Genodermatoses and Acquired Syndromes, Part I

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Genodermatoses and Acquired Syndromes, Part I

• Michael Hohnadel, D.O.
• 6/20/06

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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

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Incontinentia Pigmenti
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Incontinentia Pigmenti
Early vesicular stage of Incontinentia pigmenti,
eosinophilic spongiosis
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Incontinentia pigmenti
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Rule out these problems, then assure parents the
skin manifestations will likely begin to resolve
by age 2 and be essentially clear by adulthood.
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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

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Naegeli-Franceschetti-Jadassohn Syndrome
reticulated pattern
PERIORBITAL RETICULATION
Atrophic/absent dermatoglyphics
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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.

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Hypomelanosis of Ito
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Hypomelanosis of Ito
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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.

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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.

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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

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Stippled Epiphyses, pathognomonic of
Chondrodysplasia Punctata or Conradi Hunermann
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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.

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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
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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

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Turners Syndrome
Redundant neck skin, low set posterior hairline
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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
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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

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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

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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

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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.

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ASH LEAF MACULE
SEBACEOUS ADENOMAS, histo angiofibroma
SUBUNGUAL FIBROMAS
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CONFETTI MACULES
SHAGREEN PATCH histo connective tissue
nevus
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LEFT Retinal hamartomas of tuberous sclerosis,
angioid streaks
RIGHT Cranial CT demonstrating multiple
calcified subependymal nodules in a
paraventricular location
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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.

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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

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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.
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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
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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
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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
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Plexiform neurofibroma . Soft tissue swelling of
the left hand, note the overlying
hyperpigmentation. These feel like a
bag of worms
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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

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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.

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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

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Elephant Man Joseph Merrick may have had
Proteus Syndrome
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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.

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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

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Ataxia-Telangiectasia AKA Louis-Barr Syndrome

• Patients are hypersensitive to ionizing
  radiation.
• Screening Elevated alfa-fetoprotein. (best
  screeing test). CT for cerebellar abnormalities.

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Telangiectasia of the neck in a 20-yo woman with
ataxia telangiectasia.
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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
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Epidermolysis Bullosa Disorders
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Epidermolysis Bullosa

• Types
• EB Simplex
• Weber-Cockayne
• Koebner (generalized)
• Dowling Meara
• Junctional EB
• Herlitz
• Non-Herlitz
• JEB- Pyloric atresia
• Dystrophic EB
• Dominant
• Recessive

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Epidermolysis Bullosa Types Summary
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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.

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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

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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.

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Epidermolysis bullosa simplex, DowlingMeara.
Small clustered vesicles in an arcuate array on
the shoulder in this child.
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Epidermolysis bullosa simplex, DowlingMeara.
Diffuse keratoderma of the palm in an adult
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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.

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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

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

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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

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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.

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Dominant Dystrophic EB
Dominant Dystrophic Epidermolysis Bullosa
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Recessive Dystrophic EB
50 of pts have SCCs by age 35.
RDEB
MITTEN DEFORMITY
ESOPHAGEL STRICTURE/STENOSIS
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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

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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

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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.

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HAILEY- HAILEY
DILAPIDATED BRICK WALL pattern of ACANTHOLYSIS
ROUNDING UP of cells
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• 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

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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

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• 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

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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.

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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.

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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

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EHK defects K1 and K10
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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

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Netherton syndrome
ILC
BALL IN SOCKET DEFECT
TWISTING DEFECT
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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.
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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

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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.

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

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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.

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THE END