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.

Cutaneous and extracutaneous findings

Affected persons have a depigmented patch, often V-shaped, on the central forehead in association with a white forelock.¹⁵⁹ Premature graying of the hair may occur. Depigmented patches with irregular borders containing hyperpigmented macules, resembling piebaldism, as well as hyperpigmented macules on normal skin, have been described.¹⁶² Histology reveals a reduced number or complete absence of melanocytes within the depigmented areas.¹⁶³ Synophrys, or fusion of the medial eyebrows, is typical in Waardenburg syndrome. Heterochromia irides, or differently colored irises, may be present, as well as sectorial areas of diminished pigment in a single iris and bilateral isohypochromia iridis (pale blue eyes) (Fig. 23.11).¹⁶⁴ Type 1 Waardenburg syndrome is characterized by the presence of dystopia canthorum, or an increase in the inner canthal distance, without change in the interpupillary distance. If the inner canthal distance divided by the interpupillary distance exceeds 0.6, dystopia canthorum is present.¹⁶⁴ In type 2 Waardenburg syndrome, dystopia canthorum is absent.¹⁶⁵ Additional facial features include a broad nasal root, hypoplastic alar cartilage, a thin upper lip and a protuberant lower lip.¹⁵⁹

Congenital sensorineural hearing loss is a hallmark of all forms of Waardenburg syndrome and may be unilateral or bilateral.^159,165 Histopathologic examination of the inner ears has shown absent organs of Corti, atrophy of the spinal ganglion, and reduction of nerve fibers.¹⁶⁶ Hearing loss and heterochromia irides are more common in type 2 than in type 1 Waardenburg syndrome.¹⁶⁷ Rarely cleft lip and palate¹⁶⁸ and neural tube defects such as spina bifida¹⁶⁹ have been reported in association with Waardenburg syndrome.

Waardenburg syndrome type III (Klein–Waardenburg syndrome) is similar to type 1, but is also accompanied by musculoskeletal anomalies of upper limbs and pectoral areas.¹⁷⁰ Type IV Waardenburg syndrome (Shah–Waardenburg syndrome) is the association of Waardenburg syndrome with Hirschsprung disease (congenital aganglionic megacolon).¹⁷¹

Etiology and pathogenesis

Waardenburg syndrome types 1 and 3 are allelic variants and due to mutations in the PAX3 gene on chromosome 2q.¹⁷² PAX3 is one of a family of paired box genes that control neural crest differentiation by regulating the transcription of a number of other genes involved in embryological development. The neural crest gives rise not only to melanocytes but also to the bony and cartilaginous structures of the central face, accounting for the dysmorphic features associated with Waardenburg syndrome. Most mutations in PAX3 result in Waardenburg syndrome type 1. Simple loss of function of one allele will result in the type 1 phenotype due to haploinsufficiency for the PAX3 gene product (heterozygotes). A small fraction of PAX3 mutations result in the more severe type 3 phenotype, and some of these patients are homozygous for the PAX3 mutation, suggesting a gene dosage effect.¹⁷³

Waardenburg syndrome type 2 is caused by mutations in the gene encoding the microphthalmia association transcription factor (MITF), mapped to chromosome 3p.¹⁷⁴ The MITF gene product is a dimeric transcription factor of the basic–helix–loop–helix–leucine zipper class that is expressed in skin, hair follicles, retina and otic vesicles, and is involved in melanocyte differentiation. Type 2 Waardenburg syndrome is a heterogeneous group and some patients are heterozygous for mutations in the MITF gene, resulting in haploinsufficiency of the MITF protein due to loss of function mutations in one of the alleles of the MITF gene.¹⁷⁵ MITF is downstream of PAX3, and this hierarchy of effect explains the lesser facial abnormalities in Waardenburg syndrome type 2 compared to type 1. Homozygous deletions of the SNA12 (SLUG) gene, encoding snail homolog 2, a zinc-finger transcription factor, have been described in two patients with Waardenburg syndrome type 2.¹⁷⁶ Recently, SOX10 (SRY-sex determining region Y-box 10) mutations have also been reported to account for about 15–30% of cases of Waardenburg syndrome type 2.^177,178 SOX10 is located on chromosome 22q13.1 and is a key transcription factor of neural crest development. It is crucial for the survival and maintenance of pluripotency of migrating neural crest progenitors.¹⁷⁹

