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Table 4.10 Types of Epidermolysis Bullosa (EB)
EB Simplex (EBS)
• Level of split is intraepidermal
• Most common form of EB
• AD inheritance, except for EBS with muscular dystrophy (AR)
• Bullae generally heal without scarring
Subtype
EBS-localized (previously
called Weber-Cockayne)
EBS-generalized intermediate
(previously known as
Koebner)
EBS-generalized severe
(previously known as
Dowling-Meara or EBS
herpetiformis)
EBS-mottled pigmentation AD KRT5
EBS-muscular dystrophy AR PLEC Plectin Bulla develop
Mode of
Inheritance Gene(s) Protein(s) Onset
AD KRT5
AD KRT5
AD KRT5
KRT14
KRT14
KRT14
KRT14
Keratin 5
Keratin 14
Keratin 5
Keratin 14
Keratin 5
Keratin 14
Keratin 5
Keratin 14
Birth through
adolescence
Birth or infancy Tense bullae at any site
Birth, or within
first few weeks
of life
Childhood Acral blisters
at birth, but
muscle
weakness is
delayed (may
develop in
infancy through
adulthood)
Primary Cutaneous
Features
Tense bullae predomi-
nantly on hands and
feet, soles . palms
(Fig. 4.12); non-scarring
Worse with heat, ill-tting
shoes, and frictional
trauma from walking
of friction; non-scarring
Bullae worse with heat
Generalized blisters
After rst few months of
life, bullae take on
characteristic clus-
tered
herpetiformis appearance
May rarely heal with
some scarring and
milia
Mottled hyperpigmenta-
tion on the trunk and
limbs
Generalized blisters that
lead to atrophic scars
Associated Clinical
Features Prognosis
Rare oral blisters early in life
Occasional palmoplantar hy-
perkeratosis
Rare nail dystrophy
May have oral blisters
Palmoplantar hyperkeratosis
over time
May have nail dystrophy
Oral blisters common
Nail shedding, nail dystrophy
and hyperkeratotic nails are
common
Palmoplantar hyper-
keratosis
Characteristic clumped tono-
laments on electron mi-
croscopy
Punctate palmoplantar kerato-
derma
Common nail dystrophy
Muscular dystrophy with onset
in infancy or later in life
Common nail hyperkeratosis
Common dental
abnormalities
Associated cerebral and cere-
bellar atrophy, uretheral
stricture, and scarring alo-
pecia
Normal life span
May have worse blisters and
severe pain during summer
months
Normal life span
Most severe form of EBS
Usually normal life span
Rare associated early death
due to sepsis, anemia, or
growth failure
Very rare subtype, normal
life span
Morbidity from muscular
dystrophy
4.4 Epidermolysis Bullosa
Continued
245
246
Table 4.10 Types of Epidermolysis Bullosa (EB)—cont'd
Junctional EB (JEB)
• Cleavage plane of blister is within the lamina lucida of the BMZ
• Rarest form of EB
• AR inheritance
• Enamel hypoplasia/pitting (and possible tooth loss due to caries) occurs in all forms of JEB
Subtype
JEB-generalized severe
(previously known as JEBHerlitz or EB Lethalis)
JEB-generalized intermediate
(previously known as nonHerlitz, generalized atrophic
benign EB)
JEB-pyloric atresia AR ITGA6
Dystrophic EB (DEB)
• Level of split is below the lamina densa of the BMZ
• Two major subtypes are categorized by mode of inheritance: dominant dystrophic EB (DDEB) and recessive dystrophic EB (RDEB)
• In general, DDEB is more mild than RDEB, though there is considerable overlap between the milder forms of RDEB and DDEB
• DDEB may rarely manifest with only nail dystrophy
Mode of
Inheritance Gene(s) Protein(s) Onset
AR LAMA3
AR LAMA3
LAMB3
LAMC2
LAMB3
LAMC2
COL17A1
ITGB4
Laminin 332 (premature
termination codon)
Absent Hemidesmo-
some (or extremely ru-
dimentary)
Laminin 332
Collagen XVII (BPAG2/
BP180)
a6b4 integrin
Birth Generalized blisters; typi-
Birth Generalized blisters and
Birth Generalized blisters,
Primary Cutaneous
Features
cally heals without
scarring
Common sites are but-
tocks, perioral, and
pinnae of ears
oral involvement common in neonatal period, but improves as
child ages; heals with
atrophic scars
Granulation tissue un-
common
often with large areas
of congenital localized
absence of skin
Associated Clinical
Features Prognosis
Oral blisters common
Hoarse cry as a result of la-
ryngeal involvement
Paronychial inammation with
nail dystrophy and nail loss
Granulation tissue of nail beds
Perioral granulation tissue
may develop beyond 6
months of age
Scarring alopecia
Nail dystrophy common
Dental enamel hypoplasia
common
Corneal erosions
“EB nevi” seen in several
forms including JEB—large,
acquiried atypical nevi clini-
cally resembling melanoma
Pyloric atresia
Scarring of urinary tract, lead-
ing to ureteral stenosis
