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Disorders of pigmentation in infants and children

      Disturbances of melanin pigmentation in children comprise a heterogeneous group of diseases with different etiologies. These include genetic, metabolic, endocrine, nutritional, chemical, physical, and inflammatory disorders (see Table 1).
      Table 1Classification of Pigmentary Disorders
      EtiologyHypopigmentationHyperpigmentation
      GeneticVitiligoFreckles
      AlbinismLentigines
      PiebaldismPeutz-Jeghers syndrome
      Waardenburg syndromeCarney syndrome
      Woolf syndromeLEOPARD syndrome
      Hypomelanosis of ItoNAME syndrome
      Nevus depigmentosusXeroderma pigmentosum
      Tuberous sclerosisCafé au lait macules
      PhenylketonuriaNeurofibromatosis
      HomocystinuriaMcCune-Albright
      Histidinemiasyndrome
      Fanconi syndromeWatson syndrome
      Tietz syndromeBecker’s nevus
      Dyskeratosis congenita
      MetabolicPorphyria
      Gaucher’s disease
      Niemann-Pick disease
      Wilson’s disease
      EndocrineAddison’s disease
      ACTH therapy and/or tumors
      NutritionalVitamin B12 deficiencyPellagra
      KwashiorkorKwashiorkor
      Chronic protein deficiencyVitamin B12 deficiency
      MalabsorptionSprue
      Chemical and DrugsHydroquinoneBleomycin
      CorticosteroidsBusulfan
      PhenolCyclophosphamide
      Antimalarials5-Fluorouracil
      ArsenicalsNitrogen mustard
      Arsenicals
      PhysicalIonizing radiationIonizing radiation
      BurnsUltraviolet radiation
      Burns
      InflammationLeprosyLichen planus
      PintaLupus erythematosus
      YawsMorphea
      OnchocerciasisPostinflammatory
      Post-kala-azar
      Lupus erythematosus
      Sarcoidosis
      Tinea versicolor
      Pityriasis alba
      Mycosis fungoides
      Morphea
      Postinflammatory

      Disorders of hypopigmentation

      Vitiligo

      Vitiligo is an autoimmune disorder characterized by ivory-white patches secondary to melanocyte destruction. The disease is inherited as autosomal dominant with variable penetrance and is estimated to affect 1–2% of the population.
      • Bhatia P.S
      • Mohan L
      • Pandey O.N
      • et al.
      Genetic nature of vitiligo.
      Thirty percent of patients have either a positive family history of vitiligo or a history of halo nevi or premature hair graying.
      • Lerner A.B
      Vitiligo.
      ,
      • Bolognia J.L
      • Pawelek J.M
      Biology of hypopigmentation.
      Vitiligo usually affects young adults, with 50% of cases occurring before the age of 20 and 25% before the age of 8 years.
      • Kovacs S.O
      Vitiligo.
      The disease is uncommon in infancy.
      In most cases, symmetrical lesions develop on sun-exposed areas like the dorsa of hands, the face, and neck.
      • Lerner A.B
      • Nordlund J.J
      Vitiligo the loss of pigment in skin, hair and eyes.
      Other favored sites include body folds like the axilla and groin and body orifices such as the mouth, nose, umbilicus, genitalia, and anus. Vitiligo lesions can also arise over bony prominences like the elbows and knees. Lesions are usually variable in size and shape and consist of well-defined depigmented macules and patches. Loss of pigment may not be apparent in fair-skinned individuals but may be disfiguring in blacks. Vitiligo can appear at sites of trauma or sunburn (Koebner’s phenomenon).
      A variant of vitiligo is the segmental type, which consists of asymmetrically distributed, depigmented macules confined to one nerve segment (Fig 1). This form is more common in children and is highly associated with autoimmune disorders and premature graying.
      • Halder R.M
      Childhood vitiligo.
      Figure thumbnail GR1
      Figure 1Unilateral vitiligo in a 14-month-old baby (Courtesy of Dr. Shukrallah Zaynoun).

