Pigmentary mosaicism (hypomelanosis of Ito)

INTRODUCTION — The term "pigmentary mosaicism" refers to patterned hypo- or hyperpigmentation resulting from a clone of skin cells with altered ability to produce melanin [1]. The three major clinical patterns are streaks and swirls following the Blaschko lines (figure 1), a segmental or "checkerboard" distribution, and a phylloid (leaf-like) arrangement.

This topic will discuss the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of pigmentary mosaicism. Other inherited and acquired disorders of pigmentation are discussed separately.

●(See "Incontinentia pigmenti".)

●(See "Acquired hyperpigmentation disorders".)

●(See "Acquired hypopigmentation disorders other than vitiligo".)

●(See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

TERMINOLOGY — A variety of terms have been used for different clinical presentations within the spectrum of pigmentary mosaicism. "Hypomelanosis of Ito" (HOI) and "linear and whorled nevoid hypermelanosis" (LWNH) generally refer to hypo- and hyperpigmentation along the Blaschko lines, respectively. Extracutaneous manifestations occur in a minority of individuals with these skin findings [2,3]. However, HOI series from pediatric neurology centers describe high frequencies of neurologic abnormalities, which reflect an obvious referral bias, and some authors limit the diagnosis of HOI to patients with extracutaneous abnormalities [4,5].

To avoid unnecessary concern based upon these uses of the HOI appellation and to acknowledge the similar nature of LWNH, alternative descriptive names, such as "linear nevoid hypo-/hyperpigmentation" (used herein) and "Blaschkoid dyspigmentation," have been proposed [2,3]. Of note, the term "incontinentia pigmenti achromians" that was originally coined by Ito for linear nevoid hypopigmentation is no longer used to avoid confusion with incontinentia pigmenti, a completely separate condition.

Multiple terms have also been utilized for pigmentary mosaicism in a checkerboard pattern, including "segmental nevus depigmentosus," "segmental pigmentation disorder" (used herein), and "flag-like hypo- or hypermelanotic nevus" [6-9]. Cutis tricolor refers to patterned hypo- and hyperpigmentation in a background of skin with an intermediate level of pigmentation.

EPIDEMIOLOGY — The exact prevalence of pigmentary mosaicism is unknown. Studies in Hispanic children have found that hypomelanosis of Ito (HOI), defined as extensive linear or patchy hypopigmentation (affecting ≥3 body regions) with associated extracutaneous findings, was present in approximately 1 of 8000 general pediatric outpatients and 1 of 800 pediatric dermatology outpatients [4,10]. Pigmentary mosaicism without associated extracutaneous findings may not come to medical attention, especially when relatively subtle or not extensive, and is likely underreported in the literature. Segmental pigmentation disorder is thought to be relatively common, with one study estimating its presence in approximately 1 of 250 Israeli pediatric dermatology outpatients [7,8].

Pigmentary mosaicism has no clear sex predilection and is almost always sporadic, with rare reports of possible familial occurrence [11-13]. Although it can affect individuals of any ethnic background, pigmentary mosaicism is often more apparent in those with darkly pigmented or tanned skin. The areas of patterned hypo- or hyperpigmentation may be noticed at birth or become evident during the first few years of life. Delayed presentation is common in fair-skinned individuals, and hypopigmentation may go unnoticed until the contrast with the surrounding skin is accentuated following sun exposure.

PATHOGENESIS — Mosaicism refers to an organism composed of at least two genetically different cell populations that originate from a homogeneous zygote. Pigmentary mosaicism results from a postzygotic mutation or other genetic change that alters the pigment production potential of daughter cells destined to be located in the skin. If daughter cells also migrate to other organs (eg, central nervous system, musculoskeletal system) and the genetic change has local detrimental effects, extracutaneous manifestations may occur. The extent of involvement of the skin (and potentially of other organs) is thought to be greater when the causal genetic event occurred earlier during the embryogenesis.

