Neurocutaneous disorders Flashcards
Phakomatoses
Group of disorders with occurrence of dysplastic lesions and the tendency for tumor formation
Neurofibromatosis, tuberous sclerosis, Sturge–Weber syndrome (SWS), epidermal nevus syndrome (ENS), and HI.
Hypomelanosis of Ito
Involves multiple organ systems including the skin, eyes, brain, and skeleton. Cutaneous features of HI: multiple hypopigmented streaks or patches present at birth vs emerge in infancy and can follow Blaschko lines (skin lines that form specific patterns over the trunk and extremities, such as a V shape over the back and linear lines over the limbs), best seen in light skin children under UV light
Neurological features: ID, seizures, macrocephaly >microcephaly, cerebral hypoplasia and cerebellar hypoplasia, other malformations of cortical development: hemimegalencephaly and lissencephaly
Other: eye involvement (microphthalmia, cataracts, optic atrophy, and retinal detachment), skeletal hemihypertrophy, cleft lip and palate, and congenital heart disease such as tetralogy of Fallot
Associated with mosaicism for aneuploidy or unbalanced translocations, mosaic trisomy 18, ring chromosome 22, and translocations involving the X chromosome. There is not a clear genotypic–phenotypic correlation.
Incontinentia pigmenti
XLD, NEMO gene
Vesiculobullous lesions present at birth, verrucous lesions that appear at approximately 6 weeks of age, and then hyperpigmented lesions that follow the Blaschko lines (lines of skin development)
Neurologic manifestationsL intellectual impairment, pyramidal tract findings, and ocular abnormalities.
Neurocutaneous melanosis
Various types of congenital cutaneous lesions that are abnormally pigmented (such as giant hair pigmented nevi and congenital melanocytic nevi) in association with leptomeningeal melanosis, hydrocephalus is a common complication
Parry–Romberg syndrome
Progressive loss of facial tissue, cartilage, and bone -> hemifacial atrophy, with ipsilateral loss of eyelashes, eyebrows, and scalp hair.
Early childhood and the atrophy progression stops by the third decade of life. Neurologic manifestations: headaches, Horner’s syndrome, seizures, and hemiparesis.
At increased risk of a variety of benign tumors.
Maffucci’s syndrome
Multiple enchondromas (tumors of cartilage) with secondary hemangioma formation and various skin findings, including vitiligo, hyperpigmented patches and nevi, and café-au-lait spots. These enchondromas grow over time, leading to disfigurement and skeletal abnormalities.
Neurologic manifestations result from the association of this syndrome with various CNS tumors, including pituitary and brainstem tumors and other gliomas. Also from compression by the enchondromas.
NF1
An autosomal dominant neurocutaneous disorder caused by a mutation in the neurofibromin (NF1) gene located in chromosome 17q11.2.
To make a dx of NF1 requires two or more of the following: six or more café au lait macules (>5 mm in diameter in prepuberty or >15 mm in diameter in postpuberty), inguinal or axillary freckling (as shown in Fig. 14.7), two or more cutaneous neurofibromas or one plexiform neurofibroma (see question 54), two or more Lisch’s nodules (iris hamartomas), optic pathway glioma, b_ony lesion (such as sphenoid wing dysplasia, or thinning of long bone cortex with or without pseudarthrosis_), and/or NF1 diagnosed in a first-degree relative.
Legius’s syndrome
AD cutaneous syndrome 2/2 mutations inSPRED1 gene located at 15q14.
Skin: café au lait macules and axillary and inguinal freckling just like NF1
Unlike NF1, NOT associated with optic gliomas, neurofibromas, Lisch’s nodules, nor risk of malignancy.
See mild dysmorphisms and mild ID
Lisch’s nodules
Lisch’s nodules, or iris melanocytic hamartomas: pathognomonic for neurofibromatosis type 1 (NF1).
No clinical implications beyond their occurrence in NF1 - do not cause symptoms or progress to other ophthalmologic abnormalities.
MC appear after the age of 6 years, their absence does not exclude the diagnosis of NF1.
Asymptomatic retinal hamartomas less commonly occur.
Congenital or childhood glaucoma ipsilateral to a plexiform neurofibroma of the eyelid is another ophthalmologic manifestation of NF1.
