Ichthyoses, Erythrokeratodermas, and Related Disorders Flashcards
When do inherited ichthyoses usually show up?
Birth or in infancy/early childhood
What is the unifying finding in inherited ichthyoses?
Abnormal epidermal differentiation or metabolism –> hyperkeratosis and/or epidermal hyperplasia
What is the underlying pathology of the inherited ichthyoses?
Dysfunction of cornified cell envelope disrupts skin barrier function which leads to increased transepidermal water loss
In what conditions can a Collodion membrane be seen in?
Lamellar ichthyosis and non- bullous congenital erythroderma is most common; also Sjögren-Larsson syndrome, Gaucher disease type 2, Hay-Well syndrome, trichothyodystrophy, Netherton syndrome, ectodermal dysplasia, and neutral lipid storage disease
How long does it take for the collodion membrane to resolve?
Several weeks
What are some important findings on histology in the ichthyoses?
Ichthyosis Vulgaris = diminished or absent granular layer
- Epidermolytic ichthyosis shows epidermolytic hyperkeratosis
What are some treatments that are important in the inherited inchtyosis?
General: Emollients and keratolytics; topical and systemic retinoids can help reduce hyperkeratosis
Neonatal tx: humidified incubators, emollients and close observation for infection, dehydration, and electrolyte abnormalities (hypernatremia from dehydration)
What are the 3 main types of palmoplantar keratodermas?
focal (localized areas of hyperkeratosis, usually over pressure points), diffuse (hyperkeratosis involves entire palmoplantar surface), and punctate (1- to 2-mm keratotic papules)
What is the treatment of palmoplantar keratodermas?
Topical keratolytics like salicylic acid, urea, etc, topical retinoids, and topical corticosteroids if inflamed.
- If severe can consider oral retinoids, CO2 laser and surgical paring or excision
What gene is mutated in Ichthyosis Vulgaris?
Filaggrin (FLG)
What is the inheritance in Ichthyosis Vulgaris?
Autosomal semidominant
What is the onset of Ichthyosis Vulgaris?
Infancy/childhood
What are the main skin findings in Ichthyosis Vulgaris?
- Fine, adherent scales on extremities and trunk with sparing of flexures
- Larger scale on lower legs
- Hyperlinear palms/soles, and furrowed heels
Associated clinical findings with Ichthyosis Vulgaris?
Keratosis Pilaris
- Atopic diathesis
Histology of Ichthyosis Vulgaris?
Diminished/absent stratum granulosum w/overlying orthohyperkeratosis
- Absent/reduced filaggrin immunostaining
What is the gene involved in steroid sulfatase deficiency (x-linked recessive ichthyosis)?
STS
The inheritance pattern in steroid sulfatase deficiency (x-linked recessive ichthyosis)?
x-linked recessive (continuous gene deletion may lead to Kallmann syndrome)
What is the onset of steroid sulfatase deficiency (x-linked recessive ichthyosis)?
Infancy
What are the primary cutaneous findings in steroid sulfatase deficiency (x-linked recessive ichthyosis)?
Fine to large, dark/brown, adherent scales on extremities, trunk, neck, and lateral face spares flexures, palms, soles, and face
What are some associated clinical features of steroid sulfatase deficiency (x-linked recessive ichthyosis)?
Corneal (comma-shaped) opacities; cryptorchidism; increased risk of testicular cancer, and hypogonadism
- Female carriers: corneal opacities; prolonged labor with affected child (placental sulfatase deficiency)
What is the histologic features of steroid sulfatase deficiency (x-linked recessive ichthyosis)?
Retained corneodesmosomes within the stratum corneum
What other lab abnormalities are seen in steroid sulfatase deficiency (x-linked recessive ichthyosis)?
Lipoprotein electrophoresis (increased mobility of β-fraction); plasma cholesterol sulfate increased; decreased steroid sulfatase activity in leukocytes; FISH, array CGH, genetic testing
- Maternal carriers may have abnormal triple/ quad screen during affected pregnancy with decreased serum estriol
What gene is mutated in lamellar ichthyosis?
Mostly TGM1 is most common
Also: ABCA12, CYP4F22, CERS3
Inheritance pattern of lamellar ichthyosis?
AR
Onset of lamellar ichthyosis?
Birth
What are the primary skin findings in lamellar ichthyosis?
- Often have collodion membrane at birth w/ ectropion and eclabium
- After collodion resolves –> presence of large, thick, plate-like brown scales
- Generalized distribution w/significant flexural involvement; absent or mild erythroderma; variable palm/ sole involvement (PPK)
Other clinical features in lamellar ichthyosis?
