13 - 75 - ALBINISM AND OTHER GENETIC ORDERS OF PIGMENTATION

Question 1

pattern of inheritance of Oculocutaneous albinism

Answer 1

autosomal recessive inheritance

Question 2

of the 7 subtypes of OCA, which doesn’t have an identified gene yet?

Answer 2

OCA5

Question 3

ocular albinism pattern of inheritance

Answer 3

X-linked

Question 4

most common type of albinism in non-Hispanic white, Chinese, and Japanese patients

Answer 4

OCULOCUTANEOUS ALBINISM TYPE 1/ OCA1

Question 5

classic tyrosinase-negative OCA, there is a complete inability to synthesize melanin in skin, hair, and eyes, resulting in the characteristic “albino” phenotype

Answer 5

OCA1A

• Affected individuals are born with white hair, white skin, and blue eyes, and there are no changes as they mature.
• The phenotype is the same in all ethnic groups and at all ages
• he hair may develop a slight yellow tint as a consequence of the denaturing of the hair protein from sun exposure and/or shampoo use.

Question 6

• this phenotype of OCA can range from minimal hair pigment to skin and hair pigmentation approaching the normal pigment phenotype.
• Most individuals with OCA1B 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.
• In some cases, the melanin develops within the first year.
• The hair color changes to light yellow, light blond, or golden blond at first, as a result of residual pheomelanin synthesis, and eventually can turn dark blond or brown in adolescence and adulthood.

Answer 6

OCA1B

Question 7

• Pigmentation is found on the **extremities where body temperature is relatively low. **
• In this variation, scalp and axillary hair remain white or slightly yellow, but a**rm and leg hair becomes pigmented. **
• The skin remains white and does not tan

Answer 7

variation of OCA1B, temperature-sensitive phenotype (OCA1TS)

Question 8

has no eumelanogenesis but is limited to just pheomelanogenesis

Answer 8

OCA1 minimal pigment/ OCA1MP

• Individuals with OCA1MP show white skin and hair and severe visual impairment, resembling OCA1A, but they do develop some freckles.

Question 9

protein and gene mutated in OCA1

Answer 9

loss-of-function of the melanocytic enzyme tyrosinase resulting from mutation of the TYR gene

Question 10

gene mutated in OCA2

Answer 10

OCA2

Question 11

gene mutated in OCA3

Answer 11

TYRP-1

Question 12

genetic disorder characterized by decreased pigmentation of the eyes and visual disturbances

Answer 12

Ocular albinism (OA)

Question 13

rare autosomal recessive genetic disorder characterized by hypopigmentation of skin, hair, and eyes accompanied by nonpigmentary symptoms, including bleeding diathesis, caused by platelet storage pool deficiency and **accumulation of ceroid **in tissues

Answer 13

Hermansky-Pudlak syndrome (HPS)

Question 14

pattern of inheritance of Hermansky-Pudlak syndrome (HPS)

Answer 14

AR

Question 15

form of Hermansky-Pudlak syndrome (HPS) frequently associated with life-threatening symptoms such as interstitial pneumonia or granulomatous colitis mimicking Crohn disease in affected individuals older than age 30 years

Answer 15

HPS1 and HPS4

Question 16

form of Hermansky-Pudlak syndrome (HPS) associated with immunodeficiency and uncontrolled lymphocyte and macrophage activation, leading to subsequent hemophagocytic syndrome

Answer 16

HPS2 and HPS10

Question 17

how many forms of Hermansky-Pudlak syndrome (HPS) have been identified as of this writing?

Answer 17

10

Question 18

gold standard diagnostic finding in Hermansky-Pudlak syndrome (HPS)

Answer 18

By electron microscopy, platelets from individuals with HPS do not contain dense granules

Question 19

pattern of inheritence of Griscelli Syndrome

Answer 19

autosomal recessive

Question 20

rare autosomal recessive genetic disorder characterized by hypopigmentation of skin and hair, with large clumps of pigment in the hair shaft on light microscopy

Answer 20

Griscelli syndrome

Question 21

how many forms of Griscelli syndrome (GS) have been identified?