and hydronephrosis (re-
quires urologic surgery)
Rudimentary and mal-
formed ears
Death within rst few years
of life from respiratory
failure or septicemia
(90% die by age 1 year)
Failure to thrive and anemia
very common
Survival to adulthood
Poor prognosis with mortality
in infancy
CHAPTER 4 • Pediatric Dermatology
Subtype
DDEB AD COL7A1
Transient bullous dermolysis
of the newborn (TBDN)
RDEB, generalized severe
(previously known as
Hallopeau-Siemens)
RDEB, generalized
intermediate (previously
known as non-HallopeauSiemens type)
Kindler Syndrome (Acrokeratotic poikiloderma)
• Rare disorder characterized by skin fragility, photosensitivity, and poikiloderma
• In 2008, this disorder was grouped as a major form of EB, with mixed blister cleavage plane
• Immunohistochemical analysis shows reduced or absent staining against fermitin family homolog 1 ( FERMT1 gene, formerly known as kindlin-1; protein involved in keratinocyte adhesion and migration)
• Electron microscopy shows duplication of the lamina densa ; histology shows absence/fragmentation of elastic bers
Kindler syndrome AR FERMT1 Fermitin family homolog 1 Neonatal period Poikiloderma
Mode of
Inheritance Gene(s) Protein(s) Onset
(missense
mutation)
Often AD COL7A1 Collagen VII
AR COL7A1
AR COL7A1 Collagen VII Birth Generalized blisters
(premature
termination
codon
leads to
complete
lack of
anchoring
fibrils)
Collagen VII Birth Cockayne-Touraine Type:
Likely a form fruste of
DDEB
Collagen VII Birth Generalized mucocutane-
Birth Blistering of the skin, can
247
AD, Autosomal dominant ; AR, autosomal recessive ; SCC, squamous cell carcinoma.
Primary Cutaneous
Features
Generalized bullae, most
prominent overlying extensor joints; tends to
improve over time; heals
with atrophic scarring
and milia
Pasini type: Similar to
Cockayne-Touraine
type but also has scarlike “albopapuloid”
papules that favor
trunk and arise spontaneously (without preceding blisters)
heal with milia and/or
scarring
ous blisters (Fig. 4.13)
Heals with atrophic
scarring and milia
Heals with atrophic scars
and milia
May be difficult to
distinguish from DDEB
clinically
Acral blisters, though
may have more widespread involvement
Cigarette paper-like atro-
phy of hands/feet
Associated Clinical
Features Prognosis
Nail dystrophy common
Oral blisters may occur
Rarely may have esophageal
strictures
Anemia uncommon
Pseudosyndactyly (“mitten
deformities” of hands/feet)
common and pathognomonic
Contractures of digits and
limbs
Scarring alopecia
Corneal erosions
Oral blisters common
Microstomia
Dental caries (severe)
Esophageal strictures and other
GI complications common
Osteopenia
Growth failure
Anemia
Dilated cardiomyopathy may
(rarely) occur
Renal failure
Aggressive SCC
Fewer comorbidities than the
severe form of RDEB
Photosensitivity
Palmoplantar hyperkeratosis
Hand/foot skin atrophy
Nail dystrophy
Gingivitis
SCC of the lip and hard palate
Disease activity tends to
improve over time, typically
milder overall disease similar
to EBS
Often spontaneously resolves
in the first several months
of life
Many comorbidities of other
organ systems
SCC is leading cause of
death (affects 50% of pa-
tients by age 35 years)
Renal failure (12% mortality)
Like DDEB, disease activity
may improve slightly over
time
Skin fragility, photo-sensitivity
usually improves over time
4.4 Epidermolysis Bullosa
CHAPTER 4 • Pediatric Dermatology
Fig. 4.12 Epidermolysis bullosa simplex, localized type. Note the supercial
blistering with both intact bullae and denuded skin. This form tends to be limited
to the palms and soles. (From Paller AS, Mancini AJ. Bullous disorders of childhood. In: Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of
Childhood and Adolescence. 4th ed. Philadelphia: Elsevier; 2011:303–320.)
Fig. 4.13 Recessive dystrophic epidermolysis bullosa in a neonate. (Personal
collection, Phuong Khuu.)
syndrome, but that eponym is no longer used in the current
classication system.
The diagnosis of EB is made through ultrastructural evaluation of the cleavage plane of the blister and accompanying
immunohistochemistry. It is important that the biopsy
specimen is obtained from an induced blister, rather than
from a preexisting blister, in order to obtain an accurate
result of the level of the split. EM is the gold standard, but
is not as readily available. Thus, immunouorescence mapping is the more commonly used method for diagnosing EB.
Once a subtype of EB is identied, genetic analysis may be
pursued.