Heat intolerance (hypernatremic dehydration); often have scarring alopecia; dystrophic nails
- Hyperhidrosis
What are the histologic findings in lamellar ichthyosis?
They vary depending on the underlying gene etiology:
TGM1: Thin cornified envelope and disorganized lamellar bilayers
ABCA12: Absence of lamellar body content
NIPAL4: Defective lamellar bodies and perinuclear membranes within stratum granulosum
What is the most common cause of collodion baby?
Congenital ichthyosiform erythroderma
What are the genes involved in Congenital ichthyosiform erythroderma?
Big ones to remember: ALOXE3, ALOX12B
Others: TGM1, NIPAL4 (ICHTHYIN), PNPLA1
What is the inheritance pattern for Congenital ichthyosiform erythroderma?
AR
What is the time of onset for Congenital ichthyosiform erythroderma?
Birth
What are the primary skin findings in Congenital ichthyosiform erythroderma?
After collodion resolves, there is fine, white scale, in generalized distribution with the flexures involved
The erythroderma is variable with palm/sole involvement
Other clinical findings in Congenital ichthyosiform erythroderma?
Heat intolerance/hypohidrosis; variable scarring alopecia and ectropion
What are the genetic and clinical features of congenital self-healing collodion baby?
AR, TGM1, ALOXE3, ALOX12B, the onset is birth
- Collodion membrane at birth; after resolution, the skin appears normal without the features of ichthyosis
What is the gene and the inheritance pattern of harlequin ichthyosis?
ABCA12
AR
What is the onset of harlequin ichthyosis?
Birth
What are the primary skin findings in harlequin ichthyosis?
Very thick, yellow-brown plates of scale with large, deep and bright red fissures that tightly encase the neonate
- Also has extreme ectropion, eclabium, and ear deformities
- Survivors develop severe CIE-like phenotype
- Early initiation of systemic retinoids and specialized neonatal intensive care reduces mortality
What is the treatment for Harlequin ichthyosis?
Early initiation of systemic retinoids and specialized neonatal intensive care reduces mortality
What other lab and clinical abnormalities are important to watch for in Harlequin ichthyosis?
Premature delivery
- Neonatal hypothermia
- Hypernatremic dehydration
- Most common cuases of death are sepsis and respiratory insufficiency
Histologic findings in Harlequin ichthyosis?
Vesicular lamellar body ghosts, a paucity of secreted lamellar structures in stratum corneum
What is the inheritance pattern and genes involved in epidermolytic ichthyosis (bullous CIE)?
Genes: KRT1, KRT10
AD
May have somatic mosaicism, extensive epidermal nevi (ichthyosis hystrix); if it is gonadal mosaicism, then may have offspring with full-blown disease
What are the primary cutaneous findings in epidermolytic ichthyosis?
- At birth: erythroderma, blistering, and erosions
- Later: hyperkeratosis with cobblestone pattern (most prominent over joints), ridging of the flexures; generalized or localized; the variable degree of erythroderma, palmoplantar involvement, and blistering/ bullae
- Retinoids can exacerbate skin fragility
Other non-cutaneous findings in epidermolytic ichthyosis?
Frequent skin infections
Malodor
Gait and posture abnormalities
What is the histology of in epidermolytic ichthyosis?
Hyperkeratosis, keratinocyte vacuolization, and a prominent granular layer with clumped keratin in suprabasal cells
-Lamellar body accumulation
What is the inheritance pattern and genes involved for superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens)?
KRT2
AD
Time of onset for superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens)?
Birth
Primary cutaneous findings in superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens)?
Birth: Erythroderma and superficial blistering
Later: hyperkeratosis with accentuation over joints, flexures, and dorsal hands/ feet; “molting” of the skin; palms and soles spared
Histologic findings of superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens)?
Cytolysis of granular cells
What is the gene involved and the inheritance pattern for ichthyosis hystrix Curth-Macklin?
KRT1
AD
What is the time of onset for ichthyosis hystrix Curth-Macklin?
Birth
What are the primary cutaneous findings in ichthyosis hystrix Curth-Macklin?
- Mild to severe mutilating palmoplantar keratoderma
- Hyperkeratosis w/ verrucous, cobblestone, or hystrix-like pattern on extremities and trunk. These scales can often have a spiny appearance
Genetic inheritance pattern, gene involved, and prevalence of ichthyosis en confetti?
KRT10
AD
<20 cases described
Cutaneous findings in ichthyosis en confetti?
Birth: Erythroderma and scaling
Later: Confetti-like areas of scaling (result from revertant mosaicism); palmoplantar keratoderma
Histologic findings in ichthyosis en confetti?
Affected skin: loss of epidermal differentiation above the basal
layer with nucleolar vacuolization, loss of granular layer, and acanthosis
Revertant skin: normal
What are the involved genes in Netherton syndrome?
