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4.2 Viral Exanthems and Select Infectious Disorders of Childhood
Table 4.4 Developmental Abnormalities—cont'd
Diagnosis Pathogenesis Clinical Features
Lip pits Incomplete closure
Umbilical
granuloma
Developmental
anomalies of the
umbilicus
Amniotic band
syndrome
Dermoid cyst Faulty development
a
Branchial cleft cysts, bronchogenic cysts, median raphe cysts, and thyroglossal duct cysts are discussed in the Chapter 6, Neoplastic Dermatology.
of furrows on
mandibular process
Incomplete
epithelialization
after umbilical cord
separation
Urachal remnant or
omphalomesenteric
duct fails to regress
Premature rupture
of the amniotic sac
and formation of
fibrous strands
along embryonic
fusion lines
Bilateral indentations on ver-
milion lower lip; can be unilateral
Associated with cleft lip or
palate (Van de Woude syndrome)
Bright red, friable, broad-
based papule; not present
at birth
Red to pink nodule within
umbilicus, sometimes with
mass underneath
Persistent drainage
Circumferential constriction
band of the distal extremity;
distal lymphedema,
ischemia, and amputation;
early rupture can lead
to other extracutaneous
malformations
Firm, nontender, skin to
blue-colored subcutaneous
nodules most commonly
seen on the upper lateral
forehead, near the
eyebrow, overlying the
anterior fontanelle, or at the
junctional of sagittal and
coronal scalp sutures, but
can be seen anywhere on
the face, scalp, or spinal
axis. May adhere to the
underlying periosteum.
Histology and
Laboratory Testing
Fistulous lumen lined by
stratied squamous
epithelium with scattered mucinous acini
Evaluate for cleft lip/pal-
ate, if indicated
Inflamed vascular
granulation tissue Silver nitrate
Abrupt transition from
stratied squamous
epithelium to glandular
epithelium
Consider abdominal
ultrasound; referral to
pediatric surgery
Imaging is recommended
(MRI most often) for
those present in the
midline. Histology
shows cysts lined by
stratified squamous
epithelium, and may
contain hair follicles,
sebaceous glands, and
sweat glands.
Treatment and
Prognosis/
Clinical Course
Surgical repair
May be associ-
ated with abnormal salivation
(caution in large
lesions)
Resolve over
weeks to
months
Surgical excision
Can become in-
fected and irritated
Surgical
correction
Constriction can
lead to ischemia and amputation
Surgical excision
is the treatment
of choice.
Lesions usually
do not recur.
Additional Boards
Fodder
Fig. 4.4 Membranous aplasia cutis with a subtle hair collar sign. (From Drolet BA.
Developmental abnormalities. In: Eicheneld LF, Frieden IJ, eds. Neonatal and
Infant Dermatology. 3rd ed. Philadelphia: Elsevier; 2015, pp 94–110.)
■
Aplastic crises and pancytopenia may develop in
those with predisposing conditions (e.g., sickle cell
anemia and other hemoglobinopathies)
• Fetal infection
■
Highest risk if acquired before 20 weeks gestation
■
Fetal loss rate highest in second trimester
■
Possible fetal effects: anemia, high-output congestive
heart failure (CHF), hydrops fetalis, and intrauterine
fetal demise
Papular-purpuric gloves and socks
syndrome
• Young adult predominance; due to parvovirus B19
infection; most common in spring
• Symmetric edema and erythema of palms/soles, may
extend to dorsal surface
• Associated petechiae and purpura with sharp
demarcation at the wrists and ankles
• Resolution over 1 to 2 weeks without treatment
235
CHAPTER 4 • Pediatric Dermatology
Table 4.5 Congenital Infections
Diagnosis
Congenital rubella Maternal infection (in first
Congenital
toxoplasmosis
Congenital CMV Most common congenital
Congenital syphilis Presents at birth or rst few
Epidemiology/
Pathogenesis Clinical Features
12 weeks of gestation
leads to most severe
disease), leads to infection
of fetal cells and defective
organogenesis
Consumption of
undercooked meats and
exposure to cat feces
infection and most
common cause of EMH
Three methods of infection:
1. Reactivation of latent maternal disease → no stigmata of disease
2. Primary maternal infection
during pregnancy (earlier,
more severe)
3. Postnatal exposure during
delivery or while breastfeeding
days of life; lack of prenatal care in 30% of cases;
mothers with primary or
secondary syphilis; incidence increasing in some
areas of the United States
Invasion of placenta, blood-
stream and organs by
Treponema pallidum; adhere to endothelium and
cause vasculitis
Skin: intradermal extramed-
ullary hematopoiesis
(EMH), which appears as
soft spongy 2–20 mm erythematous to violaceous
papules (“blueberry muf-
n baby”); hemorrhage,
petechiae may be seen
Other: small for gestational
age, microcephaly, deaf-
ness (most common
symptom), cataracts,
chorioretinitis, retinopathy,
patent ductus arteriosus, intracranial calcica-
tion, and hepatosplenomegaly
Congenital: chorioretinitis, hy-
drocephalus, intracranial
calcications 1/– pete-
chial rash, extrameddulary
hematopoiesis (EMH;
“blueberry mufn baby”)
Postnatal: majority are as-
ymptomatic; very variable
presentation
“Blueberry mufn” spots
(EMH), petechiae, intrauterine growth restriction,
microcephaly, cerebral
palsy, chorioretinitis, hepatosplenomegaly, and pneumonitis
Most common infectious
cause of congenital
deafness and developmental delay!
