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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
Fig. 4.26 Pseudoxanthoma elasticum. Note the short, curled elastic bers in the
reticular dermis. (From Patterson JW. Disorders of elastic tissue. In: Weedon’s
Skin Pathology. 5th ed. Philadelphia: Elsevier; 2021:413–436.)
Fig. 4.27 Pseudoxanthoma elasticum. Note the short, curled elastic bers in the
reticular dermis. They are basophilic. (From Patterson JW. Disorders of elastic tissue. In: Weedon’s Skin Pathology. 5th ed. Philadelphia: Elsevier; 2021:413–436.)
AD inheritance; due to mutations in type I collagen
genes COL1A1 and COL1A2
■
Onset (birth to adulthood) and severity depend on type
• Cutaneous manifestations
■
Thin, atrophic, and translucent skin
■
Easy bruisability
■
Scars may be atrophic or hypertrophic
• Musculoskeletal manifestations
■
Hyperlaxity of ligaments and hypermobility of joints
■
Brittle bones 1 fractures (skull, long bones, and
vertebrae; occurs in utero in severe forms)
■
Beaded ribs
• Other manifestations
■
Blue sclerae are seen 90% of patients (not seen in
type IV)
■
Otosclerosis with hearing loss may begin during
adolescence
■
Fragile/discolored teeth
■
Dentinogenesis imperfecta (DI)
4.9 Inherited Connective Tissue Disorders
■
Mitral and aortic valve prolapse/dilatation and
regurgitation
• Variable prognosis depending on disease type and
severity:
■
Types I and IV: normal life span
■
Type II: death in perinatal period
■
Type III: increased mortality in third/fourth decade due
to respiratory failure (2° to kyphoscoliosis) or head
trauma
Ehlers-Danlos syndrome
• Heterogeneous group characterized by abnormal collagen
structure and/or function within the skin, joints, and
vasculature (Table 4.13)
• Classical EDS (most common subtype)
■
May deliver/be delivered preterm as a result of early
rupture of fetal membranes; normal life span
■
Mucocutaneous manifestations
Velvety, soft, and doughy consistency of skin
Marked hyperextensibility of skin
Poor wound healing (“cigarette paper” scars)
Widened atrophic cutaneous scars (“shmouth”
wounds)
Piezogenic pedal papules
Fragile blood vessels → hematomas and easy
bruising
Subcutaneous spheroids (fat lobules that have
calcied after losing their blood supply)
Molluscoid pseudotumors associated with scars
over knees and elbows
Blue sclerae
Gorlin’s sign: ability to touch tip of nose with
tongue (50%)
■
Musculoskeletal manifestations
Generalized joint hypermobility
Double-jointed ngers
Frequent subluxation of larger joints
Chronic joint and limb pain
Kyphoscoliosis
Pes planus
■
GI manifestations
Hiatal/inguinal hernia, postoperative hernias, and
anal prolapse
GI bleeding/rupture
■
Cardiac manifestations
Mitral valve prolapse
Aortic root dilation
• Vascular EDS
■
Life-threatening risk of blood vessel and organ
rupture → sudden death in third/fourth decade
(arterial or colonic rupture; maternal death may occur
as a result of uterine or arterial rupture)
■
Cutaneous manifestations
Easy bruising
Thin and translucent skin with visible underlying
blood vessels
Skin is not hyperextensible, but can be fragile
Lack of subcutaneous fat
■
Facial features: thin, pinched nose; prominent sunken
eyes; thin upper lip; and lobeless ears
265
CHAPTER 4 • Pediatric Dermatology
Table 4.13 Ehlers-Danlos Syndrome Classication
Type Genes Inheritance Skin Findings Joint Changes Other
Classical (formerly
type I, “gravis” and
type II, “mitis”)
Hypermobility (formerly
type III)
Vascular (formerly type
IV)
Kyphoscoliotic (formerly
type VI)
Arthrochalasic (formerly
types VIIa and VIIb)
Dermatosparaxis
(formerly type VIIc)
Periodontitis type
(formerly type VIII)
AD, Autosomal dominant; AR, autosomal recessive
Modied from Paller AS, Mancini AJ. Hereditary disorders of the dermis. In: Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood
and Adolescence. 5th ed. Elsevier. 2016:119–135.
