Diseases

Charts of complex disease classification; albinism, disorders of cornification, Ehlers-Danlos syndrome, epidermolysis bullosa, mucopolysaccharidoses, osteogenesis imperfecta, palmoplantar ectodermal dysplasias, pemphigus, porphyria.


Albinism, oculocutaneous

 

Hair

Skin

Pigment (nevi, freckles)

Eyes, RR, iris trans-illumination

Melanosomes

Gene mutation

Other

Type IA, ty-neg

white

pink to red

non-pigmented nevi

gray to blue RR: present poor vision, cartwheel in adults

stage I & II

tyrosinase gene (t-/t-)

scalp biopsy; prenatal diagnosis

Type IB, Ym

white birth, yellow-red by 6 mos.

white at birth, slight tan

present

blue infancy, darkens, RR present

stage III pheomelanosomes

tyrosine gene decreased activity

 

Type I, Ts

white birth, yellow scalp, legs brown

creamy white, slight tan

present

blue; no iris pigment, RR present

stages I, II scalp, stages II, III leg hair

tyrosinase gene

T° sensitive loss of activity of tyrosinase above 35-37° C

Type I min. pig.

White birth, white to yellow adults

pink-white, no tan

absent

gray to blue, pupil pigment RR present, clumps at limbus

sate stage II, some with melanin

tyrosinase gene

heterozygotes have zero- normal tyrosinase activity

Type II, ty-pos

white, yellow tan with age

pink-white to cream

present, may be numerous

blue, yellow-brown RR may be absent, limbus/ cartwheel

to stage III, eumelanosomes

P gene; 15q

tyrosinase assay suggests heterogeneity

Type IV, Brown

beige to light brown in Africans

cream to light tan exposed skin

un-common

hazel to lt. tan RR children, may be absent in adults, cartwheel

stage I to II some lightly pigmented stage IV

unknown

tyrosinase normal

Type V, rufous

mahogany red to deep red

reddish brown

may be present

reddish brown to brown, RR unknown

unknown

unknown

New Guineans and Africans

Type VIA, HPS

white, red, brown

cream gray to normal

present

blue-gray to brown, RR in light skinned, not dark, cartwheel

to stage III pheomelanosomes and eumelanosomes

? pallid gene

lysosomal d., heterozygotes; low thioredoxin reductase, Puerto Ricans and Dutch

Type VIB, CHS

blond to dark brown, steel-gray tint

pink to pink-white

present

blue to dark brown, RR present

macromelanosomes and normal to stage IV

unknown

lysosomal d., susceptible to infection, giant lysosomal granules, lymphoreticular malignancy

Type VII, AD

white to cream, red tint

white to cream

may be present

gray to blue, translucent to cartwheel, RR children

stage I to early stage III, no structural abnormality

unknown

 

XL, Nettleship

normal to slightly light

normal to mildly light

present

normal, cartwheel C diaphanous, X RR present X

macromelanosomes in normal skin of hemi-and heterozygotes

 

hypomelanotic macules and patches in some individuals

XL with deafness

normal to mildly light

normal to mildly light

present

normal, cartwheel C diaphanous, X RR present X

macromelanosomes in normal skin of hemi and heterozygotes

 

hegh frequency hearing loss onset puberty to 40 years

AR

normal to slightly light

normal to mildly light

present

normal, cartwheel to diaphanous RR present X

normal

 

males and females equally affected

OA-lentigines-deafness

normal

normal

lentigines

normal, cartwheel to diaphanous, RR present

macromelanosomes in lentigines

 

AD congenital sensorineural deafness

Adapted from Witkop CJ, Quevedo WC, Fitzpatrick TB, et al. Albinism. In: Scriver CR, Beaudet AL, Sly WS, et al. eds. The Metabolic Basis of Inherited Disease, 6th ed. New Your: McGraw-Hill 1989:2905-2947.

 

 

Disorders of Cornification

 

 

Name

Synonyms

Abnormality

 

DOC 1

vulgaris

ichthyosis vulgaris

keratohyalin granule; absent profilaggrin

AD

DOC 2

steroid sulfatase deficient

recessive X-linked ichthyosis

epidermal enzyme; absent cholesterol sulfatase

XR

DOC 3

bullous

epidermolytic hyperkeratosis; bullous congenital ichthyosiform erythroderma

keratin filaments; genetic defect in K1 or K10

AD

DOC 4

lamellar-recessive

lamellar ichthyosis

cornified envelope; defective transglutaminase cross-linking

AR

DOC 5

congenital erythrodermic

lamellar ichthyosis; congenital ichthyosiform erythroderma

lamellar bodies; malformed lipid bilayer; decreased enzyme function

AR

DOC 6

harlequin

harlequin fetus

lamellar bodies & keratohyalin granules; absent lipid bilayer, absent filaggrin

AR

DOC 7

lamellar dominant

autosomal dominant lamellar ichthyosis

 

AD

DOC 8

Curth-Macklin

ichthyosis hystrix type; Curth-Macklin

 

AD

DOC 9

Netherton’s

Netherton’s s., ichthyosis linearis circumflexa

 

AR

DOC 10

SjØgren-Larsson

SjØgren-Larsson s.

