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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
  • KCOM/Texas Dermatology Consortium
  • NE Regional Medical Center

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

3
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4
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 Synd.
  • Aka Chromatophore Nevus of Naegeli
  • Differs from IC, pattern is RETICULAR
  • MC neck, flexural, perioral, periorbital
  • No preceding vesiculation or inflammation
  • 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
  • J Invest Dermatol. 2000 Oct115(4)694-8.
  • The gene for Naegeli-Franceschetti-Jadassohn
    syndrome maps to 17q21.Whittock NV, Coleman CM,
    McLean WH, Ashton GH, Acland KM, Eady RA, McGrath
    JA.

10
Hypomelanosis of Ito
  • Negative Image of IP, whorls and sworls along
    Blaschkos lines hypopigmented.
  • First year of life, F gt M
  • 75 have CNS, Hair, Dental, MS or internal organ
    abnormalities
  • 50 have chromosomal mosaicism.

11
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12
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13
Hypomelanosis of Ito Whorled Marble Cake
No inflammatory or vesicular lesions. No TX
eventual repigmentation is the rule
14
Linear and Whorled Nevoid Hypomelanosis
  • Not IP because no vesicles.
  • Not NFJS because no periorbital or PPK
  • Associated with MR, CP, Cardiac defects
  • HE increased prominence of basal layer
    melanocytes with no pigment incontinence
  • May often be misdiagnosed as IP, NFJS or Linear
    Epidermal Nevus by young dermatologists looking
    to make a name for themselves.

15
Conradi Hunermann Syndrome
  • Variant of Condrodysplasia Punctata
  • Ichthyosis
  • Whirl and swirl hyperkeratosis
  • Cracked eggshell appearance of waxy shiny
    scaling skin
  • As child develops, follicular atrophoderma and
    pseudopelade emerge.

16
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17
Stippled Epiphyses, pathognomonic of
Chondrodysplasia Punctata or Conradi Hunermann
18
Klinefelters Syndrome
  • XXXY, Hypogonadism, high gonadotropins
  • Shortening of 5th digit both hands
  • Thrombophlebitis and chronic leg ulcers
  • Increase risk of cancers, male breast, germ
    tumors, hematologic malignancies, sarcomas.
  • XXYY variant has acrocyanosis, PVD, stasis
    dermatitis
  • TX Testosterone injections.

19
Behavioral disturbances None to scant body/pubic
hair Gynecomastia Truncal obesity Sterility Small
testes Venous stasis with varicosities Long lower
extremities Leg ulcers
20
Turners Syndrome
  • Aka Gonadal dysgenesis
  • XO genotype
  • 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

21
Redundant neck skin, low set posterior hairline
22
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
23
Noonans Syndrome
  • Mimics Turners except the of chromosomes is
    normal.
  • Short curly hair
  • Tendency toward keloid formation
  • Keratosis pilaris atrophicans
  • Abnormal dermatoglyphics

24
Cardio-Facio-Cutaneous Synd.
  • Variant of Noonans with characteristic
    craniofacial appearance.
  • Hair is sparse, curly, fine or thick, wooly or
    brittle. Skin is ichthyotic
  • Eyebrows and eyelashes sparse or absent
  • Keratosis pilaris atrophicans faciei, PPK
  • Café au lait, nevi, hemangiomas
  • Cutis marmorata, sacral dimples.

25
What are the Phakomatoses?
  • Inherited CNS disorders that have congenital
    retinal tumors and cutaneous involvement.
  • Tuberous Sclerosis
  • Neurofibromatosis (Von Recklinghausens)
  • Von Hippel-Lindaus
  • Ataxia-Telangiectasia
  • Basal Cell Nevus Syndrome
  • Nevus Sebaceous
  • Sturge-Weber Syndrome

26
Tuberous Sclerosis
  • Aka Bournevilles Dz or Epiloia, (Epi epilepsy,
    loi low intelligence, a adenoma sebaceum)
    triad
  • Other findings seen next 3 slides
  • 2 tumor suppressor gene mutations
  • AD, but 50 may be spontaneous mutations
  • TSC1hamartin9q34, TSC2tuberin16p13.3
  • Neuro Astrocytomas, calcified subependymal
    nodules
  • Ophtho Retinal hamartomas
  • Renal multiple, may cause renal failure
  • Pregnant pulmonary lymphangioleiomyomas

