Neurocutaneous Syndrome - by MHR Corporation


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Neurocutaneous Syndrome - by MHR Corporation

  1. 1. Neurocutaneous Syndrome MOHD HANAFI RAMLEE
  2. 2. Neurocutaneous Syndromes • The neurocutaneous syndromes include a heterogeneous group of disorders characterized by abnormalities of both the integument and central nervous system. • Most disorders are familial, believed to arise from a defect in differentiation of the primitive ectoderm.
  3. 3. Phakomatoses 1. Neurofibromatosis 2. Tuberous sclerosis 3. Ataxia telangiectasia 4. Sturge-Weber syndrome 5. von Hippel-Lindau disease 6. Incontinentia pigmenti 7. Nevoid basal cell carcinoma syndrome
  4. 4. 5 years old boy brought to your office for • behavioral evaluation PE reveals • short stature • large head • skin spots
  6. 6. Neurofibromatosis • Café au Lait spot • Discrete, well-circumscribed uniformly brown lesions with irregular border • 2 - 20 mm • Isolated lesions occur in 10 - 20% of population; 98% of normal individuals have less than three lesions
  7. 7. Café au Lait spot • cafe-au-lait spots: are not necessarily a diagnostic sign of NF • Multiple lesions occur in a variety of syndromes: N • Neurofibromatosis V • Von Hippel – Lindau disease A • Fanconi anemia • Ataxia Telangiectasia T • Tuberous sclerosis S • Silver-Russell dwarfism B • Bloom syndrome • Basal cell nevus syndrome • Gaucher disease H • Chédiak-Higashi syndrome • Hunter syndrome M • Marfan's syndrome • Maffucci syndrome • McCune-Albright syndrome • Multiple endocrine neoplasia type 2 P • Peutz-Jeghers Syndrome
  8. 8. Neurofibromatosis • NF1 and NF2 are autosomal dominant, with approximately 50% of cases having no family history • NF1 is also called von Recklinghausen disease • NF2 is also called bilateral acoustic neurofibromatosis
  9. 9. Neurofibromatosis • ETIOLOGY • NF1 is caused by DNA mutations located on the long arm of chromosome 17 responsible for encoding the protein neurofibromin. • NF2 is caused by DNA mutations located in the middle of the long arm of chromosome 22 responsible for encoding the protein merlin.
  10. 10. Neurofibromatosis EPIDEMIOLOGY& DEMOGRAPHICS • NF1 is the most common neurocutaneous syndrome, affecting approximately 1/3000 persons • NF2 occurs in about 1/50,000 • Equally affects males and females.
  11. 11. Neurofibromatosis • PHYSICAL FINDINGS & CLINICAL PRESENTATION • Common features of NF1 include: • Café-au-lait macules (100% of children by age 2) • Hyperpigmented skin lesions occurring anywhere on the body except the face, palms, and soles • Appear early in life and increase in size and number during puberty • Focal or diffuse • Axillary and inguinal freckling (70%) • Multiple cutaneous and subcutaneous neurofibromas (95%) • Firm, varying in size from mm to cm • Vary in number from a few to thousands • May be sessile, pedunculated, regular or irregular in shape • Lisch nodule (small hamartoma of the iris) found in >90% of adult cases • Visual defects possibly related to optic gliomas (2% to 5%) • Neurodevelopment problems (30% to 40%) • Common features of NF2 include: • Hearing loss and tinnitus related to bilateral acoustic neuromas (>90% of adults) • Cataracts (81%) • Headache • Unsteady gait • Cutaneous neurofibromas but less than NF1 • Café-au-lait macules (1%)
  12. 12. Neurofibromatosis Axillary freckles • Small (0.5cm) brown, well- circumscribed macules • Generally go unnoticed • High correlation with neurofibromatosis when six or more freckles are present in the axilla
  13. 13. Neurofibromatosis Lisch Nodules a pigmented hamartomatous nevus (a type of benign tumor) affecting the iris
  14. 14. Neurofibromatosis Multiple cutaneous and subcutaneous neurofibromas
  15. 15. Neurofibromatosis Acoustic Neuroma In NF2
  16. 16. Neurofibromatosis Spinal Neurofibroma
  17. 17. Neurofibromatosis • Scoliosis
  18. 18. Neurofibromatosis Intraspin al tumors
