Wyburn Syndrome

7/29/2019 Wyburn Syndrome

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The Inside Out ofThe Inside Out ofNeurocutaneous DisordersNeurocutaneous Disorders

Robert GreenwoodRobert Greenwood


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Sometimes spots and knotshave a purpose that tells you

something about theorganism that has them.


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OxymoronsOxymorons That Will Not BeThat Will Not Be

Used In This LectureUsed In This Lecture

Black LightBlack Light Never generalize!!Never generalize!!

Exact estimateExact estimate


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Neurocutaneous DisordersNeurocutaneous Disorders

General ConceptsGeneral Concepts1.1. The skin can be a window that allows you to see theThe 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 andAs in many other genetic diseases variable penetrance andexpression are the rule.expression are the rule.

4.4. Family history and examination of other family members isFamily history and examination of other family members isa 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 affectedHair and teeth are skin appendages and are often affectedwhen skin is affected.when skin is affected.

6.6. Look on the WebLook on the Webhttp://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


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IncidenceIncidence

NeurofibromatosisNeurofibromatosistype 1type 1

Tuberous SclerosisTuberous Sclerosis

AtaxiaAtaxia TelangiectasiaTelangiectasia XerodermaXeroderma

PigmentosumPigmentosum

NeurofibromatosisNeurofibromatosistype 2type 2

1/1,0001/1,000--1/7,8001/7,800(30/100,000)(30/100,000)

10.6/100,00010.6/100,000

1.7/100,0001.7/100,000 1/100,0001/100,000 -- 1/250,0001/250,000

1/200,0001/200,000


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IndentifiedIndentified Chromosome DefectsChromosome Defects

DisorderDisorder

NF1NF1

NF2NF2

TSTS

IncontinentiaIncontinentia PigmentiPigmenti HypomelanosisHypomelanosis of Itoof Ito

AA--TT

VonVon HippleHipple LindauLindau

OslerOsler RenduRendu --WeberWeberDiseaseDisease

ChromosomeChromosome

17q11.217q11.2

22q12.222q12.2

16p13.3, 12q14, 9q3416p13.3, 12q14, 9q34

Xq28Xq28 --XX--linked dominantlinked dominant ? 9q33? 9q33--qter, 15q11qter, 15q11--q13,q13,

and Xp11and Xp11

11q22.311q22.3

11q13, 3p2611q13, 3p26--p25p25

9q34.19q34.1


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InheritanceInheritance

Autosomal DominantAutosomal DominantAutosomal RecessiveAutosomal Recessive

XX--linked Recessivelinked Recessive SporadicSporadic


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Genetics Principles: NF1 andGenetics Principles: NF1 and

Other Neurocutaneous DisordersOther Neurocutaneous Disorders

PenetrancePenetrance ExpressionExpression

Variable expressivityVariable expressivity

PleiotropyPleiotropy

MosaicismMosaicism

HeterogeneityHeterogeneity-- locus and alleliclocus and allelic


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Neurocutaneous DiseasesNeurocutaneous Diseases

Autosomal Dominant InheritanceAutosomal Dominant Inheritance

NeurofibromatosisNeurofibromatosis Tuberous SclerosisTuberous Sclerosis

VonVon HippelHippel--LindauLindau DiseaseDisease LentiginosisLentiginosis--DeafnessDeafness--CardiopathyCardiopathy SyndSynd..

HypomelanosisHypomelanosis of Itoof Ito OslerOsler--WeberWeber--RenduRendu DiseaseDisease


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Neurocutaneous DiseasesNeurocutaneous Diseases

Autosomal Recessive InheritanceAutosomal Recessive Inheritance

AtaxiaAtaxia--TelangiectasiaTelangiectasia XerodermaXeroderma PigmentosumPigmentosum

CockayneCockayness SyndromeSyndrome RothmundRothmund--Thomson SyndromeThomson Syndrome

SjogrenSjogren--Larsson SyndromeLarsson Syndrome NeuroichthyosisNeuroichthyosis

Werner Syndrome andWerner Syndrome and

ProgeriaProgeria


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Neurocutaneous DiseasesNeurocutaneous DiseasesXX--Linked InheritanceLinked Inheritance

IncontinentiaIncontinentia PigmentiPigmenti


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Neurocutaneous DiseasesNeurocutaneous DiseasesSporadic Congenital andSporadic Congenital andAngiomatosesAngiomatoses

NeurocutaneousNeurocutaneous MelanosisMelanosis Linear Sebaceous NevusLinear Sebaceous Nevus

SturgeSturge--Weber SyndromeWeber Syndrome KlippelKlippel--TrenaunayTrenaunay SyndromeSyndrome

WyburnWyburn--Mason SyndromeMason Syndrome


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Classification ofClassification of

Neurocutaneous Disorders andNeurocutaneous Disorders andCancerCancer

OncogeneOncogene or tumor suppressor geneor tumor suppressor geneabnormalities.abnormalities.