Early (,2 years of age): con-
dyloma lata, bullae, or erosions favoring hands, feet,
and perioricial areas; scaling, erythema, and sec-
ondary syphilis-like papulosquamous lesions,
and mucous patches; hepatosplenomegaly, snufes,
jaundice, Parrot pseudo-
paralysis (due to painful
epiphysitis), anemia, and
edema
Late (.2 years of age): inter-
stitial keratitis, nerve deafness, saber shins, gum-
mas of bone, frontal
bossing, Higoumenakis
sign (enlargement of medial third of clavicle), mul-
berry molars, Hutchinson teeth, saddle nose,
perioral rhagades/Parrot
lines and Clutton joints
(painless, symmetric
swelling of knees), tabes
dorsalis
Histology and
Laboratory Testing
EMH: erythroid (nucle-
ated RBCs) precursors, immature granulocytes, and
megakaryocytes
Viral culture of nasophar-
ynx; serology less sensitive, but can do
acute (cord blood) and
convalescent (4–6
months) titers
EMH
Serology
PCR of amniotic uid
Histology of lymph nodes
EMH
Culture: urine and saliva
PCR: plasma
Serology (rarely used in
the neonate): rising
IgG titer, IgM not sensitive in neonate
Swelling and proliferation
of endothelial cells;
perivascular inltrate of
plasma and lymphoid
cells
Dark-eld exam of skin;
DFA; syphilis serologies—VDRL, RPR titer
in infant 4x mother’s titer, but can have false
negatives if disease
acquired late in pregnancy; IgM FTA-ABS
most specic; skin
biopsy
Treatment
Prognosis/
Clinical Course
No treatment
Universal vaccina-
tion is designed
to prevent congenital infection
Manifestations
of congenital
rubella are
lifelong, but
can present
later in childhood
Pyrimethamine,
sulfadiazine,
folinic acid 3
1 year
Prognosis im-
proves with
therapy, but
consequences
can be severe
IV gancyclovir
Oral valgancyclovir
(limited data in
newborns)
Congenital CMV
cannot be
cured, only suppressed
Penicillin (route
and course according to clinical features and
per CDC and
AAP guidelines)
Depends on se-
verity at presentation; prognosis for promptly
treated syphilis
is excellent
Additional Boards
Fodder
False positive non-
treponemal tests
(VDRL and RPR)
in: infectious diseases, malignancies, and connective tissue
diseases
FTA-ABS, MHA-TP
false positive with
other spirochetes
and Lyme disease
236
Table 4.5 Congenital Infections—cont'd
Diagnosis
Congenital
varicella
Congenital
(intrauterine)
herpes simplex
Neonatal herpes
simplex
Congenital
candidiasis/
neonatal
candidiasis
Epidemiology/
Pathogenesis Clinical Features
Fetal: infection in first 20
weeks gestation
Neonatal: maternal primary
varicella infection 7 days
before to 2 days after
delivery
Birth, first few days of life
Via ascending infection
(secondary maternal
infection) or viremia from
primary maternal infection
Congenital HSV is much less
common than Neonatal
HSV
Presents at 5–14 days
Infection during birth or
perinatal period
Risk is highest (40%) for
mothers with genital HSV
acquired near delivery, risk
is low (,2%) for mothers
with recurrence of genital
HSV
C-section decreases risk of
transmission
Risk factors: prematurity,
foreign body in cervix/
uterus, and maternal vaginal
candida colonization
Ascending intrauterine
chorioamnionitis
4.2 Viral Exanthems and Select Infectious Disorders of Childhood
Treatment
Prognosis/
Clinical Course
VZIG
Acyclovir
Fetal: varies
based on
extracutaneous
manifestations
Neonatal: infection
at ,5 days has
a fatality rate
of up to 30%;
infection after
5 days has a
benign course
IV acyclovir
IV acyclovir
Usually 5–14 days
If localized, can
be treated with
topical imidazole
or nystatin; if
extensive, or if
the infant is ill,
preterm, or very
low birth weight,
use of systemic
antifungal is
indicated
Limited disease
in healthy term
infants resolves
quickly with
topical treatment
Premature
infants may
have significant
associated
morbidity
Additional Boards
Fodder
Zoster in first year of
life without history
of primary varicella
infection is seen
with exposure
to varicella in
utero; infants ,1
year of age are
more likely to
develop secondary
streptococcal
infection
Fetal (presents at birth):
stellate deep scars; limb
paresis, hypoplasia,
chorioretinitis, and low birth
weight, developmental
delay, microphthalmia,
cataracts, nystagmus, and
hydrocephalus
Neonatal (presents at
0–14 days): vesicles on
erythematous base; lesions
usually in same stage of
development; generalized
distribution, often much
more widespread than
outside newborn period
Vesicles, pustules,
widespread erosions,
congenital scars, and areas
of aplasia cutis
Any site may be involved,
but scalp often affected
with aplasia cutis-like
areas; signs of TORCH
infections, e.g., low birth
weight; microcephaly, and
chorioretinitis; 50%–75%
mortality if untreated
Skin, eyes, and mouth (SEM);
disseminated infection;
CNS infection (
neurologic sequelae)
Skin: vesicles, pustules,
crusts, and erosions
(predilection for scalp and
torso); may involve mucosa
(Fig. 4.5)
Signs of sepsis; irritability and
lethargy
Presents at birth or first
few days to weeks of life
with erythema, small
