A Tale of Two Sides: a Rare Pediatric Neuro-Oncology Case
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
Hemimegalencephaly (HMEG) is a rare brain malformation associated with mosaic mutations in the PI3K/mTOR-pathway and increased risk of glial neoplasms, in a subset of causative genes. PI3K-pathway alterations have also been reported as somatic findings in glial neoplasms with or without alterations in the MAPK-pathway. Herein, we describe a newborn diagnosed with HMEG and an unrelated primary central nervous system tumor as confirmed by next-generation sequencing (NGS), ultimately leading to her timely treatment.
Case Presentation
A 4-week-old term female presented with a 2-week history of worsening abnormal movements, including right head deviation, and rhythmic breathing with intermittent grunting. An electroencephalogram confirmed focal hemimyoclonic seizures, while magnetic resonance imaging (MRI) demonstrated an enlarged right cerebral hemisphere with diffuse polymicrogyria and an asymmetric white matter signal. The MRI also revealed a contralateral (left-sided) lesion suspicious for a vascular malformation, focal overgrowth, or neoplastic process. Physical exam was remarkable for a flat, brown nevus on her left ear lobe and a hypermelanotic macule on her left forehead.
Diagnostic Workup
The patient’s newborn screen was negative, as was whole genome sequencing of peripheral blood. Subsequent sequencing of her nevus at 2-months of age, using a targeted-NGS panel capable of identifying mosaic variants at low variant allele fractions (VAFs) in genes involved in vascular malformations, was also negative. Due to increasing seizures, she underwent a right-hemispherectomy at 9-months, with concurrent intraventricular biopsy of the left-sided mass. Histologic examination of the hemispherectomy specimen demonstrated cortical dyslamination with abnormal clustering of neurons, and neuronal dysmorphism consistent with hemimegalencephaly. The left-sided mass was markedly hypercellular, composed of GFAP-positive cells with abundant cytoplasm in a fibrillary background with a low mitotic index, supporting the diagnosis of a low-grade glioma. Both samples were evaluated using a comprehensive NGS-cancer panel; the hemispherectomy demonstrated a PIK3CA p.Glu545Lys (10% VAF) variant, while the left-sided mass harbored a PRKAR2A::ALK fusion. Notably, the PIK3CA p.Glu545Lys variant and ALK fusion were absent in her respective contralateral lesions, and in blood tested as a germline comparator sample.
Treatment and Management
The integration of the molecular and histologic findings yielded diagnoses of an unrelated PIK3CA-associated HMEG and an ALK kinase-driven low-grade glioma, for which the patient received an ALK-inhibitor, lorlatinib.
Outcome and Follow-Up
The patient is now seizure-free 29 months post-hemispherectomy. She continues to receive targeted ALK inhibitor therapy with a demonstrated partial tumor response. She walks without support and is progressing with therapies addressing her global developmental delay, speech delay, and left-sided weakness.
Discussion
To our knowledge, the co-occurrence of PIK3CA-related overgrowth (PROS) with sporadic cancers is a rare phenomenon described in a limited number of case reports, including an individual with PROS and two associated neoplasms (a vestibular schwannoma and meningioma harboring their known PIK3CA variant). Cases (one each) of PROS patients with leukemia and retinoblastoma have also been described, though they were not molecularly characterized. Testing in this case refuted the hypothesis that these two lesions were likely to be molecularly related, and a unifying underlying etiology is yet to be determined.
Conclusion
This case highlights the indispensable role of molecular testing in providing a comprehensive diagnosis for complex neurogenetic disorders. Critical to this process was the testing of enriched lesional tissue from both affected areas and a germline sample on an assay capable of identifying a wide range of genetic alterations. Notably, testing of a subset of specimens on a more limited panel would have resulted in an incomplete understanding of the patient’s separate disease processes.
Hemimegalencephaly (HMEG) is a rare brain malformation associated with mosaic mutations in the PI3K/mTOR-pathway and increased risk of glial neoplasms, in a subset of causative genes. PI3K-pathway alterations have also been reported as somatic findings in glial neoplasms with or without alterations in the MAPK-pathway. Herein, we describe a newborn diagnosed with HMEG and an unrelated primary central nervous system tumor as confirmed by next-generation sequencing (NGS), ultimately leading to her timely treatment.
Case Presentation
A 4-week-old term female presented with a 2-week history of worsening abnormal movements, including right head deviation, and rhythmic breathing with intermittent grunting. An electroencephalogram confirmed focal hemimyoclonic seizures, while magnetic resonance imaging (MRI) demonstrated an enlarged right cerebral hemisphere with diffuse polymicrogyria and an asymmetric white matter signal. The MRI also revealed a contralateral (left-sided) lesion suspicious for a vascular malformation, focal overgrowth, or neoplastic process. Physical exam was remarkable for a flat, brown nevus on her left ear lobe and a hypermelanotic macule on her left forehead.
Diagnostic Workup
The patient’s newborn screen was negative, as was whole genome sequencing of peripheral blood. Subsequent sequencing of her nevus at 2-months of age, using a targeted-NGS panel capable of identifying mosaic variants at low variant allele fractions (VAFs) in genes involved in vascular malformations, was also negative. Due to increasing seizures, she underwent a right-hemispherectomy at 9-months, with concurrent intraventricular biopsy of the left-sided mass. Histologic examination of the hemispherectomy specimen demonstrated cortical dyslamination with abnormal clustering of neurons, and neuronal dysmorphism consistent with hemimegalencephaly. The left-sided mass was markedly hypercellular, composed of GFAP-positive cells with abundant cytoplasm in a fibrillary background with a low mitotic index, supporting the diagnosis of a low-grade glioma. Both samples were evaluated using a comprehensive NGS-cancer panel; the hemispherectomy demonstrated a PIK3CA p.Glu545Lys (10% VAF) variant, while the left-sided mass harbored a PRKAR2A::ALK fusion. Notably, the PIK3CA p.Glu545Lys variant and ALK fusion were absent in her respective contralateral lesions, and in blood tested as a germline comparator sample.
Treatment and Management
The integration of the molecular and histologic findings yielded diagnoses of an unrelated PIK3CA-associated HMEG and an ALK kinase-driven low-grade glioma, for which the patient received an ALK-inhibitor, lorlatinib.
Outcome and Follow-Up
The patient is now seizure-free 29 months post-hemispherectomy. She continues to receive targeted ALK inhibitor therapy with a demonstrated partial tumor response. She walks without support and is progressing with therapies addressing her global developmental delay, speech delay, and left-sided weakness.
Discussion
To our knowledge, the co-occurrence of PIK3CA-related overgrowth (PROS) with sporadic cancers is a rare phenomenon described in a limited number of case reports, including an individual with PROS and two associated neoplasms (a vestibular schwannoma and meningioma harboring their known PIK3CA variant). Cases (one each) of PROS patients with leukemia and retinoblastoma have also been described, though they were not molecularly characterized. Testing in this case refuted the hypothesis that these two lesions were likely to be molecularly related, and a unifying underlying etiology is yet to be determined.
Conclusion
This case highlights the indispensable role of molecular testing in providing a comprehensive diagnosis for complex neurogenetic disorders. Critical to this process was the testing of enriched lesional tissue from both affected areas and a germline sample on an assay capable of identifying a wide range of genetic alterations. Notably, testing of a subset of specimens on a more limited panel would have resulted in an incomplete understanding of the patient’s separate disease processes.