Vitreoretinal manifestations in Gorlin–Goltz syndrome: A case report

INTRODUCTION

Gorlin–Goltz syndrome (GGS), also known as nevoid basal cell carcinoma syndrome (NBCCS), is a rare autosomal dominant disorder characterised by high penetrance and variable expressivity, affecting multiple organ systems, including the ocular structures.^[1,2] Mutations in the PTCH1 tumour suppressor gene, located on chromosome 9q21–23, represent the principal genetic cause of the syndrome.^[2] The PTCH1 gene functions as a key negative regulator of the hedgehog (HH) signalling pathway, and its dysfunction leads to aberrant cellular proliferation, impaired tissue differentiation, and the development of multisystem structural abnormalities.^[3]

Ocular manifestations of GGS are heterogeneous and may involve the anterior or posterior segment. Although retinal involvement is relatively uncommon, abnormalities at the vitreoretinal interface, such as epiretinal membrane formation and hamartomatous lesions, have been attributed to PTCH1-related dysregulation during retinal development.^[3] These findings are thought to reflect altered glial cell proliferation and disrupted retinal organisation mediated by aberrant HH signalling. At the vitreoretinal level, reported lesions may present with variable morphology and distribution, underscoring the importance of detailed fundus examination and multimodal retinal imaging for accurate characterisation.^[3,4] Differentiation from other retinal pathologies is essential, as glial-derived lesions and hamartomatous changes may mimic more aggressive or progressive conditions. Comprehensive assessment allows appropriate clinical interpretation, guides follow-up strategies, and helps avoid unnecessary interventions.

In this report, we describe a genetically confirmed case of Gorlin–Goltz syndrome with characteristic systemic features and detailed multimodal documentation of vitreoretinal alterations, including epiretinal membranes and focal retinal glial lesions. This case highlights the importance of systematic retinal evaluation in patients with GGS and contributes to the growing understanding of the spectrum of vitreoretinal involvement associated with this rare condition.

CASE REPORT

A 22-year-old Hispanic woman attended for a routine ophthalmic examination. There was no relevant family history. The past medical history included resection of a maxillary odontogenic cyst [Figure 1a] and unilateral oophorectomy for an ovarian fibroma [Figures 1b and c]. Cranial computed tomography (CT) demonstrated calcification of the falx cerebri and tentorium cerebelli.

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Figure 1:

A 22-year-old hispanic woman with Gorlin–Goltz syndrome who attended for a routine ophthalmic examination. (a): Panoramic radiograph demonstrating dental crowding and a well-defined radiolucent lesion, consistent with a keratocystic odontogenic tumour (red arrow). (b): Gross specimen from a left oophorectomy showing an ovarian fibroma with a firm, whitish, fibrotic cut surface and focal cystic degeneration. (c) High-magnification photomicrograph (Haematoxylin and eosin, 50x) revealing lobulated fibrosis composed of spindle-shaped fibroblastic cells within a collagenous stroma, without histopathological evidence of malignancy.

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On physical examination, the patient was alert, cooperative and systemically stable. The inner canthal distance measured 34 mm, consistent with first-degree hypertelorism according to Tessier’s classification^[4] [Figure 2a]. Palmar and plantar pits were present [Figure 2b]. Nodular, hyperpigmented lesions, approximately 1.5 mm in diameter, were observed on the left upper and lower eyelids [Figure 2c].

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Figure 2:

A 22-year-old hispanic woman with Gorlin–Goltz syndrome who attended for a routine ophthalmic examination. (a): Grade 1 Tessier hypertelorism with an intercanthal distance of 34 mm. (b): Multiple palmar pits (red arrows), a characteristic cutaneous feature of Gorlin–Goltz syndrome. (c) Pigmented nodular lesion on the lower left eyelid, consistent with adnexal involvement.

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Best-corrected visual acuity was 20/25 bilaterally. Intermittent exotropia was noted, while slit-lamp biomicroscopy showed a normal anterior segment.

