MENke’s board review: neurocutaneous syndromes

MENke’s board review: neurocutaneous syndromes
Shilpa Reddy June 5, 2015

Neurocutaneous Disorders
Conjoined abnormalities of skin and nervous system Theory that they all are disorders of neural crest Genes that regulate neural crest formation/migration/differentiation are also tumor suppressor genes  high incidence of benign and malignant tumors Phakomatoses = group of disease in which patient is prediposed to tumors of the skin, nervous system and other organs NF, TS, SWS, von-Hippel Lindau, ataxia-telengectasia, hypomelanosis of Ito

Diagnosis of NF1 Diagnostic criteria (> 2):
Six or more café au lait macules whose greatest diameter is more than 5 mm in prepubertal patients and more than 15 mm in postpubertal patients Melanoblasts in basal layer of epidermis Increase #/size with age No correlation between # and severity of disease Two or more neurofibromas of any type, or one or more plexiform neurofibroma Freckling in the axillary or inguinal region (Crowe's sign) An optic pathway tumor Two or more Lisch nodules (iris hamartomas) Don’t affect vision A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of the cortex of the long bones (with or without pseudoarthrosis) A first-degree relative (parent, sibling, or offspring) with NF1 according to the previously mentioned criteria

Diagnosis of NF1 NF1 gene mutation on chromosome 17
Highest single gene defect to affect nervous system Neurofibromin protein  inactivates p21ras by stimulating its GTPase activity 50% cases sporadic (93% of these paternally derived) Lots of mutations  variability No genotype-phenotype correlation

Tumors of NF1 Striking feature – tumors along peripheral nerves
Ulnar and radial most common Neurofibromas most common Central and peripheral can undergo malignant transformation Tumors in CNS Optic nerve gliomas, astrocytomas, brainstem gliomas (medulla most common) Tumors elsewhere Leukemia, Wilms tumor, neuroblastoma, pheochromocytoma

Diagnosis of NF1 Macrocephaly Short stature Headache Hypertension
Renal artery stenosis or pheochromocytoma Learning disabilities (rarely severe MR/ID) Cerebral infarction 50% with occlusive disease in ICA have moyamoya

Diagnosis of NF2 Diagnostic criteria (1 or more):
Bilateral CN VIII schwannomas A parent, sibling, or child with NF2 and either unilateral CNVIII mass or any two of the following conditions: Neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity (76,89,91) Patients with unilateral vestibular schwannomas and cataracts, or meningioma, glioma, or schwannoma are suspect for NF2, as are patients with multiple meningiomas plus unilateral vestibular schwannoma, cataracts, or glioma Chromosome 22 (merlin gene which is tumor suppressor) Age/severity within families about the same but varies between families

Diagnosis of TS Mutations in TSC1 Mutations in TSC2 Autosomal dominant
Hamartin Chromosome 9 Mutations in TSC2 Tuberin  tumor suppressor gene that acts as GTPase activator for rap1 Chromosome 16 Autosomal dominant 2/3 new mutations

Diagnosis of TS Cortical tubers
Intraventricular nodules (tumors) and giant cell astrocytomas Angiofibromas

Diagnosis of TS Seizures MR/ID Autism Renal (adults)
All types (except absence) Infantile spasms MR/ID More likely if epilepsy 1/3 normal intelligence Autism Renal (adults) Renal cysts with angiomyolipomas (no renal failure) PCKD (renal failure) – APKD1 near TS loci on chromosome 16 Pulmonary lymphangiomyomatosis 40% women with TS

Ataxia-Telangiectasia
AT gene mutation on chromosome 11 ATM protein that activates cellular responsive to double-stranded breaks in DNA

Ataxia-Telangiectasia
Slowly progressive cerebellar ataxia 2nd most common cause of progressive ataxia in < 10yo Telangiectasias of skin/conjunctiva Sinobronchopulmonary infections Decreased IgA and IgE Lymphoretricular neoplasms Sensitivity to ionizing rdiation Oculomotor apraxia Choreoathetosis Clinical course declines Death from infection or malignancy