Waardenburg syndrome type 4 is a rare autosomal recessive condition caused by mutations in the genes for endothelin-3 (EDN3), or one of its receptors, endothelin β receptor (EDNRB) and to the SOX10 gene.^180,181 All of these genes are functionally interrelated and contribute to the formation of the nervous system. EDNRB mutations are dosage sensitive: heterozygosity predisposes to isolated Hirschsprung disease, whereas homozygosity results in more complex neurocristopathies associating Hirschsprung disease and Waardenburg syndrome.¹⁸² About 20–30% of cases are due to mutations within the EDN3 or the EDNRB genes and about 45–55% result from mutations within the SOX10 gene.¹⁸³ Mutations in the SOX10 gene are also responsible for an extended syndrome called PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease), which is caused mostly by mutations in the last coding exon of SOX10.¹⁸⁴

Differential diagnosis

Piebaldism should be considered in patients with dominantly inherited patchy depigmentation. The pigmentary disturbances are very similar in both Waardenburg syndrome and piebaldism, but auditory and facial developmental anomalies are absent in piebaldism.¹⁶² Fisch syndrome should be considered in cases of premature graying of the hair and congenital deafness.¹⁸⁵ The association of deafness and vitiligo with an autosomal recessive mode of inheritance is known as Rozycki syndrome.¹⁸⁶

Treatment and care

Physical findings suggestive of Waardenburg syndrome in neonates warrant a hearing evaluation, as detection of the associated deafness allows for early intervention with hearing aids and specialized education. The use of multichannel cochlear implants in Waardenburg syndrome children with profound deafness was found to be useful for the development and improvement of speech perception and production.¹⁸⁷ Spon­taneous pigmentation and contraction of the leukodermic patches in Waardenburg syndrome has been reported.¹⁸⁸ Treatment options for the leukoderma are the same as those for piebaldism.

Cutaneous findings

Hypomelanotic macules or patches are the earliest sign of tuberous sclerosis complex and are present in up to 90% of patients.¹⁹⁰ The lesions are almost always present from birth, rarely developing later in infancy or childhood. They have a partial rather than complete loss of pigmentation, and perifollicular pigmentation may be observed in some of them.¹¹⁶ Multiple hypopigmented macules are of concern for TSC, although three or fewer may be a variant of normal and occur in otherwise healthy individuals.¹⁹⁴ Examination under Wood’s lamp may be necessary to detect subtle lesions in fair-skinned individuals.¹⁹⁵ The hypopigmented macules can be polygonal (thumbprint), lance-ovate (ash leaf spot) or guttate (confetti-like) (Figs. 23.12, 23.13).¹⁹⁶ Confetti-like lesions appear as multiple small areas of stippled hypopigmentation, typically on the extremities. Poliosis of scalp hair, eyebrows, or eyelashes may be seen in patients with TSC,¹⁹⁷ as well as circumscribed hypopigmentation of the iris or fundus.¹⁹⁸ Electron microscopy of the hypopigmented macules reveals smaller organelles and a reduction in the size and number of the melanosomes, which exist mainly in the unmelanized stages.¹²⁸

