Disorders of Pigmentation

Oculocutaneous Albinism Type 1 (OCA1)

Synonym

Tyrosinase-negative albinism

Inheritance

Autosomal recessive; tyrosinase (TYR) gene on 11q14-q21

Prenatal Diagnosis

DNA mutation analysis

Incidence

1:28,000 blacks; 1:39,000 caucasians; M=F

Age at Presentation

Birth

Pathogenesis

Mutations in the TYR gene lead to absent tyrosinase activity or lack of tyrosinase transport to melanosomes

Normal number of melanocytes

Unable to produce melanin in skin, hair and eyes

Only stage I and II premelanosomes in melanocytes

Miswiring of optic fibers

Key Features

Skin

Generalized pink-white color, solar keratoses, pink-red nevi, squamous cell cancers > basal cell cancers > melanoma

Hair

Snow-white color

Eyes

Blue to gray-blue irides, severe nystagmus, photophobia, impaired visual acuity (20/200 or worse), prominent red reflex throughout life, strabismus, foveal hypoplasia

Differential Diagnosis

OCA1B (yellow mutant, minimal pigment, and temperature-sensitive albinism)

OCA2 (p. 58)

Hermansky-Pudlak syndrome (p. 60)

Chédiak-Higashi syndrome (p. 62)

Laboratory Data

DNA analysis (p. 58)

Management

See OCA2 (p. 58)

Prognosis

Skin and hair do not improve with age

Vision remains stable or worsens with age

2.1. Snow-white hair, pink skin, strabismus, and gray-blue irides in an adult. (24)

2.2. Malignant melanoma presenting as a pink macule with crust. (24)

Oculocutaneous Albinism Type II (OCA2)

Synonym

Tyrosinase-positive albinism

Inheritance

Autosomal recessive; P gene on 15q11.2-12

Prenatal Diagnosis

DNA linkage analysis and mutation detection available

Incidence

1:15,000 blacks; 1:37,000 whites; M=F

Most common form of albinism

Age at Presentation

Birth

Pathogenesis

Mutation in P gene with decrease eumelanin synthesis; gene product thought to play a role in tyrosinase transport

(+) Tyrosinase, normal number of melanocytes

Decreased melanin in skin, hair, and eyes

Miswiring of optic fibers

Key Features

Skin

Generalized pink-white to cream color

Multiple pigmented nevi, ephelides, and lentigines increase with age

Solar keratoses, squamous cell and basal cell cancers with age

Hair

Cream to yellow-brown color

Eyes

Blue to yellow-brown irides (race dependent), nystagmus, photophobia, impaired visual acuity, strabismus, foveal hypoplasia

Differential Diagnosis

OCA1, OCA1B (p. 56)

Hermansky-Pudlak syndrome (p. 60)

Chédiak-Higashi syndrome (p. 62)

Laboratory Data

DNA mutation analysis

Management

Skin

Sun avoidance (especially mid-day): broad-spectrum sunscreen, long-sleeved shirts, brim hat

Referral to dermatologist—skin cancer screening every 6 months

Eyes

UVB-blocking sunglasses, corrective lenses, tinted glasses/contact lenses

Referral to ophthalmologist

Prognosis

Skin and hair pigment increases over time; eye symptomatology may improve with age

2.3. Yellow-brown hair and pink skin in a black girl. (5)

2.4. Melanin production after hair bulb incubation test. (1)

Hermansky-Pudlak Syndrome

Inheritance

Autosomal recessive; gene loci HPS1 gene on 10q23 (most common, found in northwest Puerto Rico and a small village in Swiss Alps), AP3B1 gene on 5q14.1 (HPS2); there are five other gene loci identified to date

Prenatal Diagnosis

DNA mutation analysis if defect known

Incidence

Over 200 case reports; increased frequency in Puerto Rico, Holland

Age at Presentation

Birth

Pathogenesis

Mutation in HPS1 gene is a 16-bp duplication of the gene important in protein localization via intracellular trafficking and organelle formation

AP3B1 gene mutations cause HPS2—the gene encodes the β-3a subunit of AP3 adapter complex, which is thought to be important in protein packaging, vesicular formation, and membrane fusion within the cell

