U028 Nursery Tales: Challenging Dermatoses in …...U028 – Nursery Tales: Challenging Dermatoses...
Transcript of U028 Nursery Tales: Challenging Dermatoses in …...U028 – Nursery Tales: Challenging Dermatoses...
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U028 –
Nursery Tales: Challenging Dermatoses in Newborns
Raegan D. Hunt, MD, PhD
Assistant Professor of Dermatology & Pediatrics
Chief of Service, Pediatric Dermatology
Texas Children’s Hospital
Baylor College of Medicine
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Raegan Hunt, MD, PhD
Focus Session U020:
Case-based Challenges in Pediatric Dermatology Hospital Consults
DISCLOSURES
Up To Date, Inc. - royalties (authorship)
Medscape LLC – royalties (authorship)
DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY
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Objectives
▪ Develop a differential diagnosis for challenging dermatoses in
premature and term infants
▪ Utilize laboratory testing to diagnose skin disease in neonates
▪ Formulate management plans for newborn skin eruptions
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Case
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2 day-old FT girl with grouped vesicles on arms
– Afebrile
– Feeding, voiding, stooling well
– No seizure activity or abnormal movements
– Maternal labs: RPR NR, rubella- Immune, hepB neg, HIV neg;
GBS negative; no maternal history of herpes
– Vesicles are tense with an erythematous base and arranged in
whorled linear arrays
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Zhao, Cathy Y and Dedee F Murrell. Current Opinion in Pediatrics. 28(4), August 2016, p 500–506
Blisters in Neonates
Infectious
Autoimmune
Inflammatory
Genetic
Other
-- More common
-- Need early
diagnosis and treatment
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Pregnancy:
• Good prenatal care
• Normal infectious disease screenings
• No complications or infections
Family medical history:
• no known genetic diseases
• Mother herself was adopted internationally
➢ no information regarding mom’s birth
• Mother’s PMHx: retinal detachment
Well, afebrile neonate
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What cutaneous finding on mother may
help direct diagnostic thinking?
• Hypopigmented curvilinear streaks
• Gingival erosions
• Hyperpigmented whorling streaks
• Hypohidrosis
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What cutaneous finding on mother may
help direct diagnostic thinking?
• Hypopigmented curvilinear streaks
• Gingival erosions
• Hyperpigmented whorling streaks
• Hypohidrosis
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Patient’s mother:
• Hypopigmentation: “Chinese Characters”
• Focal alopecia of scalp
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Differential Diagnosis
Infantile herpes zoster Infantile herpes simplex virus
Infectious?
Bullous impetigo
Autommune Bullous?
Neonatal bullous pemphigoidWatanabe, et al. Clin Exp Dermatol. 2017 Jul;42(5):576-578
Hsieh and Chang. Arch Neurol. 2011;68(8):1080
Genetic?
Epidermolysis bullosa
Other?
