The Inside Out of The Inside Out of Neurocutaneous DisordersNeurocutaneous Disorders
Robert GreenwoodRobert Greenwood
Sometimes spots and knots have a purpose that tells you something about the organism that has them.
OxymoronsOxymorons That Will Not Be That Will Not Be Used In This LectureUsed In This Lecture
Black Light Black Light Never generalize!!Never generalize!!Exact estimateExact estimate
Neurocutaneous DisordersNeurocutaneous DisordersGeneral ConceptsGeneral Concepts1.1. The skin can be a window that allows you to see the The skin can be a window that allows you to see the
medical future of an infant.medical future of an infant.2.2. The cutaneous signs can be subtle.The cutaneous signs can be subtle.3.3. As in many other genetic diseases variable penetrance and As in many other genetic diseases variable penetrance and
expression are the rule. expression are the rule. 4.4. Family history and examination of other family members is Family history and examination of other family members is
a very important tool in making a diagnosis. a very important tool in making a diagnosis. 5.5. Hair and teeth are skin appendages and are often affected Hair and teeth are skin appendages and are often affected
when skin is affected. when skin is affected. 6.6. Look on the WebLook on the Web
http://tray.dermatology.uiowa.edu/DDX/macule.htmlhttp://tray.dermatology.uiowa.edu/DDX/macule.htmlhttp://http://dermatlas.med.jhmi.edu/dermdermatlas.med.jhmi.edu/derm//http://http://dermatology.cdlib.orgdermatology.cdlib.org//http://dermis.net/doia/mainmenu.asp?zugr=d&lang=ehttp://dermis.net/doia/mainmenu.asp?zugr=d&lang=e
Neurocutaneous DisordersNeurocutaneous Disorders
1.1. Neurofibromatosis I & IINeurofibromatosis I & II2.2. Tuberous SclerosisTuberous Sclerosis3.3. Von Von HippelHippel LindauLindau diseasedisease4.4. SturgeSturge Weber SyndromeWeber Syndrome5.5. KlippelKlippel--TrenaunayTrenaunay--WeberWeber SyndromeSyndrome6.6. OslerOsler--WeberWeber--RenduRendu SyndromeSyndrome7.7. WyburnWyburn--Mason SyndromeMason Syndrome8.8. Linear Linear SebaciousSebacious Nevus SyndromeNevus Syndrome9.9. Neurocutaneous Neurocutaneous MelanosisMelanosis10.10. WaardenburgWaardenburg Syndrome Type 1 & 2Syndrome Type 1 & 211.11. Fabry'sFabry's DiseaseDisease
Neurocutaneous DisordersNeurocutaneous DisordersIncidenceIncidence
Neurofibromatosis Neurofibromatosis type 1type 1Tuberous SclerosisTuberous SclerosisAtaxia Ataxia TelangiectasiaTelangiectasiaXerodermaXerodermaPigmentosumPigmentosumNeurofibromatosis Neurofibromatosis type 2type 2
1/1,0001/1,000--1/7,8001/7,800(30/100,000)(30/100,000)10.6/100,00010.6/100,0001.7/100,0001.7/100,0001/100,000 1/100,000 -- 1/250,0001/250,000
1/200,0001/200,000
Neurocutaneous DisordersNeurocutaneous DisordersIndentifiedIndentified Chromosome DefectsChromosome DefectsDisorderDisorder
NF1NF1NF2NF2TSTSIncontinentiaIncontinentia PigmentiPigmentiHypomelanosisHypomelanosis of Itoof Ito
AA--TTVon Von HippleHipple LindauLindau
OslerOsler –– RenduRendu --Weber Weber DiseaseDisease
ChromosomeChromosome
17q11.217q11.222q12.222q12.216p13.3, 12q14, 9q3416p13.3, 12q14, 9q34Xq28Xq28 -- XX--linked dominantlinked dominant? 9q33? 9q33--qter, 15q11qter, 15q11--q13, q13, and Xp11and Xp1111q22.311q22.311q13, 3p2611q13, 3p26--p25p25
9q34.19q34.1
Neurocutaneous DisordersNeurocutaneous DisordersInheritanceInheritance
Autosomal DominantAutosomal DominantAutosomal RecessiveAutosomal RecessiveXX--linked Recessivelinked RecessiveSporadicSporadic
Genetics Principles: NF1 and Genetics Principles: NF1 and Other Neurocutaneous DisordersOther Neurocutaneous Disorders
PenetrancePenetranceExpressionExpression–– Variable expressivityVariable expressivity
PleiotropyPleiotropyMosaicismMosaicismHeterogeneityHeterogeneity-- locus and alleliclocus and allelic
Neurocutaneous DiseasesNeurocutaneous DiseasesAutosomal Dominant InheritanceAutosomal Dominant Inheritance
Neurofibromatosis Neurofibromatosis Tuberous SclerosisTuberous SclerosisVon Von HippelHippel--LindauLindau DiseaseDiseaseLentiginosisLentiginosis--DeafnessDeafness--CardiopathyCardiopathy SyndSynd..HypomelanosisHypomelanosis of Itoof ItoOslerOsler--WeberWeber--RenduRendu DiseaseDisease
Neurocutaneous DiseasesNeurocutaneous DiseasesAutosomal Recessive InheritanceAutosomal Recessive Inheritance
AtaxiaAtaxia--TelangiectasiaTelangiectasiaXerodermaXeroderma PigmentosumPigmentosumCockayneCockayne’’ss SyndromeSyndromeRothmundRothmund--Thomson SyndromeThomson SyndromeSjogrenSjogren--Larsson SyndromeLarsson SyndromeNeuroichthyosisNeuroichthyosisWerner Syndrome and Werner Syndrome and ProgeriaProgeria
Neurocutaneous DiseasesNeurocutaneous DiseasesXX--Linked InheritanceLinked Inheritance
IncontinentiaIncontinentia PigmentiPigmenti
Neurocutaneous DiseasesNeurocutaneous DiseasesSporadic Congenital and Sporadic Congenital and AngiomatosesAngiomatoses
Neurocutaneous Neurocutaneous MelanosisMelanosisLinear Sebaceous NevusLinear Sebaceous NevusSturgeSturge--Weber SyndromeWeber SyndromeKlippelKlippel--TrenaunayTrenaunay SyndromeSyndromeWyburnWyburn--Mason SyndromeMason Syndrome
Classification of Classification of Neurocutaneous Disorders and Neurocutaneous Disorders and CancerCancer
OncogeneOncogene or tumor suppressor gene or tumor suppressor gene abnormalities. abnormalities.
