Journal of Pediatric Ophthalmology and Strabismus

Short Subjects 

Bilateral Combined Hamartomas of the Retina and Retinal Pigment Epithelium as the Presenting Feature of Neurofibromatosis Type 2 (Wishart Type)

Brian K. Firestone, MD; Juan D. Arias, MD; Carol L. Shields, MD; Jerry A. Shields, MD

Abstract

An 8-week-old healthy female infant manifested leukocoria and reduced vision in the left eye. She was found to have bilateral combined hamartomas of the retina and retinal pigment epithelium. There were no other features of neurofibromatosis type 2 and brain imaging was normal. At 6 months of age, subtle posterior subcapsular lens opacity was noted in the right eye. Genetic testing for neurofibromatosis type 2 was advised but not performed. At 3 years of age, leg weakness with quadriceps atrophy led to neuroimaging and detection of multiple tumors, including bilateral vestibular schwannomas and cervical, thoracic, and lumbar paraspinal schwannomas. Molecular testing revealed a nonsense mutation in the neurofibromatosis type 2 gene. Bilateral combined hamartomas were the presenting feature of a severe phenotype of neurofibromatosis type 2. [J Pediatr Ophthalmol Strabismus 2014;51:e33–e36.]

From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS); the Carlos G. Bianciotto Retinoblastoma Research Fund, Philadelphia, Pennsylvania (CLS, JAS); and the Lucille Wiedman Fund for Pediatric Eye Cancer, Philadelphia, Pennsylvania (JAS, CLS).

The authors have no financial or proprietary interest in the materials presented herein.

The authors thank Sean J. Hipp, MD, of the San Antonio Military Medical Center for providing the MRI images used in this manuscript.

Correspondence: Carol L. Shields, MD, Ocular Oncology Service, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107. E-mail: carol.shields@shieldsoncology.com

Received: November 12, 2013
Accepted: April 11, 2014
Posted Online: May 28, 2014

Abstract

An 8-week-old healthy female infant manifested leukocoria and reduced vision in the left eye. She was found to have bilateral combined hamartomas of the retina and retinal pigment epithelium. There were no other features of neurofibromatosis type 2 and brain imaging was normal. At 6 months of age, subtle posterior subcapsular lens opacity was noted in the right eye. Genetic testing for neurofibromatosis type 2 was advised but not performed. At 3 years of age, leg weakness with quadriceps atrophy led to neuroimaging and detection of multiple tumors, including bilateral vestibular schwannomas and cervical, thoracic, and lumbar paraspinal schwannomas. Molecular testing revealed a nonsense mutation in the neurofibromatosis type 2 gene. Bilateral combined hamartomas were the presenting feature of a severe phenotype of neurofibromatosis type 2. [J Pediatr Ophthalmol Strabismus 2014;51:e33–e36.]

From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS); the Carlos G. Bianciotto Retinoblastoma Research Fund, Philadelphia, Pennsylvania (CLS, JAS); and the Lucille Wiedman Fund for Pediatric Eye Cancer, Philadelphia, Pennsylvania (JAS, CLS).

The authors have no financial or proprietary interest in the materials presented herein.

The authors thank Sean J. Hipp, MD, of the San Antonio Military Medical Center for providing the MRI images used in this manuscript.

Correspondence: Carol L. Shields, MD, Ocular Oncology Service, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107. E-mail: carol.shields@shieldsoncology.com

Received: November 12, 2013
Accepted: April 11, 2014
Posted Online: May 28, 2014

Introduction

Combined hamartoma of the retina and retinal pigment epithelium is a rare ocular fundus lesion that can have variable effects on visual acuity depending on size, location, and degree of retinal traction.1 In an analysis of 77 patients with combined hamartoma, visual acuity was dependent on tumor location, as macular tumors showed visual acuity of 20/200 or less in 69% compared to 25% of extramacular lesions.2 Visual demise is related to preretinal fibrosis, retinal traction, foveal ectopia, retinal disorganization, and photoreceptor attenuation, as confirmed on optical coherence tomography.3 Amblyopia can compound the visual loss.