Sucking blister
Incontinentia pigmenti
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Biopsy: Spongiosis with vesiculation and
numerous eosinophils
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Incontinentia pigmenti (IP)
• X-linked dominant disorder; IKBKG gene (NEMO)
– Random X chromosome inactivation -> extent of disease
• Four cutaneous phases (may overlap)
Inflammatory
vesicles/bullaeVerrucous
lesions
Hyperpigmented
streaks
Hypopigmented +/-
atrophic streaks
Mane, S. Indian Pediatrics 2006; 43:1103-1104
Bruckner, A. Seminars in Cutaneous Medicine and Surgery, 2004; 23 (2) 116–124
Pacheco, T, et al. JAAD, 2006; 55(2) 251-255
IP follows Lines of Blaschko
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NEMO (IKKg)
NFkB
Transcription factor
activates pathways that
protect the cell against
apoptosis
Required for NFkB activation
Cell Death
(Apoptosis)
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Incontinentia pigmenti
Dermatologic ‘clues’• Alopecia
• Dystrophic nails
Systemic manifestationsCNS
• Seizures
• Developmental delay
• Microcephaly
• Ataxia
Dental
• Malformed ‘Peg’ teeth
Ophthalmological
• Optic nerve atrophy
• cataracts
• Strabismus
• Retinal detachment
Bruckner, A. Sem. in Cutaneous Medicine and Surgery, 2004; 23 (2) 116–124
Chan, Y, et al. JAAD, 2003; 49 (5), 929–931
Pride, H. www.dermatlas.com
Tule, S. et al. Consultant for Pediatricians, 2012; 11(10)
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Full-term baby boy with linear arrays of crusted erosions and vesicles
Biopsy: spongiotic intra-epidermal vesicles with numerous eosinophils
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Incontinentia Pigmenti (IP): X-linked dominant
• IP: X-linked dominant disorder; IKBKG gene (NEMO)
– 97% - female
– males born with IP: somatic mosaicism vs. XXY
X-linked dominant disorders
▪ Incontinentia Pigmenti
▪ Focal dermal hypoplasia (Goltz syndrome)
▪ CHILD (Congenital Hemidysplasia with ichthyosiform
erythroderma)
▪ Conradi-Hünerman
▪ Oro-Facial-Digital Syndrome
▪ Albright's hereditary osteodystrophy
▪ Bazex syndrome
Pacheco TR, et al. J Am Acad Dermatol. 2006 Aug;55(2):251-5
Kenwrick, et al. Am J Hum Genet. 2001 Dec;69(6):1210-7
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Management: Incontinentia Pigmenti
• Wound care
• Counseling on expected
skin changes
– Vesicular
– Verrucous
– Hyperpigmented
– Hypopigmented
• Referrals to:
– Genetics
– Neurology
– Ophthalmology
– Dental
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Jenna Lyons
Diagnosed with IP
President of J Crew
▪ Blaschkoid patterning is stylish (in all 4 stages!)▪ Vesicular, Verrucous, Hyperpigmented, Hypopigmented
▪ High-power corporate world isn’t “just for boys”, and IP
isn’t “just for girls”
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Case
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34 5/7 WGA premature infant born by repeat C-section after PPROM
– Widespread erosions at birth• Involves face, trunk, extremities
– Normal pregnancy and prenatal ultrasound
– Normal prenatal care
– FMHX: • no skin disorders
• no genetic diseases
– Afebrile, vital signs stable
– Breathing comfortably
– Feeding, voiding, stooling normally
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Congenital VZV
Differential Diagnosis
Staph scalded skin sndrome
Dermnet.nz
Int J Dermatol. 2015 Apr;54(4):438-42.
An. Bras. Dermatol. vol.85 2010
Indian J of Dermatology, Venereology, & Leprology, 76, 2010
Indian Pediatr 2016;53: 269
Indian Pediatr. 2014 Apr;51(4):316-7
Congenital HSV
Epidermolysis bullosa
Epidermolytic ichthyosis
Transient dermolysis
of the newborn
Genetic Infectious
AIBD
Pemphigus vulgaris
Erosive Candida
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Next diagnostic step?
• Biopsy of existing erosion
• Induced blister biopsy for immunomapping and H&E
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Next diagnostic step?