Answer 21

3

Question 22

form of Griscelli syndrome (GS) characterized by hypopigmentation with neurologic abnormalities

Answer 22

GS1

• GS1 is associated with severe developmental delay and mental retardation

Question 23

form of Griscelli syndrome that is restricted to hypopigmentation.

Answer 23

GS3

• GS3 is restricted to hypopigmentation of skin and hair.

Question 24

form of Griscelli syndrome (GS) characterized by hypopigmentation accompanied by hematologic immunodeficiency and hematologic abnormalities

Answer 24

GS2

• GS2 is associated with recurrent pyogenic infections and uncontrolled T-cell and macrophage activation leading to hemophagocytic syndrome, the so-called accelerated phase, which can be fatal without immunosuppressive treatment or stem cell bone marrow transplantation.

Question 25

genes responsible for the 3 GS types

Answer 25

* MYO5A (GS1) * RAB27A (GS2), * MLPH (GS3)

Question 26

he only method to cure the hematologic and immunologic abnormalities in Griscelli syndrome (GS)

Answer 26

Stem cell bone marrow transplantation

Question 27

pattern of inheritance of Chediak-Higashi Syndrome

Answer 27

autosomal recessive

Question 28

rare genetic disease with autosomal recessive inheritance characterized by r**educed pigmentation of skin and eye**s, si**lvery or metallic colored hair**, and **neurologic and hematologic disorders**

Answer 28

Chédiak-Higashi syndrome ## Footnote * Neurologic findings, including low IQ scores, cerebellar ataxia, and peripheral neuropathy, appear in childhood or adolescence and tend to progress gradually.

Question 29

Approximately how many % of individuals with ChédiakHigashi syndrome develop lymphoproliferative syndrome, the “accelerated phase” of the disease that tends to be fatal?

Answer 29

90%

Question 30

only treatment for hematologic and immunologic abnormalities in Chédiak-Higashi syndrome

Answer 30

Hematopoietic stem cell transplantation

Question 31

diagnostic finding in Chédiak-Higashi syndrome

Answer 31

**Large granules in polymorphonuclear neutrophils** on blood smear are diagnostic, and **pigment clumping on the hair shaft** is also seen.

Question 32

gene responsible for Chédiak-Higashi syndrome

Answer 32

LYST

Question 33

characteristic finding in Chédiak-Higashi syndrome

Answer 33

Peroxidase-positive large inclusion bodies are seen in polymorphonuclear neutrophils and, occasionally, in lymphocytes, which is a characteristic finding in CHS

Question 34

pattern of inheritance of incontinentia pigmenti

Answer 34

XLD

Question 35

possible organs involved in incontinentia pigmenti

Answer 35

eye, CNS or musculoskeletal

Question 36

responsible gene for incontinentia pigmenti

Answer 36

**IKBKG** (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma)

Question 37

patern of inheritance of piebaldism

Answer 37

autosomal dominant

Question 37

stages of incontinentia pigmenti

Answer 37

**Stage I (vesiculobullous stage)** * vesicular/bullous eruptions and erythema distributed in a linear or whorled pattern on the **trunk and extremitie**s (the face is usually spared) * appear **within 1 week of birth** * The eruption tends to be **bilateral** but can be unilateral * **Eosinophilia** is seen in approximately 30% to 60% of the cases * **eosinophilic infiltration** in the lesional skin is a characteristic histologic finding **Stage II (verrucous stage)** f * verrucous or lichen planus-like keratotic eruptions on the extremities, particularly the **dorsal hand and foot** * the distribution of lesions does not necessarily correspond to that of the stage I eruption. * **dyskeratotic keratinocytes, hyperkeratosis, and acanthosis** * asts for a **few months and occasionally, may last up to a few years ** **Stage III (hyperpigmentation stage)** * appear when individuals are **12 to 16 weeks old,** * brown to graybrown pigmentation distributed in whorled or linear patterns, respecting the Blaschko line. * **Melanophages** are prominent in the upper dermis histologically * The pigmentation **disappears almost completely by 4 or 5 years of age** and may leave focal hypopigmentation, atrophic scar, or alopecia **Stage IV (hypopigmentation stage)**

Question 38

rare genetic disorder with congenital white patches on the forehead, chest, abdomen, and extremities that result from impairment of melanoblast migration in embryonal development

Answer 38

Piebaldism

Question 39

Piebaldism results from mutations of what gene?

