Resident’s Day Submission Kelsie Morrison, OD Pediatric Optometry Resident University of Houston College of Optometry

Title: Presumed Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) with Bilateral Type I Duane’s Retraction Syndrome

Abstract: Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare congenital autosomal dominant condition characterized by bilateral ptosis, telecanthus, epicanthus inversus, and blepharphimosis. The following case highlights the management of ocular manifestations associated with BPES.

I. Case History  Patient demographics: 7 year old half Caucasian, half Asian male  Chief complaint: Annual strabismus evaluation o The patient’s father reported good vision without glasses and non-compliance with spectacle wear.  Ocular history: o (+) Bilateral Duane’s retraction syndrome type I o (+) Constant left esotropia with possible strabmismic amblyopia o (+) Telecanthus o (+) Epicanthal folds  Medical history: o (+) Unbalanced translocation genetic mutation involving chromosomes 3 and 7 o (+) Developmental delays  Systemic surgical history: o (+) Open heart surgery at 1 month old o (+) G-tube at 2 months old o (+) Hand surgery at 1 year old and 1.5 years old o (+) Current G-tube fed secondary to previous ‘failure to thrive’ diagnosis  Medications o (+) Hydrocortisone cream o (+) Murolax o No known systemic or ocular medication allergies  Family medical and ocular history: o No known family members with chromosomal anomalies  Social history: o Attends a special needs school where he is in the classroom with four other children

II. Pertinent findings  Clinical o Unaided visual acuities (Cardiff at 50 cm): 20/32 OD, 20/32 OS o Distance cover test (sc): 20 pd IAET o Near cover test (sc): Moderate esophoria (unable to confirm tropia; difficult assessment secondary to poor patient fixation and cooperation) o Hirschberg at 40 cm (sc): +0.00 mm OD, -1.00 mm OS; approximately 22 pd ILET (right eye fixating) o Krimsky(sc): 20 pd IAET with OD fixation preference o Stereopsis (sc): 550” global with Lang I at 50 cm o MEM at 40 cm (sc): +1.00 DS OD, OS o Cycloplegic refractive error: OD +1.00-2.00x180 OS +1.00-2.25x180 o EOMs: . (-) Abduction, OU . (-) Globe retraction, OU . (+) Lid fissure narrowing on attempted adduction, OU . (+) Underaction of lateral rectus, OU . (+) Smooth, full movements in all nasal quadrants as well as straight superior and inferior 0 0 -4 -4 0 0

-4 0 0 -4

-4 0 0 0 -4 0 Right Eye Left Eye

o Pupils: Equal, round and reactive to direct and consensual stimulation OD and OS. No afferent pupillary defect detected OD or OS.  Physical o (+) Telecanthus o (+) Epicanthal folds o Intraocular pressures were soft per digital tonometry, OU. o Internal and external ocular health were unremarkable, OU.

III. Differential diagnosis  Primary/leading o Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) with bilateral Type I Duane’s retraction syndrome  Others o Bilateral Duane’s Type I with telecanthus, Ohdo blepharophimosis syndrome, 3MC Syndrome 1 (Michels syndrome), Marden-Walker Syndrome, bilateral CN VI palsy

IV. Diagnosis and discussion  There are two types of BPES: o BPES Type I is characterized by blepharophimosis, ptosis, epithcanthus inversus, telecanthus, and premature ovarian insufficiency.1 o BPES Type II is characterized by blepharophimosis, ptosis, epithcanthus inversus and telecanthus. 1  Primary features: o Belpharophimosis, or narrowing of the eye opening, is characterized by horizontal palpebral fissure measuring 20-22 mm. 1 o Ptosis is caused by dysplasia of the levator palpebrae superioris, and the characteristic facial appearance (wrinkling forehead, eyebrows drawn upward) is the result of overcompensation of the musculus frontalis. 1 o Epicanthus inversus occurs when the skin fold from the lower eyelid runs inwards and upwards. o Telecanthus results from the lateral displacement of the inner canthi with normal interpupillary distance.  Other ophthalmic manifestations: nasolacrimal duct abnormalities, dysplastic eyelids, amblyopia, strabismus, and ametropia.1,2,3  Non-ocular characteristics: low-set ears and short philtrum.1  BPES has an autosomal dominant inheritance pattern with complete phenotypic penetrance. 1,4,5  There are no known differences in prevalence based on sex or race, and the worldwide prevalence is unknown. 1,6  Approximately 75% of affected individuals with BPES have cytogenic rearrangements, including unbalanced translocations and interstitial deletions of the FOXL2 gene, which is a forkhead transcription factor on the 3q23 chromosome. 1,3,4,6,7 o Affected individuals with cytogenetic rearrangements that involve FOXL2 and additional genes may have altered intelligence. Those with variations in the FOXL2 gene only typically have normal intelligence.