Facial angiofibromas (adenoma sebaceum) are made up of vascular and connective tissue elements and are present in three-quarters of patients representing the most frequent lesion in TSC.¹⁹⁹ They are first noticed between the ages of 2 and 8 years as a few small red papules on the malar area, and gradually become larger and more numerous, sometimes extending down the nasolabial folds and onto the chin (Fig. 23.14). A fibrous plaque may be seen on the forehead or scalp, is typically present from birth or early infancy, and has a similar histologic appear to an angiofibroma.¹⁹³ The shagreen patches, which are connective tissue nevi, are found in 20–30% of TSC patients, typically on the back or flank.¹⁹⁰ They appear as slightly raised areas with dimpling at areas of follicular openings, giving the appearance of ‘orange peel’ or ‘gooseflesh’. Ungual and periungual fibromas are nodular or fleshy lesions that arise adjacent to or from underneath the nails (Fig. 23.15). Ungual fibromas usually occur in adolescents or adults, and are seen in 15–20% of TSC patients.¹⁹⁰ Although they are highly suggestive of TSC, these lesions may occasionally develop spontaneously²⁰⁰ or after trauma. Examination of the mouth can reveal gingival fibromas and small dental enamel pits. Dental pits are more common in older patients with TSC than in unaffected individuals, and particularly affect the permanent teeth.²⁰¹

Extracutaneous findings

These include retinal hamartomas, seen in up to 87% of patients, which appear as classic mulberry lesions adjacent to the optic disc.²⁰² Most retinal lesions are clinically insignificant, although occasional patients may have visual impairment due to a large macular lesion, hamartoma enlargement, retinal detachment, or vitreous hemorrhage.

Up to two-thirds of infants with TSC will have cardiac rhabdomyomas, detected by echocardiography pre- or postnatally.¹⁹⁰ The lesions tend to be multiple, and there is evidence that the majority regress in early childhood.²⁰³ Complications include congestive heart failure, cardiac arrhythmia, or cerebral thromboembolism.²⁰⁴

Renal involvement includes angiomyolipomas, which are benign tumors composed of varying amounts of vascular tissue, fat or smooth muscle, and occur in about two-thirds of TSC patients.²⁰⁵ The prevalence of renal tumors increases throughout childhood, and larger lesions are more likely to become symptomatic than smaller tumors. Single or multiple renal cysts tend to appear earlier than the angiomyolipomas, and the combination of the two is characteristic of tuberous sclerosis complex.¹⁹⁰ The proximity of the TSC2 gene and the polycystic kidney disease gene may play a synergistic role in cyst development.²⁰⁶ Both angiomyolipomas and renal cysts are often asymptomatic and require no treatment. Hemorrhage is the most common complication of angiomyolipomas, causing hematuria and pain. Renal failure results from obstructive uropathy, or when cysts or tumors replace much of the normal renal parenchyma.

Pulmonary changes are rare, seldom cause symptoms, are five times more common in females, and tend to become clinically manifest in the second decade.²⁰⁷ The most common lesion is pulmonary lymphangiomyomatosis (LAM), which is characterized by a proliferation of abnormal smooth muscle-like LAM cells and leads to pulmonary cysts and pneumothorax.²⁰⁸ Exa­cerbation during pregnancy and estrogen supplementation has been noted.²⁰⁹ These lesions express estrogen and progesterone receptors, which may explain their gender predilection and sensitivity to hormonal changes. Recurrent spontaneous pneumothorax, dyspnea, cough, hemoptysis, and pulmonary failure are manifestations of pulmonary LAM.

Neurologic manifestations of TSC include mental retardation, seizures, and behavioral problems such as autism,²¹⁰ hyperkinesis, aggressiveness, and psychosis.²¹¹ Infantile spasms are common, occurring in about 70% of affected babies. Neurologic lesions result from impaired cellular interaction, resulting in disrupted neuronal migration along radial glial fibers and abnormal proliferation of glial elements.¹⁹⁰ Neuropathologic lesions include subependymal nodules, cortical hamartomas, focal cortical hypoplasia, and heterotopic gray matter. The number of cortical tubers as observed by magnetic resonance imaging (MRI) has been shown to correlate with the severity of the cerebral dysfunction, with increased numbers of cortical tubers seen in patients with more severe cerebral disease.²¹²

