Traboulsi Syndrome

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 by Derek W DelMonte, MD on July 6, 2022.


Traboulsi syndrome is an extremely rare autosomal recessive disorder caused by various Aspartate/asparagine-β-hydroxylase (ASPH) gene variants and characterized by facial dysmorphia, lens dislocation, anterior-segment abnormalities, spontaneous filtering blebs and occasional systemic manifestations. This condition is primarily diagnosed clinically, although genetic tests may be performed to confirm the genotype associated with its distinct phenotype. There is currently no cure for this condition, but medical, optical, and surgical treatments are available to decrease associated corneal manifestations and symptoms of glaucoma. Prognosis is also variable depending on the time of diagnosis and management, though visual acuity is typically poor.

Disease Entity

Shawaf-Traboulsi Syndrome ICD-10 Q87.0

Disease

Shawaf-Traboulsi Syndrome (or Traboulsi Syndrome) is a rare autosomal recessive disorder characterized by facial dysmorphia, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB) . The disorder is caused by ASPH gene mutations that encode aspartyl/asparaginyl beta-hydroxylase. Traboulsi Syndrome is extremely rare, with a prevalence of < 1 in 1 million births [1]. The disease was first reported in 1995 in a consanguineous Lebanese family, affecting six family members across three generations [2], predominantly within the Lebanese Druze community [3]. Additional reports of the rare disease are from India [4], Saudi Arabia [5], Persia [6], Pakistan [7], and China [8].

Etiology

Traboulsi Syndrome is thought to be inherited in either an autosomal recessive [3] or autosomal recessive but pseudodominant [2] manner. The genetic abnormality has been identified as the inheritance of two of the various ASPH gene variants located on chromosome 8q12.1 [9]. The ASPH protein contains a C-terminal catalytic domain that catalyzes the posttranslational hydroxylation of aspartic acid and asparagine residues within Epidermal Growth Factor (EGF)-like domains of numerous proteins [8].

EGF domains are present in many genes that cause Mendelian disorders associated with lens dislocation [5]. Several novel gene variants have been discovered in association with Traboulsi syndrome, including many missense and nonsense mutations [4,5,8,10]. This is supported by previous studies where, after the ASPH gene was knocked-out or upregulated in mouse embryos, phenotypic abnormalities were present in the eyes, snout, and limbs, corresponding to the phenotypic manifestations of Shawaf-Traboulsi syndrome [5,8,11].

Risk Factors

All known cases of Traboulsi Syndrome are of Afro-Arabian and Arabian ethnicity or from India, Pakistan, Lebanon, Persia, the United Kingdom, and, most recently, China. Presentation of the disease is often a result of consanguineous families leading to the inheritance of two ASPH gene variants [2,3,5–8,12].

General Pathology

Traboulsi syndrome is characterized by distinctive facial dysmorphism (flat cheeks and beaked nose), ectopia lentis, spontaneous filtration bleb (nontraumatic conjunctival cysts) formation, scleral thinning, and other anterior segment abnormalities [5,13]. Other skeletal, cardiac, and pulmonary abnormalities have also been reported, but more research is needed to confirm and understand these associations [8].

Pathophysiology

Patel et al. (2014) speculated that disturbed EGF hydroxylation is the mechanism that leads to lens dislocation, one of its two hallmark traits [5]. More specifically, Lei et al. (2020) performed whole-exome and Sanger sequencing of the ASPH gene and found that Traboulsi syndrome-associated variants impair the AspH oxygenase domain on the ASPH protein, thereby impairing asparagine and aspartate hydroxylation on the EGF domains of various proteins such as Fibrillin1 (FBN1) and Latent-transforming growth factor beta-binding protein2 (LTBP2), which play critical roles in the formation of the microfibrils and ciliary zonules which hold the lens in place [8]. More broadly, impaired hydroxylation of EGF domains is notable as almost all genes associated with ectopia lentis have EGF domains [5]. Decreased lens stability, therefore, may result in anterior subluxation of the lens, resulting in anterior displacement of the iris, closed iridocorneal angles, increased corneal scarring and opacity, and increased intraocular pressure due to irreversible trabecular meshwork damage [13,14]. The increased intraocular pressure, in combination with scleral thinning [2,5] may then result in the characteristic spontaneous filtering blebs observed in this condition as aqueous humor flows through fistulas connecting the anterior chamber to the subconjunctival space [14].

