From the Ocular Oncology Service, Wills Eye Institute, Philadelphia, Pennsylvania.
Supported by the Eye Tumor Research Foundation, Philadelphia (CLS and JAS), and the Retina Research Foundation of the Retina Society in Cape Town, South Africa (CLS).
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Institute, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107. E-mail: email@example.com
The term “combined hamartoma of the retina and retinal pigment epithelium” (CHRRPE) was coined by Gass to describe an uncommon benign tumor of the retina that generally presents in the pediatric age group with strabismus or vision loss.1–3 This lesion is sometimes misdiagnosed as choroidal melanoma, retinoblastoma, or other conditions.1,2 In a series of 79 eyes with CHRRPE, the referring diagnosis was unknown (n = 40; 51%) or incorrect (n = 19; 24%) as retinoblastoma (n = 4), astrocytoma (n = 1), toxocariasis (n = 2), choroidal nevus (n = 5), melanoma (n = 6), or hemangioma (n = 1).3 Characteristic features of CHRRPE include prominent or subtle slight elevation, gray pigmentation, wrinkling of the internal limiting membrane, and, most notably, tortuous retinal vasculature with dragging of the retinal vessels toward the lesion.1–3 CHRRPE can be found in association with Gorlin syndrome,1 neurofibromatosis type 1,1 neurofibromatosis type 2,1 and branchio-oculo-facial syndrome.1,4
Branchial cleft cysts are congenital anomalies that result when the fetal pharyngobranchial ducts fail to obliterate by birth and lead to subcutaneous cysts.5–7 These cysts occur along the anterior border of the sternocleiodmastoid muscle and often present as tender, inflammatory masses with fluid leakage.7 Branchial cleft cysts can be associated with branchio-oto-renal syndrome, branchio-oculo-facial syndrome, craniofacial deformities, and auricular deformities.5 Only one published report has identified an association with CHRRPE.4 Herein we describe the second case in the literature of CHRRPE in a child with branchial cleft cysts.
A 15-month-old boy without evidence of strabismus was found to have loss of red reflex in the left eye. The patient had bilateral cysts, which were found at birth. The cysts were located over the sternocleidomastoid muscle, and presented with clear fluid drainage. An internal tunnel connected the two cysts to the pharynx. Although benign, the cysts were surgically excised when the patient was 6 months old. There was no family history of neurofibromatosis or other syndromes.
Ocular examination revealed orthophoria with intact ductions and versions and visual acuity of fix and follow in both eyes. Fundus examination of the right eye was unremarkable. Fundus examination of the left eye revealed reduced foveal light reflex, a subtle plateau-shaped mass in the foveal area with gray retinal pigmentation, and slight retinal vascular dragging toward the lesion, confirmed on fluorescein angiography (Figure). B-scan ultrasonography demonstrated the minimally elevated lesion without calcification. A diagnosis of subtle foveal CHRRPE (resembling epiretinal membrane) was favored. Occlusive patching therapy for prevention of amblyopia was instituted.
Figure. Subtle combined hamartoma of the retina and retinal pigment epithelium in an infant with branchial cleft cysts. (A) The right fundus was normal. (B) The left fundus revealed loss of foveal reflex and slight retinal vascular dragging toward the foveola. (C) Normal fluorescein angiography of the right eye. (D) Fluorescein angiography of the left eye revealing tortuous dragged retinal vessels toward the foveola. (E) Facial photograph of a 15-month-old child showing no visible facial deformity and a slightly darker red reflex in the left eye.
At 3 years of follow-up, the CHRRPE and visual acuity were stable (Figure). There was no strabismus and patching 1 hour daily was tolerated.
The human head and neck develop embryonically from six paired branchial (pharyngeal) arches, which form between the fourth and sixth weeks of fetal development. Only the first four cranial arches contribute to development while the caudal two arches remain rudimentary.5–7 Each arch has an external layer of ectoderm, an internal layer of endoderm, and a core of mesenchyme.5–7 The mesenchymal cores of each arch are separated from the next by branchial clefts, which are lined by endoderm internally and ectoderm externally.5–7 Branchial pouches form on the endodermal side of the clefts.5–7 In fish, the branchial pouch migrates toward the cleft, initially forming a membrane, and then penetrates through to establish open communication with the cleft to form gills.6 In contrast, during human development the pouch penetrates into the mesenchyme but does not rupture through the cleft.
