Asymptomatic Retinal Vein Occlusion in a 13-Year-Old With Heterozygous Deletion of the PMP22 Gene and a Diagnosis of Hereditary Neuropathy With Liability to Pressure Palsies

Heterozygous deletion of the PMP22 gene causes hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 transcripts are found in myelinating Schwann cells of the peripheral nervous system (1). To the best of our knowledge, this is the first report of an asymptomatic retinal vein occlusion (RVO) in a pediatric patient with HNPP with a novel heterozygous deletion of PMP22.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Asymptomatic Retinal Vein Occlusion in a 13-Year-Old With Heterozygous Deletion of the PMP22 Gene and a Diagnosis of Hereditary Neuropathy With Liability to Pressure Palsies Norman A. Saffra, MD, Trisha S. Emborgo, DO, Emma C. Laureta, MD, David S. Kirsch, MD, Ludovico Guarini, MD H eterozygous deletion of the PMP22 gene causes hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 transcripts are found in myelinating Schwann cells of the peripheral nervous system (1). To the best of our knowledge, this is the first report of an asymptomatic retinal vein occlusion (RVO) in a pediatric patient with HNPP with a novel heterozygous deletion of PMP22. A 13-year-old female patient presented to the emergency department with complaints of right foot drop and numbness over the right lower leg and dorsum of the foot without a clear mechanism of injury or history of trauma. MRI without contrast of the lumbar spine and with contrast of the lumbar, right femur, tibia, fibula, ankle, and foot were negative. On electromyography, she was found to have a right common peroneal neuropathy with entrapment/conduction block at the fibular head and slowing of sural sensory nerves suggestive of more diffuse neuropathy. Further workup demonstrated that the patient had positive antibodies to Borrelia. It is important to note that the patient lives in a state with a high incidence of Lyme disease (2). The patient was given a preDepartment of Ophthalmology (NAS), Maimonides Medical Center, Brooklyn, New York; Department of Ophthalmology (NAS, TSE, DSK), St. John’s Episcopal Hospital, Far Rockaway, New York; Department of Pediatric Neurology (ECL), Northwell Health, New Hyde Park, New York; and Division of Pediatric Hematology/ Oncology (LG), Maimonides Children Hospital, Maimonides Medical Center, Brooklyn, New York. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). N. A. Saffra: conceptualization, data curation, formal analysis, methodology, project administration, resources, supervision, validation, writing - original draft, and writing - review and editing. T. S. Emborgo: conceptualization, data curation, formal analysis, project administration, validation, writing - original draft, and writing review and editing. E. C. Laureta: data curation, formal analysis, methodology, resources, and validation. D. S. Kirsch: formal analysis, supervision, and validation. L. Guarini: data curation, formal analysis, methodology, resources, and validation. Address correspondence to Norman A. Saffra, MD, 1229 Broadway #210, Hewlett, NY 11557; E-mail: [e-mail] Saffra et al: J Neuro-Ophthalmol 2022; 42: e367-e370 sumptive diagnosis of Lyme disease and received a full course of doxycycline hyclate 100 mg, by mouth, twice a day for 4 weeks. No clinical improvement was noted, after the course of therapy, and the patient was then referred to a geneticist as part of the expanded workup to identify the cause of the neuropathy. Genetic testing revealed a pathogenic heterozygous deletion (entire coding sequence of exons 2–5) of the PMP22 gene and received a diagnosis of HNPP (3,4). The patient’s pathogenic PMP22 variant was not detected in the biological mother’s and the biological father’s entire coding sequence of PMP22; therefore, the patient has a de novo mutation. Testing involved full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology and were performed on the patient by Invitae Clinical Diagnostic Laboratory (1,400 16th Street, San Francisco, CA 94103) (4). On December 2017, the Invitae Comprehensive Neuropathies Panel evaluated for sequence changes and exonic deletions/ duplications for 70 genes (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A459) (4). The sample was enriched for targeted regions using the hybridization-based protocol and sequenced using Illumina technology (4). Reads were aligned to a reference sequence (GRCh37) (4). Enrichment and analysis focused on the coding sequence, whereas promoters, untranslated regions, and other noncoding regions were not analyzed (4). Confirmation technologies included any of the following: Sanger sequencing, Pacific Biosciences SMRT sequencing, MLPA, MLPA-seq, and array CGH (4). Invitae noted that approximately 80% of individuals with HNPP