monomorphous papules,
and pustules (Fig. 4.6)
In extremely premature
infants presents as a scald
burn-like dermatitis with
scaling
Favors upper torso, palms,
and soles
Systemic infection is rare in
healthy term infants
40% have
Histology and
Laboratory Testing
Neonatal: intraepidermal
blisters associated with
intracellular edema and
multinucleate epithelial
cells with inclusion
bodies
Tzanck, FA, viral culture,
and serology unreliable;
prenatal imaging
(ultrasound, MRI); virus
usually not isolated from
fetal varicella syndrome
cases
Tzanck; fluorescent
antibody or
immunoperoxidase slide
test, PCR, and viral
culture
Intraepidermal blisters
associated with
intracellular edema and
multinucleate giant cells
with inclusion bodies
Tzanck; DFA or
immunoperoxidase slide
test, PCR, and viral
culture
Skin biopsy may
be helpful if KOH
negative and manifests
subcorneal pustule with
neutrophils; PAS will
highlight yeast forms
KOH: hyphae and
budding yeast
237
CHAPTER 4 • Pediatric Dermatology
Fig. 4.5 Neonatal herpes simplex virus. Multiple vesicles and crusted papules on
an erythematous base in the periumbilical area and left ank. (From Hunt RD,
Friedlander SF. Viral infections. In: Eicheneld LF, Frieden IJ, eds. Neonatal and
Infant Dermatology. 3rd ed. Philadelphia: Elsevier; 2015:176–197.)
Fig. 4.7 Lacy eruption on extensor arm of child with parvovirus B19 infection.
(From Weston WL, Lane AT, Morelli JG. Viral infections. In: Color Textbook of
Pediatric Dermatology. 4th ed. Philadelphia: Elsevier; 2007:113–147.)
Fig. 4.6 Congenital candidiasis. Diffuse erythematous and pustular eruption. (From
Morrell DS, Cathcart SD, Carder KR. Fungal infections, infestations, and parasitic
infections in neonates and infants. In: Eicheneld LF, Frieden IJ, eds. Neonatal and
Infant Dermatology. 3rd ed. Philadelphia: Elsevier; 2015:198–215.)
• Patients are viremic at the time of skin eruption; therefore,
unlike erythema infectiosum, patients are considered
infectious when rash is present
• Most infections resolve without sequelae
Exanthem subitum (roseola infantum,
“sixth disease”)
• 6 to 24 months of age; occurring most commonly in spring
• Infection with human herepesvirus (HHV)-6 (HHV-7 less
likely), a DNA virus
■
Two variants: HHV-6A (seen in HIV) and HHV-6B
(cause of exanthema subitum)
■
Transmitted by oral secretions
• Incubation period of 1 to 2 weeks → high fever (.40°C)
■
Common cause of febrile seizures
• Fever resolves in 3 to 5 days as the exanthem begins
(common clinical scenario: an infant has high fever
resolving in 3 days at which point a rash develops)
■
Exanthem: generalized but subtle maculopapular
eruption, truncal predominance; typically resolves
within 2 to 3 days
■
Enanthem: Nagayama spots, which are red macules on
soft palate and uvula
• Benign course; resolves without complications, even in
pregnant women; patients with febrile seizures are
unlikely to suffer future seizures
• Remains latent in CD41 T cells, which results in
possibility of reactivation
■
Implicated pathogenic factor in DRESS (Drug
Reaction with Eosinphilia and Systemic Symptoms)
Hand-foot-and-mouth disease (HFMD)
• Summer/fall predominance, most common in children up
to 10 yo
• Infection caused by Coxsackie A16 virus (. Coxsackie A6
and Enterovirus 71)
• Transmitted by fecal-oral and respiratory routes →
infection of pharyngeal or GI tract, followed by lymphoid
involvement, subsequent viremia, and involvement of end
organs, including skin
• Incubation period of 3 to 6 days → prodrome (fever and
malaise) → onset of cutaneous eruption
■
Vesicular eruption most commonly involving palms/
soles/buttocks/oral cavity
■
Erythematous macules and oval, deep-seated
erythematous vesicles and bullae with gray center
238
4.2 Viral Exanthems and Select Infectious Disorders of Childhood
■
Erosive lesions can be found in the oral cavity
“herpangina” (palate/uvula/tongue/buccal mucosa)
■
Onychomadesis/Beau’s lines often occur 1 to 2
months following a coxsackie infection (d/t nail matrix
arrest at time of acute infection)
■
Adult HFMD is more strongly associated with
myocarditis
■
Boards factoid: Coxsackie A6 has recently been shown
to cause more widespread and severe vesiculobullous
eruptions and is a/w atypical HFMD presentations,
including eczema coxsackium (in atopic patients,
Fig. 4.8), that tend to be most predominant on the
perioral area and extremities, and typically present
with more supercial, polymorphic clustered vesicles
and erosions (vs. eczema herpeticum which is more
monomorphic and punched out). Coxsackie A6 can
also present with Gianotti-Crosti-like eruptions and
purpuric eruptions
Gianotti-Crosti syndrome (papular
acrodermatitis of childhood)
• Peak age 5 1 to 6 years of age (90% are younger than 4 yo)
• Exanthem arising in setting of viral trigger; may also be
seen after vaccination
• #1 cause worldwide: hepatitis B
• Symmetric monomorphic skin-colored to erythematous
papular eruption with predilection for face (esp.
