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.⁴ 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.⁵

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.⁴

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.⁵ 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.⁴ 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.² Visual acuity and nystagmus tend to improve with age.

OCA2 can be found in 1% of individuals with Prader–Willi and Angelman syndromes.⁶

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–q13.⁷ 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.⁸ 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.⁶

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 9q23.¹¹ The TYRP1 gene encodes dihydroxyindolcarboxylic acid oxidase, a melanogenic enzyme essential for eumelanin synthesis.¹²

Cutaneous findings

The phenotype resembles that of OCA2 and the range of skin pigmentation is broad, from creamy white to brown.^14,15 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.¹³ 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.¹⁹ 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.^20,21

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.²²

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.²³

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.²⁴

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.^25–30

Most patients with CHS eventually develop a lymphoproliferative syndrome (‘accelerated phase’) characterized by fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, bleeding, and generalized lymphohistiocytic infiltrates.²⁶ Viral infections, particularly with the Epstein–Barr virus, have been implicated in causing the accelerated phase.^31,32

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.³³

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.^34–36 The resulting susceptibility to infections is caused by the combination of these factors.³⁷

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.³⁸ On a cellular level, abnormal intracellular transport to and from the lysosomes has been detected.³⁹ Giant granules within the phagocytic cells cannot discharge their lysosomal and peroxidative enzymes into phagocytic vacuoles.⁴⁰ Prenatal diagnosis has been successfully performed using light microscopy by examining fetal hair shafts for characteristic clumping of melanosomes.⁴¹

Treatment and care

Hematopoietic stem-cell transplantation (HSCT) is the only definitive treatment for this disorder.⁴² The NK cell defects and immunodeficiencies can be reversed, but the neurological deterioration and pigmentary dilution are not altered.^43,44

Without allogenic HSCT, patients who develop an accelerated phase usually die in childhood, usually from pyogenic infections or hemorrhage.²⁶ Patients who do not develop an accelerated phase tend to have fewer or no infections, but usually develop progressively debilitating neurologic manifestations.^45,46 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.^34,35

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.

Extracutaneous findings

In affected babies, serum phenylalanine levels begin to rise on the third or fourth day of life. Newborn screening with the Guthrie card bacterial inhibition assay test was implemented in the USA beginning in 1963, testing all newborns for PKU. Prenatal diagnosis is also possible by performing amniocentesis or chorionic villus sampling, with identification of the gene.⁵¹ Untreated PKU results in neurologic defects, including mental retardation, seizures, psychosis, hyperreflexia, and growth retardation.

Etiology and pathogenesis

Phenylalanine hydroxylase deficiency is caused by mutations in the PAH gene (mapped to 12q23.2), with more than 400 different mutations identified so far.^52,53 Hypotheses to account for the decrease in skin and hair pigmentation include a competitive inhibition of the binding of tyrosine to tyrosinase by excess phenylalanine or a decreased amount of tyrosine.⁵⁴

Treatment and care

With a low phenylalanine diet, the skin color, photosensitivity, odor, and eczema are reversible. Implementing a diet low in phenylalanine early in infancy can also dramatically reduce the mental retardation.⁵¹ Although children with treated PKU typically have a lower IQ than the general population, affected individuals can be expected to have a low-normal to normal intelligence if blood phenylalanine is maintained at a reasonable level in early childhood.⁵⁵ Supplementation with tyrosine or tryptophan in the diet may be necessary. For women with PAH deficiency who are considering pregnancy, dietary restriction must be started before conception and continued throughout pregnancy.⁵⁶ Aspartame, an artificial sweetener that contains phenylalanine, should be avoided.

Cutaneous findings

Neonates have silvery hair and generalized hypopigmentation of the skin, which may develop a bronze color after sun exposure.⁷⁹

In homozygotes, abnormal melanolysosomes are found in melanocytes and keratinocytes, cultured fibroblasts, and histiocytes of bone marrow.

Extracutaneous findings

Extracutaneous features include mental retardation, hypotonic facies, plagiocephaly, nystagmus, diplopia, micrognathia, crowded teeth, a narrow high palate, pectus excavatum, and cryptorchidism. Neurological abnormalities range from severe hypotonia and the almost complete absence of movements, to seizures and spasticity. The age of onset of neurologic signs ranges from 1 month to 11 years.⁷⁸

Differential diagnosis

Several authors have suggested that subtypes of Elejalde syndrome and Griscelli syndrome type 1 are the same entity.^80–83 However, the absence of immunologic defects allows Elejalde syndrome to be distinguished from the Griscelli syndrome type 1. Chediak–Higashi syndrome should also be considered in the differential diagnosis.