–– Caretaker Caretaker -- does not control cell growth directly does not control cell growth directly but instead controls the rate of mutation but instead controls the rate of mutation
–– GatekeeperGatekeeper-- controls either the rate of cell birth controls either the rate of cell birth or the rate of cell deathor the rate of cell death
Familial Cancer SyndromesFamilial Cancer Syndromes--Disorders of the CaretakersDisorders of the Caretakers
Nucleotide Excision Repair Syndromes: Nucleotide Excision Repair Syndromes: XerodermaXerodermaPigmentosumPigmentosum, , CockayneCockayne Syndrome, and Syndrome, and TrichothiodystrophyTrichothiodystrophyAtaxiaAtaxia--TelangiectasiaTelangiectasiaBloom SyndromeBloom SyndromeFanconiFanconi AnemiaAnemiaHereditary Hereditary NonpolyposisNonpolyposis Colorectal Cancer (HNPCC)Colorectal Cancer (HNPCC)Werner SyndromeWerner SyndromePeutzPeutz--JeghersJeghers SyndromeSyndromeJuvenile Juvenile PolyposisPolyposis SyndromeSyndrome
Nucleotide Excision Repair Nucleotide Excision Repair (NER) Defects(NER) Defects
XerodermaXeroderma pigmentosumpigmentosum (XP)(XP)CockayneCockayne syndrome (CS)syndrome (CS)Photosensitive form of Photosensitive form of trichothiodystrophytrichothiodystrophy(TTD)(TTD)
Nucleotide Excision Repair Nucleotide Excision Repair (NER) Defects(NER) Defects
All are recessiveAll are recessiveAll have extreme sunlight sensitivity and 1000X frequency All have extreme sunlight sensitivity and 1000X frequency skin cancersskin cancersProgressive degeneration of skin and eyesProgressive degeneration of skin and eyesIn some accelerated neurologic degeneration and neuronal In some accelerated neurologic degeneration and neuronal deathdeathKey features CS and TTDKey features CS and TTD–– CSCS-- short stature, severe neurological abnormalities with short stature, severe neurological abnormalities with
dysmyelination, cataracts, birddysmyelination, cataracts, bird--like facelike face–– TTDTTD-- brittle hair and nails, ichthiosis, other symptoms similar to brittle hair and nails, ichthiosis, other symptoms similar to
CSCS
XerodermaXeroderma PigmentosaPigmentosa
Skin abnormalitiesSkin abnormalities–– Erythema and Erythema and bullaebullae (acute sensitivity in infancy)(acute sensitivity in infancy)–– FrecklesFreckles–– XerosisXerosis (dryness) and scaling(dryness) and scaling–– Areas of Areas of hyperpigmentationhyperpigmentation alternating with alternating with hyporpigmentationhyporpigmentation–– TelangiectasiaTelangiectasia–– AtrophyAtrophy–– Benign lesion: actinic Benign lesion: actinic keratoseskeratoses, , keratocanthomaskeratocanthomas, , angiomasangiomas, ,
fibromasfibromas–– Malignant lesions: basal cell carcinoma, Malignant lesions: basal cell carcinoma, squamoussquamous cell cell
carcinoma, melanomacarcinoma, melanomaOphthalmologic abnormalities Ophthalmologic abnormalities ConjunctivitusConjunctivitus with with photophobia, photophobia, lacrimationlacrimation, edema, edema–– Cornea: Cornea: keratitiskeratitis, , opacificationopacification, impaired vision, impaired vision–– Neoplasms of conjunctiva, cornea, and lidsNeoplasms of conjunctiva, cornea, and lids
XX--PP
XerodermaXeroderma PigmentosaPigmentosaNeurologic ManifestationsNeurologic Manifestations
MicrocephalyMicrocephalyLow intelligenceLow intelligenceProgressive mental deteriorationProgressive mental deteriorationProgressive Progressive sensorineuralsensorineural deafnessdeafnessAbnormal motor activityAbnormal motor activityHyporeflexiaHyporeflexia or or areflexiaareflexiaPrimary neuronal degenerationPrimary neuronal degeneration
AtaxiaAtaxia--TelangiectasiaTelangiectasia (A(A--T)T)
1.1. Progressive gait and Progressive gait and truncaltruncal ataxia with ataxia with onset from 1 to 3 years of age; onset from 1 to 3 years of age; progressively slurred speech; progressively slurred speech;
2.2. ChoreoathetosisChoreoathetosis, seizures, , seizures, 3.3. OculomotorOculomotor apraxia, apraxia, 4.4. OculocutaneousOculocutaneous telangiectasiatelangiectasia, usually by 6 , usually by 6
years of age;years of age;
