Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities

Abstract

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets.

Contiguous verrucous proliferations in syringocystadenoma papilliferum: A retrospective analysis with additional evaluation via mutation‐specific BRAFV600E immunohistochemistry

“…These included a congenital anaplastic astrocytoma and multiple ocular abnormalities. Interestingly, this patient was subsequently found to have a post‐zygotic mutation in BRAF c.1799T>A p.V600E, and then went on to show significant clinical improvement after treatment with vemurafenib . In a separate investigation, BRAFV600E and HRAS mutations were identified in 12 (52%) of 23 and 6 (26%) of 23, sporadic SCAP lesions, respectively.…”

“…The lesion may develop within a pre‐existing nevus sebaceus, but the majority of cases arise sporadically . Congenital lesions in a Blaschkoid distribution have also been reported, and these cases are thought to represent genetic mosaicism . The tumor has a varied clinical appearance, but typically presents as a raised warty, hairless plaque or nodule …”

“…Although the pathogenesis of SCAP is largely unknown, there have been multiple recent reports implicating involvement of the RAS‐mitogen‐activated protein kinase (MAPK/ERK) pathway . In 2015, Watanabe et al described a patient with a linear SCAP who had anomalies similar to those seen in Schimmelpenning‐Feuerstein‐Mims syndrome . These included a congenital anaplastic astrocytoma and multiple ocular abnormalities.…”

Is Schimmelpenning Syndrome Associated with Intracranial Tumors? A Case Report

“…In a recently reported case, an infant presented with multisystem involvement similar to that of Schimmelpenning syndrome and an anaplastic astrocytoma resulting from a BRAF V600E mutation, but no mutations HRAS or KRAS [41]. These rare cases suggest the possibility that Schimmelpenning syndrome may arise through different mosaic RASopathies, and the presenting PA in our patient may be associated with Schimmelpenning syndrome independent of a HRAS or KRAS mutation.…”

“…Despite the rare incidence of Schimmelpenning syndrome patients developing astrocytomas, it is possible that these individuals have a predisposition to develop pro-oncogenic extracutaneous mutations. The strong association between HRAS and KRAS mutations in Schimmelpenning syndrome patients and lack of PA suggests a potential common signaling pathway in RASopathy, as defects in other genes regulating the RAS signaling pathway also results in an increased incidence of intracranial neoplastic involvement [10, 11, 24, 41]. Therefore, future studies will be needed to determine the convergence or involvement of different RASopathies that ultimately give rise to the intracranial tumors mentioned in Table 1.…”