Oncogenic codon 13 NRAS mutation in a primary mesenchymal brain neoplasm and nevus of a child with neurocutaneous melanosis.
Bottom Line: Her parents did not harbor the NRAS mutation.A germline single nucleotide polymorphism in MET was found in the child and her father (c.3209C>T; p.T1010I).The findings suggest NRAS mosaicism that occurred sometime after conception and imply an oncogenic role of the activating NRAS mutation in both the brain and skin lesions in this child.
A 28-month female with a clinical diagnosis of neurocutaneous melanosis and numerous intracranial abnormalities (including a right choroid plexus tumor and left hemimegalencephaly) presented with a rapidly expanding tumor in the left occipital cerebrum. Microscopic examination of the resected specimen revealed a myxoid mesenchymal neoplasm consisting of fusiform cells that were immunoreactive for vimentin, CD34, and P53 but no melanocyte markers. Focused amplicon deep sequencing on DNA extracted from the brain tumor and a cutaneous nevus revealed a heterozygous (c.37G>C; p.G13R) substitution in the NRAS gene. DNA sequencing of "normal" skin and buccal swab showed the identical NRAS change albeit at lower allelic frequency. Her parents did not harbor the NRAS mutation. The skin lesion, but not the brain tumor, had a BRAF mutation (c.1397G>T; p.G466V). A germline single nucleotide polymorphism in MET was found in the child and her father (c.3209C>T; p.T1010I). The findings suggest NRAS mosaicism that occurred sometime after conception and imply an oncogenic role of the activating NRAS mutation in both the brain and skin lesions in this child.
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Mentions: This female child was born to a healthy non-consanguineous couple after an uneventful full-term pregnancy. At birth she had numerous slightly raised, hairy melanocytic lesions on the scalp, neck, upper trunk, upper extremities, and hands; the largest was 4–5 cm in greatest dimension (Figure 1). Skin lesions from the neck, scalp, and arm were previously excised and diagnosed as intradermal and compound nevi with congenital features. She had normal height but was macrocephalic (97th percentile head circumference). She had been admitted to hospital numerous times for uncontrolled seizures starting at age 2 months. Magnetic resonance (MR) imaging of the brain and spine was performed at 3.5 months age. T1 weighted images showed a solitary 2 mm focus of increased signal intensity in the right cerebellopontine cistern; this was thought to represent melanin deposition. Cystic lesions, the largest of which was 2.7 cm diameter, with signal characteristics the same as cerebrospinal fluid (CSF) were present around the atria of the lateral ventricles in the right cerebellopontine cistern along with small cysts around the bodies of the lateral ventricles. The left cerebral hemisphere was larger than the right, and parietal white matter volume was abnormally small. The combination of giant congenital nevi along with cerebral melanin deposition led to a clinical diagnosis of NCMS . A CT scan of the head performed at 4 months age during an episode of status epilepticus showed no additional abnormalities. An abdominal sonogram performed the following day showed no abnormalities. Repeat MR imaging showed the presumed melanocytic nodule had increased to 3 mm; it was hyperintense on T1, hypointense on T2, and hyperintense on FLAIR. The periventricular cysts had increased in size and quantity. A new lesion in continuity with the choroid plexus was expanding the temporal horn of the right lateral ventricle. MR imaging of the brain at 21 months age showed a new left occipital brain tumor that was T2 hyperintense and enhanced strongly following administration of gadolinium-DTPA. It grew from 1.6 × 1.5 × 1.2 cm to 4.0 × 3.6 × 3.2 cm 4 months later (Figure 2). A left occipital craniotomy was performed at 24.5 months age. The tumor was not in contact with the meninges. It had a single vascular pedicle. There was an easily identified plane between it and the adjacent brain. The tumor was removed in one piece without complication. MR imaging of the brain 26 months after surgery (51 months age) showed no recurrence of the tumor; a vague region of non-enhancing T2 signal abnormality in the right medial occipital lobe had expanded slightly.Figure 1