4.5 TUMOR SYNDROMES
• Note: Muir-Torre syndrome, dyskeratosis congenita, Peutz-
Jeghers syndrome, and xeroderma pigmentosum (XP) are
discussed elsewhere
Basal cell nevus syndrome (BCNS; gorlin
syndrome)
• AD mutations in the PTCH gene (encodes the patched
tumor suppressor protein of sonic hedgehog signaling
pathway)
■
Patched normally inhibits smoothened (which, when
uninhibited, signals intracellularly to activate GLI1/2
[transcription factors] to promote transcription of
genes involved in cellular growth)
■
Mutations in PTCH → dysregulation of smoothened
and ↑ transcription of GLI genes → neoplasia
• Diagnostic criteria include the presence of one major
criterion 1 molecular conrmation, two major criteria, or
one major and two minor criteria.
■
Major criteria:
BCCs (.5 BCCs or 1 before 30 years of age)
◆ Multiple, early onset (typically around puberty)
◆ May resemble melanocytic nevi, milia,
acrochordons, or seborrheic keratoses
◆ Favor sun-exposed areas (face, neck, and upper
torso), but can occur in sun-protected sites
Palmoplantar pits ($2), often present in
childhood
Odontogenic keratocysts of the jaw, histologically
proven
◆ Generally asymptomatic
◆ Typically present late in the rst decade of life
Calcication of the falx cerebri
First-degree relative with BCNS
■
Minor criteria:
Rib anomalies (bid, fused, or markedly splayed)
Cleft lip/palate
Other skeletal anomalies (pectus excavatum or pectus
carinatum, polydactyly, syndactyly, kyphoscoliosis,
Sprengel deformity, or other vertebral anomalies)
Medulloblastoma, which typically presents within
the rst 3 years of life
Macrocephaly
◆ Frontal bossing, a broad nasal root, and
hypertelorism may be seen
Ovarian/cardiac broma
Lymphomesenteric cysts
Ocular abnormalities (i.e., strabismus, hypertelorism,
congenital cataracts, glaucoma, and colobomas)
■
Other features include: increased risk of brosarcoma
and rhabdomyosarcoma, cryptorchidism,
gynecomastia, agenesis of corpus callosum, ovarian
bromas, and cardiac bromas
• Treatment: standard BCC treatment methods 1/– targeted
therapy with vismodegib, a smoothened inhibitor (essentially
acts as “articial PTCH”)—of note, sonidegib is another
option with similar mechanism of action to vismodegib
• Syndromes a/w multiple BCCs (Boards favorite!):
Gorlin, Bazex-Dupré-Christol, Rombo, Brooke-Spiegler,
XP, and Schöpf-Schulz-Passarge
Birt-Hogg-Dubé syndrome
• AD disorder as a result of mutations in BHD gene
(encodes folliculin)
248
4.5 Tumor Syndromes
• Manifestations begin in the third decade or later
• Cutaneous ndings: brofolliculomas, trichodiscomas,
and acrochordons
■
Fibrofolliculomas/trichodiscomas appear as multiple
tiny skin-colored to white papules on the face
■
On histology, brofolliculomas/trichodiscomas have
slender strands of basophilic cells radiating from a
follicular unit, surrounded by a brous stroma
• Systemic ndings: renal cell carcinoma and spontaneous
recurrent pneumothorax (w/ lung cysts and bullous
emphysema)
Brooke-Spiegler syndrome
• AD disorder as a result of mutations in cylindromatosis
(CYLD) gene (a tumor suppressor); CYLD is a
deubiquinating enzyme that normally interacts with
NEMO to downregulate nuclear factor-B (NF-B)
expression
• Skin ndings (presenting in adolescence/early adulthood):
cylindromas (papules/nodules on scalp),
trichoepitheliomas (skin-colored to white small facial
papules), spiradenomas (painful nodules on head/neck and
elsewhere), and multiple BCCs; malignant degeneration into
cylindrocarcinoma and spiradenocarcinoma may occur
(increased risk compared with general population)
• Extracutaneous ndings: salivary and parotid gland
tumors
Multiple endocrine neoplasia (MEN)
syndromes
• MEN I (Wermer)
■
AD disorder as a result of mutations in MEN1 gene
(menin)
■
Tumors in pituitary (esp. prolactinoma), parathyroid
(usually hyperplasia or adenoma) and pancreas
(usually islet cell hyperplasia, adenoma, or carcinoma)
(three Ps 5 mnemonic)
■
Cutaneous ndings may be similar to tuberous
sclerosis—facial angiobromas, collagenomas, gingival
papules, hypopigmented macules, and CALMs
• MEN IIA (Sipple)
■
AD disorder as a result of mutations in the RET protooncogene
■
Parathyroid hyperplasia (not seen in MEN IIB) 1
medullary thyroid carcinoma (100%) 1
pheochromocytoma
■
Cutaneous ndings: lichen amyloidosis and macular
amyloidosis (1/– notalgia paresthetica)
• MEN IIB (multiple mucosal neuroma syndrome)
■
AD disorder as a result of mutations in RET
■
Skin ndings: mucosal neuromas on tongue/lips,
thickened lips, and marfanoid habitus
■
Endocrine ndings: medullary thyroid carcinoma
(100%; fatal if not caught early!) and
pheochromocytoma
■
Ocular ndings: conjunctival neuromas → thickened/
