Harper's Textbook of Pediatric Dermatology

The third edition of this highly regarded text continues to provide a comprehensive resource for pediatric dermatologists. The book offers evidence-based diagnosis and treatment recommendations and covers both common and rare conditions, including emerging conditions and research, especially at the genetic level. A refreshing new text design makes the book more accessible, and new editors and contributors bring a distinctly international perspective to the work.

• Language: English
• Publisher: Wiley
• Release date: Jul 28, 2011
• ISBN: 9781444345377

Book preview

Acknowledgements

The editors wish to acknowledge the work of the three founding editors, John Harper, Arnold Oranje and Neil Prose, who expertly developed the first two editions of this book and established it as an important reference work in paediatric dermatology. We would like to thank the patients and their families who gave permission for their photographs to be reprinted; these images greatly enhance the book. Our patients provide the motivation for this work. It is our great hope that the knowledge presented here will improve patient care in paediatric dermatology around the world. We also wish to thank the many people involved in the production team at Wiley-Blackwell.

ADI

PH

AY

I was very fortunate to have wonderful mentors early in my career in paediatric dermatology. Through their excellence, these physicians inspired me to develop clinical and research interests in childhood skin disease: Ann Bingham, John Harper, David Atherton, Amy Paller, Tony Mancini and Annette Wagner.

ADI

John Harper is not only one of the founders of this textbook, but one of the godfathers of paediatric dermatology as a speciality. I am very grateful for his encouragement, inspiration and support.

PH

I am grateful to exceptional mentors and wonderful teachers from whom I have learned much throughout my training and career. Their examples continue to inspire me to work harder to be a better physician. Among them, my thanks go especially to my parents who were my first teachers, as well as Paul Honig, Lawrence Eichenfield, William James, Julie Francis and the late Walter Tunnessen.

AY

List of Abbreviations

AA

alopecia areata

AAD

American Academy of Dermatology

ABC

ATP-binding cassette

ACA

anticentromere antibodies

ACC

aplasia cutis congenita

ACE

angiotensin-converting enzyme

ACR

American College of Rheumatology

ACTH

adrenocorticotropic hormone

AD

atopic dermatitis

AD

autosomal dominant

ADA

adenosine deaminase

ADHD

attention deficit hyperactivity disorder

ADR

adverse drug reaction

AEDS

atopic eczema/dermatitis syndrome

AGA

androgenetic alopecia

AGEP

acute generalized exanthematous pustulosis

aGVHD

acute GVHD

AGM

acrylate gelling material

AHA

antihistone antibody

AHO

Albright’s hereditary osteodystrophy

AIDS

acquired immune deficiency syndrome

ALL

acute lymphoblastic leukaemia

ALT

alanine transaminase

AML

acute myeloid leukaemia

AMMoL

acute myelomonocytic leukaemia

AMoL

acute monocytic leukaemia

ANA

antinuclear antibody

AP

adaptor protein complex

APC

antigen-presenting cell

APECED

autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (syndrome)

APSS

acral peeling skin syndrome

AR

autosomal recessive

ARCI

autosomal recessive congenital ichthyosis

ARD

adult Refsum disease

AR-HIES

autosomal recessive hyperimmunoglobulin E syndrome

AST

aspartate transaminase

AT

ataxia telangiectasia

ATG

anti-thymocyte globulin

ATGL

adipose triglyceride lipase

ATPase

adenosine triphosphatase

AUC

area under the concentration-time curve

AZA

azathioprine

BAL

bronchoalveolar lavage

BCC

basal cell carcinoma

BCG

bacille Calmette–Guérin

BCIE

bullous congenital ichthyosiform erythroderma

BDNG

British Dermatological Nursing Group

BMP

bone morphogenetic protein

BMT

bone marrow transplants

BO

branchio-otic

BOR

branchio-oto-renal

BP

blood pressure

CAM

cell adhesion molecule

C-ALCL

cutaneous anaplastic large cell lymphoma

CBCL

cutaneous B-cell lymphoma

CCC

congenital cutaneous candidiasis

CDP

chondrodysplasia punctata

CDPX2

X-linked dominant chondrodysplasia punctata

CE

cell envelope

CEA

carcinoembryonic antigen

CEDNIK

cerebral dysgenesis, neuropathy, ichthyosis, keratoderma (syndrome)

CFC

cardiofaciocutaneous syndrome

CGD

chronic granulomatous disease

CGRP

calcitonin gene-related product

CGS

contiguous gene syndrome

CHAND

curly hair, ankyloblepheron, nail dysplasia (syndrome)

CHH

Conradi–Hünermann–Happle syndrome

CHH

cartilage–hair hypoplasia

CHILD

congenital hemidysplasia with ichthyosiform erythroderma and limb defects (syndrome)

CHIME

colobomas, congenital heart disease, early-onset ichthyosiform dermatosis, mental retardation and ear abnormalities

CHS

Chédiak–Higashi syndrome

CIE

congenital ichthyosiform erythroderma

CLM

cutaneous larva migrans

CLOVE

congenital lipomatous overgrowth, vascular malformations and epidermal naevi (syndrome)

CMC

chronic mucocutaneous candidiasis

CML

chronic myeloid leukaemia

CMN

congenital mesoblastic nephroma

CMTC

cutis marmorata telangiectatica congenita

CMV

cytomegalovirus

CNS

central nervous system

CNTP

connective tissue naevus of the proteoglycan type

CNV

chromosome copy number variations

CRP

C-reactive protein

CSF

cerebrospinal fluid

CSMH

congenital smooth muscle hamartoma

CT

computed tomography

CTCL

cutaneous T-cell lymphoma

CTGF

connective tissue growth factor

CTL

cytotoxic T-lymphocyte

CTLA-4

cytotoxic T-lymphocyte antigen-4

CVG

cutis verticis gyrata

CVI

common variable immunodeficiency

Cx

connexin

DBPCDC

double-blind placebo-controlled drug challenge

DEJ

dermoepidermal junction

DFSP

dermatofibrosarcoma protuberans

DHEA

dihydroepiandrosterone

DIHS/AHS

drug-induced or anticonvulsant hypersensitivity syndrome

DMARD

disease modifying antirheumatic drugs

DMSO

dimethyl sulphoxide

DOC

disorders of cornification

DOPA

dihydroxyphenylalanine

DRESS

drug rash with eosinophilia and systemic symptoms

DSAP

disseminated superficial actinic porokeratosis

DSP

disseminated superficial porokeratosis

DTE

desmoplastic trichoepithelioma

EAACI

European Academy of Allergy and Clinical Immunology

EBP

emopamil binding protein

EBV

Epstein–Barr virus

EBS-DM

epidermolysis bullosa simplex Dowling–Meara

ECF

eosinophil chemotactic factor

ECP

extracorporeal photopheresis

EDP

erythema dyschromicum perstans

EEG

electroencephalogram

EGA

estimated gestational age

EGF

epidermal growth factor

EHK

epidermolytic hyperkeratosis

EKA

erythrokeratoderma with ataxia

EKC

erythrokeratoderma en cocardes

EKV

erythrokeratoderma variabilis

ELISA

enzyme-linked immunosorbent assay

EMLA

eutectic mixture of local anaesthetics

EN

epidermal naevus

EN-D

epidermal naevus – Darier type

ENDA

European Network for Drug Allergy

EOS

early-onset sarcoidosis

EP

eccrine poroma

ERA

enthesitis-related arthritus

ESPD

European Society of Pediatric Derrmatology

ESR

erythrocyte sedimentation rate

ETN

erythema toxicum neonatorum

EULAR

European League Against Rheumatism

EV-HPV

epidermodysplasia verruciformis-associated human papillomavirus

FADH

fatty alcohol dehydrogenase

FALDH

fatty aldehyde dehydrogenase

FATP

fatty acid transport protein

FDA

Food and Drug Administration (USA)

