Comprehensive Clinical Presentation in a Case of Coexisting Sturge-Weber Syndrome and Neurofibromatosis Type 1

ABSTRACT

Neurofibromatosis Type 1 (NF1) and Sturge-Weber syndrome (SWS) are both genetic disorders with distinct clinical manifestations. NF1 is characterized by multiple neurofibromas, café-au-lait spots, axillary freckling, and potential optic gliomas due to mutations in the NF1 gene on chromosome 17. In contrast, SWS is marked by capillary malformations, leptomeningeal angiofibromas, and congenital glaucoma resulting from post-zygotic mutations in the Guanine Nucleotide-Binding Protein (G Protein), subunit Alpha (GNAQ) gene. Here, we report an exceptional coexistence of both NF1 and SWS. The patient displayed multiple café-au-lait spots, neurofibromas, axillary freckling, fulfilling the criteria for NF1. Concurrently, the patient exhibited a port-wine stain in the periorbital territory aligning with the clinical features of SWS.

Introduction

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders, affecting approximately 1 in 3,000 individuals worldwide.^1,2 This condition is marked by the presence of multiple café-au-lait spots, neurofibromas, Lisch nodules, and an increased risk of developing various tumors, including optic pathway gliomas and malignant peripheral nerve sheath tumors.³ The diagnosis of NF1 is typically based on clinical criteria established by the National Institutes of Health (NIH), which include six or more café-au-lait macules, two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal freckling, optic glioma, two or more Lisch nodules, a distinctive osseous lesion, and a first-degree relative with NF1.⁴ NF1 is caused by mutations in the NF1 gene located on chromosome 17q11.2, which encodes neurofibromin, a protein involved in the regulation of cell growth.^3,5

Sturge-Weber syndrome (SWS) is a rare, sporadic neurocutaneous disorder with an incidence of approximately 1 in 20,000 to 50,000 live births.^6,7 It is characterized by a facial port-wine stain (a birthmark caused by capillary malformations), neurological abnormalities such as seizures and intellectual disability, and ophthalmological issues like glaucoma.⁷ The diagnosis of SWS is primarily clinical, involving the recognition of these key features. Imaging studies, such as Magnetic Resonance Imaging (MRI), can reveal characteristic leptomeningeal angiomas (abnormal blood vessels in the brain’s leptomeninges).⁸ The exact cause of SWS is not fully understood, but it is believed to be related to somatic mosaic mutations in the GNAQ gene, which leads to abnormal blood vessel development.^7,8

We report an 18-year-old female with both NF1 and SWS, presenting with a significant periorbital hemangioma, multiple café-au-lait spots, and bilateral axillary and inguinal freckling. To our knowledge, this is the third documented case of an individual with the coexistence of NF1 and SWS.

2. Methods

2.1. Ethical considerations

The study was approved by the Institutional Review Board. Written informed consent was obtained from the patient.

3. Results

3.1. Clinical report

The patient is an 18-year-old female, natural, and a resident of Pará, who is under follow-up with genetics and ophthalmology services. She was born at 7 months via normal delivery, with no significant prenatal or postnatal complications reported, and no hospitalization after birth.

Her past medical history is unremarkable for childhood diseases and allergies. She has been referred due to the presence of a red birthmark on her face since childhood.

Dermatologic evaluation reveals multiple café-au-lait spots distributed across her body, with the largest spot measuring 13 cm on the left lower limb. In total, over 10 spots are present, with additional notable measurements including one spot of 2.3 cm and another of 1 cm on the back, a 6.5 cm spot on the right lower limb, a 0.5 cm spot on the left lower limb, a 3.4 cm spot on the abdomen, and three spots measuring 4 cm, 3 cm, and 1 cm on the left upper limb. She also exhibits bilateral axillary and inguinal freckling. Physical examination reveals a significant hemangioma in the periorbital region, affecting the right upper eyelid and the upper third of the right hemiface, with a maximum diameter of 14 cm. Photos from birth show that this lesion was congenital.

