Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
4.12 Premature Aging Syndromes and DNA Repair Disorders
■
Patients may not develop all four cutaneous stages and
there may be some overlap of stages
■
Alopecia may affect the scalp and other parts of the
body
■
See Table 4.19
• Histology varies by stage:
■
Vesicular stage: eosinophilic spongiosis;
intraepidermal vesicles containing eosinophils;
apoptotic keratinocytes in epidermis
■
Verrucous stage: papillomatosis, hyperkeratosis, and
acanthosis of the epidermis; apoptotic cells in
epidermis forming squamous eddies
Table 4.19 Other Clinical Manifestations of Incontinentia Pigmenti
Organ Manifestation Frequency
Other cutaneous Cicatricial alopecia
Teeth Pegged or conical teeth
Central nervous
system
Eyes Retinal vascular anomalies (e.g.,
Breast Supernumerary nipples
Nail dystrophy
Subungual tumors (resembles
squamous cell carcinoma!)
Anodontia (dental 5 most com-
mon extracutaneous feature)
Delayed dentition
Seizures
Developmental delay
Spastic paresis
vascular changes → blindness)
Nonretinal anomalies (strabismus,
cataracts, and optic atrophy)
Nipple hypoplasia
Breast hypoplasia or aplasia
10%–20%
10%
Up to 10%
50%
30%
30%
11%–30%
■
Hyperpigmented stage: marked pigment incontinence
with numerous melanophages in the dermis; apoptotic
cells may be seen in epidermis
■
Hypopigmented stage: epidermal atrophy, loss of
melanin in basal layer, complete absence of
pilosebaceous units and eccrine glands; apoptotic cells
may be seen in epidermis
• Severely affected patients may develop seizures,
developmental delay and intellectual impairment, and
↓visual acuity/blindness (due to retinal vascular changes
and optic atrophy)
• Females with missense mutations in NEMO (milder
phenotype of IP) can bear children (usually male) with
hypohidrotic ectodermal dysplasia with
immunodeciency
• Review neurocutaneous syndromes in Table 4.20
4.12 PREMATURE AGING SYNDROMES
AND DNA REPAIR DISORDERS
Hutchinson-Gilford progeria
• AD disorder caused by specic mutation (1824C.T) in
the LMNA gene (encodes lamin A)
■
Mutation introduces a splice site that results in the
protein being abnormally farnesylated
■
Lamin A protein contributes to the structure/function
of the nuclear envelope
■
With abnormal farnesylation, lamin A cannot insert
normally into the nuclear envelope
• Cutaneous manifestations begin around 6 to 18 months:
■
Localized sclerodermatous changes of lower trunk/thigh
Table 4.20 Neurocutaneous Syndromes: Genetic Basis and Clinical Findings
Disease Gene/Inheritance Gene Function Cutaneous Features
Neurofibromatosis
type 1
Legius syndrome SPRED1/AD Interacts with Ras Café-au-lait macules
Neurofibromatosis
type 2
Tuberous sclerosis Hamartin or
Incontinentia pigmenti NEMO/XLD
Neurobromin/AD
Incidence 1/3000
Merlin/AD Cytoskeletal protein;
tuberin/AD
Cytoplasmic protein;
negatively regulates
Ras activation
tumor suppressor
Inhibits signal
transduction of
downstream effectors
of mTOR
Activates NF-B,
a regulator of
cell proliferation,
inflammation, and
apoptosis
Café-au-lait macules
Intertriginous freckling
Dermal neurobromas
Plexiform neurobromas
Intertriginous freckling
Schwannomas
Neurobromas
Café-au-lait macules
(33%)
Hypomelanotic macules
Angiobromas
Fibrous cephalic plaque
Shagreen patch
Ungual bromas
Intraoral bromas
Four stages: vesicular,
verrucous, hyperpigmented, and hypopig-
mented
Alopecia
Nail dystrophy
Subungual tumors
Neurologic
Features Other Distinct Features
Learning disabilities
Attention-decit disor-
der
Autistic spectrum
Pilocytic astrocyto-
mas
Meningiomas
Learning disabilities
Vestibular and cranial
schwannomas
Cranial meningiomas
Spinal cord tumors
Subependymal nod-
ules
Seizures
Subependymal giant
cell astrocytoma
Seizures
Developmental delay
Spastic paresis
Lisch nodules
Optic gliomas
Tibial dysplasia
Sphenoid wing dysplasia
Scoliosis
Juvenile posterior subcap-
sular cataract
Hearing loss
Cardiac rhabdomyoma
Renal angiolipomas and
cysts
Pulmonary lymphangioleio-
myomatosis (females)
Dental anomalies
Ocular (retinal) defects
Breast anomalies
Male children with hypohi-
drotic ectodermal dysplasia with immunodeciency
275
CHAPTER 4 • Pediatric Dermatology
Fig. 4.33 Progeria syndrome. (From Scafdi P, Gordon L, Misteli T. The cell
nucleus and aging: tantalizing clues and hopeful promises. PLoS Biol.
2005;3[11]:e395.)
