Download Document

Genodermatoses
and Acquired
Syndromes,
Part I
Michael Hohnadel, D.O.
6/20/06
Incontinentia Pigmenti
Aka Block-Sulzberger’s disease
X-linked, onset in girls age 4-6 weeks
Presentation:





Whorls and sworls along Blaschko’s lines
Initially Vesicular
6 weeks later – Verrucous
6 months later – HyperPigmented
6 years later – Hypopigmented.
Defect in Xq28
Incontinentia
Pigmenti
Incontinentia Pigmenti
Early vesicular stage of Incontinentia
pigmenti, eosinophilic spongiosis
Incontinentia pigmenti
Rule out these
problems, then
assure parents
the skin
manifestations
will likely begin to
resolve by age 2
and be essentially
clear by
adulthood.
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
Naegeli-Franceschetti-Jadassohn
Syndrome – reticulated pattern
PERIORBITAL
RETICULATION
Atrophic/absent
dermatoglyphics
Hypomelanosis of Ito
“Negative Image” of IP, Hypopigmented
whorls and sworls along Blaschko’s lines

No inflammatory or vesicular changes.
Appears in first year of life, F > M
75% have CNS, Hair, Dental, MS or
internal organ abnormalities
50% have chromosomal mosaicism.
Repigmentation is the rule.
Hypomelanosis
of Ito
Hypomelanosis of Ito
Linear and Whorled Nevoid
Hypomelanosis
Within the first few weeks of life a whorled
hyperpigmentation develops following
Blaschko’s 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
H&E increased prominence of basal layer
melanocytes with no pigment incontinence
May often be misdiagnosed as IP, NFJS or
Linear Epidermal Nevus.
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.
Conradi-Hunermann Syndrome
Hyper- or hypopigmentation along
Blaschko’s lines may coexist separately
from atrophodermic areas
Stippled Epiphyses until age 2 or 3.
Nail changes present
Teeth are normal
Stippled Epiphyses, pathognomonic
of Chondrodysplasia Punctata or
Conradi Hunermann
Klinefelter’s 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.
Klinefelter’s
Syndrome
Behavioral disturbances
None to scant body/pubic
hair
Gynecomastia
Truncal obesity
Sterility
Small testes
Venous stasis with
varicosities
Long lower extremities
Leg ulcers
Turner’s 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
Turner’s Syndrome
Redundant
neck skin,
low set
posterior
hairline
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
Noonan’s Syndrome
Autosomal dominant
Mimics Turner’s 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
Phakomatoses
Inherited CNS disorders that have
congenital retinal tumors and cutaneous
involvement.
Include:







Tuberous Sclerosis
Neurofibromatosis (Von Recklinghausen’s)
Von Hippel-Lindau’s
Ataxia-Telangiectasia
Basal Cell Nevus Syndrome
Nevus Sebaceous
Sturge-Weber Syndrome
Tuberous Sclerosis
Aka: Epiloia, (Epi = epilepsy, loi = low intelligence, a =
adenoma sebaceum) = triad
AD (75 % spon.), Birth incidence 1/10000. M=F.
**** Highly variable penetrance *****
Tumor supp. Genes. TSC1=hamartin=9q34,
TSC2=tuberin=16p13.3
Presentation:




Neuro: Astrocytomas, calcified subependymal nodules
Ophtho: Retinal hamartomas
Renal: multiple, may cause renal failure. Multiple bilateral
renal angiomyolipomas.
Pregnant: pulmonary lymphangioleiomyomas
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.
ASH LEAF MACULE
SEBACEOUS ADENOMAS,
histo = angiofibroma
SUBUNGUAL FIBROMAS
CONFETTI MACULES
SHAGREEN PATCH
histo = connective tissue
nevus
LEFT: Retinal
hamartomas of
tuberous sclerosis,
angioid streaks
RIGHT: Cranial CT
demonstrating multiple
calcified subependymal
nodules in a
paraventricular location
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 ****
1.
2.
Diagnostic criteria: 2 or more of the following
> 6 café au lait macules > 5mm prior to puberty or > 15mm
after puberty
2 or more NFs or 1 plexiform NF.
Pathognomonic “button-hole” sign
3.
4.
5.
6.
7.
Axillary or inguinal freckling (Crowe’s 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.
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
Don’t confuse with congenital nevus
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.
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 1–2 mm lentigines.
NOTE: AXILLARY FRECKLING = CROWE’S SIGN
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
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
Plexiform neurofibroma . Soft tissue swelling of the left
hand, note the overlying hyperpigmentation.
These feel like a “bag of worms”
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
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.
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
“Elephant Man” Joseph Merrick may have had Proteus Syndrome
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.
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
Ataxia-Telangiectasia
AKA Louis-Barr Syndrome
Patients are hypersensitive to ionizing
radiation.
Screening: Elevated alfa-fetoprotein. (best
screeing test). CT for cerebellar
abnormalities.
Telangiectasia of the neck in a 20-yo woman with ataxia telangiectasia.
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
Epidermolysis Bullosa Disorders
Epidermolysis Bullosa
Types
EB Simplex