Ataxia Ataxia TelangiectasiaTelangiectasiaTelangiectaticTelangiectatic lesions of lesions of conjuctivaeconjuctivae, , malarmalar eminences, ear lobes and upper eminences, ear lobes and upper neckneckAtaxia, Ataxia, choreoathetosischoreoathetosis and and nystagmusnystagmusImmunologic deficienciesImmunologic deficienciesCancer pronenessCancer proneness-- 38% 38% lymphoreticularlymphoreticular
Ataxia Ataxia TelangiectasiaTelangiectasia
AA--TT
IncidenceIncidence-- 1/40,000 births1/40,000 birthsCarrier frequency 1 %Carrier frequency 1 %Female carriers RR of 5 for breast cancerFemale carriers RR of 5 for breast cancerChromosome 11q22.3Chromosome 11q22.3-- ATMATM (ataxia(ataxia--telangiectasiatelangiectasiamutated), is a member of a family of phosphatidylinositolmutated), is a member of a family of phosphatidylinositol--33--kinasekinase––related genes involved in cell cycle control, related genes involved in cell cycle control,
intracellular protein transport, and DNA damage responseintracellular protein transport, and DNA damage response
IncontinentiaIncontinentia PigmentiPigmenti
XX--linked, lethal in linked, lethal in hemizygoushemizygous malesmalesVesicular rash in newborn periodVesicular rash in newborn periodNeonatal seizuresNeonatal seizuresPolymorphic pigmented lesions Polymorphic pigmented lesions develop in infancydevelop in infancy
IncontinentiaIncontinentia PigmentiPigmentiErythematousErythematous bullousbullous lesions at birthlesions at birthSecond stage crusting of lesions (Second stage crusting of lesions (verrucousverrucous))Third stage whorls, zebra stripes, speckles or Third stage whorls, zebra stripes, speckles or other patterns of pigmentationother patterns of pigmentationMicrocephaly and Microcephaly and micropolygyriamicropolygyriaMental retardationMental retardationDental anomalies and ocular abnormalitiesDental anomalies and ocular abnormalities
IncontinentiaIncontinentia PigmentiPigmenti
IncontinentiaIncontinentia PigmentiPigmenti
J Am Acad Dermatol 2002;47:169-87
IncontinentiaIncontinentia PigmentiPigmenti
Dental anomaliesDental anomalies——both primary and both primary and secondary dentitionsecondary dentition–– HypodontiaHypodontia (small teeth)(small teeth)–– Partial Partial anodontiaanodontia (lack of teeth)(lack of teeth)–– Delayed eruptionDelayed eruption–– Impacted dentitionImpacted dentition–– Malformed crowns (cone or pegMalformed crowns (cone or peg--shaped)shaped)
IncontinentiaIncontinentia PigmentiPigmenti
OphthalmicOphthalmic–– StrabismusStrabismus–– CataractsCataracts–– Optic atrophyOptic atrophy–– AnophthalmiaAnophthalmia (absence of eye)(absence of eye)–– MicrophthalmiaMicrophthalmia–– Retinal Retinal vasculopathyvasculopathy (Fig 1)(Fig 1)–– Changes such as Changes such as retrolentalretrolental fibroplasiafibroplasia
IncontinentiaIncontinentia PigmentiPigmenti
Central nervous system symptoms and findingsCentral nervous system symptoms and findings–– SeizuresSeizures–– Mental retardationMental retardation–– AtaxiaAtaxia–– Spastic abnormalitiesSpastic abnormalities–– Microcephaly Cerebral atrophy Microcephaly Cerebral atrophy –– HypoplasiaHypoplasia of corpus callosumof corpus callosum–– HydrocephalusHydrocephalus–– PorencephalicPorencephalic cystscysts–– Hemorrhagic necrosisHemorrhagic necrosis–– Neuronal heterotopiasNeuronal heterotopias
IncontinentiaIncontinentia PigmentiPigmenti
IncontinentiaIncontinentia PigmentiPigmenti
HypomelanosisHypomelanosis of Itoof ItoHypopigmentationHypopigmentation in whorlsin whorlsSeizuresSeizuresMental retardationMental retardationOphthalmologic anomaliesOphthalmologic anomaliesHeterotopiasHeterotopias
HypomelanosisHypomelanosis of Itoof Ito
Small 0.5Small 0.5--11--cm cm hypopigmentedhypopigmented or white or white maculesmacules coalesce to form coalesce to form reticulated patches along the lines of reticulated patches along the lines of BlaschkoBlaschko..–– The The maculesmacules cover more than 2 dermatomes and are often on both sides cover more than 2 dermatomes and are often on both sides
of the body.of the body.–– The patches are not symmetric.The patches are not symmetric.–– A Wood lamp enhances the pattern, especially in white patients.A Wood lamp enhances the pattern, especially in white patients.