cheeks), extremities, and buttocks (Fig. 4.9); relative
sparing of the chest, back, and abdomen
• Spontaneous resolution expected within 1 to 2 months
Parechovirus
• Infants with erythema of the acral surfaces combined
with a sepsis-like picture
• Other symptoms include fevers, often with associated
signs of sepsis/meningitis as well as an associated
nonspecic morbilliform rash
Fig. 4.8 Eczema coxsackium. (Personal collection, Dr. Brea Prindaville.)
Fig. 4.9 Gianotti-Crosti syndrome. Grouped pink-red papules concentrated
around the elbows and knees. (Personal collection, Dr. Jennifer Schoch.)
Unilateral laterothoracic exanthem
(asymmetric periexural exanthem of
childhood)
• Average age 5 1 to 5 years of age; female predominance;
usually in spring
• Thought to be 2° to virus, but exact cause unknown
• May have preceding prodromal symptoms of URI or GI
illness
• Unilateral erythematous macules and papules with
exural predominance, classically beginning in axilla and
lateral trunk; “Statue of Liberty sign” (a boards clue) 5
picture of young child with one arm raised to the sky to
show rash on axilla and lateral trunk
• Centrifugal spread to contralateral side may occur, but
rash usually maintains unilateral predominance
• Resolves spontaneously after 3 to 6 weeks
Chronic mucocutaneous
candidiasis (CMC)
• Most common skin manifestation of HIV in children
• If inherited, often autosomal recessive (AR)
• CMC is a heterogeneous group of disorders marked by
chronic and recurrent infections of the skin/hair/nails/
mucosa with Candida albicans (e.g., thrush, perlèche,
chronic paronychia, diaper dermatitis/intertrigo, and
dental enamel hypoplasia)
■
APECED (autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy syndrome): AR
disease; CMC and other clinical features below
AIRE (autoimmune regulator) mutation results in
failure to delete autoreactive T cells with resultant
autoimmunity—affects regulatory T cells
239
CHAPTER 4 • Pediatric Dermatology
Additional features seen in APECED
◆ Endocrinopathies:
Hypoparathyroidism (most common),
hypoadrenocorticism (second most common),
hypogonadism, thyroid disease, diabetes, and
hypopituitarism
◆ Cutaneous autoimmune conditions: alopecia
areata and vitiligo
◆ Pernicious anemia
■
Additional CMC syndromes are seen in association
with mutations in signal transducers and activators of
transcription 1 (STAT-1), interleukin-17F (IL-17F)
(important as candida infections are a side effect [SEs]
of secukinumab), caspase recruitment domaincontaining protein 9 (CARD9), and C-type lectin
domain family 7 member A (CLEC7a, dectin)
4.3 INHERITED PIGMENTARY DISORDERS
Hypo-/depigmentation
Pigmentary mosaicism
• Blaschkoid hypo- or hyperpigmentation: faintly presents
at birth and more apparent over rst 1 to 2 years
• Most patients developmentally normal; if extensive,
consider neurologic, skeletal, ocular anomalies
Oculocutaneous albinism (OCA)
• Group of AR disorders involving abnormal melanin and
melanosome biosynthesis and transport within the
melanocytes of skin, hair follicles, and eyes
■
There are four types (OCA 1–4), classied based on the
affected gene (Table 4.6)
■
OCA type 2 is the most common type, followed by
OCA type 1
• Variable pigmentary dilution of the skin, hair, and eyes
■
Many affected patients (except classic OCA1a) develop
pigmented melanocytic nevi/lentigenes/ephelides
• Photophobia, nystagmus, and reduced visual acuity of
variable severity
• On histology, ↓ melanin content w/ normal # of
melanocytes
• ↑ Risk of basal cell carcinoma (BCC), squamous cell
carcinoma (SCC; most common type of skin cancer in
these patients), and melanoma (worse in OCA1)
• Boards factoid: OCA2-like hypopigmentation is seen in
1% of patients with Prader-Willi syndrome and
Angelman syndrome, which are caused by deletions on
