Sec 11 Disorders of Melanocytes Flashcards
Ratio of melanocyte to keratinocytes
1:5-6
Pigmented polymer that is stored in cytosolic organelles
Melanin
Cytosolic organelles that are transferred to keratinocytes through melanocyte dendritic processes
Melanosomes
Describes a single epidermal melanocyte surrounded by several epidermal keratinocytes
Epidermal melanin unit
Major differentiated function of melanocytes
To synthesize melanin in specialized organelles within the melanocytes, the melanosomes, and to transfer melanosomes to neighboring keratinocytes in order to provide protection from UV irradiation
Are large (∼0.9 × 0.3 mm), elliptical in shape and contain a highly structured fibrillar glycoprotein matrix required for eumelanin synthesis.
Eumelanosomes
Are smaller (∼0.7 mm in diameter), spherical in shape and their glycoprotein matrix appears disorganized and loose
Pheomelanosomes
Dark, brown–black, and insoluble melanin
Eumelanin
Light, red–yellow sulfur-containing, and soluble melanin
Pheomelanin
Critical rate-limiting step in melanogenesis
Conversion of tyrosine to DOPA
The main function of melanin
To provide protection against UV-induced DNA damage by absorbing and scattering UV radiation (280–400 nm).
These proteins act as short cross-bridge structures connecting the organelle to the microtubules.
Kinesins (centrifugal, anterograde)
Dyneins (centripetal)
Potent stimulators of melanogenesis
MSH and ACTH
A diffusible free radical displaying pleiotropic bioregulatory effects in diverse cells and tissues which are produced by melanocytes and keratinocytes in response to inflammatory cytokines. Its production in keratinocytes is induced by UV irradiation increasing tyrosinase activity and melanogenesis
Nitric Oxide
A group of signaling molecules, primarily functioning as neurotransmitters and as endocrine hormones
Catecholamines
Most common inherited disorder of generalized hypopigmentation, with an estimated frequency of 1 in 20,000 in most populations.
Oculocutaneous albinism (OCA)
Results from the dysfunction of a normal complement of pigment cells, which results in complete or partial loss of cutaneous pigmentation.
Albinism
Caused by loss of function of the melanocytic enzyme tyrosinase resulting from mutations of the TYR gene. Most common type in non-Hispanic Caucasian patients.
OCA1
There is a complete inability to synthesize melanin in skin, hair, and eyes, resulting in the characteristic “albino” phenotype. They are born with white hair and skin and blue eyes, and there are no changes as they mature. The hair may develop a slight yellow tint due to denaturing of the hair protein due to sun exposure and/or shampoo use. The irides are translucent, appear pink early in life, and often turn a gray–blue color with time. No pigmented lesions develop in the skin.
OCA1A
Can range from minimal hair pigment to skin and hair pigmentation approaching the normal pigmentary phenotype for the individual’s genetic composition and continental ancestry. Most have very little or no pigment at birth and develop varying amounts of melanin in the hair and skin in the first or second decade of life. The hair color changes to light yellow, light blond, or golden blond first, as a result of residual pheomelanin synthesis, and eventually can turn dark blond or brown in adolescents and adults. The irides can develop light-tan or brown pigment, sometimes limited to the inner third of the iris, and iris pigment can be present on globe transillumination. Many individuals will tan with sun exposure. Pigmented lesions (nevi, freckles, lentigines) develop in the skin of individuals who have developed pigmented hair and skin.
OCA1B
Due to mutations of the P gene, which maps to chromosome arm 15q
OCA2
Hair is yellow at birth and remains so throughout life, although the color may turn darker. The skin is creamy white at birth and changes little with time. No generalized skin pigment is present, and no tan develops with sun exposure, but pigmented nevi, lentigines, and freckles often develop, since the cutaneous melanocytes in these individuals both remain susceptible to ultraviolet (UV)induced changes early in life and retain some ability to synthesize melanin later. The irides are blue–gray or light tan or brown.
OCA2
Due to mutations in the TYRP1 gene
OCA3
Distinct OCA phenotype in which the skin color is a mahogany brown with a slight reddish hue, and the hair color varies from deep mahogany to sandy red.
Rufous OCA
Due to dysfunction in trafficking cell type-specific products in cells containing lysosome-related organelles (LROs), including melanosomes in melanocytes.
Hermansky-Pudlak Syndrome (HPS)
These patients have OCA, with variable hypopigmentation of the skin, hair, and irides, and ocular abnormalities. They also lack platelet dense bodies and demonstrate a prolonged bleeding time, mucous membrane bleeding, a predisposition to epistaxis, easy bruising, and metromenorrhagia.
Hermansky-Pudlak Syndrome
Common and severe manifestation of HPS1 and HPS4.
Pulmonary fibrosis
A complex lipid-protein material said to accumulate in the cells of HPS patients, predominantly those with HPS1.
Ceroid lipofuscin
A rare autosomal recessive disorder characterized by severe immunologic defects, hypopigmentation, bleeding tendency due to absent or reduced platelet dense bodies, progressive neurologic dysfunction, and the presence of giant peroxidase-positive lysosomal granules in peripheral blood granulocytes. Mutations in the LYST (lysosomal regulator trafficking) gene have been associated with this.