Branchial arch syndrome describes the constellation of abnormalities that can arise from improper development of the branchial apparatus. Branchial cleft cysts are the most common branchial arch abnormality.5–7 Other abnormalities include branchial sinuses and fistulas.5,6 The cysts are categorized based on origin as first, second, and third cleft cysts. Second branchial cleft cysts are the most common and appear as round masses below the mandibular angle high along the anterior border of the sternocleidomastoid.7
CHRRPE is a presumed congenital tumor discovered in childhood or young adulthood. This condition occurs in the macular region (49%) or extramacular region (51%).3 In a large analysis of 79 eyes with this condition, patients with macular lesions were diagnosed at a younger age (9.5 months) than patients with extramacular lesions (14.2 months).3 The main presenting symptoms were decreased vision (n = 32; 40%) and strabismus (n = 22; 28%).3 The most common clinical features included intralesional corkscrew vessels (n = 51; 65%), feeding straight vessels (n = 50; 63%), retinal traction (n = 64; 81%), and exudation (n = 10; 13%). The mean age at diagnosis ranges from 1 to 15 years, depending on the source.1–3
In the literature, there has been one reported case noting the association of branchial cleft abnormalities and CHRRPE. In 2005, Demirci et al. described a 10-year-old girl with known branchio-oculo-facial syndrome who was diagnosed as having CHRRPE.4 The patient had a branchial cleft fistula, an orbital dermoid cyst, and lacrimal sac fistulas. Skin examination revealed café-au-lait spots.4 All of these findings were consistent with the diagnosis of branchio-oculo-facial syndrome.8 In our case, known branchial cleft defects and CHRRPE were present, but there were no other findings of branchio-oculo-facial syndrome.
A review of 43 cases of branchio-oculo-facial syndrome revealed common features to include branchial sinus defects, cleft or pseudocleft lip/palate, and pinna anomalies (> 70%).8 Renal anomalies and deafness were present in 10% to 70% of the patients.8 The ocular abnormalities include nasolacrimal duct stenosis/atresia (74%), microphthalmia/anophthalmia (62%), and coloboma (46%).8 Our patient did not show these features of branchio-oculo-facial syndrome.
Loss of visual acuity or development of amblyopia are major concerns with CHRRPE and can be the presenting symptoms. In an analysis by Shields et al., patients with macular tumors presented more often with symptoms of strabismus and decreased visual acuity compared to those with extramacular tumors.3 They found eyes with macular CHRRPE had mean visual acuity of 20/320, whereas eyes with extramacular CHRRPE had mean visual acuity of 20/80. At 4 years of follow-up, eyes with macular lesions were more likely to have vision loss of 3 or more Snellen lines (60% vs 13% in extramacular lesions).3 Macular tumors were also smaller, rounder, and more commonly presented with fibrosis or gliosis, macular edema, and macular epiretinal membrane.3 Nearly every eye with macular lesions presented with foveal dragging.3 Optical coherence tomography (OCT) imaging has helped refine the diagnostic characteristics and criteria, particularly of vitreoretinal changes, of CHRRPE.9 Improved imaging of these tumors also allows for better prediction of visual loss.9 In a study of 11 patients with CHRRPE, of which 8 had macular lesions, preretinal membrane was found in 10 eyes.9 Disorganization of the retinal layers at the lesion site was present in all patients, which explains the poor visual acuity in macular tumors.9
Amblyopia management and prevention are key in these cases. The Pediatric Eye Disease Investigator Group (PEDIG) found 2 hours of patching equivalent to 6 hours of patching for moderate amblyopia when combined with 1 hour of near visual activity daily.10 Thus, this child was treated with 1 to 2 hours patching daily for amblyopia prevention. At 3 years of follow-up, there was no strabismus and visual function was preserved.
We have described a child with two possibly related congenital malformations, branchial cleft cysts and CHRRPE. Patients with CHRRPE should have a full evaluation for related systemic conditions.
- Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In: Shields JA, Shields CL. Atlas of Intraocular Tumors, 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008:450–453.
- Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology. 1984;91:1609–1615.
- Shields CL, Thangappan A, Hartzell K, Valente P, Pirondini C, Shields JA. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual outcome based on macular versus extramacular tumor location. Ophthalmology. 2008;115:2246–2252. doi:10.1016/j.ophtha.2008.08.008 [CrossRef]
- Demirci H, Shields CL, Shields JA. New ophthalmic manifestations of branchio-oculo-facial syndrome. Am J Ophthalmol. 2005;139:362–364. doi:10.1016/j.ajo.2004.07.052 [CrossRef]
- Mandell DL. Head and neck anomalies related to the branchial apparatus. Otolaryngol Clin North Am. 2000;33:1309–1332. doi:10.1016/S0030-6665(05)70283-8 [CrossRef]
- Ford GR, Balakrishnan A, Evans JNG, Bailey CM. Branchial cleft and pouch anomalies. J Laryngol Otol. 1992;106:137–143. doi:10.1017/S0022215100118900 [CrossRef]
- Lin DT, Deschler DG. Neck masses. In: Lalwani AK. Current Diagnosis & Treatment in Otolaryngology: Head & Neck Surgery, 2nd ed. New York: The McGraw-Hill Companies, Inc.; 2008:397–401.
- Lin AE, Gorlin RJ, Lurie IW, et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet. 1995;56:42–59. doi:10.1002/ajmg.1320560112 [CrossRef]
- Shields CL, Mashayekhi A, Dai VV, Materin MA, Shields JA. Optical coherence tomographic findings of combined hamartoma of the retina and retinal pigment epithelium in 11 patients. Arch Ophthalmol. 2005;123:1746–1750. doi:10.1001/archopht.123.12.1746 [CrossRef]
- Repka MX, Beck RW, Holmes JM, et al. A randomized trial of patching regimens for treatment of moderate amblyopia in children. Arch Ophthalmol. 2003;121:603–611. doi:10.1001/archopht.121.5.603 [CrossRef]