DysmorphismDysmorphism::–– Cleft palateCleft palate–– HemihypertrophyHemihypertrophy–– Limb, hand, and/or foot abnormalitiesLimb, hand, and/or foot abnormalities–– Nail abnormalitiesNail abnormalities–– HypotoniaHypotonia–– Teeth abnormalitiesTeeth abnormalities–– Hair anomaliesHair anomalies–– Face and/or skull anomaliesFace and/or skull anomalies
HypomelanosisHypomelanosis of Itoof Ito
Familial Cancer DisordersFamilial Cancer Disorders--Disorders of GatekeepersDisorders of Gatekeepers
Von Von HippleHipple--LindauLindau SyndromeSyndromeNeurofibromatosis type 1Neurofibromatosis type 1NeurofibormatosisNeurofibormatosis type 2type 2Tuberous sclerosisTuberous sclerosis
NEUROFIBROMATOSIS TYPE 1NEUROFIBROMATOSIS TYPE 1
NF1 Molecular BiologyNF1 Molecular Biology
NF1 gene localized on chromosome 17q11.2 NF1 gene localized on chromosome 17q11.2 ~300 kb, contains 53 exons~300 kb, contains 53 exons–– intron 72b contains 3 previously identified genesintron 72b contains 3 previously identified genes–– intron 37 contains the adenylate kinase 3 pseudogeneintron 37 contains the adenylate kinase 3 pseudogene
Protein product is Protein product is neurofibrominneurofibromin–– 2818 amino acids2818 amino acids–– ? GTPase activator that regulates a tumor suppressor ? GTPase activator that regulates a tumor suppressor
genegene
NF1 GeneticsNF1 Genetics
Autosomal dominantAutosomal dominant–– Complete penetranceComplete penetrance
Half of the NF1 cases are new mutationsHalf of the NF1 cases are new mutationsMore than 200 different gene mutationsMore than 200 different gene mutations–– Most gene abnormality have been uniqueMost gene abnormality have been unique
Extremely variable expressionExtremely variable expression
Neurofibromatosis Type 1Neurofibromatosis Type 1
NF1, von Recklinghausen DiseaseNF1, von Recklinghausen DiseasePrevalencePrevalence-- 1/30001/3000No racial or ethnic predilection No racial or ethnic predilection –– 1/7800 in the USSR 1/7800 in the USSR –– 1.04/1000 in Israel military recruits1.04/1000 in Israel military recruits
Criteria for the diagnosis of NF1 Criteria for the diagnosis of NF1 requires two or more of the requires two or more of the following:following:
•• Six or more cafe'Six or more cafe'--auau--lait macules (over 5 mm in lait macules (over 5 mm in prepubertal individuals and over 15 mm in prepubertal individuals and over 15 mm in postpubertal individuals)postpubertal individuals)
•• Two or more neurofibromas of any type or one Two or more neurofibromas of any type or one plexiform neurofibroma.plexiform neurofibroma.
•• Freckling in the axillary or inguinal regionFreckling in the axillary or inguinal region•• Optic gliomaOptic glioma•• Two or more Lisch nodules (iris hamartomas)Two or more Lisch nodules (iris hamartomas)•• A distinctive osseous lesion such as sphenoid A distinctive osseous lesion such as sphenoid
dysplasia or thinning of long bone cortex with or dysplasia or thinning of long bone cortex with or without pseudarthrosiswithout pseudarthrosis
•• A firstA first--degree relative with NFdegree relative with NF--1 by the above 1 by the above criteriacriteria
NF1NF1
cafcaféé--auau--laitlait spotsspots
Pigmentation overlyingplexiform neurofibroma
Neurofibromatosis Type 1Neurofibromatosis Type 1
Axillary Freckling
Plexiform Neurofibroma of Plexiform Neurofibroma of the Facial Nervethe Facial Nerve
Clinical Feature
Incidence CONGENITAL(0-2 yrs)
PRESCHOOL (2-4 yrs)
LATE CHILDHOOD & ADOLESCENCE
(6-16 yrs)
ADULTHOOD (16+yrs)
Café au lait spots
-------------------->
Plexiform Diffuse neurofibroma-
25%
-------------------->
Superficial or nodul ar
-------------------->------------------->
Tibial dysplasia-
3 % -------------------->------------------->
Skinfold freckling
-----------------> --------------->
Optic glioma 15 – 20 % --------->-------------------> Learning disabilities
30 – 65 % -------------------> --------------->
NF1NF1Time Line For Time Line For ComplicationsComplications
CONGENITAL(0-2 yrs)
PRESCHOOL (2-4 yrs)
LATE CHILDHOOD & ADOLESCENCE
(6-16 yrs)
ADULTHOOD(16+yrs)
Hypertension -----------------> ---------------------> ------------------> Headaches 10 – 20 % -----------------> ---------------------> ------------------> Dermal neurofibroma
---------------------> ------------------>
Scoliosis 12 – 20 % ---------------------> Malignant peripheral nerve sheath tumors
1 – 4 % ----------------------> ------------------>
NF1NF1Time Line For Time Line For ComplicationsComplications
Macrocephaly and Somatic Growth in NF1Macrocephaly and Somatic Growth in NF1
•• Absolute Absolute macrocephalymacrocephaly (head (head circumference circumference > > 98 %98 %ileile) reported in 43) reported in 43--45% of patients with NF45% of patients with NF--11•• Recent NF multicenter studyRecent NF multicenter study--
•• 24% have macrocephaly (OFC >/=2 standard deviations 24% have macrocephaly (OFC >/=2 standard deviations above the population mean). above the population mean).
•• 13% of patients have short stature (>/=2 13% of patients have short stature (>/=2 standard deviations below the population mean)standard deviations below the population mean)
•• Szudek,JSzudek,J. et. al Growth in North American white children with neurofibro. et. al Growth in North American white children with neurofibromatosis 1 (NF1) matosis 1 (NF1) J. Med. Genetics 37:933, 2000J. Med. Genetics 37:933, 2000
Optic gliomaNormal
NF1NF1Other MRI AbnormalitiesOther MRI Abnormalities
Areas of increased T2 signal intensityAreas of increased T2 signal intensity–– 43 43 -- 79 % of NF1 in pediatric age group79 % of NF1 in pediatric age group–– MostMost-- multiple, no mass effect.multiple, no mass effect.–– PathPath-- atypical glial infiltrate, atypical glial infiltrate,
microcalcificaiton, and areas of microcalcificaiton, and areas of dysmyelination and spongy changes in dysmyelination and spongy changes in WM around lesion. WM around lesion.
