive correction is performed with oxygen-permeable contact lenses or glasses. For glaucoma, intraocular pressure is managed with eye drops.
Lensectomy is recommended as soon as lens subluxation is detected. It often occurs during adolescence to young adulthood. Early intervention can avoid irreversible corneal and trabecular meshwork damage due to chronic angle closure. However, after the sclera becomes fragile and hypotony occurs, the effect of surgical intervention is limited, so evaluation of scleral condition is important. Postoperatively, regular follow-up is necessary due to the risk of filtering bleb formation 1).
ASPH is a non-heme iron/2-oxoglutarate oxygenase localized in the endoplasmic reticulum. It is a large protein consisting of 758 amino acids, with a transmembrane domain, Ca²⁺ binding site, tetratricopeptide repeats (TPR), and an AspH oxygenase domain 3).
ASPH hydroxylates many proteins containing EGF domains, such as coagulation factors (VII, IX, X), protein C, thrombomodulin, LDL receptor, and Notch ligands 3). Fibrillin-1 (FBN1) and LTBP2, which are involved in lens stability, are also hydroxylation substrates of ASPH, and their dysfunction leads to weakening of the zonules 3).
Dinchuk et al. (2002) reported syndactyly, facial malformations, and cleft palate in mice with disrupted ASPH oxygenase domain. These abnormalities are similar to those in Notch ligand Serrate-2 (JAG2) knockout, suggesting interaction between EGF domain hydroxylation and Notch signaling pathway 1).
Anterior subluxation of the lens causes forward movement of the iris and angle closure, leading to increased intraocular pressure. The combination of elevated intraocular pressure and scleral thinning is thought to form a fistula connecting the anterior chamber and subconjunctival space, allowing aqueous humor to leak out and form spontaneous filtering blebs.
FBN1 protein contains EGF domains and is a substrate for hydroxylation by ASPH. Therefore, reduced FBN1 function due to ASPH mutations is considered the cause of clinical features overlapping with Marfan syndrome (lens dislocation, spontaneous pneumothorax) 3).
In Traboulsi syndrome, anterior subluxation of the lens causes angle closure and increased intraocular pressure. At the same time, connective tissue fragility due to ASPH mutations leads to scleral thinning. The combination of these two factors allows aqueous humor to leak from the thin sclera into the subconjunctival space, forming spontaneous filtering blebs. It has been reported that missense mutations have a higher rate of bleb formation than nonsense mutations 1), suggesting that differences in residual enzyme activity among mutation types may affect scleral fragility.
Ibarra-Ramírez et al. reported the first case of Traboulsi syndrome in a Mexican individual in 2024 1). They identified a novel ASPH mutation (deletion of exons 20-21), expanding the diversity of known genetic mutations.
Ibarra-Ramírez et al. reported in a review of 28 cases that filtration blebs formed in 85.7% of patients with missense mutations and 33% with nonsense mutations, suggesting a possible genotype-phenotype correlation 1).
Lei et al. reported the first Chinese case of Traboulsi syndrome in 2021, describing complications including ventricular septal defect, pulmonary cysts, and recurrent spontaneous pneumothorax 3). Whether cardiovascular and respiratory complications are directly associated with ASPH mutations requires further investigation 3).
Beniwal et al. reported a new surgical technique using cross-linked cornea for biological encirclage, presenting a minimally invasive treatment option for intercalary staphyloma 2).