COL5A1,
COL5A2
TNXB AD/AR Mild Hypermobility
COL3A1 AD Thin, translucent skin
Lysyl
hydroxylase
1 (PLOD1)
COL1A1,
COL1A2
Procollagen
N-proteinase
(ADAMTS2)
Unclear AD Hyperextensible skin with scarring
AD Hyperextensibility
Easy bruising
Fragile skin
Widened atrophic (“sh mouth” or
“cigarette paper”) scars
Molluscoid pseudotumors (over-
lying extensor joints and pressure
points)
Spheroids
Extensive bruising
Early varicosities (can visualize
veins under skin easily)
Acrogeria
AR Mild Hypermobility
AD Mild Most severe
AR Severe fragility
Sagging, redundant skin, and
bruising
(esp. pretibial) and bruising
Hypermobility and joint
dislocations
Chronic joint pain 1
arthritis
Recurrent dislocations
and subluxations
Small joint hypermobility
Severe scoliosis
hypermobility with
recurrent subluxations/
dislocations (much more
severe than hypermobility
type)
Mild Umbilical/inguinal hernias
Mild Severe periodontitis
(1) Gorlin’s sign
Absence of lingual
frenulum
Deficiency of tenascin X
Mnemonic: “IV 5 blood
vessels”
Rupture of bowel,
uterus, or arteries
Most life-threatening
form
Severe muscle hypotonia
Ruptured globe, blind-
ness, retinal detachment, or keratoconus
Marfanoid
Osteopenia
Ascorbic acid supplemen-
tation may help
Congenital hip disloca-
tion
Short stature
Premature rupture of fetal
membranes
→ teeth loss
■
Blue sclera (.90%)
■
Acrogeria
■
Hypermobility limited to digits
■
Congenital talipes (club foot)
■
Recurrent pneumothoraces
■
Arterial (including aorta) dissection, rupture, and
aneurysm of medium-sized vessels
Spontaneous rupture of arteries (medium-sized)
may occur during childhood, and incidence peaks
during third and fourth decade
Intestinal rupture is common (sigmoid colon
#1 site)
■
Intracranial aneurysms a/w CVAs
■
Obstetric complications, including uterine and arterial
rupture, massive postpartum hemorrhage, and severe
laceration from tearing at vaginal delivery
■
Short stature
• Hypermobile EDS
■
Not prone to life-threatening complications
■
Severe joint laxity, recurrent dislocations/
subluxations, and chronic joint pain 1/– arthritis
266
■
Mitral valve prolapse
■
Symptoms of autonomic dysfunction, including
postural orthostatic tachycardia syndrome (POTS)
Marfan Syndrome
• AD mutations in the FBN1 gene (encodes brillin-1)
• Manifestations may not present until adolescence or in
30 to 40s
• Tall with long extremities (marfanoid habitus)
■
Arm span is characteristically greater than height
■
After puberty, upper segment (vertex to pubis) to lower
segment (pubis to sole) ratio is ,0.86
• Lack of subcutaneous fat, presence of striae on upper
chest, arms, thighs, and abdomen and increased risk of
elastosis perforans serpiginosa
• Skeletal manifestations
■
Arachnodactyly
■
Kyphoscoliosis, pectus excavatum, and dolichocephaly
■
Pes planus
■
Joint laxity, patellar dislocation, and hip dislocation
4.9 Inherited Connective Tissue Disorders
• Ocular manifestations
■
Ectopia lentis (upward lens displacement; 60% of
patients)
■
Ocular globe elongation leading to myopia (40%)
■
Retinal detachment, cataracts, and glaucoma
• Cardiovascular manifestations (70%)
■
Dilatation of ascending aorta → regurgitation, CHF,
dissection/aneurysm, and rupture
■
Mitral valve prolapse
■
Left ventricular dilation
■
Cardiac complications may → death
• Pulmonary manifestations
■
Spontaneous pneumothorax, apical blebs, and bullous
emphysema
• AD disorder due to mutation in LEMD3/MAN1 (LEM
domain-containing-3/MAN antigen 1) gene → ↑ TGF-b
signaling
• Dermatobrosis lenticularis disseminata (typically
elastomas) on buttocks, proximal trunk, and limbs
■
Symmetric, small, uniform, yellow to skin-colored
dermal papules coalescing into plaques; onset in
childhood (typically in the rst year of life)
• Osteopoikilosis (“spotted bones”)
■
Asymptomatic circular densities in carpal bones, tarsal
bones, phalanges of hands and feet, pelvis, and
epiphyses and metaphyses of long bones
■
Often noted incidentally on plain lms (1- to 10-mm
round opacities)
• Histology: abundant thickened elastic . collagen bers
(often fragmented and clustered into nets)
• Allelic AR diseases caused by mutations in
→ abundance of hyalinized brous tissue in skin and
