What are the genetic causes of exophthalmos (proptosis)?

From the Guidelines

Proptosis is most commonly caused by genetic conditions such as Neurofibromatosis type 1 (NF1), which can lead to orbital tumors, and craniofacial syndromes like Crouzon syndrome, Apert syndrome, and Pfeiffer syndrome, due to premature fusion of skull bones, as well as thyroid eye disease (Graves' ophthalmopathy) with a strong genetic component 1.

Key Genetic Causes of Proptosis

• Neurofibromatosis type 1 (NF1) due to orbital tumors
• Craniofacial syndromes: Crouzon syndrome (FGFR2 gene mutations), Apert syndrome (FGFR2 mutations), and Pfeiffer syndrome (FGFR1 and FGFR2 mutations) due to premature fusion of skull bones
• Thyroid eye disease (Graves' ophthalmopathy) with a strong genetic component, particularly HLA-DR3 and CTLA-4
• Marfan syndrome (FBN1 gene) may cause lens dislocation and subsequent eye protrusion
• Multiple endocrine neoplasia syndromes (MEN1 or MEN2A genes) can cause pituitary adenomas leading to proptosis

Management Considerations

• Multidisciplinary management including ophthalmologists, geneticists, and sometimes endocrinologists is crucial for proper care
• Early diagnosis through genetic testing is important for proper management and genetic counseling, as many of these conditions follow autosomal dominant inheritance patterns, meaning affected individuals have a 50% chance of passing the condition to their children 1
• Treatment indications for orbital/periorbital plexiform neurofibromas in children with NF1 include visual decline, progressive tumor, or potentially progressive disfigurement, and should be managed by a multidisciplinary team including neuro-oncology, ophthalmology/neuro-ophthalmology, oculofacial plastics, craniofacial surgery, and genetics 1

From the Research

Genetic Causes of Proptosis

• Proptosis can be caused by various genetic conditions, including Neurofibromatosis type 1 (NF1) 2, 3, 4
• NF1 is a hereditary disease characterized by café-au-lait spots, peripheral neurofibromas, Lisch nodules, optic nerve glioma, and sphenoid wing dysplasia 2, 4
• Sphenoid wing dysplasia can lead to pulsating proptosis due to a bony defect in the orbit 2, 3
• Other genetic conditions that can cause proptosis include Multiple Endocrine Neoplasia type 1 (MEN-1) and von Hippel-Lindau disease, although these are not directly related to proptosis 5, 6

Neurofibromatosis Type 1 and Proptosis

• NF1 can cause pulsating proptosis due to a sphenoid bony defect, which allows the meningocele to protrude through the orbital defect and lift the globe 2
• The presentation of pulsating proptosis and heavy eye syndrome in NF1 patients can be rare and synchronous 2
• Adult-onset presentation of NF1 implies a progressive process, and orbital imaging should be performed in high myopia patients with strabismus to evaluate the extraocular muscle pathway 2

Management of Proptosis in NF1 Patients

• Management of proptosis in NF1 patients can include orbital floor decompression, superior rectus muscle resection with advancement, and maximal hang-back recession of the inferior rectus muscle 2
• These procedures can help reduce proptosis, improve eye position, and increase the range of eye movements 2
• Avoiding neurosurgery can be a viable option for managing proptosis in NF1 patients, especially when considering the risks and economic costs 2