■
Cyanosis around mouth or nasolabial folds
■
Dyspigmentation
■
Also see failure to thrive early on
• Over time, patients show signs of premature aging
■
Early skin wrinkling and xerosis
■
Hair loss (scalp, eyebrows, and eyelashes)
■
Skin atrophy with prominent veins
■
Atherosclerosis and angina
■
Bone density loss/osteoporosis (w/ susceptibility to
fractures), coxa valga, and osteolysis of distal phalanges
• Other dermatologic manifestations: lipodystrophy,
onychodystrophy, and breast hypoplasia
• Facial features: enlarged head, micrognathia with dental
crowding, small ears, and beaked nose (Fig. 4.33)
• A high-pitched voice is characteristic
• Rapid and progressive features of premature aging
develop—complications include cerebrovascular and
cardiovascular events (CHF and MI), limited mobility and
exercise tolerance, and poor growth; intelligence is
typically normal
• Complications of cardiovascular disease are the most
common cause of mortality (mean age of death 5 13 years)
Werner syndrome
• AR disorder as a result of mutations in the RECQL2/WRN
gene (encodes a DNA helicase that helps maintain
genomic stability)
■
Mutations in RECQL2/WRN → ↑ expression of
inhibitors of DNA synthesis and ↑ telomere-driven
replicative senescence → accelerated aging
■
Symptoms/signs seen in third to fourth decade
• Cutaneous ndings: premature canities, progressive
alopecia, bird-like facial appearance, sclerodermatous/
atrophic change acrally/facially, mottled pigmentation,
telangiectasias, hyperkeratotic ulcers over pressure points,
leg ulcers, calcinosis cutis, and loss of subcutaneous fat
• Extracutaneous ndings: short stature, muscle wasting,
atherosclerosis (can → CVA/MI), diabetes mellitus,
hypogonadism, osteoporosis, arthritis, posterior
subcapsular cataracts, DM2, and hypogonadism
• ↑ Risk of malignancy: brosarcoma, osteogenic sarcoma,
carcinoma of breast or ovary, thyroid adenocarcinoma,
skin cancers
• Malignancy and cerebrovascular/cardiovascular events
are main causes of mortality (mid-50s typically)
Xeroderma pigmentosum
• AR disorder due to mutations in XPA to XPG genes (as
well as variant XPV gene)—each gene encodes a protein
important in the nucleotide excision repair (NER)
pathway: XPA encodes DNA damage-binding protein 1
(DDB1), XPB encodes excision-repair cross-complementing 3
(ERCC3), XPC encodes endonuclease, XPD encodes
ERCC2, XPE encodes DDB2, XPF encodes ERCC4, XPG
encodes endonuclease, and XPV is unique in that it
encodes a DNA polymerase
■
Subtypes (complementation groups) of XP (XPA to
XPG) correspond to the affected genes
■
In the variant subtype XPV, the post-replication repair
pathway is abnormal because of mutations in the gene
that encodes DNA polymerase-
■
Affected individuals have ↑ sensitivity to UV-induced
skin damage caused by abnormalities in DNA repair
pathways (i.e., recognition of damaged DNA,
unwinding of DNA [helicases], and incision/removal of
damaged DNA [endonucleases])
■
Most common subtypes in the United States are XPA
and XPC; XPA is the most common subtype in Japan
■
Different mutations in the XP genes may lead to
different phenotypes and overlap syndromes:
XPB, XPD, and XPG: a/w XP-Cockayne overlap
syndrome; possess signs of both XP (skin cancers,
lentigines) and Cockayne syndrome (retinal
degeneration, basal ganglia calcication)
XPB, XPD: also a/w trichothiodystrophy (TTD)
• Typical cutaneous manifestations appear after 6 months,
with development of persistent erythema, scaling, and
ephelides on sun-exposed areas
• Eventually poikiloderma develops, followed by development
of numerous cutaneous malignancies (Fig. 4.34)
■
1000-fold increased risk of cutaneous malignancy in
patients ,20 years of age, including BCC, SCC,
melanoma, and brosarcoma; mean onset of cutaneous
malignancy 5 8 years of age
■
↑ Risk of solid and CNS tumors, though rare
• Ophthalmologic complications: photophobia,
conjunctivitis, ectropion, and symblepharon
• Neurodevelopmental complications, including
developmental delay, intellectual impairment,
sensorineural hearing loss, hyporeexia, and/or ataxia
occurs in 20%–30% of XP patients (esp. XPA and XPD
groups); XPV patients have no neurologic complications
■
De Sanctis-Cacchione syndrome: rare XP phenotype
with severe neurologic decits (severe developmental
delay, deafness, ataxia, and paralysis)
• Severely affected individuals usually die as a result of
complications from metastatic melanoma or invasive SCC
by 20 years of age
276
4.12 Premature Aging Syndromes and DNA Repair Disorders
Fig. 4.34 Xeroderma pigmentosum. An 8-year-old girl presenting with dry and
parchment-like skin with hyperpigmentation and multiple pigmented basal cell
carcinomas on the face. Both eyes show corneal opacication. (From Chantorn
R, Lim HW, Shwayder TA. Photosensitivity disorders in children: part II. J Am
Acad Dermatol. 2012;67[6]:1113.e1–1113.e15. Photograph courtesy of
Dr. Wisuthsarewong, Bangkok, Thailand.)