      Associations

      There is a 10–20% incidence of vitiligo in endocrine autoimmune disorders like Hashimoto’s thyroiditis, diabetes mellitus, polyendocrine deficiencies, and parathyroid abnormalities.
      • Cunliffe W.J
      • Hall R
      • Newell D.J
      • et al.
      Vitiligo, thyroid disease and autoimmunity.
      In addition, patients with lymphoma, leukemia, myasthenia gravis, scleroderma, and alopecia areata have a higher incidence of vitiligo. It is estimated that 20% of patients with malignant melanoma have vitiligo, and its presence is a poor prognostic factor.
      • Lerner A.B
      Vitiligo.
      ,
      • Nordlund J.J
      • Lerner A.B
      Vitiligo its relationship to systemic disease.
      Vitiligo patients are prone to multiple ocular abnormalities, including discrete depigmentation in the choroid and retinal pigment epithelium, chorioretinitis, uveitis, and iritis.
      The Vogt-Koyanagi-Harada syndrome is a rare disorder characterized by bilateral uveitis, alopecia, vitiligo, deafness, and possible meningeal irritation.
      • Hammer H
      Lymphocyte transformation test in sympathetic ophthalmitis and the Vogt-Koyanagi-Harada syndrome.
      The Alezzandrini syndrome consists of bilateral deafness with unilateral degenerative retinitis, unilateral vitiligo and poliosis.
      • Alezzandrini A.A
      Manifestations unilaterales de dégénérescence tapetorétinienne, de vitiligo, de poliose, de cheveux blancs et d’hypoacousie.
      The differential diagnosis of vitiligo includes postinflammatory hypopigmentation, pityriasis alba, tinea versicolor, albinism, and the ash leaf macule of tuberous sclerosis.

      Course and treatment

      The course of vitiligo is one of remission and exacerbation. Complete spontaneous repigmentation is unusual. Partial and temporary repigmentation has been reported in children for lesions of <2 years’ duration and in summer. The repigmentation process is slow, and usually the face and trunk respond better than the dorsa of hands and feet.
      • Cline D.J
      • Nordlund J.J
      Vitiligo.
      Localized patches of vitiligo can be treated with topical steroids (class III); a good response occurs in 30–50% of patients.
      • Kumari J
      Vitiligo treated with clobetasol propionate.
      ,
      • Esterly N.B
      Management of vitiligo in children.
      ,
      • Njoo M.D
      • Westerhof W
      • Bos J.D
      • et al.
      The development of guidelines for the treatment of vitiligo.
      Narrow-band UVB (311 nm) therapy is an effective and valuable option for the treatment of extensive vitiligo in children.
      • Njoo M.D
      • Bos J.D
      • Westerhof W
      Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy.
      Topical psoralen followed by sun or UVA exposure should be reserved for compliant patients because of the risk of phototoxicity and sunburn.
      • Fulton J.E
      • Leyden J.E
      • Papa C
      Treatment of vitiligo with topical methoxalen and black light.
      Oral psoralen with UVA is recommended for children > 10 years.
      • Hurwitz S
      Disorders of pigmentation.
      Significant repigmentation is seen in up to 30% of cases. Preliminary studies using topical calcipotriol in combination with either sun exposure or oral psoralen and UVA have shown some beneficial results.
      • Parsad D
      • Saini R
      • Verma N
      Combination of PUVAsol and topical calcipotriol in vitiligo.
      ,
      • Parsad D
      • Saini R
      • Nagpal R
      Calcipotriol in vitiligo a preliminary study.
      In unresponsive, localized, stable vitiligo patches, autologous skin graft or topical 5-fluorouracil with epidermal abrasion can be attempted.
      • Falabella R
      • Escobar C
      • Borrers I
      Transplantation of in-vitro cultured epidermis bearing melanocytes for repigmenting vitiligo.
      ,
      • Tsuji T
      • Hameda T
      Topically administered fluorouracil in vitiligo.
      If vitiliginous patches affect > 50% of the body, then depigmentation with 20% monobenzyl ether of hydroquinone or a Q-switched ruby laser may be an option.
      • Cline D.J
      • Nordlund J.J
      Vitiligo.
      ,
      • Thissen M
      • Westerhof W
      Laser treatment for further depigmentation in vitiligo.