Areas of increased T1 signal intensityAreas of increased T1 signal intensityVentricular enlargementVentricular enlargement
Learning is often affected in NF1 children. Learning is often affected in NF1 children. Visuospatial function is most clearly Visuospatial function is most clearly affected.affected.The brains of NF1 children are larger and The brains of NF1 children are larger and the pattern of growth of NF1 children the pattern of growth of NF1 children may be different.may be different.–– The increased brain size in NF1 children is The increased brain size in NF1 children is
due to increased gray and white matter.due to increased gray and white matter.–– Visual spatial function is one of the most Visual spatial function is one of the most
consistent deficits and has correlated with consistent deficits and has correlated with right hemisphere gray matter volume.right hemisphere gray matter volume.
ConclusionsConclusions
The brains of NF1 children also have The brains of NF1 children also have lowerlower NAA/creatine, and NAA/Cho NAA/creatine, and NAA/Cho ratios in the thalamusratios in the thalamus..T2 hyperintensities may be a marker for T2 hyperintensities may be a marker for a more diffuse processa more diffuse process..–– They may be positively correlated They may be positively correlated
with cognitive deficitswith cognitive deficits..
Conclusions Contd.Conclusions Contd.
ADC in NF1 children is significantly different from ADC in NF1 children is significantly different from other children but fractional other children but fractional aniosotropyaniosotropy is only is only different in the hippocampus. different in the hippocampus.
The areas of the brain with greatest ADC differences The areas of the brain with greatest ADC differences are those where we find significantly greater brain are those where we find significantly greater brain volume, the parietalvolume, the parietal--occipital and frontal cortex. occipital and frontal cortex. These same areas are thought to be important for These same areas are thought to be important for attention and visual spatial function. attention and visual spatial function.
Conclusions Contd.Conclusions Contd.
Neurofibromatosis Type 2Neurofibromatosis Type 2Bilateral acoustic Bilateral acoustic neuromasneuromas-- diagnosticdiagnosticOther tumorsOther tumors-- meningiomameningioma, , ependymomasependymomas, , spinal cord spinal cord astrocytomasastrocytomas, dorsal nerve , dorsal nerve schwannomasschwannomasSkin Skin hyperpigmentationhyperpigmentation is variableis variablePosterior Posterior subcapsularsubcapsular cataracts and cataracts and LischLischnodulesnodules
Tuberous SclerosisTuberous Sclerosis
Tuberous SclerosisTuberous Sclerosis
IncidenceIncidence-- 1 in 6000 1 in 6000 -- 90009000Dominant inheritance but a high frequency Dominant inheritance but a high frequency of spontaneous mutationof spontaneous mutation–– 56% to 86% spontaneous mutation56% to 86% spontaneous mutation
Variable expression within familiesVariable expression within families
Tuberous SclerosisTuberous Sclerosis
Gene LocationGene Location ProteinProteinTSC1TSC1 chromosome 9 qchromosome 9 q hamartinhamartinTSC2TSC2 chromosome 16 pchromosome 16 p tuberintuberin
Tuberous Sclerosis Tuberous Sclerosis Revised Diagnostic CriteriaRevised Diagnostic Criteria
Definite TSCDefinite TSC–– Two major feature orTwo major feature or–– One major plus 2 minorOne major plus 2 minorProbable TSCProbable TSC–– One major and one minorOne major and one minorPossible TSCPossible TSC–– One majorOne major–– 2 or more minor2 or more minor
Tuberous SclerosisTuberous SclerosisPrimary FeaturesPrimary Features–– Facial angiofibromasFacial angiofibromas–– Multiple Multiple ungualungual fibromasfibromas–– Cortical tubersCortical tubers–– SubependymalSubependymal nodules or giant cell nodules or giant cell astrocytomaastrocytoma–– Retinal Retinal hamartomashamartomas–– 3 or more 3 or more hypomelanotichypomelanotic maculesmacules–– ShagreenShagreen patchpatch–– Renal angiomyolipomaRenal angiomyolipoma–– Cardiac Cardiac rhabdomyomarhabdomyoma–– Pulmonary Pulmonary lymphangiomatosislymphangiomatosis
Tuberous SclerosisTuberous SclerosisSecondary featuresSecondary features–– Affected first degree relativeAffected first degree relative–– Dental enamel pitsDental enamel pits–– Bone cystsBone cysts–– Forehead plaqueForehead plaque–– Renal cystsRenal cysts-- renal renal angiomyuolipomaangiomyuolipoma–– Renal cystsRenal cysts-- histologichistologic–– HamartomatousHamartomatous rectal polyps rectal polyps –– Gingival Gingival fibromasfibromas
Tuberous SclerosisTuberous SclerosisCutaneous ManifestationsCutaneous Manifestations
HypomelanoticHypomelanotic maculesmacules-- 90 %90 %ShagreenShagreen patchpatch-- 20 20 -- 30 %30 %UngualUngual fibromafibroma-- 15 to 20 %15 to 20 %Facial Facial angiomaangioma (adenoma (adenoma sebaceumsebaceum))-- 75 %75 %Forehead plaqueForehead plaque““ConfettiConfetti”” hypopigmentedhypopigmented skin lesionsskin lesionsGingival Gingival fibromasfibromasPoliosisPoliosis
Tuberous SclerosisTuberous SclerosisHypopigmentedHypopigmented MaculeMacule
Tuberous SclerosisTuberous SclerosisHypopigmentedHypopigmented MaculeMacule-- WoodWood’’s s LampLamp
Tuberous SclerosisTuberous SclerosisEarly Adenoma Early Adenoma SebaceumSebaceum
Tuberous SclerosisTuberous SclerosisLate Adenoma Late Adenoma SebaceumSebaceum
Tuberous SclerosisTuberous SclerosisUngualUngual FibromaFibroma
Tuberous SclerosisTuberous SclerosisShagreenShagreen PatchPatch
Tuberous SclerosisTuberous SclerosisShagreenShagreen PatchPatch
Tuberous Sclerosis Tuberous Sclerosis Other ManifestationsOther Manifestations
CardovascularCardovascular–– cardiac cardiac rhabdomyomatarhabdomyomata-- 30 to 50 %30 to 50 %–– cardiac arrhythmiacardiac arrhythmia–– cardiac cardiac thromboembolismthromboembolism
RenalRenal–– renal angiomyolipomasrenal angiomyolipomas–– renal cystsrenal cysts
PulmonaryPulmonary–– 1%, females > males1%, females > males–– pulmonary pulmonary lymphangiomyomatosislymphangiomyomatosis–– symptoms include symptoms include pneumothoraxpneumothorax, , dyspneadyspnea, cough, , cough, hemoptysishemoptysis, ,
and pulmonary failureand pulmonary failure..