internal organs
■
ISH presents within rst 6 months of life with
cutaneous, mucosal, skeletal, and internal organ
involvement and death in early childhood
■
JHF presents during early childhood with cutaneous,
mucosal, and skeletal/joint (often debilitating)
involvement only; survival into adulthood
• Cutaneous manifestations
■
Thickened skin and hyperpigmentation overlying bony
prominences is characteristic of ISH
■
Perianal nodules
■
Small pearly papules on ears and face (perinasal and
perioral)
■
Scalp nodules are characteristic of JHF
• Oral manifestations
■
Thickening of oral mucosa
■
Gingival hypertrophy
■
Marked curvature of dental roots
■
Replacement of periodontal ligament by hyaline
brous material
■
Feeding difculty
• Musculoskeletal manifestations
■
Debilitating joint contractures and tumors
■
Osteolytic bone lesions are characteristic of JHF
• Normal intelligence
• Visceral involvement (ISH only): hyaline deposits develop
in multiple internal organs w/ recurrent infections,
malabsorption, protein-losing enteropathy, and failure to
thrive
• Histology: ↑ # of broblasts embedded in hyalinized
connective tissue stroma that is homogeneous,
amorphous, and acidophilic (PAS-positive)
• ISH has a poor prognosis with death by 2 years of age
from recurrent pulmonary infection and GI
complications
• In JHF, survival into adulthood (death often by fourth
decade)
• AR disorder due to mutations in the extracellular matrix
protein 1 (ECM1) gene; ↑ in South Africa
• Thickening of basement membrane and deposition of
hyaline material in dermis → characteristic thickening of
the skin, mucous membranes, and certain viscera
• Hoarse cry or weak cry from inltrated vocal cords is
the rst clinical sign (occurs in infancy and persists for
life)
• Cutaneous lesions develop during rst few 2 years of life
in two overlapping stages
■
First stage: vesicles and hemorrhagic crusts involving the
face, extremities, and oral mucosa develop in association
with trauma and resolve with “ice-pick” scars
■
Second stage: ↑ hyaline deposition within the dermis
→ yellow, waxy, and coalescing papules/nodules on the
face/neck and extremities; beaded eyelid papules
resembling “string of pearls” (50%); verrucous
nodules on elbows/knees/hands
• Inltration by yellow papules/plaques of the mucosa of
pharynx, soft palate, tonsils, and lips
• Thickened “woody” tongue; inability to protrude
tongue (due to shortened frenulum)
• Respiratory difculty a/w upper respiratory tract
infections and may require tracheostomy; occasionally
fatal in infancy (major cause of early death)
• Neurologic manifestations include seizures and
neuropsychiatric symptoms, a/w pathognomonic sickle or
“bean-shaped” calcifcations in temporal lobes or
hippocampus
• Histology: deposition of amorphous or laminated
basement membrane-like material containing collagen
(types II and IV) and laminin around blood vessels,
dermal-epidermal junction, adnexal epithelia, and in
connective tissues (appears as vertically oriented pink
dermal deposits)
■
Deposits are PAS-positive and diastase-resistant
• Thick furrowing of skin on scalp (vertex) 1/– neck, due to
increased dermal collagen
267
Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood
and Adolescence. 5th ed. Philadelphia: Elsevier; 2016:119–135.)
4.10 Autoinammatory Disorders (Periodic Fever Syndromes)
■
Birth typically occurs before 35 weeks of gestation as a
result of premature rupture of membranes (PROM)
• Cutaneous manifestations
■
Taut translucent, thin skin with erosions and ssures
■
Skin tears in response to stress of delivery, resuscitation,
and neonatal movements
■
Complications include infection and dehydration after
uid loss
■
Increased transepidermal water loss leads to
hypoalbuminemia and electrolyte imbalance
• Dysmorphic facies
■
Fixed round open mouth with micrognathia
■
Small pinched nose
■
Hypertelorism
■
Enlarged fontanelles
■
Widened cranial sutures
• Flexion contractures
• Restrictive pulmonary disease as a result of thoracic
stiffness and severely restricted movements
• Death 2° to respiratory insufciency shortly after
birth
Stiff skin syndrome (congenital