FDE

fixed drug eruptions

FFD

Fox-Fordyce disease

FFM

focus-floating microscopy

FGFR

fibroblast growth factor receptor

FISH

fluorescence in situ hybridization

FITC

fluorescein isothiocynate

FMF

familial Mediterranean fever

FOP

fibrodysplasia ossificans progressive

FTC

familial tumoral calcinosis

FTG

full-thickness skin graft

5-FU

5-fluoracil

GABA

γ-aminobutyric acid

GBFDE

generalized bullous fixed drug eruption

GCDFP

gross cystic disease fluid protein

GFR

glomerular filtration rate

GI

gastrointestinal

GM-CSF

granulocyte-macrophage colony-stimulating factor

GMS

Gomori’s methenamine silver

GNCST

granular nerve cell sheath tumour

GOSH

Great Ormond Street Hospital for Children

GPP

generalized pustular psoriasis

GS

Griscelli syndrome

GVH

graft-versus-host

GVHD

graft-versus-host-disease

GVHR

graft-versus-host reaction

GVL

graft-versus-leukaemia

HAE

hereditary angioedema

HCC

harlequin colour change

HCG

human chorionic gonadotropin

HCT

hemopoietic cell transplantation

HDL

high-density lipoprotein

HHD

Hailey–Hailey disease

HI

harlequin ichthyosis

HID

hystrix-like ichthyosis with deafness (syndrome)

HIES

hyperimmunoglobulin E syndrome

HIMS

hyperimmunoglobulin M syndrome

HIP

helix initiation peptide

HIV

human immunodeficiency virus

HLA

human leucocyte antigen

HPC

haemangiopericytoma

HPS

Hermansky-Pudlak syndrome

HPETE

hydroperoxyeicosatetraenoic acid

HPV

human papillomavirus

HS

hidradenitis suppurativa

HSV

herpes simplex virus

HTLV

human T-lymphotropic type 1

HTP

helix termination peptide

IBIDS

ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature

IBS

ichthyosis bullosa of Siemens

ICAM

intracellular adhesion molecule

ICD

irritant contact dermatitis

IF

infantile fibrosarcoma

IFAP

ichthyosis follicularis with atrichia and photophobia

IFN

interferon

Ig

immunoglobulin

IgA1

IgA subtype 1

IgM

immunoglobulin M

IGF

insulin-like growth factor

IGFBP

IGF binding protein

IGRA

interferon-gamma release assay

IgεRI

high-affinity IgE receptor

IHCM

ichthyosis hystrix of Curth–Macklin

HIS

ichthyosis hypotrichosis syndrome

IHSC

ichthyosis-hypotrichosis-sclerosing cholangitis (syndrome)

IL

interleukin

IL-1β

interleukin-1β

ILAR

International League of Associations for Rheumatology

ILC

ichthyosis linearis circumflexia

ILVEN

inflammatory linear verrucous epidermal naevus

IPEX

immune dysregulation, polyendocrinopathy, enteropathy, X-linked

IPS

ichthyosis prematurity syndrome

ISAAC

International Study of Asthma and Allergies in Childhood

ISD

infantile seborrhoeic dermatitis

IV

ichthyosis vulgaris

IVIG

intravenous immunoglobulin

JDM

juvenile dermatomyositis

JIA

juvenile idiopathic arthritis

JSPD

Japanese Society for Pediatric Dermatology

KFSD

keratosis follicularis spinulosa decalvans

KID

keratitis, ichthyosis and deafness (syndrome)

KIF

keratin intermediate filaments

KLK

kallikrein

KTS

Klippel–Trenaunay syndrome

KWE

keratolytic winter erythema

LAD

leucocyte adhesion deficiency

LAS

loose anagen syndrome

LCD

liquor carbonis detergens

LCH

Langherhans’ cell histiocytosis

LD

lymphoedema-distichiasis

LDF

laser Doppler flowmetry

LDL

low-density lipoprotein

LEC

lymphatic endothelial cells

LEKTI

lymphoepithelial Kazal-type inhibitor

LFA-3

lymphocyte function-associated antigen-3

LI/CIE

lamellar ichthyosis/congenital ichthyosiform erythroderma

LMP1

latent membrane protein 1

LMX

liposomal lignocaine

LOH

loss of heterozygosity

LOSSI

localized scleroderma severity index

LOX

lipoxygenase

LT-β

lymphotoxin- β

LTT

lymphocyte transformation test

LyP

lymphomatoid papulosis

MAC

membrane attack complex

MACS

magnetic-activated cell sorting

MAIC

M. avium-intracellulare complex

MBL

mannose-binding lectin

MBTPS2

membrane-bound transcription factor protease, site 2

MC

mast cells

MC

molluscum contagiosum

MC&S

microscopy, culture and (antibiotic) sensitivity

MDM

minor determinant mixture

MEDNIK

mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia

MEDOC

mendelian disorders of cornification

mHA

minor histocompatibility antigen

MHC

major histocompatibility complex

MMF

mycophenolate mofetil

MMP

matrix metalloproteinases

MPE

maculopapular exanthems

MRI

magnetic resonance imaging

MRSA

methicillin-resistant Staphylococcus aureus

MSD

multiple sulphatase deficiency

MSH

melanocyte-stimulating hormone

NADPH

nicotinamide adenine dinucleotide phosphate

NBD

nucleotide-binding domain

NBS

Nijmegan breakage syndrome

NBT

nitroblue tetrazolium

NB-UVB

narrow-band UVB

NCAM

neural cell adhesion molecule

ND

naevus depigmentosus

NF1

neurofibromatosis type 1

NFκB

nuclear factor κB

NGCO

non-gestational ovarian choriocarcinoma

NGFR

nerve growth factor receptor

NICE

National Institute of Health and Clinical Excellence (UK)

NICU

neonatal intensive care unit

NIH

National Institutes of Health (USA)

NISCH

neonatal ichthyosis-sclerosing cholangitis (syndrome)

NK

natural killer (cell)

NLSD

neutral lipid storage disease

N2O

nitrous oxide

NPSA

National Patient Safety Agency (UK)

NPY

neuropeptide Y

NS

naevus sebaceous

NS

Netherton syndrome

NSAIDs

non-steroidal anti-inflammatory drugs

NSV

non-segmental vitiligo

NTM

non-tuberculous mycobacteria

OA

ocular albinism

OC

osteoma cutis

OL-EDA-ID

osteopetrosis, lymphoedema, ectodermal dysplasia anhydrotic and immune deficiency

O/W

oil in water

P1cp

procollagen type 1 carboxy-terminal peptide

PA

phytanic acid

PAHX

phytanoyl CoA hydroxylase

p-ANCA

perinuclear antineutrophilic cytoplasmic antibody

PAR2

protease-activated receptor 2

PAS

periodic acid–Schiff

PASI

psoriasis area and severity index

PCFCL

primary cutaneous follicle-centre lymphoma

PCFH

precalcaneal congenital fibrolipomatous hamartoma

PCLBCL

primary cutaneous diffuse large B-cell lymphoma

PCMZL

primary cutaneous marginal zone B-cell lymphoma

PCOS

polycystic ovarian syndrome

PCR

polymerase chain reaction

PCT

porphyria cutanea tarda

PCT

primary care trust

PDGF

platelet-derived growth factor

PDL

pulsed-dye laser

PEPD

paroxysmal extreme pain disorder

PEN

porokeratotic eccrine naevus

PEODDN

porokeratotic eccrine ostial and dermal duct naevus

PGP 9.5

protein gene product 9.5

PH

palmoplantar hidradenitis

PHA

phytohaemagglutinin

PHP

pseudo-hypoparathyroidism

PhyH

phytanoyl-CoA 2-hydroxylase

pI

isoelectric point

PI3

proteinase inhibitor 3

PIP

proximal interphalangeal

PL

pityriasis lichenoides

PLC

pityriasis lichenoides chronica

PLEVA

pityriasis lichenoides et varioliformis acuta

PM

porokeratosis of Mibelli

PML

progressive multifocal leucoencephalopathy

POEMS

polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (syndrome)