Etiology and pathogenesis

Inactivating mutations in either of two tumor-suppressor genes – TSC1 and TSC2 – are the cause of this syndrome, with TSC2 mutations accounting for 80–90% of all mutations.²¹³ TSC1 contains 21 coding exons on chromosome 9q34.13 and encodes hamartin of 1164 amino acids; TSC2 contains 41 exons on 16p13.3, which encodes tuberin of 1807 amino acids.^214,215 Hamartin and tuberin function as a complex that suppresses a major pathway for the stimulation of cell growth. The hamartin/tuberin complex inactivates GTPase Rheb, which is an activator of the growth-promoting protein kinases rapamycin (mTOR) and P70 S6 kinase (S6K).²¹⁶ TSC1 and TSC2 are tumor suppressors that inhibit the mammalian target of rapamycin (mTOR), and if mutated, results in mTOR activation, leading to an increase in protein translation and formation of hamartomas in TSC. Moreover, proto-oncogenes and tumor suppressors, such as Ras and PTEN, were found to regulate growth via the hamartin/tuberin complex.²¹⁷ Patients with TSC1 mutations generally have milder disease than patients with TSC2 mutations, and patients in whom no mutation was found also had milder disease than patients in whom mutations were found.²¹⁸

Differential diagnosis

Lesions that should be distinguished from the hypopigmented macules of TSC include nevus depigmentosus, nevus anemicus, post-inflammatory hypopigmentation, pityriasis alba, tinea versicolor, and vitiligo.¹⁹⁴ Nevus depigmentosus is most easily confused with the hypopigmented macules of TSC.¹¹⁶ A nevus depigmentosus can only be differentiated from a single ash leaf spot by the absence of other signs or symptoms of TSC.

Treatment and care

Management is multidisciplinary. Special education may be required if mental retardation is present. Facial angiofibromas may be treated with the pulsed dye vascular laser. The more nodular lesions may be treated with shave excision and electrodesiccation or with carbon dioxide laser, but slowly recur.²¹⁹

Rapamycin (sirolimus) and the related MTOR inhibitor, everolimus, are immunosuppressive agents traditionally used in transplant recipients. Rapamycin has antineoplastic effects which may be mediated by decreasing the production of vascular endothelial growth factor and it corrects aberrant signaling pathways involved in cell growth and apoptosis.²²⁰ Oral rapamycin at standard immunosuppressive doses has been used as a targeted therapy with promising results for the renal, lung and neurological manifestations of TSC.^221,222 It can induce regression of visceral angiomyolipomas, brain astrocytomas and improve lung function in patients with lymphangioleiomyomatosis.

However, regrowth may occur with renal angiomyolipomas after stopping oral rapamycin therapy.²²¹ Topical rapamycin twice daily has been shown to be an effective and safe treatment for facial angiofibromas.^223–228 Improvement was noted within a week of starting treatment^223,228 and resolution of lesions in a month to 6 weeks.^224,227 Topical rapamycin is especially effective in younger children with flatter lesions.²²⁸ Recently, topical rapamycin twice a day for 12 weeks was noted to improve the hypomelanotic macules of TSC.²²⁶ Rapamycin has been shown to increase the transcription of microphthalmia transcription factor (MITF), which is involved in melanogenic gene expression.²²⁹ The main side-effect of topical rapamycin is cutaneous irritation with undetectable serum rapamycin levels during treatment.^225,228 Both angiofibromas and hypomelanotic macules may recur a few months after stopping treatment.²²⁶ Rapamycin and its analogues may represent a major advance in therapy.