Bloom syndrome (congenital
telangiectatic erythema)
• AR disorder due to mutations in BLM/RECQL3 (DNA
helicase) → ↑ rates of sister chromatid exchange and
chromosomal instability
• Presents early in life w/ prenatal and postnatal growth
impairment (short stature; do not exceed 5 feet in height)
• Cutaneous manifestations: photosensitivity,
telangiectatic erythema in a malar distribution, cheilitis,
CALM, and hypopigmentation
• Facies: narrow face w/ prominent ears, malar hypoplasia,
and prominent/bird-like nose
• Other features: primary hypogonadism (men are sterile,
women have decreased fertility), high-pitched voice, ↓ IgA
and IgM → bronchiectasis/chronic lung disease/recurrent
respiratory and GI infections, ↑ risk lymphoma and
leukemia (150- to 300-fold ↑ risk), ↑ risk of some solid
tissue tumors (SCCs and adenocarcinomas ([esp. GI])
• A characteristic pattern of chromosomal breakage and
rearrangement may be seen on chromosomal instability
testing, which can be performed at specialized centers
• Cutaneous and immunologic ndings improve with age,
but ↑ risk of mortality from malignancy (#1 cause of
death, esp. leukemia) in the second to third decade;
patients do not survive beyond 50 yo
Rothmund-Thomson syndrome
(poikiloderma congenitale)
• AR disorder caused by mutations in RECQL4 (DNA
helicase that facilitates DNA replication and repair of UV
damage)
• Cutaneous manifestations (present in rst year of life):
erythema, edema, and blisters that begin on the cheeks
and subsequently progress to involve the extensor surfaces
of the extremities and buttocks; poikiloderma (hypo- and
hyperpigmentation 1 atrophy) is subsequently noted at
these sites; acral verrucous keratoses (may → SCC),
photosensitivity (in 30%), alopecia of scalp/lashes/brows,
and dystrophic nails
• Short stature and skeletal dysplasia (e.g., absence or
hypoplasia of thumbs, radius, and ulna); triangular-
appearing face with frontal bossing/saddle nose/
micrognathia; juvenile cataracts; dental anomalies;
hypogonadism
• Malignancy may lead to premature death
■
Osteosarcoma (mean onset 5 14 years of age) in
30% patients
■
Non-melanoma skin cancer (esp. SCC)—mean age 5
34 years of age
Cockayne syndrome (CS)
• AR disorder due to defective transcription-coupled NER
5 inability to resume RNA synthesis after UVR exposure
(differs from XP, which has defective global genomic
NER)
• Identical phenotype may occur due to mutations occur in
either of two genes:
■
CS-A (20%): mutations in excision repair, crosscomplementing group 8 (ERCC8)
■
CS-B (80%): mutations in ERCC6
• Classic CS (CS I) presents at the end of rst decade
• CS II (severe CS) presents at birth; progresses more rapidly
• Cutaneous manifestations: photosensitivity, with
telangiectatic erythema; unlike XP, has NO ↑ risk of skin
cancer and LACKS pigmentary changes
• Typical facies: pinched, narrow “bird-like” face w/ beaked
nose, large protuberant ears, and sunken eyes; growth
failure and cachexia
• Neurologic manifestations: basal ganglia calcication,
progressive deterioration/demyelination of CNS/PNS
with ataxia and spasticity, intellectual impairment,
microcephaly, and progressive sensorineural hearing loss
• Skeletal manifestations: short stature 1 cachectic/thin body
(“cachectic dwarsm”), joint contractures, and kyphosis
• Ophthalmologic manifestations: salt-and-pepper
retinopathy, optic atrophy, cataracts, and nystagmus
• Hypogonadism may be seen in affected males
• Most patients die by fourth decade from progressive
neurologic disease complications
Trichothiodystrophy (Tay syndrome and
PIBIDS syndrome)
• AR
■
A heterogeneous group of diseases w/ brittle hair and
nails (↓ content of cysteine-rich proteins), ichthyosis,
and neurodevelopmental disability; classied as
photosensitive or non-photosensitive
TTD with photosensitivity (TTD-P): caused by
mutations in three genes (ERCC2, ERCC3, and
GTF2H5) encoding proteins (XPD, XPB, and TTDA),
277
CHAPTER 4 • Pediatric Dermatology
respectively, that function in the transcription repair
protein IIH complex, which is involved in DNA
transcription and excision repair.
