Spectrum of Ophthalmic Disorders in Prader-Willi Syndrome: Implications for Early Screening and Multidisciplinary Management

Spectrum of Ophthalmic Disorders in Prader-Willi Syndrome: Implications for Early Screening and Multidisciplinary Management | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Spectrum of Ophthalmic Disorders in Prader-Willi Syndrome: Implications for Early Screening and Multidisciplinary Management Huixia Hua, Yanhong Ren, Jiajun Wang, Jiayue Zhou, Wen Sun, Caiping Shi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8683113/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To characterize the spectrum of ophthalmic disorders in children with Prader–Willi syndrome (PWS) and to evaluate the clinical value of early ophthalmic screening and intervention. Methods A retrospective analysis was conducted on ophthalmic findings from 30 clinically and genetically diagnosed children with PWS who were followed at a tertiary pediatric center. Demographic data, genetic subtypes, ophthalmic examinations, and treatment outcomes were reviewed. Results Ophthalmic abnormalities included extraocular muscle disorders, refractive errors, amblyopia, ptosis, nystagmus, retinal and optic nerve pigmentation abnormalities, tear secretion dysfunction, and impaired stereoacuity. Strabismus was identified in 9 patients (30%), including 4 cases of esotropia and 5 cases of exotropia. Refractive errors were present in 14 patients (46.7%), comprising myopia (23.3%), hyperopia (23.3%), and astigmatism (16.7%). Amblyopia was diagnosed in 5 patients (16.7%). Tear film assessment in 12 cooperative patients demonstrated reduced tear break-up time and tear meniscus height. Stereoacuity abnormalities were detected in 6 of 7 cooperative patients (85.7%). Management included refractive correction, amblyopia therapy, strabismus surgery, and artificial tear supplementation. Conclusion Ophthalmic abnormalities are common and potentially treatable in children with PWS. Early ophthalmic evaluation and multidisciplinary management may improve visual outcomes and quality of life. Routine ophthalmic screening should be incorporated into the standard care of patients with PWS. Figures Figure 1 Figure 2 Figure 3 Introduction Prader–Willi syndrome (PWS) is a rare genetic disorder caused by the absence of expression of imprinted genes in the paternal chromosome 15q11.2–q13 region[ 1 ]. Although PWS is primarily characterized by hypotonia, hyperphagia, obesity, intellectual disability, and endocrine dysfunction. Ocular abnormalities are increasingly recognized as an important yet underappreciated component of the disease spectrum. The reported incidence of PWS in international studies ranges from 1 in 10,000 to 1 in 30,000, with no significant racial differences [ 2 , 3 ]. At present, comprehensive epidemiological data on PWS in China are lacking. Although clinical scoring systems based on international criteria are widely used, diagnosis based solely on clinical features is prone to missed or incorrect diagnoses because of variability related to age, disease course, and ethnic background. Therefore, definitive diagnosis depends on molecular genetic testing. Genetic testing is considered the gold standard for PWS diagnosis and is essential for determining the underlying genetic mechanism. Current diagnostic approaches include DNA methylation analysis, chromosomal microarray analysis (CMA), and detection of imprinting center defects. DNA methylation analysis can simultaneously identify paternal deletions, maternal uniparental disomy (UPD), and imprinting center defects, with a detection rate exceeding 99%, and is therefore recommended as the first-line diagnostic method for PWS. CMA further enables characterization of deletion size and breakpoints in deletion-type PWS and facilitates detection of isodisomy. If these tests yield negative results, imprinting center defects should be considered. Previous studies have reported that paternal deletions of the imprinting region account for approximately 70%–80% of cases, maternal UPD for 20%–30%, imprinting center mutations or microdeletions for 1%–3%, while balanced chromosomal translocations and other rare mechanisms are exceedingly uncommon [ 4 ]. In the present study, 22 cases (73.3%) were deletion type, 7 cases (23.3%) were UPD type, and 1 case (3.3%) was classified as other, findings that are consistent with those reported in the literature. Ocular manifestations in PWS are often overlooked in clinical practice, despite their potential impact on visual development, functional vision, and quality of life. Early identification and timely intervention may prevent irreversible visual impairment, particularly amblyopia and binocular dysfunction. However, systematic ophthalmic data in pediatric PWS populations, especially from Asian cohorts, remain limited. To characterize the spectrum of ophthalmic disorders in children with PWS and to evaluate the clinical value of early ophthalmic screening and intervention. A retrospective analysis was conducted on ophthalmic findings from 30 clinically and genetically diagnosed children with PWS who were followed at a tertiary pediatric center. Demographic data, genetic subtypes, ophthalmic examinations, and treatment outcomes were reviewed. Methods Patients A total of 30 children clinically diagnosed with PWS were treated at the Children's Hospital of Zhejiang University School of Medicine between November 2024 and April 2025. The cohort comprised 17 males and 13 females. Genetic testing confirmed 22 cases of deletion subtype, 7 cases of maternal uniparental disomy (UPD), and one case of another subtype. The age at first diagnosis ranged from 4 months to 15 years and 7 months. Clinical data on manifestations, ophthalmic examinations, treatment, and follow-up were collected and comprehensively analyzed. All children exhibited neonatal hypotonia, feeding difficulties, limb weakness, and hypoactivity, with 5 requiring nasogastric tube feeding due to severe issues. Characteristic facial features—almond-shaped eyes, small hands and feet, a small downturned mouth, and a prominent forehead—were universally present. Concomitant conditions included a history of obesity (n = 15), global developmental delay and cognitive dysfunction (n = 26), cryptorchidism in males (n = 13, with 10 undergoing orchiopexy), scoliosis (n = 12), bilateral hip subluxation (n = 1), and significant sleep snoring (n = 11). Data collection This research collected data from 30 children diagnosed with PWS who were evaluated in outpatient clinics. Collected information included demographic characteristics, genetic testing results, comprehensive medical histories, and detailed ophthalmologic examination findings. Best-corrected visual acuity (BCVA) was measured using a 5-meter Snellen chart and converted to logarithm of the minimum angle of resolution (LogMAR) values for analysis. All participants underwent rapid cycloplegia with compound tropicamide. Final refractive status was determined by an experienced optometrist using retinoscopy, with reference to autorefractor measurements. Refractive errors were classified as follows: myopia (spherical equivalent [SE] ≤ − 0.50 D), including low (− 3.00 D < SE ≤ − 0.50 D), moderate (− 6.00 D < SE ≤ − 3.00 D), and high myopia (SE ≤ − 6.00 D); hyperopia (SE ≥ + 2.00 