  19. 19. Neurofibromatosis • DIAGNOSIS • NF1 is diagnosed if the person has two or more of the following features: • Six or more café-au-lait macules >5 mm in prepubertal patients and >15 mm in postpubertal patients • Two or more neurofibromas of any type or one plexiform neurofibroma • Axillary or inguinal freckling • Optic glioma • Two or more Lisch nodules (iris hamartomas) • Sphenoid wing dysplasia or cortical thinning of long bones, with or without pseudarthrosis • A first-degree relative (parent, sibling, or child) with NF1 based on the previous criteria
  20. 20. Neurofibromatosis • DIAGNOSIS • NF2 is diagnosed if the person has either of the following two criteria: • Bilateral eighth nerve masses seen by appropriate imaging studies • OR • a unilateral eighth nerve mass • A first-degree relative with NF2 and either • or two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity
  21. 21. Neurofibromatosis • WORKUP • LABORATORY TESTS • Genetic testing is available. Results can only tell if an individual is affected but cannot predict the severity of the disease. • In NF2, linkage analysis testing provides a >99% certainty the individual has NF2. • IMAGING STUDIES • MRI with gadolinium is the imaging study of choice in both NF1 and NF2 patients. MRI increases detection of optic gliomas, tumors of the spine, acoustic neuromas, and “bright spots” thought to represent hamartomas.
  22. 22. Neurofibromatosis • TREATMENT • Primarily supportive • AEDs for seizures • Surgery for for accessible tumors • Orthopedic procedures for bony deformities • Routine MRI studies to screen for optic gliomas in nonsymptomatic children
  23. 23. • 14 years old girl was brought to you for facial rash. You found out that the girl has been in special education and getting treatment for seizures.
  25. 25. Tuberous Sclerosis • The classic clinical triad is skin lesions in association with epilepsy and mental retardation. • Multisystemic disorder affecting primarily tissues derived from ectoderm but also involving organs of mesodermal and endodermal origin, particularly the eyes, kidneys, and heart.
  26. 26. Tuberous Sclerosis ETIOLOGY AND EPIDEMIOLOGY • Autosomal dominant condition with variable expression and an estimated frequency of 1/6,000 . Mutations have been mapped to chromosome 9q34 (TSC1) and 16p13.3 (TSC2). • The TSC2 product is tuberin, which has sequence homology with a GTPase-activating protein and may have a role in regulating cellular growth by acting as a growth suppressor gene. • TSC1 also is postulated to act as a growth suppressor. • Approximately half of cases are due to new mutations.
  27. 27. Tuberous Sclerosis Clinical Manifestations ash-leaf macule • the most reliable early cutaneous sign. • presents at birth or in early infancy, often years before other signs of the disease. • seen in more than 90% of cases in this age group. • also appear in 2–3/1,000 normal newborns. • they are sharply demarcated, pale, 0.5– 3cm lesions that often assume the shape of a mountain ash leaflet.
  28. 28. Tuberous Sclerosis Clinical Manifestations Shagreen patch • Is present by 15 years in 50% of affected children • Most often occurs on trunk or in lumbosacral area but can occur on any glabrous skin • Discrete, usually flesh-colored, flat to slightly elevated lesions with a “pig-skin” or “orange-peel” appearance • Highly variable in size • Are plaques of subepidermal fibrosis
  29. 29. Tuberous Sclerosis Clinical Manifestations Café-au-lait spots • occur with increased frequency but are not as numerous as in neurofibromatosis
  30. 30. Tuberous Sclerosis Clinical Manifestations Adenoma sebaceum • Present in approximately 50%of patients who are > four years old; unusual before 4 years of age • Earliest manifestations are erythema that slowly progresses to flesh- colored to pink lesions at nasolabial folds, malar region, chin, forehead and, sometimes, the scalp • Often confused with acne • Are actually angiofibromas
  31. 31. Tuberous Sclerosis Clinical Manifestations Subungual fibromas • arise from the stratum lucidum of the finger and toe in many patients with TS during adolescence.