Von-Hippel Lindau Autosomal dominant VHL gene on chromosome 3
2 tumor suppressor genes Cerebellar hemangioblastomas (pediatric as earl as age 9) Associated with polycythemia Angiomas of spinal cord Renal carcinoma Pancreas cysts Pheochromocytoma

Sturge-Weber Port-wine stain
5% infants with port-wine stain have Sturge-Weber 13% of Sturge-Weber infants don’t have port-wine stain Leptomeningeal angiomatosis (posterior unilateral or bilateral hemispheres) Iron and calcium deposits in vessels and underlying cortex Compromised blood flow/repeated thromboses Creates stasis, decreased venous return, hypoxia Abnormal vessels hinder neuroglial oxygenation Leads to progressive neurodegeneration/developmental delay/MR Seizures Hard to treat Glaucoma from angioma of eye choroid Transient or permanent hemiparesis, hemianopia Chronic cerebral hypoxia

Incontinentia Pigmentosa
X-linked (fatal in males) Neurologic symptoms 30% Seizures Spasticity Microcephaly MR/ID Abnormal MRI Hypoplasia of CC, nodular heterotopias, vessel occlusion Skin symptoms Incontinence of melanin from melanocytes  erythematous and bullous lesions at birth  crusting and residual pigmentation Follow dermatomal distribution

Hypomelanosis of Ito Neurologic symptoms
MR/ID common Seizures common Infantile spasms 10% Macrocephaly Ophtho findings Hemihypertrophy Autism Abnormal MRI Heterotopias, AVMs, cerebellar atrophy Hypopigmented lesions in whorls Follow dermatomal distribution Avoid UV light

Questions A 6 month old infant with known tuberous sclerosis
develops clusters of head bobs with arm extensions. EEG is most likely to reveal: 3 per second spike and wave Hypsarrhythmia Periodic spikes Focal atrophy Periventricular hemorrhage

Questions Which of the following statements is incorrect
regarding the systemic manifestations of tuberous sclerosis complex (TSC)? Cardiac rhabdomyomas may occur and often regress over time Periodic echocardiography is indicated for patients with cardiac rhabdomyomas Renal angiomyolipomas are benign lesions Lymphangiomyomatosis is a benign disorder often occurring in TSC patients, particular in male patients Retinal hamartomas are common and usually do not affect vision

Questions Which of the following statements is incorrect
regarding the systemic manifestations of tuberous sclerosis complex (TSC)? Cardiac rhabdomyomas may occur and often regress over time (> 50% rarely cause arrhythmias, heart failure from cardiomyopathy, stroke) Periodic echocardiography is indicated for patients with cardiac rhabdomyomas Renal angiomyolipomas are benign lesions (rarely progress to carcinoma, embolize or Rapamycin for enlarging lesions) Lymphangiomyomatosis is a benign disorder often occurring in TSC patients, particular in male patients Retinal hamartomas are common and usually do not affect vision (mulberry- like lesions or plaques or depigmented lesions, can cause vision loss of macula involved and rarely if retinal detachment or hemorrhage)

Lymphangiomyomatosis
Rare but fatal pulmonary disease within few years FEMALE patients with TSC Symptoms Dyspnea, cough, hemoptysis, pneumothorax Diagnosis Chest imaging with respiratory symptoms Treatment Tamoxifen, progresterone

Questions A brain CT scan if obtained in a patient with TSC and it
demonstrates hyperdensities. Which of the following is correct regarding these lesions? These are all malignant and should be resected This patient likely has, in addition to TSC, benign hereditary calcification of the basal ganglia (Fahr disease) The burden of these lesions correlates with the severity of MR in TSC patients These are calcified subependymal nodules and are one of the major diagnostic criteria for TSC These are malignant subependymal giant cell astrocytomas

Questions

Questions A brain CT scan if obtained in a patient with TSC and it
demonstrates hyperdensities. Which of the following is correct regarding these lesions? These are all malignant and should be resected This patient likely has, in addition to TSC, benign hereditary calcification of the basal ganglia (Fahr disease) The burden of these lesions correlates with the severity of MR in TSC patients These are calcified subependymal nodules and are one of the major diagnostic criteria for TSC (cortical tuber presence and # are what correlate with cognitive function and seizures) These are malignant subependymal giant cell astrocytomas

