Peds Flashcards

Question

Which of the following findings is included in the diagnostic criteria for neurofibromatosis type 1? A. 2 or more retinal hamartomas B. 2 or more Lisch nodules C. 2 or more ungual fibromas D. 2 or more meningiomas E. 2 or more endolymphatic sac tumors

Answer 1

**2 or more Lisch nodules ** ## Footnote Diagnostic criteria for neurofibromatosis type 1 (patient has two or more of the following): A. Six or more cafe-au-lait spots (1.5 cm or larger in post-pubertal individuals, 0.5 cm or larger in pre-pubertal individuals) B. Two or more neurofibromas of any type or one or more plexiform neurofibromas C. Axillary or groin freckling D. Optic pathway glioma E. Two or more Lisch nodules (benign melanotic iris hamartomas) F. A distinctive bony lesion (dysplasia of the sphenoid bone, dysplasia or thinning of long bone cortex) G. First degree relative with neurofibromatosis type 1. Retinal hamartomas and ungual fibromas are common findings in tuberous sclerosis. Multiple meningiomas can be seen with neurofibromatosis type 2. Endolymphatic sac tumors are seen with von Hippel-Lindau disease.

Answer 2

**Lipomyelomeningocele** ## Footnote The formation of the spinal cord involves two main processes: primary neurulation, which begins on postovulatory day (POD) 18, and secondary neurulation, which begins between POD 28 and 48. Primary neurulation begins when the notochord induces the overlying ectoderm to proliferate as neuroectoderm. Initially the neural groove is formed, and with continued elevation and in- folding, it fuses to form the neural tube. Cutaneous ectoderm separates from the neuroectoderm and fuses on the midline, forming the overlying skin layer. This process, in which the cutaneous ectoderm separates from the neuroectoderm, is a critical step known as disjunction. Abnormalities during disjunction are responsible for many forms of spinal dysraphism. The most severe form of spinal dysraphism, myelomeningocele, is due to a focal interruption in this step—or nondisjunction—at the level of the lesion. Lipomyelomeningocele is due to premature disjunction, during which, mesodermal elements that form fatty tissue can migrate into the neural tube. Lipomyelomeningoceles are skin covered lesions, as ectodermal fusion proceeds normally. Dermal sinus tracts, which are persistent connections between the neural tube and the outside world, are the result of incomplete disjunction. Diastematomyelia—or split cord malformation (SCM)—can be divided into two types. In diastematomyelia type I, each hemicord has its own dural tube. In diastematomyelia type II, the two hemicords are housed within a single dural tube, divided by some sort of osseous, cartilaginous, or fibrous septum. The underlying embryonic mechanism of diastematomyelia remains unknown. Diastematomyelia may be seen in isolation, or in conjunction with other segmental anomalies.

Answer 3

**Obtain family history, parental and sibling head circumferences** ## Footnote The T2 weighted MRI reveals benign external subarachnoid spaces of infancy, or BESSI. This is evidenced by the increased T2 signal in the subarachnoid space as defined by the presence of cortical vessels and is most commonly seen over the frontal and temporal convexities. There may be associated mild ventriculomegaly. The growth chart reveals that the child’s head is macrocephalic (more than 2 standard deviations above the curve for age, sex and body size) and accelerating. BESSI is the most common cause of macrocephaly in infants, and is thought to have a genetic predisposition as a primary relative or paternal relative may also have a large head. This can be confirmed by measuring parents’ head sizes. It is thought to be due to delayed maturation of arachnoid villi. Children with BESSI may show an expansion of head growth between 3-12 months of age without symptoms of hydrocephalus or elevated intracranial pressure, but will typically decelerate by 18-24 months of age and remain with a larger than average head. BESSI must be distinguished from other pathologic forms of macrocephaly including hydrocephalus, where CSF diversion may be indicated, or obstructive pathologies which may be better elucidated with a contrast-enhanced brain MRI. Determining the location of the fluid to be in the subarachnoid space (versus the subdural space is also important in ruling out a traumatic injury, in which case a skeletal survey for further non-accidental trauma workup may be initiated. Ophthalmologic exam is important to evaluate for retinal hemorrhages (a sign of trauma) and papilledema (a sign of increased intracranial pressure) if either of these more pathologic etiologies are suspected based on imaging and history and exam.

