ABSTRACT
Background: Neurocutaneous melanosis is a devastating disease characterized by multiple congenital melanocytic nevi and melanocytic proliferation within the leptomeninges. Because optimal medical therapy at present is insufficient, further investigations into genetic pathways might offer new therapeutic options.
Observation: Herein, we present a case of a child with neurocutaneous melanosis syndrome harboring two novel genetic mutations, treated with trametinib with some response for over a year.
Conclusion: Genetic analysis revealed a gain of function mutation in GNAS gene and a loss of 10q. Based on a review of the current literature, these two mutations represent novel genetic findings in neurocutaneous melanosis.
Key Words: genetic mutation, neurocutaneous melanosis, nevi, pediatric
INTRODUCTION
Neurocutaneous melanosis (NCM) is a rare congenital condition, first described by Rokatinsky in 1861, that is associated with multiple congenital melanocytic nevi as well as melanocytic proliferation in the leptomeninges. Common neurologic manifestations of this disorder may include signs of increased intracranial pressure and spinal cord compression due to central nervous system involvement by the melanocytic lesions. NCM is usually diagnosed and visible by two or three years of age, however, some patients can present later in childhood.1 Various tumors, arachnoid cysts, hydrocephalus, syringomyelia, and Dandy-Walker malformation have also been found to be associated with NCM.2 Typically, NCM is diagnosed with magnetic resonance imaging (MRI) of the neuroaxis in concert with characteristic clinical findings on physical exam, such as large congenital melanocytic nevi. Unfortunately, malignant transformation of the nevomelanocytes is frequent in these patients and was reported in 62% of the 39 cases of NCM that were initially described by Katonaga et al.1
Symptomatic NCM is associated with lower life expectancy due to both poor functional status of the patient in addition to an increased chance for melanomatous transformation. Less than half of all patients survive three years past the time of the melanomatous transformation. Besides surgical debulking, an effective adjunct medical therapy for the treatment of NCM has yet to be described.3 Hence, investigation into the genetic pathways involved in NCM might offer new therapeutic options for these patients. In this report, we present a case of a seven-year-old boy with NCM that has underwent malignant transformation. As was described in several recent reports in the literature, genetic testing in our patient also revealed a neuroblastoma RAS viral oncogene homolog (NRAS) codon 61 mutation.4-7 However, genetic analysis revealed additional mutations in our patient, particularly a gain function of guanine nucleotide binding protein G(s) subunit alpha (GNAS) and loss of chromosome 10q. Although GNAS mutations and amplifications has been previously reported in melanomas, gain of function of GNAS and loss of 10q have yet to be reported in patients with NCM.8 By illustrating this new finding, we hope to emphasize the importance of further genetic testing and research in patients with NCM as the current treatment options for this devastating disease remain suboptimal.
CASE REPORT
A seven-year-old male with known history of NCM that was confirmed shortly after his birth via imaging studies presented with a headache, low back pain, vomiting, and restlessness. Prior to his presentation, the patient was asymptomatic and had not required any treatment for his NCM. On physical exam, a large melanotic nevus was noted on his back in addition to multiple similar but smaller lesions throughout his body. MRI of his entire neuroaxis revealed diffuse craniospinal melanomatosis involving his brain and spinal cord (Fig. 1). The Patient had significant bilateral leptomeningeal enhancement in the brain and several intradural extramedullary hyperintense lesions with associated compression of the spinal cord at multiple levels, particularly in the thoracic spine. The patient was started on dexamethazone therapy and thoracic laminectomy had to be performed to debulk the intradural mass, with subsequent radiographic improvement in his spinal cord compression.
Histopathological examination of the tissue samples obtained during the surgery from the patient’s spinal cord lesion showed intermediate grade leptomeningeal melanosis and focal necrosis. The presence of neoplastic cells with cytologic atypia and prominent nucleoli suggested a melanomatous transformation his intradural lesions has already occurred. Further genomic analysis demonstrated an NRAS codon 61 mutation, a gain of function mutation of GNAS, and a loss of 10q. At that time, he was started on trametinib (Mekinist, Warren, NJ), an oral mitogen activate protein kinase kinase (MEK) inhibitor, which he tolerated for many months without any significant side effects.
The patient initially responded to the trametinib regimen for over a year, however, fourteen months following his first spinal operation and the initiation of trametinib, the patient began to experience frequent headaches. Imaging studies now revealed a new intracranial mass suggestive of a malignant neoplasm (Fig. 2). The patient subsequently underwent a craniotomy and resection of his tumor. Histopathology demonstrated a melanoma of the brain, arising from the malignant transformation of his neurocutaneous melanosis (Fig. 3). Neoplastic cells exhibited significant pleomorphism, prominent nucleoli, irregular nuclear borders, and extensive necrosis. The patient’s disease unfortunately continued to progress, requiring more surgeries. He slowly developed obstructive hydrocephalus and papilledema, requiring placement of a ventriculoperitoneal shunt to relieve the intracranial pressure. At present, the patient’s family declined radiation therapy and his disease continues to progress despite medical and surgical treatment modalities.