      Albinism

      Albinism is an uncommon disorder characterized by congenital lack of pigment in the skin, hair, and eyes. There are two major forms of the disease, the oculocutaneous and the ocular. In oculocutaneous albinism, melanin synthesis is affected in the melanocytes of the skin, hair, and eyes, while in the ocular form, it is limited to the eyes.
      Oculocutaneous albinism consists of several variants; most are inherited as autosomal recessive.
      • Hurwitz S
      Disorders of pigmentation.
      In whites, the skin is milky white, and the hair is white to yellow or sometimes light brown (Fig 2). Affected individuals have pink pupils and grey-blue irises and suffer from photophobia. In blacks, the skin is usually white or lightly tanned with freckles on sun-exposed areas. The eyes are blue or hazel and the hair is blond. The number of melanocytes and melanosomes is normal; however, there is no melanin production because of mutations in the tyrosinase gene that result in inactive, less active, or temperature-sensitive tyrosinase.
      • Tomita Y
      The molecular genetics of albinism and piebaldism.
      Figure thumbnail GR2
      Figure 2Oculocutaneous albinism in a child (Courtesy of Dr. Shukrallah Zaynoun).
      The Hermansky-Pudlack variant of oculocutaneous albinism is characterized by a bleeding tendency secondary to a platelet storage defect. Waxlike, ceroid depositions are found in the lungs, reticuloendothelial system, oral and intestinal mucosa, and urine.
      • Depinho D.A
      • Kaplan K.L
      The Hermansky-Pudlak syndrome report of three cases and review of the pathophysiology and management considerations.
      The Chediak-Higashi syndrome of oculocutaneous albinism is characterized by giant lysosomal granules in leukocytes, platelets, and other cells.
      • Windhorst D.B
      • Zelickson A.S
      • Good R.A
      Human pigmentary dilution based on heritable subcellular structural defect Chediak-Higashi syndrome.
      Major manifestations include recurrent infections, bleeding tendency, and neurological abnormalities. Fifty percent of patients die before the age of 10 secondary to hemorrhage or infection.
      • Blume R.S
      • Wolff S.M
      The Chediak-Higashi syndrome studies in four patients and review of the literature.
      In ocular albinism the abnormal pigmentation is limited to the eyes. Male patients often present with iris translucency, photophobia, and nystagmus. Female patients usually are less affected.
      • Falls H.F
      Sex linked ocular albinism displaying typical fundus changes in the female homozygote.

      Piebaldism

      Piebaldism is an autosomal dominant disorder characterized by congenital patches of depigmentation that lack melanocytes. These include a white forelock, a depigmented triangular patch over the forehead and scalp, and variable symmetrical patches over the body. Hyperpigmented thumbprint macules may be seen within the patches of leukoderma (Fig 3). Associated abnormalities include heterochromic irises, motor incoordination, mental retardation, and defective cell-mediated immunity.
      • Goodman R.M
      • Yahav Y
      • Frand M
      • et al.
      A new white forelock (poliosis) syndrome with multiple congenital malformations in two sibs.
      Piebaldism results from mutations of the kit proto-oncogene (chromosome 4), which encodes a cell surface receptor for the stem cell growth factor.
      • Tomita Y
      The molecular genetics of albinism and piebaldism.
      ,
      • Giebel L.B
      • Spritz R.A
      Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism.
      Figure thumbnail GR3
      Figure 3Melanotic macules within patches of leukoderma in piebaldism (Courtesy of Dr. Shukrallah Zaynoun).

      Hypomelanosis of ito

      This is a neurocutaneous disorder that is usually sporadic, although there have been some reports of autosomal dominant inheritance. The disorder is characterized by bilateral, asymmetrical, hypopigmented macules in a whorled or streaked pattern, parallel to one another and often following Blaschko’s lines.
      • Pinto F.J
      • Bolognia J.L
      Disorders of hypopigmentation in children.
      The trunk and extremities are usually involved. Lesions may be present at birth or appear early in childhood; affected areas increase in number and extent initially, then stabilize, and tend to fade with time. Melanocytes may be decreased, are usually poorly dendritic and have few small melanosomes. The disease is often associated with neurological, musculoskeletal, and ocular abnormalities. These include seizures, mental retardation, developmental delay, macrocephaly, scoliosis, limb defects, hypotonia, strabismus, nystagmus, and hypertelorism, among others. In addition, alopecia, nail ridging, and dental anomalies have also been reported. Abnormal chromosomal patterns have been found in many cases of hypomelanosis of Ito, and the disorder seems to be the result of genetic mosaicism.