PPAR

peroxisome proliferator-activated receptor

PPK

palmoplantar keratodermas

PPL

penicilloyl-polylysine

POH

progressive osseous heteroplasia

PPPD

porokeratosis palmaris et plantaris disseminata

PRES

Paediatric Rheumatology European Society

PRINTO

Paediatric Rheumatology International Trials Organization

PRP

pityriasis rubra pilaris

PSEK

progressive symmetric erythrokeratoderma

PSH

premature sebaceous hyperplasia

PSS

peeling skin syndromes

PTC

premature termination codon

PTH

parathyroid hormone

PTHrP

parathyroid-hormone-related peptide

PUVA

psoralens plus UVA

PXE

pseudo-xanthoma elasticum

PWS

port wine stain

QUADAS

Quality Assessment of Diagnostic Accuracy tool

RAMBA

retinioic acid metabolism blocking agent

RCDP

rhizomelic chondrodysplasia punctata

RCT

randomized controlled trial

RF

rheumatoid factor

RMH

rhabdomyomatous mesenchymal hamartoma

ROS

reactive oxygen species

RTX

rituximab

RXLI

recessive X-linked ichthyosis

SCC

squamous cell carcinoma

SCCE

stratum corneum chymotryptic enzyme

SCID

severe combined immunodeficiency

SCT

stem cell transplantation

SCTE

stratum corneum tryptic enzyme

SD

seborrhoeic dermatitis

SEI

superficial epidermolytic ichthyosis

SFT

solitary fibrous tumour

SHP

Schönlein–Henoch purpura

SIB

self-injurious behaviour

SID

sudden infant death (syndrome)

sIgE

drug-specific IgE antibodies

SJS

Stevens–Johnson syndrome

SLADP

Latin American Society for Pediatric Dermatology

SLC27

solute carrier family 27

SLE

systemic lupus erythematosus

SLN

speckled lentiginous naevus

SLOS

Smith–Lemli–Opitz syndrome

SLPI

secretory leucocyte protease inhibitor

SLS

Sjögren–Larsson syndrome

SNP

single nucleotide polymorphism

SP

syringocystadenoma papilliferum

SPD

Society for Pediatric Dermatology

SPECT

single-photon emission computerized tomography

SPF

sun protection factor

SPINK

serine protease inhibitor Kazal type

SPRR

small proline-rich proteins

SPTL

subcutaneous panniculitis-like T-cell lymphoma

SSG

split-thickness skin graft

SSLR

serum sickness-like reactions

SSRI

selective serotonin reuptake inhibitors

SSSS

staphylococcal scalded skin syndrome

STI

sexually transmitted infection

STS

steroid sulphatase

TAC

tetracaine/adrenaline/cocaine

TBSA

total body surface area

TCS

topical corticosteroids

TCR

T-cell receptor

TEN

toxic epidermal necrolysis

TEWL

transepidermal water loss

TG

transglutaminase

TG

triacylglycerol

TG1

transglutaminase 1

TGF

transforming growth factor

TJ

tight junction

TLR

toll-like receptor

TMD

transmembrane domains

TMP-SMX

trimethoprim-sulfamethoxazole

TNF

tumour necrosis factor

TPM

transient pustular melanosis

TPMT

thiopurine methyltransferase

TRAPS

TNF receptor superfamily 1A-associated periodic fever syndrome

TRT

thermal relaxation time

TS

tuberous sclerosis

TTD

trichothiodystrophy

UD

unrelated donor

uE3

unconjugated oestriol

UV

ultraviolet

UVB

ultraviolet light

VEGF

vascular endothelial growth factor

VEGFR3

vascular endothelial growth factor receptor 3

VLCFA

very-long-chain fatty acid

VZIG

varicella zoster immunoglobulin

VZV

varicella zoster virus

WAO

World Allergy Organization

WAS

Wiskott-Aldrich syndrome

WHO

World Health Organization

W/O

water in oil

XD

X-linked dominant

XLMR

X-linked mental retardation

XR

X-linked recessive

ZIG

zoster immune globulin

ZNS

Zunich neuroectodermal syndrome

CHAPTER 1

The History of Paediatric Dermatology

John Harper

Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK

Ancient origins of paediatric dermatology

The global establishment of paediatric dermatology as a recognized subspecialty

Paediatric dermatology in North America (USA and Canada)

Paediatric dermatology in Latin America

Paediatric dermatology in Japan

Paediatric dermatology in Europe

The future for paediatric dermatology

Ancient Origins of Paediatric Dermatology

Visible skin abnormalities have been recognized since the dawn of history, dating back about 5000 years to the oldest medical text of Sumer, an ancient city of Mesopotamia. The text, in the form of a clay tablet, is a pharmacopoeia in which many salves (a medical ointment used to soothe the head or other body surface) and lotions are listed. There are other Mesopotamian medical tablets that mention conditions relating to itching, leprosy, impetigo, erysipelas and jaundice. Specifically in the newborn are recorded the vernix caseosa and some congenital skin abnormalities. Other evidence of early records of skin ailments and their treatment is found in the Egyptian papyri of 1500 BC, in the sacred books of the Hindus of ancient India and in the Hippocratic writings of the Greeks. Hippocrates drew attention to cutaneous disorders in children, restricted largely to clinical observation. In the Hippocratic writings at least six passages deal specifically with skin ailments in children. He refers to leprosy, lichen and leuke. Leuke was considered by many scholars to be a form of leprosy or vitiligo, and lichen has been variously interpreted as representing a variety of skin conditions – ringworm, eczema, psoriasis, herpes – characterized by eruptions and itching.

Rhazes (865–925), a Persian physician, alchemist, philosopher and scholar, is considered to be the father of paediatrics for writing The Diseases of Children, the first book of paediatrics. He describes infantile eczema (cradle cap), which he called ‘sahafati’ … lesions exuding fluid spread over the head and face causing the child to cry and scratch … he concluded the affliction proceeded from superfluidities of the blood and excess moisture of the skin … he recommended depilation of the scalp followed by the application of atriplex leaves to draw out the ‘poison’ … he also mentioned the use of lead ointment. His classic work was to distinguish smallpox and measles, as well as chickenpox, through his clinical characterization of these diseases. Avicenna (980–1037), whose Canon of Medicine exerted a great influence on medieval medicine, described an eruptive condition now considered to be scarlet fever. Avenzoar (1113–62), another Arabian philosopher, was the first to be credited with describing the itchy mite of scabies.

The first monograph on dermatology is Galen’s (129–200 AD) De Tumoribus Praeter Naturam on abnormal swellings. In 1572, Geronimo Mercuriali of Forlì, Italy, completed De morbis cutaneis (‘Diseases of the Skin’), and this is recognized as the first scientific work to be dedicated to dermatology.

Robert Willan (1757–1812) is considered the founder of dermatology as a medical specialty. Thomas Bateman (1778–1821) was a British physician and a pioneer in the field of dermatology. Willan died leaving Bateman to continue and expand on the work of his mentor. In 1817 Bateman published an atlas called Delineations of Cutaneous Disease (Fig. 1.1).

Fig. 1.1 From Delineations of Cutaneous Diseases. Thomas Bateman. Henry G. Bohn, London 1st edn. 1817; 2nd edn 1840: PLATE 1. The STROPHULUS intertinctus; popularly termed the Red Gum, or Gown; a pimply eruption of a vivid red colour, rising sensibly above the level of the skin, and intermixed often with dots and red patches which have no elevation. It is peculiar to very young infants; and often consistent with good health.

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The first treatise exclusively devoted to paediatric dermatology was Cutaneous Diseases Incidental to Childhood by Walter C. Dendy, published in London in 1827 (Fig. 1.2). The author was Surgeon to the Royal Universal Dispensary for Children, later to become the Royal Waterloo Hospital for Children and Women, part of St Thomas’ Hospital.

Fig. 1.2 A Treatise on the Cutaneous Diseases Incidental to Childhood. Walter C. Dendy, John Churchill, London, 1827. The first textbook of pediatric dermatology.

Courtesy of the Wellcome Library, London.

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Two decades later Charles West worked at the same hospital, where only ambulatory patients attended. In 1852 Dr Charles West played a significant role in establishing the Hospital for Sick Children, Great Ormond Street, London.