3.2. Ophthalmologic evaluation

One month prior to the consultation, she reported experiencing decreased visual acuity in her right eye as well as dyschromatopsia. Her mother also noted the onset of ptosis and strabismus in the right eye during the same period. She denies experiencing photopsias, trauma, or ocular pain.

Upon clinical admission, visual acuity was counting fingers at 0.5 m in the right eye and 1.0 in the left eye and dyschromatopsia in the right eye. The extensive choroidal detachment contributed to the dyschromatopsia and was associated with a relative afferent pupillary defect (RAPD). She presents with an exotropic deviation due to poor vision in the right eye, which aligns with a sensory exotropia (Figure S1). As ophthalmological findings of NF1, the patient had choroidal nodules on infrared examination and also several Lisch nodules on biomicroscopy.

Slit-lamp examination revealed a soft globe with mild sectoral nasal superior hyperemia, without anterior chamber reaction. Ultrasound findings demonstrated a homogeneous and hyperechoic mass. Gonioscopy showed an open angle visible at the scleral spur level, with no evidence of neovascularization. Detailed eye examination findings included a diffuse choroidal hemangioma in the right eye, serous retinal detachment in the nasal region obscuring the optic nerve, and hyperpigmentation of the trabecular meshwork and iridial processes. The left eye showed no lesions, a healthy optic disc and macula, and an open angle in all quadrants. The OCT findings reveal extensive serous detachment separating the inner retina from the retinal pigment epithelium (Figure S2). Consequently, this retinal detachment made it challenging to visualize the nerve head appearance during the fundus examination. Additionally, it was not possible to assess nerve fiber loss or color vision at this time. However, intraocular pressure measured using the Goldmann tonometer was 10 mmHg in the right eye and 12 mmHg in the left eye. In terms of color vision, the contralateral eye, tested with the Ishihara plates, showed normal results. The MRI study shows a choroidal hemangioma in the right eye (Figure S3). The patient has no neurofibromas, gliomas, or other findings in the central nervous system. Physical examination findings and additional tests are shown in Figure 1.

Figure 1.

Physical examination findings and complementary results.

(A) Hemangioma in the periorbital region affecting the right upper eyelid and upper third of the right hemiface (OD); (B) Café-au-lait spots; (C) Lisch nodules on biomicroscopic examination in the left eye (OE); (D) Color fundus photograph showing retinal detachment in the right eye (OD); (E) Ocular ultrasound indicating a diffuse choroidal hemangioma with a homogeneous, hyperechoic mass in the right eye (OD); (F) Choroidal nodules on infrared examination in the left eye (OE).

The proposed treatment plan initially included intravitreal injection of anti-VEGF (bevacizumab 0.05 mg) in a cycle of three doses every 4 weeks, aiming to reduce vascular leakage and choroidal hemangioma progression. Following this, brachytherapy was planned, with a fluorescein angiography examination to demarcate the region of highest leakage, optimizing plaque positioning for targeted treatment. Lastly, a reassessment of strabismus was scheduled, with a potential surgical approach for ocular realignment at a later stage. Given the complexity of these overlapping syndromes and their potential impact on ocular health, we recommend comprehensive ophthalmologic examinations every 3 months to monitor disease progression and treatment response. In this context, triggers for symptom exacerbation may include increased venous pressure, vascular permeability changes, or secondary complications from neurocutaneous involvement, all of which warrant close and continuous follow-up.

Discussion

Phakomatoses represent a diverse group of inherited disorders characterized by a wide range of clinical manifestations, including distinct lesions affecting the brain, skin, eyes, and other organs. Early identification of neuro-ophthalmic signs and symptoms is essential for ensuring prompt diagnosis and effective treatment. This category includes over 30 conditions, such as NF1 and SWS.⁹ In this study, we present the rare coexistence of both disorders in a single patient.

The patient presented with more than six café-au-lait spots, fulfilling one of the primary diagnostic criteria for NF1.^4,5 The presence of axillary freckling, choroidal, and Lisch nodules further supports the diagnosis of NF1. On the other hand, the patient also exhibited characteristics of SWS, a rare genetic condition marked by capillary malformations and leptomeningeal anomalies. The patient displayed a port-wine stain covering the territory of the trigeminal nerve, a classic clinical sign of SWS.