D), including low (+ 2.00 D ≤ SE < + 5.00 D), moderate (+ 5.00 D ≤ SE < + 7.00 D), and high hyperopia (SE ≥ + 7.00 D); and astigmatism (cylinder ≥ 1.00 D), classified as low (1.00 D ≤ cylinder < 2.00 D), moderate (2.00 D ≤ cylinder < 3.00 D), or high (cylinder ≥ 3.00 D). Strabismus was assessed using the cover–uncover test, prism alternate cover test, or Hirschberg/Krimsky test, depending on the child’s level of cooperation. A diagnosis of strabismus required an objective ocular deviation of at least 10 prism diopters, confirmed in at least one objective examination and independently verified by two strabismus specialists. Axial length and corneal curvature were measured using the IOLMaster 700. Anterior segment structures were evaluated by slit-lamp biomicroscopy, while fundus examinations were performed using ultra-widefield laser scanning ophthalmoscopy (OPTOS PLC P200DTx). Tear film parameters were assessed with a corneal topographer (OCULUS 77000), and stereopsis was evaluated using standardized stereo test cards (Stereo Optical Co., USA). All clinical and genetic data were extracted from standardized medical records and systematically organized to create a complete dataset for subsequent comprehensive analysis. Data analysis The principal ocular manifestations included extraocular muscle abnormalities, refractive errors, ptosis, nystagmus, retinal and optic nerve lesions, as well as other abnormalities such as iris pigmentation disorders (e.g., heterochromia), abnormal tear secretion, increased risk of dry eye, and impaired stereoacuity. In this cohort, strabismus was identified in 9 of 30 children (30.0%), including 5 cases of exotropia and 4 cases of esotropia (Fig. 1 ). Refractive assessment could not be completed in 2 children because of poor cooperation; among the remaining 28 children, refractive abnormalities included high myopia in 2 cases (4 eyes), moderate myopia in 1 case (1 eye), high astigmatism in 2 cases (3 eyes), and moderate hyperopia in 5 cases (10 eyes). Axial length abnormalities were observed in 8 cases, with excessive elongation in 2 children (maximum values of 27.22 mm and 27.10 mm) and abnormally short axial lengths in 6 children (minimum values of 18.86 mm and 18.85 mm), as shown in Fig. 2 . Corneal curvature was increased in 5 cases (maximum keratometry value, 49.47 D) and decreased in 5 cases (minimum, 40.06 D). Three children exhibited uneven or reduced iris pigmentation, and 4 showed irregular macular pigmentation. Tear film assessment was successfully completed in 12 children, all of whom demonstrated reduced tear parameters: the mean tear film break-up time was 7.60 s in the right eye and 4.57 s in the left eye, while the mean tear meniscus height was 0.075 mm and 0.0725 mm in the right and left eyes, respectively. One child presented with bilateral ptosis, and another exhibited latent nystagmus. Among the 7 children who were able to complete stereoacuity testing, 6 (85.7%) demonstrated impaired stereopsis. No optic nerve or retinal lesions were detected in this cohort. Of the 9 children with refractive errors complicated by amblyopia, 5 were able to cooperate with spectacle correction and amblyopia training. Four children underwent surgical correction for strabismus. Those with tear film abnormalities received treatment with artificial tears. In addition, 28 children received growth hormone therapy in combination with dietary intervention. Three children diagnosed with hypothyroidism were treated with oral levothyroxine sodium, resulting in normalization of thyroid function. Discussion The clinical manifestations of PWS are complex, multisystemic, and age dependent. During the neonatal period, the predominant features include severe hypotonia, weak sucking, feeding difficulties, and reduced spontaneous crying and movement. In early childhood, hyperphagia gradually develops and often leads to obesity. As patients age, additional manifestations such as short stature, hypogonadism, intellectual disability, and behavioral abnormalities become increasingly evident. Endocrine dysfunction in PWS primarily results from abnormalities of the hypothalamic–pituitary–target gland axis. The hypothalamus regulates the secretion and release of anterior and posterior pituitary hormones via neural and vascular pathways; dysfunction of this system contributes to endocrine disorders such as growth hormone deficiency and hypogonadism. Moreover, hypothalamic dysfunction affects thermoregulation, appetite control, sleep, emotional regulation, and other autonomic nervous system functions, thereby contributing to characteristic behavioral abnormalities. Compared with other systemic manifestations, ophthalmologic involvement in PWS has received relatively limited attention in both domestic and international literature, and current understanding remains incomplete. Nevertheless, available clinical reports and published studies suggest that individuals with PWS may exhibit multiple visual abnormalities. Strabismus is the most frequently reported ocular abnormality in PWS [5–8]. Reported prevalence varies widely, ranging from 52% to 62% in some studies [9–12], while others report lower rates of 28%–37% [13,14] or as high as 95% [15,16]. A 2021 analysis of data from the global PWS Comprehensive Registry, including 908 participants aged 0–62 years, reported a strabismus prevalence of 40%, with 91% of cases diagnosed before 5 years of age. Among affected individuals, 86% underwent a single strabismus surgery and 10.1% required more than one surgical intervention [17]. In the present study, strabismus was identified in 9 children (30%), including 4 cases of esotropia and 5 cases of exotropia. The underlying pathogenesis of strabismus in PWS is likely multifactorial. PWS is caused by functional defects of imprinted genes within the paternal chromosome 15q11.2–q13 region, leading to abnormal development of multiple systems, including the hypothalamus, visual pathways, and extraocular muscles. Endocrine abnormalities, such as growth hormone deficiency and thyroid dysfunction, may further impair ocular structural development, resulting in extraocular muscle dysplasia, abnormal neural innervation, and binocular fusion dysfunction, all of which may contribute to the development of strabismus. Refractive errors and anisometropia may also play a role; however, in the present cohort, only one case of strabismus was clearly attributable to refractive error, while other cases showed no such association. Refractive errors—including myopia, hyperopia, and astigmatism—as well as amblyopia, are also common visual abnormalities in patients with PWS. Multiple studies have demonstrated that the prevalence of refractive errors and amblyopia in PWS is substantially higher than that in the general population. One study involving 46 patients reported refractive errors in 32 cases (69.6%), including myopia greater than 3.75 D in 15% and astigmatism greater than 1.25 D in 41% of patients [18]. Similarly, the 2021 global PWS registry study reported prevalences of 41% for myopia, 25% for hyperopia, 25% for astigmatism, and 16% for amblyopia [17]. In the present study, refractive errors were identified in 14 children (46.7%), including 7 cases (23.3%) of myopia, 7 cases (23.3%) of hyperopia, and 5 cases (16.7%) of astigmatism. Amblyopia was diagnosed