Traboulsi syndrome also manifests with symptoms commonly shared by other genetic conditions. Some findings, such as ectopia lentis and spontaneous pneumothorax, appear to overlap with Marfan syndrome, which is caused by any of several FBN1 gene mutations resulting in impaired activity of FBN1 [8]. As mentioned previously, the FBN1 protein contains an EGF domain and therefore may exhibit decreased functionality in Traboulsi syndrome because of a lack of EGF hydroxylation caused by an ASPH gene mutation. This may explain some of the shared clinical features between Marfan syndrome and Traboulsi syndrome and provides an example of overlapping clinical features between this disorder and various other diseases [5,8,13]. Additionally, Senthil et al. (2021) identified two gene variants among three individuals with Traboulsi syndrome. They found that the two individuals who shared a specific gene variant manifested cardiac abnormalities, whereas the other variant had no cardiac involvement [10]. Therefore, particular ASPH gene variants may result in varying degrees of impaired EGF hydroxylation, which manifests as a wide degree of variable phenotypic and clinical expressivity among patients. However, further research is needed to confirm and elucidate the pathophysiology of this disease.

Primary prevention

Genetic planning is the only form of primary prevention currently known for this condition as it is most frequently reported in consanguineous families and inherited in an autosomal recessive manner [2,3], but isolated cases have been rarely reported as well [13]. Therefore, genetic counseling should be obtained by individuals with a family history of Traboulsi syndrome or in regions where the prevalence of Traboulsi syndrome is relatively high [8].

Diagnosis

Traboulsi syndrome is primarily diagnosed clinically based on the unique combination of ophthalmologic and craniofacial findings [4,5,7,8,13]. However, due to many overlapping features with other disease processes, genetic tests may be performed to confirm the diagnosis [4,5,8].

History

Patients may present with a long history of visual impairment, usually beginning in childhood or adolescence, and corneal haze or scarring. Patients often report no ocular trauma or disease history associated with their symptoms [7,13]. Although systemic manifestations of cardiac or pulmonary abnormalities have been associated, they are not required for a diagnosis and are not thought to be very prevalent within this population [7]. A family history of ocular disorders or visual impairment is also commonly reported in these patients [2,3,7,15].

Physical examination

A comprehensive eye examination includes slit-lamp microscopy assessing the anterior chamber, conjunctiva, and sclera, applanation tonometry, and visually inspecting the eyes and facial structure [1,7,9,13].

A general medicine clinician may do a focused general physical examination to determine other abnormalities. This focused examination may include cardiac and pulmonary auscultation to assess for cardiac murmurs, arrhythmias, and abnormal or decreased breath sounds. Additionally, inspecting the skeletal system may reveal associated manifestations such as pectus deformation and hypermobile joints [6].

Signs

Ophthalmologic findings often include bilateral ectopia lentis, decreased visual acuity with high myopia, iris atrophy, retinal detachment, microphthalmia, increased intraocular pressure (IOP), shallow anterior chambers, spontaneous filtering blebs, scleral thinning, and closed iridocorneal angles. Ocular hypertension, central superficial corneal opacification, and central retrocorneal nodular thickening have also been reported less commonly [1,6,9]. Additional facial features may include a long face, down-slanted palpebral fissures, dental malocclusion, underdeveloped malae, crowded teeth, and retrognathia [1,6,8,13]. Skeletal signs may include long and short or slender fingers, pectus deformation, or hypermobile joints [6,8].

Other findings reported in patients with specific ASPH gene variants include cardiac dysfunction and a combination of ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax [8,10], but further research needs to be conducted to confirm and understand these as systemic signs since Traboulsi syndrome patients who presented with these manifestations also possessed potential confounding factors in their medical history [8]. Therefore, these systemic signs may not be present in various cases of Traboulsi syndrome depending on specific ASPH gene variants and many other factors [5,8,10]. Due to the rarity of this condition and somewhat delayed disease progression, patients may not present with each of these findings initially. However, the mechanism of disease progression suggests that anterior subluxation of the lens is one of the initiating factors to anterior segment sequelae and spontaneous filtering blebs. Therefore, the combination of facial dysmorphism (e.g., flat cheeks and beaked nose) and anterior subluxation may be earlier signs [1,5,7,14].

Symptoms

The primary presenting symptom is decreased visual acuity with high myopia. However, with time, as corneal damage accumulates and intraocular pressure increases, blurry vision and decreased peripheral vision may present [2,3,7,13]. Bilateral ocular discomfort and headaches have also been reported [7].