Questions Which of the following statements is incorrect regarding
the genetics of TSC? It is autosomal recessive with complete penetrance It is autosomal dominant with variable penetrance It can be caused by a mutation in the TSC1 gene that encodes for the protein hamartin It can be caused by a mutation in the TSC2 gene that encodes for the protein tuberin The presence of specific clinical features does not reliably distinguish between the different genetic mutation that can cause this mutation

the genetics of TSC? It is autosomal recessive with complete penetrance It is autosomal dominant with variable penetrance It can be caused by a mutation in the TSC1 gene that encodes for the protein hamartin (tumor suppressor gene on chromosome 16) It can be caused by a mutation in the TSC2 gene that encodes for the protein tuberin (tumor suppressor gene on chromosome 9) The presence of specific clinical features does not reliably distinguish between the different genetic mutation that can cause this mutation

Questions Which is not a common cutaneous presentation of TS?
Ash-leaf macules Confetti macules Lisch nodules Shagreen patches Koenen tumors

Questions Which is not a common cutaneous presentation of TS?
Ash-leaf macules (use Wood’s lamp) Confetti macules (cluster of hypopigmented lesions on extremities) Lisch nodules Shagreen patches (look like orange peel on trunk/back) Koenen tumors (periungal fibromas)

Questions A 12 year old girl with a history of mental retardation
and focal motor seizures presents with the acute onset of weakness of the left face and arm. Exam was notable for a port wine stain in the right V1 distribution, in addition to the reported weakness. Imaging was obtained. This disorder may be associated with which finding(s)? Meningeal angiomas Hydrocephalus Tram tracking calcifications Intracerebral parenchymal angiomas All of the above

Questions A 12 year old girl with a history of mental retardation and focal motor seizures presents with the acute onset of weakness of the left face and arm. Exam was notable for a port wine stain in the right V1 distribution, in addition to the reported weakness. Imaging was obtained. This disorder may be associated with which finding(s)? Meningeal angiomas Hydrocephalus Tram tracking calcifications Intracerebral parenchymal angiomas All of the above Usually sporadic but possible GNAQ on chromosome 9 Weakness from post-ictal Todd’s paralysis but longet lasting/permanent vs. hemorrhage of angioma v.s TIA/stroke like episodes?

Questions Which of the following is not correct regarding NF1?
Renal artery stenosis and pheochromocytoma are on the differential diagnosis of hypertension in NF1 patients There is an association between NF1 and Moyamoya disease The majority of patients with NF1 have severe developmental delay Macrocephaly is the most common head size abnormality seen in NF1 patients and is independent of the extent of hydrocephalus NF1 patients have an increased risk of intracranial aneurysms

Questions A 16 year old boy with NF1 presents with diplopia. An MRI of the brain is done and shows abnormalities in the left optic nerve and in the pons. Which of the following statements is incorrect regarding these abnormalities? He likes has an optic nerve glioma Optic nerve gliomas are common in NF1 Schwannomas and ependymomas are the most common tumors occurring in NF1 patients Optic nerve gliomas in patients with NF1 typically are low grade and often can be monitored for years without intervention In NF1, optic gliomas can occur anywhere along the optic nerve pathways from the nerve to the optic radiations

Questions

Questions A 16 year old boy with NF1 presents with diplopia. An MRI of the brain is done and shows abnormalities in the left optic nerve and in the pons. Which of the following statements is incorrect regarding these abnormalities? He likes has an optic nerve glioma Optic nerve gliomas are common in NF1 Schwannomas and ependymomas are the most common tumors occurring in NF1 patients (more common in NF2, patients with NF1more at risk for astrocytomas – brainstem, cerebral, cerebellar and leukemia) Optic nerve gliomas in patients with NF1 typically are low grade and often can be monitored for years without intervention In NF1, optic gliomas can occur anywhere along the optic nerve pathways from the nerve to the optic radiations