Multiple types of mosaic cytogenetic abnormalities have been found to underlie linear nevoid hypo-/hyperpigmentation, including numerical (eg, trisomy 18 or 20, triploidy) and structural (eg, deletions, duplications, translocations) chromosomal aberrations. Alterations in nearly every chromosome have been reported to cause pigmentary mosaicism. However, approximately 90 percent of the cytogenetic abnormalities involve loci of genes known to be involved in skin pigmentation, with more than 50 different pigmentary genes shown to be implicated in at least one patient [5]. Smaller-scale mutations (eg, point mutations) in a specific gene have less often been implicated. For example, asymmetric megalencephaly with polymicrogyria associated with nevoid hypo- and hyperpigmentation has been associated with a mosaic point mutation in the mechanistic target of rapamycin (mTOR) gene [14].

The types of genetic changes that cause segmental pigmentation disorder remain to be determined. By contrast, phylloid hypomelanosis is a distinct clinicogenetic entity caused by mosaic trisomy (or occasionally tetrasomy) 13q [15]. There are also rare reports of phylloid hypermelanosis, which has been linked to several different chromosomal aberrations [16].

CLINICAL MANIFESTATIONS — Patients with pigmentary mosaicism present with hypo- or hyperpigmentation along Blaschko lines or in a checkerboard pattern. The use of a Wood's lamp may help to better delineate the affected areas when the hypo- or hyperpigmentation is subtle. Some patients have a combination of linear and segmental hypo- and/or hyperpigmentation. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.)

Linear nevoid hypo-/hyperpigmentation — In patients with linear nevoid hypo-/hyperpigmentation, streaks and swirls of hypo- or hyperpigmentation following Blaschko lines can occur anywhere on the body, forming V-shapes on the central back; S-shapes on the anterior trunk; and long, narrow bands on the extremities (picture 1A-B). Involvement may be unilateral or bilateral, localized or widespread [4]. When extensive, it is sometimes difficult to determine whether the lighter or darker skin represents the background color (picture 2). Occasionally, both hypo- and hyperpigmented streaks are present in different areas [3,17]. Scalp involvement can lead to spiral bands of lighter or darker hair [18]. There have been a few reports of associated hypohidrosis or separate streaks of Blaschko-linear hypertrichosis [4,9,19,20].

Extracutaneous manifestations — Extracutaneous involvement in patients with linear nevoid hypo-/hyperpigmentation most commonly affects the central nervous system and musculoskeletal system. The exact prevalence is unknown. Older series from pediatric neurology centers reported central nervous system abnormalities in over 80 percent of patients, but these findings are not generalizable due to a strong referral bias [4,10]. Series from pediatric dermatology referral centers have documented a 15 to 30 percent prevalence of extracutaneous findings in these patients [2,3]. Considering that healthy children without extensive skin involvement would be less likely to see a subspecialized pediatric dermatologist, the frequency is probably even lower. Of note, many experts recommend reserving the term "hypomelanosis of Ito" for patients with linear nevoid hypo-/hyperpigmentation associated with extracutaneous manifestations [4,5,21]:

●Signs and symptoms of central nervous system involvement usually arise during infancy, but milder manifestations occasionally have a later onset. Developmental delay and seizures are the most frequent clinical findings [2,3,22].

●Associated musculoskeletal anomalies include hemihyperplasia or hemihypoplasia, scoliosis, coarse facies, and abnormal digits [4,23].

●Ocular abnormalities and congenital heart disease have been reported in a small minority of affected individuals, with variable manifestations that reflect the diversity of the underlying genetic defects [4,10].

●Pallister-Killian syndrome due to mosaic tetrasomy 12p features linear nevoid hypo-/hyperpigmentation together with craniofacial dysmorphism, congenital heart defects, congenital diaphragmatic hernia, hypotonia, seizures, and intellectual disability [24]. (See "Congenital cytogenetic abnormalities", section on '47,+i(12p)'.)

