Hong Kong J. Dermatol. Venereol. (2018) 26, 113-121 Review Article Approach to pigmented skin disorders in children YC Giam Pigmented problems in children covers a wide area, and a simple approach may be to divide them into hypopigmentation and hyperpigmentation. Understanding the biology of the melanocyte pigment and the mechanisms allow one to diagnose the hypopigmented ones, The hyperpigmented problems are more complex and causal factors are many, some follows pigment patterns, e.g. lentigines, café au lait macules, some functions like the xerodermas and many are gene mutations like incontinentia pigmenti. Also included are acquired factors and environmental factors. Most of these childhood lesions are of cosmetic concern and may not need treatment. However, other organ systems may be involved in syndromes. Therefore other associated features in the clinical presentation play an important role in the diagnosis. Keywords: Biology of melanocytes, Genetics, Hyperpigmentation, Hypopigmentation, Pigmentary disorders Introduction comprehensive integrated algorithm for diagnosing both common and rare disorders Skin disorders can present in childhood with when confronted with pigmented-related disorders hyperpigmentation or hypopigmentation and the in children. Based on my experience with a wide pathogenesis is varied. So far, there is no spectrum of skin disorders, some simple suggestions are made in this review. Most pigmentary disorders in infancy and childhood are National Skin Centre, Singapore of cosmetic concern, but it is useful to understand YC Giam, MBBS, MMed(Paediatrics) the underlying pathogenesis as they may be associated with multisystem disease. These Correspondence to: Dr. YC Giam diseases are differentiated clinically by increased National Skin Centre, 1 Mandalay Road, 308205, Singapore or decreased pigment distributed in a localised 114 YC Giam or diffuse pattern. Five groups are suggested in 2. The Pigmented Lentigines and their an algorithm in the approach to these pigmented syndromes, including café au lait disorders (Figure 1). macules (CALM) syndromes a. Café-au-lait macule (CALM)-associated 1. Genetic disorders arising from the syndromes: biogenesis of the melanocyte or • Neurofibromatosis: Small CALM can melanocyte transfer from the neurocrest appear on the skin, axillae, 4-5 years before to the skin1-4 the neurofibromas. The eye should be The biogenesis of the melanocyte and its pathway examined for Lisch nodules, which are plays a role in understanding of the genetic confirmatory of neurofibromatosis. congenital disorders. Rare, congenital • Tuberous sclerosis: A complex with hypopigmented disorders develop at three hypopigmented ash leaf macules, Shagreen different phases of development. patches, adenoma sebaceum, and skin a. Development and differentiation: e.g. fibromas. Systemic features include central Piebaldism, Waardenburg disease. nervous system, kidney, heart and lung b. Migration/Maturation/Replication: e.g. lesions. Oculocutaneous Albinism. • McCune Albright: characterised by isolated c. Production/Packaging/Distribution: e.g. large CALM, precocious puberty in girls, Hermansky Pudlak disease, Chediak-Higashi polyostotic fibrous dysplasia. syndrome. b. Lentigo-associated syndromes(mutations): Most of the others, mainly hyperpigmented • Leopard syndrome disorders are more easily recognised and can be • Multiple lentigines classified at the level where the pigment is present, • Peutz Jegher syndrome (These will be and also in terms of the mechanism or mutation. discussed later in the paper) Figure 1. Algorithm of Pigmentary diseases ref GiamYCR. Paediatric pigmentary disorders 115 3. Some associated pigmentary The importance of some of the above syndromes, where the pathogenesis disorders are now briefly discussed. is related to functions other than the biogenesis of the melanocyte e.g. 1. Conditions arising from disorders in xeroderma pigmentosa melanocyte development and transfer1-4 • Xeroderma pigmentosa The following pathway of the biogenesis of the • Incontinentia pigmenti melanocyte highlights the pathogenesis of the rare Gene mutation studies are required in some of hypopigmented disorders: Piebaldism, these conditions. Waardenburg syndrome, Oculocutaneous albinism, Hermansky-Pudlak syndrome and 4. Disorders found in the epidermis and Chediak-Higashi syndrome and Griscelli dermis syndrome. • Congenital : Congenital naevus • Acquired : Halo nevus, Spitz naevus a. Melanoblast migration from neural crest to • Naevi that can be present at birth/or later peripheral sites/skin .1 a. Blue naevus, Naevus spilus: These are present Failure of migration leads to Piebaldism and from birth and have a brown background with the Waardenburg syndromes (types 1-4). These darker naevus macules. are characterised by localised hypopigmented b. Becker's naevus: mottled hyperpigmentation, patches. onset at puberty. Hairs may be seen. This may • Piebaldism: Patients are born with be associated with underlying smooth muscles. symmetrical localised white macules, often misdiagnosed as vitiligo (Figure 2). 