TTD, non-photosensitive (TTD-NP): results in about
10%–20% of cases from mutations in the C7Orf11
gene, M-phase-specic PLK1-interacting protein
(MPLKIP), which is thought to regulate
transcription efciency; lacks ichthyosis
• Photosensitivity (unlike XP, has NO increased skin
cancer risk)
• Ichthyosis
• Brittle hair (short/sparse on scalp/brows/lashes w/
alternating light and dark bands on polarizing light
microscopy (“tiger-tail” abnormality)
■
Trichoschisis and trichorrhexis nodosa may be seen
• Intellectual impairment and ataxia
• Decreased fertility/hypogonadism
• Short stature
• Other ndings: hypogammaglobinemia with recurrent
infections
4.13 PRIMARY IMMUNODEFICIENCY DISORDERS WITH CUTANEOUS MANIFESTATIONS
• Categorized by defects in the various components of the
innate and adaptive immune system; overlap or combined
defects often occur
■
Tables 4.21–4.23 summarize primary
immunodeciency disorders (PIDs) that are most
commonly associated with cutaneous ndings
■
Majority have AR inheritance, but some are X-linked
(anhidrotic ectodermal dysplasia with immunodeciency,
chronic granulomatous disease, severe combined
immunodeciency syndrome (SCID) (IL2Rg),
Wiskott-Aldrich syndrome, Bruton’s agammaglobulinemia,
and IPEX syndrome)
• Signs that raise suspicion for PID
■
↑ Frequency/severity/duration of bacterial, viral, and/or
fungal infections
■
Opportunistic infections including atypical
mycobacterial or deep fungal infections
■
Failure to thrive
Table 4.22 Cutaneous Findings Associated With Primary Immunodeciency
Disorders
Erythroderma
Atopic phenotype (eczematous
dermatitis and elevated
eosinophils and IgE)
Noninfectious cutaneous
granulomas
Pigmentary dilution (silvery hair
and hypopigmentation)
a
Maternal graft-versus-host disease should be considered.
IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked;
SCID, severe combined immunodeciency syndrome.
Omenn Syndrome . Other SCID
Hyper IgE syndrome (STAT3 .
DOCK8)
Wiskott-Aldrich syndrome
IgA deficiency
Omenn syndrome
IPEX syndrome
Ataxia telangiectasia
SCID (RAG1)
Common variable
immunodeficiency
Chronic granulomatous disease
Griscelli syndrome
Chédiak-Higashi syndrome
a
• Cutaneous infections may include any or all of the
following:
■
Recurrent staphylococcal or other bacterial pyodermas
■
Extensive viral infections (warts, molluscum, and HSV)
■
Widespread dermatophyte infections
■
Mucocutaneous candidiasis
• Hematopoietic stem cell transplantation may be indicated
in those with severe PIDs including:
■
SCID
■
Chronic granulomatous disease
■
Wiskott-Aldrich syndrome
■
IPEX
■
Hemophagocytic lymphohistiocytosis (CHS and GS)
■
MonoMAC syndrome
• Transplacental transfer of maternal T lymphocytes may
occur in neonates with SCID, and may → clinical and
histologic signs of graft-versus-host disease (e.g.,
morbilliform, LP-like, seborrheic dermatitis-like, and
sclerodermatous change)
• Cutaneous infections predominantly caused by one
family of organisms may ↑ suspicion of specic PIDs
(see Table 4.21)
• Distinct non-infectious cutaneous ndings may lead to
the diagnosis of a specic PID (see Table 4.22)
Table 4.21 Cutaneous Infections Associated With Primary
Immunodeciency Disorders
Mucocutaneous Candidiasis Chronic Mucocutaneous
Recurrent bacterial pyodermas AD hyper-IgE syndrome (STAT3)
Extensive viral infection (HPV,
molluscum)
AD, Autosomal dominant ; AR, autosomal recessive ; EDV, epidermodysplasia verruciformis; WHIM, warts, hypogammaglobinemia, infections,
myelokathexis.
Candidiasis Syndromes
Chronic granulomatous disease
Leukocyte adhesion deficiency
Chédiak-Higashi
Griscelli
AR hyper-IgE syndrome (DOCK8)
WHIM
EDV
Monomac
278
4.14 DISORDERS OF CORNIFICATION
• Inherited ichthyoses generally present at birth or in
infancy/early childhood
■
Heterogeneous group of genetic disorders linked by a
common nding of abnormal epidermal differentiation
or metabolism → hyperkeratosis and/or epidermal
hyperplasia
■
Dysfunction of cornied cell envelope disrupts skin
barrier function → ↑ transepidermal water loss with
possible resultant hypernatremic dehydration
■
Inherited ichthyoses characterized by localized or
generalized hyperkeratosis, scaling, or both, along with
variable additional cutaneous and/or systemic
manifestations; 1/– erythema
4.14 Disorders of Cornication
Table 4.23 Primary Immunodeciencies Most Commonly Associated With Cutaneous Findings
Class Mutation Characteristic Infections
Combined immunodeciencies
Omenn syndrome RAG1
SCID
Leiner syndrome Encompasses a variety
Combined immunodeciencies with associated or syndromic features