fascial dystrophy)
• AD disorder due to mutations in FBN1 (brillin-1)
• Progressive development of stony-hard skin on thighs,
buttocks, lower back, and shoulders
• Joint contractures (esp. large joints), scoliosis, tiptoe gait,
narrow thorax in relation to arm girdle, restrictive
pulmonary changes, growth retardation, and postural and
thoracic wall irregularities
• On histology, fascial sclerosis; ↑ broblast cellularity;
thickened, sclerotic, horizontally oriented collagen
bundles in deep reticular dermis and/or subcutaneous
septa
4.10 AUTOINFLAMMATORY DISORDERS (PERIODIC FEVER SYNDROMES)
Epidemiology
• Predominantly hereditary (rarely acquired) syndromes
characterized by recurrent, spontaneous, inammatory
episodes w/ varying degrees of severity and duration;
presenting w/ fever and variable cutaneous, serosal, mucosal,
ocular, neurologic, and osteoarticular manifestations
Pathogenesis
• Disorders of innate immunity caused by ↑ production of
proinammatory cytokines (e.g., IFN-a, IFN-g, IL-6, IL-1,
and TNF-a) as a result of aberrant signaling of cell surface
or intracellular innate immune receptors
• Cytokine receptors, receptor antagonists, and components
of the inammasome are involved and result in
intracellular protein complexes that enable the
autocatalytic activation of inammatory caspases,
driving the release of proinammatory cytokines
• These innate immune cells are activated by endogenous or
exogenous stimuli, so-called pathogen-associated
molecular patterns (PAMPs) and damage-associated
molecular patterns (DAMPs)
• Clinical features
■
Most patients present in infancy to early childhood; adultonset reported for familial Mediterranean fever (FMF) and
TNF-receptor-associated periodic syndrome (TRAPS)
■
Fever 5 key feature of most of the autoinammatory
syndromes and is periodic in nature
■
Know the key clinical features for each syndrome
(Table 4.14)
Table 4.14 Features of Selected Autoinammatory Syndromes
Diagnosis Gene (Protein) Inheritance Clinical Features Rx Other Comments
Cryopyrin-associated periodic syndromes
Familial cold
autoinflammatory syndrome
Muckle-Wells syndrome CIAS-1/NLRP3
Neonatal-onset multisystem
inflammatory disease
(NOMID)/chronic infantile
neurologic cutaneous
articular syndrome (CINCA)
CIAS-1/NLRP3 (cryo-
pyrin)
Mild on a spectrum
with below MWS and
NOMID
(cryopyrin)
CIAS-1/NLRP3
(cryopyrin)
AD Age of onset: Infancy
AD
AD Age of onset: Neonatal
Skin: Cold-induced urticaria, favors
extremities (. face, trunk)
Systemic: Arthralgia, conjunctivitis
Age of onset: Any
Skin: Widespread urticaria
Systemic: Abdominal pain, “lanc-
ing” extremity pain, conjunctivitis, optic disk edema, arthralgia/
arthritis, and sensorineural hear-
ing loss
Skin: Widespread urticaria 1/– oral
ulcers; dysmorphic facies (fron-
tal bossing and protubierant eyes)
Systemic: Deforming arthropathy,
arthritis, epiphyseal overgrowth,
signicant ocular involvement (may
→ blindness), sensorineural hearing loss, lymphadenopathy, HSM,
seizures, aseptic meningitis
IL-1 antagonists Short attacks
(minutes to 3
days)
IL-1 antagonists Febrile attacks last
1–2 days
High risk of sec-
ondary AA amyloidosis (25%)
IL-1 antagonists Febrile attacks
occur continuously
Secondary AA
amyloidosis
Signicant morbid-
ity/mortality in
childhood (if
untreated)
Continued
269
CHAPTER 4 • Pediatric Dermatology
Table 4.14 Features of Selected Autoinammatory Syndromes—cont'd
Diagnosis Gene (Protein) Inheritance Clinical Features Rx Other Comments
Monogenic periodic fever syndromes
Hyper-IgD syndrome
(Mevalonate kinase
deficiency)
TNF-receptor-associated
periodic syndrome (TRAPS)
Familial Mediterranean fever
(FMF)
Autoinammatory pyogenic disorders
Pyogenic arthritis, pyoderma
gangrenosum, acne
syndrome (PAPA)
Deficiency of the IL-1
receptor antagonist (DIRA)
Generalized pustular
psoriasis/Deficiency of the
IL-36 receptor antagonist
(DITRA)
Autoinammatory granulomatous disorders
Blau syndrome/early-
sarcoidosis
Newly described autoinammatory disorders
Chronic atypical neutrophilic
dermatosis with
lipodystrophy and elevated
temperature (CANDLE)
syndrome
MVK (mevalonate
kinase)
TNFRSF1A (TNF
receptor superfamily
1A/p55 TNF receptor)
