Hybrid phakomatosis: from initial CT observation to molecolar studies

We read with much interest the case report by Erbay et al (1) dealing with rapid development of optic glioma in an infant with both neurofibromatosis type 1 (NF-1) and tuberous sclerosis (TS). The neoplasm showed an aggressive behavior that is not commonly seen in children with NF-1, and the authors hypothesized that it might be due to what they called “hybrid” phakomatosis (ie, the coexistence of more than one phakomatosis). They concisely but accurately illustrated growing evidence in the literature indicating the genetic basis for TS- and NF-1-induced neoplasms. The formation of neoplasms in both conditions appears to be due to deficiency of tumor-suppressor genes. Although the TS and NF-1 genes are different, they appear to have common enzymatic pathways at the cellular level. Therefore, there might be an additive or synergistic effect in patients with both of these disorders. Coexistence of more than one phakomatosis is a rare condition, and Erbay et al have been able to find only eight cases reported in the literature. Their article, however, reminded us of what we observed some time ago, in the late 1970s, when the phakomatoses were a still “mysterious” part of pathology and their pathogenesis was poorly understood. In a series of 65 cases of phakomatoses examined with CT, we found three patients who simultaneously had features of two different phakomatoses. Two of the three, reported in 1980 (2), had the typical clinical features of NF and also had subependymal or intranuclear nodular calcifications showing a CT appearance identical to that of tubers in TS. At that time, CT had just become the criterion standard for neuroimaging, and it was emerging as the most valuable method to investigate patients with phakomatosis (3). It provided both an early diagnosis, by displaying all orbital and craniocerebral lesions, and a suitable follow-up of these patients, who appeared prone to develop orbital and cerebral tumors. Time has passed, and there have been advances in the diagnostic criteria of the phakomatoses. MR imaging is now widely used for the characterization of brain lesions associated with these disorders, and their molecular genetic aspects are being understood. Thus, Erbay et al could possibly explain the abnormal predisposition to neoplasm formation that we too found in what we defined as “atypical” and they as “hybrid” phakomatosis. As a matter of fact, either of the patients with both NF and TS showed an abnormal predisposition to neoplasm formation. The 27-year-old man with café-au-lait spots in case 1 had undergone surgery a few years earlier for a frontal meningioma (a rather unusual tumor in men and in young people, in general), and his CT scan showed a cerebellar tumor in addition to bilateral acoustic neurinomas. The 12-year-old girl with cutaneous manifestations of NF in case 2 presented with left hemiparesis and was found to harbor both a right deep temporal glioma and neoplastic infiltration of the left optic nerve, optic chiasm, and right optic tract. The significant advances in the genetics of these disorders made in the past few years may help us understand why.