in 5 children (16.7%), including cases associated with moderate-to-high myopia (3 cases, 5 eyes), high astigmatism (2 cases, 3 eyes), and moderate-to-high hyperopia (5 cases, 10 eyes), as shown in Fig. 3. The high prevalence of refractive abnormalities in PWS may be related to growth hormone deficiency and other endocrine disturbances that affect ocular morphological development, including abnormal axial length growth, corneal curvature alterations, and impaired lens accommodation. In addition, systemic comorbidities such as obesity and diabetes may further exacerbate refractive development. Excessive or insufficient axial elongation can lead to myopia or hyperopia, while corneal curvature abnormalities contribute to astigmatism. Furthermore, nervous system dysfunction in PWS may interfere with normal ocular motor regulation and innervation. The elevated incidence of amblyopia in PWS is likely attributable to multiple factors, including deprivation amblyopia secondary to ptosis, strabismic amblyopia, and refractive amblyopia. As a genetic disorder, PWS may also impair central nervous system processing and integration of visual information, thereby disrupting normal visual development and increasing the risk of amblyopia. Fig. 3 Percentage of refractive errors in our study. In addition to strabismus and refractive errors, a wide spectrum of other ocular abnormalities has been reported in patients with PWS, including ptosis, nystagmus, iris hypopigmentation, cataracts, congenital fibrosis of the extraocular muscles, diabetic retinopathy, congenital uveal ectopia, and a flat macula with fundus hypopigmentation. Abnormal development of stereoacuity has also been frequently documented in individuals with PWS [14]. In the present study, iris pigmentation abnormalities were observed in 3 cases, fundus pigmentation abnormalities in 4 cases, bilateral ptosis in 1 case, nystagmus in 1 case, tear secretion abnormalities in 12 cases, and stereoacuity developmental abnormalities in 6 cases. Previous studies have demonstrated that the molecular basis underlying the association between PWS, hypopigmentation, and chromosomal deletions can be explained by the close proximity of the PWS critical region (15q11–q13) to the gene responsible for oculocutaneous albinism type 2 (OCA2; 15q11.2–q12) [19,20]. The OCA2 gene encodes the transmembrane P protein, which regulates the intracellular distribution of tyrosinase. Consequently, hypopigmentation in PWS is considered an incomplete form of tyrosinase-positive albinism. Subsequent studies by Wiesner et al. [21] and Hered et al. [22] identified iris transillumination defects in 33% and 72% of PWS patients, respectively, findings that were strongly associated with chromosomal deletions. Hittner et al. [23] were the first to systematically analyze iris pigmentation abnormalities in PWS and reported that all patients with deletions involving the 15q11–q13 region exhibited iris hypopigmentation. Furthermore, Creel et al. [24] reported optic nerve axon misrouting consistent with visual evoked cortical potential (VECP) criteria for albinism in several PWS cases, suggesting that pigmentary abnormalities in PWS may share pathophysiological mechanisms with fully expressed oculocutaneous albinism. Tear film assessment in our cohort revealed that all 12 children who were able to cooperate exhibited reduced tear secretion. The mean tear film break-up time was 7.60 s in the right eye and 4.57 s in the left eye, while the mean tear meniscus height was 0.075 mm and 0.0725 mm, respectively. Decreased tear secretion in PWS may be attributable to hypothalamic dysfunction. As the hypothalamus plays a central role in regulating fluid balance and autonomic function, its impairment may disrupt lacrimal gland regulation, leading to tear film insufficiency. Among the 7 children who completed stereoacuity testing, 6 (81.7%) demonstrated abnormal stereopsis. Impaired stereoacuity in PWS likely results from the combined effects of genetic defects, neurodevelopmental abnormalities, ocular structural lesions, and behavioral factors. Strabismus disrupts binocular retinal correspondence, thereby impairing the foundation for stereopsis; prolonged strabismus may further lead to amblyopia, exacerbating stereoacuity deficits. Refractive errors and anisometropia interfere directly with binocular visual integration, while cognitive impairment common in PWS may reduce attention, compromise sustained binocular fixation, and hinder normal stereoacuity development. Interestingly, previous studies comparing genetic subtypes of PWS have reported a higher prevalence of strabismus in the maternal uniparental disomy (UPD) group than in the deletion group (53% vs. 39%; p = 0.03). In contrast, among the 30 cases in our study, strabismus was observed in 2 patients in the UPD group and 6 patients in the deletion group. This discrepancy may be attributable to the relatively small sample size of the present study, underscoring the need for larger cohorts to validate genotype–phenotype correlations. Notably, all cases with iris and fundus pigmentation abnormalities in our cohort were of the deletion type, consistent with previous reports and likely reflecting haploinsufficiency of the OCA2 gene within the 15q11–q13 region [21]. Clinical Implications Early ophthalmic evaluation—including assessment of ocular alignment, refractive status, fundus examination, stereoacuity, and tear secretion—combined with multidisciplinary intervention involving ophthalmology, neurology, endocrinology, and rehabilitation medicine, is critical for improving visual function and quality of life in patients with PWS. Given the multisystem nature of the disease, management should adopt a comprehensive, age-specific, and phenotype-oriented approach, incorporating timely endocrine therapy and targeted ophthalmic interventions. Considering the high prevalence of potentially treatable ocular abnormalities in PWS, we recommend that all patients with PWS undergo routine ophthalmologic screening, with early detection and intervention to prevent irreversible visual impairment, such as amblyopia. Conclusion Ophthalmic abnormalities are common and potentially treatable in children with PWS. Early ophthalmic evaluation and multidisciplinary management may improve visual outcomes and quality of life. Routine ophthalmic screening should be incorporated into the standard care of patients with PWS. Declarations Informed consent: Was obtained from parents of each patient included in the study. Author contributions Hua and Caiping Shi conceived and designed the present study. Yanhong Ren performed general condition inspection and follow-up management. Jiajun Wang performed the optical examination. Huixia Hua and Caiping Shi performed the data collection. Huixia Hua and Jiayue Zhou performed the analysis and interpretation. Huixia Hua and Caiping Shi wrote the manuscript. Caiping Shi and Wen Sun provided critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Funding This study received no external funding. Ethical approval : This study was approved by the Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine (Ethics Approval No. 2025-IRB-0412-P-01), and written informed consent was obtained from the parents or legal guardians of all participating children in accordance with the Declaration