NEUROECTODERMAL DISORDER - keywords
neuroectodermal disorder
references to neuroectodermal disorders
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Habibi Z, Ebrahimi H, Meybodi KT, Yaghmaei B, Nejat F. Clinical Follow-Up of Patients with Neurocutaneous Melanosis in a Tertiary Center; Proposed Modification in Diagnostic Criteria. World Neurosurg. 2021 Feb;146:e1063-e1070.
Hu J, Yu Y, Juhasz C, Kou Z, Xuan Y, Latif Z, Kudo K, Chugani HT, Haacke EM (2008) MR susceptibility weighted imaging (SWI) complements conventional contrast enhanced T1 weighted MRI in characterizing brain abnormalities of Sturge-Weber Syndrome. J Magn Reson Imaging 28: 300-7.
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Lago P, Boniver C, Casara GL, Laverda AM, Fiore A, Salvadori S, Carollo C, Saia OS (1994) Neonatal tuberous sclerosis presenting with intractable seizures. Brain Dev 16:257–259.
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Simonati A, Colamaria V, Bricolo A, Bernardina BD, Rizzuto N (1994) Microgyria associated with Sturge-Weber angiomatosis. Childs Nerv Syst 10:392–395.
Slasky SE, Shinnar S, Bello JA (2006) Sturge-Weber syndrome: deep venous occlusion and the radiologic spectrum. Pediatr Neurol 35: 343-7.Swetman, GL, Lee, DH, Benjamin LT (2011) Nevi in the newborn. NeoReviews 12,4,e207-e214.
Terpstra-Prinsen EBF, Kamphuis-Van Ulzen K, Liem KD. Early appearance of tuberous sclerosis complex on cerebral ultrasound in extremely preterm infant. J Neonatal Perinatal Med. 2017;10(2):203-206.
Vézina G. Neuroimaging of phakomatoses: overview and advances. Pediatr Radiol. 2015 Sep;45 Suppl 3:S433-42.
Wang D-D, Blümcke I, Coras R, Zhou W-J, Lu D-H, Gui Q-P, Hu J-X, Zuo H-C, Chen S-Y, Piao Y-S (2014) Sturge–Weber Syndrome Is Associated with Cortical Dysplasia ILAE Type IIIc and Excessive Hypertrophic Pyramidal Neurons in Brain Resections for Intractable Epilepsy. Brain Pathology 25; 248-255.
Barth et al. 1978, Frank et al. 1984, Legge et al. 1984, Braffman and Naidich 1994, Lago et al. 1994, Miller et al. 1998, Roach et al. 1998, Baron and Barkovich 1999, Mizuguchi and Takashima 2001, Narayanan 2003
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Tuberous sclerosis (TSC) is an autosomal-dominant disorder that may present with seizures, skin lesions and hamartomas affecting multiple organ systems such as heart, brain, eye, and kidney. 16% Present within a positive family history (Barth et al. 1978, Frank et al. 1984, Legge et al. 1984, Braffman and Naidich 1994, Lago et al. 1994, Miller et al. 1998, Roach et al. 1998, Baron and Barkovich 1999, Mizuguchi and Takashima 2001, Narayanan 2003). Cardiac rhabdomyoma(s), arrhythmia, non-immune hydrops, and stillbirth are the major presenting findings in the fetus. Respiratory distress, arrhythmia, heart murmur and cardiomegaly are the main signs in the neonate. Skin lesions and retinal hamartomas are rarely noted at birth, kidney cysts on the contrary may be observed with ultrasound. Early indicators of subependymal nodules and cortical hamartomas have been reported (Terpstra-Prinsen et al. 2017). Survivors frequently develop epilepsy and some mental retardation.
This disorder is characterized by multiple hamartomas in several organs, particularly the brain. TSC is therefore not purely ectodermal. Common features include hypomelanotic skin macules, facial angiofibromas, periungual fibromas, delayed development and seizures. The kidney (angiomyolipoma, microscopic but rarely also macroscopic cysts), heart (rhabdomyoma), and retina (astrocytoma) are among other commonly affected organs. The criteria for diagnosis were revised by Roach et al. 1998.