• Biopsy of existing erosion
• Induced blister biopsy for immunomapping and H&E
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Biopsy with Epidermolysis Bullosa high on
Differential Diagnosis: Induced Blister
▪ Select site and mark 6 mm circle
▪ Anesthetize area
▪ Twist clean pencil eraser firmly back
and forth in the marked area x 15
seconds
▪ Blister will likely not be visible
▪ May help to return after few hours
▪ Clean skin
▪ Biopsy across edge: 1/3 of induced
blister, 2/3 normal skin Images: Plastic Surgery Key.com
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Biopsy
• Hyperkeratosis
• Hypergranulosis
• Epidermolysis of superficial epidermis
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Epidermolytic Ichthyosis
• Mutations in
– KRT1: encodes keratin 1
– KRT10: encodes keratin 10
• ~ 50% new mutations
– otherwise usually autosomal dominant
• Presentation at birth may have:
– Erosions
– Severe blistering
– Erythroderma
• Later in life:
– hyperkeratotic skin especially
over joints
Spitz, J.L. Genodermatoses, LW&W, 2005
Naik, N. Dermatology Online Journal. 2003; 9: 4
Guitierrez, et al. Molecular Genetics & Genomic Medicine
2013; 1(2): 108–112
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Management: Epidermolytic Ichthyosis in newborn
• Infant:
– Conservative, gentle wound care
• Copious petrolatum
• Petrolatum coated gauze
– Minimize friction with caregiving
– Precautions to avoid infection
– Soft bedding covered with petrolatum soaked gauze
• Counseling on expected skin changes
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Case
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• 1 day-old Hispanic girl
– born by C-section in rural setting
– 38 WGA
– APGARS 9/9
• Normal pregnancy, normal infectious
labs in pregnancy, G6P5 mother
• Stable, Afebrile
• Feeding, voiding, stooling well
• Large erosions at birth
• Deep, membranous shiny plaques
• Two dark thick fingernails
• Oral and anal mucosa clear
• No natal teeth
• No periorificial granulation tissue
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Congenital VZV
Differential Diagnosis
Erosive Candida
Dermnet.nz
Int J Dermatol. 2015 Apr;54(4):438-42.
An. Bras. Dermatol. vol.85 2010
Indian J of Dermatology, Venereology, & Leprology, 76, 2010
Indian Pediatr 2016;53: 269
Congenital HSV
Epidermolysis bullosa with congenital localized absence of skin
(EB + CLAS, formerly included Bart syndrome)
Epidermolytic
ichthyosis
Transient dermolysis of the newborn
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Next diagnostic step?
• Biopsy of existing erosion
• Serum zinc level
• Serum alkaline phosphatase level
• Chromosomal microarray (CMA)
• Either induced blister biopsy or direct genetic testing
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Next diagnostic step?
• Biopsy of existing erosion
• Serum zinc level
• Serum alkaline phosphatase level
• Chromosomal microarray (CMA)
• Either induced blister biopsy or direct genetic testing
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Diagnostic Studies
• HSV and VZV cultures and PCRs negative
• Offered induced blister biopsy for H&E and EB immunomapping
– family declined
• Offered genetic testing
– GeneDx EB panel- results: 6 weeks--- Not covered by patient’s insurance plan
• Tests the following known EB causing genes:
– CD151, CDSN, CHST8, COL17A1, COL7A1, CSTA, DSG1, DSG2, DSG3, DSG4, DSP, DST, EXPH5, FERMT1,
GRIP1, ITGA3, ITGA6, ITGB4, KLHL24, KRT1, KRT10, KRT14, KRT5, LAMA3, LAMB3, LAMC2, MMP1, NID1,
PKP1, PLEC, TGM5
– Trio Whole Exome Sequencing- results: 3 weeks
• analyzes the exons/coding regions of thousands of genes using next-generation sequencing
techniques
• exome of a patient and their parents and compares to normal reference sequence
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Diagnosis: Epidermolysis Bullosa Simplex
• Trio whole exome genetic testing results
– KLHL24 mutation
• Heterozygous c.1441T>A (p.S481T) variant
• Both parents negative for above variant
• KLHL24: Kelch-like protein 24
– Kelch-like protein 24- cullin 3–RBX1 ubiquitin ligase substrate
receptor that interacts with keratin 14