27
ASH LEAF MACULE
SEBACEOUS ADENOMAS, histo angiofibroma
SUBUNGUAL FIBROMAS
28
CONFETTI MACULES
SHAGREEN PATCH histo connective tissue
nevus
29
LEFT Retinal hamartomas of tuberous sclerosis,
angioid streaks
RIGHT Cranial CT demonstrating multiple
calcified subependymal nodules in a
paraventricular location
30
Neurofibromatosis Type I
  • 85 of cases, AD
  • Diagnostic criteria 2 or more of the following
  • 1) gt 6 café au lait macules gt 5mm prior to
    puberty or gt 15mm after puberty
  • 2) 2 or more NFs or 1 plexiform NF.
  • 3) Axillary or inguinal freckling (Crowes sign)
  • 4) 2 or more Lisch nodules
  • 5) optic glioma
  • 6) bone lesion sphenoid wing dysplasia, thinning
    of long bone cortex with or without
    pseudoarthrosis
  • 7) first degree relative with NF-1.

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 JPSLO or 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 is best..
  • Neurologist MR, dementia, epilepsy,
    astrocytomas, meningiomas, schwannomas,
    neurofibrosarcomas.
  • Ophthalmologist lisch nodules, optic gliomas,
    JPSLO.
  • Endocrinologist acromegaly, cretinism,
    hyperparathyroidism, myxedema, phaeochromocytoma
  • Orthopedist erosive bone changes, lordosis,
    kyphosis, pseudoarthrosis, spina bifida,
    dislocations, atraumatic fractures, sphenoid wing
    dysplasia
  • Oncologist NF-1 pts 4 x more likely to get CA
    myeloproliferative, Wilms tumor, rhabdomyosarc,
    GI.
  • Only treatment for neurofibromas is excision.

38
Proteus Syndrome
  • Greek god Proteus (the polymorphous) mimics NF.
  • Partial gigantism of hands, feet, hemangiomas,
    lipomas, linear epidermal nevi, patchy dermal
    hypoplasia, macrocephaly, hyperostosis,
    hypertrophy of the long bones.
  • 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
  • Pancreatic cysts/microcystic adenomas (75)
  • Cerebellar/spinal hemangioblastomas (65)
  • Retinal angiomas (60)
  • Clear-cell renal carcinomas (45)
  • Bilateral renal cysts (45)
  • Bilateral pheochromocytomas (26)
  • MC skin is not involved, but a hemangioma located
    in the occipito-cervical region may occur.

41
Ataxia-Telangiectasia AKA Louis-Barr Syndrome
  • Mutated ATM gene 11q22.3 is responsible for DNA
    repair mechanisms
  • Patients are hypersensitive to ionizing
    radiation.
  • Cerebellar Ataxia, Oculocutaneous Telangiectasia
    Sinopulmonary Infections
  • Familial, first noted when child begins walking,
    awkward swaying gait leads to need for wheelchair
    by age 10
  • CA MC lymphoma, leukemia, breast

42
Telangiectasia of the neck in a 20-yo woman with
ataxia telangiectasia.
43
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
44
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45
EB Simplex Keratins 5 14 Keratin tonofilaments IE- lower basal
EBSS Type VII Collagen Unknown IE- below granular
EBS-MD Plectin Hemidesmosome IE- lower basal
JEB Laminin 5, BPA-2, Type XVII Coll. Anchoring Filament Lamina Lucida
JEB-PA a6ß4 Integrin Hemidesmosome Lamina Lucida
DDEB Type VII Collagen Anchoring Fibril Sub Lamina Densa
RDEB Type VII Collagen Anchoring Fibril Sub Lamina Densa
46
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

47
Weber Cockayne (EB Simplex)
  • Another K5 K14 mutation
  • Localized to hands feet w/ hyperhidrosis
  • Onset varies, usually infancy
  • Exacerbated by hot weather, prolonged walking
  • TX Drysol BID.

48
EB Herpetiformis (Dowling-Meara)
  • Circinate configurations, milia present
  • Oral mucosa involved
  • Nails are shed, but may regrow
  • Palmoplantar keratoderma
  • Clumped tonofilaments on EM
  • Blistering lessens with age
  • Again K5 K14 mutations

49
Epidermolysis bullosa simplex, DowlingMeara.
Small clustered vesicles in an arcuate array on
the shoulder in this child.
50
Epidermolysis bullosa simplex, DowlingMeara.
Diffuse keratoderma of the palm in an adult
51
EB Simplex w/ Muscular Dystrophy
  • AR, EBS 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.