MEFV (pyrin/
marenostrin)
PSTPIP1/
CD2BP1 (Proline-
serine-threonine
phosphataseinteracting protein
1/CD2 antigen binding
protein 1)
IL1RN (IL-1 receptor
antagonist)
IL36RN (IL-36 receptor
antagonist)
NOD2/CARD15
(nucleotide-binding
oligomerization
domain 2/caspase
recruitment domain
15)
PSMB8 (encodes
Proteasome subunit
b type)
AR Age of onset: Infancy
AD Age of onset: Any
AR Age of onset: Any
AD Age of onset: Childhood
AR Age of onset: Neonatal
AR Age of onset: Infancy, childhood
AD,
sporadic
AR Almost daily fever in early infancy
Skin: Widespread polymorphous
eruption (morbilliform or urticarial
most commonly)
Systemic: Arthralgia, abdominal pain,
vomiting, diarrhea, arthritis, cervical LAN, HSM
Skin: Painful migratory/serpigi-
nous plaques (often edematous)
on extremities; may become ecchymotic
Systemic: Serositis, periorbital
edema, scrotal pain, migratory
myalgias (underlying rash)
Skin: Erysipelas-like rash, favors
legs/feet
Systemic: Serositis and arthritis
Skin: Pyoderma gangrenosum and
nodulocystic acne
Systemic: Sterile pyogenic
oligoarthritis, afebrile
Skin: Neutrophilic pustular dermato-
sis, ichthyosis
Systemic: Sterile multifocal osteomy-
elitis, periostitis, afebrile
Skin: Generalized pustular psoria-
sis
Systemic: Malaise, multiorgan failure
Age of onset: Childhood
Skin: Sarcoidal granulomatous der-
matitis, ichthyosiform dermatitis
Systemic: Fever (30%), polyarticular
arthritis (favors hands/feet), synovitis and tenosynovitis
Pernio like lesions of hands and feet
Recurrent annular plaques worst
on trunk that progress to purpura
and hyperpigmentation
Swollen, violaceous eyelids and lips
Also lipodystrophy, lymphadenopa-
thy, hepatosplenomegaly, arthral-
gias, other systemic inammation
IL-1 antagonists,
TNF-a
antagonists
Corticosteroids,
TNF-a
antagonists
Colchicine,
NSAIDs, IL-1
and TNF-a
antagonists
TNF-a antagonists,
IL-1 antagonists
IL-1 antagonists
NSAIDs, Vitamin D
analogs, systemic
retinoids, TNF-a
inhibitors, IL-1
inhibitors
Corticosteroids,
IL-1 antagonists,
TNF-a
antagonists
May respond to
JAK inhibitor
(tofacitinib)
Febrile attacks last
up to 7 days
↑ Incidence in
Dutch and
Northern Europeans
↑ Serum IgD and
urinary mevalonate levels
Febrile attacks of-
ten long
(1–6 weeks)
Secondary AA
amyloidosis
(15%)
Labs: ↓ serum sol-
uble TNF receptor levels
Febrile attacks last
1–3 days
↑ Incidence in
Mediterranean
populations
Secondary AA
amyloidosis
(mainly in homozygotes; prevented by colchicine)
Multiorgan failure
270
4.11 Neurocutaneous Syndromes
Table 4.14 Features of Selected Autoinammatory Syndromes—cont'd
Diagnosis Gene (Protein) Inheritance Clinical Features Rx Other Comments
STING-associated
vasculopathy with onset in
infancy (SAVI) syndrome
Aicardi-Goutières Several reported
Deficiency of ADA2 (DADA2) ADA2 AR Vasculopathy leads to livedo reticu-
VEXAS (Vacuoles, E1
enzyme, X-linked,
Autoinflammatory, Somatic)
syndrome
TMEM173 AD Acral vasculopathy with violaceous
including TREX1,
SAMHD1
UBA1 gene on
X-chromosome
Mainly AR Chilblains-like lesions and acrocy-
Somatic
mutation
in males
40–80
years old
plaques of cold exposed acral
surfaces, ears, and nose
Progresses to soft tissue loss, with
ulceration, necrosis, and sometimes auto-amputation and nasal septum perforation
Can also have fevers, nail dystro-
phy, adenopathy, severe intersti-
tial lung disease
anosis especially of cold exposed
areas of ngers, toes, ears
Variable neurodevelopmental ab-
normalities including encephalopathy, abnormal tone, seizures, fever,
hepatosplenomegaly, thrombocytopenia, glaucoma
laris, necrosis, and Raynaud’s
phenomenon. Recurrent
strokes, intermittent fevers, and
hepatosplenomegaly may occur
along with mild immunodeciency
including hypogammaglobulinemia
Systemic features: MDS, MGUS,
uveitis, fever, LAD, pulmonary inltrates, vasculitis, VTE
Cutaneous features: relapsing poly-
chondritis, EN, livedo reticularis,
Sweet syndrome-like erythematous
nodules, periorbital edema, PAN
Lab features: macrocytic anemia,
thrombocytopenia, vacuolization
of erythroidand myeloid precursors
in bone marrow
May respond to
JAK inhibitor
(tofacitinib)
Mainly
symptomatic
treatment
May respond to
