66 Flashcards
1
Q
leukoderma and hypo pigmentation may be results of..? (generally)
A
1) decreased epidermal melanin content (melanin-related)
2) decreased blood supply to the skin (hemoglobin-related)
2
Q
hypomelanosis vs amelanosis ?
A
Hypomelanosis is a more specific term that denotes a reduction of melanin within the skin; amelanosis signifies the total absence of melanin
3
Q
depigmentation vs pigment dilution?
A
Depigmentation usually implies a total loss of skin color, most commonly due to disappearance of pre-existing melanin pigmentation, as in vitiligo. The term pigmentary dilution is used to describe a generalized lightening of the skin and hair, as in oculocutaneous albinism; this may only be apparent if the affected individuals are compared with unaffected relatives.
4
Q
Cutaneous hypomelanosis general classification?
A
1) melanocytopenic hypomelanosis, caused by a reduction in the number of epidermal and/or follicular melanocytes
2) melanopenic hypomelanosis, in which the number of epidermal and/or follicular melanocytes is normal, but the pigment cells fail to synthesize normal amounts of melanin and/or transfer it to surrounding keratinocytes.
5
Q
כלי עזר להערכת leukoderma?
A
woods lamp - 365 nm
Under visible light, it is sometimes difficult to distinguish between hypomelanosis and amelanosis, but the greater the loss of epidermal pigmentation, the more marked the contrast on Wood’s lamp examination.
This technique is also helpful in differentiating hypomelanotic macules from hemoglobin-related leukodermas; for example, nevus anemicus becomes inapparent.
6
Q
מתי השימוש ב woods lamp
הוא קריטי ושימושי בהערכת
leukoderma?
A
woods lamp is particularly useful in circumscribed leukodermas, individuals who have very lightly pigmented skin (phototypes I or II), and neonates.
7
Q
histology in leukoderma diagnosis?
A
Histologic examination of involved skin is most useful for several of the hypomelanoses associated with inflammatory processes (e.g. sarcoidosis, lichen sclerosus, mycosis fungoides).
8
Q
leukoderma distribution and diagnosis?
A
circumscribed (e.g. vitiligo), diffuse (e.g. albinism), linear, or guttate (e.g. idiopathic guttate hypomelanosis) helps to narrow the differential diagnosis.
9
Q
useful and key factors in leukoderma הערכה ראשונית של המטופל?
A
1) distribution
2) histology
3) woods lamp
4) The age of onset
5) presence or absence of preceding inflammation
6) anatomic location
7) degree of pigment loss
10
Q
what is vitiligo?
A
acquired disorder characterized by circumscribed depigmented macules and patches due to the loss of epidermal melanocytes.
also - Leukotrichia within areas of involvement is due to a loss of follicular melanocytes.
11
Q
vitiligo prevalence worldwide?
A
vitiligo affects ~0.5%–1% of the general population
12
Q
age onset of vitiligo?
A
shortly after birth to late adulthood, with an average age of ~30 years3 at onset.
13
Q
triggers of vitiligo onset?
A
Although patients with vitiligo may attribute the development of their disease to specific life events (e.g. physical injury, sunburn, emotional distress, illness, pregnancy), with the exception of the Koebner phenomenon, it has not been proven that these factors directly precipitate vitiligo.
14
Q
genetic factors in pathogenesis of vitiligo? examples?
A
1) 7% of the first-degree relatives of vitiligo probands had vitiligo.
2) 23% concordance rate in monozygotic twins supported the additional role of environmental factors
3) Genome-wide linkage analyses - identification of a number of susceptibility loci and candidate genes.
genes are involved in melanogenesis, immune regulation, or apoptosis
these are associated with other pigmentary, autoimmune, or autoinflammatory disorders
15
Q
explain the pathogenic pathway of vitiligo in general?