chromosome 15q (which includes the OCA2 gene), if a
second mutation is present in the remaining OCA2 gene
Silvery hair syndromes
• Includes Chédiak-Higashi syndrome (CHS), Griscelli
syndrome (GS), and Elejalde syndrome (Table 4.7)
• All are AR
• Characterized by impaired synthesis, storage, and/or
transport of melanosomes and in the case of CHS, other
intercellular proteins
• All have pigmentary dilution of the skin and hair w/
variable immunologic and neurologic features
■
Under light microscopy, giant granules or melanosomes
may be seen in the hair shaft and keratinocytes
• CHS: severe multisystem disease that presents in infancy
with silvery hair, OCA, immunodeciency, bleeding
diathesis, and neurologic degeneration; death typically
occurs by age 10 as a result of the lymphoproliferative
accelerated phase/hemophagocytic syndrome →
pancytopenia and lymphocytic inltration of liver/spleen/
lymph nodes
Table 4.6 Oculocutaneous Albinism (OCA)
Type Mutation (all are AR) Phenotype Comments
OCA1a TYR (absent) Tyrosinase negative Generalized and near-complete lack of pigmentation at birth—white hair and skin
OCA1b TYR (decreased to 5%–10%
of normal level)
OCA2 OCA2 (previously called
P gene; pink-eyed dilution)
OCA3 TYRP1 “Rufous” Very rare; most commonly occurs in Africa and New Guinea
OCA4 Solute carrier family 45
member 2 (SLC45A2,
formerly MATP)
“Yellow mutant
albinism”; minimal
pigment
Tyrosinase positive Most common OCA, usually seen in Africans
Resembles OCA2 Exceedingly rare except in Japan (where it accounts for 25% of OCA)
(hair becomes light yellow over time)
Nevi are amelanotic/pink
Gray-blue irides
Markedly reduced visual acuity , severe photosensitivity, markedly increased risk of
squamous cell carcinoma
No pigmentation of skin/hair at birth → over time, develop some pigmentation
Can have amelanotic or pigmented nevi
Milder ocular complications compared to OCA1a
Temperature-sensitive variant (OCA1b TS): tyrosinase functions at low tempera-
tures, leading to hair pigmentation at cooler anatomic sites (mainly extremities) and
white hairs in warmer sites (trunk, intertriginous zones)
Pigmentary dilution variable, but develop pigmented nevi/lentigines over time
Light brown hair and gray/tan irides
Reddish-bronze skin and red hair color
Blue-brown irides
Variable clinical presentation ranging from white skin/hair to mild pigmentation of skin/
yellow-brown hair; distinguish from OCA2 via molecular studies
240
4.3 Inherited Pigmentary Disorders
Table 4.7 Features of Chédiak-Higashi Syndrome (CHS) and Griscelli Syndrome (GS)
CHS GS1
Gene defect LYST/CHS1 MYO5A RAB27A MLPH
Major sites of gene
expression
Cellular defect Impaired biosynthesis and
Pigmentary dilution of the
b
skin
Silvery/metallic hair
Trichoscopy: clumps of
melanin
Melanocytes Giant melanosomes Lacks giant melanosomes Lacks giant melanosomes Lacks giant melanosomes
Neutrophils Giant granules Normal-appearing granules Normal-appearing granules Normal-appearing granules
Ocular findings
Bleeding diathesis
Recurrent infections
Other features/comments Severe gingivitis,
Accelerated phase
Primary neurologic
abnormalities
a
Elejalde syndrome likely represents a variant of GS1 (MYO5A) and presents with the pigmentary features of GS with severe neurologic dysfunction but is
not associated with immunodeciency.
b
Often accompanied by hyperpigmentation 6 guttate hypopigmented macules in acral and sun-exposed sites.
c
May develop neurologic symptoms secondary to the hemophagocytic syndrome of the accelerated phase.
CNS, Central nervous system; EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis.
Modied from Schaffer JV, Paller AS. Primary immunodeciencies. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia: Elsevier;
2018:955–984.