Fundus examination demonstrated three similar, small, whitish, nodular, slightly elevated micro-retinal lesions, each mildly elevated and measuring ≤0.5mm in basal diameter and ≤1mm in thickness. Two lesions were located just superior to the fovea, and one was situated immediately temporal to the superior vascular arcade [Figures 3a and b]. A bilateral cellophane reflex suggested epiretinal membranes [Figures 3c and d]. Fundus autofluorescence demonstrated hypoautofluorescence in all lesions. Fluorescein angiography revealed blocking-related hypofluorescence in the superior perifoveal lesion and staining hyperfluorescence in the inferior lesions, with a normal angiogram in the left eye.

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Figure 3:

A 22-year-old hispanic woman with Gorlin–Goltz syndrome who attended for a routine ophthalmic examination. (a and b): Ultra-widefield colour fundus imaging and fundus autofluorescence of the right eye showing foveal, parafoveal and superotemporal lesions, all demonstrating hypoautofluorescence. (c and d): Clinical imaging of the left eye revealing a macular cellophane-like sheen, without corresponding abnormalities on autofluorescence.

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Spectral-domain optical coherence tomography showed a hyperreflective layer on the retinal surface of both eyes, consistent with epiretinal membranes. In the right eye, medium-to-high reflectivity was seen in the vitreous over the superior perifoveal region. Full-thickness hyperreflective intraretinal lesions were observed in the foveal and parafoveal areas, producing posterior shadowing and foveal depression loss, with preservation of the outer retinal layers [Figures 4a-d]. These features [Table 1] were suggestive of possible retinal micro-hamartomas or solitary circumscribed retinal astrocytic proliferations (SCRAP).

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Figure 4:

A 22-year-old hispanic woman with Gorlin–Goltz syndrome who attended for a routine ophthalmic examination. (a-c): Spectral-domain optical coherence tomography (OCT) scans of the right eye at the foveal, superior parafoveal and superotemporal levels, respectively, showing: (a) An epiretinal membrane; (b) a hyperreflective intraretinal lesion extending through the full retinal thickness, consistent with an astrocytic hamartoma; and (c) a hyperreflective lesion protruding into the vitreous. (d) Spectral-domain OCT scan of the left eye demonstrating an epiretinal membrane.

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Genetic analysis confirmed a pathogenic mutation in PTCH1 (NM_000264.5:c.1602+2T>*), thereby establishing a molecular diagnosis of GGS.

DISCUSSION

GGS, also known as NBCCS, is a rare autosomal dominant disorder characterised by the early onset of basal cell carcinomas (BCC), most commonly affecting the facial region. The condition involves multisystem abnormalities, resulting in a wide phenotypic spectrum. The estimated prevalence ranges from 1:57,000 to 1:254,000, with no sex predilection.^[2,4]

The clinical manifestations of GGS are extensive and diagnostic criteria are classically divided into major and minor categories. Major criteria include: (1) more than two BCC, or one BCC occurring at ≤20 years of age (71.7%); (2) histologically confirmed odontogenic keratocysts (74%); (3) ≥2 palmar or plantar pits, the most frequent clinical sign (77%); (4) ectopic intracranial calcifications, particularly of the falx cerebri (65%); (5) rib anomalies; and (6) a positive family history of GGS. Minor criteria include: (1) Macrocephaly; (2) medulloblastoma, most frequently diagnosed before the age of seven; (3) skeletal anomalies such as Sprengel deformity, syndactyly, polydactyly, vertebral segmentation defects or bridging of the sella turcica; (4) ocular alterations such as strabismus (60%), hypertelorism (45.5%), epiretinal membranes (36%), myelinated retinal nerve fibre layers (36%), congenital cataract (18%), coloboma (9%), nystagmus (9%) and microphthalmia; (5) PTCH1 mutation; (6) cardiac fibromas (3%) or ovarian fibromas (17%); and (7) cleft lip and palate.^[1,4-6] A diagnosis is established when two major criteria, or one major and two minor criteria, are fulfilled. Genetic testing, when available, provides confirmation.^[2,3,7,8]

