Hypopigmentation Disorders

Cutaneous findings

In OCA1A, there is marked generalized hypopigmentation at birth, with white hair and skin ( Figs. 23.1 , 23.2 ). As the child matures, the skin remains white. Nevi are not pigmented and sun tanning does not occur. The hair may acquire a slightly yellowish tint as a result of denaturing of hair keratins.

In OCA1B, the variable decrease in tyrosinase activity results in several clinical phenotypes: yellow, minimal pigment, platinum, and temperature-sensitive. Individuals with OCA1B form pheomelanin, which requires less tyrosinase activity, and this results in some pigment production during the first two decades of life. Affected individuals have a similar appearance to those with OCA1A at birth, but with time develop some pigment. Hair color can change from white to light blond and even progress to light brown in adolescence. With sun exposure, some individuals with OCA1B may be able to tan, although it is more common to burn without tanning. Pigmented nevi and freckles may develop.

An interesting subtype of OCA1B is the temperature-sensitive phenotype in which the tyrosinase activity is seen mainly on the extremities. In these patients, the enzyme has no activity at 37°C, but some activity at 35°C. These individuals have white or lightly pigmented hairs on the scalp and trunk (axillae, pubic area) and darkly pigmented hair peripherally (legs, arms). The pattern is similar to that observed in Siamese cats.

Extracutaneous findings

In OCA1A, the irises are pale blue at birth and throughout life. In bright light, the entire iris can appear pink or red, which is caused by its translucency. Severe photophobia results from a lack of retinal pigment. Other ocular abnormalities include decreased visual acuity, nystagmus, and strabismus.

In OCA1B, the irises can progressively darken to light tan or brown. In both subtypes, vision may remain stable or deteriorate with age.

Etiology and pathogenesis

OCA1 is caused by loss-of-function mutations in the tyrosinase gene ( TYR ), which is mapped to chromosome 11q14.3. Tyrosinase is the key enzyme that catalyzes the first two steps in melanin synthesis, converting tyrosine to L-DOPA (L-3,4-dihyroxyphenylalanine), and L-DOPA to DOPAquinone. The OCA1A subtype is characterized by mutations that result in complete loss of tyrosinase activity, whereas OCA1B is caused by mutations that result in markedly reduced tyrosinase activity (5–10% of the normal level).

Cutaneous findings

There is a spectrum of clinical phenotypes, depending on the ethnic background and the dilution of hair and skin pigment, which may be minimal to moderate. Comparison with a first-degree relative may be necessary to distinguish the degree of lightening. Most individuals are born with creamy white skin, and light yellow or blond hair. Depending on the individual's ethnic background, hair may also be reddish blond or brown. Pigmented birthmarks may be present. With maturity, the amount of pigment in the skin and hair tends to increase. In sun-exposed areas, pigmented nevi and freckles can develop.

Extracutaneous findings

The dilution of iris pigment may be mild to moderate. With age, the amount of pigment in the eyes tends to increase. Ocular manifestations are generally not as severe as those seen in OCA1A. Visual acuity and nystagmus tend to improve with age.

OCA2 can be found in 1% of individuals with Prader–Willi and Angelman syndromes.

Etiology and pathogenesis

OCA2 results from loss-of-function mutations of the OCA2 gene (previously called the P gene), which is mapped to chromosome 15q11.2–q13. The OCA2 gene encodes the P protein, a melanosomal membrane protein. The specific function of the P protein is currently not known, but is believed to be involved in tyrosine transport within the melanocyte, regulation of melanosome pH and tyrosinase processing and transport. The melanocytes of affected individuals are able to synthesize some melanin, but the majority is yellow pheomelanin rather than black-brown eumelanin.

Prader–Willi syndrome involves deletions of the 15q region, including the OCA2 gene, on the paternally inherited copy of chromosome 15, whereas Angelman syndrome involves loss of the maternally inherited allele. Deletion of one copy of the OCA2 gene associated with a mutation in the second copy results in OCA2 in these patients.

Cutaneous findings

At birth, individuals with this tyrosinase-positive OCA have light brown to red-brown skin and hair. With age, the hair becomes more pigmented. Mild sun tanning is possible.