SPINK5 (encodes LEKT1, a serine protease inhibitor)
What is the mode of inheritance in Netherton Syndrome?
AR
What are the primary cutaneous findings in Netherton syndrome?
Congenital erythroderma w/ scaling
- There are 2 principle phenotypes of the dz:
- Ichthyosis linearis circumflexa (annular or serpiginous plaques w/ double-edged scale
- CIE-like: pruritus and eczematous plaques
What treatment should not be used in Netherton syndrome?
Tacrolimus ointment
- There is increased absorption due to skin barrier defect and there can be toxic effects from this
- Also should avoid keratolytics as these can be irritating
What are the other non-skin findings in Netherton syndrome?
Trichorrehexis invaginata
trichorrhexis nods can also be seen and pili tori (short/sparse hair and borws)
Increased IgE
Neonatal temperature instability, electrolyte abnormalities (hyponatremia), failure to thrive and infections
- Food and other allergies/analphylaxis are important to be aware of
Histology seen in Netherton syndrome?
Psoriasiform morphology
- Hair shaft light microscopy cna show trichorrhexis invaginata (bamboo hair, looks like ball in socket up close)
What is the inheritance pattern and genes seen in Sjögren-Larsson syndrome?
ALDH3A2/FALDH
- AR
Primary skin findings in Sjögren-Larsson syndrome?
Birth: Erythema and hyperkeratosis
Later: Fine to plate-like/dark scaling or nonscaling hyperkeratosis
- Tends to favors abdomen, neck, flexures; lichenification
- Can see palmoplantar keratoderma
- The pruritus can be severe
Other non-skin associated findings in Sjögren-Larsson syndrome?
Progressive spastic di- and tetraplegia; developmental delay; intellectual disability; seizures; perifoveal glistening white dots; white matter disease of the brain; photophobia
What is the genetic inheritance and gene involved in Neutral lipid storage disease with ichthyosis/Chanarin-Dorfman syndrome?
ABHD5 (CGI-58)
AR
What are the primary cutaneous findings in Neutral lipid storage disease with ichthyosis/Chanarin-Dorfman syndrome?
Generalized, fine, white scales with variable erythema
Other non-cutaneous findings in Neutral lipid storage disease with ichthyosis/Chanarin-Dorfman syndrome?
Developmental delay; hepatomegaly with liver fibrosis, elevated liver enzymes, and creatine kinase; myopathy; hearing impairment; cataracts
What histologic findings are seen in Neutral lipid storage disease with ichthyosis/ Chanarin-Dorfman syndrome?
Globular electron- lucent inclusions in the epidermis
What other lab abnormalities can be seen in Neutral lipid storage disease with ichthyosis/ Chanarin-Dorfman syndrome?
Peripheral blood smear to detect lipid vacuoles in granulocytes, eosinophils, and monocytes; oil stains of frozen tissue
What are the genes involved and the mode of inheritance for Refsum disease?
PHYH/PEX7
AR
What is the time of onset for Refsum disease?
Childhood to adulthood
What are the primary cutaneous findings in Refsum disease?
Fine, white scales on extremities and trunk, resembling ichthyosis vulgaris (50%)
What are the non-cutaneous other findings in Refsum disease?
Peripheral motor and sensory neuropathy
- Cranial nerve dysfunction (deafness, anosmia)
- Cerebellar ataxia
- Atypical retinitis pigmentosa (“salt and pepper pigment”)
- Cardiac: cardiomyopathy, arrhythmias w/ heart block
- Muscle wasting
Histologic findings in Refsum dz?
Orthokeratotic hyperkeratosis and lipid-containing vacuoles in basal keratinocytes
What are the other lab abnormalities seen in Refsum disease?
Increased plasma phytanic acid; phytanoyl-CoA hydroxylase activity assay in cultured fibroblasts
What is the important dietary modification needed in Refsum disease?
Diet is essential: decrease green vegetables, dairy products, and ruminant fats
What is the mode of inheritance and gene involved in Keratitis-ichthyosis-deafness syndrome?
GJB2 (encodes connexin 26)
AD (usually sporadic)
What are the primary cutaneous findings in Keratitis-ichthyosis-deafness syndrome?
Transient neonatal erythroderma
- Erythematous, hyperkeratotic plaques w/ well-demarcated, borders on face and extremities
- Follicular keratoses
- Thickening of the skin with an appearance of “coarse-grained leather;” stippled palmoplantar keratoderma
What are the main non-cutaneous findings in Keratitis-ichthyosis- deafness syndrome?