      Nevus depigmentosus

      This uncommon congenital, nonhereditary, hypomelanotic lesion appears mostly over the trunk as a unilateral hypopigmented macular patch with irregular, serrated borders (Fig 4).
      • Coupe R.L
      Unilateral systematized achromic nevus.
      The patch is off-white and remains stable in its size and distribution throughout life. It has very rarely been associated with seizures and limb hypertrophy.
      • Solomon L.M
      • Esterly N.B
      Pigmentary abnormalities, nevus achromicus.
      On histopathology, there is a normal complement of melanocytes but a reduction in the number of melanosomes in melanocytes and keratinocytes as well as membrane-bound melanosomal aggregates.
      • Lee H.-S
      • Chun Y.-S
      • Hann S.-K
      Nevus depigmentosus clinical features and histopathologic characteristics in 67 patients.
      Nevus depigmentosus has to be differentiated from segmental vitiligo, hypomelanosis of Ito, and the ash leaf spot of tuberous sclerosis.
      Figure thumbnail GR4
      Figure 4Nevus depigmentosus over the arm that appeared at 5 months of age (Courtesy of Dr. Shukrallah Zaynoun).

      Pityriasis alba

      Pityriasis alba is a very common finding in prepubertal children with a personal or family history of atopy. Lesions most commonly appear on the face, neck, and arms. They consist of ill-defined, hypopigmented macules, a few centimeter in size with a powdery white scale (Fig 5). Extensive pityriasis alba involving the trunk and extremities is an unusual form observed mainly in adolescents and young adults.
      • Zaynoun S.T
      • Aftimos B.G
      • Tenekjian K.K
      • et al.
      Extensive pityriasis alba a histological, histochemical, and ultrastructural study.
      Figure thumbnail GR5
      Figure 5Pityriasis alba over the cheeks of an atopic child (Courtesy of Dr. Shukrallah Zaynoun).

      Tinea versicolor

      Tinea versicolor, uncommonly reported in children, is a chronic, asymptomatic skin infection caused by the yeast Malassezia furfur. The condition is common in warm, humid climates and is characterized by hypopigmented, scaly macules located mainly over the upper trunk in adults, whereas in children there is a preferential facial localization (Fig 6).
      • Bouassida S
      • Boudaya S
      • Ghorbel R
      • et al.
      Pityriasis versicolor in children a retrospective study of 164 cases.
      Figure thumbnail GR6
      Figure 6Tinea versicolor over the face in a baby (Courtesy of Dr. Shukrallah Zaynoun).

      Mycosis fungoides

      Hypopigmented mycosis fungoides is an uncommon presentation of the disease.
      • Akaraphanth R
      • Douglass M.C
      • Lim H.M
      Hypopigmented mycosis fungoides treatment and a 6(1/2)-year follow-up of 9 patients.
      It has an earlier age of onset and is more prevalent in individuals with dark skin color. Hypopigmented macules and patches that may be scaly, most commonly located over the trunk, characterize it clinically (Fig 7). The diagnosis is often delayed because it may be mistaken for vitiligo, tinea versicolor, generalized pityriasis alba, and postinflammatory hypopigmentation. The biological behavior of hypopigmented mycosis fungoides seems to be similar to that of the nonhypopigmented stage Ia disease. Microscopic features include lack of epidermal atrophy, epidermotropism of infiltrating mononuclear cells, and a reduced number of melanocytes. The treatment of choice appears to be oral psoralen with UVA.
      • Lambroza E
      • Cohen S.R
      • Phelps R
      • et al.
      Hypopigmented variant of mycosis fungoides demography, histopathology, and treatment of seven cases.
      Figure thumbnail GR7
      Figure 7Hypopigmented mycosis fungoides over the trunk (Courtesy of Dr. Jasmin Abd-El-Baki).

      Disorders of hyperpigmention

      Freckles

      Freckles, or ephelids, are light brown macules usually < 5 mm in diameter. They appear between the ages of 2 and 4 years in fair-skinned individuals and occur mostly on the face, shoulders, and upper back. They darken in summer and fade in winter. Freckles could be inherited as an autosomal dominant trait in individuals with red-blond hair and blue eyes.
      • Brues A.M
      Linkage of body build with sex, eye color and freckling.
      They are present in several disorders, including xeroderma pigmentosum, progeria, and neurofibromatosis. The melanocyte number is normal.
      • Breathnach A.S
      • Wyllie L.M
      Electron microscopy of melanocytes and melanosomes in freckled human epidermis.