In the Western world, the first generally accepted paediatric hospital is the Hôpital des Enfants Malades, opened in Paris in June 1802, on the site of a previous orphanage. From its beginning, this famous hospital accepted patients up to the age of 15 years and it continues to this day as the paediatric division of the Necker-Enfants Malades Hospital, created in 1920 by merger with the Necker Hospital, founded in 1778 for adults.

The Global Establishment of Paediatric Dermatology As A Recognized Subspecialty

It was not until 1972 that paediatric dermatology was ‘officially born’ at the first International Symposium of Paediatric Dermatology in Mexico City (Fig. 1.3). Distinguished physicians met at the famous San Angelin Restaurant and founded the International Society of Pediatric Dermatology. These pioneers included: Martin Beare (Ireland); Ferdinando Gianotti (Italy); Joan Hodgeman (USA); Coleman Jacobson (USA); Guinter Kahn (USA); Andrew Margileth (USA); Edmund Moynahan (England); Dagoberto Pierini (Argentina); Ramon Ruiz-Maldonado (Mexico); Lawrence Solomon (USA); Eva Torok (Hungary) and Kazuya Yamamoto (Japan). Prior to this children and adolescents with skin maladies were mainly looked after by paediatricians and primary care physicians, with only a few dermatologists and academics interested in the research and management of these children. Following that historic meeting in Mexico City, interest in this discipline of medicine has grown dramatically throughout the world and is now integral to all major dermatological and paediatric meetings. Since then, 10 World Congresses of Paediatric Dermatology have taken place: Chicago (Fig. 1.4), Monte Carlo, Tokyo, Milan, Toronto, Buenos Aires, Paris, Cancun, Rome and Thailand.

Fig. 1.3 Poster advertising the first International Symposium on Pediatric Dermatology held in Mexico City in 1973.

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Fig. 1.4 Delegates attending the Second International Congress of Pediatric Dermatology in Chicago, including Ruggero Caputo, Nancy Esterly, Sidney Hurwitz, Alvin Jacobs, Coleman Jacobson, Gunter Kahn, Al Lane, Marc Larregue, Arthur Norins, Jim Rasmussen, Ramon Ruiz Maldonado, Jean-Hilaire Saurat, Laurence Schachner, Lawrence Solomon, Loudes Tamayo, Sam Weinberg, William Weston.

Courtesy of Dr Susan Bayliss.

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There are now journals specifically dedicated to the subject published in the USA, Japan and Europe. The Society of Pediatric Dermatology in the USA was founded in 1975, the Japanese Society for Pediatric Dermatology in 1977 and the European Society for Pediatric Dermatology in 1983. The past two decades have seen a plethora of textbooks on paediatric dermatology, but it is important to highlight two authors, Sidney Hurwitz and William Weston, whose books respectively had a profound influence on the establishment of the specialty and its teaching. There are two up-to-date encyclopaedic textbooks of pediatric dermatology; one edited by Schachner and Hanson and the other edited by Harper, Oranje and Prose (first two editions) and Irvine, Hoeger and Yan (third edition).

Mexico has led the way in training with a programme for both paediatricians and dermatologists, founded in 1973 by Ramon Ruiz Maldonado and Lourdes Tamayo. More than 100 specialists now working in most Latin American countries have been trained in that programme. In the USA paediatric dermatology became an independent board-certified subspecialty as recently as 2004. Elsewhere in the world training remains ad hoc and includes paediatricians with a special interest in dermatology, dermatologists with a special interest in children, and a select handful who have a full training in both specialties. In some countries the lack of cooperation between the two disciplines can be a stumbling block to the establishment of the specialty.

Paediatric Dermatology in North America (USA and Canada)

Henry Harris Perlman was the first physician to be board certified by both the American Academy of Pediatrics and the American Academy of Dermatology (AAD), the first to limit his practice to diseases of the skin in children (1946) and the first in the USA to write a textbook dedicated solely to Pediatric Dermatology (see Moynahan, 1961, p. 954 for a review).

In the 1960s and 1970s interest in pediatric dermatology was pursued by a group of physicians in the USA, who made a major contribution to the establishment of the subject as a recognized specialty (in alphabetical order): Carroll Burgoon Jr, Philadelphia; Sidney Hurwitz, New Haven, Connecticut; Alvin Jacobs, Palo Alto, California; Gunter Kahn, Miami, Florida; Peter Koblenzer, Morristown, New Jersey; Arthur Norins, Indianapolis, Indiana; James Rasmussen, Buffalo, New York; Lawrence Solomon and Nancy Esterly, Chicago; Samuel Weinberg, New York City; and William Weston, Denver, Colorado.

At the AAD meeting in Chicago in December 1974, four paediatric dermatologists met for the purpose of starting a Society for Pediatric Dermatology (SPD). They were Sidney Hurwitz, Sam Weinberg, William Weston and Alvin Jacobs. A meeting was organized in Dallas, Texas, in February 1976, hosted by Coleman Jacobson. Thirty-eight interested in membership attended. Sidney Hurwitz was elected President, Sam Weinberg and Alvin Jacobs Vice-Presidents, and William Weston Secretary-Treasurer (Fig. 1.4). The first Scientific Meeting of the Society was hosted by William Weston in Aspen, Colorado, in July 1976.

Subsequent annual meetings attracted more and more individuals and now the SPD is recognized internationally to be one of the leading groups representing our specialty worldwide. In addition to the summer annual meeting, the one-day meeting prior to the AAD has been very successful and attracts a high attendance.

At the 10th annual meeting in Cape Cod, the first annual Sidney Hurwitz lectureship was inaugurated. Dr Tomisaku Kawasaki of Tokyo, who first described the disorder that bears his name, gave an update on Kawasaki’s disease.

The AAD now recognizes paediatric dermatology as a board certified subspecialty, for which there are designated training programmes with defined certification requirements (http://www.abderm.org/subspecialties/qualification.html).

The Journal of Pediatric Dermatology was first published in 1983 with Lawrence Solomon and Nancy Esterly as editors. It is the main journal worldwide for the subspecialty with a high profile of clinical and research contributions. It is published by Wiley Blackwell and the current editors are Ilona Frieden and Lawrence Eichenfield.

Paediatric dermatology in the USA has seen a rapid growth of interest, with many new young paediatric dermatologists (too many to list) who are making significant contributions to our understanding and treatment of skin ailments in children and adolescents. Many of these clinicians and research workers have contributed to this textbook.

In Canada, paediatric dermatology has been led by Bernice Krafchik in Toronto, with Julie Prendiville (Vancouver) and Julie Powell and Danielle Marcoux (Montreal). In 1981, Bernice Krafchik hosted the meeting of the Society of Pediatric Dermatology, with over 150 attendees from Canada and the USA. In 1992, Bernice Krafchik and Jim Rasmussen organized the sixth World Congress of Pediatric Dermatology in Toronto.

Paediatric Dermatology in Latin America

Modern day paediatric dermatology owes much to the dedication, enthusiasm and commitment of Ramon Ruiz Maldonado and Lourdes Tamayo of Mexico City in establishing paediatric dermatology as a subspecialty, not just in Mexico but throughout Latin America. Their influence, in promoting and supporting paediatric dermatology, has been worldwide. The first Symposium of Pediatric Dermatology was in 1972 in Mexico City (Fig. 1.3) and at that time the International Society of Pediatric Dermatology was founded. The first training programme in the world was established at the National Institute of Pediatrics in Mexico City in 1973, for both paediatricians and dermatologists. Certified paediatricians do 3 years of training in paediatric dermatology, and certified dermatologists do 1 year’s training in paediatric dermatology to obtain a diploma in paediatic dermatology.

Subsequently, Dagoberto Pierini launched the Paediatic Dermatology training programme in Argentina, where there are currently two training institutes, headed by Adrian Pierini and Margarita Larralde. The seventh World Congress of Pediatric Dermatology was held in Buenos Aires under the Presidency of Adrian Pierini.