 

AR

DOC 11

phytanic acid storage

Refsum’s d.; heredopathia atactica polyneuritiformis

 

AR

DOC 12

neutral lipid storage

neutral lipid storage d; Chanarin-Dorfman s.

 

AR

DOC 13

multiple sulfatase deficiency

multiple sulfatase deficiency s.

 

AR

DOC 14

trichothiodystrophy

Tay’s s.; trichothiodystrophy; IBIDS s.

 

AR

DOC 15

keratitis-deafness

KID s.; atypical ichthyosiform erythroderma with deafness

 

AD,AR

DOC 16

unilateral hemidysplasia

CHILD s

 

XD?

DOC 17

chondrodysplasia punctata

Conradi-Hunermann s.; chondrodysplasia punctata

 

AR,XD

DOC 18

erythrokeratoderma viriabilis

erythrokeratoderma viriabilis

 

AD

DOC 19

erythrokeratolysis heimalis

erythrokeratolysis heimalis

 

AD

DOC 20

erythrokeratoderma progressiva symmetrica

erythrokeratoderma progressiva symmetrica

 

AD

DOC 21

peeling skin

peeling skin s.; familial continuous skin peeling

 

AR

DOC 22

Darier’s

Darier’s d’; keratosis follicularis

 

AD

DOC 23

Giroux-Barbeau

Giroux-Barbeau s.

 

AD

DOC 24

keratosis follicularis spinulosa decalvans

keratosis follicularis spinulosa decalvans

 

XD?

Williams ML, Elias PM. Genetically transmitted, generalized disorders of cornification. The ichthyoses. Dermatol Clin 1987; 5: 155-78.

 

 

Ehlers-Danlos Syndrome

 

Type

Inheritance

Defect

Skin Bruising

Skin Elasticity

Skin Fragility

Joint laxity

Complications

I (gravis)

AD

?

++

+++

+++

+++

aorta, bowel rupture, poor healing

II (mitis)

AD

?

+

++

++

++

minimal; mild form of I

III (hyper-mobile)

AD

?

+

+

+

+++

arthritis, muscle pain

IV (ecchy-motic)

AD/AR

type III collagen

+++

-

+++

+

ruptured aneurysm, obstetric hemorrhage, pneumothorax

V

XLR

lysyl oxidase deficiency

+

+++

+

++

mitral/tricuspid valve prolapse, bowel rupture, arthritis, muscle pain

VI

AR

lysyl hydoxylase deficiency

++

+++

++

+++

hypotonia, kyphoscoliosis, osteoporosis; ocular fragility

VII

AD

Missing N-telo-peptide of a1/a2 chains type I collagen

+

++

+

++++

severe ligament and joint laxity, hip arthritis and dislocations

VIII (peri-odontal)

AD

?

+

+

+++

+

severe periodontitis

IX (X-linked cutis laxa

XLR

lysyl oxidase deficiency, abnormal Cu2+ metabolism

+

+

++

+

hernia

X

AR

abnormal fibronectin

++

++

+

++

 

XI

AD

?

+

+

+

+++

joint dislocations

 

 

Epidermolysis Bullosa

 

epidermolysis bullosa simplex

AD, basal cell mutation K5 (ch 12q) K14 (ch 17q)

Weber-Cockayne; palmoplantar bullae, callous, hyperhidrosis, superinfections

Generalized (Koebner); generalized bullae

Dowling-Meara; widespread herpetiform lesions, milia, nail dystrophy, mucous membranes erosions, high morbidity & mortality.

epidermolysis bullosa,  junctional

AR, mutation in laminin 5 protein gene, intra-lamina lucida bullae 

Herlitz; bullae without scarring, milia, absent nails, dysplastic teeth, pyloric atresia, anemia, growth retardation, mortality

Non-Herlitz; bullae of extremities, heal with atrophic scarring, scarring alopecia

epidermolysis bullosa, dystrophic

AD

Cockayne-Touraine; bullae on extremities, milia, scarring, dystrophic nails

Albopapuloid Pasini variant; widespread bullae, healing with atrophy, no milia, hypopigmented scars on trunk, dystrophic nails