Extracutaneous findings

At birth, the irises are light brown and become more pigmented with age. Ocular manifestations are present, but less severe. Red reflex on transillumination of the iris and nystagmus are important clues to the diagnosis in dark-skinned people.

Etiology and pathogenesis

OCA3 is due to loss-of-function mutations of tyrosinase-related protein-1 gene ( TYRP1 ), which is mapped to chromosome 9q23. The TYRP1 gene encodes dihydroxyindolcarboxylic acid oxidase, a melanogenic enzyme essential for eumelanin synthesis.

Cutaneous findings

The phenotype resembles that of OCA2 and the range of skin pigmentation is broad, from creamy white to brown. The hair is silvery white to light yellow at birth, and may darken in childhood.

Extracutaneous findings

Ocular manifestations include nystagmus, decreased iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia associated with reduction in visual acuity, and strabismus.

Etiology and pathogenesis

OCA4 results from mutations in the SLC45A2 gene, which is mapped to chromosome 5p13.2. The gene encodes a melanosomal membrane protein that is likely to function as a transporter. The similar functions of the OCA2 and SLC45A2 genes may explain the phenotypic resemblance of OCA2 and OCA4.

Differential diagnosis

The diagnosis of OCA is usually made clinically and can be confirmed by DNA mutation analysis. Historically, the hair bulb incubator test for tyrosinase activity was used to differentiate between tyrosinase-positive and tyrosinase-negative OCA. In tyrosinase-negative albinism, there is the lack of pigment formation in hair bulbs when incubated with tyrosine, whereas in tyrosinase-positive albinism, pigment is produced. Prenatal diagnosis of OCA using DNA mutation analysis is available.

OCA can be differentiated from other disorders with cutaneous and ocular albinism by the absence of neurological defects, immunodeficiency, and bleeding diathesis.

Treatment and care

No specific treatment is available for OCA. The importance of photoprotection, including sun avoidance, broad-spectrum sunscreen, protective eyewear and clothing, should be stressed to reduce the risk of photodamage and cutaneous malignancies. Early ophthalmologic evaluation and management is important. As squamous cell carcinomas and basal cell carcinomas have been known to develop in all types of OCA, yearly examination by a dermatologist is recommended.

Cutaneous findings

The degree of pigmentary dilution in the skin and hair is highly variable. The color of the skin and hair ranges from white to brown.

Extracutaneous findings

The degree of pigmentary dilution in the eyes is highly variable. Other ocular findings include nystagmus, reduced retinal pigment, and foveal hypoplasia with significant reduction in visual acuity. The nystagmus is most obvious during periods of fatigue or emotional change. The bleeding diathesis is caused by platelet storage pool deficiency and results in epistaxis, gingival, menstrual, colonic or post-surgical bleeding. Platelet numbers, prothrombin time, and partial thromboplastin time are normal but bleeding time is prolonged. The absence of dense bodies on electron microscopy of platelets is pathognomonic of HPS. Lysosomal ceroid accumulation can result in interstitial pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure. These life-threatening complications usually develop in adulthood. Some patients with HPS type 2 have persistent neutropenia and suffer from recurrent bacterial infections.

Etiology and pathogenesis

Most of the HPS-related genes encode proteins involved in the biogenesis of lysosome-related organelles. Ceroid is produced by degradation of lipids and glycoproteins within lysosomes. Ceroid accumulation in HPS suggests a defect in the elimination mechanisms of lysosomes.

Differential diagnosis

The diagnosis of HPS is made on clinical findings of oculocutaneous albinism, bleeding diathesis, and absence of dense bodies on electron microscopy of platelets. Molecular genetic testing of some HPS types, e.g. HPS1, HPS3, is available on a clinical basis. The differential diagnosis includes the Griscelli, Elejalde and Cross syndromes.

Treatment and care

Photoprotection is important, as patients have a predisposition to develop basal cell carcinoma and squamous cell carcinoma. An examination by a dermatologist should be performed annually. Patients should avoid aspirin and trauma to minimize the chance of a bleeding episode. Platelet transfusions may be considered prior to surgical procedures. Cigarette smoking should be avoided, as this reduces pulmonary function and may hasten progression of pulmonary fibrosis.