everted upper eyelids
■
GI ndings: ganglioneuromatosis → megacolon,
diarrhea, and constipation
Cowden syndrome (multiple hamartoma
syndrome)
• AD disorder as a result of mutations in the PTEN tumor
suppressor gene → proliferation of cutaneous/GI/
mucosal/thyroid/breast tissues; manifestations begin in
second to third decade
• Other PTEN hamartoma syndrome (Bannayan-Riley-
Ruvalcaba) has many features of Cowden syndrome 1
pigmented macules on glans penis, lipomas,
macrocephaly, and developmental delay
• Cutaneous ndings: sclerotic bromas, facial
tricholemmomas (skin-colored to light brown small
papules), punctate palmoplantar keratoses, keratotic
papules (acral keratoses) on dorsal hands/feet/
forearms/legs, lipomas, skin tags, and inverted
follicular keratoses
• Oral ndings: small skin-colored grouped papillomas →
“cobblestone” appearance on lips and gingival/buccal/
labial mucosa
• Thyroid ndings: goiter, adenomas, and carcinoma
(follicular carcinoma is the most common type)
• Breast ndings: brocystic disease, broadenomas, and
adenocarcinoma (most common malignancy overall; in
up to 50% of female patients)
• GI ndings: hamartomatous polyps along the GI tract
(most common in colon)—low risk of malignant
transformation
• Other ndings: ovarian cysts (benign), uterine
leiomyomas, endometrial carcinoma (in up to 10% of
female patients), menstrual irregularities, various GU
carcinomas/cysts, craniomegaly (.80% of patients),
adenoid facies, kyphoscoliosis, bone cysts, large hands/
feet, myopia, angioid streaks, and intracranial venous
anomalies
• Lhermitte-Duclos disease (dysplastic gangliocytoma of
cerebellum): pathognomonic criterion for Cowden’s; p/w
overgrowth of cerebellar ganglion cells → ataxia, seizures,
and ↑ intracranial pressure
Gardner syndrome
• AD mutations in adenomatous polyposis coli (APC) gene
(tumor suppressor gene that regulates b-catenin)
• Cutaneous manifestations: epidermoid cysts (classically
with pilomatricoma changes), bromas (skin/
subcutaneous/mesentery/ retroperitoneum), lipomas
• GI manifestations:
■
Premalignant polyposis throughout GI tract → ↑↑↑ risk
adenocarcinoma (esp. colon/rectum; 100% affected)
■
Desmoid tumors: locally aggressive, but do not
metastasize; female . male; may arise post-surgically
after colectomy; can → small bowel and/or ureter
obstruction
• Ocular manifestations: congenital hypertrophy of retinal
pigment epithelium (CHRPE; 70%)
• Other ndings: osteomas (skull/mandible/maxilla; 80%
patients; painless), odontomas of teeth, supernumerary
teeth, papillary thyroid carcinoma (women),
hepatoblastoma, adrenal adenomas, sarcomas, pancreatic
carcinomas, and brain tumors (e.g., glioblastomas and
249
CHAPTER 4 • Pediatric Dermatology
medulloblastomas; in subtype of Gardner syndrome
called Turcot syndrome)
• Treatment 5 prophylactic colectomy when polyp
formation is rst evident (second to third decade)
4.6 VASCULAR TUMORS, MALFORMATIONS, AND RELATED VASCULAR DISORDERS
Vascular tumors
Vascular tumors are discussed more extensively in Chapter 6
(Neoplastic Dermatology).
PHACE syndrome
• Female predominance; 9:1
• Large segmental hemangioma on head/neck (highest risk
are S1, 3, and/or 4 distribution)
• Cerebrovascular anomalies most common
extracutaneous nding
■
Those with frontotemporal segment involvement may
be at most risk of cerebrovascular abnormalities
■
Those with mandibular segment involvement may be
at most risk of cardiac defects
• Posterior fossa malformations (e.g., Dandy-Walker and
cerebellar hypoplasia)
• Hemangioma, segmental
• Arterial anomalies (internal carotid arteries and cerebral
arteries)
• Cardiac anomalies (coarctation of aorta, ventral and
atrial septal defects, and patent ductus arteriosus)
• Eye anomalies (microphthalmos, optic atrophy, cataracts,
strabismus, and exophthalmos)
• Sternal cleft or supraumbilical raphe
• MRI/MRA of the head and neck to evaluate for
cerebrovascular anomalies, echocardiogram, and
ophthalmology evaluation
• Oral propranolol is rst-line therapy, though coarctation
of the aorta or other signicant congenital heart disease
should be ruled out before starting therapy
LUMBAR/SACRAL syndrome
• Segmental hemangioma of the lower back (lumbar or
sacral spine) or buttocks and genitalia (Fig. 4.14)
• Lower body hemangioma
• Urogenital anomalies/ulcerations
• Myelopathy (myelomeningocele)
• Bony deformities
• Anorectal malformation
• Renal anomalies
• Spinal dysraphism
• Anogenital anomalies
• Cutaneous anomalies
• Renal and anal anomalies
• Angioma with Lumbosacral location
■
Evaluate with MRI of the pelvis and spine
Fig. 4.14 LUMBAR (SACRAL) syndrome. (Personal collection, Dr. Jane Bellet.)