Answer 4

**The cerebellopontine angle** ## Footnote Epidermoid cysts are benign cysts filled with keratinaceous debris. They are thought to occur from abnormal inclusion of ectodermal or skin elements during embryological development. The most- common body-wide site of occurrence is in the skin, where the cysts are usually limited in size and can be easily excised. They are rare in the CNS, representing about 1% of intracranial tumors. Among those cysts of neurosurgical concern, the cerebellopontine angle is by far the most common location, accounting for up to 50% of CNS epidermoid lesions. When they occur in the middle ear or petrous apex, they are often called cholesteatomas. Though histologically benign, the cyst wall can be densely adherent to critical neurovascular structures, making a complete curative resection challenging. Of the available answer choices, the cerebellopontine angle is the best response.

Answer 5

**6 months** ## Footnote While early developmental milestones are variable from child to child, the clinician should be aware of when most children reach a milestone to watch for gross motor delay. Some infants may be able to roll over prone to supine and supine to prone as early as 4 months of age, but infants should be able to perform this task by age 6 months. A 2-month-old would be expected to push up when lying prone. A 9-month-old would be expected to crawl. A 12-month-old would be expected to be able to get into a sitting position without help and likely will be able to pull to a stand.

Answer 6

**Diffuse intrinsic pontine glioma** ## Footnote This patient likely harbors a diffuse intrinsic pontine glioma (DIPG), also referred to as diffuse midline glioma. These tumors are unresectable and are treated with palliative radiation therapy and referral to clinical trials. Patients have a median survival of less than one year, with fewer than 10% of children surviving more than two years. Mutations in histone H3.3 result in replacement of lysine by methionine and are found in approximately 60% of these tumors. This histone modification results in altered gene expression profiles characteristic of this disease. Active research in this area is focused on clinically targetable mutations in both genetic and epigenetic modifications found in these tumors. Histone modifications are not commonly seen in the other listed answer choices, with the exception of pediatric glioblastoma. The mutation seen in pediatric supratentorial glioblastoma is G34R/V in H3F3A.

Answer 7

**Teratoma** ## Footnote Teratomas are heterogenous germ cell tumors with endodermal, mesodermal and ectodermal components that occur along the midline. A workup including alpha fetoprotein, human chorionic gonadotropin, and alkaline phosphatase is indicated as teratomas can be mixed with other germ cell type tumors. These lesions commonly occur in children. Subependymal giant cell astrocytomas are other third ventricle tumors that occur in tuberous sclerosis. Subependymomas are more common in elderly patients. Ependymomas more commonly arise from the 4th ventricle in children.

Answer 8

**Hereditary hemorrhagic telangiectasia** ## Footnote Arteriovenous malformations (AVMs) are congenital developmental anomalies of blood vessels that typically occur sporadically, arising during development of the embryonic cerebral circulation. AVMs may be a part of an inherited disease with a clearly identified genetic factor (e.g. Hereditary hemorrhagic telangiectasia (HHT)), associated with familial cases without a genetic cause, or as a feature of developmental neurocutaneous disorders (e.g. Wyburn-Mason syndrome). The criteria of HHT, also known as Osler-Weber-Rendu syndrome, are epistaxis, telangiectasia, visceral lesions, and a concordant family history. HHT is caused by loss-of-function mutations in one of three genes, ENG, ACVRL1, or SMAD4, and is inherited as an autosomal-dominant condition. Polycystic kidney disease is associated with intracranial aneurysms. Ehlers Danlos syndrome is associated with craniocervical instability. Von Hippel Lindau disease is associated with CNS hemangioblastomas.