Clinical diagnosis

The diagnosis of Traboulsi syndrome is primarily clinical as one observes the unique constellation of ocular and facial signs [7,13].

Diagnostic procedures

One study found anterior segment imaging with ultrasound biomicroscopy (UBM) especially helpful in identifying the ophthalmologic findings associated with Traboulsi syndrome [14]. Also, due to the potential association with cardiac and pulmonary diseases, various computed tomography imaging modalities may be utilized to verify whether patients are also experiencing the systemic manifestations of this condition [8].

Laboratory test

Whole-exome and Sanger sequencing followed by PCR may be utilized to confirm the presence of an ASPH gene variant [8].

Differential diagnosis

  1. Isolated ectopia lentis
  2. Marfan syndrome
  3. Homocystinuria
  4. Scleritis
  5. Pellucid marginal degeneration
  6. Scleroderma
  7. Systemic Lupus Erythematosus (SLE)
  8. Axenfeld-Rieger syndrome
  9. DiGeorge syndrome (Chromosome 22q11.2 deletion syndrome)
  10. Peter’s anomaly

Management

Due to its progressive and complex pathogenesis, patients with Traboulsi syndrome must be monitored closely for symptomatic treatment of glaucoma and corneal disease and for ophthalmologists decide when and how surgical intervention should be approached [4,13]. A variety of ophthalmologic specialists, including glaucoma, cornea, and pediatrics, may be consulted, as well as genetic, cardiac, and pulmonary specialists to co-manage any other systemic manifestations.

General treatment

Although many cases of ectopia lentis may be treated without surgery and instead with proper spectacle or contact lens correction, the lens subluxation and accompanying ocular sequelae in Traboulsi syndrome are progressive and appear to worsen without surgery [13,14,16]. Therefore, surgical intervention is often required for effective treatment.

Medical therapy

Medical therapy is indicated primarily in the symptomatic treatment of corneal manifestations and glaucoma [13].

Medical follow up

Regular medical follow-up is recommended to prevent worsening glaucoma and corneal manifestations [7,13].

Surgery

Surgical treatment consists of managing lens subluxation with lensectomy followed by gas-permeable contact lenses [15]. Further, early lensectomy helps avoid irreversible corneal and trabecular meshwork damage from chronically closed iridocorneal angles [14]. Therefore, lensectomy is currently recommended once lens subluxation is detected, which has most often been reported to occur in adolescence to young adulthood. However, Awais et al. have found from their experience that incisional surgical procedures do not lead to better long-term prognosis once the eyes have gone into hypotony and a filtration bleb is fully formed, possibly due to a weakened scleral coat [7].

In one case report, instead of lensectomy, a patient with corneal decompensation underwent a penetrating keratoplasty. This option avoids the attendant problems with lensectomy such as an untreatable permanent aqueous leak [13].

Surgical follow up

Good surgical outcomes have been documented where surgery was followed up by topical steroids and regular intraocular pressure and fundus monitoring. After surgery, spectacles may also be administered to improve visual acuity [13].

Complications

Unintentional filtering blebs were reported at the sites of multiple sclerotomies several years after surgery in a patient with Traboulsi syndrome [4]. Also, as mentioned previously, lensectomy in a patient with corneal decompensation may result in a permanent aqueous leak due to blebs and scleral thinning [13]. Therefore, alternative surgeries or approaches to lensectomy, sclerotomies, or other invasive procedures should be considered prior to surgery.

Prognosis

Visual prognosis is variable based on time of diagnosis and management of ocular conditions, though typically, visual acuity is poor.

Additional Resources

Cystic bleb:

  1. https://www.semanticscholar.org/paper/Traboulsi-Syndrome-in-Pakistan.-Awais-Ali/98dce412dc4c9139591fe70e209462b96f19da97

Craniofacial dysmorphism and skeletal abnormalities:

  1. https://www.semanticscholar.org/paper/Anterior-Segment-Imaging-and-Treatment-of-a-Case-of-Mansour-Younis/20959ed50466e0e647ae473c081053784b4ef0ee
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963421/