Questions Regarding the arm finding in a patient with NF1 depicted
in the picture, which of the following statements is incorrect? It is a plexiform neurofibroma These types of neurofibromas can invade the skin, causing thickening and skin hypertrophy Plexiform neurofibromas consist of mainly Schwann cells and fibroblasts In a minority of cases, plexiform neurofibromas undergo malignant degeneration into malignant peripheral nerve tumors Plexiform neurofibromas typically regress with age, particularly when they first form at a younger age

Questions

Questions Regarding the arm finding in a patient with NF1 depicted
in the picture, which of the following statements is incorrect? It is a plexiform neurofibroma Enlarge in 50% of patients (especially < 10 yo) Can have cutaneous (arise from dermis) or plexiform (arise from peripheral nerves) neurofibromas Can arise from dorsal root ganglion and invade spinal cord or GI track causing hemorrhage or obstruction These types of neurofibromas can invade the skin, causing thickening and skin hypertrophy (and hyperpigmentation) Plexiform neurofibromas consist of mainly Schwann cells and fibroblasts (and mast cells) In a minority of cases, plexiform neurofibromas undergo malignant degeneration into malignant peripheral nerve tumors Plexiform neurofibromas typically regress with age, particularly when they first form at a younger age

disorders that involve the skin and CNS? Multiple arteriovenous malformations are a manifestation of hereditary hemorrhage telangiectasia (Osler-Weber-Rendu syndrome) Patients with pseudoxanthoma elasticum are at increased risk of cerebral arterial occlusive disease Ehlers-Danlos syndrome is associated with increased risk of intracranial aneurysms and carotid dissection Xeroderma pigmentosa is associated with peripheral neuropathy, cognitive decline, ataxia and hyperkinetic involuntary movements Fabry disease is a multiorgan disorder associated with neuropathy and cerebral artery ectasia and and results from a defect in the enzyme sphingomyelinase

disorders that involve the skin and CNS? Multiple arteriovenous malformations are a manifestation of hereditary hemorrhage telangiectasia (Osler-Weber-Rendu syndrome) (mutation in HHT1gene on chromosome 9) Patients with pseudoxanthoma elasticum are at increased risk of cerebral arterial occlusive disease (connective tissue disorder with yellowish xanthomas in mucosa/skin/retina) Ehlers-Danlos syndrome is associated with increased risk of intracranial aneurysms and carotid dissection Xeroderma pigmentosa is associated with peripheral neuropathy, cognitive decline, ataxia and hyperkinetic involuntary movements (sensitivity to UV light, autosomal recessive mutation in DNA repair enzyme on chromosome 9) Fabry disease is a multiorgan disorder associated with neuropathy and cerebral artery ectasia and and results from a defect in the enzyme sphingomyelinase (X-linked mutation in lysosomal enzyme A-galacosidase)

Questions Regarding the phakomatoses, which of the following
features is not appropriately paired with the specific disorder? Hyperpigmented cutaneous lesions and leptomeningeal melanoma: Neurocutaneous melanosis Hemifacial atrophy: Parry-Romberg syndrome Multipke endochondromas and secondary hemangiomas: Maffucci syndrome Hypopigmented streaks of patches that follow skin lines: Incontinentia pigmenti Retinal, cerebellar, and spinal hemangioblastomas: Von Hippel-Lindau disease

Questions Regarding the phakomatoses, which of the following
features is not appropriately paired with the specific disorder? Hyperpigmented cutaneous lesions and leptomeningeal melanoma: Neurocutaneous melanosis Hemifacial atrophy: Parry-Romberg syndrome Multipke endochondromas and secondary hemangiomas: Maffucci syndrome Hypopigmented streaks of patches that follow skin lines: Incontinentia pigmenti Hypopigmented streaks – Hypomelanosis of Ito Vesiculobullous lesions and “splashed on” hyperpigmented lesions, X-linked dominant (females only), mental retardation, ocular abnormalities – Incontinentia pigmenti Retinal, cerebellar, and spinal hemangioblastomas: Von Hippel-Lindau disease

Questions A 13 year old boy recently diagnosed with TSC undergoes an
MRI of the brain as part of routine surveillance and an image from it is shown. Which of the following statements is incorrect regarding the findings on this MRI? These are known cortical tubers These lesions are hamartomas The burden of such lesions correlates with cognitive function The burden of such lesions correlates with the occurrence and severity of seizures These lesions are premalignant