anti-TNF agents
Replacement of
ADA2 with fresh
frozen plasma
May respond to
systemic steroids (+/- colchicine)
Long-term
prognosis is poor
with high mortality
rate
Histopathology
• Histology (all except PAPA and Blau): moderate-dense
dermal perivascular and interstitial neutrophils
(“neutrophilic urticarial dermatitis”) 1/– dermal
edema
Treatment
• The treatment of each autoinammatory syndrome is
disease-specic—agents such as anakinra, etanercept, and
canakinumab are commonly used
• Colchicine is crucial in preventing amyloidosis in
patients with FMF
Prognosis/clinical course
• Untreated, many of the autoinammatory syndromes →
signicant morbidity and mortality
• DITRA, DIRA, and NOMID may be fatal during infancy
or childhood
• Secondary AA amyloidosis is a complication of FMF
and the cryopyrin-associated periodic syndromes
(CAPS)
4.11 NEUROCUTANEOUS SYNDROMES
Neurobromatosis (NF)
• Encompasses three distinct disorders (NF1, NF2, and
schwannomatosis), characterized by ↑ propensity toward
tumor development, particularly of the nerve sheath
■
90% of cases are NF1
• NF1 (von Recklinghausen’s disease)
■
AD disorder caused by mutations in neurobromin
(NF1), a tumor suppressor gene
Neurobromin is a cytoplasmic protein that
negatively regulates Ras activation
50% are sporadic mutations and mosaic/segmental
disease can occur
Diagnostic criteria for NF1 (Box 4.1)
Box 4.1 Diagnostic Criteria for NF1
Must have two or more of the following:
Six café-au-lait macules $0.5 cm prepubertal or $1.5 cm postpubertal
Intertriginous freckling
Plexiform neurobroma or .2 dermal neurobromas
.2 Lisch nodules
Optic nerve glioma
Pathogenomic skeletal dysplasia (tibial or sphenoid wing dysplasia)
Affected rst-degree relative
271
CHAPTER 4 • Pediatric Dermatology
Manifestations by age of presentation listed
in Table 4.15
■
Cutaneous manifestations:
Neurobroma: soft papule that invaginates upon
nger pressure (“buttonholing”)
Plexiform neurobroma: overlying CALMs and/or
hypertrichosis; “bag of worms” texture (seen in
25% of patients)
Malignant peripheral nerve sheath tumor
(MPNST): rapid enlargement or pain of plexiform
neurobroma (10% risk)
CALMs (typically $ 6, ↑ #/size in rst 5 years)
Axillary and/or inguinal freckling (Crowe’s sign)
■
Ocular manifestations
Lisch nodules (.90% of patients by 10 years of age)
Optic glioma, choroid nevus, and glaucoma
■
Skeletal manifestations
Sphenoid wing dysplasia: pulsating exophthalmos
may be noted, though often asymptomatic
Macrocephaly
Scoliosis
Table 4.15 Manifestations of NF1 by Age of Presentation
Average Age of Onset Cutaneous Ocular Neurologic Skeletal
Infancy to early childhood Café-au-lait macules
Prepubertal Intertriginous freckling ( Fig. 4.29) Brainstem gliomas
Adolescence Dermal or subcutaneous neurofibromas Lisch nodules
Adulthood Malignant peripheral nerve sheath tumors
Plexiform neurofibromas (first cutaneous sign—
probably all congenital according to Bolognia)
Congenital tibial pseudarthroses (tibial)
Additional skeletal abnormalities: thoracic cage
asymmetry, osteoporosis, and pathologic fractures
Short stature
■
Neurologic manifestations:
Learning disability, ADHD, and autism
Seizures
Hydrocephalus
Optic glioma (can → blindness; seen w/
precocious puberty), astrocytomas, meningiomas,
vestibular/acoustic schwannoma/neuroma, and
ependymoma
■
Other manifestations:
Other tumors: neurobrosarcoma,
rhabdomyosarcoma, pheochromocytoma, Wilms’
tumor, and chronic myelogenous leukemia
Hypertension may develop as a result of a
pheochromocytoma (rare) or renal vascular
stenosis (most common cause in children) 2° to
bromuscular dysplasia; most common cause of
HTN in adults is essential
Optic gliomas Learning disabilities
Attention deficit disorder
Autism
Macrocephaly
Meningiomas
Tibial dysplasia
Sphenoid wing dysplasia
Scoliosis
A B
Fig. 4.29 von Recklinghausen’s neurobromatosis. (A) Café-au-lait spots vary in size and have a smooth border. (B) Axillary freckling (Crowe’s sign) is a pathognomonic
sign. (From Dinulos JGH. Cutaneous manifestations of internal disease. In: Habif’s Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 7th ed. Philadelphia:
Elsevier; 2021:990–1012.)