Tyrosinase-positive

Bleeding diathesis secondary to platelet storage pool defect with decreased adenosine diphosphate (ADP), adenosine triphosphate (ATP), and serotonin granules—impairs platelet aggregation

Lysosomal membrane defect—accumulation of ceroid lipofuscin in macrophages within the lung and gastrointestinal tract

Key Features

Skin

Pigment dilution dependent on race

Pigmented nevi, solar keratoses, squamous cell cancer, basal cell cancer

Ecchymoses, petechiae

Hair

Cream to red-brown color

Eyes

Photophobia, nystagmus, decreased visual acuity, strabismus, foveal hypolasia

Hematologic

Epistaxis, gingival bleeding, menorrhagia, prolonged bleeding during childbirth, dental extraction, surgery

Lymphohistiocytic

Ceroid (chromolipid) deposition in macrophages in the lung (pulmonary fibrosis), gastrointestinal tract (granulomatous colitis), cardiac muscle (cardiomyopathy)

Differential Diagnosis

OCA2 (p. 58)

Chédiak-Higashi syndrome (p. 62)

Laboratory Data

Bleeding time prolonged; prothrombin time/partial thromboplastin time (PT/PTT), platelet count normal

Wet-mount electron microscopy—demonstrates platelets without dense granules

Management

Avoid aspirin and other prostaglandin synthesis inhibitors

Baseline chest x-ray at early age

Pulmonary function test and colonoscopy if symptomatic

Solar protection and avoidance

Referral to dermatologist, hematologist-oncologist, ophthalmologist, and symptom-specific subspecialist

Educate dentist, obstetrician, and surgeon prior to dental extraction, delivery, and surgical procedure

Prognosis

Premature death secondary to hemorrhage, colitis, pulmonic disease, squamous cell cancer; otherwise normal life span

2.5. Female with showers of petechiae and creamcolored hair and skin. (25)

2.6 Top: Normal platelets with dense granules. Bottom: Platelets from Hermansky-Pudlak patient with absent granules. (26)

Chédiak-Higashi Syndrome

Inheritance

Autosomal recessive; LYST gene on 1q42; high consanguinity

Prenatal Diagnosis

Fetoscopy—fetal hair shafts reveal clumping of melanosomes on light microscopy; fetal blood reveals characteristic neutrophilic granules

Incidence

Rare; fewer than 100 cases reported; M=F

Age at Presentation

Birth to a few months old

Pathogenesis

LYST gene mutation codes for a lysosomal tracking protein that regulates microtubule-mediated lysosomal fusion/fission and protein sorting; this defect leads to accumulation of giant lysosomal granules in a variety of cells:

Neutrophils—defective phagocytosis, decreased chemotaxis
Melanocytes—pigmentary dilution
Neurons—progressive neurologic deterioration

Platelet storage pool deficiency—bleeding diathesis

Decreased natural killer cell and antibody-dependent cell-mediated cytolysis function

Key Features

Skin

Light cream to slate-gray color, recurrent bacterial infections—Staphylococcus aureus most common

Hair

Light blonde color (in caucasians) with a silver sheen

Eyes

Photophobia, strabismus, nystagmus, decreased uveal pigment

Upper and Lower Respiratory Tract

Recurrent bacterial sinusitis, pneumonia

Central Nervous System

Progressive neurologic deterioration with ataxia, muscle weakness, sensory loss, seizures (rare)

Accelerated Phase (approximately 85% of patients):

Hematologic

Lymphohistiocytic proliferation with infiltration of liver, spleen, and lymph nodes; associated anemia, neutropenia, thrombocytopenia manifested as petechiae, ecchymoses, gingival bleeding, epistaxis, gastrointestinal hemorrhage, overwhelming infection

Differential Diagnosis

OCA2 (p. 58)

Hermansky-Pudlak syndrome (p. 60)

Chronic granulomatous disease (p. 258)

Griscelli syndrome (p. 64)

Elejalde syndrome

Laboratory Data

Diagnostic complete blood cell count (CBC) revealing giant granules in neutrophils

Management

Referral to pediatric hematologist-oncologist-bone—marrow transplant, chemotherapy, high-dose ascorbic acid

Antibiotics, sun protection

Referral to dermatologist, infectious disease specialist, immunologist, neurologist, and ophthalmologist