Answer 39

c-KIT ## Footnote cause failure of melanoblast migration from the neural crest to the skin.

Question 40

A diamond-shaped white forelock is present in how many % of affected individuals with piebaldism?

Answer 40

90%

Question 41

are genetic diseases with congenital pigment disorder plus sensorineural deafness.

Answer 41

Waardenburg and Tietz syndromes

Question 42

pattern of inheritance of Waardenburg and Tietz syndromes

Answer 42

AD

Question 43

Question 44

# Identify the subtype of Waardenburg Syndrome White forelock, heterochromia irides, dystopia canthorum

Answer 44

WS1 ## Footnote Depigmented macules or patches, synophrys, broad nasal root, and nose hypoplasia are sometimes accompanying symptoms.

Question 45

# Identify the subtype of Waardenburg Syndrome White forelock, heterochromia irides *no dystopia canthorum**

Answer 45

WS2

Question 46

# Identify the subtype of Waardenburg Syndrome White forelock, heterochromia irides, dystopia canthorum , plus **axial and limb musculoskeletal anomalies**

Answer 46

WS3

Question 47

# Identify the subtype of Waardenburg Syndrome White forelock, heterochromia irides, dystopia canthorum , plus **Hirschsprung disease** (neonatal intestinal obstruction, megacolon)

Answer 47

WS4

Question 48

gene mutated in Waardenburg Syndrome 1 and 3

Answer 48

PAX3 ## Footnote encodes a transcription factor regulating expression of MITF

Question 49

kind of variation of Waardenburg syndrome with a **diffuse pigmentary phenotype plus severe hearing loss.**

Answer 49

Tietz syndrome

Question 50

Question 51

major criteria of Waardenburg Syndrome

Answer 51

* Characteristic white forelock * Pigmentary anomalies of the iris * Congenital sensorineural deafness * Dystopia canthorum * An affected first-degree relative

Question 52

Tietz syndrome is caused by specific mutations of what?

Answer 52

**MITF**—Asn210Lys and Arg217del

Question 53

RETICULATE PIGMENT DISORDERS

Answer 53

1. dyschromatosis symmetrica hereditaria (DSH), 2. dyschromatosis universalis hereditaria (DUH), 3. reticulate acropigmentation of Kitamura (RAK), 4. Dowling-Degos disease (DDD)

Question 54

* autosomal dominant disease characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal aspects of the extremities, and freckle-like macules on the face. * skin lesions usually appear in infancy or early childhood.

Answer 54

DYSCHROMATOSIS SYMMETRICA HEREDITARIA

Question 55

A mixture of hyperpigmented and hypopigmented macules distributed only on the dorsal aspects of the extremities, not on the body

Answer 55

DYSCHROMATOSIS SYMMETRICA HEREDITARIA

Question 55

mutation present in DYSCHROMATOSIS SYMMETRICA HEREDITARIA

Answer 55

Identification of a pathologic mutation in **ADAR1** makes a definite diagnosis

Question 56

asymptomatic hypopigmented and hyperpigmented macules of irregular size and shape in a generalized distribution over the trunk and limbs, and sometimes the face.

Answer 56

DYSCHROMATOSIS UNIVERSALIS HEREDITARIA

Question 57

* characterized by **angulate reticulate hyperpigmentation** of the **dorsum** of the extremity * palms and soles contain **punctate pits** and breaks in the epidermal rete ridge pattern * Hypopigmented macules are never included in the lesions * The phenotype appears within the first or second decade of life, and continues throughout life.

Answer 57

RETICULATE ACROPIGMENTATION OF KITAMURA ## Footnote * rare genetic pigmentary disorder that usually shows an autosomal dominant pattern of inheritance with high penetrance

Question 58

mutation seen in RETICULATE ACROPIGMENTATION OF KITAMURA

Answer 58

ADAM10

Question 59

* Small**, hyperkeratotic, dark-brown papules** that affect mainly the **flexures** and great skin folds appear **after puberty**. * **Pitted perioral acneiform scars** and **genital and perianal reticulated pigmented lesions** also have been described. * Patients usually show no abnormalities of the hair or nails

Answer 59

DOWLINGDEGOS DISEASE

Question 60