Answer 9

**Midline facial anomalies** ## Footnote As the most common malformation of the developing human forebrain, the error underlying holoprosencephaly occurs between 18- and 28-days post-conception and involves partial or complete failure of separation of the prosencephalon into bilateral cerebral hemispheres. With an incidence of 1/10,000 live births, holoprosencephaly impacts neonates along a continuous spectrum of severity: alobar (most severe form), semi-lobar, lobar, and middle interhemispheric (MIH) variant (least severe). Common clinical associations include: midline facial anomalies most prevalently, like cleft lip/palate, midface hypoplasia, hypotelorism, cyclopia (in more severe forms), ethmocephaly or cebocephaly (in more severe forms), and single maxillary central incisor; chronic lung disease; gastro-esophageal reflux disease; and constipation. Common central nervous system associations include hydrocephalus (most commonly in alobar holoprosencephaly), epilepsy (up to 40% of patients with holoprosencephaly), motor deficits, oropharyngeal dysfunction with aspiration risks, hypothalamic dysfunction, and endocrinologic abnormalities like diabetes insipidus (up to 70% of patients with classic holoprosencephaly). Common genetic associations include trisomy 13 (most common), trisomy 18, and Smith-Lemli-Opitz Syndrome (SLOS). Severity of the brain malformation in holoprosencephaly often reflects severity of the mid-facial anomalies. Furthermore, severity of neurological impairments and cognitive deficits typically follow the magnitude of cerebral malformation demonstrated radiographically. Alobar holoprosencephaly, the most severe variant, involves complete lack of cerebral hemispheric division resulting in a mono-ventricle and absent interhemispheric fissure. The cerebral hemispheres demonstrate partial separation posteriorly (but not anteriorly) in semi-lobar holoprosencephaly. Lobar holoprosencephaly involves continuity across the bilateral frontal cortices while the middle interhemispheric (MIH) variant shows a lesser degree of continuity between posterior frontal and parietal lobes. More severe forms of holoprosencephaly are associated with higher mortality rates during the neonatal period (often during the first month of life), while milder forms offer chances for survival beyond infancy. The remaining answer choices (Dermal Sinus Tract, Occipital Encephalocele, Spinal Dysraphism, Sacral Agenesis) involve different components or chronological portions of neuro-embryologic development and do not represent common associations with holoprosencephaly. While holoprosencephaly and spina bifida may co-exist in the setting of trisomy 18, this represents a much less common association.

Answer 10

**Von Hippel-Lindau disease** ## Footnote Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder that causes retinal hemangioblastomas, central nervous system (CNS) hemangioblastomas, endolymphatic sac tumors, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas, and other less common manifestations. Metastatic renal cell carcinoma can present with CNS lesions; however, enhancing lesions of the cerebellum and spine are classic for hemangioblastomas associated with VHL. Lhermitte-Duclos disease is a dysplastic gangliocytoma of the cerebellum and does not have visceral manifestations. Turcot syndrome is the association of primary brain tumor with colorectal cancer.

Answer 11

**Diencephalon** ## Footnote During week 4 of development, the rostral neural tube forms three primary vesicles: the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hindbrain). These then further divide into five secondary vesicles. The prosencephalon forms the telencephalon and the diencephalon; and the rhombencephalon forms the metencephalon and the myelencephalon. The adult derivations of each secondary brain vesicle are highly regulated. The telencephalon gives rise to the cerebral cortex, the basal ganglia, the basal forebrain nucleus and the hippocampus. The diencephalon gives rise to the thalamus, hypothalamus, posterior pituitary, and optic vesicles. The mesencephalon gives rise to the midbrain; the metencephalon gives rise to the pons and cerebellum; and the myelencephalon gives rise to the medulla.

Answer 12

**Cellular proliferation** ## Footnote Ki-67 index measures the proliferative index of cells and higher values can be a marker of increased risk of tumor progression or grade. While cell apoptosis often correlated with higher proliferation rates, especially as tumor cells outgrow their blood supply, apoptosis is not measured by Ki-67 and is better marked by Annexin or caspases. Cellular necrosis can be identified early with specific markers such as RIP3 but later become more difficult to detect with a specific marker. Instead, their pattern on histology is characteristic. Immune cell infiltration of tumors is identified by specific markers of T and B cells such as CD4 and CD8 for T-cells as well as CD24 for B-cells. Cell nuclei are identified on routine H&E stains alone but can be stained with nucleus specific transcription factors.

