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Mosaic Skin Conditions


  • A mosaic organism is composed of ≥2 genetically distinct cell populations derived from a homogeneous zygote.

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      Genomic mosaicism results from alteration in the DNA sequence, affecting genes or chromosomes

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      Functional (epigenetic) mosaicism results from changes in gene expression (but not the DNA sequence) that are passed on during cellular replication; an important example is lyonization in female embryos, where random inactivation of one of the two X chromosomes occurs in each cell during early development

  • Clinical findings in mosaic skin conditions depend not only on the underlying genetic alteration but also on: (1) the timing of its origin, with earlier onset generally leading to more widespread involvement; and (2) the types of cells or tissues affected (cutaneous ± extracutaneous).

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      For example, mosaicism for an activating HRAS mutation can produce the combination of a nevus sebaceus (keratinocytes affected), speckled lentiginous nevus (melanocytes affected), and occasionally CNS abnormalities (nerve cells affected) in patients with phakomatosis pigmentokeratotica

  • The accessibility of the skin allows visualization of mosaic patterns.

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      The lines of Blaschko are streaks and swirls that represent pathways of epidermal cell (e.g. keratinocyte) migration during embryonic development ( Fig. 51.1 )

      Fig. 51.1, Lines of Blaschko.

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      Segmental (e.g. block-like) patterns can also reflect cutaneous mosaicism involving melanocytes, mesodermal cells, or nerve cells

  • Types of cutaneous lesions that can follow the lines of Blaschko or have a block-like/segmental pattern are outlined in Tables 51.1 and 51.2 , respectively ( Fig. 51.2 ).

    Table 51.1
    Skin findings that can occur along the lines of Blaschko.
    IP, incontinentia pigmenti; PEODDN, porokeratotic eccrine ostial and dermal duct nevus.
    Inflammation
    Examples Clinical clues
    Lichen striatus ( Fig. 51.2A )

    • Pink to hypopigmented flat-topped papules; common in children (see Ch. 9 )

    Linear lichen planus ( Fig. 51.2B )

    • Violaceous flat-topped papules with Wickham striae; often in adults

    “Blaschkitis”

    • Pruritic erythematous papulovesicles in multiple streaks on the trunk; usually develops in adults and often recurs

    Inflammatory linear verrucous epidermal nevus (ILVEN) ( Fig. 51.2C )

    • Scaly, erythematous psoriasiform plaques with prominent pruritus and lack of response to therapy; onset usually by childhood

    Linear psoriasis ( Fig. 51.2D )

    • Psoriasiform plaques, often responding to therapy and associated with psoriasis elsewhere

    Other conditions resembling lichen planus : linear GVHD, lupus erythematosus > dermatomyositis, drug eruptions
    Other conditions with a keratotic and/or vesiculobullous component :

    Verrucous lesions – e.g. epidermal/sebaceous nevi ( Table 51.3 ; see Fig. 51.3 ), IP stage 2 (see Fig. 51.7B )
    Spines/comedones – e.g. nevus comedonicus ( Table 51.3 ; see Fig. 51.3G ), PEODDN (favors palms/soles), linear lichen planopilaris (later onset; see Fig. 9.5 H)
    Hypopigmentation (see Table 54.3 )
    Hyperpigmentation (see Table 55.4 )
    Hairlessness – e.g. X-linked hypohidrotic ectodermal dysplasia (female “carriers”; Fig. 51.6A ), Goltz syndrome, IP stage 4 ( Fig. 51.7C )
    Atrophy – e.g. linear lichen sclerosus (epidermal wrinkling), linear atrophoderma of Moulin (hyperpigmented and depressed; Fig. 51.6B ), Goltz syndrome ( Fig. 51.8A,B ), IP stage 4, Conradi–Hünermann–Happle syndrome (follicular atrophoderma)
    Papulonodular lesions ∗∗ – e.g. adnexal neoplasms (e.g. trichoepitheliomas), BCCs, basaloid follicular hamartomas

    ∗ Inflammatory manifestations occur primarily during infancy.

    ∗∗ In addition to conditions with inflammatory or verrucous papulonodules noted above.

    Table 51.2
    Skin findings that can have a segmental pattern that reflects mosaicism.
    CALM, café-au-lait macule; CMTC, cutis marmorata telangiectatica congenita.
    Hypopigmentation – e.g. nevus depigmentosus, segmental vitiligo (see Ch. 54 )
    Hyperpigmention ± hypertrichosis – e.g. CALM, Becker melanosis (nevus)/smooth muscle hamartoma (see Table 50.3 and Ch. 55 )
    Hypertrichosis – e.g. X-linked congenital generalized hypertrichosis (female “carriers”)
    Vascular lesions – e.g. port wine stain, † CMTC, unilateral nevoid telangiectasia, venous malformation, ∗ plaque-type glomuvenous malformation, ∗∗ segmental infantile hemangioma (see Ch. 85 )
    Papulonodular lesions – e.g. segmental leiomyomas ∗∗ or neurofibromas ∗∗

    † Associated with mosaic activating mutations in the GNAQ gene encoding the Q-class G protein α-subunit; mutations in this gene have also been associated with dermal melanocytosis, which occurs as “twin spots” with port wine stains in phakomatosis pigmentovascularis.