Questions

Questions A 13 year old boy recently diagnosed with TSC undergoes an
MRI of the brain as part of routine surveillance and an image from it is shown. Which of the following statements is incorrect regarding the findings on this MRI? These are known cortical tubers (cells contain abnormal glia, astrocytes, hypomyelinated axons, bizarre neurons) These lesions are hamartomas The burden of such lesions correlates with cognitive function The burden of such lesions correlates with the occurrence and severity of seizures These lesions are premalignant

Questions A 6 month old boy is seen in the outpatient pediatric neurology department. At birth, he was noted to have hypopigmented streaks on his skin that occurred in a V-shaped on his back and in a linear pattern on his legs, following the skin lines. He also had seizures. Ophthalmologic examination revealed cataracts. Head circumference was 2 standard deviations above the mean. What is the most likely diagnosis in this patient? Neurocutaneous melanosis Incontinentia pigmenti Hypomelanosis of Ito Sturge-Weber syndrome Epidermal nevus syndrome

Questions The skin lesion show below is seen in a neurocutaneous
disorder associated with seizures and hamartomas in multiple body parts. What is the most likely diagnosis in a patient with such a lesion? Tuberous sclerosis complex Neurofibromatosis type 1 Hypomelanosis of Ito Sturge-Weber syndrome Epidermal nevus syndrome

Questions The skin lesion show below is seen in a neurocutaneous
disorder associated with seizures and hamartomas in multiple body parts. What is the most likely diagnosis in a patient with such a lesion? Tuberous sclerosis complex (forehead plaque) Neurofibromatosis type 1 Hypomelanosis of Ito Sturge-Weber syndrome Epidermal nevus syndrome

Questions An 8 year old boy with seizures presents with headache. A
MRI of the brain is obtained and image shown below. What disorder does this patient likely have? Tuberous sclerosis complex Neurofibromatosis type 1 Neurofibromatosis type 2 Sturge-Weber syndrome He probably does not have a neurocutaneous disorder, this tumor is most often seen sporadically

Questions

Questions An 8 year old boy with seizures presents with headache. A
MRI of the brain is obtained and image shown below. What disorder does this patient likely have? Tuberous sclerosis complex (SEGA) Neurofibromatosis type 1 Neurofibromatosis type 2 Sturge-Weber syndrome He probably does not have a neurocutaneous disorder, this tumor is most often seen sporadically

the genetics and molecular biology of NF1? NF1 results from a mutation in the neurofibromin gene on chromosome 17 Neurofibromin activates a GTPase that inhibits the ras proto-oncogene, a protein involved in cell proliferation Several mutations in the NF1 gene have been identified, but in general, strong phenotype-genotype correlations do not occur NF1 in an autosomal recessive disorder

the genetics and molecular biology of NF1? NF1 results from a mutation in the neurofibromin gene on chromosome 17 Neurofibromin activates a GTPase that inhibits the ras proto-oncogene, a protein involved in cell proliferation Several mutations in the NF1 gene have been identified, but in general, strong phenotype-genotype correlations do not occur NF1 in an autosomal recessive disorder (autosomal dominant but 50% causes sporadic)

Questions A 52 year old man presents for evaluation of right ear hearing loss with vertigo. His MRI shows bilateral vesticular schwannomas. He has family history of bilateral vestibular schwannomas and multiple meningiomas in his mother. Which of the following statements is incorrect regarding the disorder depicted? It is autosomal dominant in inheritance It results from a mutation in the merlin gene on chromosome 22 Various CNS tumors including schwannomas, meningiomas, astrocytomas, and ependymomas can occur in this disorder Cutaneous findings such as neurofibromas and axillary freckling are common in this disorder Subcapsular cataracts are a feature of this disorder