Prognosis

Death by late childhood from overwhelming infection or hemorrhage during lymphoma-like phase; may reverse deterioration with bone marrow transplantation

2.7. Black child with silver-gray hair and skin. (27)

2.8. Giant lysosomal granules in a polymorphonuclear neutrophil. (27)

Griscelli Syndrome

Inheritance

Autosomal recessive

Prenatal Diagnosis

Fetal scalp biopsy at 21 weeks’ gestation: hair evaluation; fetal blood sample: leukocyte evaluation

DNA analysis

Incidence

Rare—less than 40 cases reported; M=F

Age at Presentation

First year of life

Pathogenesis

Mutations in gene encoding for myosin Va or RAB27a, proteins involved in organelle trafficking and membrane transport; melanophilin gene mutations also implicated in subset of patients

Key Features

Skin

Pigmentary dilution; cutaneous pyogenic infections, abscesses

Hair

Silver-gray hair, eyebrows, eyelashes

Hematologic

Neutropenia, thrombocytopenia, without leukocyte inclusions

Immunologic

Lymphohistiocytic infiltration leading to hepatosplenomegaly, combined T- and B-cell immunodeficiency; accelerated lymphoma-like phase (i.e., Chediak-Higashi) often occurs

Infectious Disease

Episodic fever with/without infection, pyogenic systemic infections

Neurologic

Progressive deterioration with hypotonia, psychomotor retardation, seizures

Differential Diagnosis

Chédiak-Higashi syndrome (p. 62)

Elejalde syndrome

Chronic granulomatous disease (p. 258)

OCA2 (p. 58)

Laboratory Data

Hair—uneven clumps of melanin in medulla of hair shaft on light microscopy

Complete blood count (CBC)—absent cytoplasmic inclusion bodies in neutrophils

Management

Referral to hematology-oncology-bone marrow transplant

Referral to infectious disease

Referral to neurologist

Referral to dermatology-assist in diagnosis

Prognosis

Progressive deterioration may be aborted with bone marrow transplantation

2.9. Hair with metallic silvery-gray sheen. (28)

2.10. Light microscopy of hair reveals irregular, large clumps of melanin pigment. (28).

Piebaldism

Synonym

Familial white spotting

Inheritance

Autosomal dominant; mutation in c-kit proto-oncogene on chromosome 4q12

Prenatal Diagnosis

DNA linkage analysis and mutation detection available

Incidence

Less than 1:20,000; all races; M=F

Age at Presentation

Birth

Pathogenesis

A mutation in the c-kit proto-oncogene results in abnormal tyrosine kinase transmembrane receptors, decreases signal transduction, and causes abnormal melanocyte embryogenesis with defective melanoblast proliferation, migration and distribution.

Key Features

Skin

Depigmented patches on mid-forehead, central eyebrows, neck, anterior trunk, mid-extremities; often bilateral, sparing the hands, feet, back, shoulders, hips Islands of hyperpigmented to normally pigmented patches within and at the borders of hypopigmentation

Hair

White forelock (80% to 90%)

Rare Case Reports

Hirschsprung disease, mental retardation, deafness, cerebellar ataxia

Differential Diagnosis

Waardenburg syndrome (p. 68)

Vitiligo

Nevus depigmentosus

Laboratory Data

Histology from depigmented area reveals decreased number or absent melanocytes and melanin

Management

Autologous cultured melanocyte grafts

Sunscreen

Camouflage—hair dye, Dermablend; 20% topical monobenzyl ether of hydroquinone

Prognosis

Pigmentary alteration usually stable and permanent; normal life span

2.11. Black female with white forelock and depigmented patches with islands of hyperpigmentation on her mid-face and central trunk. (29)

2.12. Family of patient in Figure 2.11 with similar cutaneous findings. (29)

Waardenburg Syndrome

Inheritance

Autosomal dominant; Pax3 gene on 2q35 in I and III, MITF gene on 13q in II, and the SOX1O and endothelin-3 genes on 22q13 and 20q13 respectively in IV

Prenatal Diagnosis

DNA analysis if gene defect known

Incidence

1:42,000; M=F; all races; 1% to 3% of all congenitally deaf children

Age at Presentation

Birth

Pathogenesis

Four distinct types have been defined by their unique clinical and genetic features: Types I and III are caused by mutations in PAX3, a transcription factor that controls neural crest differentiation and regulates transcription of other genes downstream including those responsible for melanoblast activation and migration, inner ear structures and facial bony and cartilaginous structures.