Based on two comprehensive publications on a total of 124 cases of combined hamartoma, this tumor was unilateral in 98% and unassociated with systemic disease in 99%.2,4 Bilateral involvement is strongly suggestive of underlying systemic syndromes, including Gorlin Goltz syndrome, Poland anomaly, branchio-oculofacial syndrome, and neurofibromatosis type 2 (NF-2).1 In patients with NF-2, the detection of combined hamartoma occurs most often after the diagnosis of NF-2 has been established. Furthermore, patients with NF-2 who have combined hamartoma classically manifest extensive central nervous system disease burden. Herein, we describe an 8-week-old female infant whose first manifestation of NF-2 was leukocoria from the intraocular tumor. Three years later, extensive central nervous system involvement with schwannomas was evident.

Case Report

An 8-week-old female infant presented with poor fixation and leukocoria in the left eye. Family history was negative for retinoblastoma or neurofibromatosis. There were no cutaneous abnormalities. Ocular examination disclosed visual acuity of fix and follow with each eye. The anterior segment was unremarkable in both eyes.

Funduscopy of the right eye revealed subtle, ill-defined gelatinous retinal thickening in the foveal region, measuring 3 mm in basal dimension with retinal pigment epithelium hyperplasia and atrophy on the inferior margin. There was no visible retinal traction (Figure 1A). Funduscopy of the left eye revealed a sessile pigmented lesion encompassing the macula and peripapillary region measuring 8 mm in basal dimension, with associated vitreoretinal traction, dragging of retinal vessels toward the mass, and preretinal fibrosis (Figure 1B). A similar second lesion was identified along the nasal periphery as a subtle retinal thickening, measuring 1 mm in diameter. Fluorescein angiography confirmed vascular dragging with minimal intrinsic tumor vascularity. Peripheral retinal nonperfusion temporally was observed in the left eye. Ultrasonography disclosed a noncalcified intraocular mass of 1.7-mm thickness in the right eye and 3.8-mm thickness in the left eye. Computed tomography showed normal brain findings and confirmed the absence of calcification. These findings were consistent with combined hamartomas of the retina and retinal pigment epithelium versus astrocytic hamartomas. Funduscopy of both parents was unremarkable. Genetic testing was negative for neurofibromatosis type 1 and tuberous sclerosis complex. Genetic testing was advised for NF-2 but was not performed. The lesions were monitored conservatively without change over time.

Severe phenotype of neurofibromatosis type 2 presenting as bilateral combined hamartomas of the retina and retinal pigment epithelium. A healthy 8-week-old female infant presented with leukocoria and reduced vision in the left eye. Funduscopic examination disclosed a subtle area of retinal thickening associated with atrophy and hyperplasia of the retinal pigment epithelium (RPE) in the (A, arrow) right macula and a larger pigmented mass associated with retinal traction in the (B) left macula and peripapillary region. Fluorescein angiography revealed slight hypofluorescence of the (C) right macular lesion and retinal vascular dragging and late peripheral leakage associated with the (D) left fundus lesion. (E) Spectral-domain optical coherence tomography (SD-OCT) of the right macular lesion demonstrated focal retinal thickening with overlying vitreous debris and underlying RPE alterations. (F) SD-OCT of the left fundus mass demonstrated epiretinal membrane, severe retinal disorganization and thickening, hyporeflective outer retina, and irregular RPE thickening. At 3 years of age, leg weakness prompted magnetic resonance imaging, revealing several (G, arrows) paraspinal schwannomas and (H, arrows) bilateral vestibular schwannomas.

Figure 1.

Severe phenotype of neurofibromatosis type 2 presenting as bilateral combined hamartomas of the retina and retinal pigment epithelium. A healthy 8-week-old female infant presented with leukocoria and reduced vision in the left eye. Funduscopic examination disclosed a subtle area of retinal thickening associated with atrophy and hyperplasia of the retinal pigment epithelium (RPE) in the (A, arrow) right macula and a larger pigmented mass associated with retinal traction in the (B) left macula and peripapillary region. Fluorescein angiography revealed slight hypofluorescence of the (C) right macular lesion and retinal vascular dragging and late peripheral leakage associated with the (D) left fundus lesion. (E) Spectral-domain optical coherence tomography (SD-OCT) of the right macular lesion demonstrated focal retinal thickening with overlying vitreous debris and underlying RPE alterations. (F) SD-OCT of the left fundus mass demonstrated epiretinal membrane, severe retinal disorganization and thickening, hyporeflective outer retina, and irregular RPE thickening. At 3 years of age, leg weakness prompted magnetic resonance imaging, revealing several (G, arrows) paraspinal schwannomas and (H, arrows) bilateral vestibular schwannomas.