of Helsinki. Clinical trial number : Not applicable. Informed consent : Was obtained from parents of each patient included in the study. Conflict of interest : There is no potential conflict of interest. Competing interest : The authors declare no competing interests. Disclosure of potential conflicts of interest : None. References Prader A, Labhart A, Willi H (1956) Ein Syndrom von Adipositas, Klein-wuchs, Kryptorchidismus und Oligophrenie nach myotonier-tigem Zustand im Neugerborenenalter. Schweiz Med Wochenschr 86:1260–1261 Cassidy SB, Schwartz S, Miller JL, et a, Driscoll DJ Prader-Willi syndrome. Genet Med, 2012Jan, 14(1): 10–26 Vogels A, Ende J, Van Den, Keymolen K, Mortier G, Devriendt K, Legius E, Fryns JP Minimum prevalence, birth incidence, and cause of death for Prader-Willi syndrome in Flanders. Eur J Hum Genet 2004Mar, 12(3):238–240 Cheon CK Genetics of Prader-Willi syndrome and Prader-Will-like syndrome. Ann Pediatr Endocrinol Metab 2016Sep ;21(3):126–135 Bistrian BR, Blackburn GL, Stanbury JB Metabolic aspects of a protein-sparing modified fast in the dietary management of Prader-Willi obesity. N Engl J Med 1977Apr 7; 296(14):774–779 Fraccaro M, Zuffardi O, Buhler EM, Jurik LP (1977) 15/15 translocation in Prader-Willi syndrome. M ed Genet 14(4):275–276 Butler MG, Weaver DD, Meaney FJ (1982) Prader-Willi syndrome: are there population differences? Clin Genet 22(5):292–294 Roy MS, Milot JA, Polomeno RC, Barsoum-Homsy M (1992) Ocular findings and visual evoked potential response in the Prader-Willi syndrome. Can J Ophthalmol 27(6):307–312 Wiesner GL, Bendel CM, Olds DP, White JG, Arthur DC, Ball DW (1987) King R A. Hypopigmentation in the Prader-Willi syndrome. Am J Hum Genet 40(5):431–442 Hered RW, Rogers S, Zang YF, Biglan AW (1988 May-Jun) Ophthalmologic features of Prader-Willi syndrome. J Pediatr Ophthalm ol Strabismus 25(3):145–150 Butler MG (1990) Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet 35(3):319–332 Butler JV, 1, Whittington JE, Holland AJ, Boer H, Clarke D, Webb T (2002) Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: a population-based study. Dev Med Child Neurol 44(4):248–255 Zellweger H, Schneider HJ (1968) Syndrome of hypotonia-hypomentia-hypogonadism-obesity (HHHO) or Prader-Willi syndrome. Am J Dis Child 115(5):588–598 Fox 1 R, Sinatra RB, Mooney MA, Feurer ID, Butler MG (1999 Nov-Dec) Visual capacity and Prader-Willi syndrome. J Pediatr Ophthalmol Strabismus 36(6):331–336 Bray GA, Dahms WT, Swerdloff RS, Fiser RH, Atkinson RL, Carrel RE (1983) The Prader-Willi syndrome: a study of 40 patients and a review of the literature. Med (Baltim) 62(2):59–80 Robinson 1 WP, Bottani A, Xie YG, Balakrishman J, Binkert F, Mächler M, Prader A (1991) A Schinzel.Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients. Am J Hum Genet 49(6):1219–1234 Bohonowych JE, Vrana-Diaz CJ, Miller JL, McCandless SE, Strong TV (2021) Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry. BMC Ophthalmol 21(1):296 Hered 1RW, Rogers S, Zang YF, Biglan AW (1988 May-Jun) Ophthalmologic features of Prader-Willi syndrome. J Pediatr Ophthalmol Strabismus 25(3):145–150 Lee ST, Nicholls RD, Bundey S et al (1994) Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism. N Engl J Med 330(8):529–534 Butler MG, Hypopigmentation A common feature of Prader-Labhart-Willi syndrome. Am J Hum Genet 1989 Jul 45(1): 140–146 Wiesner GL, Bendel CM, Olds DP et al (1987) Hypopigmentation in the Prader-Willi syndrome. Am J Hum Genet 40(5):431–442 Hered RW, Rogers S, Zang YF et al Ophthalmologic features of Prader-Willi-syndrome. J Pediatr Ophthalmol Strabismus 1988 May-Jun 25(3):145–150 Hittner HM, King RA, Riccardi VM et al (1982) Oculocutaneous albinoidism as a manifestation of reduced neural crest derivatives in the Prader-Willi syndrome. Am J Ophthalmol 94(3):328–337 Creel DJ, Bendel CM, Wiesner GL et al Abnormalities of the central visual pathway in Prader-Willi syndrome associated with hypopigmentation. N Engl J Med 1986Jun 19; 314(25): 1606–1609 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8683113","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":581257232,"identity":"095396ae-f9f6-4b92-b5b8-b6a5b666bd9e","order_by":0,"name":"Huixia Hua","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Huixia","middleName":"","lastName":"Hua","suffix":""},{"id":581257233,"identity":"7545f0f0-3cda-4e6c-ab6d-02dc8f870e56","order_by":1,"name":"Yanhong Ren","email":"","orcid":"","institution":"Zhejiang 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01:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8683113/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8683113/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101364648,"identity":"722e0007-f1e6-4fa0-a4f2-eb24ea2a97f8","added_by":"auto","created_at":"2026-01-29 00:51:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25264,"visible":true,"origin":"","legend":"\u003cp\u003eStatistic numbers of eyes after refractive examination.\u003c/p\u003e","description":"","filename":"Statisticnumbersofeyesafterrefractiveexamination.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8683113/v1/4d7cee943d8d69fc1ec22ce1.jpg"},{"id":101364650,"identity":"7a623f6e-7b97-4291-ad87-4050d34a564f","added_by":"auto","created_at":"2026-01-29 00:51:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":195133,"visible":true,"origin":"","legend":"\u003cp\u003eStatistic results of ocular characteristics with PWS\u003c/p\u003e","description":"","filename":"StatisticresultsofocularcharacteristicswithPWS.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8683113/v1/2e454f117530d7a5e89ea591.jpg"},{"id":101364649,"identity":"e932e79f-1bfc-429f-a38b-4f44e55773e6","added_by":"auto","created_at":"2026-01-29 00:51:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":138227,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage of refractive errors in our study\u003c/p\u003e","description":"","filename":"Percentageofrefractiveerrorsinourstudy.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8683113/v1/82bdd7a909d982615bbbd839.jpg"},{"id":101881425,"identity":"1f0ba6eb-1d6c-404a-8f1c-4384c7fc7a7c","added_by":"auto","created_at":"2026-02-04 15:12:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":775492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8683113/v1/21ab8105-d610-4554-9cac-f508a62add02.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Spectrum of Ophthalmic Disorders in Prader-Willi Syndrome: Implications for Early Screening and Multidisciplinary Management","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrader\u0026ndash;Willi syndrome (PWS) is a rare genetic disorder caused by the absence of expression of imprinted genes in the paternal chromosome 15q11.2\u0026ndash;q13 region[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although PWS is primarily characterized by hypotonia, hyperphagia, obesity, intellectual disability, and endocrine dysfunction. Ocular abnormalities are increasingly recognized as an important yet underappreciated component of the disease spectrum.