Melanocytes, platelets,
granulocytes, and the CNS
storage of melanosomes,
platelet dense granules,
and lysosomes within
leukocytes
1 Acral sun-exposed skin
may be hyperpigmented
1 1 1 1
Small, regularly spaced Larger , irregularly
1
1 Prolonged bleeding
time, easy bruising
1 Especially skin, lungs, and
upper respiratory
May have EBV-induced lym-
phoproliferative syndrome
periodontitis, and oral
mucosal ulceration
1 85%
1 Progressive deterioration 1
a
Melanocytes, CNS Melanocytes, cytotoxic T
Aberrant translocation
of melanosomes along
microtubules within
melanocytes
1 1 1
distributed
– – –
– – –
Neurologic sequelae are
most severe complication
GS2 GS3
cells
Aberrant translocation
of melanosomes along
microtubules within
melanocytes
1 1
1
Recurrent infections,
immunodeficiency, and
accelerated phase/
HLH are most prominent
features
1 Development of HLH
c
Melanocytes
Aberrant translocation
of melanosomes along
microtubules within
melanocytes
Generally mild disease;
skin-limited
■
Severe neurologic degeneration over time
■
On peripheral blood smear, characteristic giant
granules within cytoplasm of neutrophils, eosinophils,
platelets, melanocytes, and granulocytes; on bone
marrow smear, giant inclusion bodies within leukocyte
precursors in CHS
Griscelli syndrome
• GS1: Myosin 5A, severe neurologic impairment
developing during early childhood
• GS2: Rab27A, combined T- and B-cell
immunodeciency → numerous infections and
hemophagocytic syndrome
• GS3: least severe GS subtype, primarily cutaneous
ndings
• Elejalde syndrome: pigmentary features of GS 1 severe
neurologic dysfunction without immunodeciency (may
represent a variant of GS1, Myosin 5A)
Hermansky-Pudlak syndrome
• AR disorder with OCA, bleeding diathesis (due to
platelet storage pool defect), and lysosomal accumulation
of ceroid lipofuscin
■
Disorder of biogenesis of melanosomes and other
lysosomal-related organelles, such as platelet-dense
granules
• More common in Puerto Ricans (especially HPS1)
• Nine associated genes have been described: HPS1, AP3B1/
(HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1/(HPS7),
BLOC1S3/(HPS8), and BLOC1S6 (HPS9)
• Variable pigmentary dilution of the skin, hair with a slight
sheen, and pale irides
• Extensive ecchymoses, nosebleeds, and menorrhagia
■
Avoid aspirin and other anti-platelet medications
• Photophobia, strabismus, and nystagmus
• Other complications are granulomatous colitis,
progressive pulmonary brosis, cardiomyopathy, and
241
CHAPTER 4 • Pediatric Dermatology
renal failure as a result of lysosomal ceroid
accumulation
• Absence of dense bodies in platelets noted on electron
microscopy (EM)
• Most common cause of death is pulmonary brosis
• ↑ rates of skin cancer
Piebaldism
• Autosomal dominant (AD) disorder caused by mutations
in the c-KIT proto-oncogene (c-KIT inhibitor imatinib
can lead to leukoderma) or deletions in the snail family
zinc nger 2 (SNAI2, SLUG)
• Defective migration of melanoblasts from neural crest to
the ventral midline and failed differentiation of
melanoblasts to melanocytes
• White forelock (poliosis; seen in 90%) 1 congenital
patterned midline and ventral patches of leukoderma; in
photos can often differentiate from vitiligo by the
presence of hyperpigmented macules especially at the
periphery (rare in vitiligo)
• Depigmentation is stable and permanent, but otherwise
benign
Waardenburg syndrome
• Primarily AD disorder of neural crest development →
absence of melanocytes in the skin/hair/eyes/striae
vascularis of cochlea
• Features may include a depigmented patch on the
forehead w/ white forelock (poliosis), congenital
deafness, heterochromia irides, synophrys, broad nasal
root, and dystopia canthorum
• Four clinical types have been described (WS 1–4) (Table 4.8)
Hyperpigmentation
McCune-Albright syndrome
• Caused by a non-inherited postzygotic somatic
activating mutation in the GNAS1 gene
• Females .. males
• Triad: large café-au-lait macules (CALMs),
polyostotic brous dysplasia, and endocrine
dysfunction
■
Typical CALMs are segmental and have jagged borders
(“coast of Maine”) (Fig. 4.10)
Fig. 4.10 Large, segmental café-au-lait macules with a “coast of Maine” border
in an infant with McCune-Albright syndrome. (From Lucky AW, Powell J, Herbert
AA. Cutaneous manifestations of endocrine, metabolic, and nutritional disorders.
In: Schachner LA, Hansen RC, eds. Pediatric Dermatology. 4th ed. Philadelphia:
Elsevier; 2011:1219–1268. Courtesy Philippe Backeljauw, Cincinnati Children’s
Hospital.)
Table 4.8 Disorders of Melanocyte Development
Human Disease Inheritance Gene Protein Clinical Features
Piebaldism AD c-KIT KIT tyrosine kinase Congenital patterned areas of depigmentation,
AD SNAI2 Snail homolog 2 transcription
WS1 AD PAX3 Paired box 3 transcription factor White forelock (20%–60%), synophrys, heterochromia
WS2 AD MITF Microphthalmia-associated
AR SNAI2 Snail homolog 2 transcription
WS3 (Klein-Waardenburg
syndrome)
WS4 AD, AR EDNRB Endothelin B receptor Similar to WS1, plus Hirschsprung’s disease
a
Homozygous PAX3 mutations have been described in individuals with WS3 whose parents were affected with WS1.