Wiskott-Aldrich WAS (XLR) Recurrent encapsulated bacte-
Ataxia telangiectasia ATM Telangiectasias of skin
AD hyper IgE STAT3 Pyodermas, cellulitis, furuncles,
AR hyper IgE DOCK8 Any No dysmorphic
Antibody deciencies
IgA deficiency IGAD1 Sinopulmonary bacterial
RAG2
IL2RG (IL-2Rg chain)—
most common; XLR
inheritance
ADA → ↑ adenosine →
lymphocyte toxicity;
AR inheritance
ZAP70
JAK3; AR inheritance
of conditions, often
low C3 and/or C5
Any Erythroderma
Any
Candida albicans (esp. oral),
Staphylococcus. aureus, and
Streptococcus pyogenes
Cutaneous infections caused by
various organisms, including
those listed above
Sepsis of blood
Viral diarrhea
Otitis media
Pneumonia (PCP and parainu-
enza, in addition to bacteria)
Recurrent skin infections Severe, generalized
rial infections (e.g., otitis me-
dia, pneumonia, and meningi-
tis), HSV (as eczema
herpeticum), HPV, and PCP
Infection can → death in rst
decade
abscesses, and paronychia
S. aureus, Candida, and Strepto-
coccus
30% of abscesses are cold
Bronchitis, otitis media, empy-
emas, sinusitis, pneumatoceles,
lung abscesses, and pneumo-
nia (can → early death)
S. aureus, H. inuenzae , and fun-
gal infections
infections and Giardia
gastroenteritis
Distinct Cutaneous
Features Extracutaneous Features
Alopecia
Erythroderma (less
common)
See above re: GVHD-
like presentation
seborrheic
dermatitis-like
eruption
Eczematous
dermatitis (scalp,
face, and flexures)
w/ 2° infections
and conjunctivae
Noninfectious granu-
lomas
Coarse facial fea-
tures (broad nasal
bridge and big
nose)
Diffuse dermatitis
features
Eczematous
dermatitis
Autoimmune
conditions
Hepatosplenomegaly and
lymphadenopathy
No palpable lymph nodes
No tonsillar buds/lymphoid tissue
Failure to thrive
Failure to thrive, diarrhea
Thrombocytopenia (→ pete-
chiae/purpura/epistaxis),
small platelets, and bloody
diarrhea
↑Food allergies/asthma/
urticaria
↑ IgA, IgD, and IgE; ↓ IgM Both
cell-mediated and humoral
immune response are
compromised
↑ Risk non-Hodgkin’s lympho-
mas (and other hematologic
malignancies)
Truncal . peripheral ataxia
Neurologic deterioration
Sensitivity to ionizing radiation
↑ Risk of hematologic malig-
nancies
Female heterozygotes at
increased risk for breast cancer
Retained 1° teeth w/ issues in
2° teeth
Osteopenia → fractures, scoliosis,
and hyperextensibility
↑ IgE and eosinophilia
Must test for IgA deficiency
(is the most common
immunoglobulin deficiency)
before giving ANY patient IVIG!
Continued
279
CHAPTER 4 • Pediatric Dermatology
Table 4.23 Primary Immunodeciencies Most Commonly Associated With Cutaneous Findings—cont'd
Class Mutation Characteristic Infections
CVID (heterogeneous
disorder currently classified
into types CVID1-CVID11)
Bruton’s
hypogammaglobinemia
Defects in phagocyte number or function
Chronic granulomatous
disease
Leukocyte adhesion
deficiency type 1
Chédiak-Higashi LYST Pyodermas
Griscelli (Fig. 4.35) Rab27A Pyodermas Pigmentary dilution
Innate immunity
Hypohidrotic ectodermal
dysplasia with
immunodeficiency
Chronic mucocutaneous
candidiasis/familial
candidiasis
WHIM CXCR4 HPV (extensive verrucae) Myelokathexis (peripheral
EDV EVER1
MonoMAC GATA2 HPV, atypical mycobacteria, and
Immune dysregulation
Immune dysregulation,
polyendocrinopathy,
enteropathy, and X-linked
(IPEX)
CVID, Common variable immunodeciency; EDV, epidermodysplasia verruciformis; SCID, severe combined immunodeciency; WHIM, warts, hypogammaglo-
binemia, infections, myelokathexis.
ICOS
CD19
CD20
CD21
CD81
LRBA1
TACI
BAFFR
NFKB2
IL21
PRKCD
BTK Helicobacter bilis associated
CYBB (p91- phagocyte
oxidase (phox) beta
subunit
CYBA (p22-phox alpha
subunit)
NCF1 (neutrophil
cytosolic factor
1/p47-phox)
NCF2 (p67-phox)
NCF4 (p40-phox)
AR, ITGB2
↓ b2 integrin (CD18)
NEMO Conical incisors
CARD9
IL-17RA
IL-17F
CLEC7A
STAT1
TRAF3IP2
EVER2
FOXP3 Eczematous
Bacterial infections Noninfectious
pyoderma gangrenosum
Pneumonia (Nocardia, Aspergillo-
sis, and Staphylococcus), peri-
anal abscesses, perioral derma-
titis, and pyodermas due to
catalase-(1) organisms
(Staphylococcus aureus #1)
Pyodermas
Bacterial ulcerations can mimic
pyoderma gangrenosum
Bacterial ulcerations can mimic
pyoderma gangrenosum
Mucocutaneous candidiasis and
deep dermatophytosis
HPV 5, 8, 10, 14, 20, 21, 25 and
47 (extensive verruca plana,
along with thicker verrous warts)
deep fungal infections
Distinct Cutaneous
Features Extracutaneous Features
granulomas
Autoimmune
conditions
Noninfectious
granulomas
Noninfectious granu-
lomas (cutaneous
AND extracutaneous, esp. GI tract)
Gingivitis/stomatitis
Delayed separation
of umbilical cord
Poor wound healing
