Beyond the Eyes: Diplopia as an Early Manifestation of a Life-Threatening Condition in a Young Adult

Dear Editor,While most patients with diplopia have benign underlying causes, in 16% of cases this condition is associated with potentially life-threatening etiologies. 1 We present a rare case of a genetic connective-tissue defect manifesting as acute diplopia.A 24-year-old female presented with a 7-day history of binocular diplopia.Upon awakening, she experienced diagonal diplopia and ptosis of the left eyelid.She denied ocular pain, headache, nausea, or vomiting, and her diplopia and ptosis did not show diurnal variations.Notably, she had easily developed bruises and small hematomas throughout her body since childhood.Her mother died unexpectedly at 38 years of age.A physical examination revealed a body height of 160 cm and a weight of 41 kg, giving a body mass index (BMI) of 16.0 kg/m 2 .Her skin was thin and translucent, and there was a small hematoma in her left fifth finger (Fig. 1A).The physical examination also revealed right hypertropia in the primary position, which increased during upward, leftward, and rightward gaze (Fig. 1B).Diplopia and eyelid ptosis are uncommon in young adults.A dysimmune state or neuromuscular-junction disorder was not strongly suspected in our patient based on her clinical presentation and the findings of a neuroophthalmologic examination.Conversely, her family history of sudden death as well as her easy bruising, hematoma, markedly slender build, and low BMI suggested that an inherited coagulopathy or connective-tissue disease could underlie her strabismus.Thus, extensive laboratory and systemic imaging workups were conducted, as detailed in Supplementary Table 1 (in the online-only Data Supplement).Brain CT angiography revealed an aneurysm at the cervical segment of the right internal carotid artery (Fig. 1C).The findings of brain MRI with fat-suppression sequences and venography were unremarkable (Fig. 1D).Digital subtraction angiography was not conducted.A genomic sequencing test revealed the pathogenic heterozygous c.2771G>A (p.Gly924Asp) mutation in the COL3A1 gene, confirming a diagnosis of vascular Ehlers-Danlos syndrome (EDS).The diplopia and strabismus had resolved in a follow-up examination performed 1 month later.The clinical manifestations of EDS are heterogeneous depending on the presence of variants in 20 different genes that encode the fibrillar collagen and enzymes that modify these collagens.2 Vascular EDS is the rarest form, comprising only 5% of the entire disease entity.A mutation can be found in the COL3A1 gene, which generates chains of type III procollagen.This is inherited in an autosomal dominant manner and is often revealed by a high frequency of bruising and hematoma caused by physical trauma.Unfortunately, most patients (up to 70%) are not diagnosed until the occurrence of vascular rupture, dissection, or internal bleeding, 2 and this represents a potentially underestimated cause of stroke in young adults.3,4 As in our patient, the skin is often sufficiently thin to reveal the subcutaneous venous networks.