AR; generalized bullae with atrophic scarring, hyper/hypopigmentation, dystrophic nails, mitten deformities, flexural contractions, malnutrition, mucous membrane erosions, dysplastic teeth, anemia, SCC

 

 

Epidermolysis bullosa                                                                     

 

Type

Inheritance

onset

clinical features

cleavage

notes

EB simplex

AD

 

 

 

 

1) localized (Weber-Cockayne)

 

infancy, early childhood

palmoplantar blisters

intraepidermal (basilar)

hyperhidrosis

2) generalized (Koebner)

 

birth, early infancy

bullae on dorsal hands and feet

intraepidermal, vacuolated basal layer

negative Nikolsky sign

3) herpetiformis (Dowling-Meara)

 

birth

bullae generalized circinate grouping

intraepidermal, clumped tonofilaments

palmoplantar keratoderma, mucosal erosions

4) superficialis

 

birth/infancy

peeling skin generalized or extremities

subcorneal, granular

 

Junctional EB

1) generalized lethal

(Herlitz, gravis)

AR

Birth

severe generalized blistering and denuded skin, milia, scarring, atrophy, dystrophic or absent nails, pitted tooth enamel

intralamina lucida; hemidesmosome defect

oral erosisons, growth retardation, severe anemia, granulation tissue

2) generalized non-lethal (mitis)

 

 

as above with no milia and no mucous membrane lesions

 

 

Dystrophic EB

1) generalized-recessive (Hallopeau-Siemans, gravis)

AR

Birth

hemorrhagic bullae and scarring with milia, mitten deformity, scarring alopecia, mucosal erosions

sublamina densa; anchoring fibril defect, decreased or absent type VII collagen

severe anemia, growth retardation, caries, SCC, high mortality

2)generalized dominant

a) Pasini

AD

 

severe expression; claw-like hands, albopapuloid lesions, white atrophy, scarring with milia

sublamina densa defect; anchoring fibrils

normal growth, ichthyosis, keratosis pilaris, hyperhidrosis

b) Cockayne-Touraine

 

 

hemorrhagic bullae, atrophic scars, milia, rare oral cavity lesiion, normal teeth

 

 

 

 

Epidermolysis Bullosa

 

Type

Inheritance

Level of split

Scarring

Associated features

EB simplex-generalized Koebner

AD

basal cells

none

hyperhidrosis of feet, UVL

EBS localized (Weber-Cockayne)

AD

basal cells

none

hyperhidrosis of feet, hyperkeratotic lesions of palms

EBS-mottled hyperpigmentation

AD

basal cells

none

punctate hyperkeratoses; nails

EBS-herpetiformis (Dowling-Meara)

AD

basal cells

rare

hyperkeratoses of palms/soles

EBS-mottled pigmentation, punctate keratoderma

AD

basal cells

none

nail loss, carous teeth

EBS-localized, anodontia (Kallin s.)

AR

intraepidermal level

none

anodontia, deafness

EBS-Ogna

AD

basal cells

?

onychogrophysis of great toe

EBS-Bart

AD

basal cells

fine

dystrophic nails

EBS-Letalis

AR

basal cells

probably

anemia, frequent fatal

EBS-Mendes de Costa

XLR

basal cells

?

alopecia, microcephaly

 

 

Lamina Lucidiolytic Epidermolysis Bullosa (Junctional)

 

LEB-Gravis (Herlitz, EB hereditaria letalis, generalized atrophic EB gravis)

AR

lamina lucida

atrophy and scarring

nail loss, vegetting lesions, dystrophic teeth (cobblestoning), niciene absent , kalinin decreased

LEB-mitis (generalized atrophic EB mitis)

AR

lamina lucida

atrophic lesions

hair/nail loss, decreased life span, dystrophic teeth

LEB-localized, minimus

AR

lamina lucida

?

nail loss, dystrophic teeth, normal growth and development

LEB-cicatricial

AR

lamina lucida

scarring

syndactyly, hair, esophageal

LEB-inversa

AR

lamina lucida

atrophy

inverse involvement, nail loss

LEB-progressiva (neurotropica)

AR

lamina lucida

atrophy

onset 5-8 years, palmoplantar involvement

 

 

Dermolytic Epidermolysis Bullosa (Dystrophic EB)

 

DEB-Cockayne-Touraine

AD

below basal lamina, anchoring fibrils decreased

scarring

nail/teeth involvement, SCC, esophageal stenosis, nail involvement

DEB-minimus

AD

sub-basal lamina

?