DISCUSSION
Diffuse proliferation of melanocytes within the leptomeninges contributes to leptomeningeal melanocytosis observed in NCM. Kadonga et al reviewed 39 cases of NCM and concluded that most patients with NCM present with variable neurologic manifestations in the first two years of life.1 Hydrocephalus, seizures, increased intracranial pressure, developmental delay, hypotonia, and neurogenic bowel and bladder dysfunction are some of the symptoms recognizable with NCM.3 Once neurological symptoms develop, NCM carries a poor prognosis with main treatment option being surgical intervention to relieve the intracranial pressure or spinal cord compression. Moreover, the usefulness of chemoradiation in the treatment of NCM has yet to be established.4
In this report, we present a case of NCM characterized by NRAS codon 61 mutation, gain of function GNAS mutation, as well as a loss of the long arm (q) of chromosome 10, that was experimentally treated with trametinib with subsequent clinical improvement for over a year. The gain of function mutation in GNAS and the loss of chromosome 10q have not previously been described in NCM and are presented here for the first time.
Several recent reports in the literature have already confirmed that congenital melanocytic nevi, NCM, as well as primary childhood melanoma are associated with postzygotic somatic mutations in the codon 61 of the NRAS gene.4-7 Similarly, our patient was found to harbor the same NRAS mutation. The constitutive activation of NRAS that is seen in NCM is known to stimulate melanocytic proliferation through the extracellular signal related kinase (ERK) pathway, which is the best studied of the mitogen activated protein kinase (MAPK) pathways.9 When NRAS is guanosine triphosphate bound, it is activated and the pathway is turned on, contributing to the cellular proliferation. Codon 61 of the NRAS gene is associated with the guanosine triphosphate binding site that plays a key role in its normal inactivation. Thus, mutations in codon 61 of NRAS lead to constitutive activation of NRAS and subsequent melanocyte proliferation.5
A key event in the ERK cascade is the phosphorylation of the ERK1 and ERK2 proteins, which is achieved through the rapidly accelerated fibrosarcoma (RAF)-dependent activation of MEK1 and MEK2.9 Hence, it was proposed that MEK 1/2 inhibition might be an effective, therapeutic option for congenital melanocytic nevi and similar disorders. Trametinib recently became an orally available, FDA-approved selective inhibitor of MEK1/2, and has shown improved survival when compared to other chemotherapy options in serine/threonine protein kinase B-Raf (BRAF) mutant melanoma.10 Additionally, a recent phase II clinical trial showed some promising efficacy in terms of response rate with another MEK1/2 inhibitor, MEK 162, in advanced NRAS mutant metastatic melanoma. The study concluded that MEK 162 is well tolerated with mostly minor dermatological and gastrointestinal side effects, however, long term studies are still needed to determine the effectiveness and long term side effects of MEK 162.11 In our case, the patient was treated with trametinib and tolerated the drug for over a year without any major side effects. Our experience with trametenib as described herein, combined with recent published data from a cohort of four NCM patients also treated with trametinib after presentation with significant neurological deficits, suggests that further investigation of the effects of MEK1/2 inhibition on the disease progression of NCM may be warranted.12
Even with the possible impediment to the disease progression offered by MEK1/2 inhibition, NCM continues to carry a grim prognosis. The novel mutations in GNAS and loss of 10q reported herein contribute to the molecular characterization of this poorly understood pediatric disease and represent possible avenues for future investigation. GNAS gene, found on the long (q) arm of chromosome 20, encodes for a stimulatory alpha subunit, which is part of a larger G protein complex. GNAS gene mutations have been implicated in various cancers such as melanomas and pancreatic cancers.8 This is important to note as recent genetic sequencing studies in human malignancies have showed frequent mutations in guanine nucleotide binding protein receptor (GPCRs) and G proteins. Thus, targeting GPCRs, G proteins, or their aberrant signaling pathways can serve as a novel therapeutic option for various cancers.13 Although GNAS mutations and amplification has been reported in melanomas, review of the current literature has not revealed gain of function of GNAS and loss of 10q mutations specifically in patients with NCM.8 The copy number loss of the 10q region likely reflects a larger structural alteration involving chromosome 10 rather than a focal loss. However, these copy number alterations have not been described in this rare clinical disorder and therefore the clinical and therapeutic significance is currently unknown, but may be worthwhile investigating further as the current treatment options remain ineffective.