A
With a background of genetic susceptibility, intrinsic abnormalities of melanocytes are thought to render them more vulnerable to damage from oxidative stress. Oxidative stress also results in impairment of WNT signaling; the latter normally promotes differentiation of melanocyte precursors
16
Q
explain the inflammatory and immune cascade in vitiligo?
A
fig 66.1 page 1101 :
melanocyte release damage associated molecular patterns (DAMPs) such as HSP-70 (heat shock protein 70) and HMGB1 (high mobility group box protein B1) –>
stimulation of plasmacytoid dentritic cells and innate lymphoid cells in the skin –>
secretion of IFN alpha and gamma
also:
activated keratinocyte produce CXCL9 CXCL10 –>
recruitment of both CD4+ helper and CD8+ cytotoxic T cells which express CXCR3 –>
T cells produce pro-inflammatory cytokines such as IFN-γ and TNF resulting in the destruction of melanocytes
17
Q
recurrence of vitiligo within previously affected skin?
A
resident memory T cells which have a distinct transcriptional program and express characteristic cell surface markers such as CD69, CD103 and CD49a
18
Q
the most common presentation of vitiligo?
A
totally amelanotic (milk- or chalk-white) macules or patches surrounded by normal skin.
19
Q
describe vitiligo typical well developed lesions?
A
Well-developed lesions typically have discrete margins and may be round, oval, irregular, or linear in shape. The borders are usually convex,
20
Q
less typical lesions in vitiligo?
A
at their onset or when actively spreading, areas of vitiligo may be more ill-defined and hypomelanotic rather than amelanotic.
occasionally the lesions have a hyperpigmented border, and a blue color can result when vitiligo develops in areas of post-inflammatory dermal pigmentation.
21
Q
vitiligo symptoms?
A
usually asymptomatic, but pruritus is occasionally noted, especially within active lesions.
Clinical erythema or pruritus rarely precedes vitiligo.
22
Q
vitiligo typical distribution?
A
Vitiligo may develop anywhere on the body.
it frequently localizes to sites that are normally relatively hyperpigmented, such as the face, dorsal aspect of the hands, nipples, axillae, umbilicus, and sacral, inguinal, and anogenital regions
Common sites of involvement also include areas subjected to repeated trauma, pressure, or friction (e.g. in body folds or via contact with clothing)
23
Q
typical facial vitiligo?
A
typically, facial vitiligo occurs around the eyes and mouth (i.e. periorificial)
24
Q
vitiligo on the extremities?
A
favors the elbows, knees, digits, flexor wrists, dorsal ankles, and shins
25
palmoplantar and oral mucosa vitiligo involvement in lightly pigmented individuals?
often difficult to visualize without Wood’s lamp examination.
26
in acrofacial vitiligo, periungual involvement associated with?
eriungual involvement of one or more digits may be associated with lip depigmentation; however, either can be an isolated finding.
27
The incidence of body leukotrichia In vitiligo?
varies from 10% to >60%, as vitiligo often spares follicular melanocytes. The occurrence of leukotrichia does not correlate with disease activity.
28
Isomorphic Koebner phenomenon in vitiligo?
development of vitiligo within sites of trauma, such as a surgical excision or thermal burn. It is more common in patients with progressive vitiligo.
29
what types of Clinical classification of vitiligo do you know? elaborate
- The 2012 Vitiligo Global Issues Consensus Conference:
1) vitiligo: be used as the umbrella term for all non-segmental forms of vitiligo
2) Segmental vitiligo: clinically unambiguous segmental distribution of depigmented lesions
3) mixed vitiligo: the coexistence of segmental and non-segmental vitiligo.
- An additional classification:
1) localized:
- Segmental: involves one or more body segments, usually with roughly quadrilateral shapes and not crossing the midline. typically has rapid onset and often associated leukotrichia
- Focal: undetermined/unclassified form, depigmented macules are localized to one area but not clearly in a segmental distribution. after 1–2 years of follow-up, more definitive classification is possible.