    ∗ Type 1 segmental manifestation of an autosomal dominant disorder ( Fig. 51.5 ).

    ∗∗ Type 2 segmental manifestation of an autosomal dominant disorder ( Fig. 51.5 ).

    Fig. 51.2, Inflammatory lesions along the lines of Blaschko.

  • In chimerism , different cell populations reflect a genetically heterogeneous zygote, e.g. from fusion of two zygotes or fertilization of one egg by two sperm; this may manifest with a checkerboard, linear, or irregular pattern of pigmentary variation.

Epidermal Nevi and “Epidermal Nevus Syndromes”

  • Epidermal nevi (see Ch. 89 ) present as streaks and swirls of thickened (e.g. verrucous, hyperkeratotic, or velvety) skin along the lines of Blaschko, usually with hyperpigmentation and sometimes with adnexal involvement (e.g. in a nevus sebaceus or nevus comedonicus) ( Fig. 51.3 ).

    Fig. 51.3, Epidermal nevi (EN).

  • The heterogeneous genetic etiologies and potential systemic associations (“epidermal nevus syndromes”) of various types of epidermal nevi are presented in Table 51.3 ( Fig. 51.4 ).

    Table 51.3
    Epidermal nevi: selected variants and potential syndromic associations.
    CHILD, congenital hemidysplasia with ichthyosiform erythroderma/nevus and limb defects; FGF, fibroblast growth factor; GJA1/B2, gap junction α1/β2; KRT, keratin; PPK, palmoplantar keratoderma; SADDAN, severe achondroplasia with developmental delay and acanthosis nigricans.
    Type of epidermal nevus (EN) Gene Generalized conditions caused by constitutional mutations ∗ Potential syndromic associations with the EN
    Epidermolytic verrucous EN KRT1,
    KRT10     		Epidermolytic ichthyosis, PPK (KRT1) None
    Non-epidermolytic verrucous EN Mosaic RASopathies (also nevus sebaceus [see below] and woolly hair nevi)
    HRAS > NRAS > KRAS, BRAF Costello, Noonan, and cardio-facio-cutaneous syndromes (see Table 50.3 ) Cutaneous skeletal hypophosphatemic syndrome (CSHS); phakomatosis pigmentokeratotica with speckled lentiginous nevus
    Mosaic FiGRopathies (also nevus sebaceous and acneiform nevi; see below)
    FGFR3n7 § > FGFR2 Thanatophoric dysplasia, SADDAN, Beare–Stevenson cutis gyrata Asymmetric craniofacial malformations, intellectual disability
    Mosaic AKTopathies (see Ch. 85 )
    PIK3CA § Cowden syndrome variant (rare) Asymmetric overgrowth, lipomatosis, vascular anomalies, digital anomalies, macrocephaly; cerebriform connective tissue nevi of palms/soles (Proteus)
    AKT1 Not reported
    PTEN PTEN hamartoma (e.g. Cowden) syndrome
    Nevus sebaceus HRAS >
    KRAS ; rarely FGFR2     		See above Schimmelpenning syndrome (CNS, ocular, skeletal); CSHS (see above)
    Munro acne nevus (hypopigmented background skin) FGFR2 Apert syndrome Digital anomalies, intellectual disability
    Nevus comedonicus NEK9 Skeletal dysplasia (with biallelic mutations) Digital anomalies, scoliosis
    Porokeratotic adnexal ostial nevus GJB2 Keratitis–ichthyosis–deafness (KID) syndrome
    Inflammatory linear verrucous epidermal nevus (ILVEN) GJA1 ? NSHDL Erythrokeratodermia variabilis et progressiva
    ? CHILD syndrome (mosaic)     		Distal limb reductions

    ∗ Could potentially occur in the offspring of an epidermal nevus patient who has gonadal as well as cutaneous mosaicism.

    § Somatic activating mutations are also found in seborrheic keratoses, dermatosis papulosa nigra, stucco keratoses, and solar lentigines; the PIK3CA-related overgrowth spectrum includes Klippel–Trenaunay syndrome, megalencephaly–capillary malformation, and CLOVES (see Ch. 85 ).

    Includes porokeratotic eccrine ostial and dermal duct nevus (PEODDN) and other spiny hyperkeratotic EN.Mosaic RAS mutations found in epidermal nevi are often (but not always) different from those in generalized conditions, suggesting that the former represent more severe, lethal mutations rescued by mosaicism.

    Fig. 51.4, Plantar cerebriform connective tissue nevus in a man with Proteus syndrome.

Mosaicism in Autosomal Dominant Skin Conditions

  • When evaluating a patient with skin lesions in a mosaic pattern, it can be helpful to consider whether the findings would resemble an autosomal dominant genodermatosis if present in a more generalized distribution.

  • Type 1, type 2, and revertant forms of mosaicism occurring in autosomal dominant skin disorders are summarized in Fig. 51.5 .

    Fig. 51.5, Mosaicism for autosomal dominant (AD) traits.

  • Some dominant mutations in autosomal genes are only observed in a mosaic state, as they would not be compatible with life if present in all the cells of the body; examples include Proteus, Schimmelpenning (nevus sebaceus), and McCune–Albright syndromes (see Tables 50.3 and 51.3 ).

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