52
JEB (Herlitz, EB Letalis)
  • AR, Laminin 5, BPA-2, Collagen XVII
  • 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 variant heals with atrophic scarring,
    but remits with time lacks granulation tissue,
    anemia, growth retardation and has normal lifespan

53
Junctional epidermolysis bullosa, Herlitz.
Blisters on the elbow and large areas of denuded
skin note the bright red color in the axilla and
groin.
54
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

55
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

56
Cicatricial JEB
  • Blisters heal with scarring
  • Syndactyly and contractures
  • Stenosis of anterior nares
  • EM junctional bullae with rudimentary
    hemidesmosomes
  • Basal lamina and anchoring fibrils intact

57
Dominant Dystrophic EB (DDEB)
  • Bullae on extensor extremities and joints
  • Albopapuloid-Pasini (most severe) spontaneous
    scar-like lesions on trunk
  • Nails often thickened, teeth normal.
  • Nikolski sign present
  • Healing w/ scarring, atrophy
  • Milia present, mild oral involvement, typically
    scarring at the tip of the tongue.
  • Cockayne-Touraine - milder, no albopapuloid
    lesions present.
  • Sub-Lamina Densa, Anchoring Fibrils, Coll. VII

58
Dominant Dystrophic Epidermolysis Bullosa
59
Barts Syndrome
  • AD
  • Mildly scarring mechanobullous dermatosis with
    nail deformities and a favorable prognosis
  • Variant of DDEB
  • COL7A1 gene defect encoding for Type VII collagen

60
Transient Bullous Dermolysis of the Newborn
  • 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

61
Acrokeratotic Poikiloderma (Weary-Kindler)
  • Acral bullae
  • Generalized poikiloderma with prominent atrophy
  • Photosensitivity
  • Acral keratoses
  • Absence of elastic fibers in papillary dermis and
    fragmented ones in the mid-dermis

62
Recessive Dystrophic EB (RDEB)(Hallopeau-Siemens
severe)
  • AR, Generalized skin and mucosal blistering
  • Mitten deformity, SCC
  • Severe dental esophageal complications
  • Anemia, Growth retardation
  • Reported cases with cardiomyopathy or amyloidosis
  • Tx Autologous or allogenic split thickness skin
    grafts, palliative, Dental care.

63
50 of pts have SCCs by age 35.
RDEB
MITTEN DEFORMITY
ESOPHAGEL STRICTURE/STENOSIS
64
Hailey Hailey DiseaseFamilial Benign Chronic
Pemphigus
  • 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, AD
  • Genetic defect in Calcium ATPase
  • TX TS, TAbx, OA, Oral retinoids, steroids.

65
HAILEY HAILEY
DILAPIDATED BRICK WALL pattern of ACANTHOLYSIS
ROUNDING UP of cells
66
  • ICHTHYOSIS VULGARIS, Profillagrin synthesis
    defect, AD
  • Ichthysis is Greek for fish. scales
  • 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 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
  • Serum cholesterol sulfate INCREASED
  • TX emollients

68
  • LAMELLAR ICHTHYOSIS TRANSGLUTAMINASE defect
    Collodion 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
  • 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)
  • 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

72
EHK defects K1 and K10
73
Restrictive Dermopathy
  • 24 cases
  • Lethal, AR
  • Prematurity, fixed facial expression,
    micrognathia, mouth in O position
  • Rigid and tense skin with erosions and
    denudations multiple joint contractures

74
Ichthyosis Linearis Circumflexa
  • 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 AD
    Nethertons Syndrome
  • May clear completely in summertime

75
ILC
BALL IN SOCKET DEFECT
TWISTING DEFECT
76
Chanarin-Dorfman Syndrome Neutral Lipid Storage
Disease
  • 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.
77
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

78
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.

79
  • SJOGREN LARSSON SYNDROME - atypical retinitis
    pigmentosa glistening dots pattern on slit lamp
    exam.

80
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)
  • TX dietary restriction of phytanic acid.

81
Ruds Syndrome
  • AR or X-linked
  • Ichthyosis
  • Hypogonadism
  • Small stature
  • MF, Epilepsy
  • Macrocytic anemia
  • Rule out Steroid sulfatase deficiency, Refsums
    Syndrome or Sjogren-Larsson Syndrome

82
KID Syndrome
  • Keratitis
  • Ichthyosis
  • Deafness

DISTINCTIVE LEATHERY VERRUCOID PLAQUES AVOID
ISOTRETINOIN, IT WORSENS THE KERATITiS!!!
83
THE END.
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