Paediatic dermatology is now a recognized subspecialty in most Latin American countries. Past and present leading paediatric dermatologists include: Evelyne Halpert (Colombia); Hector Caceres, Leonardo Sanchez (Peru); Luiz Alfredo Gonzales Aveledo (Venezuela); Adrian Pierini, Margarita Larralde, Rita Garcia Diaz, Maria Rosa Cordisco, Jose Antonio Massimo (Argentina); Ramon Ruiz Maldonado, Lourdes Tamayo, Carola Duran McKinster (Mexico); Fausto Forin Alonso, Susana Giraldi (Brazil); Julia Oroz, Winston Martinez, Sergio Silva (Chile); and Raul Vignale, Marcelo Ruvertoni (Uruguay).

In 1996 in Lima, the Latin American Society for Pediatric Dermatology (SLADP) was founded. The first Congress was held in Bogota in 1997, organized by Evelyne Halpert. The SLADP has grown significantly over the years and now includes representation of 15 countries, meeting every 3 years. Hector Caceres and his working group are responsible for the journal Revista de Dermatología Pediátrica Latinoamericana.

Paediatric Dermatology in Japan

Kazuya Yamamoto was Head of the Department of Dermatology at the National Children’s Hospital in Tokyo and in 1977 established the Japanese Society for Pediatric Dermatology (JSPD). The first President was Professor Toshiaki Yasuda. The JSPD met annually and at each meeting invited both national and international guest speakers. The number of members of the JSPD has risen to over 1000. In 1986 Tokyo hosted the fourth World Congress of Pediatric Dermatology, with Professor Harukuni Urabe as President and Kazuya Yamamoto as the Head of the Secretariat. The Journal of the JSPD was first published in 1982 and has continued biannually to the present time.

Paediatric Dermatology in Europe

This new medical discipline has become established in most European countries over the past 25 years. Physicians who have made major contributions to paediatric dermatology in Europe include: Jean-Hilaire Saurat, Marc Larregue, Jean Maleville, Yves de Prost and Alain Taieb (France); Ruggero Caputo, Carlo Gelmetti, Giuseppe Fabrizi and Ernesto Bonifazi (Italy); Rudolph Happle, Heiko Traupe (Germany); Martin Beare, Edmund Moynahan, Charles Wells, David Atherton and John Harper (UK); Micheline Song and Linda de Raeve (Belgium); Arnold Oranje, Flora de Waard-van der Spek and Henk Sillevis Smit (The Netherlands); Talia Kakourou (Greece); Juan Ferrando, Ramon Grimalt, Antonio Torrelo (Spain); and Daniel Hohl (Switzerland). This list does not include a number of eminent physicians who predate the past 25 years, physicians in other European countries and new young doctors trained in paediatric dermatology.

National societies have been established in many European countries: Belgium, Croatia, France, Germany, Greece, Hungary, Italy, The Netherlands, Portugal, Spain, Switzerland, Turkey and the UK.

Research in Europe has made major contributions to our understanding and treatment of skin conditions in children. Examples include: acrodermatitis enteropathica and zinc deficiency (Edmund Moynahan); graft-versus-host disease of the skin (Jean-Hilaire Saurat); the histiocytoses (Ruggero Caputo) and most recently propranolol treatment for haemangiomas (Alain Taieb).

The European Society of Pediatric Derrmatology (ESPD) was established in 1983. European Congresses have been held in: Munster, 1984; Bari, 1987; Bordeaux, 1990; Bournemouth, 1993; Rotterdam, 1996; Rome, 1999; Barcelona, 2002; Budapest, 2005; and Athens, 2008.

The first paediatric dermatology course in Europe was set up in 1977 by Marc Larregue and Jean Maleville, held in Arcachon in France and continued annually. Other courses have since been established in Paris, Bari, Rome, Rotterdam, Dundee and Birmingham.

As well as the journal Pediatric Dermatology to which the ESPD is affiliated, the first edition of Pediatric Dermatology News, edited by Ernesto Bonifazi, was in 1982. In 1991 this publication became the European Journal of Pediatric Dermatology.

The Future for Paediatric Dermatology

The inspired vision of our predecessors has firmly established paediatric dermatology as a recognized subspecialty internationally. Compared to other medical subspecialties, paediatric dermatology is in its infancy in development. The main issue that needs addressing is an agreed international training programme. This has been achieved in Mexico and in the USA and must be a priority for the International Society for Pediatric Dermatology (ISPD) as we strive forward in this new millennium. To quote Sidney Hurwitz, in Pediatric Dermatology in 1988: ‘Those of us who have committed ourselves to this discipline are proud of the accomplishments of the past, appreciate the rapidly growing interest in this field in the present and look forward to the challenges of the future with continued optimism and enthusiasm.’

Further reading

Copeman PWM. The creation of global dermatology. J Roy Soc Med 1995;88:78–84.

Galimberti R, Pierini AM, Cervini AB. (eds) History of Latin American Dermatology. Toulouse: Edicions Privat, 2007.

Hurwitz S. The history of pediatric dermatology in the United States. Pediatr Dermatol 1988;5:280–5.

Moynahan EJ. Review of Pediatric Dermatology by Henry H Perlman. BMJ;1961(1 April):954.

Radbill SX. Pediatric dermatology in antiquity: part I. Int J Dermatol 1975;14:363–8.

Radbill SX. Pediatric dermatology in antiquity: part II. Roman Empire. Int J Dermatol 1976;15:303–7.

Radbill SX. Pediatric dermatology in antiquity: part III. Int J Dermatol 1978;17:427–34.

Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part I. Pediatric dermatology in general medical texts. Int J Dermatol 1985;26:250–6.

Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part II. Pediatric dermatology in pediatric texts. Int J Dermatol 1987;26:324–31.

Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part III. DermatologicTexts. Int.J Dermatol. 1987; 26(6):394–400.

Radbill SX. Pediatric Dermatology: chronological excursions into the literature. Part IV. Pediatric dermatology texts. Int J Dermatol 1987;26:474–9.

Ruiz-Maldonado R. Pediatric dermatology accomplishments and challenges for the 21st century. Arch Dermatol 2000;136:84.

Taieb A, Larregue M, Maleville J. The development of paediatric dermatology. In: Wallach D, Tilles G (eds) Dermatology in France. Toulouse: Editions Privat, 2002; 127–31. http:www.bium.univ-paris5.fr/histmed/medica/cote?extwall00001.

Yamamoto K. The Society: early days. J Jpn Soc Pediatr Dermatol 2009;28:158–162 [in Japanese].

CHAPTER 2

Embryogenesis of the Skin

Karen A. Holbrook

Department of Physiology and Cell Biology, Ohio State University, Columbus, OH, USA

Introduction

Time-scale of skin development

Embryonic skin

Embryonic–fetal transition

Fetal skin

Unique features of developing human skin

Conclusion

Introduction

The skin is an ideal organ in which to study development through ageing because it is readily accessible for observation, sampling and evaluation. As an interface, it straddles the internal, systemic world of the individual and the external environment and is vulnerable to and can be modified by both. The skin itself is a remarkably complicated and complex organ, with the normal structure and function of each ‘part’ highly dependent upon what happens in other parts of the skin. In other words, one cannot understand, for example, changes that occur in the epidermis without understanding the nature of the dermis since the dermis has major influences on the activities and functions of the epidermis. This is the case for each region or structure of the skin.

Development, however, offers an opportunity to study skin structure and function under more ‘controlled’ conditions because, except for changes in the composition of the amniotic fluid (similar to maternal plasma in the embryo but more characteristic of fetal urine in the second trimester [1,2]), the environment of the developing skin is reasonably constant (controlled light, temperature, pressure, etc.). It is possible therefore to investigate how the properties of the different regions and structures of the skin are coordinately established, presumably under the directions of a genetic program, and spared from the assaults of the external world.

