Pathology – Lecture 8: Pigmentation Disorders
1/9/13
Albinism
 Group of Disorders




Oculocutaneous Albinism 1 (OCA 1)
o Results from mutation to the tyrosinase gene found on chromosome 11
 Tyrosinase is the enzyme involved in several steps in the synthesis of melanin
 AR inheritance, thus mutations in both copies are required to  clinical phenotype
o OCA 1A
 Nonsense and frameshift mutations w/ complete absence of tyrosinase activity 
incapable of any melanin production
 Classic phenotype of complete lack of melanin synthesis in skin, hair, eyes
 Pts have no tanning potential and at risk for sunburn and skin cancer
  visual acuity, photophobia, nystagmus, foveal hypoplasia, misrouting of optic
fibers
 Morphology
 Melanocytes appear as clear cells in stratum basale
 No melanin visible
o OCA 1B
 Missense mutations w/ some residual activity of tyrosinase activity
 Thus, some pigment formation remains
o Same clinical appearance as OCA 1A at birth
o  tyrosinase activity during first decade of life
Hair Bulb Pigmentation Test
o Used to identify the exact type of albinism a person has by incubating a freshly plucked hair
with the bulb intact from the scalp in a solution of tyrosine or DOPA
o If the hair turns dark, it means the hair is making melanin (tyrosinase-positive), light hair
means there is no melanin
o Helps distinguish b/t the two types of albinism:
 “tyrosinase-negative albinism” (OCA 1)
 “tyrosinase-positive albinism” (OCA 2)
Oculocutaneous Albinism Type 2 (OCA 2)
o Most prevalent type of albinism
o AR inheritence, which mutations affecting the P protein gene
 When the P genes have deletions or mutations the majority of tyrosinase is not
transported to melanosomes but is rather stored into the endoplasmic reticulum
and/or Golgi complex
o Common among Africans and African Americans
o Varied phenotype
 Absent pigmentation to almost normal pigmentation


 Most OCA 2 albinos have no eumelanin in the skin, hair, eyes at birth
 Pigmentation develops w/ age
o Ocular presentation similar to OCA 1, but less severe photophobia and nystagmus
Ocular Albinism
o Results from mutations in a gene on the X chromosome, which maps to band Xp22.3 and is
inherited as an X-linked recessive trait
 Thus, occurs exclusively in men
 Passed from mothers who carry the gene
o Evidence of severe ocular involvement, including nystagmus, photophobia and foveal
hypoplasia, without diminished pigmentation of the skin, hair and even irides
 Not progressive and no deterioration of visual acuity w/ age
o Morphology
 Despite absence of cutaneous involvement clinically, histological examination of the
patients’ skin shows giant melanosomes
Pathophysiology of Impaired Vision in Albinism
o “Blond” fundus
 D/t absence of melanin pigment in the retinal pigment epithelium and choroids
o Foveal hypoplasia
 The fovea is the centermost part of the macula in the center retina, responsible for
our central sharpest vision
 No blood vessels but many cones
 Problem
 Central cones are spaced apart so central visual acuity is  while peripheral
visual acuity is normal
 The fovea fails to develop properly if melanin is absent during development
o Reduced visual acuity
 D/t foveal hypoplasia
 One of the most disabling features of albinism
o Photophobia
 Photophobia in albinism represents reduced filtering of light by the deficient ocular
melanin pigment
o Strabismus
 The eyes don’t point at the same object together
o Iris transillumination
 It is common notion that albinos must have red eyes, but in fact the color of the iris
is usually blue
 B/c of deficient melanin pigment in the iris stroma, light reflected from retina is not
filtered, and individuals with albinism can show pink irides
o Nystagmus
 The involuntary movement of the eyes back and forth
 Typically horizontal in albinism
 May disappear as melanin pigment accumulates
o Misrouting of optic nerve fibers
 In normally pigmented individuals about 50% of the retinal fibers decussate at the
optic chiasm
 However, in albinism, an increased number of decussating axons at the chiasm leads
to an abnormal arrangement of fibers in the lateral geniculate bodies and an altered
representation of the eye in the visual cortex
 The amount of retinal pigmentation appears closely related to the number of
uncrossed optic chiasm axons


Detected by a test called “visually evoked potential” (VEP)
o Evoked by visual stimuli such as flashing lights and the responses of
the visual cortex (occipital cortex) are recorded with EEG electrodes
placed on the scalp over the occiput
 Functional significance
 The visual input from the right eye is almost exclusively directed toward the
left brain hemisphere and vice versa
o This accounts for the typical absence of stereoscopic vision in albino
individuals
Complications of Oculocutaneous Albinism
o
Unusual Forms of Albinism Assoc. w/ Systemic Conditions
 Hermansky-Pudlak Syndrome (HPS)
o A rare type of oculocutaneous albinism associated with bleeding diathesis and ceroid-like
material accumulation within the reticulo-endothelial system (RES)
o Most common genetic disorder in Puerto Rico
o Etiology
 AR disorder characterized by lysosomal dysfunction
 8 subtypes, but the three most prevalent are:
 HPS-1
o Greatest frequency
o Mutations in the HPS1 gene
  the mislocalization of tyrosinase and tyrosinase related
protein 1 results in reduced melanin synthesis
 PHS-2
 HPS-3
o Clinical Presentation
 Cutaneous manifestations
 Tyrosinase-positive albinism  varying degrees of hypopigmentation
 Most pts are blind, w/ the usu. albinism visual defects
 Bleeding diathesis
 Results from platelet dysfunction (platelet count is normal but platelet
aggregation is abnormal)
o  easy bruisability, epistaxis, gingival bleeding
 Accumulation of ceroid-like material w/in RES
 Lungs and the gastrointestinal system are affected by the accumulation of
ceroid material in the lysosomes of macrophages of the lung and the gut, b/c
the removal of residual bodies containing this material is impaired
o Morphology
 Melanocytes are structurally normal but have little melanin
 Platelets show virtual absence of dense granules
o Prognosis
 Pulmonary fibrosis and granulomatous colitis develop in the 3rd decade and most
patients (70%) die in the 4th decade from complications
 Chediak-Higashi Syndrome (CHS)