nails involved, minimal disability

DEB-pretibial

AD

separation in sublamina

scarring, atrophy

normal teeth

DEB-albopouloidea (Pasini)

AD

subbasal lamina blistering

mild scarring

teeth near normal, nails involved, chondroitin sulfate

DEB-Hallopeau-Siemens

AR

sub basal lamina blistering

profound

mitten deformity, syndactyly, dystrophy, SCC, teeth dystrophy, nails normal, esophageal involvement

DEB-inversa

AR

sub basal lamina

?

nails normal, esophageal involvement severe

 

 

 

Mucopolysaccharidoses

 

 

Eponym

Inheritance

Enzyme defect

Urine MPS

I-H

Hurler

AR

a-L-iduronidase

DS, HS

I-S

Scheie

AR

a-L-iduronidase

DS, HS

I-H-S

Hurler-Scheie

AR

a-L-iduronidase

DS, HS

II-A

Hunter (severe)

XR

iduronate sulfatase

DS, HS

II-B

Hunter (mild)

XR

iduronate sulfatase

DS, HS

III-A

Sanfilippo A

AR

heparan N-sulfatase

HS

III-B

Sanfilippo B

AR

N-acetylglucosaminidase

HS

III-C

Sanfilippo C

AR

acetyl coenzyme A; a-glucosamine-N-acetyltransferase

HS

III-D

Sanfilippo D

AR

N-acetyl-a-glucosamine-6-sulfatase

HS

IV-A

Morquio A (classic)

AR

N-acetyl-a-glucosamine-6-sulfatase

KS

IV-B

Morquio B (mild)

AR

b-galactosidase

KS

VI

Maroteaux-Lamy (severe)

AR

N-acetylgalactosamine-4-sulfatase (arylsulfatase B)

DS

VI

Maroteaux-Lamy (intermediate, mild)

AR

arylsulfatase B

DS

VII

Sly

AR

b-glucuronidase

DS, HS

DS= dermatan sulfate   HS= heparan sulfate   KS= keratan sulfate

 

 

Osteogenesis Imperfecta

 

O. I.

defective biosynthesis of type I collagen; brittle, osteoporotic bones, blue sclerae, lax joints

Biochemical defect

Type I

AD; classic, mild, AKA OI with blue sclerae normal stature, hearing loss (50%), dentinogenesis imperfecta (rare)

decreased type I procollagen production; substitution other than glycine in a1(I)

Type II

AD, AR, AD new mutation; perinatal lethal, beaded ribs, compressed femurs, platyspondylisis AKA OI congenita

rearranged COL1A1 & COL1A2 genes; substitution for glycyl residues in a1(I) or a2(I) chain

Type III

AD, AR (rare), new mutation; progressive deforming type, very short stature, variable sclerae hue, dentinogenesis common, hearing loss common

frame shift mutation prevents incorporation of proa2(I) into molecules (non-collagenous defect)

Type IV

AD; normal sclerae, mild bone deformity, short stature, dentinogenesis common, hearing loss (some)

point mutation in a2(I) chain, rare point mutation in a1(I) chain, small deletions in a2(I) chain

 

 

Palmoplantar Ectodermal Dysplasias

 

 