AD, Autosomal dominant; AR, autosomal recessive.
Modied from Passeron T, Ortonne JP. Vitiligo and other disorders of hypopigmentation. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed.
Philadelphia: Elsevier; 2018:1087–1114.
AD PAX3
AD, AR EDN3 Endothelin-3
AD SOX10 SRY-box containing 10
a
factor
transcription factor
factor
Paired box 3 transcription factor Similar to WS1, plus upper limb abnormalities
white forelock (90%), and islands of normal and
hyperpigmented skin within depigmented patches; no
internal sequelae
irides, dystopia canthorum (eyes appear widely spaced
due to lateral displacement of inner canthi; interpupillary
distance is normal), and deafness (20%–40%)
Similar to WS1, but no dystopia canthorum; 1 deafness
is more common
(hypoplasia, contractures and syndactyly)
242
4.3 Inherited Pigmentary Disorders
■
Skeletal lesions (polyostotic brous dysplasia) usually
occur under CALMs, and manifest as gait
abnormalities, bone pain, visible skeletal deformity,
and recurrent pathological fractures
■
Endocrinologic abnormalities include precocious
puberty, hyperthyroidism, acromegaly,
hypophosphatemic rickets, and infantile Cushing
syndrome
Reticulate acropigmentation
of Kitamura
• Rare—majority of patients are Japanese
• AD—caused by mutations in ADAM10 (encodes a
disintegrin and metalloproteinase 10)
• Slightly depressed, lentigo-like hyperpigmented macules
coalescing into a reticulated pattern on the dorsal hands
and feet
• Hyperpigmented macules may darken, and distribution
may expand over time
• Palmoplantar pits and abnormal dermatoglyphics may be
noted
Dowling-degos disease (DDD)
• Rare—AD inheritance
• Mutations in keratin 5 gene (also a/w epidermolysis
bullosa [EB] simplex with mottled pigmentation—K5 and
14 cause several genetic disorders with reticulate
hyperpigmentation)
• Onset usually during adulthood w/ reticulated
hyperpigmentation involving axilla and groin, may spread
to gluteal and inframammary folds, neck, torso, inner thighs
• Comedone-like lesions on the back or neck and cystic
lesions have also been reported
• Galli-Galli disease: variant of DDD in which suprabasilar
acantholysis is noted on histology
• AD/AR—mutations in ABCB6 (ATP-binding cassette
subfamily B, member 6)
• Generalized or torso-predominant, well-demarcated
brown macules interspersed with variously sized
hypopigmented macules with a mottled appearance
• Nail dystrophy and pterygium
Dyskeratosis congenita (ZinsserEngman-Cole syndrome)
• X-linked recessive (XLR) (most common), AD, and AR
forms
• Males . females (females may have less severe clinical
features)
• Occurs 2° to mutations in DKC1 (XLR inheritance) .
TERT, TERC (AD inheritance), or TINF2 genes
■
Involved in telomere maintenance—affected patients
manifest reduced telomerase activity and abnormally
shortened telomeres → chromosomal instability
• Clinical features: bone marrow failure (up to 90%) 1
triad of abnormal skin pigmentation, premalignant oral
leukoplakia, and onychodystrophy
■
Dyspigmentation: reticulated, poikilodermatous
patches of the face/neck/upper torso
■
Nail abnormalities: anonychia, pterygium, and
longitudinal ridging and splitting
■
Oral manifestations: leukoplakia (premalignant)
■
Other dermatologic features: palmoplantar
hyperkeratosis and diffuse non-scarring alopecia
■
Other features: progressive periodontal disease,
developmental delay, pulmonary brosis, and hepatic
cirrhosis ↑ risk for malignancy (SCC [especially
mucosal] and hematopoietic malignancies)
■
Causes of mortality include bone marrow failure (most
common), pulmonary brosis, and malignancy (third
to fourth decade)
Median age at death 5 16 years
Lentiginoses syndromes
See Table 4.9
Hereditary dyschromatoses
Dyschromatoses 5 both hypo- and hyperpigmentation
Dyschromatosis symmetrica hereditaria (acropigmentation of Dohi)
• Majority of patients are Japanese or Chinese
• AD—caused by heterozygous mutations in the ADAR
(SRAD) gene (encodes an RNA-specic adenosine
deaminase)
• Presents by 6 years of age with dyschromia and
hyperpigmented/hypopigmented macules restricted to
sun-exposed skin on the dorsal aspects of the extremities
and face
Dyschromatosis universalis hereditaria
• Most cases are Japanese
Naegeli-Franceschetti-Jadassohn syndrome (NFJS)/dermatopathia pigmentosa reticularis (DPR)
• Rare—AD inheritance
• Mutations in keratin 14 (NFJS and DPR are allelic
ectodermal dysplasia disorders that share many clinical
features including reticulate hyperpigmentation and
absent dermatoglyphs)
• NFJS: brown-gray reticulated hyperpigmentation typically
localized to the abdomen, develops in early childhood
(around age 2), and improves after puberty
■
Other ndings: palmoplantar keratoderma (PPK),
onychodystrophy, hypohidrosis, and dental anomalies
(not seen in DPR) including early loss of teeth
• DPR: diffuse non-scarring alopecia (not seen in NFJS),
onychodystrophy, and diffuse, persistent reticulated
hyperpigmentation of the torso and proximal
extremities
■
Pigmentary changes fade in NFJS, but persist in DPR;
only DPR has alopecia; only NFJS has teeth
abnormalities
243
CHAPTER 4 • Pediatric Dermatology
Table 4.9 Lentiginoses Syndromes
Syndrome Gene/Inheritance Cutaneous Findings Extracutaneous Findings
LEOPARD syndrome
Lentigines
ECG defects
Ocular hypertelorism
Pulmonic stenosis
Abnormal genitalia
Retardation of growth
Deafness-sensorineural
Carney complex
NAME: nevi, atrial myx-
omas, ephelides
LAMB: lentigines, atrial
myxomas, blue nevi
Peutz-Jeghers
syndrome
Laugier-Hunziker
syndrome
Cronkhite-Canada
syndrome
Centrofacial lentiginosis
(Touraine’s syndrome)
Bannayan-Riley
Ruvalcaba syndrome
AD, Autosomal dominant.