• If a segmental hemangioma crosses over the midline
lower spine, imaging is required. Ultrasound can be
considered in very young infants; however, MRI of the
spine is the gold standard.
• Propranolol should be considered for large, ulcerated, or
otherwise complicated segmental hemangiomas
■
Best to start in rst 1 to 2 months of life
■
Goal dose 2 to 3 mg/kg/day, divided BID to TID
■
Documented normal cardiac exam and history before
starting
■
SEs: hypotension, bradycardia, hypoglycemia
Multiple hemangiomas
• If ve or more hemangiomas are present, especially small,
miliary infantile hemangioma (IH), an ultrasound of the
liver should be strongly considered to r/o hepatic
hemangiomas (may also rarely occur in intestines, brain,
eyes, spleen, kidney, and lungs)
• For cosmetic treatment of supercial IH, topical beta
blockers (timolol) may be used judiciously
■
For patients with signicant visceral involvement
leading to liver failure and/or high output CHF,
propranolol is rst-line therapy
• When present, liver hemangiomas can produce the
enzyme type 3 deiodinase, which can lead to
consumptive hypothyroidism
Kasabach-Merritt phenomenon
• Usually occurs in the rst few weeks to months of life
• Occurs in association with tufted angioma or kaposiform
hemangioendothelioma (KHE)
• Pathogenesis: abnormal endothelium and convoluted
architecture of KHE or tufted angioma promote platelet
adhesion and trapping with subsequent consumptive
coagulopathy
• Sudden growth of a vascular lesion with induration,
edema, and advancing purpuric edge
■
Severe thrombocytopenia (from platelet trapping),
consumptive coagulopathy, hypobrinogenemia,
250
4.6 Vascular Tumors, Malformations, and Related Vascular Disorders
elevated D-dimer, hemolytic anemia, and disseminated
intravascular coagulation
■
Hematuria, hematochezia, and epistaxis may occur
■
High-output cardiac failure and signicant risk of
internal hemorrhage → 10%–30% mortality
• Systemic corticosteroids and vincristine are primary
therapeutic interventions. Systemic sirolimus is an
emerging treatment in this setting. Response to
propranolol has been poor
• Do not administer platelets as Kasabach-Merritt is
due to platelet trapping and this may worsen the
condition
Vascular malformations
Capillary malformations (CM)
Capillary malformation (“Port Wine Stain,”
PWS, nevus ammeus)
• Sporadic, affecting 0.1%–2% of newborns
• Understanding of mutations is evolving; mutations in
GNAQ reported in classic PWS; geographic CMs more
commonly due to mutations in PIK3CA
• Red-purple vascular macule or patch present at birth
• Often located on the face, but may be found anywhere on
the body
• Usually an isolated cutaneous nding, but may be seen in
many syndromes (Sturge-Weber syndrome [SWS], KlippelTrenaunay syndrome [KTS], Parkes-Weber syndrome,
Proteus, PTEN hamartoma syndromes, Cobb syndrome,
Beckwith-Wiedemann syndrome, phakomatosis
pigmentovascularis, and capillary malformationarteriovenous malformation [CM-AVM])
• On histology, dilated venules in dermis with normal
number of vessels and no endothelial proliferation (is a
malformation rather than true neoplasm)
■
In adults, brosis around the vessels and vascular
dilation can be seen
• Pulsed dye laser 5 rst-line therapy; typical settings
include 1.5-ms pulse duration; areas over bony
prominences on face (e.g., forehead) respond better than
cheeks, distal extremities may respond less well
• Lesions do not resolve spontaneously; ↑ in size
proportionately to the child’s growth; may become
gradually darker and hypertrophic over time, especially if
located on the face
Sturge-Weber syndrome (encephalotrigeminal angiomatosis)
• 2° to somatic mosaic mutations in the GNAQ gene
• CM involving the frontonasal (forehead) placode
(formerly V1—ophthalmic branch of trigeminal nerve)
distribution (Fig. 4.15)
■
Only 5%–10% with a CM of the forehead will have
SWS; more extensive often corresponds to increased
risk
■
Soft tissue/skeletal hypertrophy often develop over time
under the CM
• Ipsilateral leptomeningeal CM (angiomatosis) of the brain
and eye
Fig. 4.15 Sturge-Weber syndrome. This patient has a classic capillary malformation in the distribution of the ophthalmic, nasociliary, and maxillary branches of
the trigeminal nerve. The lesion extends backward over the anterior two thirds of
the crown of the head. (From Forbes CD, Jackson WD. Color Atlas and Text
of Clinical Medicine. 2nd ed. London: Mosby; 1996.)