Examination of the parents and other family members of seemingly sporadic patients with TSC is indicated to exclude the possibility of a mild phenotype of which parents are not aware. Gonadal mosaicism is possible in around 2% of families where parents show no signs of TSC after full clinical evaluation.²³⁰

Extracutaneous findings

Nevus anemicus may be seen in close association with port wine stains.²³² These twin anomalies may be a result of somatic recombination of allelic mutations for vasoconstriction and vasodilatation.²³⁴ Phakomatosis pigmentovascularis, where vascular and pigmented nevi occur in association with nevus anemicus, has been used to support this concept.²³⁵ Lesions of nevus anemicus occur with increased frequency in patients with neurofibromatosis.²³¹

Etiology and pathogenesis

Examination by light and electron microscopy reveals no abnormality, and the nevus is best characterized as a pharmacological abnormality, rather than an anatomical one.²³³ The pallor is due to an increased local vascular reactivity to catecholamines. Donor dominance was demonstrated by grafting lesional skin from nevus anemicus to normal skin, which retained its pale appearance, emphasizing that nevus anemicus is due to increased sensitivity of the blood vessels to catecholamines rather than to increased sympathetic stimulation.²³⁶

Differential diagnosis

Under diascopic pressure with a glass microscope slide, the lesion becomes indistinguishable from the blanched surrounding skin.²³⁷ Wood’s lamp examination does not accentuate the lesion, and rubbing or temperature change causes erythema in the surrounding area but not within the lesion itself. These maneuvers help to distinguish nevus anemicus from vitiligo, nevus depigmentosus, tuberous sclerosis macules, tinea versicolor, and leprosy.²³⁸Treatment is cosmetic, and if desired the discoloration can be concealed with camouflage make-up.

Cutaneous findings

There are several methods of clinical classification. A useful method that provides an indication of the prognosis and treatment is to categorize vitiligo into non-segmental and segmental types.

Segmental vitiligo describes unilateral depigmented patches arranged in a segmental, non-dermatomal pattern (Fig. 23.17). It is seen more commonly in children as compared to adults.²⁴⁰ The face is most commonly affected. It progresses rapidly but tends to be confined within the affected segment and remains stable thereafter.²⁴¹

Non-segmental vitiligo may be generalized, where depigmented patches are distributed symmetrically in more than one region of the body, or localized (focal, acrofacial, acral or mucosal). Children with non-segmental disease are more likely to have more extensive involvement, more frequent progression of disease and thyroid abnormalities on laboratory investigations than children with segmental disease.²⁴²

Extracutaneous findings

Autoimmune diseases like thyroiditis, alopecia areata, diabetes mellitus, pernicious anemia and Addison’s disease have been reported in children with non-segmental vitiligo. As the frequency of occurrence of these autoimmune diseases is low, thyroid function tests, full blood count and fasting blood glucose can be performed selectively, for example, in a child who fails to thrive.

Etiology and pathogenesis

There is destruction of functional melanocytes by mechanisms that are not fully understood. The autoimmune theory suggests that melanocytes are destroyed by humoral and cell-mediated immunity.²⁴³ Other theories suggest that melanocytes are intrinsically defective, injured by oxidative stress or nerve cells.

Genetic studies provide support for the autoimmune pathogenesis theory in non-segmental vitiligo. NLRP1 and XBP1 are vitiligo susceptibility genes that control key aspects of immune regulation. Non-segmental generalized vitiligo has been epidemiologically and genetically associated with some of the other autoimmune diseases, for example, type 1 diabetes mellitus and Addison disease.²⁴⁴

Differential diagnosis

The differential diagnoses of vitiligo include pityriasis alba, tinea versicolor, post-inflammatory hypopigmentation, piebaldism and nevus depigmentosus.²⁴⁵ Pityriasis alba and tinea versicolor, in contrast to vitiligo, are hypopigmented rather than depigmented and often have scaling and indistinct borders. In post-inflammatory hypopigmentation, irregular mottling of both hyperpigmented and hypopigmented areas is often seen. Piebaldism is an autosomal dominant condition presenting at birth with anterior midline depigmentation and a white forelock (poliosis). Nevus depigmentosus is a segmental hypopigmentation detectable at birth or within the first year of life and grows in proportion to the child’s growth. With a Wood’s lamp, the contrast between lesional and normal skin is less marked than in vitiligo.²⁴⁶

Treatment and care

All children with vitiligo should have photoprotection with a broad-spectrum sunscreen of SPF-30+ during daytime outdoor activity so that sunburn and subsequent koebnerization does not occur.