→ ulcers
Pigmentary dilution
(silvery hair and hypopigmentation of
skin)
Hyperpigmentation
may develop in acral
sun-exposed areas
(silvery hair and hypopigmentation of
skin)
Decrease or absence
of sweat glands
and hair follicles
dermatitis
Hypogammaglobinemia
↑ risk for hematologic malignan-
cies
↑ risk for hematologic
malignancies
Hepatosplenomegaly, diarrhea,
and lymphadenopathy (cervical
#1; suppurative → abscess/stula), granulomas of lung/liver/
GU/GI
Female carriers of x-linked
CGD may have higher risk of
lupus
Can test diagnosis with nitroblue
tetrazolium test
Periodontitis → loss of teeth
Accelerated lymphohistiocytic
phase
Neurologic deterioration
Giant granules or melanosomes in
leukocytes and melanocytes
Accelerated lymphohistiocytic
phase
Neurologic deterioration (primarily
with MYO5A mutation)
Allelic to incontinentia pigmenti
neutropenia with retention of
neutrophils in bone marrow)
Malignant transformation of warts
to SCC
Pulmonary alveolar proteinosis
↑ risk for hematologic malignancies
Severe diarrhea (enteropathy)
Type 1 diabetes mellitus
Hypothyroidism
Autoimmune hemolytic anemia
280
A
B
Fig. 4.35 Silvery hair syndromes. The giant melanosomes are easily seen in the
hair shaft of individuals with Chédiak-Higashi syndrome (A) and Griscelli syndrome (B). Note the more regular spacing of the melanosomes in the hair from
a patient with Chédiak-Higashi syndrome. (From Paller AS, Mancini AJ. Disorders of pigmentation. In: Hurwitz Clinical Pediatric Dermatology: A Textbook of
Skin Disorders of Childhood and Adolescence. 5th ed. Philadelphia: Elsevier;
2016:245–278.)
Fig. 4.36 Collodion baby: collodion membrane in a 1-day-old newborn. (From
Prado R, Ellis LZ, Gamble R, Funk T, Arbuckle A, Bruckner AL. Collodion baby:
an update with a focus on practical management. J Am Acad Dermatol
2012;67[6]:1362–1374.)
■
Collodion membrane at birth seen with AR congenital
ichthyosis (non-bullous congenital erythroderma
most commonly; transglutaminase 1 is the most
common mutation to result in collodion) and
lamellar ichthyosis; also Sjögren-Larsson syndrome,
Gaucher disease type 2, Hay-Well syndrome, TTD,
Netherton syndrome, ectodermal dysplasia, and neutral
lipid storage disease); monitor for hypernatremia,
approximately 5% are “self-healing” and shedding
reveals normal skin; phenotype reveals itself once the
collodion resolves, after several weeks (Fig. 4.36)
■
Routine histology is generally non-diagnostic, but may
demonstrate epidermal hyperplasia and variable
orthohyperkeratosis; ichthyosis vulgaris shows a
diminished or absent granular layer and
epidermolytic ichthyosis shows epidermolytic
hyperkeratosis
■
Treatments for inherited ichthyosis: emollients
and keratolytics; topical and systemic retinoids
can help reduce hyperkeratosis and are useful for some
disorders; neonatal care includes humidied
incubators, emollients and close observation
for infection, dehydration, and electrolyte
abnormalities
• PPKs are a heterogeneous group of inherited and acquired
disorders marked by hyperkeratosis of the palms and soles
■
Three types of PPK: focal (localized areas of
hyperkeratosis, usually over pressure points), diffuse
4.15 Miscellaneous Pediatric Dermatologic Disorders
(hyperkeratosis involves entire palmoplantar surface),
and punctate (1- to 2-mm keratotic papules)
■
PPK can be an isolated nding or a/w other
abnormalities
■
Treatment: topical keratolytics (salicylic acid 2%–5%,
lactic acid 5%–12%, and urea 10%–40%), topical
retinoids, and topical corticosteroids when inammation
is present; use of oral retinoids may be helpful in some
disorders; CO
laser ablation and surgical paring or
2
excision helpful for more severe PPK
• See Tables 4.24 and 4.25
4.15 MISCELLANEOUS PEDIATRIC
DERMATOLOGIC DISORDERS
Hydroa vacciniforme
• Mean age 5 8 years; equal sex ratio
• UVA is most common trigger, but mechanism unclear
■
Probable role of chronic or latent Epstein-Barr virus
(EBV) infection
a/w Atypical hydroa vacciniforme or hydroa
vacciniforme-like lymphoproliferative disorder
EBV also detected in lesional skin and blood of
patients with classical hydroa vacciniforme
• Outbreaks typically occur only in summer; eruption
begins within a few hours of sun exposure
• Most common on face and dorsal hands, but can occur
on any sun-exposed area
• Starts with burning or itching sensation that may be
associated with mild constitutional symptoms
• Primary lesion is a pink macule or papule that progresses
to vesicles and crusted erosions
• Lesions resolve, leaving punched out varioliform scars