• Neurologic complications include seizures (usually
develop in rst year of life), developmental delay,
intellectual disability, and focal neurologic decits
■
Head CT 5 cortical calcications that resemble “tram
track lines”
• Ophthalmologic complications affect 60% (#1 is
glaucoma)
• Clinical course depends on extent of leptomeningeal
involvement
• Bilateral facial CMs involving forehead distribution 5
worst prognosis (↑ risk of seizures and more profound
developmental delay)
Phakomatosis pigmentovascularis
• Widespread CM in addition to other cutaneous ndings
• Five dened types, a 5 no extracutaneous involvement;
b 5 extracutaneous involvement
■
I: PWS 1 epidermal nevus
■
II (phakomatosis cesioammea): PWS 1 dermal
melanocytosis 1/– nevus anemicus; most common
form (85%); may have complications (SWS,
overgrowth); identied mutation GNAQ in pluripotent
progenitor cells
■
III (phakomatosis spilorosa): PWS 1 nevus spilus 1/–
nevus anemicus
■
IV: PWS 1 dermal melanocytosis 1 nevus spilus 1/–
nevus anemicus
■
V (phakomatosis cesiomarmorata): cutis marmorata
telangiectatica congenital (CMTC) 1 dermal
melanocytosis
• Extracutaneous features include neurologic,
musculoskeletal, and ocular ndings
Phakomatosis pigmentokeratotica
• 2° to post-zygotic mutation in HRAS
251
CHAPTER 4 • Pediatric Dermatology
• Speckled lentiginous nevus (nevus spilus) in
conjunction with nevus sebaceus
• Neoplasms (trichoblastoma . syringocystadenoma
papilliferum . BCC) may develop within nevus sebaceus
• Neurologic abnormalities may be present and include
seizures, hemiparesis, and intellectual impairment
• Hypophosphatemic vitamin D–resistant rickets can develop
PIK3CA-related overgrowth spectrum (PROS)
• Somatic mutations in the phosphatidylinositol/AKT/mTOR
pathway cause segmental progressive overgrowth disorders
often associated with enlarged, splayed digits, vascular
malformations (esp. geographic CM), and lipomatous
changes among other manifestations. This spectrum now
encompasses a variety of conditions including KlippelTrenaunay syndrome, CLOVES, and megalencephalycapillary malformation (M-CM), all discussed below.
Klippel-Trenaunay syndrome
• Recently reported association with mutations in
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic
subunit alpha (PIK3CA)
• CM, venous malformation (VM), and/or lymphatic
malformation (LM) with soft tissue and/or bone
hypertrophy of one limb
■
Lower extremities (95%) are affected much more
commonly than upper extremities
■
Venous varicosities are common
• Complications include deep vein thrombosis and
thrombophlebitis, pulmonary embolism (PE), GI bleeding,
vascular blebs and pain, and high-output cardiac failure
Macrocephaly capillary malformation syndrome
• M-CM mutations in AKT3, PIK3CA, or PIK3R2
• Macrocephaly and frontal bossing
• Widespread reticulated CM often prominently involving
mid-face (philtrum and glabella)
• Hemihypertrophy involving contralateral side of the body
from the CM
• Progressive neurologic dysfunction → developmental
delay, seizures, and hypotonia
■
Polymicrogyria, cerebral asymmetry, white matter
abnormalities, ventriculomegaly, cortical dysplasia,
and/or cerebellar tonsillar herniation
• Syndactyly (esp. second–third toes), polydactyly, joint
laxity, and hyperplastic skin
• ↑ Risk of Wilms’ tumor
CLOVES syndrome
• Congenital lipomatous overgrowth (asymmetric,
progressive)
• Vascular malformations (including geographic CM)
• Epidermal nevi
• Scoliosis/spinal and skeletal anomalies
• PIK3CA postzygotic activating mutation
• ↑ Risk of Wilms’ tumor; screening protocol with
ultrasound q3mo until age 8
• Risk for thromboembolic events, PE, cerebrovascular
accident (CVA)
Proteus syndrome
• Sporadic, due to AKT1 somatic activating mutation →
asymmetric progressive overgrowth
• Skin:
■
Cerebriform connective tissue nevi (plantar
collagenoma): pathognomonic if present
■
CM/VM/LM
■
Epidermal nevi
■
Lipomas
■
CALMs
■
Focal atrophy/dermal hypoplasia
■
Varicosities
■
Partial lipohypoplasia
• Central nervous system (CNS): hemimegalencephaly and
impaired intelligence
• Ophthalmologic: nystagmus, strabismus, cataracts, and
myopia
• Musculoskeletal
■
Typical facies: dolichocephaly, down-slanting palpebral
ssures, depressed nasal bridge, anteverted nares, and
open mouth position at rest
■
Overgrowth of one or more of the following (involves
soft tissue and bone): extremities, digits, cranium
(hemifacial macrosomia), vertebrae, and external
auditory meatus
■
Hyperostoses
■
Scoliosis
• Bilateral ovarian cystadenoma and parotid
monomorphic adenoma
• Organomegaly
• Cystic lung malformations
■
Restrictive lung disease
■
Pulmonary emphysema
■
Recurrent pneumonia
• Risk of venous thrombosis and PE
Beckwith-Wiedemann syndrome
• Associated with chromosome 11 abnormalities at
p57(KIP2) gene
• 85% of cases are sporadic
• Clinical features:
■
Macrosomia/gigantism (height and weight . 97%)
■
Facial CM of glabella, mid-forehead, and upper eyelids
■
Hemihyperplasia (asymmetric overgrowth)
■
Macroglossia
■
Omphalocele/exomphalos
■
Anterior linear earlobe creases and posterior helical
ear pits
■
Visceromegaly (kidney, liver, pancreas, spleen, and
heart)
■
Neonatal hypoglycemia
• ↑ risk for embryonal tumors (Wilms’ tumor [#1],
rhabdomyosarcoma, neuroblastoma, and
hepatoblastoma)
Diffuse capillary malformation with overgrowth (DCMO)
• More extensive reticulate CMs, can be one extremity or
truly diffuse
• Proportional nonprogressive overgrowth 2° to
hypertrophy of the bones and soft tissues
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4.6 Vascular Tumors, Malformations, and Related Vascular Disorders
• Overgrowth may affect only one extremity, ipsilateral or
contralateral to the stain, or, less frequently, an entire side
of the body
• Otherwise healthy
Venous malformations
• Sporadic, but 50% of sporadic VMs have TIE2 (aka TEK)
mutations
■
Familial cutaneous and mucosal venous
malformation syndrome (VMCM): widespread VMs
of skin, mucosa and visceral organs due to TIE2 (aka
TEK) mutations; has signicant overlap w/ Blue
rubber bleb syndrome!