Segmental pigmentation disorder — In patients with segmental pigmentation disorder, hypo- or hyperpigmented patches have a segmental pattern that has been referred to as block-like, flag-like, or resembling a checkerboard (picture 3). Any site can be affected, but the trunk is favored. Midline demarcation is more often present ventrally (approximately 80 percent of cases) than dorsally. Lesions tend to be less well-defined laterally and occasionally extend past the midline by a few centimeters [7,8]. The shape is frequently quadrangular, and the margins may be serrated [9].

Segmental pigmentation disorder is not usually associated with extracutaneous abnormalities. Affected areas occasionally develop multiple superimposed lentigines or melanocytic nevi, including Spitz nevi. If the background patch is hyperpigmented, this leads to a diagnosis of speckled lentiginous nevus (nevus spilus). (See 'Differential diagnosis' below.)

Segmental hyperpigmentation sometimes coexists with a light red-pink capillary malformation; this association is referred to as "phacomatosis melanorosea" [9]. (See "Vascular lesions in the newborn", section on 'Phakomatosis pigmentovascularis'.)

Phylloid hypomelanosis and hypermelanosis — The phylloid pattern is composed of leaf-like, pear-shaped, and oblong lesions in an arrangement reminiscent of a floral ornament (picture 4).

Phylloid hypomelanosis is a distinct clinicogenetic entity associated with mosaic abnormalities of chromosome 13 (trisomy and tetrasomy 13q). It presents with additional cutaneous and extracutaneous features, including telangiectatic macules, thick eyebrows, long eyelashes, low frontal hairline, seizures, intellectual disability, agenesis of the corpus callosum, conductive hearing loss, colobomas, and skeletal defects that often involve the digits [15,25].

Only a few cases of phylloid hypermelanosis have been reported, with variable extracutaneous manifestations [16,26]. Mosaic abnormalities of chromosome 13 have been documented in some but not all cases of phylloid hypermelanosis [27].

PATHOLOGY — Hypopigmented lesions have a normal or reduced number of melanocytes [28,29]. Hyperpigmented lesions typically show increased pigmentation in the basal layer of the epidermis and a normal or slightly increased number of melanocytes [30-32].

DIAGNOSIS — The diagnosis of the various types of pigmentary mosaicism is made clinically. Although the histopathologic findings are nonspecific, a skin biopsy is occasionally helpful in excluding alternative diagnoses when the clinical findings are atypical. (See 'Differential diagnosis' below.)

History and physical examination — A thorough history and physical examination should be performed to assess for extracutaneous involvement, with further evaluation directed by any abnormal findings. Neurodevelopmental progress should be followed by the child's pediatrician, with additional intervention if needed.

Genetic analysis — Identification of the underlying genetic alteration does not usually affect the management of patients with pigmentary mosaicism. However, genetic analysis should be considered in children with extracutaneous abnormalities, as it may provide a more accurate diagnosis.

Karyotyping of peripheral blood lymphocytes reveals mosaic chromosomal abnormalities in up to one-third of patients with linear nevoid hypopigmentation. In an additional one-fourth of affected individuals, chromosomal abnormalities can be detected by genetic analysis of lesional skin fibroblasts [33].

Because Blaschko lines reflect pathways of ectodermal cell migration during embryonic development, the mosaic abnormality may be confined to epidermal cells. Although analysis of lesional keratinocytes or melanocytes rather than fibroblasts would likely be of higher yield, keratinocyte and melanocyte cultures are not routinely performed at most cytogenetic laboratories [34].

More sensitive techniques such as array comparative genomic hybridization (aCGH) may also be useful in identifying submicroscopic genetic abnormalities (eg, microdeletions, microduplications) that are not detected with conventional cytogenetic methods. Analysis of specific genes or whole exome/genome sequencing utilizing lesional samples may be helpful in patients with extracutaneous manifestations suggestive of a particular diagnosis or type of disorder [14].