Tuberous Sclerosis Tuberous Sclerosis Neurologic ManifestationsNeurologic Manifestations
SeizuresSeizures-- often infantile spasmsoften infantile spasmsMental retardation and autisticMental retardation and autistic--like like behaviorbehavior-- 60%60%Focal neurologic deficitsFocal neurologic deficitsBrain tumorsBrain tumors–– 66--14% of TSC patients14% of TSC patients–– giant cell astrocytomagiant cell astrocytoma
Tuberous Sclerosis Gene Tuberous Sclerosis Gene FunctionFunction
Tumor suppressor genesTumor suppressor genesHamartomasHamartomas of tuberous sclerosis patients of tuberous sclerosis patients show loss of heterozygosity show loss of heterozygosity Sequence homologies at the protein level Sequence homologies at the protein level reveal a region of similarity between reveal a region of similarity between tuberintuberinand the and the GTPaseGTPase activating protein GAP3 activating protein GAP3
TS and Adjacent GenesTS and Adjacent Genes
A contiguous deletion that affects both A contiguous deletion that affects both TSC2 and PKD1 genes results in early onset TSC2 and PKD1 genes results in early onset polycystic kidney diseasepolycystic kidney diseaseSome patients with contiguous deletions are Some patients with contiguous deletions are milder because of somatic milder because of somatic mosaicismmosaicism
SturgeSturge WeberWeber
SturgeSturge--Weber SyndromeWeber SyndromeUnilateral or bilateral facial Unilateral or bilateral facial angiomaangioma in the in the distribution of the first branch of the distribution of the first branch of the trigeminal nervetrigeminal nerveIpsilateral intracranial vascular Ipsilateral intracranial vascular anomalieanomalie of of the capillaries and the capillaries and venulesvenules of the of the leptomeningesleptomeningesGlaucomaGlaucoma
SturgeSturge--Weber Syndrome MRIWeber Syndrome MRI
SturgeSturge Weber Neurological Weber Neurological ComplicationsComplications
HemiparesisHemiparesisSeizuresSeizuresDevelopmental DelayDevelopmental DelayHeadachesHeadaches
WyburnWyburn Mason SyndromeMason Syndrome
An uncommon disorder characterized by a An uncommon disorder characterized by a vascular malformation of the midbrain vascular malformation of the midbrain associated with a unilateral retinal AVM, associated with a unilateral retinal AVM, facial nevi, and mental changesfacial nevi, and mental changes
WyburnWyburn Mason SyndromeMason Syndrome
ArteriovenousArteriovenous malformations of the retina malformations of the retina and central nervous systemand central nervous systemRareRareNo sex predilectionNo sex predilectionVariable neurological abnormalities Variable neurological abnormalities
WyburnWyburn--Mason SyndromeMason Syndrome
Retina showing dilated vasculature in a child with reduced vision, seizures and facial vascular lesions.
von von HippelHippel LindauLindau DiseaseDisease
Diagnostic CriteriaDiagnostic Criteria–– One or more One or more hemangioblastomashemangioblastomas either at the either at the
same or different sitessame or different sites–– Other visceral lesionsOther visceral lesions–– Familial tumors Familial tumors
Urinary Urinary metanephrinemetanephrine level, and VMA are level, and VMA are elevated. elevated.
KlippelKlippel--TrenuanwayTrenuanway--WeberWeberSyndromeSyndrome
An uncommon neurocutaneous disorder An uncommon neurocutaneous disorder characterized by extensive skin characterized by extensive skin hemangiomashemangiomas appearing in a appearing in a dermatomaldermatomalpattern, and associated with pattern, and associated with hemangiomashemangiomasof the spinal cord. of the spinal cord. The lesions are unilateral and are often The lesions are unilateral and are often associated with osseous or muscular associated with osseous or muscular hypertrophy of the involved area. This may hypertrophy of the involved area. This may be a spinal variant of be a spinal variant of SturgeSturge--Weber. Pattern Weber. Pattern of inheritance unknown.of inheritance unknown.