272
Vascular anomalies of the CNS, including stenoses,
moyamoya disease, and aneurysms
Nevus anemicus found in up to 50% of patients;
also associated with glomus tumor
Malignant transformation of neurobroma 2° to
second mutation, most commonly in p53
Possible triple association between NF1, juvenile
xanthogranulomas, and juvenile chronic
myelogenous leukemia (questionable but still
asked on exams)
Of note, Watson syndrome 5 NF1 features 1
pulmonic stenosis ↑
• NF2 (bilateral acoustic schwannomas)
■
AD disorder caused by mutations in SCH gene (encodes
schwannomin/merlin; tumor suppressor gene)
■
Symptoms appear later than NF1 (usually in second to
third decade)
■
Cutaneous ndings: neurobromas (in lower #s than
NF1)—more commonly subcutaneous type w/
overlying pigment/hair rather than intradermal (seen
mainly in NF1), CALMs (usually # 2 lesions)
■
Neurologic ndings: bilateral vestibular schwannomas
(acoustic neuromas) is diagnostic; may → deafness,
tinnitus, unsteadiness, headache; patients should NOT
swim alone, meningiomas, astrocytomas, and
ependymomas
■
Ocular ndings: juvenile posterior subcapsular
lenticular opacity/cataract
■
Poor prognosis with worsening hearing, vision,
ambulation; CNS tumors are most common cause of
death
■
Selumetinib — mitogen-activated protein kinase (MEK)
inhibitor approved for patients aged .2 years, for
inoperable symptomatic plexiform neurobromas; SEs:
↑ creatine kinase, acneiform rash, paronychia, and GI
symptoms (most common SE) like nausea, vomiting,
and diarrhea
Tuberous sclerosis complex (TSC)
• AD disorder caused by mutations in hamartin (TSC1) or
tuberin (TSC2) (tumor suppressor genes); TSC2 is most
common and is contiguous with polycystic kidney disease
(PKD)
■
Tuberin and hamartin form a complex that inhibits
signal transduction of downstream effectors of mTOR
(mammalian target of rapamycin) → abnormal
regulation of cellular differentiation, proliferation, and
migration of affected cell types with the formation of
multiple hamartomas
• Mosaic/segmental disease can occur
■
Cutaneous ndings: adenoma sebaceum (facial
angiobromas), hypopigmented “ash-leaf” macules
(confetti pattern pretibially; rst cutaneous nding),
Shagreen patch (collagen connective tissue nevus),
periungual bromas (“Koenen tumors”), and CALMs
■
Histology of angiobromas: dermal brosis with
stellate broblasts, atrophic sebaceous glands, dilated
capillaries, and loss of elastin
■
Histology of Shagreen patch: broad sclerotic collagen
bundles and reduced elastin
4.11 Neurocutaneous Syndromes
■
Histology of hypomelanotic macules: normal # of
melanocytes with ↓ pigmentation
• Treatment of facial angiobromas: pulsed dye laser,
ablative laser, excision, and topical rapamycin
• Neurologic ndings: cortical tubers, subependymal
nodules (may → hydrocephalus), subependymal giant
cell astrocytomas, seizures/infantile spasms,
hypsarrhythmia, intellectual impairment, and
paraventricular calcication
■
Infantile spasms, large number of cortical tubers, and
early age of onset of seizures or intractable seizures
associated with worse prognosis
■
#1 cause of mortality 5 complications related to
seizures
• Renal ndings: renal cysts, angiomyolipomas, and renal
cell carcinoma
■
Systemic mTOR inhibitors (i.e., sirolimus and
everolimus) used for management of renal and hepatic
angiomyolipomas and subependymal giant cell
astrocytomas
■
Complications of renal disease (renal failure,
catastrophic hemorrhage within a renal
angiomyolipoma, and renal hypertension) 5 #2 cause
of premature death
• Ocular ndings: retinal phakomas (hamartomas)
• Cardiac ndings: cardiac rhabdomyomas → Wolff-Parkinson-
White arrhythmia; notably most rhabdomyomas
spontaneously involute in early childhood
• GI ndings: hepatic cysts, hepatic angiomyolipomas
(usually asymptomatic), and GI polyps/hamartomas
• Dental ndings: pits in enamel and gingival bromas
• Lung ndings: pulmonary lymphangioleiomyomatosis
and pulmonary cysts
■
Pulmonary complications: pneumothorax, chylothorax,