- Mucosal: only the mucous membranes are involved
2) Generalized:
● Vulgaris: scattered patches that are widely distributed
● Acrofacial: distal extremities and face
● Universal: complete or, more commonly, nearly complete depigmentation
30
prevalence of different variants of vitiligo? which is the most common? pediatric?
Overall, >90% of vitiligo patients have vulgaris or acrofacial variants. Segmental vitiligo is more common in children than adults, accounting for ~15%–30% of pediatric vitiligo
31
the most common location for segmental vitiligo?
the face
32
poliosis?
localised patch of white hairs due to decreased melanin in hair follicle
33
Follicular vitiligo presentation?
presents with leukotrichia in the absence of depigmentation of the surrounding epidermis
34
Vitiligo ponctué presentation?
an unusual clinical presentation of vitiligo, is characterized by multiple, small, discrete amelanotic macules (confetti-like), sometimes superimposed upon a hyperpigmented macule.
35
inflammatory vitiligo?
Erythema at the margin of a vitiligo macule is referred to as “vitiligo with raised inflammatory borders” or inflammatory vitiligo.
36
Trichrome vitiligo presentation?
a hypopigmented zone between the normal and depigmented skin.
This intermediate zone has a fairly uniform hue rather than a gradual progression from white to normally pigmented skin.
The number of melanocytes is also intermediate in this zone, suggesting a slower centrifugal progression compared to classic vitiligo.
37
Hypochromic vitiligo presentation? in which skin types? distribution?
described in patients with skin photo- types V and VI.
They present with persistent hypopigmented macules in a seborrheic distribution, with lesions coalescing on the face and scattered on the neck, trunk, and scalp.
There was no history of prior inflammation and a few individuals had additional achromic macules. Decreased melanocyte density was noted histologically.
38
the onset of vitiligo?
usually insidious
39
Clinical features associated with active progression of vitiligo?
hypomelanotic lesions with poorly defined borders and confetti-like lesions
40
The natural course of generalized vitiligo?
usually one of slow spread, but it may stabilize for a long period of time or evolve rapidly. Rarely, total body involvement develops within a few weeks or even days.
41
The natural course of segmental vitiligo? relevant clinical signs that affect spreading?
usually reaches its full extent within 1–2 years and remains restricted to the initial segmental area.
The presence of halo nevi and leukotrichia increases the likelihood of evolution from segmental to mixed vitiligo
42
vitiligo clinical scores and staging?
1) The vitiligo area scoring index (VASI), 2) Vitiligo European Task Force (VETF) score
3) vitiligo extent score (VES)
4) physician global assessment (PGA) that categorizes vitiligo extent
5) vitiligo signs of activity score (VSAS)
43
Ocular involvement in vitiligo? examples of syndromes?
- Uveitis is the most significant ocular abnormality associated with vitiligo.
- Non-inflammatory depigmented lesions of the ocular fundus evident in some patients with vitiligo, representing focal areas of melanocyte loss.
- Vogt–Koyanagi–Harada syndrome
- Alezzandrini syndrome
44
Vogt–Koyanagi–Harada syndrome? histology?
characterized by: (1) uveitis; (2) aseptic meningitis; (3) otic involvement (e.g. dysacusia); and (4) vitiligo, especially of the face or sacral region, and associated poliosis.
Histologic examination of amelanotic skin, which classically appears after the extracutaneous symptoms, demonstrates an infiltrate consisting primarily of CD4+ lymphocytes, suggesting a prominent role for cell-mediated immunity.
45
pigment cells in the eye?
The uveal tract (iris, ciliary body, and choroid) and retinal pigment epithelium contain pigment cells
46
otic involvement in vitiligo?
An association between vitiligo and high-frequency sensorineural hearing loss was documented, possibly reflecting the role of cochlear melanocytes in regulation of auditory function. However, there is no clearcut evidence of otic abnormalities
47
Alezzandrini syndrome ?
a rare disorder characterized by unilateral whitening of scalp hair, eyebrows, and eyelashes as well as ipsilateral depigmentation of facial skin and visual changes.