DIFFERENTIAL DIAGNOSIS — Several conditions can present with hypo- or hyperpigmentation along Blaschko lines or in a checkerboard pattern. The clinical and histopathologic clues highlighted below may help determining the correct diagnosis.

Hypopigmentation along Blaschko lines

●Lichen striatus – Lichen striatus is a benign, self-limited, inflammatory dermatitis that most often develops in children. It typically has a sudden onset and favors the extremities. In individuals with darker or tanned skin, lichen striatus can present as hypopigmented streaks composed of macules and barely elevated papules (picture 5). If the diagnosis is uncertain, a skin biopsy showing a lymphocytic infiltrate centered on eccrine glands and hair follicles can clarify the diagnosis. (See "Lichen striatus".)

●Epidermal nevus – Epidermal nevus is a benign, hamartomatous growth of the skin. Lesions usually become apparent during the first year of life and are occasionally hypopigmented, especially in children with darker skin (picture 6). Subtle elevation and textural changes that are most evident in flexural and acral sites suggest the diagnosis. Histology shows hyperkeratosis, acanthosis, and papillomatosis. (See "Epidermal nevus and epidermal nevus syndrome".)

●Nevus comedonicus – Nevus comedonicus may present at birth or later in childhood as grouped comedones superimposed on hypopigmented streaks. The clinical diagnosis is usually straightforward.

●Linear lichen sclerosus – Extragenital lichen sclerosus is a chronic inflammatory disorder typically presenting with porcelain white, atrophic plaques on the skin. Hypopigmented bands with a shiny, wrinkled surface and follicular plugging can develop at any age. Biopsy shows characteristic homogenization of the upper dermis with epidermal thinning and a variable lymphocytic infiltrate. (See "Extragenital lichen sclerosus: Clinical features and diagnosis".)

●Focal dermal hypoplasia (Goltz syndrome) – Focal dermal hypoplasia is a rare multisystem connective tissue genodermatosis characterized by streaks of hypopigmentation typically accompanied by congenital cribriform dermal atrophy and fat "herniation" (picture 7). Additional findings in this X-linked dominant condition include raspberry-like papillomas, ectrodactyly, other bony defects, and anomalies of the eyes, nails, hair, and teeth. (See "Focal dermal hypoplasia (Goltz syndrome)".)

●Incontinentia pigmenti, stage 4 – Incontinentia pigmenti is an X-linked dominant genodermatosis presenting in females as a staged, linear cutaneous eruption. Stage 4 is characterized by hypopigmented, hairless, and atrophic streaks resembling "Chinese characters." It often has onset in the teens and favors the calves, with variable preceding vesicular, verrucous, and/or hyperpigmented stages. This X-linked dominant disorder may also affect the teeth, hair, nails, and eyes. (See "Incontinentia pigmenti".)

●Menkes syndrome, female carrier – Menkes syndrome is an X-linked recessive disease of copper metabolism characterized by neurologic, connective tissue, skin, hair, bone, bladder, and arterial abnormalities [35]. Hypopigmented streaks and pili torti of scalp hair may be present in carriers of this X-linked condition. (See "Overview of dietary trace elements", section on 'Menkes disease'.)

●Linear Darier disease – Darier disease is a rare genodermatosis characterized by a persistent eruption of greasy hyperkeratotic papules in seborrheic regions. In the linear variant, affected streaks may contain guttate hypopigmented macules and/or keratotic papules. A skin biopsy showing acantholytic dyskeratosis is diagnostic. (See "Darier disease".)