Cosmetic camouflage such as make-up and self-tanning agents help with the psychosocial burden of vitiligo, especially when extensive and with lesions on exposed skin.²⁴⁷ Self-tanning agents containing dihydroxyacetone (DHA) may be used in older children. It causes the skin to turn brown by polymerizing the amino acids in the skin and is useful to camouflage the depigmented lesions. The desired results usually appear after about 6 h and the resulting pigmentation remains for about 3–4 days.²⁴⁸

In children, mid-potency topical steroids are commonly used as a first-line therapy for localized vitiligo.²⁴⁹ Corticosteroids modulate the immune response by decreasing melanocyte destruction and induces melanocyte repopulation in vitiligo.²⁵⁰ Higher response rates occur in children compared to adults and head and neck lesions respond better.²⁵¹ Complete repigmentation rates have been reported to be as high as 49.3%.²⁵² Frequent monitoring is required to avoid local side effects like atrophy, telangiectasia, striae and steroid folliculitis.

As monotherapy, calcipotriene is inferior to topical corticosteroids, but when combined with topical steroids, repigmentation rates increase with a faster onset of repigmentation along with greater stability of repigmentation compared with either as monotherapy.²⁵³ Eyelid and facial skin respond best to this combination therapy.²⁵⁴ Off-label use of the fixed stable combined preparation of calcipotriene 0.005%-betamethasone dipropionate 0.064% ointment once daily, is a simple treatment option.²⁵⁵ Calcipotriol has been shown to downregulate the production of IL-8, which is believed to enhance the inflammatory destruction of melanocytes.²⁵⁵

Topical calcineurin inhibitors (TCI), tacrolimus and pimecrolimus, are advantageous in treating vitiligo without the side-effect profile of topical steroids. Tacrolimus inhibits T-cell activation, blocking the production and release of pro-inflammatory cytokines like TNF-α.²⁵⁶ A comparative study revealed 0.1% tacrolimus ointment to be almost as effective as 0.05% clobetasol propionate cream, both used twice a day for the treatment of childhood vitiligo, and tacrolimus may be useful for sensitive areas like the eyelids.²⁵² Repigmentation occurs after 4–6 weeks with 0.1% tacrolimus ointment twice daily and pigmentation is maintained for at least 6–9 months after discontinuation of treatment.²⁵⁷ Pimecrolimus 1% cream twice daily has been shown to be effective in repigmentation of vitiligo in the head and neck region after 6 months of treatment.²⁵⁸ This repigmentation effect of topical pimecrolimus on the face is enhanced by the addition of narrow-band ultraviolet B (NB-UVB) thrice weekly.²⁵⁹ Tacrolimus 0.1% ointment has also been shown to enhance the effect of NB-UVB for the treatment of vitiligo.²⁶⁰

Topical psoralen-ultraviolet A (PUVA) can be used in older children with limited body surface area involvement.²⁶¹ Narrow-band ultraviolet B phototherapy twice or thrice weekly is an effective and safe modality for the treatment of generalized childhood vitiligo with >20% body surface involvement.^262–265 Better results are seen in children with recent onset disease (<1 year) with best repigmentation over the face and neck and moderate response on the trunk and proximal extremities.²⁶⁴ If no response is seen after 6 months of NB-UVB phototherapy, treatment should be stopped.²⁶⁵ The monochromatic excimer laser (308 nm) allows for the targeted treatment of specific lesions of vitiligo, avoiding the risk of photoaging of the surrounding skin. Cho and colleagues treated 30 children with localized vitiligo with the 308 nm excimer laser and noted a repigmentation rate of 50–75%, especially over the face, neck and trunk.²⁶⁶

Surgical methods may be chosen for older children with stable vitiligo lesions unresponsive to other treatment modalities. Various surgical techniques have been used such as suction blister epidermal grafting²⁶⁷ and autologous non-cultural epidermal cellular grafting. Better results are seen in segmental vitiligo compared to generalized vitiligo.