V. Treatment, management  Treatment specific to this patient: o Spectacle correction with patching for presumed strabismic amblyopia has been performed in the past. The patient now has equal visual acuities and went from a constant left esotropia to an intermittent alternating esotropia. o Surgical consultations regarding both strabismus and telecanthus have been done in the past. At this time, the parents have opted for the patient to not have surgery. o The parents have been counseled regarding the importance of allowing the patient to adapt various head positions while at school as well as allowing him to bring objects close to his face. Explained that he is likely binocular at close working distances. o The patient is scheduled for a follow-up evaluation on 09/03/2015. The following will be assessed at this time: measurement of interpupillary distance, measurement of intercanthal distance, cover test, measurement of marginal reflex distance, and further review of previous genetic testing records.  General treatment for ocular manifestations of BPES: o Ametropia correction as needed. o Management of strabismus if present. o Amblyopia therapy as needed. o Genetic testing and counseling . BPES is inherited in an autosomal dominant pattern, meaning each child of an individual with BPES has a 50% chance of inheriting the pathogenic variant of the FOXL2 gene. o Referral and co-managment . Females with BPES should be referred to pediatric endocrinology and/or gynecology due to possible ovarian insufficiency. . Surgical intervention: . Strabismus: . Strabismus surgery may be necessary in order to attempt to regain binocular vision and/or improve cosmesis. . Oculoplastics . Surgery is typically performed between the ages of 3 to 5, however, if the ptosis is thought to be amblyogenic then surgery is performed as soon as possible. . Previous protocol included medial canthoplasty followed by ptosis correction one year later. The more recent protocol includes a one stage surgical repair.8,9  Diagnostic testing: o Diagnosis is made primarily based on clinical findings. o Genetic testing: . Most patients with BPES have cytogenetic rearrangements involving 3q23. Currently, the only gene associated with BPES is FOXL2. 1,10

VI. Conclusion  Clinical diagnosis of BPES can be confirmed with genetic testing.  The coexistence of BPES and Duane’s retraction syndrome suggests that the phenotypic expression of the FOXL2 gene may be greater than previously thought. Further cytological investigation is warranted.  Clinical pearls: o Knowing and understanding basic genetic principles can aid in your understanding of inheritance patterns and affect how you educate your patients. o If your patient is not a good candidate for surgical intervention or if your patient declines surgery, then consider what recommendations you can make to maximize the patient’s functional vision.

(1) Verdin H, De Baere E. Blepharophimosis, Ptosis, and Epicanthus Inversus. 2004 Jul 8 [Updated 2015 Feb 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.

(2) Dawson EL, Hardy TG, Collin JR, Lee JP. The incidence of strabismus and refractive error in patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). Strabismus.2003;11:173–7h.

(3) Choi KH, Kyung S, Oh SY. The factors influencing visual development in blepharophimosis-ptosis- epicanthus inversus syndrome. J Pediatr Ophthalmol Strabismus. 2006;43:285–8.

(4) Fukushima Y, Wakui K, Nishida T, Ueoka Y. Blepharophimosis sequence and de novo balanced autosomal translocation [46,XY,t(3;4)(q23;p15.2)]: possible assignment of the trait to 3q23. Am J Med Genet. 1991;40:485–7. (5) Zahanova S, Meaney B, Łabieniec B, Verdin H, De Baere E, Nowaczyk MJ. Blepharophimosis-ptosis- epicanthus inversus syndrome plus: deletion 3q22.3q23 in a patient with characteristic facial features and with genital anomalies, spastic diplegia, and speech delay. Clin Dysmorphol. 2012 Jan; 21(1):48-52.

(6) Vincent, A., Watkins, W., Sloan, B. and Shelling, A. (2005), Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation. Clinical Genetics, 68: 520–523. doi: 10.1111/j.1399- 0004.2005.00527.x

(7) de Ru MH, Gille JJ, Nieuwint AW, Bijlsma JB, van der Blij JF, van Hagen JM. Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation an growth delay: clinical report and review of the literature. Am J Med Genet A. 2005;137:81–7.

(8) Sebastiá R, Herzog Neto G, Fallico E, Lessa S, Solari HP, Ventura MP. A one-stage correction of the blepharophimosis syndrome using a standard combination of surgical techniques. Aesthetic Plast Surg. 2011;35:820–7

(9) Liu H, Shao Y, Zhao Z, Zhang D. One-stage correction of blepharophimosis-ptosis-epicanthus inversus syndrome using a frontalis muscle transfer technique. J Plast Surg Hand Surg.2014;48:74–9.

(10) Alao MJ, Lalèyè A, Lalya F, Hans Ch, Abramovicz M, Morice-Picard F, Arveiler B, Lacombe D, Rooryck C. Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female. Eur J Med Genet. 2012 Nov; 55(11):630-4. Epub 2012 Aug 3.