• Mutations that overstabilize KLH24 cause excessive ubiquitination and
degradation of KRT14 in basal keratinocytes
– AD mutation: epidemolysis bullosa simplex
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Lin Z, et al. Nat Genet. 2016 Dec;48(12):1508-1516
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KLHL24: Kelch-like protein 24 “Epidermolysis bullosa simplex”
Features
– Widespread erosions at birth
• Healing with whorled hypopigmented,
atrophic appearance
– Aplasia cutis congenita on
extremities at birth
– Alopecia
– Toenail fragility- improves over time
– Skin fragility- improves over time
He Y, et al. Am J Hum Genet. 2016 Dec 1;99(6):1395-1404
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• Management
• Conservative EB wound/skin
care
• Whole exome sequencing
• For this case, more prognostic
information than biopsy
• 3 week turn-around time
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Full term neonate with progressive violaceous erythema and flaccid bullae on
trunk
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▪ Full term neonate
▪ C-section for non-reassuring fetal heart tones
▪ Respiratory distress
▪ Anemia
▪ Reticulocytosis (retic 20%)
▪ Hyperbilirubinemia (direct and indirect)
▪ Transaminitis
▪ Ultrasound: Decreased hepatic perfusion
▪ Infant Blood Type A +
▪ Circulating anti-Rh antibody
❖ Diagnosis: Hemolytic disease of the newborn
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Transfusions: PRBCs, platelets
Triple phototherapy [ started 7 hours-of-life ]
IVIG
Patchy erythema on abdomen [ noted 10-hours-of-life ]
− Antibiotic coverage broadened
− Serial abdominal radiographs & blood cultures negative
Oligouria
− Furosemide x 1
− Dopamine drip
Progression of erythema on trunk
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▪ Phototherapy was discontinued
▪ Patient had received a single dose of furosemide
▪ No other photosenstitizing medications given
▪ No family history of photosensitivity disorders
▪ Skin biopsy: H&E and cultures
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Skin biopsy
• full-thickness epidermal necrosis
• intravascular fibrin thrombi
• PAS-positive deposits in/around superficial dermal blood
vessels
• no vasculitis or RBC extravasation
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McMahon P, Yan A. Arch Pediatr AdolescMed. 2008 Jul;162(7):689-90.
Erythropoietic protoporphyria (EPP) Congenital erythropoietic porphyria (CEP)
Soylu A, Kavukçu S, Türkmen M. Eur J Pediatr. 1999 Jun;158(6):526-7.
Bhavasar R, Santoshkumar G, Prakash BR. J Oral MaxillofacPathol. 2011 Jan;15(1):69-73
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Porphyrin Testing
Plasma fluorescence peak 619nm (normal range= no peak)
[↑ uro- and coproporphyrins]
TOTAL PORPHYRINS
Plasma 19.8 mcg/dl (normal < 0.9)
Erythrocyte (RBC) 486 mcg/dl (normal < 80)
5% uroporphyrin
55% coproporhyrin
40% protoporphyrin
RBC Protoporphyrin Fractions 39% zinc-protoporphyrin
61% free-protoporphyrin
Urine 24 nmoles/24 hrs (normal 0-300)
Image : Singh S, et al.
Indian J Dermatol
Venereol Leprol
2012;78:108-11
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ENZYME ACTIVITY
Porphobilinogen deaminase
89 nmol/ml RBC/hr (normal 20-50)
Elevated: suggests increased circulating young RBCs
Uroporphyrinogen decarboxylase
39.7 nmol/ml RBC/hr (normal 30-60)
Normal: Inconsistent with hepatoerythropoietic porphyria
Porphyrin Testing
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Heme biosynthetic pathway
MIT
OC
HO
ND
RIO
N
Glycine
Succinyl CoA
Porphobilinogen
(PBG)
d-aminolevulinic acid
(ALA)
Protoporphyrinogen IX+
ALA-SYNTHASE
FERROCHELATASE
UROPORPHYRINOGEN
COSYNTHASE
PBG-DEAMINASEALA-
DEHYDRATASE
Coproporphyrinogen IIIUroporphyrinogen IIIHydroxy-
methylbilane
PROTOPORPHYRINOGEN
OXIDASE
UROPORPHYRINOGEN
DECARBOXYLASE
COPROPORPHYRINOGEN
OXIDASE
Protoporphyrin IX
HEME
CY
TO
SO
L
Uroporphyrinogen I Coproporphyrinogen I
↑
↑
↑
↑
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4 months
Follow Up
• Healed with post-inflammatory
hypopigmentation at 4 months
of age
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Day of life 2 4 Months