For the sake of simplicity, the period of skin development can be correlated with the in utero life of the individual. This is not an absolute correspondence, however, because some of the structures of the skin may be fully formed early in the fetal period whereas other structures or regions are not complete until well into the postnatal years. Also, full establishment of adult functions of the skin always requires an extended period of development beyond the stages in utero. Development is therefore the first period in a continuum of events that modifies the skin; it is characterized by morphogenetic processes, the activation of new genes and the gain of function. In contrast, ageing may involve morpholytic processes in which genes are turned off, resulting in a loss of function. Consideration of this continuum, and the genetic and environmental interactions that come into play at progressive ages throughout life, provides a conceptual framework for discussing the place and role of the events in skin morphogenesis.

Understanding the stages and events of normal human skin development is also important from a biomedical perspective: it allows the definition of critical periods when the skin may be more vulnerable to developmental errors; it provides an opportunity to study the evolution of skin function, establishing a background for understanding the natural history of expression of genetic skin disease in its earliest form; and it provides the essential information for the evaluation of skin samples used in the prenatal diagnosis of genodermatoses for which molecular methods are still not adaptable. Studies of skin development can also shed light on a number of basic problems in contemporary biology: epithelial–mesenchymal interactions that establish organs (in skin, these tissue interactions occur in follicle, sweat gland and nail formation); cell–cell interactions through soluble mediators; gene regulation; apoptosis; differentiation (structural, biochemical and functional); and certain longstanding basic phenomena of development such as induction, pattern formation and differentiation. They provide an opportunity to ask how a molecule is expressed and how expression of that molecule may modify the properties of the tissue over a time sequence that begins in the simple embryonic environment and builds progressively to more complex fetal conditions. Samples of fetal skin and fetal skin-derived cells are easily established in culture for experimental studies designed to probe some of these questions, and many of the studies of skin development can be performed in animal models. But the animals that are typically used for this work (primarily rodents) lack the advantage of the long gestation period of the human, which allows for the events of development to unfold slowly and thus permits a more systematic analysis of change.

The unique morphological properties of developing human skin have always intrigued investigators who have had access to this tissue. Specific aspects of the skin that are found only in the fetus, such as the periderm, and specific events that result in the formation of complex structures, such as follicle or sweat gland, were often described for specific ages only (reviewed in refs [3–6]). These descriptions, coupled with speculation as to function, led inevitably to more systematic and comprehensive studies to characterize the complete ontogeny of the tissue, region or structure (reviewed in refs [3–6]). Such studies then began to include data derived from biochemical or immunohistocytochemical assays for the expression of specific molecules that were known to correlate with the state of differentiation or with a specific property such as barrier function adhesion and so on. Culturing and grafting human embryonic and fetal skin (reviewed in refs [7–10]) and skin-derived cells [11,12] and evaluation of skin from fetuses affected with genodermatoses (reviewed in refs [13–15]), or under conditions of growth retardation, have also provided insight into human skin development. Our understanding of skin development continues to increase as we apply more modern tools of biology to study the skin at all stages of life.

References

1 Lind R, Parkin FM, Cheyne GA. Biochemical and cytological changes in liquor amnii with advancing gestation. J Obstet Gynaecol Br Commonw 1971;76: 673–83.

2 Benzie RJ, Doran TA, Harkins JL et al. Composition of the amniotic fluid and maternal serum in pregnancy. Am J Obstet Gynecol 1974;119:798–810.

3 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110.

4 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51.

5 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144.

6 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995.

7 Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: characterization of events in vivo and in vitro. NY Acad Sci 1991;642:167–96.

8 Zeltinger J, Holbrook KA. A model system for long term, serum-free, suspension organ culture of human fetal tissues: experiments using digits and skin from multiple body regions. Cell Tissue Res 1997;290:51–60.

9 Lane AT, Scott GA, Day KH. Development of human fetal skin transplanted to the nude mouse. J Invest Dermatol 1989;93:787–91.

10 Gilhar A, Gershoni-Baruch R, Margolis A et al. Dopa reaction of fetal melanocytes before and after skin transplantation onto nude mice. Br J Dermatol 1995;133:884–9.

11 Oliver AM. The cytokeratin expression of cultured human foetal keratinocytes. Br J Dermatol 1990;123:707–16.

12 Scott G, Ewing J, Ryan D et al. Stem cell factor regulates human melanocyte–matrix interactions. Pigment Cell Res 1994;7:44–51.

13 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples. Arch Dermatol 1993;129:1437–54.

14 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol 1992;7:179–209.

15 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In: Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: Pathology, Radiology and Genetics. New York: Cockburn, Chapman & Hall, 1995: 755–68.

Time-Scale of Skin Development

There are several schemes for categorizing stages of skin development (Fig. 2.1). All of them are arbitrary and overlapping, and based on some parameter that is relevant to human development per se, to a period defined for purposes of medical intervention, a specific event that is considered a landmark in the evolution of skin structure, composition and function, or on the basis of the surface properties of the developing skin [1].

Fig. 2.1 Time-scale diagram identifying specific stages of skin development and identifying the ages at which prenatal diagnosis can be performed using each of the various methods currently employed.

Modified from Polin RA, Fox WW. Fetal and Neonatal Physiology, 2nd edn, Vol. 1. Philadelphia: W.B. Saunders, 1998: 730.

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Human development is separated into embryonic (before the onset of bone marrow function) and fetal periods, corresponding, respectively, to conception until approximately 2 months estimated gestational age (EGA), and to 2 months EGA until birth. The first trimester includes the entire embryonic period and the first stages of the fetal period. Histogenesis of all skin regions is initiated in the embryo, and differentiation of some of those tissues begins to occur [2]. The boundary between the first and second trimesters, at 3 months of age, is based only on fetal age and not on any remarkable changes in structure, composition or function of any region of the skin.

The second trimester includes many important events in skin development that can be correlated with changes in function and, at the same time that morphogenesis of new structures is initiated, there is terminal differentiation of others. During the third trimester, as far as we know, all parts of the skin are assembled and the functions of each of them are unfolding. The end of this period is not the final state of the skin, as there is significant reorganization of certain units of the skin (e.g. the vasculature), additions to the skin in volume (e.g. the dermal matrix) and functional maturation of many structures of the skin (e.g. nerves, sweat glands and stratum corneum) after the newborn faces the environment of the external world [3–6,7].

Other important times that should be recognized in skin development are the ages at which chorionic villus sampling, amniocentesis and fetal skin biopsy are performed for the purpose of evaluating the condition of a fetus at risk for a genetic skin disease. Fetal DNA can be extracted from chorionic villi sampled around 10 weeks EGA, amniotic fluid cells can be obtained at around 14–16 weeks EGA, and fetal skin can be sampled as early as 16 weeks EGA. More typically, the skin is biopsied at 19–21 weeks [8–10]. The older age is necessary when diseases of keratinization are in question.

This chapter is organized to describe specific periods, unique features and special events or processes of skin development using EGA, the age from the date of conception, to represent the age of the embryo or fetus in utero. In the literature gestational age is used interchangeably with menstrual age, which is calculated from the date of the last known menstrual period and thus records the timing of developmental events about 2 weeks later than EGA. Unanswered questions will be raised for the reader’s thoughtful consideration.

References

1 Holbrook KA, Odland GF. The fine structure of developing human epidermis: light, scanning and transmission electron microscopy of the periderm. J Invest Dermatol 1975;65:16–38.

2 Holbrook KA, Dale BA, Smith LT et al. Markers of adult skin expressed in the skin of the first trimester fetus. Curr Prob Dermatol 1987;16:94–108.

3 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110.

4 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51.

5 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144.

6 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995.

7 Holbrook KA. A histologic comparison of infant and adult skin. In: Boisits E, Maibach HI (eds) Neonatal Skin: Structure and Function. New York: Marcel Dekker, 1982: 3–31.

8 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples. Arch Dermatol 1993;129:1437–54.

9 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol 1992;7:179–209.

10 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In: Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: Pathology, Radiology and Genetics. New York: Cockburn, Chapman & Hall, 1995: 755–68.