      Lentigines

      Lentigines are small, dark brown to black, oval to circular macules usually 1–2 cm in diameter. They appear in childhood and increase in number up to adulthood. Lesions can appear on any skin surface, including mucous membranes. Lentigines are unaffected by sun exposure, and their color is darker and more uniform than freckles. They have an increased number of melanocytes.
      • Gartmann H
      The malignity of nevoid lentigo.
      Multiple syndromes manifest lentigines as part of their cutaneous manifestations, and these include Peutz-Jeghers, Leopard, and Lamb syndromes.
      • Nordlund J.J
      • Lerner A.B
      • Braverman I.M
      • et al.
      The multiple lentigines syndrome.
      ,
      • Rhodes A.R
      • Silverman R.A
      • Harrist T.J
      • et al.
      Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi the LAMB syndrome.
      Peutz-Jeghers Syndrome is an autosomal dominant disorder characterized by hyperpigmented macules and multiple gastrointestinal polyps.
      • Dormandy T.L
      Peutz-Jeghers syndrome.
      Multiple brown, blue, or black macules can appear on the lips, buccal mucosa, perinasal, periorbital, perianal, and labial regions as well as on the dorsa of fingers and toes and on the palms and soles (Fig 8). The majority of the gastrointestinal polyps are found in the small intestine; they have a low malignant potential.
      • McKittrick J.E
      • Lewis W.M
      • Doane W.A
      • et al.
      The Peutz-Jeghers syndrome report of two cases, one with 30-year follow-up.
      This syndrome usually occurs in the second decade of life and is uncommon in children. Presenting symptoms in the pediatric age group include abdominal pain, melena, intussusception, and hematemesis. Patients with Peutz-Jeghers Syndrome are also at risk of developing carcinomas in the uterus, ovary, breast, and other organs.
      Figure thumbnail GR8
      Figure 8Multiple lentigines in a patient with Peutz-Jeghers syndrome (Courtesy of Dr. Shukrallah Zaynoun).
      The Peutz-Jeghers Syndrome gene (LKB1) encoding a serine/threonine kinase STK11 was mapped to chromosome 19p13.3.
      • Nakagawa H
      • Koyama K
      • Tanaka T
      • et al.
      Localization of the gene responsible for Peutz-Jeghers syndrome within a 6-cM region of chromosome 19p13.3.
      ,
      • Jenne D.E
      • Reimann H
      • Nezu J
      • et al.
      Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
      LKB1 is a tumor suppressor gene; germline mutations of this gene have been detected in many Peutz-Jeghers Syndrome families.
      Treatment consists of relieving obstructions and of multiple individual polypectomies with regular endoscopic and cytological examinations.
      • Tovar J.A
      • Eizaguirre I
      • Albert A
      • et al.
      Peutz-Jeghers syndrome in children report of two cases and review of the literature.

      Café au lait macules (CALMs)

      CALMs are oval to round, light brown macules measuring 0.5–20 cm in diameter. They appear at birth or shortly thereafter. They are present in 10–20% of normal people; however, they can be a sign of neurofibromatosis as 90% of neurofibromatosis patients have multiple CALMs (Fig 9).
      • Growe F.W
      • Schull W.J
      Diagnostic importance of café au lait spot in neurofibromatosis.
      ,
      • Benedict P.H
      • Szabo G
      • Fitzpatrick T.B
      • et al.
      Melanotic macules in Albright’s syndrome and in neurofibromatosis.
      According to Growe and Schull,
      • Growe F.W
      • Schull W.J
      Diagnostic importance of café au lait spot in neurofibromatosis.
      the presence of six or more CALMs, > 1.5 cm in diameter each in adults, or > 0.5 cm in prepubertal children, is a presumptive sign of the presence of neurofibromatosis. Other syndromes that have a definite association with CALMs are McCune-Albright syndrome, Watson syndrome, and ring chromosome syndromes.
      • Landau M
      • Krafchik B.R
      The diagnostic value of café-au-lait macules.
      CALMs have also been reported in tuberous sclerosis, epidermal nevus syndrome, ataxia telangiectasia, Bloom’s syndrome, LEOPARD syndrome, Silver-Russell syndrome, and Turner syndrome. In CALMs, there is an increased number of melanosomes with a variable number of melanocytes.
      • Takahashi M
      Studies on café au lait spots in neurofibromatosis and pigmented macules of nevus spilus.
      Figure thumbnail GR9
      Figure 9Multiple freckles and café au lait macules in a patient with neurofibromatosis (Courtesy of Dr. Shukrallah Zaynoun).

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