KlippelKlippel--TreTre´́naunaynaunaysyndromesyndrome
J Am Acad Dermatol 2004;51:391-8.
OslerOsler--Weber Weber --RenduRendu SyndromeSyndrome
An uncommon disorder characterized by An uncommon disorder characterized by angiomasangiomasof the skin, mucous membranes, and nervous of the skin, mucous membranes, and nervous system. system. Autosomal dominant disorder Autosomal dominant disorder Development of multiple small red or purple Development of multiple small red or purple angiomasangiomas. These enlarge and may be the source of . These enlarge and may be the source of recurrent recurrent epistaxisepistaxis or GI or GU hemorrhages. or GI or GU hemorrhages. Scattered Scattered angiomasangiomas may develop in the brain or may develop in the brain or spinal cord, producing hemorrhage or localized spinal cord, producing hemorrhage or localized cerebral spinal dysfunction.cerebral spinal dysfunction.
Linear Linear SebaciousSebacious NevusNevus
Linear Nevus Linear Nevus SebaceusSebaceusSyndromeSyndrome
Linear patches of yellow papulesLinear patches of yellow papulesMental retardationMental retardationSeizuresSeizuresHemiparesisHemiparesisOcular abnormalitiesOcular abnormalities-- microphthalmiamicrophthalmia, , anophthalmiaanophthalmia, , choristomaschoristomas, and , and colobomatacolobomataof lids, iris, choroids and optic nerve.of lids, iris, choroids and optic nerve.
Linear Nevus Linear Nevus SebaceusSebaceusSyndromeSyndrome
Brain AbnormalitiesBrain Abnormalities–– HemiatrophyHemiatrophy–– LipomasLipomas
Congenital NevusCongenital Nevus
Congenital nevi are Congenital nevi are melanocyticmelanocytic nevi present at nevi present at birth. birth. –– They are probably best recognized as the large bathing They are probably best recognized as the large bathing
suit nevi that may cover large portions of the body. suit nevi that may cover large portions of the body. Giant congenital neviGiant congenital nevi–– InfantInfant-- usually larger than 6 cm on the trunk, 9 cm on usually larger than 6 cm on the trunk, 9 cm on
the scalp.the scalp.–– AdultAdult-- greater than 20 cm in its largest diameter in an greater than 20 cm in its largest diameter in an
adult. adult. The management of these larger lesions is The management of these larger lesions is controversial. controversial.
Neurocutaneous Neurocutaneous melanosismelanosis and and encephalocraniocutaneousencephalocraniocutaneouslipomatosislipomatosis
J Am Acad Dermatol 2002;47:S196-200.
Neurocutaneous Neurocutaneous melanosismelanosis and and encephalocraniocutaneousencephalocraniocutaneous lipomatosislipomatosis
Funduscopic View- Right eye fundoscopic view demonstrating multiple large chorioretinallacunae.
NEUROCUTANEOUS MELANOSISNEUROCUTANEOUS MELANOSIS
SignsSigns–– HydrocephalusHydrocephalus
MacrocephalyMacrocephalyIncreasing head circumferenceIncreasing head circumferenceBulging Bulging fontanellefontanelleSeizuresSeizuresDevelopmental delayDevelopmental delay
SymptomsSymptoms–– HeadacheHeadache
VomitingVomitingFailure to thriveFailure to thriveWeaknessWeaknessGait abnormalitiesGait abnormalitiesBladder or bowel dysfunctionBladder or bowel dysfunction
Neurocutaneous Neurocutaneous MelanosisMelanosis
–– DiagnosisDiagnosispresence of neurologic symptomspresence of neurologic symptomsincreased number of increased number of melanocytesmelanocytes within the central within the central nervous system associated with large cutaneous nevi nervous system associated with large cutaneous nevi or multiple smaller nevi. or multiple smaller nevi.
–– CNS CNS melanocytesmelanocytes are usually found in the are usually found in the anterior temporal lobes, cerebellum, thalami, anterior temporal lobes, cerebellum, thalami, and base of the frontal lobe and base of the frontal lobe
LargeLarge CongenitalCongenital MelanocyticMelanocytic NevusNevusMalignancy RiskMalignancy Risk
Lifetime risk for melanoma estimated between 4.5Lifetime risk for melanoma estimated between 4.5--10%10%
5 year cumulative risk of 2.3% and relative risk of 101 5 year cumulative risk of 2.3% and relative risk of 101 If melanoma develops, >50% develop <5 years and 70% If melanoma develops, >50% develop <5 years and 70% by age 10by age 10
Greater risk occurring on the axial site (head, neck, and/or Greater risk occurring on the axial site (head, neck, and/or trunk)trunk)
No reports of melanomas arising in nevi restricted to an No reports of melanomas arising in nevi restricted to an extremity or within congenital satellite neviextremity or within congenital satellite nevi
J Am Acad Dermatol 1997;36:409-416Arch Dermatol 1996;132:170-175Pediatrics 2000;106:736-741
ASSOCIATED FINDINGS WITH GIANT ASSOCIATED FINDINGS WITH GIANT CONGENITAL MELANOCYTIC NEVICONGENITAL MELANOCYTIC NEVI
LOCAL CHANGES LOCAL CHANGES
MALIGNANCIES MALIGNANCIES
MALFORMATIONSMALFORMATIONS
Loss of subcutaneous fatLoss of subcutaneous fatLimb Limb hypoplasiahypoplasiaRhabdomyosarcomaRhabdomyosarcomaLiposarcomaLiposarcomaNeuroblastomaNeuroblastomaPrimitive Primitive neuroectodermalneuroectodermaltumorstumorsMixed malignant Mixed malignant neoplasmsneoplasmsVascularVascularSupernumerary digitsSupernumerary digitsEar deformitiesEar deformitiesPreauricularPreauricular appendagesappendagesCryptorchidismCryptorchidismClub feetClub feet