\u003c/p\u003e \u003cp\u003eThe reported incidence of PWS in international studies ranges from 1 in 10,000 to 1 in 30,000, with no significant racial differences [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. At present, comprehensive epidemiological data on PWS in China are lacking. Although clinical scoring systems based on international criteria are widely used, diagnosis based solely on clinical features is prone to missed or incorrect diagnoses because of variability related to age, disease course, and ethnic background. Therefore, definitive diagnosis depends on molecular genetic testing.\u003c/p\u003e \u003cp\u003eGenetic testing is considered the gold standard for PWS diagnosis and is essential for determining the underlying genetic mechanism. Current diagnostic approaches include DNA methylation analysis, chromosomal microarray analysis (CMA), and detection of imprinting center defects. DNA methylation analysis can simultaneously identify paternal deletions, maternal uniparental disomy (UPD), and imprinting center defects, with a detection rate exceeding 99%, and is therefore recommended as the first-line diagnostic method for PWS. CMA further enables characterization of deletion size and breakpoints in deletion-type PWS and facilitates detection of isodisomy. If these tests yield negative results, imprinting center defects should be considered.\u003c/p\u003e \u003cp\u003ePrevious studies have reported that paternal deletions of the imprinting region account for approximately 70%\u0026ndash;80% of cases, maternal UPD for 20%\u0026ndash;30%, imprinting center mutations or microdeletions for 1%\u0026ndash;3%, while balanced chromosomal translocations and other rare mechanisms are exceedingly uncommon [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the present study, 22 cases (73.3%) were deletion type, 7 cases (23.3%) were UPD type, and 1 case (3.3%) was classified as other, findings that are consistent with those reported in the literature.\u003c/p\u003e \u003cp\u003eOcular manifestations in PWS are often overlooked in clinical practice, despite their potential impact on visual development, functional vision, and quality of life. Early identification and timely intervention may prevent irreversible visual impairment, particularly amblyopia and binocular dysfunction. However, systematic ophthalmic data in pediatric PWS populations, especially from Asian cohorts, remain limited. To characterize the spectrum of ophthalmic disorders in children with PWS and to evaluate the clinical value of early ophthalmic screening and intervention. A retrospective analysis was conducted on ophthalmic findings from 30 clinically and genetically diagnosed children with PWS who were followed at a tertiary pediatric center. Demographic data, genetic subtypes, ophthalmic examinations, and treatment outcomes were reviewed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eA total of 30 children clinically diagnosed with PWS were treated at the Children's Hospital of Zhejiang University School of Medicine between November 2024 and April 2025. The cohort comprised 17 males and 13 females. Genetic testing confirmed 22 cases of deletion subtype, 7 cases of maternal uniparental disomy (UPD), and one case of another subtype. The age at first diagnosis ranged from 4 months to 15 years and 7 months.\u003c/p\u003e \u003cp\u003eClinical data on manifestations, ophthalmic examinations, treatment, and follow-up were collected and comprehensively analyzed. All children exhibited neonatal hypotonia, feeding difficulties, limb weakness, and hypoactivity, with 5 requiring nasogastric tube feeding due to severe issues. Characteristic facial features\u0026mdash;almond-shaped eyes, small hands and feet, a small downturned mouth, and a prominent forehead\u0026mdash;were universally present. Concomitant conditions included a history of obesity (n\u0026thinsp;=\u0026thinsp;15), global developmental delay and cognitive dysfunction (n\u0026thinsp;=\u0026thinsp;26), cryptorchidism in males (n\u0026thinsp;=\u0026thinsp;13, with 10 undergoing orchiopexy), scoliosis (n\u0026thinsp;=\u0026thinsp;12), bilateral hip subluxation (n\u0026thinsp;=\u0026thinsp;1), and significant sleep snoring (n\u0026thinsp;=\u0026thinsp;11).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eThis research collected data from 30 children diagnosed with PWS who were evaluated in outpatient clinics. Collected information included demographic characteristics, genetic testing results, comprehensive medical histories, and detailed ophthalmologic examination findings. Best-corrected visual acuity (BCVA) was measured using a 5-meter Snellen chart and converted to logarithm of the minimum angle of resolution (LogMAR) values for analysis. All participants underwent rapid cycloplegia with compound tropicamide. Final refractive status was determined by an experienced optometrist using retinoscopy, with reference to autorefractor measurements. Refractive errors were classified as follows: myopia (spherical equivalent [SE]\u0026thinsp;\u0026le;\u0026thinsp;\u0026minus;\u0026thinsp;0.50 D), including low (\u0026minus;\u0026thinsp;3.00 D\u0026thinsp;\u0026lt;\u0026thinsp;SE\u0026thinsp;\u0026le;\u0026thinsp;\u0026minus;\u0026thinsp;0.50 D), moderate (\u0026minus;\u0026thinsp;6.00 D\u0026thinsp;\u0026lt;\u0026thinsp;SE\u0026thinsp;\u0026le;\u0026thinsp;\u0026minus;\u0026thinsp;3.00 D), and high myopia (SE\u0026thinsp;\u0026le;\u0026thinsp;\u0026minus;\u0026thinsp;6.00 D); hyperopia (SE\u0026thinsp;\u0026ge;\u0026thinsp;+\u0026thinsp;2.00 D), including low (+\u0026thinsp;2.00 D\u0026thinsp;\u0026le;\u0026thinsp;SE\u0026thinsp;\u0026lt;\u0026thinsp;+\u0026thinsp;5.00 D), moderate (+\u0026thinsp;5.00 D\u0026thinsp;\u0026le;\u0026thinsp;SE\u0026thinsp;\u0026lt;\u0026thinsp;+\u0026thinsp;7.00 D), and high hyperopia (SE\u0026thinsp;\u0026ge;\u0026thinsp;+\u0026thinsp;7.00 D); and astigmatism (cylinder\u0026thinsp;\u0026ge;\u0026thinsp;1.00 D), classified as low (1.00 D\u0026thinsp;\u0026le;\u0026thinsp;cylinder\u0026thinsp;\u0026lt;\u0026thinsp;2.00 D), moderate (2.00 D\u0026thinsp;\u0026le;\u0026thinsp;cylinder\u0026thinsp;\u0026lt;\u0026thinsp;3.00 D), or high (cylinder\u0026thinsp;\u0026ge;\u0026thinsp;3.00 D).\u003c/p\u003e \u003cp\u003eStrabismus was assessed using the cover\u0026ndash;uncover test, prism alternate cover test, or Hirschberg/Krimsky test, depending on the child\u0026rsquo;s level of cooperation. A diagnosis of strabismus required an objective ocular deviation of at least 10 prism diopters, confirmed in at least one objective examination and independently verified by two strabismus specialists. Axial length and corneal curvature were measured using the IOLMaster 700. Anterior segment structures were evaluated by slit-lamp biomicroscopy, while fundus examinations were performed using ultra-widefield laser scanning ophthalmoscopy (OPTOS PLC P200DTx). Tear film parameters were assessed with a corneal topographer (OCULUS 77000), and stereopsis was evaluated using standardized stereo test cards (Stereo Optical Co., USA). All clinical and genetic data were extracted from standardized medical records and systematically organized to create a complete dataset for subsequent comprehensive analysis.