• Ocular involvement: photophobia, keratoconjunctivitis, or
uveitis
• Histology: dense perivascular inltrate composed of
lymphohistiocytes and neutrophils
■
The epidermis is edematous with reticular
degeneration and necrotic keratinocytes
■
Dermal vessels may demonstrate thrombosis or
hemorrhage
• Photoprovocation testing with UVA can be performed to
help conrm diagnosis
• Children with severe or atypical cutaneous involvement
or constitutional symptoms of fever, lymphadenopathy,
and hepatosplenomegaly should be evaluated for a
concomitant EBV-associated lymphoproliferative
disorder
• Treatment: sun avoidance/photoprotection, narrowband
UVB (NB-UVB) phototherapy in the spring to “harden”
skin; hydroxychloroquine, beta-carotene, thalidomide,
azathioprine, and cyclosporine may help
• Usually resolves during adolescence or young adulthood
Actinic prurigo
• Most common in Native American children; female
. male; onset , 10 years of age
• Caused by UVR (esp. UVA)
281
282
Table 4.24 Features of Selected Ichthyoses and Erythrokeratodermas
Diagnosis Gene Inheritance Onset Primary Cutaneous Features
Ichthyosis vulgaris FLG Autosomal
Steroid sulfatase
deficiency (X-linked
recessive ichthyosis)
Lamellar ichthyosis
(Fig. 4.37)
Congenital
ichthyosiform
erythroderma (CIE)
Congenital self-
healing collodion
baby
STS XLR
TGM1
a
ABCA12
a
CYP4F22
CERS3
TGM1
b
ALOXE3
b
ALOX12B
NIPAL4
b
(ICHTHYIN)
b
PNPLA1
TGM1ALOXE3, ALOX12B AR Birth Collodion membrane at birth; after
semidominant
Contiguous gene
deletion may
→ Kallmann
syndrome
AR Birth Frequently collodion membrane at
AR Birth Frequently collodion membrane
Harlequin ichthyosis ABCA12 AR Birth Very thick, yellow-brown plates
Infancy/
childhood
Infancy Fine to large, dark/brown,
Fine, adherent scales on
extremities and trunk with
sparing of flexures; larger scale on
lower legs; hyperlinear palms/
soles, and furrowed heels
adherent scales on extremities,
trunk, neck, and lateral face
spares flexures, palms, soles,
and face
birth with ectropion and eclabium;
after collodion resolves, presence
of large, thick, plate-like brown
scales in generalized distribution
w/significant flexural
involvement; absent or mild
erythroderma; variable palm/sole
involvement (PPK)
(#1 cause) at birth; after collodion
resolves, fine, white scale in
generalized distribution (flexures
involved); erythroderma; variable
palm/sole involvement
resolution, skin appears normal
without features of ichthyosis
of scale with large, deep and
bright red fissures that tightly
encase the neonate; extreme
ectropion, eclabium, and ear
deformities; survivors develop
severe CIE-like phenotype; early
initiation of systemic retinoids
and specialized neonatal intensive
care reduce mortality
Associated Clinical
Features
Keratosis pilaris;
atopic diathesis
Corneal (comma-
shaped) opacities;
cryptorchidism;
↑ Risk of testicular
cancer, and
hypogonadism
Female carriers:
corneal opacities;
prolonged labor
with affected child
(placental sulfatase
deficiency)
Heat intolerance
(hypernatremic
dehydration);
frequent scarring
; dystrophic
alopecia
nails
Hypohidrosis
Heat intolerance/
hypohidrosis;
variable scarring
alopecia and
ectropion
Histology and
Ultrastructural Features
Diminished/absent
stratum granulosum
w/ overlying
orthohyperkeratosis;
absent/reduced filaggrin
immunostaining
Retained
corneodesmosomes
within stratum corneum
TGM1: thin cornified
envelope and
disorganized lamellar
bilayers
ABCA12: absence of
lamellar body content
NIPAL4: defective lamellar
bodies and perinuclear
membranes within
stratum granulosum
Same as for lamellar
ichthyosis
Ancillary Diagnostic
Studies
Genetic testing
Lipoprotein
electrophoresis
(increased mobility of
b-fraction); plasma
cholesterol sulfate
increased; decreased
steroid sulfatase activity
in leukocytes; FISH,
array CGH, genetic
testing
Maternal carriers may
have abnormal triple/
quad screen during
affected pregnancy with
decreased serum estriol
In situ transglutaminase-1
expression and activity
assay; genetic testing
Genetic testing
None Nondiagnostic Genetic testing
Premature delivery;
risk of neonatal
hypothermia, and
hypernatremic
dehydration; often
neonatal death
from sepsis
or respiratory
insufficiency
Vesicular lamellar body
ghosts, paucity of
secreted lamellar
structures in stratum
corneum
Genetic testing
CHAPTER 4 • Pediatric Dermatology
Epidermolytic
ichthyosis (bullous
CIE)
Superficial
epidermolytic
ichthyosis
(ichthyosis bullosa
of Siemens)
Ichthyosis prematurity
syndrome
Ichthyosis hystrix
Curth-Macklin
Ichthyosis en confetti KRT10 AD At birth, erythroderma and scaling;
KRT1 (has PPK)