Embryonic Skin

The primitive ectoderm of the developing blastocyst is established at 1 week EGA, and by 20–50 days EGA the major organs and organ systems of the human embryo are becoming established. The integumentary system exhibits characteristics of the skin at 30 days EGA, the earliest age at which specimens can be realistically obtained for study. Sampling of skin at this age is remarkable considering that the 6-week-old embryo has a crown–rump length of only 20 mm – no larger than a 20 pence piece (or a dime). Nonetheless, the epidermis, dermoepidermal junction (DEJ) and dermis are well delineated and the tissue is innervated and vascularized (Fig. 2.2). The boundary between the dermis and subcutaneous tissue is not clearly defined in all body sites, but in some regions these two zones are distinct from one another on the basis of a greater density of cells and matrix in the dermis compared with the hypodermis. The skin is closely associated with the underlying developing striated muscle or cartilage on the appendages. There is no morphological evidence that epidermal appendages have begun to form.

Fig. 2.2 (a) Tissue of the body wall of a 36-day EGA human embryo and (b) the skin from a 45-day EGA human embryo. Note the two-layered epidermis, dermis and subcutaneous tissue and the more linear orientation of dermal cells in contrast to the pleiomorphic shapes of the subcutaneous mesenchyme. In (b) note the periderm and basal cells of the epidermis, the closely associated fibroblastic cells in the dermis proximal to the epidermis and a nerve–vascular plane separating the dermis from the subcutaneous tissue (×200).

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In most regions of the embryo, the epidermis is a simple, flat, two-layered epithelium consisting of basal and periderm cells (see below) (Figs 2.2 and 2.3). Both types of cells are mostly filled with glycogen, a molecule that is characteristic in the cytoplasm of developing and regenerating tissues, where it most likely serves as a source of energy [1] (Fig. 2.3). The nucleus is centrally located in periderm and basal cells, and the cytoplasmic organelles are sparse and distributed either around the nucleus or at the periphery of the cell (Fig. 2.3b). The structural characteristics of these cells therefore fail to reveal significant differences between the two layers or to verify that either layer is composed of keratinocytes. Evaluation of the structural proteins, however, indicates that both contain keratin intermediate filament proteins (Fig. 2.4), but different species [2,3], and some cell-surface molecules are unique to each layer [4]. The latter markers may reflect the differences in environments surrounding each layer.

Fig. 2.3 Transmission electron micrographs of the embryonic epidermis. In (a) note the glycogen (G)-filled basal (B) and periderm (P) layer cells. Desmosomes are evident between basal cells and between basal cells and periderm cells. The DEJ is flat and shows few sites of increased density, suggesting sites of desmosome formation. In (b) one periderm cell and portions of two basal cells are shown. Note the nature and disposition of cytoplasmic organelles within both cell types, the keratin filaments associated with desmosomes (arrow) and the microvilli extending from the periderm surface (a, ×11,525; b, ×25,000).

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Fig. 2.4 Immunostained samples of (a) early (∼50-day EGA) and (b–d) later (∼60-day) human embryonic epidermis showing positive staining of both periderm and basal layers with the AE1 (a) and AE3 (d) monoclonal antibodies that recognize keratins. Both layers are negative when reacted with the AE2 (c) antibody, which recognizes the differentiation-specific keratins (×350).

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The columnar-shaped basal cells of the embryonic epidermis express the keratins that are characteristic of adult basal layer keratinocytes – K5 (58 kDa) and K14 (50 kDa) [2,3] – and additional keratin polypeptides – K19 (40 kDa) and K8 (52 kDa) – are specific to embryonic/fetal basal cells and periderm cells [2,3]. The latter keratins are not characteristic of normal adult basal keratinocytes, but they are identified in glandular and simple epithelial cells [5]. In contrast to the adult tissue, the filaments in fetal embryonic epidermis are dispersed in the cytoplasm or assembled in small, seemingly short, bundles that are associated primarily with desmosomes and hemidesmosomes (see Fig. 2.3b). Periderm cells and basal cells also differ in the expression of many growth factors, growth factor receptors (Fig. 2.5) [6,7], cell adhesion molecules [8] and other cytoplasmic and cell-surface molecules.

Fig. 2.5 Section of skin from a 78-day EGA human fetus showing differential expression of the A-chain of PDGF in the basal and intermediate cell layers (green) and an absence of staining in peridermal cells. The receptor for PDGFA, PDGFR-α (red), is expressed by cells in the dermis (×350).

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About 15–19% of the basal cells incorporate label when viable tissue is incubated in culture medium containing [³H]-thymidine for 1 h, rinsed and then processed for autoradiography. This is a higher labelling index than the fetal or adult epidermis, which was recorded at 10% and 6.7% labelling, respectively, under the same conditions [9]. It is possible that only the basal layer is truly epidermis.

A thin, flattened layer of periderm cells covers the basal layer, with no apparent correspondence in number with the cells beneath it, i.e. one polygonal periderm cell lies above several basal cells. Microvilli project from the peridermal surface into the amniotic fluid (Figs 2.3b and 2.6). At least one keratin polypeptide expressed in periderm cells is different from those in the basal cells, K18 (45 kDa), although it is a marker for Merkel cells [10,11].

Fig. 2.6 Scanning electron micrograph of the surface of 55-day EGA embryonic skin from the surface of the developing foot. The layer of cells shown is the periderm. Note the microvilli and the variable size and shape of the cells (×1000).

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Two of the immigrant cells that are prominent in adult epidermis, melanocytes (neural crest in origin) and Langerhans cells, are present in the embryonic epidermis among basal cells and associated with the basement membrane. Sheets of embryonic epidermis immunostained with an antibody that recognizes melanocytes specifically (HMB-45, an inducible, cytoplasmic antigen common to melanoma and embryonic/fetal melanocytes [12,13]) show a remarkably high density (∼1000 cells/mm²) of these cells organized in a regular pattern of distribution (Fig. 2.7). They are dendritic as early as 50 days EGA in general body skin but there is no evidence of melanosomes in the cytoplasm [14]. Langerhans cells are recognized in embryonic skin as early as 42 days EGA on the basis of a reaction product for membrane-bound Mg²+ adenosine triphosphatase (ATPase) and histocompatibility locus antigen (HLA-DR) on the plasma membrane [15–17] and by their truncated or dendritic morphology (Fig. 2.8). They are probably derived from the yolk sac or fetal liver at this age because they are present in skin before the bone marrow begins to function. At 7 weeks EGA, the density of Langerhans cells is about 50 cells/mm² [16,17].

Fig. 2.7 Embryonic skin from a 54-day EGA human embryo immunostained with the HBM-45 monoclonal antibody, which recognizes an antigen in the melanocyte. (a) Section of skin. Note the abundance and position of these cells within the two-layered epidermis. (b) Epidermal sheet. Note the density, spacing and dendritic morphology of these cells (a, ×350; b, ×25).

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Fig. 2.8 Epidermal sheet from a 53-day EGA human embryo immunostained to recognize HLA-DR antigen in epidermal Langerhans cells (×400).

Micrograph courtesy of Dr Carolyn Foster.

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The third immigrant cell, the Merkel cell, can be recognized in embryonic palmar skin as early as 55–60 days EGA (see Eccrine sweat gland formation) at a density of ∼130 cells/mm² [10,18], using as a marker any one of the set of keratins expressed by Merkel cells (K8, K18, K10 and K20) [10,11,19–21]. K20 is the only keratin found exclusively in Merkel cells [21]. At this embryonic age, they are distributed randomly and in a suprabasal position. Merkel cells are neuroendocrine cells that were originally thought to function primarily as slow-adapting mechanoreceptors. More recently, studies that have catalogued soluble mediators produced by these cells, for example nerve growth factor (NGF) [22], suggest that it is likely that Merkel cells are targets for ingrowing nerve fibres or other cells such as the smooth muscle cells of the arrector pili muscle [23,24]. Their presence in selected sites of developing epidermal appendages (e.g. sweat glands and hair follicles) has also been suggested to stimulate or to correlate with active proliferation of the tissue. It is generally accepted that Merkel cells are derived from keratinocytes in situ [10,19,21,25,26].