hemoptysis, and pulmonary insufciency
• Denite diagnosis of TSC requires either the presence of a
pathogenic mutation in TSC1 or TSC2 OR the presence of
two major criteria or one major criteria and two minor
criteria (Table 4.16)
• A possible diagnosis of TSC requires the presence of one
major or two minor criteria (see Table 4.16)
• Cutaneous features are seen in 90% of affected patients,
and may be the rst presenting sign Table 4.17
Table 4.16 Diagnostic Criteria for Tuberous Sclerosis Complex
Major Features Minor Features
$3 Angiobromas or brous
cephalic plaque
$3 Hypomelanotic macules
.5 mm in diameter
$2 Ungual bromas
Shagreen patch
Multiple retinal hamartomas
Cortical dysplasias
Subependymal nodules
Subependymal giant cell
astrocytoma
Cardiac rhabdomyoma
Lymphangioleiomyomatosis
$2 Angiomyolipomas
$3 Dental enamel pits
$2 Intraoral bromas
“Confetti”-like skin lesions
Nonrenal hamartomas
Multiple renal cysts
Retinal achromic patch
273
CHAPTER 4 • Pediatric Dermatology
Table 4.17 Cutaneous Manifestations of Tuberous Sclerosis Complex by
Average Age of Presentation
Average Age of
Onset Cutaneous Other
Infancy to early
childhood
Prepubertal Angiobromas
Adolescence Ungual fibromas
Adulthood Intraoral fibromas Pulmonary
Fig. 4.30 Tuberous sclerosis. Facial angiobromas (“adenoma sebaceum”) are
typically 1- to 4-mm, skin-colored to red, dome-shaped papules with a smooth
surface. (From Paller AS, Mancini AJ. Disorders of pigmentation. In: Hurwitz
Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and
Adolescence. 4th ed. Philadelphia: Elsevier; 2011:234–267.)
Hypomelanotic
macules
“Confetti”-like skin
lesions
(Fig. 4.30)
Shagreen patch
Fibrous cephalic
plaque
Dental pits
(Fig. 4.31)
Cardiac rhabomyomas
Subependymal nodules
Seizures
Renal hamartomas
lymphangioleiomyomatosis
(females)
Renal cysts
Incontinentia pigmenti (IP)
• XLD loss-of-function mutation in NF-B essential
modulator (NEMO; IKBKG)
■
Mutation in NEMO prevents activation of NF-B, a
regulator of cell proliferation, inammation, and
TNF-a–induced apoptosis
■
Mutation is lethal in males; seen primarily in women
and possible in XXY (Klinefelter’s) males
■
Functional mosaicism from lyonization in affected
females (random inactivation of affected X
chromosome) results in Blaschkoid pattern of
cutaneous involvement
• IP is a neuroectodermal disorder that affects the skin,
teeth (hypodontia/anodontia), CNS, and eyes
■
Cutaneous lesions are typically arranged in streaks and
whorls, following Blaschkoid pattern
■
Four distinct morphologic stages (Table 4.18)
Table 4.18 Findings in Incontinentia Pigmenti
Stage Manifestation Timing Comments
Vesicular Inflammatory
vesicles or
pustules
(Fig. 4.32)
Verrucous Warty papules Up to 2 years
Hyperpigmented Blue to brown
streaks
Hypopigmented Atrophic
hypopigmented
streaks
Birth to 1
month
(usually
resolved by
8 weeks)
Up to
adolescence
(may resolve
by 1 year)
May persist
through
adulthood
Reactivation
may occur
with illness or
trauma
May not
involve
previously
vesicular or
verrucous
areas
Fig. 4.31 Periungual brous nodules (Koenen’s tumors) on the toes of an adolescent with tuberous sclerosis.(From Weston WL, Lane AT, Morelli JG. Disorders
of pigmentation: the white lesions and the brown lesions. In: Color Textbook of
Pediatric Dermatology. 4th ed. Philadelphia: Elsevier; 2007:309–333.)
274
Fig. 4.32 Incontinentia pigmenti. The lesions of incontinentia pigmenti tend to follow a curvilinear pattern along lines of Blaschko, lines of the embryological development of ectoderm, as a manifestation of functional mosaicism (i.e., the X chromosome with the mutation in the NEMO gene is the activated X chromosome in
the skin at these sites). The lesions of the vesicular phase may range from largely
papular with a minor vesicular component to vesiculopustular as shown here and
occasionally to bullous. (From Paller AS, Mancini AJ. Disorders of pigmentation. In:
Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood
and Adolescence. 4th ed. Philadelphia: Elsevier; 2011:234–267.)