Pigmentary Disorders Flashcards
What is the inheritance pattern for oculocutaneous albinism?
There are 4 different types, all AR
What is the underlying pathology of oculocutaneous albinism?
Abnormal melanin and melanosome biosynthesis and transport
- Occurs in the skin, hair follicles and eyes
What is the most common type of oculocutaneous albinism?
Type II (OCA2 gene affected)
- Type I is the second most common type
What type of oculocutaneous albinism do melanocytic lesions not occur in?
These do not occur in classic OCA1a, otherwise these lesions form in the other types
What are the eye sx’s associated with oculocutaneous albinism?
Photophobia, nystagmus, and reduced visual acuity of variable severity
What is the histology of oculocutaneous albinism?
Decreased melanin content but normal melanocyte count
Is there a difference in skin cancer risk among those with oculocutaneous albinism?
Increased risk of BCC, SCC (most common type of skin cancer in these patients), melanoma (worse w/ OCA1)
In what conditions can an OCA2-like hypopigmentation be seen in and why?
Can be seen in Prader-Wili syndrome and Angelman syndrome which are caused by deletions on chromosome 15q (has the OCA2 gene on it) and occurs if the remaining version of 15q has a mutation on it in the OCA2 gene
What gene is mutated and what is the “phenotype” for OCA1a?
TYR (absent), tyrosinase negative
What are the clinical findings in oculocutaneous albinism type 1a (OCA1a)?
- Generalized and near-complete lack of pigmentation at birth – white hair and skin (hair becomes light yellow over time)
- Nevi are amelanotic/pink
- Gray-blue irides
- Markedly reduced visual acuity, severe photosensitivity, markedly
- increased risk of SCC
What are the clinical findings in oculocutaneous albinism type 1b (OCA1b)?
- No pigmentation of skin/hair at birth but over time, can develop some pigmentation.
- Can have amelanotic or pigmented nevi
- Milder ocular complications compared to OCA1a
What is temperature sensitive OCA1b?
Temperature sensitive variant (OCA1b TS): tyrosinase functions at low temperatures, leading to hair pigmentation at cooler anatomic sites (mainly extremities) and white hairs in warmer sites (trunk, intertriginous zones)
What is the gene affected and the “phenotype” of OCA1b?
TYR (decreased to 5-10% of normal functioning)
- Phenotype: “Yellow mutant albinism” minimal pigment
What is the gene affected and the “phenotype” of OCA 2?
OCA2 gene (Was called P gene previously; pink-eyed dilution)
Tyrosinase + phenotype
What are the clinical findings in OCA type 2?
Most common OCA, usually seen in Africans (Sub-Saharan African populations)
- Pigmentary dilution variable, but develop pigmented nevi/lentigines over time
- Light brown hair and gray/tan irides
What is the gene affected and the phenotype of the OCA type 3?
TYRP1
Phenotype: “Rufous”
Clinical findings in OCA type 3?
Very rare
- most commonly occurs in Africa and New Guinea Reddish-bronze skin and red hair color
- Blue-brown irides
What is the gene affected and the phenotype of OCA type 4?
Gene: Solute carrier family 45 member 2 (SLC45A2)
Phenotype: Resembles OCA2
What are the clinical manifestations of OCA type 4?
- Extremely rare outside of Japan (where it accounts for 25% of OCA)
- Variable clinical presentation ranging from white skin/hair to mild pigmentation of skin/yellow-brown hair
- Distinguished from OCA2 via molecular studies
What are the 3 silvery hair syndromes?
Chediak-Higashi syndrome, Griscelli syndrome, and Elejalde syndrome
What is the mode of inheritance for the Silvery hair syndromes?
AR for all
What is the overall phenotype of the Silvery hair syndromes?
All have pigmentary dilution of the skin and hair w/ variable immunologic and neurologic features
What are the histologic findings in the Silvery hair syndromes?
- Light microscopy: Giant granules or melanosomes can be seen in hair shaft and keratinocytes
- Skin bx: hyperpigmented oval melanocytes and poorly pigmented adjacent karatinocytes
How many types of Griscelli syndrome are there?
3 (Types I-III)
What are the differences between the 3 types of Griscelli syndrome?
- All have pigmentary dilution of the skin and hair
- Type I: Severe neurologic impairment developing during early childhood
- Type II: Combined T and B-cell immunodeficiency which leads to numerous infections and hemophagocytic syndrome
- Type III: Least severe, mostly just has the cutaneous findings
What is the clinical findings of Chediak-Higashi syndrome?