Cutaneous findings

Compared with unaffected family members, the skin and the hair of affected individuals are lighter in color. Cutaneous pigmentation is often slightly to moderately decreased. The hair is blond to light brown, often with a silvery tint ( Fig. 23.3 ). Recurrent skin and systemic pyogenic infections occur in early childhood. Cutaneous involvement usually manifests as a pyoderma, and there are a few reports of deeper involvement resembling pyoderma gangrenosum.

Extracutaneous findings

Loss of ocular pigmentation results in a translucent iris and pale retina, leading to photophobia and an increased red reflex. Visual acuity is normal, but strabismus and nystagmus are common.

Infections typically involve the skin, lungs, and upper respiratory tract. These intractable infections are often fatal before the age of 10 years. Common culprits include Staphylococcus aureus , Streptococcus pyogenes and S. pneumoniae .

Periodontitis is an important manifestation of the immunologic dysfunction.

Progressive neurologic deterioration with clumsiness, abnormal gait, paresthesias, and dysesthesias is often apparent later in childhood. Other neurologic abnormalities include peripheral and cranial neuropathies, spinocerebellar degeneration, ataxia, seizures, decreased deep tendon reflexes, cranial nerve palsies, and motor weakness.

Most patients with CHS eventually develop a lymphoproliferative syndrome (‘accelerated phase’) characterized by fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, bleeding, and generalized lymphohistiocytic infiltrates. Viral infections, particularly with the Epstein–Barr virus, have been implicated in causing the accelerated phase.

Etiology and pathogenesis

CHS results from mutations in the lysosomal trafficking regu­lator gene ( LYST ) gene. The LYST gene (1q 42.1–q42.2) encodes a large cytoplasmic protein that appears to function as an adapter protein to mediate intracellular membrane fusion reactions.

Natural killer (NK) cell function is drastically decreased. Diminished chemotaxis of granulocytes, monocytes, and lymphocytes has also been reported, as well as decreased antibody-dependent cytotoxicity and reduced suppressor T-cell function. The resulting susceptibility to infections is caused by the combination of these factors.

The diagnostic hallmark of CHS is the finding of giant lysosomal granules within leukocytes, melanocytes, platelets, and other cells due to uncontrolled fusion of lysosomes. In bone marrow myeloid cells, the giant granules appear prominent. In melanocytes, giant melanosomes result from uncontrolled fusion of melanosomes, and this failure to disperse melanin to adjacent keratinocytes accounts for the decrease in pigmentation. On a cellular level, abnormal intracellular transport to and from the lysosomes has been detected. Giant granules within the phagocytic cells cannot discharge their lysosomal and peroxidative enzymes into phagocytic vacuoles. Prenatal diagnosis has been successfully performed using light microscopy by examining fetal hair shafts for characteristic clumping of melanosomes.

Treatment and care

Hematopoietic stem-cell transplantation (HSCT) is the only definitive treatment for this disorder. The NK cell defects and immunodeficiencies can be reversed, but the neurological deterioration and pigmentary dilution are not altered.

Without allogenic HSCT, patients who develop an accelerated phase usually die in childhood, usually from pyogenic infections or hemorrhage. Patients who do not develop an accelerated phase tend to have fewer or no infections, but usually develop progressively debilitating neurologic manifestations. Supportive treatments in early infancy include antibiotics for infections, and intravenous γ-globulin. Nonsteroidal anti-inflammatory drugs can exacerbate the bleeding tendency and should be avoided. Ascorbic acid has been shown to partially correct the granulocytic function in some patients.

Cutaneous findings

The affected neonate has cutaneous generalized hypopigmentation and silvery hair.

Extracutaneous findings

Ocular defects include microphthalmos, a small opaque cornea, and nystagmus. Neurological defects include mental retardation, ataxia, and spasticity.

Treatment and care

Treatment is supportive.

Cutaneous findings

At birth, the neonate appears normal but may have a musty odor secondary to urinary and sweat phenylacetic acid or phenyl­acetaldehyde. Caucasian children with PKU almost invariably have blond hair, blue eyes, fair skin, and photosensitivity. African-American and Asian children tend to be lighter in color than their parents and unaffected siblings. The ability to tan is normal. Endogenous eczema often develops in these patients.