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eThe principal ocular manifestations included extraocular muscle abnormalities, refractive errors, ptosis, nystagmus, retinal and optic nerve lesions, as well as other abnormalities such as iris pigmentation disorders (e.g., heterochromia), abnormal tear secretion, increased risk of dry eye, and impaired stereoacuity. In this cohort, strabismus was identified in 9 of 30 children (30.0%), including 5 cases of exotropia and 4 cases of esotropia (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Refractive assessment could not be completed in 2 children because of poor cooperation; among the remaining 28 children, refractive abnormalities included high myopia in 2 cases (4 eyes), moderate myopia in 1 case (1 eye), high astigmatism in 2 cases (3 eyes), and moderate hyperopia in 5 cases (10 eyes).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAxial length abnormalities were observed in 8 cases, with excessive elongation in 2 children (maximum values of 27.22 mm and 27.10 mm) and abnormally short axial lengths in 6 children (minimum values of 18.86 mm and 18.85 mm), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Corneal curvature was increased in 5 cases (maximum keratometry value, 49.47 D) and decreased in 5 cases (minimum, 40.06 D). Three children exhibited uneven or reduced iris pigmentation, and 4 showed irregular macular pigmentation.\u003c/p\u003e \u003cp\u003eTear film assessment was successfully completed in 12 children, all of whom demonstrated reduced tear parameters: the mean tear film break-up time was 7.60 s in the right eye and 4.57 s in the left eye, while the mean tear meniscus height was 0.075 mm and 0.0725 mm in the right and left eyes, respectively. One child presented with bilateral ptosis, and another exhibited latent nystagmus. Among the 7 children who were able to complete stereoacuity testing, 6 (85.7%) demonstrated impaired stereopsis. No optic nerve or retinal lesions were detected in this cohort.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOf the 9 children with refractive errors complicated by amblyopia, 5 were able to cooperate with spectacle correction and amblyopia training. Four children underwent surgical correction for strabismus. Those with tear film abnormalities received treatment with artificial tears. In addition, 28 children received growth hormone therapy in combination with dietary intervention. Three children diagnosed with hypothyroidism were treated with oral levothyroxine sodium, resulting in normalization of thyroid function.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe clinical manifestations of PWS are complex, multisystemic, and age dependent. During the neonatal period, the predominant features include severe hypotonia, weak sucking, feeding difficulties, and reduced spontaneous crying and movement. In early childhood, hyperphagia gradually develops and often leads to obesity. As patients age, additional manifestations such as short stature, hypogonadism, intellectual disability, and behavioral abnormalities become increasingly evident. Endocrine dysfunction in PWS primarily results from abnormalities of the hypothalamic\u0026ndash;pituitary\u0026ndash;target gland axis. The hypothalamus regulates the secretion and release of anterior and posterior pituitary hormones via neural and vascular pathways; dysfunction of this system contributes to endocrine disorders such as growth hormone deficiency and hypogonadism. Moreover, hypothalamic dysfunction affects thermoregulation, appetite control, sleep, emotional regulation, and other autonomic nervous system functions, thereby contributing to characteristic behavioral abnormalities.\u003c/p\u003e\n\u003cp\u003eCompared with other systemic manifestations, ophthalmologic involvement in PWS has received relatively limited attention in both domestic and international literature, and current understanding remains incomplete. Nevertheless, available clinical reports and published studies suggest that individuals with PWS may exhibit multiple visual abnormalities. Strabismus is the most frequently reported ocular abnormality in PWS [5\u0026ndash;8]. Reported prevalence varies widely, ranging from 52% to 62% in some studies [9\u0026ndash;12], while others report lower rates of 28%\u0026ndash;37% [13,14] or as high as 95% [15,16]. A 2021 analysis of data from the global PWS Comprehensive Registry, including 908 participants aged 0\u0026ndash;62 years, reported a strabismus prevalence of 40%, with 91% of cases diagnosed before 5 years of age. Among affected individuals, 86% underwent a single strabismus surgery and 10.1% required more than one surgical intervention [17]. In the present study, strabismus was identified in 9 children (30%), including 4 cases of esotropia and 5 cases of exotropia.\u003c/p\u003e\n\u003cp\u003eThe underlying pathogenesis of strabismus in PWS is likely multifactorial. PWS is caused by functional defects of imprinted genes within the paternal chromosome 15q11.2\u0026ndash;q13 region, leading to abnormal development of multiple systems, including the hypothalamus, visual pathways, and extraocular muscles. Endocrine abnormalities, such as growth hormone deficiency and thyroid dysfunction, may further impair ocular structural development, resulting in extraocular muscle dysplasia, abnormal neural innervation, and binocular fusion dysfunction, all of which may contribute to the development of strabismus. Refractive errors and anisometropia may also play a role; however, in the present cohort, only one case of strabismus was clearly attributable to refractive error, while other cases showed no such association.\u003c/p\u003e\n\u003cp\u003eRefractive errors\u0026mdash;including myopia, hyperopia, and astigmatism\u0026mdash;as well as amblyopia, are also common visual abnormalities in patients with PWS. Multiple studies have demonstrated that the prevalence of refractive errors and amblyopia in PWS is substantially higher than that in the general population. One study involving 46 patients reported refractive errors in 32 cases (69.6%), including myopia greater than 3.75 D in 15% and astigmatism greater than 1.25 D in 41% of patients [18]. Similarly, the 2021 global PWS registry study reported prevalences of 41% for myopia, 25% for hyperopia, 25% for astigmatism, and 16% for amblyopia [17].\u003c/p\u003e\n\u003cp\u003eIn the present study, refractive errors were identified in 14 children (46.7%), including 7 cases (23.3%) of myopia, 7 cases (23.3%) of hyperopia, and 5 cases (16.7%) of astigmatism. Amblyopia was diagnosed in 5 children (16.7%), including cases associated with moderate-to-high myopia (3 cases, 5 eyes), high astigmatism (2 cases, 3 eyes), and moderate-to-high hyperopia (5 cases, 10 eyes), as shown in Fig. 3.\u003c/p\u003e\n\u003cp\u003eThe high prevalence of refractive abnormalities in PWS may be related to growth hormone deficiency and other endocrine disturbances that affect ocular morphological development, including abnormal axial length growth, corneal curvature alterations, and impaired lens accommodation. In addition, systemic comorbidities such as obesity and diabetes may further exacerbate refractive development. Excessive or insufficient axial elongation can lead to myopia or hyperopia, while corneal curvature abnormalities contribute to astigmatism. Furthermore, nervous system dysfunction in PWS may interfere with normal ocular motor regulation and innervation.\u003c/p\u003e\n\u003cp\u003eThe elevated incidence of amblyopia in PWS is likely attributable to multiple factors, including deprivation amblyopia secondary to ptosis, strabismic amblyopia, and refractive amblyopia. As a genetic disorder, PWS may also impair central nervous system processing and integration of visual information, thereby disrupting normal visual development and increasing the risk of amblyopia.