Chediak-Higashi Syndrome (CHS)
Asyndrome combining pigmentary defects of the hair (poliosis or white forelock) and iris, congenital deafness, and developmental craniofacial abnormalities.
Waardenburg Syndrome (WS)
AD, usually heterozygous for mutations in PAX3; Individuals with have pigmentation abnormalities associated with craniofacial abnormalities. Dystopia canthorum, is seen virtually all cases. A broadening of the nasal root, the presence of hypoplastic alae nasi, and synophrys are other craniofacial abnormalities. Poliosis, such as the presence of a white forelock, is the most common pigmentation abnormality. Depigmented white spots on the skin occur less commonly, but are often located at the ventral midline reflecting the compromised migration of dysfunctional melanocyte precursors from their origin in the dorsal neural crest. Pigmentary abnormalities of the iris, including complete heterochromia irides (differently colored irises), partial heterochromia irides (variations of color within an iris), or hypoplastic blue irides, can also be seen as well as premature praying. Congenital deafness is present in 57% of cases.
WS1
This lateral displacement of the medial canthi of the eyes is the hallmark craniofacial defect found in virtually all cases of WS1.
Dystopia canthorum
MITF locus (15%) as a candidate locus for the disease gene. Notable for featuring only auditory-pigmentary symptoms.
WS2
Diagnostic criteria for WS2
Individuals fulfilling two of the following four criteria, in the absence of dystopia canthorum, limb deformity, or Hirschsprung disease, should be counted as affected:
- Congenital sensorineural hearing loss
- Pigmentary disturbance of iris
a. Complete heterochromia irides (two eyes of different color)
b. Partial or segmental heterochromia (segments of blue or brown pigmentation in one or both eyes)
c. Hypoplastic blue irides (characteristic brilliant blue, with thin iris stroma, in both eyes) - Pigmentary disturbance of the hair
a. White forelock from birth or in teens
b. Premature graying before age 30 years - A first- or second-degree relative with two or more of criteria 1–3
Also known as Klein–Waardenburg syndrome; heterozygous for a mutation in PAX3; patients have musculoskeletal abnormalities, manifested as limb contractures and hypoplasia of the limb musculature (in addition to features of WS1)
WS3
Also known as Shah–Waardenburg syndrome, is caused by heterozygous mutations in the transcription factor gene SOX10, or by homozygous mutations in the gene encoding the peptide ligand endothelin-3, EDN3, or its receptor, EDNRB. Associated with Hirschsprung’s disease or congenital aganglionosis of the colon.
WS4
A hypopigmentation–deafness syndrome resulting, like WS2, from mutations in MITF. These individuals exhibit generalized cutaneous hypopigmentation similar to that found in OCA2, rather than distinct depigmented patches. Reduced melanosomes in keratinocytes found in one affected individual 132 may account for the generalized hypopigmentation that is observed. Affected individuals invariably exhibit profound hearing loss.
Tietz Syndrome
Caused by mutations in the KIT proto-oncogene. Have depigmented patches on the ventral or lateral trunk and/ or the mid-extremities, sparing the hands and feet. Poliosis is a common feature. The depigmented patches tend to be larger than those observed in WS. Typically, not associated with deafness.
Piebaldism
Piebaldism with deafness
Woolf syndrome
AD condition, was recently shown to be caused by mutations in ADAR1. Patients exhibit speckled hypopigmentation, which is limited to the dorsa of the hands and feet.
Dyschromatosis symmetrica hereditaria
A multifactorial, polygenic disorder, with a complex pathogenesis, considered as most frequent depigmenting disorder (0.3-0.5%)
Vitiligo
May occur in individuals who encounter large doses of phenolic compounds, usually 4-tertiary butyl phenol (4-TBP) and other phenolic compounds that may be contained in cleaning solutions; usually initially involves the hands and forearms. It may appear at sites of skin trauma (Koebner’s phenomenon).
Occupational vitiligo
Principal clinical manifestation is the appearance of acquired milk-white macules with fairly homogeneous depigmentation and well-defined borders often demonstrates a predilection for sunexposed regions, body folds, and periorificial areas.
Vitiligo
Multiple scattered lesions distributed in a more or less symmetrical pattern; the most common presentation of GV
Vitiligo vulgaris
Affects the distal end of fingers and facial orifices in a circumferential pattern; a subtype of GV
Acrofacial vitiligo
Combination of acrofacial and vulgaris, or segmental and acrofacial types.
Mixed vitiligo
Complete or nearly complete depigmentation of the whole body; the most severe form of GV.
Vitiligo universalis
Characterized by the presence of one/few macule(s) in one area but not distributed in a segmental pattern; considered a precursor form of GV.
Focal vitiligo
A term reserved for depigmentation of mucous membrane alone.
Mucosal vitiligo
Characterized by macules having unilateral dermatomal distribution that do not cross the midline. It generally affects young children and typically remains localized, the depigmented lesions persisting unchanged for many years. The occurrence of concomitant other autoimmune diseases is uncommon, compared with GV.
Segmental vitiligo