Treatment and care

Treatment is supportive and prognosis is poor.

Cutaneous findings

The cutaneous manifestations include alterations in hair, pigmentation, and elasticity of the skin.⁸⁶ The scalp hair may appear normal at birth, but by about 3 months of age, it becomes sparse, light colored, lusterless, with a ‘steel wool’ quality. The hair is fragile and fractures easily, resulting in generalized alopecia (Fig. 23.4). Pili torti is the most common hair shaft abnormality (Fig. 23.5), demonstrating a flattened appearance under light microscopy with multiple twists of 180° around the long axis of the shaft.⁸⁷ The twisted hairs result from excessive free sulfhydryl groups and a decrease in copper-dependent disulfide bonds. Cutaneous hypopigmentation is common, may be generalized or localized to the skin folds, and is caused by decreased tyrosinase, a copper-containing enzyme. Scaly dermatitis in a seborrheic distribution occurs frequently⁸⁸ and transient neonatal erythroderma has been reported as an initial manifestation of Menkes disease.⁸⁹ The skin is lax, and this doughy laxity is most prominent over the posterior neck, eyebrows, and leg folds (Fig. 23.6).⁸⁶ Generalized puffiness of the cheeks and feet has been noted.

Extracutaneous findings

Progressive neurodegeneration begins at about 2 months of age as a result of gliosis and demyelination of the cerebrum and cerebellum.⁸⁴ Patients present with seizures, hypothermia, developmental retardation, spontaneous subdural hematomas, muscle hypotonia, and feeding difficulties.⁹⁰ Urogenital problems include undescended testes, hydronephrosis, hydro-ureter, recurrent urinary tract infections, diverticula of the ureters and bladder, and rupture of the bladder. Chronic intractable diarrhea resulting in malnutrition^88,91 and increased frequency of congenital heart defects are seen.⁹² Skeletal abnormalities are manifested as wormian bones of the skull and spurring of long bone metaphyses. Connective tissue changes are evidenced by loose joints and tortuous blood vessels, such as the carotid and cerebellar arteries, which may cause intracranial hemorrhages. This increased tortuosity is secondary to fragmentation of the internal elastic lamina of the arteries. Low copper and ceruloplasmin levels in the serum and high copper levels in cultured fibroblasts are useful in the diagnosis.⁹³ Menkes disease can be considered a disorder of copper maldistribution.

Etiology and pathogenesis

Menkes disease and occipital horn syndrome are rare, allelic, X-linked recessive copper deficiency disorders caused by mutations in the ATP7A gene (mapped to Xq21.1), which encodes a copper-transporting P-type ATPase involved in transport of copper to copper-requiring proteins.^94,95 ATPase is localized in the trans-Golgi membrane of cells. The clinical features are due to malfunction of one or more copper-requiring enzymes, such as lysyl oxidase, tyrosinase, cytochrome C oxidase, and dopamine beta-hydroxylase, caused by the deficiency of the ATP7A protein (Table 23.2).⁸⁶ Most patients are males, although a few female patients have also been reported. Most of the female patients have an X; autosome translocation, where the normal X-chromosome is preferentially inactivated.⁹⁶

Occipital horn syndrome, formerly classified as Ehlers–Danlos syndrome type IX or X-linked cutis laxa, is now recognized as a milder form of Menkes disease and is caused by mutations in the same gene. Occipital horn syndrome is characterized primarily by connective tissue abnormalities, including skin laxity, hyperextensible joints, urinary tract diverticuli, hernias, and bony changes such as osteoporosis, arthrosis, and exostoses, such as the presence of a spike of ossification within the occipital insertion of the paraspinal muscles trapezius and sternocleidomastoid muscles at their attachments to the occipital bone (occipital horns), which gives the syndrome its name.⁹⁷ Intelligence is normal or borderline, and patients can survive into adulthood. The milder phenotype results from the presence of low levels of functional ATP7A, unlike Menkes disease, in which no normal ATP7A activity exists.^85,98

Treatment and care

Daily subcutaneous administration of copper-histidine has been shown to be helpful in preventing the severe neurodegenerative problems in some patients with Menkes disease when the treatment is initiated early in life before the onset of significant neurological symptoms.^99,100 This treatment, however, does not prevent the development of connective tissue problems, and cannot be regarded as a cure for Menkes disease.^100–102

Cutaneous findings

Hypopigmented whorls and streaks are distributed along the lines of Blaschko. They tend to be stable, although there are reported cases in which the pigmentary changes become more or less pronounced over time.¹⁰⁹ In some cases, both hypopigmented and hyperpigmented streaks are evident. Wood’s lamp examination may help to determine the extent of the lesions in fair-skinned patients.