\u003c/p\u003e\n\u003cp\u003eFig. 3 Percentage of refractive errors in our study.\u003c/p\u003e\n\u003cp\u003eIn addition to strabismus and refractive errors, a wide spectrum of other ocular abnormalities has been reported in patients with PWS, including ptosis, nystagmus, iris hypopigmentation, cataracts, congenital fibrosis of the extraocular muscles, diabetic retinopathy, congenital uveal ectopia, and a flat macula with fundus hypopigmentation. Abnormal development of stereoacuity has also been frequently documented in individuals with PWS [14].\u003c/p\u003e\n\u003cp\u003eIn the present study, iris pigmentation abnormalities were observed in 3 cases, fundus pigmentation abnormalities in 4 cases, bilateral ptosis in 1 case, nystagmus in 1 case, tear secretion abnormalities in 12 cases, and stereoacuity developmental abnormalities in 6 cases.\u003c/p\u003e\n\u003cp\u003ePrevious studies have demonstrated that the molecular basis underlying the association between PWS, hypopigmentation, and chromosomal deletions can be explained by the close proximity of the PWS critical region (15q11\u0026ndash;q13) to the gene responsible for oculocutaneous albinism type 2 (OCA2; 15q11.2\u0026ndash;q12) [19,20]. The OCA2 gene encodes the transmembrane P protein, which regulates the intracellular distribution of tyrosinase. Consequently, hypopigmentation in PWS is considered an incomplete form of tyrosinase-positive albinism. Subsequent studies by Wiesner et al. [21] and Hered et al. [22] identified iris transillumination defects in 33% and 72% of PWS patients, respectively, findings that were strongly associated with chromosomal deletions. Hittner et al. [23] were the first to systematically analyze iris pigmentation abnormalities in PWS and reported that all patients with deletions involving the 15q11\u0026ndash;q13 region exhibited iris hypopigmentation. Furthermore, Creel et al. [24] reported optic nerve axon misrouting consistent with visual evoked cortical potential (VECP) criteria for albinism in several PWS cases, suggesting that pigmentary abnormalities in PWS may share pathophysiological mechanisms with fully expressed oculocutaneous albinism.\u003c/p\u003e\n\u003cp\u003eTear film assessment in our cohort revealed that all 12 children who were able to cooperate exhibited reduced tear secretion. The mean tear film break-up time was 7.60 s in the right eye and 4.57 s in the left eye, while the mean tear meniscus height was 0.075 mm and 0.0725 mm, respectively. Decreased tear secretion in PWS may be attributable to hypothalamic dysfunction. As the hypothalamus plays a central role in regulating fluid balance and autonomic function, its impairment may disrupt lacrimal gland regulation, leading to tear film insufficiency.\u003c/p\u003e\n\u003cp\u003eAmong the 7 children who completed stereoacuity testing, 6 (81.7%) demonstrated abnormal stereopsis. Impaired stereoacuity in PWS likely results from the combined effects of genetic defects, neurodevelopmental abnormalities, ocular structural lesions, and behavioral factors. Strabismus disrupts binocular retinal correspondence, thereby impairing the foundation for stereopsis; prolonged strabismus may further lead to amblyopia, exacerbating stereoacuity deficits. Refractive errors and anisometropia interfere directly with binocular visual integration, while cognitive impairment common in PWS may reduce attention, compromise sustained binocular fixation, and hinder normal stereoacuity development.\u003c/p\u003e\n\u003cp\u003eInterestingly, previous studies comparing genetic subtypes of PWS have reported a higher prevalence of strabismus in the maternal uniparental disomy (UPD) group than in the deletion group (53% vs. 39%; \u003cem\u003ep\u003c/em\u003e = 0.03). In contrast, among the 30 cases in our study, strabismus was observed in 2 patients in the UPD group and 6 patients in the deletion group. This discrepancy may be attributable to the relatively small sample size of the present study, underscoring the need for larger cohorts to validate genotype\u0026ndash;phenotype correlations. Notably, all cases with iris and fundus pigmentation abnormalities in our cohort were of the deletion type, consistent with previous reports and likely reflecting haploinsufficiency of the OCA2 gene within the 15q11\u0026ndash;q13 region [21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEarly ophthalmic evaluation\u0026mdash;including assessment of ocular alignment, refractive status, fundus examination, stereoacuity, and tear secretion\u0026mdash;combined with multidisciplinary intervention involving ophthalmology, neurology, endocrinology, and rehabilitation medicine, is critical for improving visual function and quality of life in patients with PWS. Given the multisystem nature of the disease, management should adopt a comprehensive, age-specific, and phenotype-oriented approach, incorporating timely endocrine therapy and targeted ophthalmic interventions. Considering the high prevalence of potentially treatable ocular abnormalities in PWS, we recommend that all patients with PWS undergo routine ophthalmologic screening, with early detection and intervention to prevent irreversible visual impairment, such as amblyopia.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOphthalmic abnormalities are common and potentially treatable in children with PWS. Early ophthalmic evaluation and multidisciplinary management may improve visual outcomes and quality of life. Routine ophthalmic screening should be incorporated into the standard care of patients with PWS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInformed consent: Was obtained from parents of each patient included in the study.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHua and Caiping Shi conceived and designed the present study. Yanhong Ren performed general condition inspection and follow-up management. Jiajun Wang performed the optical examination. Huixia Hua and Caiping Shi performed the data collection. Huixia Hua and Jiayue Zhou performed the analysis and interpretation. Huixia Hua and Caiping Shi wrote the manuscript. Caiping Shi and Wen Sun provided critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis study received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e This study was approved by the Ethics Committee of the Children\u0026rsquo;s Hospital, Zhejiang University School of Medicine (Ethics Approval No. 2025-IRB-0412-P-01), and written informed consent was obtained from the parents or legal guardians of all participating children in accordance with the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eWas obtained from parents of each patient included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e There is no potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e None.