A continuous basal lamina (lamina densa) underlies the two-layered epidermis and defines, morphologically, one structural component of the basement membrane zone [27–29]. The basal lamina is patchy, however, in regions of the body where the epidermis may be only a single layer, for example superior to the spinal cord. The molecules and antigens characteristic of all basal laminae (type IV collagen, laminin, heparan sulphate proteoglycan, nidogen/entactin) are present in the earliest recognized basal lamina of the skin; skin-specific molecules are recognized later during the first trimester in accord with the more prominent development of the attachment structures (see below) [30,31]. A thin, mat-like layer of microfilaments lies just inside the basal plasma membrane of the basal cell keratinocytes (Fig. 2.9). It may reinforce this surface of the epidermis and add to the strength of the DEJ at this stage when the structural modifications associated with dermoepidermal adhesion (hemidesmosomes, anchoring filaments, anchoring fibrils) are rudimentary [32]. The same organization of filaments is observed in cultured keratinocytes, which do not typically form hemidesmosomes and anchoring fibrils in vivo, and in basal keratinocytes under pathological situations, such as junctional epidermolysis bullosa, in which the epidermis separates from the dermis.

Fig. 2.9 Enlarged view of the DEJ of human embryonic epidermis showing the microfilament network within the basal epidermal cell (arrows), sites where desmosomes are forming (arrowheads) and the lamina densa. Note collagen fibrils (C) surrounding the dermal fibroblastic cells (×11,625).

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The antigens associated with the attachment structures (laminin 5/epiligrin/kalinin and 19 DEJ-1 for hemidesmosomes and anchoring filaments [33–36]; type VII collagen for anchoring fibrils [37]) are not seen by light microscopic immunostaining methods until early in the fetal period. It is likely, however, that keratinocytes begin to synthesize these proteins in the embryonic period but that the methods used for detection are not sensitive enough to demonstrate their low levels of expression. The dermoepidermal boundary is flat in the embryonic skin (Figs 2.2, 2.3 and 2.9) and thus presents a limited surface area for nutrients to traverse between the dermis and the epidermis. This may be relatively less important in the developing skin than in infant and adult skin because the dermis is thin and the small, dispersed bundles of dermal matrix proteins and the hydrated condition of the interstitial matrix permit more rapid diffusion of substances than the mature skin.

The dermis in the embryo is highly cellular (Figs 2.2 and 2.10), but it also contains the extracellular fibrous matrix proteins, types I, III, V and VI interstitial collagens, characteristic of adult dermis [32,38–40,41–45]. Small bundles of collagen accumulate in a thin, dense layer, called the reticular lamina, immediately beneath the dermoepidermal interface (Figs 2.2b, 2.5 and 2.9). They are also dispersed throughout the dermis in varying densities according to the collagen type and age of the embryo. Types I, III and VI collagen are distributed uniformly throughout the dermis whereas type V collagen is concentrated primarily along basement membranes (at the DEJ and around blood vessels) and surrounding cells (Fig. 2.11). Fibre bundles within the interstitial spaces are widely dispersed by a hydrated, hyaluronic acid-rich proteoglycan matrix [46–48] (Fig. 2.12). The fluidity of the matrix at this stage permits migration of mesenchymal cells to sites of active tissue morphogenesis.

Fig. 2.10 Transmission (a) and scanning (b) electron micrographs of the embryonic dermis at 48 days EGA beginning at the DEJ. The matrix is less evident in the sectioned sample (a) than in the whole-mount specimen (b) (a, ×4500; b, ×1500).

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Fig. 2.11 Samples of embryonic skin immunostained with antibodies that recognize type I (a), III (b), V (c) and VI (d) collagens. Note that all of the collagens are concentrated beneath the DEJ but types III and V, especially, are found in association with all basement membranes. Types I, III and VI are found in the matrix throughout the dermal and subcutaneous tissue (a–c, ×150; d, ×300).

Immunostaining courtesy of Dr Lynne T. Smith.

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Fig. 2.12 Section of the body wall from a 57-day EGA embryo treated with the Alcian blue/periodic acid–Schiff (PAS) histochemical stains. The bright pink staining of the epidermis (glycogen) and DEJ (glycoproteins) indicates a PAS-positive reaction. The blue dermis reflects the high content of hyaluronic acid. The dermal–subcutaneous boundary is marked by a transition to a lighter slightly purple reaction indicating more of the collagen–glycosaminoglycan complex (×300).

Immunohistochemistry courtesy of Dr Richard Frederickson.

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A broader zone of sulphated proteoglycan-rich matrix, called the compact mesenchyme, is delineated beneath the epidermis on the basis of its rich concentration of cells that express growth factor receptors – the platelet-derived growth factor receptor β (PDGFR-β) and PDGFR-α (see Fig. 2.5), nerve growth factor receptor (NGFR) – and cell adhesion molecules (e.g. neural cell adhesion molecule, NCAM) [49,50]. Evidence from the skin of non-human species during development has shown enlargement of the composition of growth factors and receptors and adhesion molecules that are included in this dermal zone (reviewed in refs [49] and [51–53]). The compact mesenchyme may be involved in the exchange of signals between the epidermis and dermis and may be very important in stimulating the onset of appendage formation. Many of the growth factors that correspond to the receptors on the mesenchymal cells are produced by cells of the developing epidermis (e.g. PDGF-AA, PDGF-BB and NGF) (Fig. 2.5). The compact mesenchyme may also be the earliest evidence of a papillary dermis. In the adult, the modified composition and structure of the papillary dermis probably reflects molecular interactions between the epidermal and dermal cells, similar to the situation of the compact mesenchyme.

Elastic fibres per se are not formed in the embryonic skin, but fibrillin (the microfibrils of elastic fibres) (Fig. 2.13) and elastin proteins of the elastic fibre can be identified immunohistochemically [32,38–42,44] and microfibrils can be seen by electron microscopy [32].

Fig. 2.13 Section of skin from a 57-day EGA human embryo immunostained with an antifibrillin antibody. Note staining throughout the dermis (×200).

Immunostaining courtesy of Dr Lynne T. Smith.

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Fine nerve fibres and capillaries are present within the compact mesenchyme and deeper dermis (Fig. 2.14a), and large nerve trunks and vessels are readily apparent in the subcutaneous region. Reconstructions of vessels from serial sections of developing first-trimester skin have shown that the the basic pattern of cutaneous vasculature is established in the first trimester [54]. New vessels presumably both form de novo from dermal mesenchyme and sprout from deeper, established vessels through a process that includes endothelial cell migration, capillary budding and vessel remodelling [55]. The events and mechanisms of these processes have not been explored beyond the morphological descriptions and antigenic characterization of the endothelial cells at various ages during development [55,56]. Pieces of full-thickness skin and sections of skin immunostained with an antibody that demonstrates all cutaneous nerves (protein gene product 9.5 or PGP 9.5) [57,58] reveal finely beaded nerve filaments distributed in an impressive density in the subepidermal region and in association with blood vessels (Fig. 2.14b and c). The number of fibres recognized by this antibody increases during development as the fibres become organized in networks throughout the dermis and in relation to developing epidermal appendages [59]. At 7 weeks EGA, a few calcitonin gene-related product (CGRP)-immunopositive fibres, denoting sensory fibres, are also evident [59], but autonomic nerves are not yet recognized in the skin. Staining the tissue with the p75 low-affinity NGFR antibody also reveals the patterns of nerve fibres and specific concentrations of mesenchymal cells (e.g. around developing hair follicles; see below) [60]. Both nerves and vessels are visible in stained, full-thickness samples of the nearly transparent skin (Fig. 2.15).

Fig. 2.14 Sections of human embryonic skin at 42 days EGA (a) and 59 days EGA (b) immunostained with PGP 9.5, which recognizes all cutaneous nerves, and of a sample of 52-day EGA embryonic skin (c) immunostained with p75 antibody, which recognizes the low-affinity NGFR. Note the large nerve trunks deep in the subcutaneous tissue (a), the significant density of the fine fibres in the tangential section of the dermis of (b) and the distribution of both nerves and vessels (c) (a, ×100; b, ×200; c, ×200).

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Fig. 2.15 Nerves and vessels in the skin of a 79-day EGA human fetus immunostained with an anti-neurofilament