Extracutaneous findings

Extracutaneous findings are variable, and include central nervous, musculoskeletal, and/or ocular abnormalities.¹¹⁰ Defects of teeth, hair, nails, and sweat glands, as well as aplasia cutis, fibromas, and generalized or focal hypertrichosis, have been reported.^109,111,112 Additional abnormalities reported include limb-length discrepancies, facial hemiatrophy, scoliosis, sternal abnormalities, dysmorphic facies, genitourinary and cardiac anomalies. Nearly all of the defects are detectable by a thorough physical examination and regular follow-up. Infants should be observed for evidence of CNS involvement, reflected by developmental delay or seizures.¹⁰⁹ Most children with CNS involvement manifest with neurological abnormalities before 2 years of age.

Etiology and pathogenesis

Embryonic somatic mutations are the likely pathogenesis, with distribution and pattern of lesions determined by the type of progenitor cell affected and the timing of mutation during embryogenesis. Multiple chromosomal abnormalities have been associated with HI, and most cases are sporadic and have negligible risk of recurrence.^106,111,113 On histologic examination, the hypopigmented areas have either normal or reduced numbers of melanocytes, and those melanocytes that are present demonstrate a reduction in the number of melanosomes.¹¹⁴

Differential diagnosis

This includes nevus depigmentosus (also known as nevus achromicus) and Goltz syndrome. Patients with Goltz syndrome have both hyper- and hypopigmentation, as well as depressed areas of depigmentation following Blaschko’s lines.

Treatment and care

Cosmetic cover-up products can be used to conceal the hypopigmented areas but are usually not needed. The use of sunscreens can prevent or lessen the accentuation of pigmentary differences.¹⁰⁹

Extracutaneous findings

Systemic manifestations are rare in patients with nevus depigmentosus. Neurologic abnormalities such as seizures and mental retardation have been reported,¹²¹ as well as ipsilateral hypertrophy of the extremities.¹²² In a survey of 50 patients with nevus depigmentosus, none had any extracutaneous features on examination.¹²³ In two studies involving 29 patients with nevus depigmentosus, extracutaneous abnormalities were present in about 10% of the children.^118,124 Occasionally, lentigines can develop within the achromic nevi, and this could be explained by the reversion of a mutation in one of the genes involved in pigmentation.^125,126 There is a report of an infant developing multiple primary milia within a nevus depigmentosus.¹²⁷

Etiology and pathogenesis

With dopa-staining, normal melanocytes are seen in nevus depigmentosus, and electron microscopic studies suggest a reduced synthesis of melanosomes and also a defect in their transfer to the keratinocytes, which could account for the hypopigmentation.¹²⁸ Transfer of melanosomes from melanocytes to keratinocytes is essential for normal pigmentation.

Differential diagnosis

Other entities with which nevus depigmentosus is sometimes confused include nevus anemicus, segmental vitiligo, hypopigmented lesions of tuberous sclerosis, and hypomelanosis of Ito. The distinction between nevus depigmentosus and hypomelanosis of Ito may be artificial, as many patients with segmental hypopigmented macules also have linear pigmentary anomalies, similar to those seen in hypomelanosis of Ito, and underlying mosaicism is the common factor.¹⁰⁹ Patients currently diagnosed with either of these conditions might simply be categorized as having nevoid hypopigmentation with or without extracutaneous anomalies. Genetic analysis may be considered in all patients with segmental or linear pigmentary abnormalities, and those with extracutaneous abnormalities to investigate cytogenic anomalies.¹⁰⁹

Treatment and care

There has been a report of spontaneous resolution of nevus depigmentosus after a 6-year period.¹²⁹ One patient with a nevus depigmentosus had partial repigmentation following autologous melanocyte grafting.¹³⁰ The use of noncultured epidermal cellular grafting has been reported to be successful in the treatment of nevus depigmentosus and a mottled repigmentation of 78% was observed.¹³¹ Repigmentation however, may not be permanent and recurrence of a successfully repigmented nevus depigmentosus 6 years after blister roof grafting has been noted.¹³² Twice weekly narrow-band UVB for 32 sessions was helpful in repigmenting a nevus depigmentosus lesion,¹³³ as was the 308 nm excimer laser.¹³⁴ Cosmetic camouflage may be helpful.