References

  1. Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome [Internet]. Orphanet encyclopedia. 2022 [cited 2022 Apr 20]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=412022
  2. Shawaf S, Noureddin B, Khouri A, Traboulsi EI. A family with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. Ophthalmic Genetics. 1995;16(4):163–9.
  3. Haddad R, Uwaydat S, Dakroub R, Traboulsi EI. Confirmation of the Autosomal Recessive Syndrome of Ectopia Lentis and Distinctive Craniofacial Appearance. Vol. 99, American Journal of Medical Genetics. 2001.
  4. Shanmugam P, Sagar P, Konana V, Simakurthy S, Ramanjulu R, Sheemar A, Divyansh Mishra K. Recurrent unintentional filtering blebs after vitrectomy: A case report. Indian Journal of Ophthalmology [Internet]. 2020 Apr 1 [cited 2022 May 30];68(4):660. Available from: /pmc/articles/PMC7210861/
  5. Patel N, Khan AO, Mansour A, Mohamed JY, Al-Assiri A, Haddad R, Jia X, Xiong Y, Mégarbané A, Traboulsi EI, Alkuraya FS. Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome. Am J Hum Genet [Internet]. 2014 May 1 [cited 2022 May 30];94(5):755–9. Available from: https://pubmed.ncbi.nlm.nih.gov/24768550/
  6. Abarca Barriga HH, Caballero N, Trubnykova M, Castro-Mujica M del C, la Serna-Infantes JE, Vásquez F, Hennekam RC. A novel ASPH variant extends the phenotype of Shawaf-Traboulsi syndrome. American Journal of Medical Genetics Part A [Internet]. 2018 Nov 1 [cited 2022 May 30];176(11):2494–500. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.40508
  7. Awais T, Ali M, Khan S. Traboulsi Syndrome in Pakistan. Journal of the College of Physicians and Surgeons Pakistan. 2019 Jun 1;29(06):S37–40.
  8. Lei C, Guo T, Ding S, Liao L, Peng H, Tan Z, Luo H. Whole-exome sequencing identified a novel homozygous ASPH frameshift variant causing Traboulsi syndrome in a Chinese family. Molecular Genetics & Genomic Medicine [Internet]. 2021 Jan 1 [cited 2022 May 30];9(1):e1553. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1553
  9. OMIM Entry - # 601552 - FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS; FDLAB [Internet]. [cited 2022 May 30]. Available from: https://www.omim.org/entry/601552
  10. Senthil S, Sharma S, Vishwakarma S, Kaur I. A novel mutation in the aspartate beta-hydroxylase ( ASPH) gene is associated with a rare form of Traboulsi syndrome. Ophthalmic Genet [Internet]. 2021 [cited 2022 May 30];42(1):28–34. Available from: https://pubmed.ncbi.nlm.nih.gov/33251883/
  11. Dinchuk JE, Focht RJ, Kelley JA, Henderson NL, Zolotarjova NI, Wynn R, Neff NT, Link J, Huber RM, Burn TC, Rupar MJ, Cunningham MR, Selling BH, Ma J, Stern AA, Hollis GF, Stein RB, Friedman PA. Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia. J Biol Chem [Internet]. 2002 Apr 12 [cited 2022 May 30];277(15):12970–7. Available from: https://pubmed.ncbi.nlm.nih.gov/11773073/
  12. Kulkarni N, Lloyd IC, Ashworth J, Biswas S, Black GCM, Clayton-Smith J. Traboulsi syndrome due to ASPH mutation: an under-recognised cause of ectopia lentis. Clin Dysmorphol [Internet]. 2019 Oct 1 [cited 2022 May 30];28(4):184–9. Available from: https://pubmed.ncbi.nlm.nih.gov/31274573/
  13. Anitha V, Rangappa R, Ravindran M, Kader M. Aftermath in Traboulsi syndrome: A case report. Indian Journal of Ophthalmology - Case Reports. 2022;2(1):207.
  14. Mansour AM, Younis MH, Dakroub RH. Anterior segment imaging and treatment of a case with syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. Case Rep Ophthalmol [Internet]. 2013 Jan [cited 2022 May 30];4(1):84–90. Available from: https://pubmed.ncbi.nlm.nih.gov/23687502/
  15. van Hoorde T, Nerinckx F, Kreps E, Roels D, Huyghe P, van Heetvelde M, Verdin H, de Baere E, Balikova I, Leroy BP. Expanding the clinical spectrum and management of Traboulsi syndrome: report on two siblings homozygous for a novel pathogenic variant in ASPH. Ophthalmic Genet [Internet]. 2021 [cited 2022 May 30];42(4):493–9. Available from: https://pubmed.ncbi.nlm.nih.gov/34018898/
  16. Chandra A, Charteris D. Molecular pathogenesis and management strategies of ectopia lentis. Eye [Internet]. 2014;28:162–8. Available from: www.nature.com/eye
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