Although the majority of cases are sporadic, genetic linkage studies of familial cases led to the discovery of two separate genes linked to tuberous sclerosis complex: TSC1, located at chromosome 9q34, encoding a protein called hamartin; and TSC2, located at chromosome 16p13.3, encoding a protein called tuberin. Tuberin is functioning in a cellular signaling pathway. Hamartin binds to ezrin and other proteins, which link the cell membrane to the cytoskeleton. The tuberin-hamartin complex can participate in many pathways, including those that involve cell growth, cell proliferation, intracellular trafficking, cell adhesion, and cell migration.
other neurocutaneous disorders
typical images
algorithm
most common neuroectodermal (neurocutaneous) disorders: tuberous sclerosis complex
neurofibromatosis and Sturge-Weber syndrome
As early as the second trimester, TSC may present with cerebral anomalies. Three are characteristic: subependymal nodule, giant cell astrocytoma and (sub)cortical hamartoma (tuber)(Vezina 2015). In all giant cells of undefined lineage are present: they share characteristics with neurons and astrocytes alike. Already in neonatal cases calcified spherules may occur in both periventricular and peripheral hamartomas. All these lesions can be normo- or hyperechoic, and may be iso- or hypodense on CT, unless calcified. Gadolinium-enhancement is obvious in giant cell astrocytomas, less pronounced but present in tubers and in between in subependymal nodules. Tubers are hypometabolic, relatively hypoperfused on SPECT scans. There are exceptional cases of TSC with hemimegalencephaly. Cerebellar tubers develop also in many patients.
Subependymal nodules, consisting of abnormal glial cells, are spread against the ependyma of the lateral and possibly third or fourth ventricles, like fat dripping off a candle (candle gutterings). Those nodules may allow a provisional diagnosis in newborn infants presenting with cardiac failure due to an associated rhabdomyoma or, much less common, with large renal cysts. Especially in parasagittal sonographic sections they show up as small round echoic figures in the floor or lateral wall of the body of the lateral ventricle, typically protruding into the cavity. They are typically found near the caudothalamic groove, but may appear anywhere in any ventricle. Their longest axis is often perpendicular to the ventricle wall.
Sturge-Weber syndrome
dizygous twin at 30w GA, scans at 33w PMA; this twin cardiac rhabdomyoma
term infant with tuberous sclerosis and neonatal seizures
linear nevus sebaceus
MegalencephalyCM
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term boy with anal atresia, asymmetric face and eyes (right microphtalmia) and seizures: hemidysplasia on the right (see axial T2 MRI), bilateral colpocephaly and callosal agenesis.
term infant with third day seizures and skin lesions on the forehead and in the neck diagnostic of linear nevus sebaceus: callosal agenesis and abnormal gyrational pattern of the right insular area
term infant with complete callosal agenesis and familial neurofibromatosis
courtesy dr Schwarz, Essen
3 months old girl, with focal right seizures; left facial nevus flammeus, ocular angioma
tuberous sclerosis
hemidysplasia
term infant with marbled skin and megalencephaly with seizures
neurofibromatosis
tuberous sclerosis: hemiM
neurocutaneous disorders: typical imaging
Epidermal nevus syndrome (linear nevus sebaceus) may present with pigmented nevi on the forehead and neck, and hemihypertrophy of the body from birth. Patients develop intractable seizures, mental retardation and hemiparesis. Neuroimaging shows hemimegalencephaly (‘hemipachygyria with colpocephaly’)(Wang et al. 1983, El-Shanti et al. 1992). Exceptionally hamartomas, arachnoid cysts, arterial aneurysm, cerebellar agenesis and callosal agenesis were described.