• Present at birth, but may become more apparent in
childhood
• Erythematous to violaceous, soft, compressible nodule or
plaque without warmth, vascular thrill, or pulsations 1/–
radiating veins
• On histology, dilated vascular spaces with single-layer
endothelial wall that is surrounded by brous tissue;
involves deep dermis or subcutaneous fat
• Ultrasound shows slow-ow lesion; MRI is the best
imaging modality to determine the extent; on plain lms,
calcication can be seen 2° to phleboliths; brinogen may
be ↓ and D-dimer may be ↑
Maffucci syndrome (enchondromas with multiple angiomas)
• 80% cases caused by mutations in isocitrate
dehydrogenase (IDH1 and IDH2); characterized
by mesodermal dysplasia of skin and skeletal
systems
• First sign in early infancy 5 deep VMs (soft, compressible,
and bluish nodules) on the hands and feet
• Enchondromas develop on the phalanges and long
bones, and predispose to short stature, fractures, and
limb length discrepancies; can occur in cranium/vertebrae
→ neurological problems
• LMs, hemangioendotheliomas, and spindle cell
hemangiomas may be present
• Extracutaneous sites of vascular malformations:
leptomeninges, eyes, oropharynx, and GI tract
• Clinical course: bone fractures 2° to non-ossication;
50% risk for chondrosarcoma (occurs within
enchondromas); lymphangiosarcoma and
hemangiosarcoma also reported
Blue rubber bleb nevus syndrome
• Usually sporadic
• Presents at birth to early childhood with VMs (multiple
blue-violaceous compressible papules and nodules with
hyperhidrosis overlying lesions; with compression, an
empty wrinkled sac is noted that quickly lls with release
of pressure)
■
VMs involve the trunk/extremities, mucosa, GI tract
(esp. small intestine), liver, and CNS
■
↑ Size/# with age
• Small intestine blebs → hemorrhage (which may →
death if severe) or occult/chronic bleeding (melena and
iron-deciency anemia)
Glomulovenous malformations (GVMs; previously termed “glomangiomas”)
• Variant of VM (is not a neoplasm → no longer referred to
as “glomangioma”) where ectatic vessels are lined by a
small number of glomus cells
■
Glomus cells are modied smooth muscle cells of
Sucquet-Hoyer canal origin
■
AD inheritance, due to loss-of-function mutations in
glomulin (GLMN) gene
• Clinical presentation: presents in infancy or childhood
with multiple lesions (soft, partially compressible blue
nodules . conuent plaques); favors lower extremities;
usually asymptomatic (pain is more common with
glomus tumors)
• Histology: large, dilated vessels surrounded by a small
number of glomus cells
• Treatment: sclerotherapy, CO
may help
■
Surgical excision generally not feasible for GVM, since
multiple lesions and high rate of recurrence
laser, and Nd:YAG laser
2
• Comparison with glomus tumor
■
Glomus tumor: more common (accounts for 80% of
all glomus lesions); affects young adults (20–40 yo);
solitary blue papule or nodule with triad of
tenderness, sensitivity to cold, and paroxysmal pain;
most common on palms and subungual area (may
result in bony erosion); histology shows dense
proliferation of many glomus cells surrounding small
vascular spaces; easily treated with excision
Lymphatic malformations
Microcystic lymphatic malformations
(supercial lymphatic malformation,
“lymphangioma circumscriptum”)
• More common than macrocystic LMs
• Present in rst few months to years of life
• Always conned to one anatomic region; most common
sites 5 abdomen, axillae, mouth (esp. tongue), and
genital region
• Presents w/ clusters of papulovesicles with clear or
blood-tinged uid (red-purple in color), either discrete
or coalescing into a plaque, resembling “frog spawn”
(Fig. 4.16)
• On histology, collections of small dilated lymphatic
channels in the dermis are lined by endothelial cells
■
D2-40 (podoplanin) and LYVE-1 positive
• Can perform surgical excision, sclerotherapy or destructive
measures (CO
Macrocystic lymphatic malformations (cystic hygroma)
• Congenital lesions are thought to result from abnormal
lymphatic development during embryogenesis
• Associated with fetal aneuploidy, including Turner
syndrome and Down syndrome; also associated with
Noonan syndrome and achondroplasia (note: congenital
lymphedema of the hands and feet may also be a clue to
these conditions)
or pulsed dye lasers) for localized lesions
2
253
CHAPTER 4 • Pediatric Dermatology
Fig. 4.16 Microcystic lymphatic malformation—irregularly grouped, translucent,
and red papules. (From Marks JG Jr, Miller JJ. Dermal and subcutaneous growths.