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePrader A, Labhart A, Willi H (1956) Ein Syndrom von Adipositas, Klein-wuchs, Kryptorchidismus und Oligophrenie nach myotonier-tigem Zustand im Neugerborenenalter. Schweiz Med Wochenschr 86:1260\u0026ndash;1261\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCassidy SB, Schwartz S, Miller JL, et a, Driscoll DJ Prader-Willi syndrome. Genet Med, 2012Jan, 14(1): 10\u0026ndash;26\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVogels A, Ende J, Van Den, Keymolen K, Mortier G, Devriendt K, Legius E, Fryns JP Minimum prevalence, birth incidence, and cause of death for Prader-Willi syndrome in Flanders. Eur J Hum Genet 2004Mar, 12(3):238\u0026ndash;240\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheon CK Genetics of Prader-Willi syndrome and Prader-Will-like syndrome. Ann Pediatr Endocrinol Metab 2016Sep ;21(3):126\u0026ndash;135\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBistrian BR, Blackburn GL, Stanbury JB Metabolic aspects of a protein-sparing modified fast in the dietary management of Prader-Willi obesity. N Engl J Med 1977Apr 7; 296(14):774\u0026ndash;779\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraccaro M, Zuffardi O, Buhler EM, Jurik LP (1977) 15/15 translocation in Prader-Willi syndrome. M ed Genet 14(4):275\u0026ndash;276\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler MG, Weaver DD, Meaney FJ (1982) Prader-Willi syndrome: are there population differences? Clin Genet 22(5):292\u0026ndash;294\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoy MS, Milot JA, Polomeno RC, Barsoum-Homsy M (1992) Ocular findings and visual evoked potential response in the Prader-Willi syndrome. Can J Ophthalmol 27(6):307\u0026ndash;312\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiesner GL, Bendel CM, Olds DP, White JG, Arthur DC, Ball DW (1987) King R A. Hypopigmentation in the Prader-Willi syndrome. Am J Hum Genet 40(5):431\u0026ndash;442\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHered RW, Rogers S, Zang YF, Biglan AW (1988 May-Jun) Ophthalmologic features of Prader-Willi syndrome. J Pediatr Ophthalm ol Strabismus 25(3):145\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler MG (1990) Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet 35(3):319\u0026ndash;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler JV, 1, Whittington JE, Holland AJ, Boer H, Clarke D, Webb T (2002) Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: a population-based study. Dev Med Child Neurol 44(4):248\u0026ndash;255\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZellweger H, Schneider HJ (1968) Syndrome of hypotonia-hypomentia-hypogonadism-obesity (HHHO) or Prader-Willi syndrome. Am J Dis Child 115(5):588\u0026ndash;598\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFox 1 R, Sinatra RB, Mooney MA, Feurer ID, Butler MG (1999 Nov-Dec) Visual capacity and Prader-Willi syndrome. J Pediatr Ophthalmol Strabismus 36(6):331\u0026ndash;336\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBray GA, Dahms WT, Swerdloff RS, Fiser RH, Atkinson RL, Carrel RE (1983) The Prader-Willi syndrome: a study of 40 patients and a review of the literature. Med (Baltim) 62(2):59\u0026ndash;80\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobinson 1 WP, Bottani A, Xie YG, Balakrishman J, Binkert F, M\u0026auml;chler M, Prader A (1991) A Schinzel.Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients. Am J Hum Genet 49(6):1219\u0026ndash;1234\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohonowych JE, Vrana-Diaz CJ, Miller JL, McCandless SE, Strong TV (2021) Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry. BMC Ophthalmol 21(1):296\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHered 1RW, Rogers S, Zang YF, Biglan AW (1988 May-Jun) Ophthalmologic features of Prader-Willi syndrome. J Pediatr Ophthalmol Strabismus 25(3):145\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee ST, Nicholls RD, Bundey S et al (1994) Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism. N Engl J Med 330(8):529\u0026ndash;534\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler MG, Hypopigmentation A common feature of Prader-Labhart-Willi syndrome. Am J Hum Genet 1989 Jul 45(1): 140\u0026ndash;146\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiesner GL, Bendel CM, Olds DP et al (1987) Hypopigmentation in the Prader-Willi syndrome. Am J Hum Genet 40(5):431\u0026ndash;442\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHered RW, Rogers S, Zang YF et al Ophthalmologic features of Prader-Willi-syndrome. J Pediatr Ophthalmol Strabismus 1988 May-Jun 25(3):145\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHittner HM, King RA, Riccardi VM et al (1982) Oculocutaneous albinoidism as a manifestation of reduced neural crest derivatives in the Prader-Willi syndrome. Am J Ophthalmol 94(3):328\u0026ndash;337\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCreel DJ, Bendel CM, Wiesner GL et al Abnormalities of the central visual pathway in Prader-Willi syndrome associated with hypopigmentation. N Engl J Med 1986Jun 19; 314(25): 1606\u0026ndash;1609\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8683113/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8683113/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo characterize the spectrum of ophthalmic disorders in children with Prader\u0026ndash;Willi syndrome (PWS) and to evaluate the clinical value of early ophthalmic screening and intervention.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A retrospective analysis was conducted on ophthalmic findings from 30 clinically and genetically diagnosed children with PWS who were followed at a tertiary pediatric center. Demographic data, genetic subtypes, ophthalmic examinations, and treatment outcomes were reviewed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOphthalmic abnormalities included extraocular muscle disorders, refractive errors, amblyopia, ptosis, nystagmus, retinal and optic nerve pigmentation abnormalities, tear secretion dysfunction, and impaired stereoacuity. Strabismus was identified in 9 patients (30%), including 4 cases of esotropia and 5 cases of exotropia. Refractive errors were present in 14 patients (46.7%), comprising myopia (23.3%), hyperopia (23.3%), and astigmatism (16.7%). Amblyopia was diagnosed in 5 patients (16.7%). Tear film assessment in 12 cooperative patients demonstrated reduced tear break-up time and tear meniscus height. Stereoacuity abnormalities were detected in 6 of 7 cooperative patients (85.7%). Management included refractive correction, amblyopia therapy, strabismus surgery, and artificial tear supplementation.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOphthalmic abnormalities are common and potentially treatable in children with PWS. Early ophthalmic evaluation and multidisciplinary management may improve visual outcomes and quality of life. Routine ophthalmic screening should be incorporated into the standard care of patients with PWS.\u003c/p\u003e","manuscriptTitle":"Spectrum of Ophthalmic Disorders in Prader-Willi Syndrome: Implications for Early Screening and Multidisciplinary Management","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 00:51:00","doi":"10.21203/rs.3.rs-8683113/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4a79100-f28b-4f7f-9f06-edcd808ff746","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-03T17:40:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 00:51:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8683113","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8683113","identity":"rs-8683113","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}