Answer 13

**Persistent Trigeminal Artery ** ## Footnote The most common anomaly of the primitive carotid-basilar anastomotic embryological system is the primitive trigeminal artery (PTA). As a result, the persistent trigeminal artery is the most common fetal circulatory anomaly associated with aneurysms. During embryonic development there are anastomoses between the carotid arteries and the precursor arteries of the vertebrobasilar system. Upon formation of the posterior communicating artery these anastomotic connections begin to involute, leaving the mature carotid and vertebrobasilar systems. In some individuals, fetal connections remain. The primitive trigeminal artery is the most common of these persistent remnants. It persists in 0.1-0.6% of individuals and is typically associated with hypoplasia or absence of the ipsilateral posterior communicating artery. This persistent fetal connection is associated with vascular malformation, aneurysms, hemangiomas, and aortic arch alterations. The other persistent primitive arterial anastomoses occur less commonly.

Answer 14

**GM2-gangliosides** ## Footnote GM2 gangliosides accumulate in the cells of patients with Tay-Sachs disease. Tay-Sachs disease is an autosomal recessive progressive neurodegenerative disorder. While rare, it is more common among people of Ashkenazi Jewish descent. This disease alters the metabolism of sphingolipids. Sphingolipids are important components of the plasma membrane, affecting signal transduction and cellular recognition, particularly in cells of the nervous system. They are continuously synthesized and degraded. This degradation occurs in lysosomes. Tay-Sachs disease results from mutation in the HEXA gene on chromosome 15. The HEXA gene encodes the enzyme hexosaminidase-A. Hexosaminidase-A is a hydrolytic lysosomal enzyme that is important in the metabolism of specific sphingolipids, the gangliosides, to ceramides. It hydrolyzes GM2 gangliosides into GM3 gangliosides. When hexosaminidase-A activity is reduced, this results in the accumulation of its substrate GM2 gangliosides in the lysosomes of neurons, resulting in cellular toxicity and death. This leads to developmental disability and progressive lethal neurodegeneration. Sphingomyelin accumulates in cells of patients affected with Niemann-Pick disease due to deficiency in the enzyme sphingomyelinase. Glucocerebroside accumulate in the cells of patients with Gaucher disease as a result of deficiency in the enzyme Glucocerebrosidase. Sulfatides accumulate in the cells of patients with metachromatic leukodystrophy as a result of deficiency in the enzyme Arylsulfatase A. Ceramide-Trihexoside accumulates in the cells of patients with Fabry disease as a result of deficiency in the enzyme α-galactosidase A.

Answer 15

**Mesial temporal sclerosis with loss of neuronal density of CA1 and CA4** ## Footnote Abdominal epilepsy is a relatively uncommon presentation of temporal lobe epilepsy that may manifest through abdominal aura or pain. Patients may present with chronic or recurrent gastrointestinal tract symptoms including nausea, vomiting, and short-term repetitive abdominal pain with one or more neurological complication. Electroencephalograms will localize to the temporal lobe and this syndrome is typically responsive to anticonvulsants. Mesial temporal sclerosis (MTS) is often used interchangeably with hippocampal sclerosis, but typically has been described to additionally involve the amygdala and entorhinal cortex. The International League Against Epilepsy (ILAE) defines hippocampal sclerosis as neuronal loss and gliosis in hippocampal areas CA1 and CA4 (endplate/hilus/end folium). Blümcke and associates suggested that the patterns of MTS be categorized into 1. no MTS 2. MTS type 1 (neuronal loss predominantly in areas CA1 and CA4) 3. MTS type 2 (CA1 sclerosis) 4. MTS type 3 (end folium sclerosis) From the answer choices provided, MTS with neuronal loss in CA1 and CA4 is correct as these areas are preferentially decreased rather than increased. Additionally, CA2 and CA3 have not played a prominent role in pathologically defining MTS.

Answer 16

**Neuronal migration** ## Footnote Lissencephaly and subcortical band heterotopia comprise a spectrum of malformations of cortical development caused by insufficient neuronal migration. Lissencephaly is characterized by an abnormally thick cortex, reduced or absent formation of a normal gyral pattern, and significant disorganization of cortical laminar cytoarchitecture. Due to abnormal neuronal migration, the neuronal progenitor cells fail to move to the correct laminar location, resulting in a four-layer cortex rather than the normal six-layer cortex. Disorders of cellular proliferation include hemimegalencephaly, cortical tubers, and focal cortical dysplasia. Disorders of cortical organization include polymicrogyria and schizencephaly.

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