CaretakerCaretaker -- does not control cell growth directlydoes not control cell growth directly

but instead controls the rate of mutationbut instead controls the rate of mutation

GatekeeperGatekeeper-- controls either the rate of cell birthcontrols either the rate of cell birth

or the rate of cell deathor the rate of cell death


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Familial Cancer SyndromesFamilial Cancer Syndromes--

Disorders of the CaretakersDisorders of the Caretakers Nucleotide Excision Repair Syndromes:Nucleotide Excision Repair Syndromes: XerodermaXeroderma

PigmentosumPigmentosum,, CockayneCockayne Syndrome, andSyndrome, andTrichothiodystrophyTrichothiodystrophy

AtaxiaAtaxia--TelangiectasiaTelangiectasia

Bloom SyndromeBloom Syndrome FanconiFanconiAnemiaAnemia

HereditaryHereditary NonpolyposisNonpolyposis Colorectal Cancer (HNPCC)Colorectal Cancer (HNPCC)

Werner SyndromeWerner Syndrome PeutzPeutz--JeghersJeghers SyndromeSyndrome

JuvenileJuvenile PolyposisPolyposis SyndromeSyndrome


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Nucleotide Excision RepairNucleotide Excision Repair

(NER) Defects(NER) Defects

XerodermaXeroderma pigmentosumpigmentosum (XP)(XP) CockayneCockayne syndrome (CS)syndrome (CS)

Photosensitive form ofPhotosensitive form oftrichothiodystrophytrichothiodystrophy(TTD)(TTD)


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Nucleotide Excision RepairNucleotide Excision Repair

(NER) Defects(NER) Defects All are recessiveAll are recessive

All have extreme sunlight sensitivity and 1000X frequencyAll have extreme sunlight sensitivity and 1000X frequencyskin cancersskin cancers

Progressive degeneration of skin and eyesProgressive degeneration of skin and eyes

In some accelerated neurologic degeneration and neuronalIn some accelerated neurologic degeneration and neuronaldeathdeath

Key features CS and TTDKey features CS and TTD

CSCS-- short stature, severe neurological abnormalities withshort stature, severe neurological abnormalities withdysmyelination, cataracts, birddysmyelination, cataracts, bird--like facelike face

TTDTTD-- brittle hair and nails, ichthiosis, other symptoms similar tobrittle hair and nails, ichthiosis, other symptoms similar toCSCS


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XerodermaXeroderma PigmentosaPigmentosa Skin abnormalitiesSkin abnormalities

Erythema andErythema and bullaebullae (acute sensitivity in infancy)(acute sensitivity in infancy) FrecklesFreckles XerosisXerosis (dryness) and scaling(dryness) and scaling Areas ofAreas ofhyperpigmentationhyperpigmentation alternating withalternating with hyporpigmentationhyporpigmentation

TelangiectasiaTelangiectasia AtrophyAtrophy Benign lesion: actinicBenign lesion: actinic keratoseskeratoses,, keratocanthomaskeratocanthomas,, angiomasangiomas,,

fibromasfibromas

Malignant lesions: basal cell carcinoma,Malignant lesions: basal cell carcinoma, squamoussquamous cellcell

carcinoma, melanomacarcinoma, melanoma Ophthalmologic abnormalitiesOphthalmologic abnormalities ConjunctivitusConjunctivitus withwith

photophobia,photophobia, lacrimationlacrimation, edema, edema Cornea:Cornea: keratitiskeratitis,, opacificationopacification, impaired vision, impaired vision Neoplasms of conjunctiva, cornea, and lidsNeoplasms of conjunctiva, cornea, and lids


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XX--PP


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XerodermaXeroderma PigmentosaPigmentosa

Neurologic ManifestationsNeurologic Manifestations

MicrocephalyMicrocephaly Low intelligenceLow intelligence

Progressive mental deteriorationProgressive mental deterioration ProgressiveProgressive sensorineuralsensorineural deafnessdeafness

Abnormal motor activityAbnormal motor activity HyporeflexiaHyporeflexia oror areflexiaareflexia

Primary neuronal degenerationPrimary neuronal degeneration


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AtaxiaAtaxia--TelangiectasiaTelangiectasia (A(A--T)T)

1.1. Progressive gait andProgressive gait and truncaltruncal ataxia withataxia withonset 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 6years of age;years of age;


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AtaxiaAtaxia TelangiectasiaTelangiectasia

TelangiectaticTelangiectatic lesions oflesions ofconjuctivaeconjuctivae,,malarmalar eminences, ear lobes and uppereminences, ear lobes and upperneckneck

Ataxia,Ataxia, choreoathetosischoreoathetosis andand nystagmusnystagmus

Immunologic deficienciesImmunologic deficiencies

Cancer pronenessCancer proneness-- 38%38% lymphoreticularlymphoreticular


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AtaxiaAtaxia TelangiectasiaTelangiectasia


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AA--TT

IncidenceIncidence-- 1/40,000 births1/40,000 births Carrier frequency 1 %Carrier frequency 1 %

Female carriers RR of 5 for breast cancerFemale carriers RR of 5 for breast cancer Chromosome 11q22.3Chromosome 11q22.3-- ATMATM(ataxia(ataxia--telangiectasiatelangiectasia

mutated), is a member of a family of phosphatidylinositolmutated), is a member of a family of phosphatidylinositol--

33--kinasekinaserelated 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


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XX--linked, lethal inlinked, lethal in hemizygoushemizygous malesmalesVesicular rash in newborn periodVesicular rash in newborn period

Neonatal seizuresNeonatal seizures Polymorphic pigmented lesionsPolymorphic pigmented lesions

develop in infancydevelop in infancy


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ErythematousErythematous bullousbullous lesions at birthlesions at birth Second stage crusting of lesions (Second stage crusting of lesions (verrucousverrucous))

Third stage whorls, zebra stripes, speckles orThird stage whorls, zebra stripes, speckles or

other patterns of pigmentationother patterns of pigmentation Microcephaly andMicrocephaly and micropolygyriamicropolygyria

Mental retardationMental retardation Dental anomalies and ocular abnormalitiesDental anomalies and ocular abnormalities


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J Am AcadDermatol 2002;47:169-87


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Dental anomaliesDental anomaliesboth primary andboth primary andsecondary dentitionsecondary dentition

HypodontiaHypodontia (small teeth)(small teeth)

PartialPartial anodontiaanodontia (lack of teeth)(lack of teeth)

Delayed eruptionDelayed eruption

Impacted dentitionImpacted dentition Malformed crowns (cone or pegMalformed crowns (cone or peg--shaped)shaped)



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OphthalmicOphthalmic StrabismusStrabismus CataractsCataracts

Optic atrophyOptic atrophyAnophthalmiaAnophthalmia (absence of eye)(absence of eye)

MicrophthalmiaMicrophthalmia

RetinalRetinal vasculopathyvasculopathy (Fig 1)(Fig 1)

Changes such asChanges such as retrolentalretrolental fibroplasiafibroplasia



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Central nervous system symptoms and findingsCentral nervous system symptoms and findings SeizuresSeizures Mental retardationMental retardation AtaxiaAtaxia

Spastic abnormalitiesSpastic abnormalities Microcephaly Cerebral atrophyMicrocephaly Cerebral atrophy HypoplasiaHypoplasia of corpus callosumof corpus callosum

HydrocephalusHydrocephalus PorencephalicPorencephalic cystscysts Hemorrhagic necrosisHemorrhagic necrosis Neuronal heterotopiasNeuronal heterotopias



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HypomelanosisHypomelanosis of Itoof Ito

HypopigmentationHypopigmentation in whorlsin whorls SeizuresSeizures

Mental retardationMental retardation Ophthalmologic anomaliesOphthalmologic anomalies

HeterotopiasHeterotopias


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HypomelanosisHypomelanosis of Itoof Ito Small 0.5Small 0.5--11--cmcm hypopigmentedhypopigmented or whiteor white maculesmacules coalesce to formcoalesce to form

reticulated patches along the lines ofreticulated patches along the lines ofBlaschkoBlaschko.. TheThe maculesmacules cover more than 2 dermatomes and are often on both sidescover more than 2 dermatomes and are often on both sidesof 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


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HypomelanosisHypomelanosis of Itoof Ito


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Familial Cancer DisordersFamilial Cancer Disorders--

Disorders of GatekeepersDisorders of Gatekeepers

VonVon HippleHipple--LindauLindau SyndromeSyndrome Neurofibromatosis type 1Neurofibromatosis type 1

NeurofibormatosisNeurofibormatosis type 2type 2 Tuberous sclerosisTuberous sclerosis


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NEUROFIBROMATOSIS TYPE 1NEUROFIBROMATOSIS TYPE 1


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NF1 Molecular BiologyNF1 Molecular Biology

NF1 gene localized on chromosome 17q11.2NF1 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 isProtein product is neurofibrominneurofibromin

2818 amino acids2818 amino acids ? GTPase activator that regulates a tumor suppressor? GTPase activator that regulates a tumor suppressor

genegene


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NF1 GeneticsNF1 Genetics

Autosomal dominantAutosomal dominant Complete penetranceComplete penetrance

Half of the NF1 cases are new mutationsHalf of the NF1 cases are new mutations

More 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


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Neurofibromatosis Type 1Neurofibromatosis Type 1

NF1, von Recklinghausen DiseaseNF1, von Recklinghausen Disease PrevalencePrevalence-- 1/30001/3000

No racial or ethnic predilectionNo racial or ethnic predilection 1/7800 in the USSR1/7800 in the USSR

1.04/1000 in Israel military recruits1.04/1000 in Israel military recruits


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Criteria for the diagnosis of NF1Criteria for the diagnosis of NF1

requires two or more of therequires two or more of the

following:following:

Six or more cafe'Six or more cafe'--auau--lait macules (over 5 mm inlait macules (over 5 mm in

prepubertal individuals and over 15 mm inprepubertal individuals and over 15 mm inpostpubertal individuals)postpubertal individuals)

Two or more neurofibromas of any type or oneTwo 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 sphenoidA distinctive osseous lesion such as sphenoiddysplasia or thinning of long bone cortex with ordysplasia or thinning of long bone cortex with orwithout pseudarthrosiswithout pseudarthrosis

A firstA first--degree relative with NFdegree relative with NF--1 by the above1 by the above

criteriacriteria


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NF1NF1

cafcaf--auau--laitlait spotsspots


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Pigmentation oveplexiform neurofib


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Axillary Freckling


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Plexiform Neurofibroma ofPlexiform Neurofibroma of

the Facial Nervethe Facial Nerve


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NF1NF1


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ClinicalFeature

Incidence CONGENITAL(0-2 yrs)

PRESCHOOL(2-4 yrs)

LATECHILDHOOD &

ADOLESCENCE(6-16 yrs)

ADULTHOOD(16+yrs)

Caf au laitspots

-------------------->

PlexiformDiffuseneurofibroma

-

25%-------------------->

Superficial ornodul ar

--------------------> ------------------>

Tibialdysplasia-

3 % --------------------> ------------------>

Skinfold

freckling

-----------------> --------------->

Optic glioma 15 20 % --------->------------------>Learningdisabilities

30 65 % ------------------> --------------->

NF1NF1

Time Line ForTime Line ForComplicationsComplications

Ti Li F


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CONGENITAL(0-2 yrs)

PRESCHOOL(2-4 yrs)

LATECHILDHOOD &ADOLESCENCE

(6-16 yrs)

ADULTHOOD(16+yrs)

Hypertension ----------------> --------------------> ------------------>

Headaches 10 20 % ----------------> --------------------> ------------------>Dermalneurofibroma

--------------------> ------------------>

Scoliosis 12 20 % --------------------> Malignant

peripheralnerve sheathtumors

1 4 % ---------------------> ----------------->

Time Line ForTime Line For

ComplicationsComplications

Macrocephaly and Somatic Growth in NF1Macrocephaly and Somatic Growth in NF1


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Macrocephaly and Somatic Growth in NF1Macrocephaly and Somatic Growth in NF1

AbsoluteAbsolute macrocephalymacrocephaly(head(headcircumferencecircumference >> 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 deviations24% have macrocephaly (OFC >/=2 standard deviationsabove the population mean).above the population mean).

13% of patients have short stature (>/=213% of patients have short stature (>/=2standard 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


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Optic gliomaNormal


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NF1NF1

Other MRI AbnormalitiesOther MRI Abnormalities Areas of increased T2 signal intensityAreas of increased T2 signal intensity

4343 -- 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 ofmicrocalcificaiton, and areas ofdysmyelination and spongy changes indysmyelination and spongy changes inWM around lesion.WM around lesion.

Areas of increased T1 signal intensityAreas of increased T1 signal intensity Ventricular enlargementVentricular enlargement


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Learning is often affected in NF1 children.Learning is often affected in NF1 children.Visuospatial function is most clearlyVisuospatial function is most clearlyaffected.affected.

The brains of NF1 children are larger andThe brains of NF1 children are larger andthe pattern of growth of NF1 childrenthe pattern of growth of NF1 childrenmay be different.may be different. The increased brain size in NF1 children isThe 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 mostVisual spatial function is one of the most

consistent deficits and has correlated withconsistent deficits and has correlated withright hemisphere gray matter volume.right hemisphere gray matter volume.

ConclusionsConclusions


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The brains of NF1 children also haveThe brains of NF1 children also have

lowerlower NAA/creatine, and NAA/ChoNAA/creatine, and NAA/Cho

ratios in the thalamusratios in the thalamus.. T2 hyperintensities may be a marker forT2 hyperintensities may be a marker for

a more diffuse processa more diffuse process.. They may be positively correlatedThey may be positively correlated

with cognitive deficitswith cognitive deficits..

Conclusions Contd.Conclusions Contd.


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ADC in NF1 children is significantly different fromADC in NF1 children is significantly different fromother children but fractionalother children but fractional aniosotropyaniosotropy is onlyis onlydifferent in the hippocampus.different in the hippocampus.

The areas of the brain with greatest ADC differencesThe areas of the brain with greatest ADC differencesare those where we find significantly greater brainare 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 forThese same areas are thought to be important forattention and visual spatial function.attention and visual spatial function.

Conclusions Contd.Conclusions Contd.


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Bilateral acousticBilateral acoustic neuromasneuromas-- diagnosticdiagnostic Other tumorsOther tumors-- meningiomameningioma,, ependymomasependymomas,,

spinal cordspinal cord astrocytomasastrocytomas, dorsal nerve, dorsal nerve

schwannomasschwannomas

SkinSkin hyperpigmentationhyperpigmentation is variableis variable

PosteriorPosterior subcapsularsubcapsular cataracts andcataracts and LischLischnodulesnodules


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IncidenceIncidence-- 1 in 60001 in 6000 -- 90009000 Dominant inheritance but a high frequencyDominant 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


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Gene LocationGene Location ProteinProteinTSC1TSC1 chromosome 9 qchromosome 9 q hamartinhamartin

TSC2TSC2

chromosome 16 pchromosome 16 p

tuberintuberin

T b S l iT b S l i


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Revised Diagnostic CriteriaRevised Diagnostic Criteria Definite TSCDefinite TSC

Two major feature orTwo major feature or

One major plus 2 minorOne major plus 2 minor

Probable TSCProbable TSC One major and one minorOne major and one minor

Possible TSCPossible TSC One majorOne major 2 or more minor2 or more minor


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Tuberous SclerosisTuberous Sclerosis Primary FeaturesPrimary Features

Facial angiofibromasFacial angiofibromas MultipleMultiple ungualungual fibromasfibromas Cortical tubersCortical tubers

SubependymalSubependymal nodules or giant cellnodules or giant cell astrocytomaastrocytoma RetinalRetinal hamartomashamartomas 3 or more3 or more hypomelanotichypomelanotic maculesmacules

ShagreenShagreen patchpatch Renal angiomyolipomaRenal angiomyolipoma CardiacCardiac rhabdomyomarhabdomyoma PulmonaryPulmonary lymphangiomatosislymphangiomatosis


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Tuberous SclerosisTuberous Sclerosis Secondary featuresSecondary features

Affected first degree relativeAffected first degree relative

Dental enamel pitsDental enamel pits

Bone cystsBone cysts

Forehead plaqueForehead plaque

Renal cystsRenal cysts-- renalrenal angiomyuolipomaangiomyuolipoma

Renal cystsRenal cysts-- histologichistologic HamartomatousHamartomatous rectal polypsrectal polyps

GingivalGingival fibromasfibromas

T b S l iT b S l i


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Cutaneous ManifestationsCutaneous Manifestations HypomelanoticHypomelanotic maculesmacules-- 90 %90 %

ShagreenShagreen patchpatch-- 2020 -- 30 %30 %

UngualUngual fibromafibroma-- 15 to 20 %15 to 20 %

FacialFacial angiomaangioma (adenoma(adenoma sebaceumsebaceum))-- 75 %75 % Forehead plaqueForehead plaque

ConfettiConfettihypopigmentedhypopigmented skin lesionsskin lesions GingivalGingival fibromasfibromas

PoliosisPoliosis

T b S l iT b S l i


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HypopigmentedHypopigmented MaculeMacule



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HypopigmentedHypopigmented MaculeMacule-- WoodWoodssLampLamp

T b S l iT b S l i


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Early AdenomaEarly Adenoma SebaceumSebaceum

T b S l iT be o s Scle osis


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Late AdenomaLate Adenoma SebaceumSebaceum

T b S l iTuberous Sclerosis


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UngualUngual FibromaFibroma

T b S l iTuberous Sclerosis


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ShagreenShagreen PatchPatch

T be o s Scle osisTuberous Sclerosis


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ShagreenShagreen PatchPatch



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Other ManifestationsOther Manifestations CardovascularCardovascular

cardiaccardiac rhabdomyomatarhabdomyomata-- 30 to 50 %30 to 50 % cardiac arrhythmiacardiac arrhythmia

cardiaccardiac thromboembolismthromboembolism

RenalRenal renal angiomyolipomasrenal angiomyolipomas

renal cystsrenal cysts

PulmonaryPulmonary 1%, females > males1%, females > males pulmonarypulmonary lymphangiomyomatosislymphangiomyomatosis

symptoms includesymptoms include pneumothoraxpneumothorax,, dyspneadyspnea, cough,, cough, hemoptysishemoptysis,,

and pulmonary failureand pulmonary failure..



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Neurologic ManifestationsNeurologic Manifestations

SeizuresSeizures

--

often infantile spasmsoften infantile spasms

Mental retardation and autisticMental retardation and autistic--likelikebehaviorbehavior-- 60%60%

Focal neurologic deficitsFocal neurologic deficits

Brain tumorsBrain tumors

66--14% of TSC patients14% of TSC patients

giant cell astrocytomagiant cell astrocytoma


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Tuberous Sclerosis GeneTuberous Sclerosis Gene


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Tuberous Sclerosis GeneTuberous Sclerosis Gene

FunctionFunction

Tumor suppressor genesTumor suppressor genes

HamartomasHamartomas of tuberous sclerosis patientsof tuberous sclerosis patientsshow loss of heterozygosityshow loss of heterozygosity

Sequence homologies at the protein levelSequence homologies at the protein levelreveal a region of similarity betweenreveal a region of similarity between tuberintuberin

and theand the GTPaseGTPase activating protein GAP3activating protein GAP3


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TS and Adjacent GenesTS and Adjacent Genes

A contiguous deletion that affects bothA contiguous deletion that affects bothTSC2 and PKD1 genes results in early onsetTSC2 and PKD1 genes results in early onsetpolycystic kidney diseasepolycystic kidney disease

Some patients with contiguous deletions areSome patients with contiguous deletions aremilder because of somaticmilder because of somatic mosaicismmosaicism


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SturgeSturge WeberWeber


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SturgeSturge--Weber SyndromeWeber Syndrome

Unilateral or bilateral facialUnilateral or bilateral facial

angiomaangioma

in thein the

distribution of the first branch of thedistribution of the first branch of thetrigeminal nervetrigeminal nerve

Ipsilateral intracranial vascularIpsilateral intracranial vascular anomalieanomalie ofofthe capillaries andthe capillaries and venulesvenules of theof the

leptomeningesleptomeninges GlaucomaGlaucoma


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SturgeSturge--Weber Syndrome MRIWeber Syndrome MRI

SturgeSturge Weber NeurologicalWeber Neurological


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SturgeSturge Weber NeurologicalWeber Neurological

ComplicationsComplications

HemiparesisHemiparesis

SeizuresSeizures

Developmental DelayDevelopmental Delay

HeadachesHeadaches


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WyburnWyburn Mason SyndromeMason SyndromeAn uncommon disorder characterized by aAn uncommon disorder characterized by a

vascular malformation of the midbrainvascular malformation of the midbrainassociated with a unilateral retinal AVM,associated with a unilateral retinal AVM,

facial nevi, and mental changesfacial nevi, and mental changes


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WyburnWyburn Mason SyndromeMason SyndromeArteriovenousArteriovenous malformations of the retinamalformations of the retina

and central nervous systemand central nervous system

RareRare

No sex predilectionNo sex predilection

Variable neurological abnormalitiesVariable neurological abnormalities


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WyburnWyburn--Mason SyndromeMason Syndrome

Retina showing dilated vasculaturein a child with reduced vision,seizures and facial vascular

lesions.


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vonvon HippelHippel LindauLindau DiseaseDisease Diagnostic CriteriaDiagnostic Criteria

One or moreOne or more hemangioblastomashemangioblastomas either at theeither at thesame or different sitessame or different sites

Other visceral lesionsOther visceral lesions Familial tumorsFamilial tumors

UrinaryUrinary metanephrinemetanephrine level, and VMA arelevel, and VMA areelevated.elevated.

KlippelKlippel--TrenuanwayTrenuanway--WeberWeber


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KlippelKlippel-TrenuanwayTrenuanway-WeberWeber

SyndromeSyndrome

An uncommon neurocutaneous disorderAn uncommon neurocutaneous disordercharacterized by extensive skincharacterized by extensive skinhemangiomashemangiomas appearing in aappearing in a dermatomaldermatomal

pattern, and associated withpattern, and associated with hemangiomashemangiomasof the spinal cord.of the spinal cord.

The lesions are unilateral and are oftenThe lesions are unilateral and are often

associated with osseous or muscularassociated with osseous or muscularhypertrophy of the involved area. This mayhypertrophy of the involved area. This maybe a spinal variant ofbe a spinal variant ofSturgeSturge--Weber. PatternWeber. Patternof inheritance unknown.of inheritance unknown.

KlippelKl ppel--TreTrenaunaynaunaydd

J Am AcadDermatol 2004;51:39


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syndromesyndrome

OslerOsler--WeberWeber --RenduRendu SyndromeSyndrome


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OslerOsler WeberWeber RenduRendu SyndromeSyndrome

An uncommon disorder characterized byAn uncommon disorder characterized by angiomasangiomas

of the skin, mucous membranes, and nervousof the skin, mucous membranes, and nervoussystem.system.

Autosomal dominant disorderAutosomal dominant disorder

Development of multiple small red or purpleDevelopment of multiple small red or purpleangiomasangiomas. These enlarge and may be the source of. These enlarge and may be the source ofrecurrentrecurrent epistaxisepistaxis or GI or GU hemorrhages.or GI or GU hemorrhages.