The patient’s complex presentation, including findings from the ophthalmologic tests and detailed dermatologic examination, underscores the unique challenges posed by the coexistence of NF1 and SWS. The concurrent presence in the same patient is reported for the third time in literature.^10,11 These findings underscore the importance of a comprehensive and multidisciplinary diagnostic approach for the appropriate management of patients with multiple genetic conditions. The comparison of clinical features of SWS and NF1 is shown in Table 1.

Table 1.

Comparison of clinical features of Sturge Weber, neurofibromatosis type 1 and our patient.

Clinical features	Sturge Weber (OMIM #185300)	Neurofibromatosis type 1 (OMIM #16220)	Our patient
Eyes and vision
Optic glioma	–	(+)	–
Glaucoma	(+)	–	–
Lisch nodules	–	+	+
Choroidal nodules.	–	+	+
Skin
Café-au-lait spots	(–)	+	+
Port-wine stain	+	–	+
Axillary freckling	–	+	+
Neurologic findings
Plexiform neurofibromas	–	+	–
Seizures	+	+	–

+: normally present; (+): sometimes present; −: absent; (−): normally absent.

Regarding ophthalmologic findings in SWS, the most common is glaucoma, which can be congenital or develop later in life due to increased episcleral venous pressure. Choroidal hemangiomas are also frequent and may be detected via fundoscopy or using enhanced-depth imaging with spectral-domain OCT. Other ocular findings include retinal vascular abnormalities, episcleral hemangiomas, and strabismus, which can result from asymmetric visual impairment or central nervous system involvement.

In NF1, characteristic ophthalmologic findings include Lisch nodules, which are melanocytic hamartomas of the iris and one of the hallmark diagnostic criteria for the disease. Other common ocular manifestations include optic pathway gliomas, which can lead to progressive visual impairment, and choroidal abnormalities, typically identified through near-infrared imaging. Patients may also present with eyelid neurofibromas, which, when extensive, can cause mechanical ptosis and amblyopia.

In this patient, the presence of serous retinal detachment in the right eye prevents an adequate evaluation of the optic nerve head, making it difficult to assess the cup-to-disc ratio accurately. Therefore, no significant increase in the rim-to-disc ratio is observed in comparison to the left eye, and intraocular pressure alone is not a sufficient parameter to exclude glaucoma. Furthermore, choroidal nodules were observed in the left eye, as evidenced in Figure 1F. Due to the retinal detachment in the right eye, it was not possible to assess the presence of choroidal nodules in this region, which explains their apparent absence. Since the right eye is affected by retinal detachment, a direct comparison between both eyes is not feasible.

The coexistence of NF1 and SWS in the patient raises several questions about the pathogenesis and interaction between these two syndromes. It is believed that the underlying mutations in different genes may contribute to the complexity of the clinical picture. In the case of NF1, mutations in the NF1 gene on chromosome 17 are responsible for the disease manifestations.⁵, while SWS is caused by post-zygotic mutations in the GNAQ gene.^7,8 The interaction of these mutations and their phenotypic effects may result in the unique presentation observed in the patient. In this case, both a choroidal detachment caused by the hyperechoic hemangioma and a serous retinal detachment were documented. This coexistence, observed on ocular ultrasound and OCT, contributes to the complex pathophysiology of the visual impairment and should be considered when evaluating visual prognosis and treatment planning.

Each condition carries its own potential complications – NF1 with risks of benign and malignant tumors, learning disabilities and SWS with neurological complications such as seizures, developmental delays, and glaucoma.¹² The coexistence of these syndromes could potentially exacerbate symptoms and increase the likelihood of complications, making the clinical outcome less predictable. Considering the complex interaction of NF1 and SWS in this patient, the clinical management must be tailored to monitor and address the various complications that may arise, ensuring a comprehensive and multidisciplinary approach to care.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/01658107.2025.2544332