inheritance

ainhum

bone

cardiac

cysts

deafness

eye

hair

infection

malignancy

nail

neural

oral

pigment

teeth

I

AD

-

-

-

-

-

-

-

-

-

+

-

+

-

-

II

AD

-

-

-

+

-

-

+

-

-

+

-

-

-

+

III

AD

-

-

-

-

-

-

-

-

+

-

-

+

-

-

IV

AR

-

+/-

-

-

-

-

+/-

+

-

+

-

+

-

+

V

AR

-

-

-

-

-

+

-

-

-

-

+/-

-

-

-

VI

AR/AD

+

-

-

-

+

+

+

-

-

+

-

+

-

+

VII

AD

+

-

-

-

+

-

+

-

-

+

+

-

-

-

VIII

AR

+

+/-

-

-

-

-

-

-

+

+

+/-

+

-

-

IX

AD

-

+/-

-

-

-

-

-

-

+

+/-

-

-

-

-

X

AD

-

+/-

-

-

+/-

+

+

-

+

+

+/-

+

-

-

XI

AD

-

-

-

-

-

-

-

-

-

+/-

-

-

+

+/-

XII

AD

-

-

-

-

-

-

-

-

-

-

-

-

+

-

XIII

AD

+/-

-

-

-

-

+

+

-

-

+

-

+/-

+

+/-

XIV

AR/AD

-

-

+

-

-

-

+

-

-

-

-

-

-

-

XV

AD

+

-

-

-

+

-

-

-

-

+/-

-

-

-

-

XVI

AR

-

+

-

-

+

+

+/-

+

+

+/-

+

+

-

-

XVII

AD

-

+

-

-

-

+

-

-

-

+

-

-

-

+

XVIII

AD

-

+/-

-

-

-

-

-

-

-

+/-

+

-

-

-

XIX

AR

-

-

-

+

-

-

+

-

+

+

-

-

-

+

XX

AR

-

-

+

-

-

-

+

-

-

+

-

-

-

+

modified from: Fitzpatrick, p. 607

 

Pemphigus Diseases

 

 

pemphigus vulgaris

pemphigus foliaceus

IgA pemphigus foliaceus

paraneoplastic pemphigus

Epidemiology

Most common. Ashkenazi jews

idiopathic, drug-induced, endemic

rare

neoplasms

Antigen

desmoglein 3, 130-kd cadherin

desmoglein 1, 160-kd cadherin

unknown, some desmocollins I and II

250-kd desmoplakin I

230-kd BP1 antigen

210-kd desmoplakin II

HLA

DR4, DR6

DR1, DQ1 and DR4

 

 

Clinical Features

flaccid bullae, denuded areas, Nikolsky sign, painful oral erosions

superficial crusts, erosions, hypertrophic lesions

superficial crusts

mucosal erosions progress to intractable stomatitis, polymorphous skin eruption, lichenoid eruptions

Sites of predilection

mouth, spread to head, neck, upper trunk, intertriginous areas, esophagus, cervix.

Central face, then head, neck, upper trunk, extremities.  Rare oral lesions

 

stomatitis orally, head and neck, trunk, extremities, palms and soles

Histology

suprabasilar cleft, basal “row of tombstones” acantholytic cells in blister.  Eos and spongiosis in lower epidermis.  Scant infiltrate; eos, PMN, lymphs

vacuolization, acantholytic clefting in granular or subgranular layer.  Denuded roof, epidermal spongiosis with eos, perivascular infiltrate with eos, lymphs

1) subcorneal pustule with acantholytic cells

2) intraepidermal pustule with eos and rare acantholytic cells

variable, most suprabasilar acantholysis and inflammation.  Lichenoid infiltrate, keratinocyte necrosis

Immunofluorescence

linear IgG and C3 on epidermal cell surfaces

linear/granular IgA on epidermal cell surfaces

linear/granular IgA

IgG and complement in epidermal intercellular spaces, granular/linear complement along basement membrane zone

Notes

p. vegetans is variant: persistent hypertrophic lesions of flexures and umbilicus. Ab titers and d. activity correlate well.  Loss of attachment of cell membrane between desmosomes.

 

 

Poor prognosis, stomatitis is refractory

Treatment

prednisone, azathioprine, chlorambucil, methotrexate, cyclophosphamide, gold, cyclosporine, plasmapheresis

Prednisone, topical steroids, antimalarials, methotrexate, cyclophosphamide, azathioprine

dapsone, prednison, ?etretinate

treat the tumor, prednisone or immunosuppressive medications

 

Porphyria

 

Porphyria

Inheritance

Enzyme deficiency

Erythrocyte

Feces

Plasma

Urine

acute intermittent porphyria

AD

porphobilinogen deaminase

----

----

----

ALA, PBG

ALA dehydratase deficiency porphyria

AR

ALA dehydratase

ZnPROTO

COPRO, PROTO

ALA

ALA

congenital erythropoietic porphyria

AR

uroporphyrinogen III cosynthase

URO I  > COPRO I

COPRO I > URO I

URO I > COPRO I

URO I > COPRO I

erythropoietic protoporphyria

AD, variable

ferrochelatase

PROTO

PROTO

PROTO

----

hepatoerythropoietic porphyria

AR

uroporphyrinogen decarboxylase

ZnPROTO

COPRO, ISOCOPRO

URO, COPRO

URO, ISOCOPRO

hereditary coproporphyria

AD

coproporphyrinogen oxidase

----

PROTO > COPRO

COPRO

COPRO; acutely, ALA, PBG

porphyria cutanea tarda

AD, acquired

uroporphyrinogen decarboxylase

----

ISOCOPRO

URO, COPRO

URO I> III; 7-COOH-P III > I

variegate porphyria

AD

protoporphyrinogen oxidase

----

PROTO > COPRO

COPRO, PROTO

COPRO > URO acutely, ALA, PBG

 

 

 

 

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