KRT10 (no significant
PPK)
KRT2 AD Birth Erythroderma and superficial
SCL27A4 AR Birth Thick caseous desquamating scale
KRT1 AD Birth Mild to severe, mutilating
AD
May have somatic
mosaicism
→ extensive
epidermal nevi
(ichthyosis
hystrix); if it
is gonadal
mosaicism,
then may have
offspring with full
blown disease
Birth At birth: erythroderma, blistering,
and erosions
Later: hyperkeratosis with
cobblestone pattern (most
prominent over joints), ridging
of the flexures; generalized or
localized; variable degree of
erythroderma, palmoplantar
involvement, and blistering/bullae;
retinoids can exacerbate skin
fragility
blistering at birth; later,
hyperkeratosis with accentuation
over joints, flexures, and dorsal
hands/feet; “molting” of the skin;
palms and soles spared
at birth
Progresses to perifollicular
hyperkeratosis
palmoplantar keratoderma;
hyperkeratosis with verrucous,
cobblestone, or hystrix-like
pattern on extremities and trunk
later, confetti-like areas of scaling
(result from revertant mosaicism);
palmoplantar keratoderma
Frequent skin
infections; malodor;
gait and posture
abnormalities
Patients are often
born premature
Often associated
eosinophilia
And respiratory
distress
Pseudoainhum; digital
contractures
Joint contractures Affected skin: loss of
Hyperkeratosis,
keratinocyte
vacuolization, and a
prominent granular
layer with clumped
keratin in suprabasal
cells; lamellar body
accumulation
Cytolysis of granular cells Genetic testing
Binuclear cells; particular
concentric perinuclear
“shells” of aberrant
putatively keratin material
epidermal differentiation
above the basal
layer with nucleolar
vacuolization, loss of
granular layer, and
acanthosis, Revertant
skin: normal
Genetic testing
Genetic testing
4.15 Miscellaneous Pediatric Dermatologic Disorders
Continued
283
284
Table 4.24 Features of Selected Ichthyoses and Erythrokeratodermas—cont'd
Diagnosis Gene Inheritance Onset Primary Cutaneous Features
Netherton syndrome
(Fig. 4.38)
Sjögren-Larsson
syndrome
Neutral lipid storage
disease with
ichthyosis/ChanarinDorfman syndrome
Refsum disease PHYH
SPINK5 (encodes LEKT1,
serine protease inhibitor)
ALDH3A2/FALDH AR Birth At birth, erythema and
ABHD5
(CGI-58)
PEX7
AR Birth/infancy Congenital erythroderma and
AR Birth Generalized, fine, white scales with
AR childhood to
adulthood
scaling; two principal phenotypes:
ichthyosis linearis circumflexa
(annular or serpiginous plaques
w/ double-edged scale) and
CIE-like; pruritus and eczematous
plaques are common
Caution with tacrolimus
ointment (↑ absorption → toxic)
or keratolytics (irritating)
hyperkeratosis; later, fine to platelike/dark scaling or nonscaling
hyperkeratosis; favors abdomen,
neck, flexures; lichenification;
palmoplantar keratoderma;
pruritus can be severe
variable erythema
Fine, white scales on extremities
and trunk, resembling ichthyosis
vulgaris (50%)
Associated Clinical
Features
Trichorrhexis
invaginata,
trichorrhexis
nodosa, and pili
torti (short/sparse
hair and brows;
↑ IgE; neonatal
temperature
instability, electrolyte
imbalance
(hypernatremia),
and failure to
thrive; recurrent
infections; food and
other allergies/
anaphylaxis;
nonspecific
aminoaciduria
Progressive spastic
di- and tetraplegia;
developmental delay;
intellectual disability;
seizures; perifoveal
glistening white
dots; white matter
disease of the brain;
photophobia
Developmental
delay;
hepatomegaly
with liver fibrosis,
elevated liver
enzymes, and
creatine kinase;
myopathy; hearing
impairment;
cataracts
Peripheral motor
and sensory
neuropathy; cranial
nerve dysfunction
(deafness, anosmia);
cerebellar ataxia;
atypical retinitis
pigmentosa
(“salt-and-
pepper pigment”);
cardiomyopathy,
arrhythmias w/
heart block; muscle
wasting
Histology and
Ultrastructural Features
Psoriasiform
histopathology; light
microscopy of hair shafts
may reveal trichorrhexis
invaginata (“bamboo
hair”)
Nonspecific;
hyperkeratosis,
acanthosis, and
preservation of granular
layer
Globular electron-lucent
inclusions in epidermis
Orthokeratotic
hyperkeratosis and lipidcontaining vacuoles in
basal keratinocytes
Ancillary Diagnostic
Studies
Genetic testing
Fatty aldehyde
hydrogenase activity
assay in cultured
fibroblasts; genetic
testing (preferred
method)
Peripheral blood smear to
detect lipid vacuoles in
granulocytes, eosinophils,
and monocytes; oil stains
of frozen tissue; genetic
testing
Increased plasma
phytanic acid;
phytanoyl-CoA
hydroxylase activity
assay in cultured
fibroblasts; genetic
testing
Diet is essential: ↓ green
vegetables, dairy products,
and ruminant fats
CHAPTER 4 • Pediatric Dermatology