5. Dermal melanocytic disorders However, there is the characteristic "white • Congenital: Mongolian spots, Naevus of Ota forelock," patch of white hair on the • Acquired: Pigmentary mosaicism, Idiopathic prefrontal scalp. The mutation is in the c- eruptive macular pigmentation, Dermal Kit proto-oncogene. melanocytosis. • Waardenburg syndrome: Types 1-4. Type 1: this shows the white forelock of hair, 6. Some skin diseases associated with heterochromia irides (irises of different inflammation or infections colour), broad nasal root, dystopia These are associated with inflammatory, canthorum, and deafness. The affected infectious, autoimmune, malignancy. genes are PAX3, MITF genes. Type 3 does not exhibit any hearing loss. These are common and result in a patchy depigmented dermatitis. A compatible history and b. Melanin synthesis familiarity with the clinical features are required Failure of melanin production leads to to differentiate among the disorders. oculocutaneous albinism types 1-4.5 Newer • Common diseases: Pityriasis alba, types are now being recognised. Visual phytophotodermatosis, tuberculoid leprosy, dysfunction includes photophobia, nystagmus, lymphomatois papulosis, mycosis fungoides. poor vision, red eyes. Gene mutations include OA1/GPR143, and TRYP1, MAP/SCLASA2, SCL24AS. 116 YC Giam c. Melanosome formation and reduced d. Transfer of pigment granules to keratinocytes tyrosinase activity and defects in Lysosomal Failure of transfer of pigment granules to Trafficking LRO keratinocytes causes the Griscelli syndrome (types The following enzymes are needed for 1-3). melanosome trafficking from the endoplasmic reticulum (ER) via Golgi apparatus to the 2. Conditions characterised by developing melanosome: TYR (tyrosinase) epidermal, dermal and gene mutations TYRP1 (Tyrosinase-related protein 1). Lentigo-associated syndromes: • Multiple Lentiginosis syndrome without Mutations in the genes that regulate this systemic involvement (Figure 3). function, BLOC-1, BLOC-2, BLOC-3, AP-3 • Peutz Jegher syndrome.7 lead to structural abnormalities of the melanosomes leading to Hermansky Pudlak a. LEOPARD syndrome:8 syndrome and Chediak-Higashi syndrome LEOPARD syndrome (LS) was described by (CHS).6 Gorlin in 1969. It is of autosomal dominant inheritance. The affected gene in Chediak-Higashi syndrome is the LYST gene. In CHS, there is white light skin, brown to blond hair, decreased iris pigment manifesting as brown eyes. There may be life-threatening bleeding disorders although the platelet defect is not a great problem in children. Giant inclusions are found in white blood cells. The immunodeficiency manifests as infections by Staphylococcus aureus, Streptococcus pyogenes and pneumococci. Figure 2. Piebaldism, white macules on knees, lesions Figure 3. Male with multiple lentiginosis without look like vitiligo. no systemic involvement. Paediatric pigmentary disorders 117 Mutation is in the PTPN11 gene on 3. Other syndromes where functions are chromosome 12q24.1 (present in 80% of affected cases). PTPN11 encodes for protein tyrosinase phosphate, SHP2, a positive regulator of RAS- a. Incontinenti pigmenti MAPK signalling. Clinically, there is progressive Mutation in the IKBKG or NEMO gene which macular hyperpigmentation with sparing of the encodes the inhibitor of nuclear factor kappa mucosa. NF-KB, leads to incontinenti pigmenti (IP). Clinically, there are four stages, starting from This syndrome includes the following: birth, there are blistering linear lesions which • LLentigines may become infected showing pustules. These • EECG conduction defects become verrucous, then macular lesions in a • OOcular hypertelorism whorled fashion (Figure 4). The fourth stage is • PPulmonary stenosis hypopigmention within the previous lesions. A • AAbnormal genitalia differential diagnosis is the whorled bizarre • RRetardation of growth hyperpigmented naevus (pigmentary • DDeafness-sensorineural (rare) mosacism) although it does not go through these four stages. Dental, ocular, central b. Lentiginosis syndrome9 nervous systems may also be affected in IP. In lentiginosis syndrome (LS), there are multiple lentigines but no systemic involvement. b. Xeroderma pigmentosa (with malignancy) Management includes exclusion of organ Xeroderma pigmentosa is a rare autosomal involvement in LS. recessive condition with 2.3/million people affected in Western countries. Patient present with c. Café au lait-associated syndromes10 skin dryness,