Weber-Cockayne
Koebner (generalized)
Dowling Meara
Junctional EB



Herlitz
Non-Herlitz
JEB- Pyloric atresia
Dystrophic EB


Dominant
Recessive
Epidermolysis Bullosa Types Summary
EB
Simplex
EBS-MD
Keratins 5 & 14
JEB
Laminin 5, BPA-2,
Type XVII Coll.
JEB-PA
α6ß4 Integrin
Hemidesmosome Lamina
Lucida
D-DEB
Type VII Collagen
Anchoring Fibril
R-DEB
Type VII Collagen
Anchoring Fibril
Plectin
Keratin
IE- lower
tonofilaments
basal
Hemidesmosome IE- lower
basal
Anchoring
Lamina
Filament
Lucida
Sub Lam.
Densa
Sub. Lam.
Densa
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.
EB Simplex (Koebner)
Keratins 5 & 14, defective intermediate keratin
filaments affected, split is @ 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
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.
Epidermolysis bullosa simplex, Dowling–Meara. Small
clustered vesicles in an arcuate array on the
shoulder in this child.
Epidermolysis bullosa
simplex, Dowling–Meara.
Diffuse keratoderma of
the palm in an adult
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.
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
Junctional epidermolysis
bullosa, Herlitz. Blisters
on the elbow and large
areas of denuded skin;
note the bright red color
in the axilla and groin.
JEB with Pyloric Atresia
AR, Similar to JEB because defect is at
the level of the lamina lucida
Defect is α6ß4 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
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
Dystrophic EB
Two types: Dominant and Recessive (D>R)
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 scarlike 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.
Dominant Dystrophic EB
Dominant Dystrophic
Epidermolysis Bullosa
Recessive Dystrophic EB
RDEB
50% of pts have SCCs by age 35.
MITTEN
DEFORMITY
ESOPHAGEL
STRICTURE/STENOSIS
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
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 middermis
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 20’s
Genetic defect in Calcium ATPase
TX: TS, TAbx, OAbx, Oral retinoids, steroids.
HAILEYHAILEY
“DILAPIDATED BRICK WALL”
pattern of ACANTHOLYSIS =
ROUNDING UP of cells
ICHTHYOSIS VULGARIS
Profillagrin synthesis
defect, AD
Incidence 1/250
Fine, whitish adherent
scale SPARING THE
FLEXURES, but worse on
extensor extremities
Atopic Dermatitis >50%,
Keratosis Pilaris,
Hyperlinear palms
TX: Emollients.
Histo: Hyperkeratosis,
absent granular layer
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
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
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.
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.
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
EHK defects
K1 and K10
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
Netherton syndrome
ILC
BALL IN SOCKET DEFECT
TWISTING DEFECT
Chanarin-Dorfman Syndrome
(Neutral Lipid Storage Disease)
Presentation:
Ichthyosis, Myopathy
and lipid vacuoles ->
Impaired degradation
of triacylglycerolderived diacylglycerol
Dietary modulation of
fats aids in controlling
Lipid vacuoles in granulocytes and
the disease
monocytes but not lymphocytes or
erythrocytes. -- ML Williams, M.D.
Ichthyosis Follicularis
(IFAP Syndrome)
IFAP = Ichthyosis Follicularis, Alopecia,
Photophobia
Generalized spiny follicular lesions with
xerosis of non-follicular skin, striking
alopecia.
M>F 5:1
X-linked recessive and AD forms reported
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.
•SJOGREN LARSSON
SYNDROME - atypical
retinitis pigmentosa
“glistening dots” pattern on
slit lamp exam.
Refsum’s 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.
THE END