  32. 32. Tuberous Sclerosis Clinical Manifestations Periungual Fibroma • Also called Koenen tumors • Generally do not manifest until puberty • May involve and eventually destroy the entire nail
  33. 33. Tuberous Sclerosis Clinical Manifestations • Mental deficiency occurs in 60–70%; nearly all have epilepsy. • Epilepsy is also present in approximately 70% of those patients without mental retardation. • Epilepsy begins in infancy (IS) or early childhood and is often progressively more severe. Clinical Manifestations • Retinal tumors • Rhabdomyoma of the heart • Renal tumors • Cysts of the kidney,bones and lungs
  34. 34. Tuberous Sclerosis • two astrocytic hamartomas. One is calcified.
  35. 35. Tuberous Sclerosis • Renal Angiomyolipomas
  36. 36. Tuberous Sclerosis Diagnosis • Diagnosis of TS relies on a high index of suspicion when assessing a child with infantile spasms. • A careful search for the typical skin and retinal lesions should be completed in all patients with a seizure disorder. • Head CT scan or MRI confirms the diagnosis in most cases. • The CT scan typically shows calcified tubers in the periventricular area, but these may not be apparent until 3–4 yr of age.
  37. 37. Tuberous Sclerosis • CT of the brain revealed ventriculomegaly and multiple calcified subependymal nodules in the lateral ventricles
  38. 38. Tuberous Sclerosis • periventricular tubers
  39. 39. Tuberous Sclerosis Diagnosis • Molecular genetic testing of the TSC1 and TSC2 genes is complicated by the large size of the two genes, the large number of disease-causing mutations, and a 10% to 25% rate of somatic mosaicism • However, the molecular testing for both genes is available
  40. 40. Tuberous Sclerosis Management consists of : • seizure control • baseline studies, including • brain CT/MRI • renal ultrasonography • echocardiogram • chest X-ray • In Europe and Canada, infantile spasms associated with TS are often treated with vigabatrin (rather than ACTH), with good results. Vigabatrin is not available in the United States.
  41. 41. Tuberous Sclerosis Prognosis: • 75% of patients with tuberous sclerosis die before the age of 25 yr, most commonly as a complication of: • Epilepsy • intercurrent infection • cardiac failure • pulmonary fibrosis
  42. 42. 5 years old mentally retarded girl with recurrent sinopulmonary infections and gait disturbance.
  44. 44. Ataxia Telangiectasia (Louis-Bar syndrome) INCIDENCE: 1/40,000 live births (the most common degenerative ataxias) PREDOMINANT SEX: Males = Females
  45. 45. Ataxia Telangiectasia • GENETICS: • Autosomal recessive • chromosome 11q22-23 • More than 100 mutations have been discovered • The gene product is involved in cell-cycle progression and the checkpoint response to DNA damage.
  46. 46. Ataxia Telangiectasia PHYSICAL FINDINGS & CLINICAL PRESENTATION • Children show normal early development until they start to walk, when gait and truncal ataxia become apparent. • Choreoathetosis • Occulomotor apraxia 90% • Intellectual development normal at first but often lags with time.1/3 ultimately mildly MR. • Telengiectasia usually develops after age of 2 years: • bulbar conjunctivae • upper half of the ears • on the flexor aspects of the limbs • in a butterfly distribution on the face • Dull or expressionless face
  47. 47. Ataxia Telangiectasia COMPLICATIONS: • Recurrent sinopulmonary infections occur secondary to impaired humoral and cellular immunity • Increased frequency of cancers is noted, particularly T- cell leukemia and lymphoma.