Plasma fluorescence peak 619 nm No peak
Plasma porphyrins (normal 0-0.9) 19.8 mcg/dl 0.2 mcg/dl
RBC porphyrins (normal 20-80) 486 mcg/dl 335 mcg/dl
RBC uroporphyrin (0-5%) 5% 0%
RBC coproporphyrin (0-2%) 55% 0%
RBC protoporphyrin (90-100%) 40% 100%
% Free-protoporphyrin 61 % 30 %
% Zinc-protoporphyrin 39 % 70 %
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Transient porphyrinemia due to
hemolytic disease of the newborn
❖ Induration and cutaneous necrosis mimicking a severe infection
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Transient porphyrinemia
▪ Phototherapy-induced purpuric eruptions reported in 9 neonates with increased hematopoesis▪ Hemolytic disease of the newborn (n = 8)
▪ Twin-twin transfusion (n = 1)
▪ Clinical findings▪ Macular purpura
▪ Hemorrhagic bullae
▪ Histopathology (n = 3)▪ Extravasated RBCs
▪ No vascular changes
▪ No necrosis
Paller, AS, et al. Pediatrics. 1997 Sep;100(3):360-4
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Karl Anderson, MD
The Porphyria Laboratory
The University of Texas Medical Branch
Galveston, Texas
Julie V. Schaffer, MD
Hackensack University Medical Center
Hackensack, New Jersey
Acknowledgements
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Case
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• 2-hour old infant
• Born with flaccid vesicles and erosions
– Annular appearing erosions noted on face
• Normal prenatal care without complication
• Afebrile
• Feeding, voiding, stooling well
• FMH: mother- Hashimoto’s thyroiditis
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Diagnostic tests recommended?
• Skin biopsy
• HSV/VZV PCR and bacterial culture
• EKG
• ANA
• All of the above
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Diagnostic tests recommended?
• Skin biopsy
• HSV/VZV PCR and bacterial culture
• EKG
• ANA
• All of the above
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• HSV/VZV PCR neg
• Bacterial culture neg
• Fungal/yeast culture neg
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Biopsy
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Histopathology: neonatal lupus
• FANA > 1:1280
• Anti-Ro neg
• Anti-La neg
• Anti-RNP neg
• EKG wnl
• Platelets wnl
• LFTs wnl
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Neonatal lupus erythematosus
• Cutaneous findings– Mean age of onset: ~4-6 weeks
• Photosensitive
• Annular scaly plaques
• Predilection for scalp and periorbital areas
– Present at birth in ~20%
– Improves by age 6-9 months
• Maternal antibodies
– Anti-Ro in ~95% of mothers
– +/- anti-La
– +/- anti-RNP
– Majority of mothers asymptomaticWisuthsarewong W et al Pediatr Derm 2011
Boros et al Arth Rheum 2007
Chitayat et al Am J Med Genet 2008
Courtesy of J.V. Schaffer, MD
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Admani S and A. Krakowski, J Clin Aesthet Dermatol.
May 2013; 6(5): 19–23
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Neonatal LE: associated disease
• Classic findings– Cutaneous neonatal LE:
• ~25-30% of patients
– Cardiac neonatal LE: heart block, prolonged QT, cardiomyopathy
• ~ 50-60% of patients
• combination of cutaneous and cardiac manifestations seen only in 4-10%
– Hepatic: cholestasis, transaminitis
– Hematologic: thrombocytopenia > anemia, neutropenia
- rare reports of DIC
Eronen et al, Pediatrics, 2000
Lee et al, Arch Derm Res 2008
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Neonatal LE: associated disease
Other manifestations
CNS: Subclinical central nervous system (CNS)
Hydrocephalus (~10%)
Macrocephaly (~15% at 8-24 months)
Rhizomelic chondrodysplasia punctataphenotype:
Short long bones with epiphyseal stippling
Brachydactyly
Hypoplastic nasal boneBoros et al, Arth Rheum 2007.
Shanske AL et al, Pediatrics 2007.
Prendiville J et al, Pediatric Derm 2004.
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Derm Atlas
Summary: Neonatal Lupus
Erythematosus
▪ Scaly annular plaques
▪ Predilection to periorbital area and scalp
▪ Photosensitive
▪ Frequently Anti-Ro positive
▪ Improves by 6-9 months of age
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THANK YOU