In the affected eye, there is decreased visual acuity and an atrophic iris.
The pathogenesis of Alezzandrini syndrome is unknown, but it is believed to be closely related to VKH syndrome.
48
associated autoimmune diseases with vitiligo? prevalence%?
Up to 20% of patients with vitiligo have at least one comorbid autoimmune disorder
1) most commonly autoimmune thyroid disease, which affects ~15% of adults and ~5%–15% of children with vitiligo
2) alopecia areata (~2%–4% of vitiligo patients)
3) pernicious anemia
4) type 1 diabetes mellitus
5) myasthenia gravis
49
connective tissue diseases associated with vitiligo?
lupus erythematosus (discoid and systemic)
Sjögren syndrome
rheumatoid arthritis
50
skin and systemic diseases associated with vitiligo?
psoriasis, atopic diseases, inflammatory bowel disease, and metabolic syndrome.
Vitiligo can also occur in the setting of chronic graft-versus-host disease
51
congenital autoimmune syndrome and vitiligo? mechanism?
Patients with the autosomal recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome often develop vitiligo.
gene AIRE mutation --> failure to delete autoreactive T cells leads to autoimmune disease.
AIRE deficiency was found to result in tyrosinase-related protein-1 (TYRP1)- specific T cells that enhanced immune responses against melanoma
52
Childhood vitiligo? common subtypes? endocrinopathy? family history?
vitiligo vulgaris is the most common clinical type
the frequency of segmental vitiligo (~15%–30%) is significantly increased compared to that in adults (<5%–10%)
The incidence of associated endocrinopathies is less than in the adult vitiligo population.
A family history of vitiligo is associated with an earlier age of onset
53
histopathology of vitiligo? specific stains?
In lesions of vitiligo, melanocytes are typically absent or present in very small numbers.
The epidermal melanocyte density can be assessed with melanocyte-specific immunohistochemical stains:
Melan-A (MART-1), MITF, and HMB45, or via incubation of biopsy specimens with dihydroxyphenylalanine (DOPA; detects tyros- inase activity)
54
DD of vitiligo? complete depigmentation/amelanosis
- chemical or drug-induced (e.g. imatinib) leukoderma
- postinflammatory depigmentation
- the leukodermas associated with melanoma and scleroderma
- the late stages of treponematosis and onchocerciasis
- piebaldism (for congenital lesions)
55
DD of vitiligo? A single lesion in the young
A single circular depigmented lesion on the trunk of a young person may represent a stage III halo nevus
56
DD of vitiligo? lesions with partial loss of pigment?
1) postinflammatory hypopigmentation 2) idiopathic guttate hypomelanosis
3) tinea versicolor and other cutaneous infections (e.g. leprosy).
4) nevus depigmentosus can be distinguished by its stability and early onset
5) Treatment with potent topical corticosteroids can also lead to hypomelanosis.
57
how long does it take to determine whether a particular treatment is effective in vitiligo?
a period of at least 6 months
58
ares with good response vs resistant to treatment in vitiligo?
The face, neck, mid extremities, and trunk tend to have the best response to therapy, while the distal extremities and lips are the most resistant to treatment.
59
Repigmentation pattern after treatment in vitiligo?
Repigmentation initially appears in a perifollicular pattern (unless the affected site is hairless or has depigmented hairs) and/or at the periphery of the lesions.
60
rate of recurrent depigmentation after therapeutic repigmentation? vitiligo
the rate of recurrent depigmentation of vitiligo lesions is ~40%
61
topical treatment vitiligo? corticosteroid
intralesional?