  48. 48. Ataxia Telangiectasia DEFERENTIAL DIAGNOSIS • Friedreich’s ataxia • Abetalipoproteinemia (Bassen-Kornzweig Syndrome) • Acquired Vitamin E deficiency • Early onset cerebellar ataxia with retained reflexes (EOCA) • Ataxia associated with biochemical abnormalities: associated with • ceroid lipofuscinosis • xeroderma pigmentosa • Cockayne’s syndrome • adrenoleukodystrophy • metachromatic leukodystrophy • mitochondrial disease • sialidosis, • Niemann Pick
  49. 49. Ataxia Telangiectasia WORKUP • IgA is absent in 70-80% • IgE is diminished or absent in 80-90% • IgM may be elevated • AFP elevated in 90% • Karyotype: high incidence of chromosomal breaks, especially on chromosome 14 • Fibroblasts can be screened in vitro for x-ray sensitivity and radioresistant DNA synthesis • Pathology shows cerebellar degeneration, loss of pigmented neurons, and posterior column degeneration in the spinal cord
  50. 50. Ataxia Telangiectasia • Cerebellar atrophy
  51. 51. Ataxia Telangiectasia TREATMENT • Supportive, no effective treatment to date • Surveillance for infections and neoplasms • Infections should be treated vigorously • IVIG • Minimize radiation as may induce further chromosomal damage and lead to neoplasms PROGNOSIS • 67% of children die by age 20, typically from infection or neoplasm
  53. 53. Sturge-Weber disease Port-wine stain
  54. 54. Sturge-Weber Syndrome • It occurs sporadically, with a frequency of approximately 1/50,000 and consists of: • Facial nevus (port-wine stain) • Seizures • Hemiparesis • Intracranial calcifications • Mental retardation
  55. 55. Sturge-Weber Syndrome Clinical Manifestations • The facial nevus is present at birth and tends to be unilateral and always involves the upper face and eyelid. The nevus may also be evident over the lower face, trunk, and in the mucosa of the mouth and pharynx. • Unilateral in 70% and ipsilateral to the venous angioma of the pia • Even when the facial nevus is bilateral,the pial angioma is usually unilateral. • The size of the cutaneous angioma does not predict the size of the intracranial angioma. • Not all children with facial nevi have Sturge-Weber disease. • Buphthalmos and glaucoma of the ipsilateral eye are a common complication.
  56. 56. Sturge-Weber Syndrome Clinical Manifestations • Seizures develop in most patients during the 1st year of life • typically focal tonic-clonic and contralateral to the side of the facial nevus • seizures tend to become refractory to AEDs and are associated with a slowly progressive hemiparesis in many cases.
  57. 57. Sturge-Weber Syndrome Clinical Manifestations • Although neurodevelopment appears to be normal during the 1st year of life, mental retardation or severe learning disabilities are present in at least 50% during later childhood.
  58. 58. Sturge-Weber Syndrome Diagnosis. • The CT scan highlights the extent of the calcification that is usually associated with unilateral cortical atrophy and ipsilateral dilatation of the lateral ventricle.
  59. 59. Sturge-Weber disease • Axial CT without and with contrast in a one-year-old boy with seizures. • In (a) no calcifications have yet formed; cortical atrophy is seen on the left. • In (b) marked cortical enhancement following contrast injection.
  60. 60. Sturge-Weber Syndrome Treatment • Treat seizure • hemispherectomy or lobectomy may be needed • Because of the risk of glaucoma, regular measurements of intraocular pressure with a tenonometer is indicated. • Flashlamp-pulsed laser therapy holds considerable promise for clearing of the port-wine stain. • because of the high frequency of developmental disabilities, special educational facilities are frequently required.
  62. 62. Von Hippel-Lindau Disease • von Hippel-Lindau disease affects many organs, including the cerebellum, spinal cord, medulla, retina, kidney, pancreas, and epididymis. • von Hippel-Lindau disease is inherited as an autosomal dominant trait with variable penetrance and delayed expression. • The gene for von Hippel-Lindau disease has been mapped to chromosome 3p25.
  63. 63. Von Hippel-Lindau Disease • The major neurologic features of the condition include • cerebellar hemangioblastomas • retinal angiomas • Patients with cerebellar hemangioblastoma present in early adult life or beyond with symptoms and signs of increased intracranial pressure.
  64. 64. Von Hippel-Lindau Disease
  65. 65. Von Hippel-Lindau Disease • Approximately 25% of patients with cerebellar hemangioblastoma have retinal angiomas. • Retinal angiomas are usually located in the peripheral retina so that vision is unaffected. However, exudation in the region of the angiomas may lead to retinal detachment and visual loss. • Retinal angiomas are treated with photocoagulation and cryocoagulation, with good results.
  66. 66. Von Hippel-Lindau Disease • Retinal angiomas before and after cryocoagulation.
  67. 67. Von Hippel-Lindau Disease • Cystic lesions of the kidneys, pancreas, liver, and epididymis as well as pheochromocytoma are frequently associated with von Hippel-Lindau disease.
  68. 68. Von Hippel-Lindau Disease
  69. 69. Von Hippel-Lindau Disease • Renal carcinoma is the most common cause of death. Regular follow-up and appropriate imaging studies are necessary to identify lesions that may be treated at an early stage.
  70. 70. Von Hippel-Lindau Disease
  71. 71. • 2 days old newborn with streaks of vesicular lesions and erythema along the body lines.