Severe multisystem disease
Starts in infancy w/ silvery hair, oculocutaneous albinism, immunodeficiency, bleeding diathesis, and neurologic degeneration
- Death usually occurs by age 10 from lymphoproliferative accelerated phase/hemophagocytic syndrome (Presents w/ pancytopenia and lymphocytic infiltration of liver/spleen/lympho nodes
What is the most common cause of death in Chediak-Higashi syndrome?
Death usually occurs by age 10 from lymphoproliferative accelerated phase/hemophagocytic syndrome (Presents w/ pancytopenia and lymphocytic infiltration of liver/spleen/lymph nodes
What is the characteristic finding on peripheral blood smear in patients w/ Chediak-Higashi syndrome?
Peripheral blood smear: Characteristic giant granules within cytoplasm of neutrophils, eosinophils, platelets, melanocytes and granulocytes
Bone marrow bx/smear: Giant inclusion bodies within leukocyte precursors
What is Elejalde syndrome?
Pigmentary features of Griscelli syndrome + severe neurologic dysfunction without immunodeficiency (may represent a variant of GS1)
What is the gene defect in Chediak-Higashi syndrome?
LYST/CHS1
What is the cellular defect from LYST/CHS1 mutation in Chediak-Higashi syndrome?
Impaired biosynthesis and storage of melanosomes, platelet dense granules, and lysosomes within leukocytes
What is the appearance of the trichoscopy clumps of melanin in Chediak-Higashi syndrome?
Small, regularly spaced
What is the appearance of the melanocytes in Chediak-Higashi syndrome?
Giant melanosomes
The appearance of neutrophils in Chediak-Higashi syndrome?
Giant granules
Differences in ocular findings in Chediak-Higashi syndrome compared with Griscelli syndrome?
There are no ocular findings in Griscelli as compared with Chediak-Higashi syndrome
Bleeding abnormalities in Chediak-Higashi syndrome and Griscelli syndrome?
There are no bleeding issues in Griscelli syndrome, there is in Chediak-Higashi syndrome due to issues w/ platelets = increase in bleeding time and bleeding diathesis
Are recurrent infections seen in Chediak-Higashi syndrome and Griscelli syndrome?
Yes in Chediak-Higashi syndrome and only in Griscelli syndrome type 2
What types of infections occur in Chediak-Higashi syndrome?
Skin, lungs, and upper respiratory
- Can have EBV-induced lymphoproliferative syndrome
Which silver hair syndrome can cause severe gingivitis, periodiontis, and oral mucosal ulceration?
Chediak-Higashi syndrome
What is the most severe complication of Griscelli syndrome type I
Neurologic sequelae
Which form of Griscelli syndrome is usually mild and skin-limited?
Griscelli type 3
In what silver hair syndromes does an accelerated phase occur?
Chediak-Higashi syndrome = 85%
Also occurs in Griscelli syndrome type II
Which silver hair syndromes have neurologic disorder?
Progressive deterioration seen in Chediak-Higashi syndrome
- Also in type I Griscelli syndrome
What is the gene mutation in Griscelli syndrome type I and what is the resulting pathophysiology?
MY05A - Aberrant translocation of melanosomes along microtubules within melanocytes
What is the gene mutation in Griscelli syndrome type II and what is the resulting pathophysiology?
RAB27A - Results in aberrant translocation of melanosomes along microtubules within melanocytes
What is the gene mutation in Griscelli syndrome type III and what is the resulting pathophysiology?
MLPH - Aberrant translocation of melanosomes along microtubules within melanocytes
What are the major types of tissues affected by mutations in the MYO5A gene seen in Griscelli syndrome type I?
Melanocytes, CNS
What are the major types of tissues affected by mutations in the RAB27A gene seen in Griscelli syndrome type II?
Melanocytes, Cytotoxic T-cells
What are the major types of tissues affected by mutations in the MLPH gene seen in Griscelli syndrome type III?
Melanocytes only
What are the genes are involved and what is the inheritance pattern involved in Hermansky-Pudlak syndrome?
9 genes involved: HPS1, AP3B1/(HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1/(HPS7), BLOC1S3/(HPS8), and BLOC1S6 (HPS9)
-AR
Clinical appearance of Hermansky-Pudlak syndrome?
Oculocutaneous albinism, bleeding diathesis (platelet storage pool defect) and lysosomal accumulation of ceroid lipofuscin
Pathogenesis of Hermansky-Pudlak syndrome?
Disorder of biogenesis of melanosomes and other lysosomal-related organelles, such as platelet dense granules
In what population is Hermansky-Pudlak more common in?