Questions A 52 year old man presents for evaluation of right ear hearing loss with vertigo. His MRI shows bilateral vesticular schwannomas. He has family history of bilateral vestibular schwannomas and multiple meningiomas in his mother. Which of the following statements is incorrect regarding the disorder depicted? It is autosomal dominant in inheritance It results from a mutation in the merlin gene on chromosome 22 Various CNS tumors including schwannomas, meningiomas, astrocytomas, and ependymomas can occur in this disorder Cutaneous findings such as neurofibromas and axillary freckling are common in this disorder More common in NF1 NF2 with plexiform cutaneous schwannomas, café-au-lait Subcapsular cataracts are a feature of this disorder

Questions A 2 month old infant is being evaluated for developmental delay. MRI of the brain shows atrophy with bilateral subdural hematomas. Examination shows hypotonia, coarse brittle hair, hyperelastic skin and absent eyebrows. What is the most likely diagnosis in this patient? Menke’s disease Wilson disease Ehlers-Danlos syndrome Nonaccidental injury (child abuse) Hypomelanosis of Ito

Questions A 2 month old infant is being evaluated for developmental delay. MRI of the brain shows atrophy with bilateral subdural hematomas. Examination shows hypotonia, coarse brittle hair, hyperelastic skin and absent eyebrows. What is the most likely diagnosis in this patient? Menke’s disease X-linked recessive ATP7A gene mutation (copper transporter) resulting in copper deficiency everywhere Various enzymes use copper as cofactor so leads to loss of neurons and gliosis in cortex, subcortical, thalamus, cerebellum Wilson disease ATP7B gene mutation leading to copper toxicity Ehlers-Danlos syndrome Nonaccidental injury (child abuse) Hypomelanosis of Ito

Questions A 15 year old girl was noted to have several café-au-lait
spots on her trunk and limbs, axillary freckling and several subcutaneous neurofibromas. Upon further questioning, it was found that her mother had similar features. As the patient was complaining of new onset headaches, imaging was performed. Associated MRI/MRA findings may include: A moyamoya vascular pattern An optic nerve glioma Cranial nerve schwannomas Thalamic and basal ganglia hyperintensities All of the above

Questions Which of the following does not cause megalencephaly?
Thickened skull Cerebral edema Canavan disease Neurofibromatosis type 1 Fragile X

Questions What term best describes this lesion? Periungual hematoma
Cutaneous neurofibroma Subungual fibroma Periungal fibroma Angiokeratoma

Questions What term best describes this lesion?
Periungual hematoma (traumatic and resolve with time, darker) Cutaneous neurofibroma Subungual fibroma (under fingernail also major criteria for TSC) Periungal fibroma Angiokeratoma (purplish lesions see in intertriginous areas in Fabry disease)

Questions What is the following lesion? Kayser-Fleisher rings
Brushfield spots Lisch nodules Iris coloboma Iris mamillations

Questions What is the following lesion?
Kayser-Fleisher rings (Wilson disease) Brushfield spots (white spots in Down syndrome) Lisch nodules (iris melanocytic hamartomas seen in NF1, no clinical implications) Iris coloboma (defect in iris seen in CHARGE, epidermal nevus syndrome) Iris mamillations (hyperpigmented iris lesions)

Questions What is the following is incorrect regarding epidermal
nevus syndrome (ENS)? This syndrome is a manifestation of a hetereogenous group of disorders that share in common the presence of epidermal nevi Hemimegalencephaly may occur ipsilateral to a facial nevus The epidermal nevi in this disorder may undergo malignant transformation There is an increased risk of astrocytoma and other tumors in patients with ENS Lisch nodules are a feature of ENS

Questions A 9 year old presents to pediatrician for
routine follow-up. On exam he has more than 6 hyperpigmented lesions. He also has the lesions depicted in the picture on trunk, face, extremities. What term best describes these lesions? Ash-leaf spots Plexiform neurofibromas Cutaneous neurofibromas Shagreen patches Café-au-lait spots

Questions Which of the following is NOT a feature of tuberous
sclerosis? Facial angiofibromas Cardiac rhabdomyomas Lisch nodules Renal angiomyolipomas

Questions Which of the following is NOT a feature of tuberous
sclerosis? Facial angiofibromas Cardiac rhabdomyomas Lisch nodules (associated with NF1) Renal angiomyolipomas

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