Naevoid basal cell carcinoma syndrome (Gorlin syndrome) is caused by heterozygous mutations in the tumour suppressor PTCH1. It may present at birth with macrocephaly, retinal tumour, myocardial tumour, bifid ribs and/or hemivertebrae. Brain findings: mild communicating hydrocephalus, cysts in choroid plexus, intraluminal ependymal nodules, agenesis of the corpus callosum and medulloblastoma (Cramer and Niederdellmann 1983, Bholah et al. 2014).
PHACES syndrome is described with stroke and arterial anomalies. Incontinentia pigmenti is described with genetic inflammatory vasculopathies.
Rhombencephalosynapsis (RES) is a rare congenital anomaly of the hindbrain characterized by fusion of the cerebellar hemispheres, cerebellar peduncles, and dentate nuclei with vermian absence or hypogenesis. It has been associated with VACTERL and Gomez-Lopez-Hernandez syndrome (GLHS). The most common congenital syndrome associated with RES is GLHS. Presentation is with RES, bi-parietal scalp alopecia, trigeminal aneesthesia, borderline hypertelorism, midface retrusion, and motor delay.
Neurocutaneous melanosis is a non-familial neurocutaneous syndrome characterized by large melanocytic nevi and excessive proliferation of melanocytes cells in the leptomeninges. Patients present with hydrocephalus, seizures, cranial nerve palsies and myelopathy. MRI findings are hypersignal lesions in the temporal lobe (75%), cerebellum (62.5%), brainstem (50%) and thalamus (12.5%)(Habibi et al. 2021). Dandy-Walker syndrome and shunt-dependent hydrocephalus are not uncommon. Malignancy affects skin and brain in about 1/3. Hemimegalencephaly is possible (Kumar et al. 2019).
other neuroectodermal (neurocutaneous) disorders
Hypomelanosis of Ito can trigger encephaloclastic brain lesions (Rosemberg et al. 1984, Glover et al. 1989, Gordon 1994). Focal or global brain atrophy may occur together with porencephaly. Involvement of white matter imitates a leukodystrophic process; this shows on MRI with abnormal signals, mostly in the parietal lobes. Extensive and deep changes are associated with more severe neurologic abnormalities and delayed language. These anomalies of white matter underly a disarray of cortical lamination and neuronal loss.
Encephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome is characterized by unilateral lipomatous hamartomata of the scalp, eyelid, and outer globe of the eye and ipsilateral brain malformations presenting with epilepsy.
Klippel-Trenaunay-Weber syndrome (KTW) is a rare phacomatosis presenting with cutaneous angiomas (vascular nevi), varicose veins (arteriovenous fistulae), hemihypertrophy of bones and soft tissues and hemimegalencephaly.
Proteus syndrome may present with hemimegalencephaly and asymmetric overgrowth of tissues, skin abnormalities and hypotonia.
Megalencephaly due to phakomatosis may present in with neonatal seizures, macrocrania without widening of the subarachnoid spaces. The affected zones (gliomatosis cerebri) can initially be asymmetric, giving rise to hemimegalencephaly (most often, not necessarily) without ventriculomegaly (Jennings et al. 1995, Gooskens et al. 1998, Putra and Al-Ibraheemi 20025). Hemimegalencephaly is exceptionally recognized in a neonatal ultrasound scan. Perfectly symmetrical scanning may not permit to have the interhemispheric fissure exactly sagittal due to a shift toward the smaller (normal) hemisphere.
Clinically recognizable types: MCM (megalencephaly with capillary malformation)(Andrade et al. 2025); MPPH (megalencephaly, polymicrogyria, polydactyly and hydrocephalus).
Sturge-Weber syndrome is exclusively sporadic. It presents at birth with a capillary malformation on the face (port-wine birthmark) with later diagnosis of abnormal vasculature in the eye and the brain which result in a range of complications. The underlying somatic mosaic mutation is an activating mutation in GNAQ (Comi 2015, Vezina 2015). GNAC defects cause a dysregulation of endothelin, resulting in vascular endothelial dysgenesis, cortical venous capillary hypogenesis, and potentially small vessel thromboses —> leading to venous congestion and collateral flow in relation to the extent of the dysplasia.