Puerto Ricans (HPS1), dutch, and Indians of Madras
Features of albinism in Hermansky-Pudlak?
Variable level of pigmentary dilution in the skin, hair (slight sheen), and the irises are pale
What are the blood-related issues seen in Hermansky-Pudlak?
Has platelet dysfunction, so there are extensive ecchymoses, nosebleeds, and menorrhagia
What medications need to be avoided in Hermansky-Pudlak?
Aspirin and anti-platelet medications
What eye findings are seen in Hermansky-Pudlak?
Photophobia, strabismus, and nystagmus
What organs can be affected in Hermansky-Pudlak?
Granulomatous colitis, progressive pulmonary fibrosis, cardiomyopathy, and renal failure from lysosomal ceroid accumulation
What are the histologic findings in Hermansky-Pudlak?
Non sun-exposed skin = decreased number of melanosomes and short dendritic processes
What is the prognosis of patients in Hermansky-Pudlak?
Life expactancy = 30-50 yrs
Most common cause of death is pulmonary fibrosis
Most common cause of death in Hermansky-Pudlak?
Pulmonary Fibrosis
Are rates of skin cancer affected in Hermansky-Pudlak?
Increased rates of skin cancer
What is the affected gene and mode of inheritance in piebaldism?
c-KIT proto-oncogene or deletions in snail family zinc finger 2 (SNAI2, SLUG)
AD
What is the underlying pathology of piebaldism?
Defective migration of melanoblasts from neural crest to the ventral midline and fialed differentiation of melanoblasts to melanocytes
Clinical appearance in piebaldism?
White forelock (poliosis = in 90%) + congenital patterned midline adn ventral patches of leukoderma
Prognosis of piebaldism?
Depigmentation is stable and permanent, but there are otherwise no systemic symptoms/associations = benign
What is a key clinical distinguisher of piebaldism vs nevus depigmentosus/vitiligo?
Islands of normal and hyperpigmentation within depigmented patches
How many types of Waardenburg syndrome are there?
4 clinical types (WS 1-4)
What is the inheritance pattern of the Waardenburg syndromes?
AD
What is the underlying pathology in Waardenburg syndromes?
Absence of melanocytes in the skin/hair/eyes/striae vascularis of the cochlea
What are the general clinical features in Waardenburg syndromes?
Depigmented patch on the forehead w/ white forelock (poliosis), congenital deafness, heterochromia irides, synophrys, broad nasal root, and dystopia canthorum
What gene is involved in Waardenburg syndrome type I?
PAX3
What are the clinical features of Waardenburg syndrome type I?
White forelock (20%–60%), synophrys, heterochromia irides, dystopia canthorum (eyes appear widely spaced due to lateral displacement of inner canthi; interpupillary distance is normal), and deafness (20%–40%)
What are the genes and inheritance pattern in Waardenburg syndrome type II?
MITF = AD
SNAI2 = AR
Clinical features in Waardenburg syndrome type II?
LIke WS1 but no dystopia canthorum and deafness is MORE common
What gene is involved and what is the inheritance pattern in Waardenburg syndrome type III?
PAX3
AD
Clinical appearance in Waardenburg syndrome type III?
Similar to type I but there are also upper limb abnormalities (hypoplasia, contractures, and syndactyly)
What are the genes involved and the inheritance pattern in Waardenburg syndrome type IV?
EDNRB = AD, AR
EDN3 = AD, AR
SOX10 = AD
Clinical appearance in Waardenburg syndrome type IV?
Similar to WS1 + Hirschsprung’s disease
What is the gene and the inheritance pattern in McCune-Albright syndrome?
GNAS1
- Non-inherited postzygotic somatic activating mutations in the gene
What is the gender predilection in McCune-Albright syndrome?
Females >> Males
What is the triad of clinical findings in McCune-Albright syndrome?
Café au lait macules (CALM), polyostotic fibrous dysplasia, and endocrine dysfunction
What is the typical appearence of the CALM’s in McCune-Albright syndrome?
“Coast of Maine” appearance i.e. jagged borders and segmental
Where do skeletal abnormalities in McCune-Albright syndrome usually occur?
The polyostotic fibrous dysplasia usually happens under the CALM’s
- Sx’s include bone pain, gait abnormalities, visible skeletal deformity, and recurrent pathologic fractures
What endocrinologic abnormalities can occur in McCune-Albright syndrome?
Precocious puberty, hyperthyroidism, acromegaly, infantile Cushing syndrome and hypophosphatemic rickets
What is the affected gene and the mode of inheritance for Reticulate acropigmentation of Kitamura?