Topical corticosteroids:
useful for localized areas of vitiligo in adults and children. highest response rates in newer lesions and those on the face and neck. approximately half of patients with vitiligo affecting ≤20% of the BSA achieved >75% repigmentation with super potent or high potent corticosteroid.
problem? atrophy (2-14%)
how to use it?
class 1 corticosteroids can be used in 6- to 8-week cycles or on a twice- weekly basis, alternating with topical tacrolimus, topical ruxolitinib, or a less potent topical corticosteroid. Treatment should be discontinued if there is no visible improvement after 4–6 months.
IL > less common due to pain and atrophy 30%
62
topical treatment vitiligo? Topical calcineurin inhibitors
face and neck lesions? efficacy similar to steroids. 65% of adults who applied tacrolimus 0.1% ointment twice daily for 24 weeks achieved ≥75% repigmentation of facial vitiligo,
extra facial? less effective than steroids (2% vs 35% on face lesions)
combination of TCI with NBUVB or laser provide synergistic effect (50%<)
may be used in combination with CS topical or maintenance after repigmentation (recurrence 10% vs 40% in placebo)
63
JAKI topical in vitiligo?
Ruxolitinib 1.5% cream is a Janus kinase 1/2 (JAK1/2) inhibitor FDA-approved for treatment of non-segmental vitiligo involving ≤10% BSA in patients ≥12 years of age
30% of individuals treated with ruxolitinib 1.5% cream *2 daily for 24 weeks achieved ≥75% improvement in the facial VASI, compared to 7%–11% placebo
common side effect? Acne at application sites
64
NBUVB in vitiligo?
311 nm
first-line therapy for adults and children ≥6 years of age with generalized vitiligo, especially if ≥15% BSA or cosmetically sensitive areas that typically respond to treatment.
initiating 200mJ/cm2 for all skin phototypes, increased by 10%–20% at each subsequent treatment until mild erythema
maximum dose? 1500mj/cm face 3000mj/cm body
if there is no evidence of repigmentation after 50 mildly erythrogenic exposures, discontinue therapy
Short-term side effects? painful erythema, pruritus, and xerosis
65
PUVA in vitiligo?
usually local PUVA for local lesions, although there is a risk of phototoxicity with blistering or koebnerization.
NBUVB is better than oral psoralen Duse to less side effects and higher efficacy
66
Excimer laser and lamp in vitiligo? combination treatment?
UVB light at a peak wavelength of 308nm
equal to superior efficacy compared with NBUVB, shorter duration, avoiding darkening of unaffected skin
however - primarily indicated for segmental vitiligo and other forms involving <10% BSA
2-3 times weekly, total 25-50 sessions
The repigmentation rate depends on the total number of sessions, not their frequency
combination ?
TCIs, topical corticosteroids, topical JAK inhibitors, or short-term oral corticosteroid mini-pulses
67
Oral corticosteroid mini-pulse therapy in vitiligo? when to use?
option for rapidly progressive vitiligo
use? oral dexamethasone 2.5–5mg on two consecutive days each week for 3 to 6 months.
טיפול שעוזר לעצור את התפשטות המחלה ב 90% מהמטופלים
it doesnt induce significant repigmentation.
relapse after discontinuation --> recommend maintenance therapy (NBUVB..)
side effects? insomnia, agitation, weight gain, acne, and hypertrichosis
68
systemic immunomodulators in vitiligo?
methotrexate and oral JAK inhibitors (e.g. tofacitinib, ruxolitinib, baricitinib)
anti IL 15
20% of patients treated with the oral JAK3/TEC inhibitor ritlecitinib for 24 weeks achieved ≥75% improvement in the facial VASI, compared to ~2% for placebo
69
Antioxidants in vitiligo?
increased repigmentation in combination with NBUVB compared with NBUVB alone
examples? Oral α-lipoic acid, Polypodium leucotomos, Ginkgo biloba, and various vitamins (e.g. C, E)
70
what is Afamelanotide?
