Ptosis, Visual Blurring, and Multiple Cranial Nerve Tumors: Do We Know the Culprit

Abstract

Neurofibromatosis type 2 (NF2) is a monogenic condition caused by mutations in the NF2 gene. Examination of skin and eyes and parental screening play a key role in the diagnosis of pediatric NF2. We report a four-year-old boy, who presented sub-acutely with unilateral vision loss, ptosis and exotropia with a positive family history of NF2.

Introduction

Neurofibromatosis type-2 (NF2), also called bilateral acoustic neurofibromatosis or Merlin syndrome, is an autosomal dominant disorder caused due to mutations in the NF2 gene on chromosome 22q12.2, encoding a protein called merlin [1]. Merlin plays a key role in cellular growth, protein translation, and cellular proliferation. Any defect in the merlin formation predisposes to the development of tumors [1, 2]. In the present report, we report a four-year-old boy who presented with unilateral blurring of vision, drooping of eyelid, and exotropia for past 10 days. The neuroimaging revealed unilateral optic nerve sheath meningioma (ONSM) and vestibular schwannoma (VS). The peculiarities of pediatric NF2 along with the treatment modalities were discussed in this comprehensive literature review.

Case Report

A four-year-old previously healthy boy presented with blurring of vision in right eye, drooping of the right eyelid, and outward deviation of the right eye for the past 10 days. There was no history of nystagmus, hearing loss, vomiting, seizures, headaches, tinnitus, paraesthesias, cognitive decline, and any other focal neurological deficits. His antenatal and perinatal history was uneventful. There was a history of surgery in the father for bilateral vestibular schwannomas. Examination revealed ptosis, relative afferent pupillary defect (RAPD), restrictive exotropia (due to the large optic nerve sheath meningioma), and limited elevation of the eye with visual acuity of perception of light on the right eye, and normal vision in the left eye. Fundus revealed the presence of optociliary shunt vessels and optic atrophy in the right eye. The rest of the systemic examination was unremarkable. Brain Magnetic Resonance Imaging (MRI) along with orbital sections revealed nodular enhancing lesion along the right vestibulocochlear nerve and an intraorbital intraconal mass lesion encasing the entire right intraorbital optic nerve suggestive of VS and ONSM respectively (Fig. 1). Visual Evoked Potentials showed no clear waveforms on either side whereas brainstem-evoked response audiometry revealed normal latency between waves I, III, and V. The ONSM was removed surgically via the lateral trans-orbital approach with preservation of extraocular muscles. Radiotherapy was not considered in view of significant side effects. A conservative approach was followed regarding the management of VS as the child was asymptomatic. A diagnosis of neurofibromatosis type 2 was concluded as the diagnostic criteria for NF-2 was fulfilled [3]. A close follow-up was planned to identify additional features of NF2.

Fig. 1.

Neuroimaging of the child. Legend: Axial T2- (A), T1-(B) and contrast enhanced T1-weighted fat-saturated (C and D) MR images showing homogeneously enhancing intraconal lesion which is hypointense on T2-weighted images and isointense on T1-weighted MR images around the intra-orbital part of the right optic nerve (white arrows) consistent with optic nerve sheath meningioma. The lesion is circumferential surrounding the optic nerve. Note is also made of right axial proptosis. A small intracanalicular enhancing lesion is also seen in right internal auditory canal (white thick broken arrow) suggestive of schwannoma

Discussion

The clinical criteria used in adults for the diagnosis of NF2 are less helpful in children as they present with different signs and symptoms (such as visual, spinal cord compression, or neurologic symptoms from other intracranial tumors) [1, 3]. Examination of skin and eyes, and parental screening for any tumors play a key role in the diagnosis during childhood. Around 50% are first affected in their family and are described as having de novo mutations [2]). Despite the requirement of bilateral VS for the diagnosis, some children may have unilateral VS with ipsilateral meningiomas. These are due to true somatic mutations of the NF2 gene (mosaic NF2) in which only a proportion of cells carry the mutation [2, 4]. Around 83% of the patients of less than 20 years of age presenting with unilateral VS have detectable NF2 mutation compared to 7.7% when looking at all ages [4]. In children, it has been reported that those with unilateral VS might develop bilateral VS in a shorter time when compared to adults (3.25 years vs 6.5 years) [3–5].

ONSM are the second most common tumors and are usually bilateral, occur early in life, and can be associated with complete vision loss by compression or vascular compromise of the nerve’s axons. Vision impairment, optic atrophy, and presence of optociliary shunt vessels form a pathognomonic triad for ONSM, although the triad as an entirety is rarely seen. Both VS and ONSM together occur in 10–18% of the children with NF2 [5]. Other tumors such as ependymomas and astrocytomas also occur in 24% of the children with NF2 [6]. Although the index child did not have any skin tumors at presentation however three types of skin tumors can be present in NF2: NF2 plaques, nodular schwannomas, and neurofibromas. As the burden of skin tumors increases, the severity of the disease also increases [7]. Therefore, specific skin manifestations can also be diagnostic clue for NF-2 like other neurocutaneous syndromes such as Neurofibromatosis 1, tuberous sclerosis, etc. [8, 9].

Ophthalmologic findings other than meningiomas include subcapsular cataracts, epiretinal membranes, strabismus, amblyopia, and extra-ocular movement abnormalities [5–7]. Whole-body MRI plays a crucial role in assessing total tumor burden in patients with NF2. Saltatory growth (alternating periods of growth and quiescence) is classical of NF2-associated tumors in children. It has also been observed that hearing loss is not directly related to tumor growth [9, 10]. As children are prone to develop multiple cranial, spinal, and peripheral nerve tumors, surgical resection is not always possible or advisable. Hence the primary goal is to preserve function and increase the quality of life. Other than surgery, other options include fractionated conformal radiotherapy, biologically targeted therapies such as lapatinib, bevacizumab, etc. are available [10]. Predictors such as early age at diagnosis and presence of intracranial meningiomas are associated with greater mortality whereas the mosaic phenotype is associated with lesser mortality [7–9]. For confirmed cases of NF2, annual follow-ups are required for neurological, skin, and eye examination and every 6 monthly for audiological examination and neuroimaging [10].

Conclusion

The clinical presentation of pediatric NF2 is different from that of adults and ophthalmologic and skin examination can give us clues for the diagnosis. Children with unilateral tumors have a high risk to develop bilateral tumors on follow-up.

Authors’ contribution

BS and PM: Patient management, literature review, and initial draft manuscript preparation; LS: Patient management, literature review, concept, design and critical review of manuscript for important intellectual content. SV: provided radiological inputs for the manuscript. All authors were involved in patient management and approved the final version for publication.

Funding

This study was not supported by any funding.

Declarations

Conflict of interest

None of the authors have conflicts of interest.

Consent

Written informed consent obtained from parents.

Ethical statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.