Grand Rounds Conference Janelle Fassbender, MD, PhD University of Louisville Department of Ophthalmology and Visual Sciences February 21, 2014

Subjective CC: Rubbing eyes a lot and sensitive to sunlight HPI: 3 year old boy presents with light sensitivity and squinting since birth per mother.

History POH: None PMH: Noonan syndrome Eye Meds: Artificial tears Meds: Zyrtec prn Allergies: NKDA FOH: Glaucoma (Grandmother)

Objective OD OS OD OS VA: CSM CSM CRx: x x 090 Pupils: 4 to 2 mm OU, no RAPD IOP: SoftSoft EOM: FullFull

Objective SLE: External Low set ears, webbed neck Lids Fine cilia arising from meibomian glands all 4 eyelids Conjunctiva/ScleraNormal OU CorneaClear OU Anterior ChamberDeep, quiet OU IrisNormal OU LensClear OU VitreousNormal OU

Clinical Photographs Low-set ears Short, webbed neck

Mock clinical photo Patil et al, 2004

Differential Diagnosis Distichiasis Distichiasis Congenital Congenital Acquired Acquired Trichiasis Trichiasis

Assessment 3 year old boy with symptomatic, congenital distichiasis. 3 year old boy with symptomatic, congenital distichiasis.

Operation Initial procedure: Bilateral upper lid lash margin rotation with mucous membrane grafts (MMG). Initial procedure: Bilateral upper lid lash margin rotation with mucous membrane grafts (MMG). Follow up procedure for lower eyelids. Follow up procedure for lower eyelids.

Operation Report Incision elongated across the horizontal extent of the posterior side of the gray line. Incision elongated across the horizontal extent of the posterior side of the gray line. The anterior lamellae of the eyelid was advanced to the superior margin of the tarsus and secured. The anterior lamellae of the eyelid was advanced to the superior margin of the tarsus and secured. Thin block of tarsus excised to remove lash follicles. Thin block of tarsus excised to remove lash follicles. Full-thickness buccal mucous membrane graft placed on the eyelid margin and sutured. Full-thickness buccal mucous membrane graft placed on the eyelid margin and sutured.

Follow-up Upper lid procedure follow-up Upper lid procedure follow-up Post-op month 2 – Grafts healing well, new cilia arising through grafts Post-op month 2 – Grafts healing well, new cilia arising through grafts Procedure #2 Procedure #2 2/13/14 – MMG bilateral lower lid 2/13/14 – MMG bilateral lower lid

Congenital distichiasis Accessory cilia arise from meibomian gland orifices Accessory cilia arise from meibomian gland orifices Second month of gestation, cilia and meibomian glands differentiate. Second month of gestation, cilia and meibomian glands differentiate. Congenital distichiasis  specialized sebaceous gland improperly differentiates into pilosebaceous unit Congenital distichiasis  specialized sebaceous gland improperly differentiates into pilosebaceous unit Acquired distichiasis  Chronic irritation/inflammation Acquired distichiasis  Chronic irritation/inflammation Patients may become symptomatic early in life Patients may become symptomatic early in life Hairs are fine, lanugo-like, and curl away from the globe Hairs are fine, lanugo-like, and curl away from the globe

Lymphedema-distichiasis syndrome First described in 1899 by Kuhnt First described in 1899 by Kuhnt Distichiasis with lower limb lymphedema Distichiasis with lower limb lymphedema Autosomal dominant, mutation of FOXC2, chromosome 16q24.3 Autosomal dominant, mutation of FOXC2, chromosome 16q24.3 Abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects (Petrova et al, 2004) Abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects (Petrova et al, 2004) Ptosis (31%), congenital heart defects (6.8%), cleft palate (4%) (Brice et al, 2002) Ptosis (31%), congenital heart defects (6.8%), cleft palate (4%) (Brice et al, 2002) 94.6% have distichiasis 94.6% have distichiasis 6 patients were under 11 yrs old and had not developed lymphedema (Brice et al, 2002) 6 patients were under 11 yrs old and had not developed lymphedema (Brice et al, 2002) 50% males symptomatic by age 11 50% males symptomatic by age 11 50% females symptomatic by age 20 50% females symptomatic by age 20