α-melanocyte stimulating hormone (α-MSH) analogue that stimulates melanogenesis and melanocyte proliferation by binding to the melanocortin-1 receptor (MC1R)
71
Afamelanotide in vitiligo treatment?
addition of afamelanotide (monthly subcutaneous implants) to NB-UVB therapy increased the speed and extent of repigmentation compared to NB-UVB alone in patients with generalized vitiligo, especially those with skin phototypes IV–VI.
side effects? excessive tanning of non-lesional skin can increase the contrast with lesional skin
72
surgical therapy in vitiligo?
autologous transplantation
criteria?
stable disease for ≥6–12 months, absence of the Koebner phenomenon, no tendency for scar or keloid formation, and age >12 years.
73
effective Combination therapies in vitiligo?
1) phototherapy following surgical procedures
2) combining topical or systemic agents (e.g. TCIs, corticosteroids, JAK inhibitors, antioxidants) with NB-UVB or excimer laser therapy
74
relapse rate for repigmented vitiligo? Maintenance therapies?
relapse of repigmented vitiligo is ~40%
twice weekly application of tacrolimus 0.1% ointment can significantly reduce recurrent depigmentation in adults
75
Micropigmentation in vitiligo?
permanent dermal micropigmentation utilizes a non-allergenic iron oxide pigment to camouflage recalcitrant areas of vitiligo. This tattooing method is especially useful for the lips, nipples, and distal fingers, which have a poor rate of repigmentation with currently available treatments.
76
Depigmentation treatment in vitiligo?
in patients with limited normal skin areas
most common used agent?
20% monobenzyl ether of hydroquinone (MBEH) 1-2 daily for 9-12 months or more
it takes 1–3 months to initiate a response
other?
- Monomethyl ether of hydroquinone (MMEH) in a 20% cream
- Q-switched ruby laser, also combined with topical 4-methoxyphenol
side effects?
contact dermatitis, exogenous ochronosis, and leukomelanoderma en confetti
77
PATHOGENIC HYPOTHESES FOR VITILIGO?
1) Autoimmune destruction of melanocytes
2) An intrinsic defect in melano- cytes, their adhesive properties, and/or factors critical to their survival
3) Defective defense against oxidative stress leading to destruction of melanocytes
less supported:
4) destruction of melanocytes by neurochemical substances or a viral infection (e g cytomegalovirus)
OR:
A “convergence theory” that vitiligo results from a combination of several of these pathogenic mechanisms
78
what is Oculo-cutaneous Albinism?
OCA is the most common inherited disorder that leads to diffuse hypomelanosis. It includes a group of genetic disorders characterized by diffuse pigmentary dilution due to a partial or total absence of melanin pigment within melanocytes of the skin, hair follicles, and eyes. The number of epidermal and follicular melanocytes is normal.
79
what is ocular albinism?
Hypopigmentation involving primarily the retinal pigment epithelium
80
what is the most common HEREDITARY HYPOMELANOSIS disorder?
Oculocutaneous Albinism
81
prevalence of Oculocutaneous Albinism?
1:20,000
however, it is as high as 1:1500 in some African tribes.
82
inheritance pattern of OCA?
mostly - AR
rarely - AD
83
how many types of OCA?
8 types
OCA1-OCA8
84
pathogenesis of OCA1?
- OCA1:
mutation in tyrosinase gene (TYR) causing reduced (OCA1B) or absent (OCA1A) activity
85
pathogenesis of OCA2?
- OCA2:
mutation in P protein/OCA2, a transmembrane protein present in melanosomes and the endoplasmic reticulum (ER) and influence tyrosinase activity (by melanosomal PH or glutathione levels)
86
pathogenesis of OCA3?
OCA3:
mutations in TYRP1 (tyrosinase-related protein 1), melanocyte-specific protein that stabilizes tyrosinase and is involved in eumelanin synthesis
In both OCA1 and OCA3, the abnormal protein (tyrosinase or TYRP1) never leaves the ER to become incorporated into melanosomes
87
pathogenesis of OCA4?
