MSK - Disorders of Pigmentation

LOs - (1) Describe the clinical characteristics of the hyperpigmentation disorders acanthosis nigricans, lentigo, melasma, and post-inflammatory hyperpigmentation. (2) Describe the clinical characteristics and pathophysiology of the hypopigmentation disorders albinism and vitiligo. (3) Describe the synthesis of melanin.

Melanin

Determines the color of skin and hair

• pigment produced by melanocytes to show color of skin and hair

People can have too much melanin (hyperpigmentation) or too little melanin (hypopigmentation)

• genetic variations will produce melanin which cause difference in skin color and hair from person to person

• UV radiation can also stimulate melanocytes to produce more melanin, which can cause “tanning”

Two major types of melanin in the skin

Eumelanin - responsible to produce brown or black color

Pheomelanin - responsible for a yellow or red color

Melanin is produced by melanocytes located in ; melanin pathway

the basal layer of the epidermis, created from phenylalanine (Phe) which is converted in tyrosine

• Phe is converted into tyrosine and then tyrosinase oxidase turns tyrosine into DOPA, which is the rate limiting step

• DOPA will be converted to melanin through multiple steps including tyrosinase-related protein 1 (TYRP1)

• In albinism, tyrosinase is mutated in one form of melanin and TYRP1 is also mutated

Once formed, melanin gets packaged into specialized lysosomes called melanosomes

• Melanosomes are responsible for

• Defects in this pathway result in

transferring melanosomes into the epidermal keratinocytes

excess or deficient pigment

Two common disorders that lead to absent or reduce pigment

albinism and vitiligo

albinism is a ______ disorder leading to

diffuse hypopigmentation of the skin, hair and eyes

vitiligo leads to __ areas of ; vitiligo is secondary to

hypopigmentation; abnormal immune regulation, leading to autoimmune attack on melanocytes

Albinism refers to defect in normal synthesis of ____, leading to

albinism; white hair, pale skin, eyes and poor eyesight

Oculocutaneous albinism (OCA) is what most patients have, invoving

hair, skin and eyes — this is different from ocular albinism which is an X linked hypopigmentation disorder restricted to the eyes

Almost all types of albinism are inherited in

an AR pattern. Different gene defects can cause oculocutaneous albinism (OCA)

Enzymes relating to OCA1, OCA2, OCA3, OCA4

OCA1 — tyrosinase

OCA2 — P protein

OCA3 — TYRP1

OCA4 — membrane associated transport protein

Albinism is associated with another AR syndrome known as and explain pathophys

Chediak-Higashi syndrome, which is an immunodeficiency disorder that causes frequent infections in children, neutropenia (reduced PMNs), recurrent infections, neuro abnormalities, peripheral neuropathy, coagulation defects and lymphohistiocytosis — abnormal immune activation or infiltration or macrophages and lymphocytes

• Due to mutation in CHS1/LYST gene, which causes defective lysosomal trafficking regulation; melanosomes and lysosomes are dysfunction, which leads to albinism

Characteristics of Chediak-Higashi - PLAIN

Progressive neurodegeneration

Lymphohistiocytosis (abnormal infiltration of macrophages and leukocytes)

Albinism (partial)

Recurrent pyogenic Infections (due to neutropenia)

Peripheral Neuropathy

Vitiligo is an autoimmune skin disorder that causes destruction of

melanocytes in the epidermis, causing depigmented macules and patches

Vitiligo is an acquired condition, unlike albinism, and it due to

destruction of innate immune response, which causes an autoimmune destruction of melanocytes

Vitiligo is associated with other ___ disorders like

autoimmune ; endocrine disorders like hypothyroidism and type 1 diabetes

Vitiligo lesions are asymptomatic ____ and ____ type lesions

macule and patch with irregular borders

Vitiligo can impact mental health as it often presents on the

face, hands and genitals, leading to anxiety, especially in Black + Brown populations

Clinical course of vitiligo is unpredictable, patients can undergo periods of

progression, stabilization and re-pigmentation

First line treatment for vitiligo and severe cases

Topical glucocorticoids and phototherapy; immunosuppressive agents

The deadliest hyperpigmented lesion is

malignant melanoma, a form of skin cancer

Acanthosis Nigricans, pigmentation disorder

Hyperpigmentation with velvety plaques, usually in the axilla and posterior neck. Has regular borders

Acanthosis nigricans can be present due to an underlying disease such as the following 3 causes

1. metabolic syndrome —> Acanthosis nigricans is associated with obesity and type 2 DM due to insulin resistance, which could be due to high levels of insulin causing skin findings like velvety, hyperpigmented plaques in axilla and posterior neck

2. Paraneoplastic syndrome and gastric adenocarcinomas are highly associated

3. Medications can cause acanthosis which are sometimes used for diabetes treatment such as insulin and glucocorticoids

Acanthosis can be genetic but

secondary causes should be ruled out before making diagnosis

Lentigo will lead to darkened

skin lesions which are macules, that are hyperpigmented, flat, and <1 cm wide

• resemble lentils and looks like big freckles

• The hyperpigmented macules are known as lentigines, with a circular sharp border

Lentigines are the hyperpigmented macules that are flat and less than 1 cm, caused in Lentigo

• Simple vs solar types

Simple lentigines are small, benign, <5mm, tan to brown macules that are often seen in children and can form on mucosal surfaces

Solar lentigines are found on sun-exposed regions of the body, which means solar lentigines can cause a multitude of solar lentigines and are called liver spots sometimes

• More common in older patients

Melasma, hyperpigmentation

benign disorder of hyperpigmentation that results in brown or tan macules and patches, primarily on the face.

• major concern is cosmetic disfigurement

Sun exposure and melasma

Sun exposure worsens melasma because it stimulates production of melanin from melanocytes, which can cause progressive darkening of the skin

• More common in women and starts occurring after puberty

Melasma is called the mask of pregnancy

50% of melasma patients are due to pregnancy or hormonal contraception, and women tend to have their melasma worsen

• Both of these situations cause increase levels of female hormones

Post-inflammatory hyperpigmentation

benign syndrome of pigmentation that often leads to cosmetic concerns. It occurs after an episode of inflammation such as acne, psoriasis, burns, or trauma

• The inflammation is due to release of cytokines which force development of the lesions seen

• Lesions will have deposits of excess melanin in the epidermis

• Excess melanin gets deposited in macrophages of dermis, called pigment incontinence

• Those with darker skin are at an increased rate of getting this due to higher melanin content in skin

A 31-year old woman presents to her primary care physician with complaints of skin darkening over the cheeks of her face. Detailed history taking elicits that the patient also has been experiencing amenorrhea, nausea, and breast tenderness over the past 2 months. Physical examination shows nontender, 4- to 6-cm brown macules on the face. Which of the following diagnoses is most likely?

Which of the following pigmentation disorders most likely has an autoimmune component involved in its pathogenesis?

Which pigmentation disorder would be best described as a velvety plaque?