Patients suspected of having GGS should undergo a comprehensive baseline systemic evaluation, including brain CT or magnetic resonance imaging (MRI), cardiac ultrasound, pelvic ultrasound in females, spinal radiography and orthopantomography.^[7] In individuals at risk –particularly children – skull, rib and spine radiographs are advised to detect congenital skeletal anomalies such as bifid, fused or accessory ribs or vertebral malformations. Due to the risk of medulloblastoma in childhood, neurological follow-up every 6 months with annual MRI until the age of 7 is strongly recommended. Dermatological surveillance is also essential throughout life, beginning in childhood, with increased frequency during and after adolescence.^[8]

This patient exhibited several characteristic features, including hypertelorism, palmar pits, strabismus and retinal abnormalities. At the vitreoretinal level, bilateral epiretinal membranes were noted, along with three unilateral micro-retinal hamartomas without feeder vessels or subretinal fluid, displaying features consistent with SCRAPs. SCRAPs are rare retinal lesions derived from retinal glial cells and have been previously reported in association with GGS in only a single patient, as well as in isolated solitary presentations.^[7]

SCRAP lesions are typically unilateral, whitish yellow, opaque and abruptly appearing, and they are not associated with feeder vessels, intrinsic vasculature, vitreoretinal traction or systemic disease. Differentiation from similar retinal entities is essential. Astrocytic hamartomas generally originate from the nerve fibre layer, may show dragging, intrinsic vessels and can present bilaterally. Acquired retinal astrocytomas, representing reactive gliosis following trauma or infection, may demonstrate intrinsic vasculature and exudation. Retinoblastoma arises from the outer nuclear layer and should also be considered in the differential diagnosis. In contrast, SCRAP lesions remain stable over time and do not exhibit progressive enlargement.^[7]

While radiographic evaluation revealed a unilocular mandibular lesion consistent with a keratocystic odontogenic tumour. These ocular and systemic findings correlated with a pathogenic mutation in the PTCH1 gene, which encodes the Patched receptor, a key component of the HH signalling pathway. PTCH1 functions as a negative regulator of the HH pathway and plays a central role in embryogenesis, morphogenesis and retinal differentiation. Mutations lead to pathway dysregulation and have been implicated in the development of medulloblastoma, basal cell carcinoma, rhabdomyosarcoma and a range of gastrointestinal malignancies.^[9,10] Additional susceptibility genes include SUFU (chromosome 10q) and PTCH2 (chromosome 1p), with SUFU variants associated with a significantly increased risk of medulloblastoma.^[4,9]

The three mammalian HH ligands – Desert HH, Indian HH and Sonic HH (SHH) – play distinct but overlapping roles in tissue development, with SHH being the most widely studied.^[2,9] Ligand binding to PTCH1 triggers downstream signalling essential for cell differentiation, organogenesis and stem cell maintenance. Conversely, pathway dysregulation promotes neoplastic transformation, contributing to malignancies such as basal cell carcinoma, medulloblastoma, glioma, pancreatic adenocarcinoma, small-cell lung cancer and oesophageal carcinoma.^[9] Advances in understanding this molecular cascade have facilitated the development of targeted therapies, including vismodegib, the first food and drug administration -approved HH pathway inhibitor (2013), offering promising therapeutic potential in selected patients.^[7]

CONCLUSION

GGS is a hereditary disorder that requires multidisciplinary management. Although ocular manifestations are relatively uncommon, they may compromise visual function and can serve as early diagnostic indicators. Both GGS and SCRAP lesions are rare entities, and a previously unrecognised association between them may exist. Annual follow-up with multimodal imaging is advisable to monitor for structural changes, as these lesions typically remain stable over time; this includes assessment for alterations in membrane configuration, retinal thickening or the development of vitreoretinal traction. Patients should also undertake home monitoring with an Amsler grid to detect early metamorphopsia or other functional changes. Long-term surveillance involving dermatology, neurology, dentistry and ophthalmology is recommended. Given the increased risk of malignancy, strict sun protection and avoidance of ionising radiation are strongly advised.