Treatment of Distichiasis Lubricants and soft contacts Lubricants and soft contacts Electrolysis, radiofrequency epilation or cryoepilation Electrolysis, radiofrequency epilation or cryoepilation Surgical options: Surgical options: Lid splitting and posterior lamella cryosurgery (Anderson et al, 1981) Lid splitting and posterior lamella cryosurgery (Anderson et al, 1981) Eyelid splitting with excision (Vaughn et al, 1997) Eyelid splitting with excision (Vaughn et al, 1997) Tarsal resection and mucous membrane grafting (White et al, 1975) Tarsal resection and mucous membrane grafting (White et al, 1975) High rate of recurrence High rate of recurrence

Noonan Syndrome Prevalence: 1:1000 to 1:2500 live births Prevalence: 1:1000 to 1:2500 live births Mutations in genes of the RAS/MAPK signaling pathway Mutations in genes of the RAS/MAPK signaling pathway PTPN11 mutations (chromosome 12q24.1) – 50% patients PTPN11 mutations (chromosome 12q24.1) – 50% patients Characteristic facies: Characteristic facies: Low-set ears, malar flattening, low hairline Low-set ears, malar flattening, low hairline Systemic manifestations: Systemic manifestations: Malignancy – hematologic, rhabdomyosarcoma, giant cell granulomas Malignancy – hematologic, rhabdomyosarcoma, giant cell granulomas Cardiac defects, short stature, hearing loss Cardiac defects, short stature, hearing loss

Noonan Syndrome continued Orbital manifestations: Orbital manifestations: Downward-sloping palpebral fissures (38-74%), hypertelorism (57- 74%), ptosis (48-51%), epicanthal folds (39%) Downward-sloping palpebral fissures (38-74%), hypertelorism (57- 74%), ptosis (48-51%), epicanthal folds (39%) Refractive error (61%), strabismus (48%), amblyopia (33%), anterior segment changes (57-63%), abnormal fundoscopy (8-20%) Refractive error (61%), strabismus (48%), amblyopia (33%), anterior segment changes (57-63%), abnormal fundoscopy (8-20%) Lymphedema-distichiasis masquerade? Lymphedema-distichiasis masquerade? Pterygium colli as a feature of 10 individuals from 5 generations (Falls and Kertesz, 1964) Pterygium colli as a feature of 10 individuals from 5 generations (Falls and Kertesz, 1964) 2 females considered to have Turner syndrome, found to have distichiasis with peripubertal onset lymphedema (Toro et al, 1991) 2 females considered to have Turner syndrome, found to have distichiasis with peripubertal onset lymphedema (Toro et al, 1991)

Example

References Dagenais SL, et al FOXC2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expression Patterns, 4: Dagenais SL, et al FOXC2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expression Patterns, 4: Sola P, et al Distichiasis-lymphedema syndrome and the Turner phenotype. Medical association of Puerto Rico Bulletin, 83(12): Sola P, et al Distichiasis-lymphedema syndrome and the Turner phenotype. Medical association of Puerto Rico Bulletin, 83(12): Randolph JR, et al Orbital manifestations of Noonan Syndrome. Ophthal Plast Reconstr Surg, 27(6): e Randolph JR, et al Orbital manifestations of Noonan Syndrome. Ophthal Plast Reconstr Surg, 27(6): e Fang, J, et al Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet, 67:1382–8. Fang, J, et al Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet, 67:1382–8. Brice G, et al Analysis of the phenotypic abnormalities in lymphoedema- distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet, 39:478–83. Brice G, et al Analysis of the phenotypic abnormalities in lymphoedema- distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet, 39:478–83. Patil BB, et al Distichiasis without lymphoedema. Eye, 18: Patil BB, et al Distichiasis without lymphoedema. Eye, 18: Falls and Kertesz A new syndrome combining pterygium colli with developmental abnormalities of the eyelids and lymphatics of the lower extremities. Trans Am Ophthalmol Soc, 62: Falls and Kertesz A new syndrome combining pterygium colli with developmental abnormalities of the eyelids and lymphatics of the lower extremities. Trans Am Ophthalmol Soc, 62: