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Genodermatoses and Acquired Syndromes, Part I

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Title: Genodermatoses and Acquired Syndromes, Part I


1
Genodermatoses and Acquired Syndromes, Part I
  • Michael Hohnadel, D.O.
  • 6/20/06

2
Incontinentia Pigmenti
  • Aka Block-Sulzbergers disease
  • X-linked, onset in girls age 4-6 weeks
  • Presentation
  • Whorls and sworls along Blaschkos lines
  • Initially Vesicular
  • 6 weeks later Verrucous
  • 6 months later HyperPigmented
  • 6 years later Hypopigmented.
  • Defect in Xq28

3
Incontinentia Pigmenti
4
Incontinentia Pigmenti
Early vesicular stage of Incontinentia pigmenti,
eosinophilic spongiosis
5
Incontinentia pigmenti
6
Rule out these problems, then assure parents the
skin manifestations will likely begin to resolve
by age 2 and be essentially clear by adulthood.
7
Naegeli-Franceschetti-Jadassohn Syn.
  • Aka Chromatophore Nevus of Naegeli
  • Differs from IC, pattern is RETICULAR and no
    preceeding inflamatory or vesicular changes.
  • Involves neck, flexural, perioral, periorbital
  • Also
  • Vasomotor changes and hypohidrosis
  • Abnormal dermatoglyphics and PPK.
  • Dental and nail abnormalities

8
Naegeli-Franceschetti-Jadassohn Syndrome
reticulated pattern
PERIORBITAL RETICULATION
Atrophic/absent dermatoglyphics
9
Hypomelanosis of Ito
  • Negative Image of IP, Hypopigmented whorls and
    sworls along Blaschkos lines
  • No inflammatory or vesicular changes.
  • Appears in first year of life, F gt M
  • 75 have CNS, Hair, Dental, MS or internal organ
    abnormalities
  • 50 have chromosomal mosaicism.
  • Repigmentation is the rule.

10
Hypomelanosis of Ito
11
Hypomelanosis of Ito
12
Linear and Whorled Nevoid Hypomelanosis
  • Within the first few weeks of life a whorled
    hyperpigmentation develops following Blaschkos
    lines. No vesicles or inflammation.
  • Spares mucous membranes, eyes palms and soles.
    Not NFJS because no periorbital or PPK.
  • Associated with MR, cerebral palsy, Cardiac
    defects
  • HE increased prominence of basal layer
    melanocytes with no pigment incontinence
  • May often be misdiagnosed as IP, NFJS or Linear
    Epidermal Nevus.

13
Conradi Hunermann Syndrome
  • Variant of Condrodysplasia Punctata
  • X-linked dominant
  • Presentation Whorl and swirl hyperkeratosis
    Ichthyosis with adherent scale present at birth.
    Cracked eggshell appearance of waxy shiny
    scaling skin.
  • Erythroderma usually present with linear streaks
    and whorls of hyperkeratosis
  • As child develops, follicular atrophoderma and
    pseudopelade emerge.

14
Conradi-Hunermann Syndrome
  • Hyper- or hypopigmentation along Blaschkos lines
    may coexist separately from atrophodermic areas
  • Stippled Epiphyses until age 2 or 3.
  • Nail changes present
  • Teeth are normal

15
(No Transcript)
16
Stippled Epiphyses, pathognomonic of
Chondrodysplasia Punctata or Conradi Hunermann
17
Klinefelters Syndrome
  • XXXY
  • Presentation
  • Hypogonadism, high gonadotropins
  • Shortening of 5th digit both hands
  • Thrombophlebitis and chronic leg ulcers
  • Increase risk of cancers, male breast ca., germ
    tumors, hematologic malignancies, sarcomas.
  • XXYY variant has acrocyanosis, PVD, stasis
    dermatitis
  • TX Testosterone injections.

18
Klinefelters Syndrome
Behavioral disturbances None to scant body/pubic
hair Gynecomastia Truncal obesity Sterility Small
testes Venous stasis with varicosities Long lower
extremities Leg ulcers
19
Turners Syndrome
  • Aka Gonadal dysgenesis
  • XO genotype
  • Short stature, Shield Chest, Coarctation of
    Aorta.
  • Skin
  • Webbed Neck.
  • Wide set nipples
  • Triangular mouth
  • Alopecia of frontal scalp
  • Koilonychia
  • Cutis laxa
  • Increased risk of melanoma suggested due to
    plenty of melanocytic nevi
  • TX with growth hormone is controversial

20
Turners Syndrome
Redundant neck skin, low set posterior hairline
21
Short stature Spatial relations
deficit Hypertelorism Low set ears Triangular
facies Webbed neck Coarctation of the
aorta Nevus Shield chest Wide set nipples Kidney
malformations Nails hypoplastic, hyperconvex,
deep-set Short 4th 5th digits Amenorrhea,
infertility\ Lymphedematous legs
22
Noonans Syndrome
  • Autosomal dominant
  • Mimics Turners except the of chromosomes is
    normal.
  • Presentation (Turners plus.)
  • Pulmonic valve stenosis Short curly hair
  • Tendency toward keloid formation
  • Keratosis pilaris atrophicans
  • Abnormal dermatoglyphics
  • May have multiple café au lait macules
  • Mutation in PTPN 1

23
Phakomatoses
  • Inherited CNS disorders that have congenital
    retinal tumors and cutaneous involvement.
  • Include
  • Tuberous Sclerosis
  • Neurofibromatosis (Von Recklinghausens)
  • Von Hippel-Lindaus
  • Ataxia-Telangiectasia
  • Basal Cell Nevus Syndrome
  • Nevus Sebaceous
  • Sturge-Weber Syndrome

24
Tuberous Sclerosis
  • Aka Epiloia, (Epi epilepsy, loi low
    intelligence, a adenoma sebaceum) triad
  • AD (75 spon.), Birth incidence 1/10000. MF.
  • Highly variable penetrance
  • Tumor supp. Genes. TSC1hamartin9q34,
    TSC2tuberin16p13.3
  • Presentation
  • Neuro Astrocytomas, calcified subependymal
    nodules
  • Ophtho Retinal hamartomas
  • Renal multiple, may cause renal failure.
    Multiple bilateral renal angiomyolipomas.
  • Pregnant pulmonary lymphangioleiomyomas

25
Tuberous Sclerosis
  • Skin
  • Hypomelanotic macules. Hypopigmented, not
    depigmented
  • Thumbprint macule, ash leaf spot, confetti
    macules
  • Fibrous plaque of forehead seen in 20
  • Variant of angiofibroma
  • Firm, yellow brown grow slowly
  • Shagreen patches
  • Facial angiofibromas
  • Periungal fibromas
  • Café au lait.

26
ASH LEAF MACULE
SEBACEOUS ADENOMAS, histo angiofibroma
SUBUNGUAL FIBROMAS
27
CONFETTI MACULES
SHAGREEN PATCH histo connective tissue
nevus
28
LEFT Retinal hamartomas of tuberous sclerosis,
angioid streaks
RIGHT Cranial CT demonstrating multiple
calcified subependymal nodules in a
paraventricular location
29
Neurofibromatosis Type I
  • NF-1 85 of cases of NF. 50 are new
    mutations.
  • Birth incidence 1/3000, AD
  • NF-1 pts 4 x more likely to get CA
  • Diagnostic criteria 2 or more of the following
  • gt 6 café au lait macules gt 5mm prior to puberty
    or gt 15mm after puberty
  • 2 or more NFs or 1 plexiform NF.
  • Pathognomonic button-hole sign
  • Axillary or inguinal freckling (Crowes sign)
  • 2 or more Lisch nodules
  • optic glioma
  • Bone lesion sphenoid wing dysplasia, thinning of
    long bone cortex with or without pseudoarthrosis
  • First degree relative with NF-1.

30
Neurofibromatosis 1
  • Café au lait macules randomly distributed except
    scalp, palms, and soles
  • Triple association of NF1 with JXG and JCML
  • 10 will develop plexiform neurofibromas
  • Tender, firm nodules
  • Composed of hypertrophied nerves in myxoid matrix
  • 1-5 will become malignant peripheral nerve
    sheath tumor
  • May be hyperpigmented with hypertrichosis
  • Dont confuse with congenital nevus

31
NF1 is located on chromosome 17q11.2 and encodes
for the GAP-related protein NEUROFIBROMIN. One of
the functions of neurofibromin is to negatively
regulate the activity of RAS proteins. RAS, like
other related G proteins, is dependent upon GTP
binding for its full activity, and GAP proteins
shut off the signal by accelerating the
hydrolysis of GTP to GDP.
32
Café-au-lait macule and axillary freckling . An
oval-shaped light-brown patch is present in the
axilla of this child along with multiple small
12 mm lentigines.
NOTE AXILLARY FRECKLING CROWES SIGN
33
Cutaneous neurofibromas. Small, soft,
skin-colored to pink polypoid papules that
characterize NF1. They exhibit button-holing
they can be pressed down into the panniculus by
light pressure and spring back when released
34
Left Lisch nodules. Multiple yellow-brown
papules on iris. These are a late finding,
usually seen in older pts. Eye exam may also
reveal Juvenile Posterior Subcapsular Lenticular
Opacity
35
Plexiform neurofibroma . Soft tissue swelling of
the left hand, note the overlying
hyperpigmentation. These feel like a
bag of worms
36
Neurofibromatosis Type II, etc
  • NF-2 resembles NF-1 but it has Bilateral acoustic
    neuromas and the affected gene is MERLIN or
    SCHWANNOMIN, 22q11-q13
  • NF-3 (mixed) and NF-4 (variant) have higher risk
    of optic neuromas, neurilemomas and meningiomas
  • NF-5 segmental (dermatomal)
  • NF-6 only café au lait, no neurofibromas
  • NF-7 late onset

37
Dx/Tx for Neurofibromatosis
  • Multidisciplinary approach.
  • Neurologist Ophthalmologist, Endocrinologist,
    Orthopedist, Oncologist.
  • Only treatment for neurofibromas is excision.
  • Recommended screening yearly exam with problem
    focused workup. A screening CT or MRI may be of
    value in higher risk patients.

38
Proteus Syndrome
  • Greek god Proteus (the polymorphous) mimics NF.
  • Presentation Partial gigantism of hands, feet,
    hemangiomas, lipomas, linear epidermal nevi,
    patchy dermal hypoplasia, macrocephaly,
    hyperostosis, hypertrophy of the long bones.
    Planter hyperplasia.
  • Skull on the right exhibits hyperostosis and
    partial gigantism

39
Elephant Man Joseph Merrick may have had
Proteus Syndrome
40
Von Hippel-Lindau Syndrome
  • AD, mutation in VHL tumor suppressor gene
  • Presentation
  • Pancreatic cysts/microcystic adenomas (75)
  • Cerebellar/spinal hemangioblastomas (65)
  • Retinal angiomas (60)
  • Clear-cell renal carcinomas (45)
  • Bilateral renal cysts (45)
  • Bilateral pheochromocytomas (26)
  • Normally, skin is not involved, but a hemangioma
    located in the occipito-cervical region may occur.

41
Ataxia-Telangiectasia AKA Louis-Barr Syndrome
  • Triad Cerebellar Ataxia, Oculocutaneous
    Telangiectasia Sinopulmonary Infections.
  • Autosomal recessive.
  • First noted when child begins walking, awkward
    swaying gait leads to need for wheelchair by age
    10
  • Telangiectasias on exposed surfaces (ears
    conjunctiva, face ect.) by age of 3 yrs.
  • Other IgA deficiencies. CA MC lymphoma,
    leukemia, breast. Nystagmus

42
Ataxia-Telangiectasia AKA Louis-Barr Syndrome
  • Patients are hypersensitive to ionizing
    radiation.
  • Screening Elevated alfa-fetoprotein. (best
    screeing test). CT for cerebellar abnormalities.

43
Telangiectasia of the neck in a 20-yo woman with
ataxia telangiectasia.
44
By age 3 fine venous telangiectasias seen on
exposed surface of ocular conjunctiva
Café au lait patches Hypopigmented
macules Premature graying/alopecia Chronic skin
granulomas
45
Epidermolysis Bullosa Disorders
46
(No Transcript)
47
Epidermolysis Bullosa
  • Types
  • EB Simplex
  • Weber-Cockayne
  • Koebner (generalized)
  • Dowling Meara
  • Junctional EB
  • Herlitz
  • Non-Herlitz
  • JEB- Pyloric atresia
  • Dystrophic EB
  • Dominant
  • Recessive

48
Epidermolysis Bullosa Types Summary
49
Weber Cockayne (EB Simplex)
  • K5 K14 mutation
  • Localized to hands feet w/ hyperhidrosis
  • Onset varies, usually infancy
  • Exacerbated by hot weather, prolonged walking
  • TX Drysol BID.

50
EB Simplex (Koebner)
  • Keratins 5 14, defective intermediate keratin
    filaments affected, split is _at_ lower basal layer
  • Generalized form, AD, onset at birth.
  • Vesicles, bullae, milia on areas of repeated
    trauma, ie. joints of hands, elbows, knees, feet
  • Nikolski sign negative
  • Worse in summer, improves in winter
  • Mucous membranes and nails not involved
  • TX decompression of large blisters, treat
    infections. With time this condition improves

51
EB Herpetiformis (Dowling-Meara)
  • K5 K14 mutations
  • Circinate, herpetiform configurations. Milia
    present.
  • Oral mucosa involved
  • Nails are shed, but may regrow
  • Palmoplantar keratoderma
  • Clumped tonofilaments on EM
  • Blistering lessens with age.

52
Epidermolysis bullosa simplex, DowlingMeara.
Small clustered vesicles in an arcuate array on
the shoulder in this child.
53
Epidermolysis bullosa simplex, DowlingMeara.
Diffuse keratoderma of the palm in an adult
54
EB Simplex w/ Muscular Dystrophy
  • Autosomal recessive with late onset MD.
  • Mutation in PLECTIN gene
  • PLECTIN is absent in skin and muscles
  • Widespread blistering at birth associated with
    scarring, milia, atrophy, nail dystrophy, dental
    anomalies, laryngeal webs, urethral strictures.

55
Junctional EB
  • Herlitz
  • AR, LAM gene mutations coding for proteins of
    Laminin 5 Anchoring filaments Lamina Lucida
    split.
  • Anemia and Growth Retardation
  • Dental enamel pits, mouth erosions
  • Nails- dystrophic or absent
  • Generalize bullae with non-healing granulation
    tissue, often prone to infections.
  • Usually fatal by age 3-4 years of age.
  • Non-Herlitz
  • AR, laminin and collagen 17 (bp180)
  • Similar to Herlitz but more mild variant. Heals
    with atrophic scarring, but remits with time
    lacks granulation tissue, anemia, growth
    retardation and has normal lifespan

56
Junctional epidermolysis bullosa, Herlitz.
Blisters on the elbow and large areas of denuded
skin note the bright red color in the axilla and
groin.
57
JEB with Pyloric Atresia
  • AR, Similar to JEB because defect is at the level
    of the lamina lucida
  • Defect is a6ß4 Integrin genes ITGA6 ITGA4
    Hemidesmosome is defective
  • Severe mucocutaneous fragility and gastric outlet
    obstruction, urethral strictures
  • Prognosis is poor, but if they survive the
    neonatal period the blistering diminishes

58
Generalized Atrophic Benign EB (GABEB)
  • Onset at birth, Autosomal recessive
  • Cleavage at the lamina lucida
  • Type XVII collagen BPA-2
  • Generalized blisters, atrophy, mucosal
    involvement, thickened, dystrophic or absent
    nails, dental defects
  • In contrast to EB Herlitz, pts often survive to
    adulthood

59
Dystrophic EB
  • Two types Dominant and Recessive (DgtR)
  • Type 7 collagen malformation poor anchoring
    fibrils. Sub lamina densa split.
  • Dominant Dystrophic EB
  • Bullae on extensor extremities and joints
  • Albopapuloid-Pasini (most severe) spontaneous
    scar-like lesions on trunk
  • Nails often thickened, teeth normal.
  • Healing w/ scarring, atrophy
  • Milia present, mild oral involvement, typically
    scarring at the tip of the tongue.
  • Normal life span
  • Recessive Dystrophic EB
  • Mitten deformities, mucosal erosions and
    scarring, carries, anemia. Squamous CA in scar.

60
Dominant Dystrophic EB
Dominant Dystrophic Epidermolysis Bullosa
61
Recessive Dystrophic EB
50 of pts have SCCs by age 35.
RDEB
MITTEN DEFORMITY
ESOPHAGEL STRICTURE/STENOSIS
62
Transient Bullous Dermolysis of the Newborn
  • Rare
  • Newborns who suffer blisters from every minor
    trauma
  • Separation below the basal lamina with
    degeneration of collagen and anchoring fibrils
  • Rapid healing at 4 months, no scarring, no nail
    abnormalities
  • Again a COL7A1 defect for Type VII collagen

63
Acrokeratotic Poikiloderma (Weary-Kindler)
  • 100 cases
  • Acral bullae and generalized poikiloderma with
    prominent atrophy.
  • Photosensitivity
  • Acral keratoses
  • Absence of elastic fibers in papillary dermis and
    fragmented ones in the mid-dermis

64
Hailey Hailey Disease(Familial Benign Chronic
Pemphigus)
  • AD
  • Presentation Persistent recurrent bullae on the
    lateral neck, axillae, flexures that rupture and
    may resemble impetigo. May have annular spreading
    border creating circinate and configurate
    patterns.
  • Worse in summer, onset teens to 20s
  • Genetic defect in Calcium ATPase
  • TX TS, TAbx, OAbx, Oral retinoids, steroids.

65
HAILEY- HAILEY
DILAPIDATED BRICK WALL pattern of ACANTHOLYSIS
ROUNDING UP of cells
66
  • ICHTHYOSIS VULGARIS
  • Profillagrin synthesis defect, AD
  • Incidence 1/250
  • Fine, whitish adherent scale SPARING THE
    FLEXURES, but worse on extensor extremities
  • Atopic Dermatitis gt50, Keratosis Pilaris,
    Hyperlinear palms
  • TX Emollients.
  • Histo Hyperkeratosis, absent granular layer

67
X-Linked Recessive Ichthyosis
  • Xp22.32, steroid sulfatase deficiency
  • Retention hyperkeratosis, brown adherent scale
  • SPARES FLEXURES, PALMS SOLES
  • Comma-shaped corneal opacities
  • Cryptorchidism 20, check for undescended
    testicles Urologist
  • Prolonged labor with affected infant
  • Serum cholesterol sulfate INCREASED
  • TX emollients

68
  • LAMELLAR ICHTHYOSIS
  • TRANSGLUTAMINASE defect
  • Collodion baby. Membrane desquamates 3 weeks
  • 5-15mm grayish brown scales, strikingly
    quadrilateral, free at the edges, adherent in the
    center.
  • Moderate HK of palms/soles.
  • TX AHAs, Emollients, Calcipotriol, Top/Oral
    Retinoids

69
Non-Bullous Congenital Ichthyosiform Erythroderma
  • Autosomal dominant.
  • tgm defects
  • Born in collodion membrane, Ectropion of eyelids
    resolves in 2 weeks
  • Redness and scaling is generalized
  • Cicatricial alopecia, nail dystrophy
  • Consider r/o Neutral Lipid Storage Disease.
  • Tx Emollients and humid environment, attention
    to infection in fissured areas, avoid
    keratolytics.