ScatteredScattered angiomasangiomas may develop in the brain ormay develop in the brain orspinal cord, producing hemorrhage or localizedspinal cord, producing hemorrhage or localizedcerebral spinal dysfunction.cerebral spinal dysfunction.


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LinearLinear SebaciousSebacious NevusNevus

Linear NevusLinear Nevus SebaceusSebaceus


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SyndromeSyndrome Linear patches of yellow papulesLinear patches of yellow papules

Mental retardationMental retardation

SeizuresSeizures

HemiparesisHemiparesis

Ocular abnormalitiesOcular abnormalities-- microphthalmiamicrophthalmia,,anophthalmiaanophthalmia,, choristomaschoristomas, and, and colobomatacolobomataof lids, iris, choroids and optic nerve.of lids, iris, choroids and optic nerve.



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SyndromeSyndrome Brain AbnormalitiesBrain Abnormalities

HemiatrophyHemiatrophy

LipomasLipomas


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Congenital NevusCongenital Nevus Congenital nevi areCongenital nevi are melanocyticmelanocytic nevi present atnevi present at

birth.birth. They are probably best recognized as the large bathingThey 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 onusually larger than 6 cm on the trunk, 9 cm onthe scalp.the scalp.

AdultAdult-- greater than 20 cm in its largest diameter in angreater than 20 cm in its largest diameter in an

adult.adult. The management of these larger lesions isThe management of these larger lesions is

controversial.controversial.

ur u uencephalocraniocutaneousencephalocraniocutaneous J Am AcadDermatol 2002;47:S196-


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lipomatosislipomatosis

NeurocutaneousNeurocutaneous melanosismelanosis andand


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NeurocutaneousNeurocutaneous melanosismelanosis andand

encephalocraniocutaneousencephalocraniocutaneous lipomatosislipomatosis

FunduscopicView- Right eyefundoscopicview demonstratingmultiple large chorioretinal

lacunae.


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NEUROCUTANEOUS MELANOSISNEUROCUTANEOUS MELANOSIS

SignsSigns

HydrocephalusHydrocephalusMacrocephalyMacrocephalyIncreasing head circumferenceIncreasing head circumferenceBulgingBulging fontanellefontanelleSeizuresSeizures

Developmental delayDevelopmental delay SymptomsSymptoms

HeadacheHeadacheVomitingVomiting

Failure to thriveFailure to thriveWeaknessWeaknessGait abnormalitiesGait abnormalitiesBladder or bowel dysfunctionBladder or bowel dysfunction


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NeurocutaneousNeurocutaneous MelanosisMelanosis DiagnosisDiagnosis

presence of neurologic symptomspresence of neurologic symptoms

increased number ofincreased number ofmelanocytesmelanocytes within the centralwithin the centralnervous system associated with large cutaneous nevinervous system associated with large cutaneous nevior multiple smaller nevi.or multiple smaller nevi.

CNSCNS melanocytesmelanocytes are usually found in theare usually found in the

anterior temporal lobes, cerebellum, thalami,anterior temporal lobes, cerebellum, thalami,and base of the frontal lobeand base of the frontal lobe

LargeLarge CongenitalCongenital MelanocyticMelanocytic NevusNevus


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LargeLarge CongenitalCongenital MelanocyticMelanocytic NevusNevus

Malignancy 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 1015 year cumulative risk of 2.3% and relative risk of 101 If melanoma develops, >50% develop 50% develop


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ASSOCIATED FINDINGS WITH GIANTASSOCIATED FINDINGS WITH GIANT

CONGENITAL MELANOCYTIC NEVICONGENITAL MELANOCYTIC NEVI

LOCAL CHANGESLOCAL CHANGES

MALIGNANCIESMALIGNANCIES

MALFORMATIONSMALFORMATIONS

Loss of subcutaneous fatLoss of subcutaneous fat

LimbLimb hypoplasiahypoplasia RhabdomyosarcomaRhabdomyosarcoma

LiposarcomaLiposarcomaNeuroblastomaNeuroblastomaPrimitivePrimitive neuroectodermalneuroectodermaltumorstumorsMixed malignantMixed malignant neoplasmsneoplasms

VascularVascularSupernumerary digitsSupernumerary digitsEar deformitiesEar deformitiesPreauricularPreauricular appendagesappendagesCryptorchidismCryptorchidismClub feetClub feet

Treatment of Giant CongenitalTreatment of Giant Congenital MelanocyticMelanocytic


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Treatment of Giant CongenitalTreatment of Giant Congenital MelanocyticMelanocytic