ADAM10
AD
What is the clinical appearance of Reticulate acropigmentation of Kitamura?
Slightly depressed, lentigo-like hyperpigmented macules coalescing into a reticulated pattern on the dorsal hands and feet
- Hyperpigmented macules can darken and the distribution may expand over time
- Palmoplantar pits and abnormal dermatoglyphics can also be seen
What is the histology of Reticulate acropigmentation of Kitamura?
Epidermal atrophy w/ elongated rete and increased melanin + increased number of melanocytes
What is the gene and mode of inheritance for Dowling-Degos disease?
Rare, AD
Mutations in keratin 5 gene
What other condition is associated w/ mutations in the keratin 5 gene?
Epidermolysis bullosa simplex w/ mottled pigmentation
Clinical appearance of for Dowling-Degos disease?
Onset usually during adulthood
- Presents w/ reticulated hyperpigmentation in the axilla and groin. Can also spread to gluteal and inframammary folds, neck, torso, inner thighs
- Comedone-like lesions on the back or neck, pitted perioral scars, epidermoid cysts, and hidradenitis suppurativa have also been reported
Histology of Dowling-Degos disease?
Increased pigmentation of the basal layer and “angler-like” pattern w/ finger-like rete ridges
- Dermal melanophages and mild perivascular lymphohistiocytic infiltrate
What is Galli-Galli disease?
It is a variant of Dowling-Degos disease that looks like DDD but has suprabasal acantholysis on histology
What is dyschromatosis?
Both hypo and hyperpigmentation
What is the gene and the mode of inheritance of Dyschromatosis symmetrica hereditaria (acropigmentation of Dohi)?
Heterozygous mutations in ADAR (SRAD) gene (RNA-specific adenosine deaminase)
- AD
Presentation of Dyschromatosis symmetrica hereditaria (acropigmentation of Dohi)?
Presents by 6 years of age
- Patients have dyschromia and hyperpigmented/hypopigmented macules restricted to sun-exposed skin on dorsal aspects of extremities and face
What is the gene and mode of inheritance for Dyschromatosis universalis hereditaria?
AD/AR
- Mutations in ABCB6 (ATP-binding cassette subfamily B, member 6)
Clinical presentation of Dyschromatosis universalis hereditaria?
Generalized or torso-predominant, well-demarcated brown macules interspersed with variously sized hypopigmented macules with a mottled appearance
- Nail dystrophy and pterygium
- Reports of associations with short stature, idiopathic torsion dystonia, X-linked ocular albinism, photosensitivity, and neurosensory hearing loss
What is the most common form of inheritance for Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
XLR (can also be AD or AR)
What are the gene mutations involved in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
Mutations in TERT, TERC ( AD); DKC1 (XLR), or TINF2
What is the underlying pathology in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
The genes involved are involved in telomere maintenance –> patients have reduced telomerase activity and abnormally shortened telomeres –> chromosomal instability/cellular replication dysfunction
Skin features in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
Triad: abnormal skin pigmentation, oral leukoplakia, and onychodystrophy
- Can also see palmoplantar hyperkeratosis, hyperhidrosis, and diffuse non-scarring alopecia
What is the distribution of the skin lesions often in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
Reticulated poikilodermatous patches of the face/neck/upper torso
Is there an increased risk of malignancy in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
Yes –> Hematopoietic malignancies and squamous cell of the oral mucosa/anus/genitalia/esophagus/skin
What is the primary cause of mortality in pts w/ Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
Bone marrow failure, pulmonary fibrosis, and malignancy (3rd adn 4th decade)
What is the median age of death in Dyskeratosis congenita (Zinsser-Engman-Cole syndrome)?
16 y/o
What is the gene and mode of inheritance for Naegeli-Franceschetti-Jadassohn Sydnrome (dermatophathia pigmentosa reticularis)?
AD
Keratin 14 (NFJS and DPR are allelic ectodermal dysplasia disorders that share many features)
Clinical appearance of Naegeli-Franceschetti-Jadassohn Syndrome?
Brown-Gray reticulated hyperpigmentation typically on the abdomen, develops in early childhood (2 y/o), and improves after puberty
- Can also see palmoplantar keratoderma, adermatoglyphia, onychodystrophy, hypohidrosis, and dental anomalies including early loss of teeth
What is the clinical presentation of Dermatophathia pigmentosa reticularis?
Diffuse non-scarring alopecia, onychodystrophy, adermatoglyphia, and diffuse, persistent reticulated hyperpigmentation of the torseo and proximal extremities