In: Lookingbill and Marks’ Principles of Dermatology. 6th ed. Philadelphia: Elsevier;
2019:75–94.)
• Majority (60%) are present at birth
• Presents as a large, soft, bluish, and sometimes translucent
mass, with normal overlying skin
■
Transilluminates with light
■
Head, neck, and axilla/chest most common locations,
favoring left side
• Sudden size ↑ may herald infection or intralesional
hemorrhage
• On histology, large, multicystic, irregular lymphatic sinuses
with a single layer endothelial lining, a brous adventitia,
and both smooth and striated muscle component
■
D2-40 (podoplanin) and LYVE-1 positive
• Mortality (,6%), usually as a result of airway obstruction
or pneumonia
• Complications include pleural/abdominal/pericardial
effusions, lymphedema, cardiac failure, and respiratory
failure
Gorham-Stout (disappearing bone) disease
• LM proliferates to involve the underlying bone and leads
to osteolysis; may also be associated with chylothorax if
upper trunk is involved
Congenital lymphedema (hereditary congenital lymphedema, Nonne-Milroy syndrome)
• Female . male
• Developmental aplasia, hypoplasia, and/or functional
failure of lymphatic vessels
• AD inheritance; due to loss-of-function mutations in FLT4
gene (encodes VEGFR3, which is required for lymphatic
development)
• Presents at birth (or soon after) and persists for life
• Painless pitting edema of bilateral lower extremities
■
Over time, involved area becomes rm and brotic
■
Associated features: hydrocele, prominent veins, and
upslanting toenails
• Treatment options: massage (manual lymphatic drainage),
use of compression garments, and surgical interventions
• Contrast with lymphedema-distichiasis syndrome: also a
form of hereditary lymphedema but has peripubertalonset (10–30 yo); AD inheritance; FOXC2 mutation;
lower-limb lymphedema 1 distichiasis (extra eyelashes
ranging from a single hair to a full set)
Arteriovenous malformations
AVMs
• Rarest but most dangerous type of vascular malformation
• Developmental anomaly arising early in embryogenesis →
abnormal communication between an artery and vein
causing high-ow (fast-ow) shunting of blood from the
arterial circulation to the venous circulation (AV shunting)
• Erythematous to violaceous patches/nodules/tumors that
are warm to touch and have palpable thrill or pulsation;
most commonly cephalic (70%)
• Peripheral edema, pain, varicosities, ulceration, and limb
hypertrophy may develop
• Small, hemodynamically stable AVMs are asymptomatic,
but larger, hemodynamically unstable AVMs may →
tachycardia/CHFs
• Puberty, pregnancy, and trauma are common exacerbating
factors
• MRI and ultrasound studies conrm diagnosis and assess
disease extent
• On histology, circumscribed, unencapsulated, and thick-
walled arterioles w/ direct connection to veins (thinwalled), and abundant supercial capillaries
• Embolization 1 excision is the treatment of choice for
symptomatic lesions; amputation may be required as a
result of aggressive growth
• Consumptive coagulopathy may develop in larger AVM
Parkes-Weber syndrome
• Mutations in RASA1 have been noted, can be isolated or
noted in patients with CM-AVM (also caused by RASA1)
• Characterized by CMs, VMs, LMs, and multiple fast-ow
AVMs/shunts (differentiates it from KTS, which only has
slow-ow malformations)
• Typically affects the lower extremities
■
Soft tissue and bony hypertrophy
• Diagnose with duplex ultrasound and MRI/MRA
• High-output cardiac failure can occur in infancy or later
in life
• The development of lytic bone lesions can be seen
• Poor prognosis after puberty with continued growth of
the AV malformation
Cobb syndrome (cutaneomeningospinal angiomatosis)
• Spinal hemangioma or AVM (most common) 1
cutaneous AVM or CM (depending on source cited) of
the same metamere of the torso
• Cutaneous manifestations: faint erythema (elicited with
rubbing the affected area, often with Valsalva maneuver)
to violaceous patches and plaques
■
Located on lumbar back
■
Painful throbbing (due to AVM) may develop
• Neurologic abnormalities (due to enlarging AVM, which
causes a mass effect on spinal cord) typically develop in
254