have a 1.5 Mb deletion at 17p11.2 (which includes PMP22) on one chromosome (4); however, the laboratory noted that our patient had a gross deletion of the genomic region encompassing the full coding sequence, exons 2–5, of the PMP22 gene and therefore determined to be pathogenic (3,4). Limitations of this report include the boundaries of the event that cannot be determined by Invitae’s assay because it is outside their analysis range; therefore, the exact size of the e367 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Cirrus spectral-domain optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). A. Optic nerve head (ONH) and retinal nerve fiber layer (RNFL) analysis. B. Ganglion cell analysis in both eyes. Normative data are not available for patients younger than 18 years. GCL + IPL, ganglion cell-inner plexiform layer; INF, inferior; NAS, nasal; OD, right eye; OS, left eye; OU, both eyes; SUP, superior; TEMP, temporal. deletion cannot be described (3). To the best of our knowledge, this is the first report of a large entire coding sequence PMP22 deletion with a diagnosis of HNPP. Three years after diagnosis, a retinal vascular abnormality was noted on a routine eye examination, and the patient was referred for additional evaluation. The patient denied any ophthalmic complaints or new neurological complaints at that time. The review of systems was negative. The patient denied any other significant ocular history, medical history, surgical history, medications, or drug allergies. The patient and patient’s parents denied a family history of peripheral neuropathy or cardiac disease. Ophthalmic examination revealed the following: bestcorrected visual acuities of 20/20 in both eyes, correct identification of 14 of the 14 of the Ishihara color plates, 24-2 visual fields in both eyes were within normal limits (WNLs), normal pupillary examination, normal ocular motility, and unremarkable slit-lamp examination of the anterior segment. Dilated funduscopic examination was significant for an age-appropriate optic nerve and macula. The patient had an average retinal nerve fiber layer (RNFL) thickness of 82.0 mm in the right eye and 86.0 mm in the left eye (Fig. 1A) and average ganglion cell-inner plexiform layer (GCIPL) of 77.0 mm in the right eye and 80.0 mm in the left eye (Fig. 1B). RNFL and GCIPL were measured using Cirrus spectral-domain optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). Retinal vascular examie368 nation of the right eye was WNLs, while the left eye revealed severely dilated and tortuous veins, venous collaterals, and a ghost vessel. Fluorescein angiography (FA) of the left eye (Fig. 2C) demonstrated capillary dropouts and confirmation of the fundus findings. Fundus photographs and FA of the right eye (Fig. 2B, D) were unremarkable. Hematologic and cardiac consultations were obtained to evaluate for a causative risk factor for the RVO. Workup included evaluation of protein S and protein C antigen and activity, PAI-1 4 G/5 G, factor V Leiden and APC resistance, antithrombin III, cardiolipin antibodies, and D-dimer; all workup results were negative and did not support a hypercoagulable state. Antinuclear antibody and vasculitis panels were negative. The patient’s bilateral blood pressure and heart rate for sitting and standing positions were WNLs. The patient’s echocardiogram and Doppler report demonstrated good biventricular systolic function, trace tricuspid regurgitation without pulmonary hypertension, and an ejection fraction of 62%. No patent foramen ovale or other thrombus was identified. The patient did not receive ocular treatment at this time because of her asymptomatic state with no macular involvement. Patients with HNPP typically present with symptoms such as muscular weakness, muscular atrophy, and numbness when caused by mechanical stress (5). Bai et al (5) concluded that the constricted axons caused by abnormal Saffra et al: J Neuro-Ophthalmol 2022; 42: e367-e370 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Fundus montage (A, B) and ultra-widefield fluorescein angiography (C, D) of both eyes. A. The fundus of the left eye is remarkable for severely dilated and tortuous veins (white arrows), venous anastomoses (yellow arrows), and a ghost vessel (*). B. The fundus of the right eye is normal. C. The course of the nasal-superior, nasal, and nasal-inferior veins of the left eye shows severely dilated and tortuous veins (white arrows). Note venous collaterals (yellow arrows) on the nasal-superior and nasal side. A capillary dropout (**) is visible on the nasal side. D. The normal right eye. swelling of myelin sheaths in HNPP led to conduction block. These conduction blocks may explain why our patient had episodes of a foot drop and numbness over the right lower leg and dorsum of the foot. Brandt et al (6) noted decreased peripapillary RNFL thickness in the nasal sector of their patients with HNPP. For pediatric RNFL and GCIPL values, Totan et al (7) found the mean RNFL to be 96.9 ± 10.2 and mean GCIPL to be 83.4 ± 5.5 in 296 right eyes, ages 3–17 years. Totan et al (7) and this report both used Cirrus spectral-domain optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). The right eye of our patient with HNPP had a decreased RNFL and GCIPL thickness by at least one SD. RVOs cause disrupted venous flow from the retinal circulation. Although the patient was asymptomatic and cardiac and hematologic workups were WNLs, her FA demonstrated severely dilated and tortuous veins, venous collaterals, and a ghost vessel. Retinal vasculitis secondary to Saffra et al: J Neuro-Ophthalmol 2022; 42: e367-e370 Lyme disease is unlikely because ocular manifestations of Lyme disease usually accompany ocular inflammation. Although most studies focused on the myelination of Schwann cells by PMP22 transcripts (1,8–10), Roux et al found that PMP22 can also be associated with the endothelial cell junctions of the blood–nerve barrier (11). Roux et al identified elevated levels of PMP22 mRNA expression in developing rat brain microvasculature and choroid plexus tissues (11). No documentation of human brain microvasculature and choroid plexus tissues with PMP22 proteins have been investigated at this time. Our patient’s retinal venous findings may possibly be connected with her heterozygous deletion of PMP22 during development but further studies are needed to attribute causality between the 2 conditions. No other genes in this patient’s panel demonstrated a pathogenic deletion that may have increased her risk for a retinal vein occlusion (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A459). e369 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence We are unaware of previous reports of an asymptomatic RVO in association with a heterozygous deletion of the PMP22 gene and a diagnosis of HNPP in a pediatric patient. Physicians should be aware of this finding, and its significance and association will require further studies. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: N. A. Saffra and T. S. Emborgo; b. Acquisition of data: N. A. Saffra, T. S. Emborgo, E. C. Laureta, and L. Guarini; c. Analysis and interpretation of data: N. A. Saffra, T. S. Emborgo, E. C. Laureta, D. S. Kirsch, and L. Guarini. Category 2: a. Drafting the manuscript: N. A. Saffra and T. S. Emborgo; b. Revising it for intellectual content: N. A. Saffra and T. S. Emborgo. Category 3: a. Final approval of the completed manuscript: N. A. Saffra, T. S. Emborgo, E. C. Laureta, D. S. Kirsch, and L. Guarini. REFERENCES 1. Snipes GJ, Suter U, Welcher AA, Shooter EM. Characterization of a novel peripheral nervous system myelin protein (PMP-22/ SR13). J Cell Biol. 1992;117:225–238. 2. Centers for Disease Control and Prevention. Map of Lyme Disease Incidence Categories—United States 2018. Available at: https://www.cdc.gov/lyme/datasurveillance/maps-recent.html. Accessed September 26, 2020. e370 3. Plain K. Invitae Clinical Consult Team. San Francisco, Ca: Invitae Corporation; 2020. 4. Invitae Clinical Diagnostic Laboratory. Invitae Comprehensive Neuropathies Panel. Available at: https://www.invitae.com/ en/physician/tests/03200/. Accessed on December 4, 2017. 5. Bai Y, Zhang X, Katona I, Saporta MA, Shy ME, O’Malley HA, Isom LL, Suter U, Li J. Conduction block in PMP22 deficiency. J Neurosci. 2010;30:600–608. 6. Brandt AU, Meinert-Bohn E, Rinnenthal JL, Zimmermann H, Mikolajczak J, Oberwahrenbrock T, Papazoglou S, Pfüller CF, Schinzel J, Tackenberg B, Paul F, Hahn K, Bellmann-Strobl J. Afferent visual pathway affection in patients with PMP22 deletion-related hereditary neuropathy with liability to pressure palsies. PLoS One. 2016;11:e0164617. 7. Totan Y, Guragac FB, Guler E. Evaluation of the retinal ganglion cell layer thickness in healthy Turkish children. J Glaucoma. 2015;24:e103–e108. 8. Boose F, Brodbeck J, Muller HW. Post-transcriptional regulation of the peripheral myelin protein gene PMP22/gas3. J Neurosci Res. 1999;55:164–177. 9. Boose F, Zoidl G, Wilms S, Gillen CP, Kuhn HG,Müller HW. Differential expression of two mRNA species indicates a dual function of peripheral myelin protein PMP22 in cell growth and myelination. J Neurosci Res. 1999;37:529–537. 10. Bongrazio M, Baumann C, Zakrzewicz A, Pries AR, Gaehtgens P. Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress. Cardiovasc Res. 2000;47:384–393. 11. Roux KJ, Amici SA, Notterpek L. The temporospatial expression of peripheral myelin protein 22 at the developing blood-nerve and blood-brain barriers. J Comp Neurol. 2004;474:578–588. Saffra et al: J Neuro-Ophthalmol 2022; 42: e367-e370 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.