NeviNevi

DermabasionDermabasion

12 patients treated between the first and fourteenth12 patients treated between the first and fourteenthweek of life.week of life. 1010-- appreciable and stable reduction of theappreciable 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 outcome

No melanomaNo melanoma

Scand J PlastReconstrSurgHand Surg2000 Dec;34(4):321-

Arch Dermatol 2002 Jul;138(7):943-7

WaardenburgWaardenburg SyndromeSyndrome


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WaardenburgWaardenburg SyndromeSyndrome

Type 1 & 2Type 1 & 2 Major criteriaMajor criteria

CongenitalCongenital sensorineuralsensorineural hearing losshearing loss PigmentaryPigmentary disturbances of irisdisturbances of iris

CompleteComplete heterochromiaheterochromia iridumiridum, two eyes of different color, two eyes of different color

Partial or segmentalPartial or segmental heterochromiaheterochromia; segments of blue or brown; segments of blue or brownpigmentation in one or both eyespigmentation in one or both eyes

HypoplasticHypoplastic blue eyes, characteristic brilliant blue in both eyesblue eyes, characteristic brilliant blue in both eyes

HairHair hypopigmentationhypopigmentation, white forelock, white forelock

DystopiaDystopia canthorumcanthorum, W > 1.95 averaged over affected family, W > 1.95 averaged over affected familymembers (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

WaardenburgWaardenburg Syndrome Type 1Syndrome Type 1


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Minor criteriaMinor criteria

CongenitalCongenital leukodermaleukoderma, several areas of, several areas ofhypopigmentedhypopigmented skinskin

SynophyrysSynophyrys or medial eyebrow flareor medial eyebrow flare Broad and high nasal rootBroad and high nasal root

HypoplasiaHypoplasia ofofalaealae nasinasi PrematurePremature greyinggreying of hair, scalp hairof hair, scalp hair

predominantly white before age 30predominantly white before age 30

WaardenburgWaardenburg Syndrome Type 1Syndrome Type 1

& 2& 2

Pl R b


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Please RememberPlease Remember

No matter how hard you try, you can'tNo matter how hard you try, you can'tbaptize cats.baptize cats.

Never lick a steak knife.Never lick a steak knife.

KlippelKlippel--TreTrenaunaynaunay SyndromeSyndrome


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Lymphatic InvolvementLymphatic Involvement Definite:Definite:

LymphangiomaLymphangioma circumscriptumcircumscriptum MacrocysticMacrocystic disease seen on MRIdisease seen on MRI Malformation ofMalformation oflymphaticslymphatics onon lymphoscintigraphylymphoscintigraphy

Probable:Probable: PseudoverrucousPseudoverrucous lymphedemalymphedema changes orchanges or lymphedemalymphedema

RecurrentRecurrent cellulitiscellulitis VascularVascular ectasiasectasias (blebs)(blebs) VerrucousVerrucous changes over stainchanges over stain

Possible:Possible:

One episode ofOne episode ofcellulitiscellulitis NonNon--pitting edemapitting edema No LM:No LM: Lacking any of the features aboveLacking any of the features above

J Am AcadDermatol 2004;51:391-8.

F b ' Di


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Fabry'sFabry's

DiseaseDisease

Caused by a deficit in alphaCaused by a deficit in alpha--galactosidasegalactosidase

leading to an accumulation ofleading to an accumulation ofceramideceramidetrihexosidetrihexoside in the endothelium and media ofin the endothelium and media ofblood vessels. Although the skin lesions areblood vessels. Although the skin lesions are

diagnostic, the vascular involvement tendsdiagnostic, the vascular involvement tendsto be more diffuse.to be more diffuse.

An XAn X--linked recessive disorder found mostlylinked recessive disorder found mostly

in males. Females tend to bein males. Females tend to be aysmptomaticaysmptomaticheterozygotesheterozygotes who can be diagnosed bywho can be diagnosed byassaying alphaassaying alpha--galactosidasegalactosidase activityactivity

F b ' Di


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Fabry'sFabry's

DiseaseDisease

Neurologic involvement consists of aNeurologic involvement consists of a

painfulpainful polyneuropathypolyneuropathy caused bycaused by

ceramideceramide trihexosidetrihexoside deposition bothdeposition both

perineurallyperineurally andand intraneurallyintraneurally..CerebralCerebral thromboembolicthromboembolic lesions maylesions may

be seen early in teens.be seen early in teens.

Fab 's Disease


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Fabry'sFabry's

DiseaseDisease

AngiokeratomaAngiokeratoma corporiscorporis diffusumdiffusum aa

genetic disorder of the nervousgenetic disorder of the nervous

system, and skin.system, and skin.

Multiple small, flat, or slightly raisedMultiple small, flat, or slightly raisedtelangiectasestelangiectases on the abdomen andon the abdomen and

lower extremities ,lower extremities ,

Wyburn Syndrome

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