Congenital sensorineural hearing impairment
- Progressive keratitis with corneal neovascularization that may lead to blindness, conjunctivitis
- Recurrent mucocutaneous infections, especially with Candida albicans
- Increased susceptibility to oral and cutaneous squamous cell carcinoma
- Other: nail, hair, and dental anomalies; cheilitis
What is the mode of inheritance and the involved gene in Eryhthrokeratodermia variabilis?
GJB3/GJB4 (encode connexion 31, GJA1 and 30.3)
AD
Primary skin findings in Eryhthrokeratodermia variabilis?
Transient, variable, erythematous patches
- More stable, geographic, hyperkeratotic plaques over knees, elbows, Achilles tendons, extremities, buttocks, and lateral trunk
- Face and scalp often spared
- Less common generalized hyperkeratosis
- Palmoplantar keratoderma in ~50% of patients
What are the genes and mode of inheritance for progressive symmetric erythroderkatoderma?
LOR, GJB4, other
AD or AR
Primary cutaneous findings in progressive symmetric erythroderkatoderma?
Fixed, slowly progressive, erythematous, hyperkeratotic plaques with sharp, figurate borders; on cheeks, over knees, elbows, extremities, and rarely trunk
- Palmoplantar keratoderma common
What is the mode of inheritance and gene involved in Acral peeling skin syndrome?
TGM5
AR
Primary cutaneous findings in Acral peeling skin syndrome?
Recurrent spontaneous painless superficial peeling on dorsal hands and feet, followed by the development of mild erythema;
resolves without scarring
- Exacerbated by heat and humidity
Histologic findings in Acral peeling skin syndrome?
Separation occurs between the junction of the stratum granulosum and the stratum corneum
What is the mode of inheritance and gene involved in congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD sydnrome)
NSDHL ( 3beta-hydroxysteroid-dehydrogenase)
XLD (occurs nearly exclusively in women)
What are the primary cutaneous sx’s of congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD sydnrome)
Birth: Unilateral (right > left-sided) erythema and waxy, yellowish adherent scale on 1/2 of the body (trunk/ extremities)
Later: Verrucous hyperkeratosis of variable extent, with an affinity for skin folds
What are the non-clinical associated clinical features of Congenital hemidysplasia with ichthyosisiform erythroderma
and limb defects (CHILD) syndrome
Ipsilateral skeletal hemidysplasia (hypoplastic limbs)
- Ipsilateral organ hypoplasia; ipsilateral alopecia
- May also see stippled epiphyses/ chondrodysplasia punctata (similar to Conradi-Hunermann- Happle)
What is the gene affected and the inheritance of Conradi-Hünermann- Happle syndrome (X-linked dominant chrondrodysplasia punctata)?
EBP (emopamil-binding protein)
XLD (exclusively affects women)
Primary cutaneous findings in Conradi-Hünermann- Happle syndrome (X-linked dominant chrondrodysplasia punctata)?
Birth: Ichthyosiform erythroderma (generalized, vs unilateral in CHILD syndrome) with feathery, adherent scale along Blaschko’s lines
Later: The erythema resolves in first few months of life (unlike CHILD syndrome) and is replaced by follicular atrophoderma along Blaschko’s lines, most prominently on the forearms and dorsal hands
What are the main non-cutaneous clinical features of Conradi-Hünermann- Happle syndrome (X-linked dominant chrondrodysplasia punctata)?
Unilateral cataracts; stippled epiphyses/chondrodysplasia punctata seen only during infancy; asymmetric skeletal abnormalities, including scoliosis and rhizomelic limb shortening, but less severe than CHILD syndrome; frontal bossing w/ macrocephaly; patchy scarring alopecia
What can be seen on x-ray in Conradi-Hünermann- Happle syndrome (X-linked dominant chrondrodysplasia punctata)?
Epiphyseal stippling on X-ray only visible during infancy
What is the mode of inheritance and gene involved in ichthyosis follicularis-atrichia-photophobia (IFAP) syndrome?
MBTPS2
XLR
What are the primary cutaneous findings in ichthyosis follicularis-atrichia-photophobia (IFAP) syndrome?
Erythroderma, scaling, and follicular hyperkeratosis; generalized alopecia, including eyebrows and eyelashes
Non-cutaneous findings in Ichthyosis follicularis-atrichia- photophobia (IFAP) syndrome?
Growth retardation and microcephaly; corneal opacities and ulcerations; photophobia; vascularizing keratitis; variable hearing loss; nail dystrophy; variable intellectual impairment, developmental delay, seizures, and structural CNS anomalies; genitourinary anomalies and skeletal anomalies
Histologic features of Ichthyosis follicularis-atrichia- photophobia (IFAP) syndrome?
Follicular plugging and hypoplastic pilosebaceous structures