At 6 months of age, subtle posterior subcapsular cataract in the right eye was detected. At 3 years of age, progressive leg weakness with right quadriceps atrophy was noted. Magnetic resonance imaging of the spine revealed multiple schwannomas involving the cervical, thoracic, and lumbar paraspinal regions (Figure 1C). Additionally, bilateral small vestibular schwannomas within the internal auditory canals were found (Figure 1D). The clinical diagnosis of NF-2 was confirmed by molecular testing, showing a heterozygous nonsense mutation (c.784C > T;p. Arg262*) in the NF-2 gene on chromosome 22. The intraocular tumors remained stable.

Discussion

Combined hamartoma of the retina and retinal pigment epithelium is generally a nonhereditary fundus lesion of uncertain etiology. The characteristic clinical features include preretinal gliosis with associated retinal traction and vascular tortuosity, variable retinal pigment epithelium hyperplasia, and occasionally peripheral retinal nonperfusion with secondary neovascularization.1 In 1984, the Macula Society Research Committee reviewed 60 cases of combined hamartoma and found that all cases were unilateral. Due to the frequency with which it was diagnosed in children, it was believed to be a congenital lesion. There were no related systemic diseases.4 Although rare, bilateral involvement has since been recognized.2,5–10 In 2008, Shields et al. described 77 patients with combined hamartoma.2 In this series, 2 patients had bilateral disease, neither of whom had identifiable systemic disease, but 1 patient with unilateral disease was found to have NF-2.

Meyer and Witschel evaluated 15 patients with NF-2 and found combined hamartoma/epiretinal membrane in 12 (80%). In 1 case, unilateral combined hamartoma eventually manifested bilaterally at 8 years of age, challenging the traditional belief that these lesions are congenital.8 Palmer et al. reported a case of bilateral macular combined hamartomas in a 5-month-old female infant with neurofibromatosis type 1, remarking that “this is the earliest reported case of bilateral macular involvement” at that time.6 They indicated that the presence of bilateral tumors strongly suggests underlying phakomatoses. Our patient, presenting at 8 weeks of age, an unusually early detection, further supports the congenital origin of this mass.

Multifocal or bilateral combined hamartomas are highly associated with neurofibromatoses, most notably NF-2.6–7,10–11 The National Institutes of Health diagnostic criteria for NF-2 include (1) bilateral vestibular schwannomas or (2) a first-degree relative with NF-2 and either a unilateral vestibular schwannoma or two of the following: meningioma, schwannoma, glioma, or posterior subcapsular lens opacity.12 Meyers et al. observed epiretinal membrane/combined hamartoma in 80% and lens opacity in 73% of patients with NF-2 and concluded that epiretinal membrane and combined hamartoma in young patients should be considered part of the diagnostic criteria for NF-2.13 In most cases, other clinical features of NF-2 are evident when the fundus lesions are detected. However, in 2008 Grant et al. reported 2 cases in which bilateral combined hamartomas were present prior to other clinical manifestations of NF-2. In 1 case, genetic testing was performed solely on the basis of the fundus lesions, establishing the diagnosis before other NF-2 manifestations were evident.10 Similarly, in our case, genetic testing for NF-2 was advised at presentation based on the appearance of the fundus lesions but was delayed by the parents until other features prompted its necessity.

Despite their benign nature, combined hamartoma and epiretinal membrane are markers for severe central nervous system tumors in patients with NF-2. Parry et al. divided patients with NF-2 into subtypes based on severity of disease.14 Patients with the mild (Gardner) subtype had only bilateral vestibular schwannomas and presented in adulthood, usually after age 25 years. Patients with the severe (Wishart) subtype had multiple other central nervous system tumors and presented in childhood, often with severe handicap or death before reproductive age. Bosch et al. evaluated 30 patients with NF-2 and found that all patients with combined hamartoma were in the childhood-onset (Wishart) group.15 Sisk et al. also confirmed Wishart subtype in 4 patients with NF-2 with epiretinal membrane formation, similar to our patient.16 Genetic analysis of patients with NF-2 who have combined hamartoma and epiretinal membrane has revealed nonsense mutations, providing a genotype-phenotype correlation, as seen in our patient.17

We describe a newborn with bilateral macular combined hamartomas that proved to be the presenting feature of aggressive (Wishart type) NF-2. The presence of combined hamartoma or epiretinal membrane in a young patient, particularly if bilateral or multifocal, could be a marker for the severe (Wishart) subtype of NF-2.

References

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10.3928/01913913-20140521-02

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