Treatment of Giant Congenital Treatment of Giant Congenital MelanocyticMelanocyticNeviNevi
DermabasionDermabasion–– 12 patients treated between the first and fourteenth 12 patients treated between the first and fourteenth
week of life. week of life. 1010-- appreciable and stable reduction of the appreciable and stable reduction of the hyperpigmentationhyperpigmentation..66-- reconstruction using grafts and flaps was required.reconstruction using grafts and flaps was required.11-- developed minimal deviation melanomadeveloped minimal deviation melanoma
CurettageCurettage–– 16 patients treated during first 2 weeks of life16 patients treated during first 2 weeks of life
All had good cosmetic outcomeAll had good cosmetic outcomeNo melanoma No melanoma
Scand J Plast Reconstr Surg Hand Surg 2000 Dec;34(4):321-6
Arch Dermatol 2002 Jul;138(7):943-7
WaardenburgWaardenburg Syndrome Syndrome Type 1 & 2Type 1 & 2
Major criteriaMajor criteria–– Congenital Congenital sensorineuralsensorineural hearing loss hearing loss –– PigmentaryPigmentary disturbances of irisdisturbances of iris–– Complete Complete heterochromiaheterochromia iridumiridum, two eyes of different color , two eyes of different color –– Partial or segmental Partial or segmental heterochromiaheterochromia; segments of blue or brown ; segments of blue or brown
pigmentation in one or both eyes pigmentation in one or both eyes –– HypoplasticHypoplastic blue eyes, characteristic brilliant blue in both eyesblue eyes, characteristic brilliant blue in both eyes–– Hair Hair hypopigmentationhypopigmentation, white forelock , white forelock –– Dystopia Dystopia canthorumcanthorum, W > 1.95 averaged over affected family , W > 1.95 averaged over affected family
members (this was modified from the original proposal of W > members (this was modified from the original proposal of W > 2.07 in the light of experience) 2.07 in the light of experience)
–– Affected first degree relativeAffected first degree relative
Minor criteriaMinor criteria–– Congenital Congenital leukodermaleukoderma, several areas of , several areas of
hypopigmentedhypopigmented skin skin –– SynophyrysSynophyrys or medial eyebrow flare or medial eyebrow flare –– Broad and high nasal root Broad and high nasal root –– HypoplasiaHypoplasia of of alaealae nasinasi–– Premature Premature greyinggreying of hair, scalp hair of hair, scalp hair
predominantly white before age 30predominantly white before age 30
WaardenburgWaardenburg Syndrome Type 1 Syndrome Type 1 & 2& 2
Please RememberPlease Remember
No matter how hard you try, you can't No matter how hard you try, you can't baptize cats.baptize cats.
Never lick a steak knife. Never lick a steak knife.
KlippelKlippel--TreTre´́naunaynaunay SyndromeSyndromeLymphatic InvolvementLymphatic Involvement
Definite:Definite:–– LymphangiomaLymphangioma circumscriptumcircumscriptum–– MacrocysticMacrocystic disease seen on MRIdisease seen on MRI–– Malformation of Malformation of lymphaticslymphatics on on lymphoscintigraphylymphoscintigraphy
Probable:Probable:–– PseudoverrucousPseudoverrucous lymphedemalymphedema changes or changes or lymphedemalymphedema–– Recurrent Recurrent cellulitiscellulitis–– Vascular Vascular ectasiasectasias (blebs)(blebs)–– VerrucousVerrucous changes over stainchanges over stain
Possible:Possible:–– One episode of One episode of cellulitiscellulitis–– NonNon--pitting edemapitting edema–– No LM:No LM:–– Lacking any of the features aboveLacking any of the features above
J Am Acad Dermatol 2004;51:391-8.
Fabry'sFabry's DiseaseDisease
Caused by a deficit in alphaCaused by a deficit in alpha--galactosidasegalactosidaseleading to an accumulation of leading to an accumulation of ceramideceramidetrihexosidetrihexoside in the endothelium and media of in the endothelium and media of blood vessels. Although the skin lesions are blood vessels. Although the skin lesions are diagnostic, the vascular involvement tends diagnostic, the vascular involvement tends to be more diffuse.to be more diffuse.An XAn X--linked recessive disorder found mostly linked recessive disorder found mostly in males. Females tend to be in males. Females tend to be aysmptomaticaysmptomaticheterozygotesheterozygotes who can be diagnosed by who can be diagnosed by assaying alphaassaying alpha--galactosidasegalactosidase activityactivity
Fabry'sFabry's DiseaseDisease
Neurologic involvement consists of a Neurologic involvement consists of a painful painful polyneuropathypolyneuropathy caused by caused by ceramideceramide trihexosidetrihexoside deposition both deposition both perineurallyperineurally and and intraneurallyintraneurally. . Cerebral Cerebral thromboembolicthromboembolic lesions may lesions may be seen early in teens.be seen early in teens.
Fabry'sFabry's DiseaseDisease
AngiokeratomaAngiokeratoma corporiscorporis diffusumdiffusum a a genetic disorder of the nervous genetic disorder of the nervous system, and skin.system, and skin.Multiple small, flat, or slightly raised Multiple small, flat, or slightly raised telangiectasestelangiectases on the abdomen and on the abdomen and lower extremities ,lower extremities ,