Missense mutations in
PTPN11/SHP2
seen in 90%
RAF1 mutations in 3%
AD
50% with mutations in
PRKAR1A gene,
chromosome
17q22–24
Others with changes at
chromosome 2p16
AD
Serine/threonine kinase
STK11/LBK1 gene,
chromosome
19p.13.3 in up to
70%
AD
Acquired, usually older
men
AD Lentigines in rst year of life—especially on
PTEN (on a spectrum
with Cowden
syndrome)
Lentigines involving the face, neck, and upper
trunk are the most common presenting feature (86%) and develop at 4–5 years of age
as pinpoint to 5-mm brown-black macules
Café noir spots larger and more pigmented
Numerous café-au-lait macules
Abnormal dermatoglyphics
Perioricial lentigines are seen in 77%; fade
with time
Blue nevi are seen in 43%; fade with time
Epithelioid blue nevi (highly specic)
Cutaneous myxomas
Café-au-lait macules
Skin myxomas involving the eyelids, ear, nip-
ple, breast, and mucosa are seen in 33%
Pigmented macules on lips , buccal mucosa,
digits, and other mucosa are seen in 50%–
60% by age 20 (Fig. 4.11)
May fade with time
No relationship between severity of pigmenta-
tion and polyps
Pigmented macules on lips, buccal mucosa,
genitals, and other mucosa
Melanonychia in 50%
Lentigines of hands, feet, and buccal mucosa
Nail dystrophy
Alopecia
nose and cheeks
Sacral hypertrichosis
Lipomas
Penile lentigines
Hypertrophic cardiomyopathy in 71%
Facial dysmorphism
Genital abnormalities– gonadal hypoplasia, delayed
puberty
Skeletal–mandibular prognathism and short stature
Granular cell myoblastomas
Cardiac myxomas (50%–80%; may embolize)
Endocrine neoplasms, especially primary pig-
mented adrenocortical disease (26%–45%)
Sertoli cell tumor seen in 33%
Thyroid nodules/carcinoma
Psammomatous melanotic schwannoma
Breast ductal carcinoma
GI polyps, most common in the jejunum and
ileum → can cause intussusception (most
common), GI bleeding, anemia, and vomiting
93% develop cancer before age 65: GI most com-
mon (small intestine, stomach, esophagus, colon
or pancreas), lung, and breast
Adenocarcinoma seen in younger patients
No increased cancer risk
Intestinal polyposis
Developmental delay
Congenital mitral valve stenosis
Seizures
Absent middle incisors
Skeletal abnormalities
Dwarsm
Endocrine dysfunction
Macrocephaly
Vascular anomalies–deep, high ow
Developmental delay
Intestinal polyps
Macrodactyly
Pseudopapilledema
Hashimoto thyroiditis
Increased risk of malignancy
Fig. 4.11 Peutz-Jeghers syndrome. Note lentigines on mother’s ngers also.
(Personal collection, Dr. Megha Tollefson.)
244
4.4 EPIDERMOLYSIS BULLOSA
Epidermolysis bullosa (Table 4.10)
EB is a group of heterogeneously inherited mechanobullous
disorders that are manifested as fragile skin leading to blisters.
There are four major forms of EB, which are categorized by the
level of blister cleavage. The fourth major form, Kindler syndrome, was added to the classication system of EB in 2008.
• EB simplex: intraepidermal blister with split at the basal
layer
• Junctional EB: blister through the lamina lucida of the
basement membrane zone (BMZ)
• Dystrophic EB: blister below the lamina densa
• Kindler: mixed levels
Congenital localized absence of skin may be associated
with any of the subtypes of EB. Previously this was termed Bart