- OCA4:
mutations in SLC45A2 which encodes solute carrier family 45 member 2 (MATP) a proton/glucose exporter that maintains the deacidification in later stage melanosomes that is required for tyrosinase activity
88
in which types of OCA protein never leaves the ER?
In both OCA1 and OCA3, the abnormal protein (tyrosinase or TYRP1) never leaves the ER to become incorporated into melanosomes
89
pathogenesis of OCA5?
linked to chromosome 4q24, but the responsible gene has not yet been identified.
90
pathogenesis of OCA6?
mutations in SLC24A5, which encodes a cation exchanger localized to the melano- somal membrane.
this gene was previously identified as one of the determinants of the physiologic variation in human pigmentation
91
pathogenesis of OCA7?
Mutations in LRMDA (formerly C10orf11); leucine rich melanocyte differentiation-associated protein is expressed in melanoblasts as well as melanocytes and is thought to have a role in melanocyte differentiation
92
pathogenesis of OCA8?
mutations in DCT (TYRP2) which encodes DOPAchrome tautomerase, an enzyme that catalyzes tautomerization of DOPAchrome to 5,6-dihidroxyindole-2-carboxylic acid in the melanin biosynthetic pathway
93
what is OA type 1? is it a distinct disorder?
an X-linked recessive disorder caused by mutations in GPR143 (G protein-coupled receptor 143; formerly OA1)
pigment cell-specific intracellular G protein-coupled receptor regulates melanosome formation and transport within melanocytes and cells of the retinal pigment epithelium --> retention of the aberrant protein within the ER.
it's no longer regarded as a distinct disorder
94
what causes ocular manifestations of OCA?
1) reduction in melanin within eye structures which leads to a translucent iris that transmits light upon globe transillumination, relatively hypopigmented retina and fovea that are associated with photophobia and reduced visual acuity
severity = amount of reduction in melanin pigment
2) misrouting of optic nerve fibers during development which leads to characteristic strabismus, nystagmus, and lack of binocular vision.
95
what is the difference between OCA1A or OCA1B?
OCA1B: tyrosinase activity is reduced OCA1A: tyrosinase activity is absent
96
which variant of OCA is "tyrosinase-negative"?
OCA1A
97
characteristic phenotype of OCA1A? ocular findings?
at birth: white hair, milky white skin, and blue–gray eyes
with age - the hair may develop a slight yellow tint due to denaturing of hair keratins
extreme sensitivity to UV light
strong predisposition to skin cancer
ocular?
Reduced visual acuity is most severe in OCA1A, and some patients are legally blind.
98
clinical features of OCA1B? phenotypes?
tyrosinase activity variable - phenotype varies from obvious to subtle pigmentary dilution.
examples of phenotypes?
- yellow albinism
- minimal pigment OCA
- platinum OCA
- temperature-sensitive OCA
at birth - little/no pigment
first and second decades of life - they develop some pigmentation of the hair and skin
99
what is the clinical features of temperature-sensitive OCA1B?
born with white hair and skin and blue eyes.
During puberty, scalp and axillary hairs remain white, but arm hairs turn light reddish brown and leg hairs turn dark brown.
The abnormal tyrosinase enzyme is temperature-sensitive, losing its activity above 35°C.
100
what is "tyrosinase-positive" OCA
OCA1B
OCA2
The vast majority of Black individuals with “tyrosinase-positive” OCA have OCA2.
101
clinical features of OCA2?
broad clinical spectrum
With time, the develop pigmented melanocytic nevi and lentigines in sun-exposed areas. lentigines can become large and darkly colored
102
clinical features of "brown OCA"?
in Black populations
primarily mutations in the P gene.
the hair and skin are light brown, the irides are gray to tan at birth, and sunburns are unusual.
103
OCA2 correlation with other genetic disorders ?
1% of Prader–Willi syndrome (PWS) and Angelman syndrome (AS) has OCA2
cause?
deletions of the 15q region which includes OCA2
PWS - paternal chromosome
AS - maternal chromosome
(deletion + another mutation in th second allele)
104
clinical features of OCA3?
most common in Black individuals
The “rufous” phenotype includes a red–bronze skin color, ginger-red hair, and blue or brown irides.
another phenotype - brown, but more often in OCA2
105
OCA4 - in which population most common?
most common in: Japan (~25% of patients), China (10%–20% of patients), or India (~10% of patients), and only ~5% of albinism in White individuals
106
OCA4 phenotype?
variable
hair color ranges from white to yellow or brown, and patients may or may not develop increased pigmentation of the skin and hair over time.
107
OCA5 - which population? phenotype?
Pakistani family
white skin and golden hair
108
OCA6 population? phenotype?
patients from Asia, Africa, and Europe. Affected individuals have white to light brown skin with a variable ability to tan, yellow to brown hair that often darkens with age, and blue to light brown irides
109
OCA7 population? phenotype?
primarily in patients from the Faroe Islands of Denmark
affected individuals have lighter skin than their relatives and hair color ranging from light yellow to brown
110
OCA8 clinical features?
mild pigmentary dilution of the skin and hair, often together with more pronounced ocular findings including nystagmus, reduced visual acuity, and foveal hypoplasia
111
clinical features of OA1?
substantial reduction in visual acuity, hypopigmentation of the retina, and the presence of macromelanosomes in the eyes.
they have nystagmus, photophobia, and foveal hypoplasia
skin?
normal or hypopigmented macules
histology of skin?
Macromelanosomes
112
female carriers of OA1 mutations - clinical features?
may have a “mud-splattered” fundus due to interspersed regions of pigmentation.
113
histology of OCA?
Although there is a reduction in melanin content, a normal number of melanocytes are present within the epidermis.
114
treatment options of OCA?
- Photoprotection
- Ophthalmologic evaluation
- Nitisinone: FDA approved for treating hereditary tyrosinemia type 1, potential therapy for OCA
115
what is Piebaldism?
AD disorder
uncommon
clinical features?
poliosis and congenital, stable, circumscribed areas of leukoderma due to an absence of melanocytes within involved sites.
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prevalence of Piebaldism?
1: 40,000 white individuals
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pathogenesis of Piebaldism?
mutation in KIT proto-oncogene (TK family receptor on the melanocytes)
A functioning KIT receptor is required for the normal development of melanocytes, both immediately before melanoblast migration from the neural crest and postnatally.
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distribution of leukoderma in Piebaldism?
characteristic distribution pattern favors the central anterior trunk, mid extremities, central forehead, and midfrontal portion of the scalp
classically spare the posterior midline.
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white forelock in Piebaldism?
found in 80%–90% of patients
the most familiar feature of piebaldism
its absence does not exclude the diagnosis.
white hair and amelanotic skin
midline location
triangular or diamond-shaped, and often symmetrical
may include the medial third of the eyebrow
nose involvement is rare
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typical leukoderma in Piebaldism?
irregular in shape, well-circumscribed, and milk-white in color. Normally pigmented and hyperpigmented macules and patches are typically apparent within the leukodermic patches
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extra-leukoderma findings in Piebaldism?
Hyperpigmented patches within uninvolved skin
axillary freckling
Poliosis of the eyebrows and eyelashes is a common finding, as are white hairs within areas of leukoderma
premature graying of the hair
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histopathology of Piebaldism?
By light and electron microscopy:
absence of melanocytes in the interfollicular epidermis & the hair follicles of amelanotic skin
The hyperpigmented macules?
characterized by an abundance of melanosomes in the melanocytes and keratinocytes.
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DD of Piebaldism?
- Waardenburg syndrome: exclude by ocular examination and evaluation of hearing
- Albinism–deafness syndrome: rare X-linked disorder, congenital sensorineural deafness and a severe piebald-like phenotype with extensive areas of hypopigmentation
- isolated white forelock can also be inherited as AD trait.