Whatever treatment is used, certain clinical features are poor prognostic markers for repigmentation. These include acral vitiligo, presence of leukotrichia over the vitiligo, and lesions over bony prominences like the elbows, knees and ankles.²⁴⁹

Etiology and pathogenesis

Post-inflammatory hypopigmentation can appear in the newborn period after inflammatory conditions such as atopic dermatitis, seborrheic dermatitis, diaper dermatitis, psoriasis, pityriasis lichenoides, and infectious conditions.

Differential diagnosis

The differential diagnosis of post-inflammatory hypopigmentation includes pityriasis alba, pityriasis versicolor and vitiligo. Pityriasis alba is characterized by ill-defined, hypopigmented, minimally scaly macules and patches, commonly seen on the face without erythema or pruritus. It is common, being present in 25–40% of dark-skinned children,^268,269 and occasionally seen in the neonatal period. The histology of post-inflammatory hypopigmentation shows nonspecific findings, such as decreased epidermal melanin, superficial lymphohistiocytic infiltration and presence of melanophages in the upper dermis.²⁷⁰ Wood’s lamp will enhance the hypopigmented areas in light skin and helps to distinguish depigmentation from hypopigmentation. Wood’s lamp may help to exclude pityriasis versicolor which displays a coppery-orange fluorescence and a potassium hydroxide wet-mount preparation will show the presence of yeast (‘spaghetti and meatballs’ appearance).

Treatment and care

Treatment of the underlying cause of inflammation will improve the discoloration. Twice-daily application of a mid-strength topical steroid in combination with coal tar has been used to treat post-inflammatory hypopigmentation with some success, although the mechanisms behind this are not well understood.²⁷⁰ Twice-daily application of 1% pimecrolimus cream for 16 weeks has been shown to be beneficial for the treatment of seborrheic dermatitis with associated post-inflammatory hypopigmentation in dark-skinned patients.²⁷¹ Other treatment options for post-inflammatory hypopigmentation include topical psoralen UVA (PUVA), narrowband UVB phototherapy and the 308 nm excimer laser, which had a response rate of 60–70% after 9 bi-weekly treatments.²⁷² In pityriasis alba, repigmentation is achieved with avoidance of excessive sunlight and topical steroids applied daily for several weeks.

Etiology and pathogenesis

The nevus cells appear to be destroyed by cytotoxic CD8⁺ T-lymphocytes recognizing class 1 HLA antigens on their surfaces.²⁸⁰ This theory of an immunologic mechanism is supported by the fact that a lymphocytic infiltrate is seen around the nevus cells and the nevus cells show cytotoxic changes.²⁸¹ Unlike acquired halo nevi, congenital halo nevi may have an absence of inflammation on histology and may not involute.^273,274

Treatment and care

Usually no treatment is required. Education about the prolonged natural history of halo nevi reassures patients and avoids unnecessary excision.

Etiology and pathogenesis

The mode of inheritance is X-linked recessive and the ADFN gene has been mapped to Xq24-q26.^290,291 The mutation affects the migration of neural crest-derived precursors of the melanocytes. Female carriers of the diseases can demonstrate sensorineural hearing impairment.²⁹²

Treatment and care

Cochlear implantation for hereditary deafness has been reported to improve the speech perception abilities in patients with the albinism–deafness syndrome.²⁹³

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