Ophthalmologic Manifestations of Noonan Syndrome

Ileana Anika Domondon

Introduction

Noonan Syndrome (NS) is a genetic disease involving mutations in the RAS/MAPK (mitogen-activated protein kinase) signaling pathway or “RASopathies” with heterogeneous and phenotypic expression (1). Multiple genetic mutations have been identified in NS, with other genes having genotype-phenotype correlations. The most common pathogenic variants implicated in NS are in genes PTPN11 (50%), SOS1 (10-13%), LZTR1 (8%), RAF1 (5%), KRAS (5%), and RIT1 (5%) (2).

Common clinical manifestations of NS include craniofacial dysmorphism, congenital heart disease, ocular abnormalities, short stature, skeletal and neurodevelopment abnormalities, and other comorbidities (3). Other systemic manifestations of NS have been extensively studied, whereas limited reports focus on the ophthalmologic manifestations of NS.

Ophthalmologic Manifestations

Ocular abnormalities are one of the most consistent features of NS with external ocular manifestations playing a key role in its facial characteristics, aiding in clinical diagnosis (4). It is estimated that 95% of patients with NS will also have at least one of the following ocular abnormalities: strabismus, nystagmus, refractive errors, and amblyopia. These abnormalities do not have any genotype-phenotype association (3). NS patients may also have variable external ocular features such as hypertelorism, ptosis, down slanting of the palpebral fissure, and epicanthic folds. On the other hand, proptosis is an uncommon ocular manifestation in NS patients with an unclear pathophysiology (5,6).

More than half of patients also have anterior segment changes, including prominent corneal nerves, anterior stromal dystrophy, cataracts, and panuveitis (7, 8). To our knowledge, glaucoma in NS has only been reported once in literature, involving a female patient with an SOS1 mutation who developed bilateral acute-angle closure glaucoma and was managed with medications and laser peripheral iridotomy (9).

Posterior segment changes have been documented in approximately 20% of NS patients. These abnormalities include optic head drusen, optic nerve head paleness, optic disk hypoplasia, coloboma, myelinated nerves, non-glaucomatous optic disc excavation and much rarer findings such as tortuous retinal vessels and exudative retinopathy (3,6,9).

NS patients may also present with visual impairment that is possibly attributed to congenital or developmental disorders of the optic nerve.  On the other hand, permanent visual impairment in NS was seen in those with mutations in RAF1, SHOC2 and KRAS (4).

Diagnosis & Management

The diagnosis of NS is based on clinical features and genetic analysis is used to confirm this. Noonan Syndrome is caused by an inherited genetic mutation and there is no cure. Thus, management is aimed at improving symptoms and providing supportive care. From an ophthalmologist’s perspective, NS patients should undergo early complete ophthalmologic evaluation, with regular surveillance in childhood and adolescence depending on pathology (2). Refractive errors and other amblyogenic factors should be identified and treated early to prevent further sight-threatening changes (6).

References

  1. Baldo F, Fachin A, Da Re B, Rubinato E, Bobbo M, Barbi E. New insights on Noonan syndrome’s clinical phenotype: a single center retrospective study. BMC Pediatr. 2022;22(1):734. Published 2022 Dec 24. doi:10.1186/s12887-022-03804-2
  2. Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1124/
  3. Roberts AE, Allanson JE,Tartaglia M, Gelb BD. Noonan syndrome. Lancet 2013; 381: 333–42.
  4. van Trier DC, van der Burgt I, Draaijer RW, Cruysberg JRM, Noordam C, Draaisma JM. Ocular findings in Noonan syndrome: a retrospective cohort study of 105 patients. Eur J Pediatr. 2018;177(8):1293-1298. doi:10.1007/s00431-018-3183-1
  5. Marchione G, Pilotto E, Midena G. Proptosis secondary to bilateral extraocular muscle enlargement in Noonan syndrome with hypertrophic cardiomyopathy: A case report. Eur J Ophthalmol. 2023;33(5):NP67-NP70. doi:10.1177/11206721221125035
  6. Christou EE, Zafeiropoulos P, Rallis D, et al. A Narrative Review of the Ocular Manifestations in Noonan Syndrome. Semin Ophthalmol. 2022;37(2):215-221. doi:10.1080/08820538.2021.1955134
  7. Lee NB, Kelly L, Sharland M. Ocular manifestations of Noonan syndrome. Eye (Lond). 1992;6 ( Pt 3):328-334. doi:10.1038/eye.1992.
  8. Reynolds DJ, Rubin SE, Fox J, Kodsi SR. Ocular manifestations of Noonan syndrome in the pediatric patient. J AAPOS. 2004;8(3):282-283. doi:10.1016/j.jaapos.2003.12.011
  9. Padrón-Pérez N, Sanz-Moreno S, Lillo-Sopena J, Arruga J. Noonan syndrome with bilateral acute angle-closure. Clin Exp Ophthalmol. 2015;43(1):90-92. doi:10.1111/ceo.12389

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