  73. 73. Incontinentia pigmenti
  74. 74. Incontinentia pigmenti (Bloch-Sulzberger syndrome) • Rare, X-linked, dominantly inherited disorder of skin pigmentation that often is associated with CNS, ocular, and dental abnormalities. • Female carriers may have only subtle findings with stage IV skin and teeth abnormalities. • Lethal in the majority of affected males in utero.
  75. 75. Incontinentia pigmenti Skin: • Stage 1: • at birth • vesicular stage, with linear vesicles, pustules, and bullae with erythema along the lines of Blaschko. • Stage 2: • between ages 2 and 8 weeks • the verrucous stage, with warty, keratotic papules and plaques. • Stage 3: • between ages 12 and 40 weeks. • the hyperpigmented stage, with macular hyperpigmentation in a swirled pattern along the lines of Blaschko. These changes often involve the nipples, axilla, and groin. • Stage 4 • from infancy through adulthood. • the hypopigmented stage, with hypopigmented streaks and/or patches and cutaneous atrophy.
  76. 76. Incontinentia pigmenti
  77. 77. Incontinentia pigmenti
  78. 78. Incontinentia pigmenti
  79. 79. Incontinentia pigmenti • Ocular changes are seen in about 1/3 of patients. The changes can include the following: • Retinal pigmentary changes with mottled diffuse hypopigmentation, which is nearly pathognomonic • Abnormal peripheral retinal vessels with areas of nonperfusion, which is also nearly pathognomonic • Microphthalmia • Retrolental mass formation • Cataracts or leukocoria • Strabismus • Optic atrophy or foveal hypoplasia • Exudative retinal detachment (occurs only in a minority of patients) • Teeth and jaw changes occur in approximately 65-90% of patients. These changes can include delayed eruption of teeth; hypodontia; microdontia; abnormally shaped teeth—round, conical, or peg; micrognathia; and prognathia. • The CNS is involved in 10-40% of patients. The manifestations can include the following: • Microcephaly • Mental retardation • Spasticity • Seizures • Strokes
  80. 80. Incontinentia pigmenti • Onychodystrophy (nail dysplasia) occurs in 40-60% of patients. Other nail changes can include subungual keratotic tumors.
  81. 81. Incontinentia pigmenti • The hair is thin and sparse; alopecia is seen in 35-70% of patients. The hair changes can include a wooly hair nevus, which is a coarse, lusterless, and wiry patch of hair. • Skeletal and structural anomalies can occur in approximately 14% of patients but usually are associated with severe neurological deficits. The anomalies can include the following: • Somatic asymmetry • Hemivertebrae • Scoliosis • Spina bifida • Syndactyly • Ear anomalies • Extra ribs • Skull deformities • Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary.
  82. 82. Incontinentia pigmenti Work Up • Complete blood count (CBC) frequently shows eosinophilia. • CT scan or MRI of brain may show abnormalities. • Skin biopsy. • MOLECULAR GENETICS: NEMO gene.
  83. 83. Incontinentia pigmenti Medical Care: • No specific treatment is available for incontinentia pigment. • The stage 1 lesions should be left intact and kept clean. • Meticulous dental care is very important. Consultations: • Ophthalmology • Dentistry • Neurology, only if neurological abnormalities are present
  84. 84. Incontinentia pigmenti Patient Education: • As incontinentia pigmenti is an X-linked dominant disease, genetic counseling regarding the risk of affected offspring is very important.
  85. 85. Nevus Sebaceous of Jadassohn • Predilection for scalp but may be present in any anatomic site including mucous membranes • Usually solitary • Yellow to yellowish brown waxy- appearing lesion during the neonatal period; becomes verrucoid as child ages • May increase in size and become more verrucoid during puberty • Has potential to undergo malignant degeneration • Rx: Excision
  86. 86. Neurofibromatosis • NF1 • 1:4000 patients • Often inherited but 30-50% occur as mutations • 5 or more café au lait spots (some may be present at birth) • 2 or more neurofibromas • Most lead healthy normal lives, occasionally surgery may be required e.g. painful disfiguring lesions • NF 2 • 1:40,000 patients • Bilateral 8th nerve tumours • Presents in early teens with hearing loss and symptoms of pressure on adjacent cranial nerves and structures e.g. headache, facial numbness, poor balance, tinnitus