Although being one of the main manifestations of Warburg-Cinotti syndrome, ocular abnormalities have not been thoroughly investigated in previous reports in which the term ‘corneal vascularization’ was usually used. Corneal neovascularization refers to the invasion of blood vessels from the conjunctiva to the normally avascular cornea due to limbal stem cell deficiency (LSCD) or inflammation, primarily caused by infection, burns, and autoimmune disease [4]. We found the case of Warburg-Cinotti syndrome different, for the former is thought to begin with the transition of epithelial type from corneal to conjunctival, while the latter presents as fibrovascular neoplasm extending onto the cornea, which subsequently disrupts the limbal stem cell barrier.

The child was originally diagnosed with pseudopterygium, given the history of trauma. Pseudopterygium is a non-progressive conjunctival adhesion to the peripheral cornea secondary to trauma or corneal inflammation. Unlike a true pterygium, a probe may be passed at the limbus under a pseudopterygium because there is an interspace between the mass and the underlying corneal epithelium [5, 6]. This diagnosis was later ruled out because the mass showed rapid growth, extending over the unharmed cornea. Ocular surface squamous neoplasia has also been considered a possible diagnosis, but histopathological examination showed no neoplastic cells.

There are other syndromes with similar manifestation described in the literature. Abarca et al. reported an entity named Ocular pterygium-digital keloid dysplasia characterized by ocular pterygia and keloids on the digits [7]. They described the ocular abnormality as ingrowth of conjunctival tissue that gradually covered the entire cornea, which is similar to our case. However, the genetic mutation of the two reported families were different with our case, one in PDGFRB and the other in PELI2; DDR2 remained normal [8, 9]. Activating variants in PDGFRB is associated with a spectrum disorders, notably Penttinen syndrome. The ocular malformations of Penttinen syndrome includes proptosis, abnormal orbital telorism, and pterygium (some described as corneal pannus) presents in adolescence [10,11,12]. The age of onset clearly distinguishes this pterygium-like abnormality form the conventional pterygium. However, the progression and treatment of the pterygium was not reported in more detail.

According to reported Warburg-Cinotti syndrome cases, surgical removal could worsen the condition and lead to symblepharon formation, which is probably related to DDR2 ’s role in wound healing. DDR2 is a collagen-activated receptor tyrosine kinase that participates in various cellular processes, especially extracellular matrix remodeling [13, 14]. By activating epithelial-mesenchymal transition signaling and expression of matrix metalloproteinases, DDR2 could regulate fibroblasts proliferation and migration [15, 16]. Research has demonstrated that DDR2 is associated with fibrosis and pathological scarring in the skin, liver, and heart [17,18,19,20]. It’s reported that DDR2 mRNAs and protein are expressed in the cornea [21]. However, no studies have elucidated the role of DDR2 in ocular diseases. We speculate that DDR2 mutation may lead to abnormal fibrosis after injury, manifested as cutaneous keloid formation and excessive conjunctival growth in Warburg-Cinotti syndrome. Moreover, it seems that the older the patient, the more severe their clinical manifestations, which may be attributed to the accumulated microtrauma induced by daily dust, wind, or drying. Admittedly, a prospective study on DDR2 and relevant pathways in corneal and conjunctival diseases is required.

In conclusion, patients with progressive conjunctival invasion of the cornea should cause our alert of systemic syndrome. Surgical excision can induce inflammation and fibrinous exudation, leading to conjunctival hyperplasia and symblepharon formation. Genetic testing is recommended when there is doubt regarding the diagnosis.