This neurocutaneous entity presents with facial port-wine nevus, followed by glaucoma, seizures and hemiparesis. Involvement of the skin is typically in the trigeminus V1 and V2 territory. Characteristic is leptomeningeal angiomatosis with disturbed pial venous drainage compensated for by centripetal escape via enlarged medullary collaterals or anomalous deep veins (a.o. choroidal) into the great cerebral vein. Non-thrombotic veno-occlusive processes start in utero and progress after birth. The underlying parenchyma may undergo necrosis, with calcification. Lobar haemorrhage is one of the complications (Aguglia et al. 2008). A subgroup of infants with Sturge-Weber syndrome present with focal cortical dysplasia that can be classified as polymicrogyria, especially associated with early postnatal seizures (Simonati et al. 1994, Wang et al. 2014), which indicates onset during the second trimester of pregnancy.
(progressive) Deep venous outflow occlusion with frontal venous collaterals can be an imaging finding (Cure et al. 1995, Slasky et al. 2006). Hydrocephalus and megalencephaly may be related to venous changes (Fishman and Baram 1986). MRI features include leptomeningeal angiomatosis, cortical-pial calcification and vascular changes in choroid plexus. SWI is superior to T1-Gd in identifying enlarged veins, cortical gyriform abnormalities and grey matter/white matter junction abnormalities (Hu et al. 2008). High-resolution BOLD MR venography also allows early diagnosis of venous anomalies in Sturge-Weber syndrome. (Mentzel et al. 2005). Highlighting of sulci by hyperechoic change in underlying white matter is also visible in sonograms, in the pericentral and insular area (Ferraz et al. 2019). Brain abnormalities tend to be progressive, resulting in focal or diffuse hemiatrophy with compensatory calvarial thickening and sinus hyperpneumatization.
most common neuroectodermal disorders: neurofibromatosis and Sturge-Weber syndrome
Noonan syndrome (NS) and neurofibromatosis type I (NF1), autosomal dominant disorders, belong to a group sharing dysregulation of the RAS-MAPK pathway. Skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Neurofibromatosis (NF1 gene, neurofibromin) presents with unexplained neonatal seizures, callosal agenesis or congenital hydrocephalus due to aqueduct stenosis and megalencephaly (Vezina 2015). Rare presentations is with a neurofibroma at the craniocervical junction inducing upper cervical cord and lower brainstem compression with complete apnoea from birth (Clarke et al. 1994, DiPaolo et al. 1995, Marcorelles et al. 2005). Characteristic of neurofibromatosis are hyperintense T2 (whitening, spongiotic) lesions (iso- or midly hyperintense on T1) seen in up to 75–90% of pediatric patients with NF-1; decreasing in prominence with aging. They are found in the brainstem, middle cerebellar peduncles, cerebellar white matter, cerebral peduncles, basal ganglia (especially pallidum), thalamus and internal capsule. Never in subcortical cerebral white matter. They are multiple, have little or no mass effect and do not enhance after administration of paramagnetic contrast. They reflect myelin vacuolization, leading to edema and increased diffusion characteristics on MR.
Suggestive neonatal presentations are renovascular hypertension and hypertrophic cardiomyopathy, due to vascular dysplasia. Later develop optic glioma, gradual macrocephaly, hamartomas of hypothalamus and brainstem, neurofibromas.
neuroectodermal (neurocutaneous) disorders algorithm
Neurocutaneous syndromes (NCS), also known as phakomatoses, form a heterogeneous group with abnormal differentiation of ectoderm inducing abnormalities of integument and central nervous system. Most are autosomal dominant with variable penetrance. The diagnosis is based on a combination of characteristic clinical features (non-infectious skin changes and/or asymmetric overgrowth, seizures, neurological deficit and vascular abnormalities) and relevant findings with neuroimaging, genetic analysis and skin histology.
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