Title: Genodermatoses and Acquired Syndromes, Part I
1Genodermatoses and Acquired Syndromes, Part I
- Michael Hohnadel, D.O.
- 6/20/06
2Incontinentia 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
3Incontinentia Pigmenti
4Incontinentia Pigmenti
Early vesicular stage of Incontinentia pigmenti,
eosinophilic spongiosis
5Incontinentia pigmenti
6Rule out these problems, then assure parents the
skin manifestations will likely begin to resolve
by age 2 and be essentially clear by adulthood.
7Naegeli-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
8Naegeli-Franceschetti-Jadassohn Syndrome
reticulated pattern
PERIORBITAL RETICULATION
Atrophic/absent dermatoglyphics
9Hypomelanosis 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.
10Hypomelanosis of Ito
11Hypomelanosis of Ito
12Linear 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.
13Conradi 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.
14Conradi-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)
16Stippled Epiphyses, pathognomonic of
Chondrodysplasia Punctata or Conradi Hunermann
17Klinefelters 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.
18Klinefelters Syndrome
Behavioral disturbances None to scant body/pubic
hair Gynecomastia Truncal obesity Sterility Small
testes Venous stasis with varicosities Long lower
extremities Leg ulcers
19Turners 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
20Turners Syndrome
Redundant neck skin, low set posterior hairline
21Short 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
22Noonans 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
23Phakomatoses
- 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
24Tuberous 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
25Tuberous 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.
26ASH LEAF MACULE
SEBACEOUS ADENOMAS, histo angiofibroma
SUBUNGUAL FIBROMAS
27CONFETTI MACULES
SHAGREEN PATCH histo connective tissue
nevus
28LEFT Retinal hamartomas of tuberous sclerosis,
angioid streaks
RIGHT Cranial CT demonstrating multiple
calcified subependymal nodules in a
paraventricular location
29Neurofibromatosis 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.
30Neurofibromatosis 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
31NF1 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.
32Café-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
34Left 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
35Plexiform neurofibroma . Soft tissue swelling of
the left hand, note the overlying
hyperpigmentation. These feel like a
bag of worms
36Neurofibromatosis 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
37Dx/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.
38Proteus 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
39Elephant Man Joseph Merrick may have had
Proteus Syndrome
40Von 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.
41Ataxia-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
42Ataxia-Telangiectasia AKA Louis-Barr Syndrome
- Patients are hypersensitive to ionizing
radiation. - Screening Elevated alfa-fetoprotein. (best
screeing test). CT for cerebellar abnormalities.
43Telangiectasia of the neck in a 20-yo woman with
ataxia telangiectasia.
44By age 3 fine venous telangiectasias seen on
exposed surface of ocular conjunctiva
Café au lait patches Hypopigmented
macules Premature graying/alopecia Chronic skin
granulomas
45Epidermolysis Bullosa Disorders
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47Epidermolysis Bullosa
- Types
- EB Simplex
- Weber-Cockayne
- Koebner (generalized)
- Dowling Meara
- Junctional EB
- Herlitz
- Non-Herlitz
- JEB- Pyloric atresia
- Dystrophic EB
- Dominant
- Recessive
48Epidermolysis Bullosa Types Summary
49Weber 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.
50EB 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
51EB 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.
52Epidermolysis bullosa simplex, DowlingMeara.
Small clustered vesicles in an arcuate array on
the shoulder in this child.
53Epidermolysis bullosa simplex, DowlingMeara.
Diffuse keratoderma of the palm in an adult
54EB 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.
55Junctional 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
56Junctional epidermolysis bullosa, Herlitz.
Blisters on the elbow and large areas of denuded
skin note the bright red color in the axilla and
groin.
57JEB 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
58Generalized 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
59Dystrophic 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.
60Dominant Dystrophic EB
Dominant Dystrophic Epidermolysis Bullosa
61Recessive Dystrophic EB
50 of pts have SCCs by age 35.
RDEB
MITTEN DEFORMITY
ESOPHAGEL STRICTURE/STENOSIS
62Transient 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
63Acrokeratotic 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
64Hailey 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.
65HAILEY- 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
67X-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
69Non-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.
70Harlequin 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.
71Epidermolytic 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
72EHK defects K1 and K10
73Ichthyosis 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
74Netherton syndrome
ILC
BALL IN SOCKET DEFECT
TWISTING DEFECT
75Chanarin-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.
76Ichthyosis 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
77Sjogren-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.
79Refsums 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.
80THE END