NF1 cancers
Cancers in NF1: Optic nerve gliomas are the most common tumor of the CNS seen in patients with NF1: can be unilateral or bilateral, often low-grade lesions but may cause symptoms due to mass effect and _may cause precocious puberty when they compress diencephalic strctures, can occur anywhere along the optic pathway_s, from the optic nerve to the optic radiations. Lesions are often benign, so serial imaging over time is often used to monitor these tumors, with chemotherapy, radiation, or surgery instituted as necessary. On MRI, nonspecific subcortical T2 hyperintensities (in the basal ganglia, thalamus, and other regions) are common in patients with NF1 and are of unclear etiology and significance; these may be hamartomatous or dysmyelinating and are referred to commonly by their appearance as “unidentified bright objects” or UBOs.
Schwannomas and ependymomas can occur but are rare in NF1, more commonly occur in NF2. Patients with NF1 are at an increased risk of cerebral, cerebellar, and brainstem astrocytomas. Since the NF1 gene functions as a tumor suppressor, patients with NF1 are also at an increased risk for leukemia and other malignancies.
Tuberous sclerosis
AD, mutations in either TSC1 (HAMARTIN, 9q34.13) or TSC2 (TUBERIN, 16p13.3)
Major features: Hypomelanotic macules (three or more of at least 5 mm in diameter, including ashleaf spots), angiofibromas (three or more) or fibrous cephalic plaque, ungual fibromas (two or more), shagreen patch, multiple retinal hamartomas, cortical dysplasias (including tubers and cerebral white matter radial migration lines), subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, angiomyolipomas (two or more)
Minor features: “Confetti” skin lesions (hypopigmented, stippled lesions on the extremities), dental enamel pits (more than three), intraoral fibromas (two or more), retinal achromic patch, multiple renal cysts, nonrenal hamartomas
Definitive dx: 2 major features or 1 major and 2 minor features
Possible dx: 1 major feature or two or more minor features.
The combination of lymphangioleiomyomatosis and angiomyolipomas without other features does not meet criteria for a definite diagnosis.
A genetic diagnosis of TSC can be made by identifying TSC1 or
TSC2 pathogenic mutation in DNA from normal tissue, in which the mutation clearly inactivates the function of either of these proteins. A normal result on genetic testing does not exclude TSC, since approximately 10% to 25% of patients with TSC have no mutation found on conventional genetic testing.
Ungual fibromas
This is one of the cutaneous findings of tuberous sclerosis complex (TSC) and is one of the major criteria for diagnosis. This should be distinguished from traumatic periungual hematomas, which are typically darker in color and resolve with time.
SEGA
Subependymal giant cell astrocytoma (SEGA): uncommon tumor, seen almost exclusively in patients with tuberous sclerosis complex (TSC) and is a major diagnostic criterion for TSC.
This is a benign, low-grade astrocytoma but leads to symptoms due to mass effect and ventricular obstruction. Surgery is usually curative. Rapamycin=sirolimus, mTOR kinase inhibitor may be of benefit in the treatment of SEGA and other TSC-related tumors.
NF1
Neuropsychiatric - normal condition, mild developmental delay, behavioral problems, learning disabilities - 1/2 of patients
HTN 2/2 renal artery stenosis/renal artery dysplasia, pheochromocytoma
Moya-moya and other intracranial arterial abnormalities including intracranial aneurysms
Macrocephaly is common, occurs independent of hydrocephalus, although aqueductal stenosis may occur in NF1.
Thinning of the cortex of long bones and other long bone dysplasias -> pathologic fractures and pseudarthrosis. Other skeletal abnormalities in NF1 include scoliosis and sphenoid wing dysplasia.
TSC dx
Cardiac: Single or multiple cardiac rhabdomyomas - majority regress over time but some may cause HF due to obstruction/cardiomyopathy, arrhythmias, strokes and required surgical/medical management
Renal: Renal angiomyolipomas: benign tumors consisting of vessels, smooth muscle, and fat, occur in >=1/2 patients. Large lesions may need to be embolized, rapamycin inhibits growth. They can evolve into RCC so periodic RUS is record.
Pulmonary: Lymphangiomyomatosis is a rare, often fatal pulmonary disease occurring most often in female patients with TSC. Treatment: progesterone or estrogen receptor modulator tamoxifen, but disease is often fatal a few years after onset. Patients with TSC, especially women, should undergo chest imaging if respiratory symptoms arise.
Eye: Retinal hamartomas, retinal detachment, vitreous hemorrhage