70
Harlequin Fetus
  • AR, severe, often stillborn or dies soon after
    delivery, but aggressive systemic retinoids have
    allowed some have lived 9 years.
  • Thick, armor-like plates covering entire surface,
    ectropion, eclabium
  • Failure to convert profillagrin to fillagrin, K6
    and K16.

71
Epidermolytic Hyperkeratosis(Bullous Congenital
Ichthyosiform Erythroderma)
  • K1, K10 defect
  • Newborn widespread bullae, erosions,
    erythroderma, focal hyperkeratosis
  • Infancy to adulthood Localized to generalized
    hyperkeratosis with rare focal bullae secondary
    to bacterial infection. Warty scales with spiny
    ridges. corrugated pattern to scales.
  • TX Neonatal ICU for fluid, electrolyte and
    sepsis work-up, broad spectrum antibiotics until
    cultures are negative. Adult oral retinoids,
    Abx emoliants

72
EHK defects K1 and K10
73
Ichthyosis Linearis Circumflexa(Netherton
syndrome)
  • Disorder of keratinization in which bizzare
    migratory annular and polycyclic patches occur.
    Leave no scarring or pigmentary changes.
  • Inheritance AR, patients are born erythrodermic
    and 1/3 can have fatal complications.
  • Most also have trichorrhexis invaginata and
    atopic derm.
  • May clear completely in summertime.
  • Adverse response to oral retinoids

74
Netherton syndrome
ILC
BALL IN SOCKET DEFECT
TWISTING DEFECT
75
Chanarin-Dorfman Syndrome (Neutral Lipid
Storage Disease)
  • Presentation Ichthyosis, Myopathy and lipid
    vacuoles -gt
  • Impaired degradation of triacylglycerol-derived
    diacylglycerol
  • Dietary modulation of fats aids in controlling
    the disease

Lipid vacuoles in granulocytes and monocytes but
not lymphocytes or erythrocytes. -- ML Williams,
M.D.
76
Ichthyosis Follicularis (IFAP Syndrome)
  • IFAP Ichthyosis Follicularis, Alopecia,
    Photophobia
  • Generalized spiny follicular lesions with xerosis
    of non-follicular skin, striking alopecia.
  • MgtF 51
  • X-linked recessive and AD forms reported

77
Sjogren-Larsson Syndrome
  • Fatty alcohol oxidoreductase deficiency.
  • Infancy generalized erythroderma, ichthyosis,
    fine to large lamellar scaling
  • After Infancy generalized darker scale without
    erythema accentuated in flexures and lower
    abdomen spares central face.
  • CNS MR, spastic diplegia with scissor gait
  • Eyes atypical retinitis pigmentosa glistening
    dots pattern on slit lamp exam.
  • Dental dysplasia
  • Tx Low fat diet with MCT oil anecdotal, but
    worth trying.

78
  • SJOGREN LARSSON SYNDROME - atypical retinitis
    pigmentosa glistening dots pattern on slit lamp
    exam.

79
Refsums Syndrome
  • Phytanol-CoA hydroxylase deficiency
  • Leads to phytanic acid deposition in
  • Skin (ichthyosis)
  • CNS (ataxia, peripheral neuropathy)
  • Eyes (retininitis pigmentosa salt pepper)
  • Ears (deafness)
  • Cardiac (arrhythmias, block, CHF)
  • Musculoskeletal (wasting, skeletal anomalies)
  • Signs and symptoms very dependant on diet.
  • TX dietary restriction of phytanic acid.

80
THE END
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