o A rare genetic disease characterized by partial oculocutaneous albinism, susceptibility to
pyogenous infections (Staphylococcus aureus is the most common causative agent) and
bleeding tendency (easy bruisability)
o Etiology
 Arises from a mutation in the lysosomal trafficking regulator gene (CHS1 gene)
 Studies suggest a role in the regulation of lysosome-related organelle size
and movement and disordered intracellular trafficking
o Clinical Manifestations
 Varying degrees of altered pigmentation of both hair and eyes
 Photosensitivity and  visual acuity
 Recurrent bacterial infections, esp. in respiratory tract and skin
 Staph aureus is the most common cause
 Mild coagulation defect  bruising and mucosal bleeding d/t defective platelets
o Diagnosis
 Recognition of the characteristic giant granules in neutrophils, eosinophils, and
granulocytes by using light microscopy of a routine peripheral blood smear
Griscelli Syndrome (GS)
o A rare autosomal recessive disorder that results in partial albinism combined with
immunodeficiency
o Pathogenesis
 Mutations in either myosin Va, melanophilin, or Rab27a
 Involved in movement of melanosomes w/in cells
  perinuclear accumulation of melanosomes & hypopigmentation of skin and
hair
 The gene products are also involved in the control of the immune system
because gene mutations are associated with defective cytotoxic granule
release in T lymphocytes and reduced T cell cytotoxicity
o Clinical Manifestations
 1st sign = silver gray sheen of hair and pale skin
 Later, immunologic defects are noted
 Lead to episodes of a life-threatening uncontrolled T lymphocyte and
macrophage proliferation known as hemophagocytic syndrome (HS)
o  massive tissue damage, organ failure, and death in the absence of a
bone marrow transplantation
o Onset assoc. w/ a viral or bacterial infection
 Characterized by fever, splenomegaly, hepatomegaly, jaundice
and the pathologic finding of hemophagocytosis, i.e.
phagocytosis by macrophages of erythrocytes, leukocytes,
platelets and their precursors in bone marrow and other
tissues (liver and lymph nodes)
o Pathological Findings
 Perinuclear accumulation of melanosomes in the melanocytes
 Large clumps of melanin irregularly distributed along the hair shaft medulla
Vitiligo
 A common, acquired (often heritable) depigmentation of the skin characterized by well
circumscribed, milky-white macules devoid of melanocytes
 Clinical Classification
o Generalized vitiligo
Characterized by depigmented macules involving both sides of the body in a
remarkably symmetrical fashion
 Can occur at any age
 Slow and progressive disorder
o Segmental vitiligo
 Depigmented macules involve a definite dermatome in the same manner as herpes
zoster
 Generally affects younger people
 Activity usu. ceases after one year
 Clinical Manifestations
o The milky-white macules are round and/or oval in shape often with scalloped margins
 Pathology
o Melanocytes are completely absent from the lesional skin
o A constant presence of immune infiltrates at the margins of vitiliginous lesions, composed
of T lymphocytes and macrophages
 Diagnosis
o Clinical, via inspection w/ a Wood lamp
 Depigmented areas appear pure white and hyperpigmented areas appear darker
 Pathogenesis
o The autoimmune hypothesis
 6 vitiligo-associated autoimmune diseases that also occur at increased frequencies
in patient’s first degree relatives: Hashimoto thyroiditis, pernicious anemia, Addison
disease, diabetes mellitus, SLE, and inflammatory bowel disease
 CD4 and CD8 T lymphocytes have been found in the vitiliginous skin but not B
lymphocytes
 Several Abs, some specific for melanocytes, have been found
o The neural hypothesis
 Melanocytes and neurons are both derived from the neural crest.
 The dermatomal distribution of segmental vitiligo constitutes evidence
o The primary intrinsic melanocyte abnormality
o Triggering/precipitating factors
 Stressful events (major illness, emotional stress, pregnancy, surgery, trauma)
Piebaldism
 A rare autosomal dominant disorder of melanocyte development characterized by a congenital
white forelock and multiple hypopigmented and depigmented macules on the face, trunk and
extremities, usually in a symmetrical fashion
 Pathogenesis
o D/t an absence of melanocytes in affected skin and the hair follicles as a result of mutations
of the KIT proto-oncogene
 A deficient KIT-dependent signaling pathway results in a defect of the migration of
melanoblasts from neural crest to the skin during the embryologic development
 Clinical Manifestations
o White forelock
 Both hair and skin in the central frontal scalp are permanently white from birth
o White skin spots may be observed on the face, trunk and extremities
o Pigmentation of the retina is normal and there is no visual tract misrouting such as occurs
in albinism
 Pathology
o Melanocytes are absent or considerably reduced in depigmented patches, histologically and
ultrastructurally