Type II is caused by a mutation in the MITF gene, the melanocyte transcription factor.

Three genetic etiologies involving control of neural crest development have been described for producing the phenotype seen in type IV: SOX1O transcription factor mutations, endothelin-3 signaling gene mutations and endothelin receptor gene mutations.

Key Features

Skin

May have depigmented patches on body

Hair

White forelock (< 50%), synophrys (70%)

Teeth

Caries

Nose

Broad nasal root (80%)

Eyes

Dystopia canthorum (99% but not in II)—lateral displacement of medial canthi with normal interpupillary distance, complete or partial heterochromia irides (25%), hypopigmented fundus

Ears

Congenital sensorineural hearing loss (20%, most common in II)

Colon

Hirschsprung disease (< 5%, exclusively IV)

Musculoskeletal

Cleft lip/palate (I), upper limb, and pectoral anomalies (III)

Differential Diagnosis

Piebaldism (p. 66)

Vogt-Koyanagi-Harada syndrome

Vitiligo

Alezzandrini syndrome

Laboratory Data

Management

Referral to audiologist, otolaryngologist, ophthalmologist

Referral to gastroenterologist and surgeon if symptomatic

Prognosis

Heterochromia irides and white forelock may fade after 1 year; normal life span

2.13. Boy with heterochromia irides, strabismus, broad nasal root, and dystopia canthorum. (1)

2.14. X-ray depicting tapering of normal colon in patient with Hirschsprung disease. (30)

Hypomelanosis of Ito

Synonym

Incontinentia pigmenti achromians

Inheritance

Not inherited; chromosomal or single gene mosaicism

Prenatal Diagnosis

None

Incidence

Rare; all races; M=F

Age at Presentation

Birth to 1 year old

Pathogenesis

The cutaneous phenotype reflects many different forms of genomic mosaicism

Key Features

Skin

Unilateral and bilateral whirled marble cake hypopigmentation in Blaschko’s lines

Hair

Alopecia

Associated Findings (seen in 75% of cases):

Central Nervous System

Seizures, mental and motor retardation

Eyes

Strabismus, hypertelorism

Musculoskeletal

Scoliosis, limb length discrepancy

Teeth

Anodontia, dental dysplasia

Differential Diagnosis

Nevus depigmentosus

Tuberous sclerosis (p. 88)

Incontinentia pigmenti (p. 72)

Segmental vitiligo

Laboratory Data

None

Management

Complete physical examination by primary care physician

Referral to subspecialist if symptomatic

Camouflage cosmetics

Prognosis

Hypopigmentation may fade with time; normal life span

2.15. Eighteen year-old girl with marble-cake hypopigmentation who suffered from intractable seizures, mental and motor retardation.

2.16. Same patient with anodontia.

Incontinentia Pigmenti

Synonym

Bloch-Sulzberger syndrome

Inheritance

X-linked dominant; rare male survivors thought to have Klinefelter syndrome; NEMO gene on Xq28

Prenatal Diagnosis

DNA analysis if gene known in family

Incidence

Over 700 cases reported; 97% female

Age at Presentation

Birth to first few weeks of life

Pathogenesis

Mutation in NEMO (NF-κB essential modulator) gene leads to defective NF-κB activation (80% have identical mutation secondary to gene rearrangement in paternal meiosis). NF-κB is a transcription factor essential for several inflammatory, immune and apoptotic pathways

Key Features

Skin

Stage I

Vesicular (birth to 1 to 2 weeks): vesicles and bullae in a linear arrangement on extremities, trunk, and scalp; erythematous macules and papules

Stage II

Verrucous (2 to 6 weeks): streaks of hyperkeratotic papules, pustules, and papules on extremities

Stage III

Hyperpigmentation (3 to 6 months): whorls and swirls of hyperpigmentation along Blaschko’s lines

Stage IV

Hypopigmentation (second to third decade): hypopigmented whorls and swirls replacing hyperpigmentation; with/without follicular atrophy

Hair

Scarring alopecia (30%)