●Conradi-Hünermann-Happle syndrome – Congenital X-linked dominant chondrodysplasia punctata type 2 (Conradi-Hünermann-Happle syndrome) presents at birth as a congenital ichthyosiform erythroderma that clears over months and is replaced by linear hyperkeratosis, follicular atrophoderma, and pigmentary abnormalities. Follicular atrophoderma is typically present in the hypopigmented streaks, and there is usually a history of neonatal ichthyosiform erythroderma with feathery scale following the Blaschko lines (picture 8). Other features of this X-linked dominant disorder include patchy scarring alopecia, unilateral cataracts, and asymmetric skeletal anomalies. (See "Overview and classification of the inherited ichthyoses", section on 'X-linked dominant disorders'.)

Hyperpigmentation along Blaschko lines

●Epidermal nevus – Early or minimally elevated lesions can be mistaken for pigmentary mosaicism. Subtle textural changes tend to be most evident in flexural and acral sites (picture 9). When performed, biopsy shows hyperkeratosis, acanthosis, and papillomatosis. (See "Epidermal nevus and epidermal nevus syndrome".)

●Incontinentia pigmenti, stage 3 – Streaks of reticulate gray-brown hyperpigmentation with characteristic scalloped borders favor the trunk and intertriginous sites (picture 10). Stage 3 typically occurs from infancy through early adolescence, often but not always preceded by vesicular and verrucous stages. This X-linked dominant disorder may also affect the teeth, hair, nails, and eyes. Biopsy shows prominent dermal melanophages. (See "Incontinentia pigmenti".)

●X-linked hypohidrotic ectodermal dysplasia (female patients) – Hyperpigmented swirls (most evident on the back) are smooth and lack adnexa. They tend to be more obvious and have earlier onset in patients with darker skin. This X-linked condition also features peg-shaped or missing teeth and decreased hair density [36].

●Linear atrophoderma of Moulin – Atrophoderma of Moulin is a rare disorder characterized by unilateral bands of hyperpigmented and atrophic plaques that follow the lines of Blaschko [37]. Hyperpigmented streaks are slightly depressed with "cliff-drop" borders and can develop at any age.

●Linear forms of lichen planus, lichen planus pigmentosus, and fixed drug eruption – A gray-brown color due to pigment incontinence is often evident in these inflammatory conditions, which can develop at any age. Biopsy is helpful in confirming the diagnosis. (See "Lichen planus" and "Fixed drug eruption" and "Acquired hyperpigmentation disorders", section on 'Lichen planus pigmentosus'.)

Hypopigmentation or depigmentation in a block-like pattern

●Segmental vitiligo – In children, vitiligo may present with completely depigmented lesions with sharply defined borders in a patchy segmental distribution (picture 11). The stark white color typically accentuated with Wood's lamp examination and presence of perifollicular repigmentation suggest the diagnosis. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

Hyperpigmentation in a block-like pattern

●McCune-Albright syndrome – This rare sporadic disorder is caused by a postzygotic activating mutation in GNAS, the gene encoding the alpha-subunit of the G protein that stimulates adenylate cyclase activity. The segmental hyperpigmentation of McCune-Albright syndrome may follow the lines of Blaschko in broad bands and tends to be darker than a typical café-au-lait macule (CALM), with sharply demarcated, irregular ("coast of Maine") borders (picture 12) [38]. Other manifestations include polyostotic fibrous dysplasia of the bone and endocrine activation (classically precocious puberty). (See "Congenital and inherited hyperpigmentation disorders", section on 'McCune-Albright syndrome'.)

●Neurofibromatosis type 1 and Legius syndrome – In neurofibromatosis type 1 (NF1) and NF1-like syndrome (Legius syndrome), a large block-like CALM is occasionally seen in association with multiple smaller CALMs in a widespread distribution. The CALMs of NF1 typically have regular borders, and sometimes large lesions have an underlying plexiform neurofibroma with a "bag of worms" consistency upon palpation. Other stigmata of NF1 (such as intertriginous freckling, Lisch nodules, and neurofibromas) may be evident, depending upon the age of the patient. In segmental NF1, multiple CALMs and often lentigines are found in a segmental distribution, with slightly darker background pigmentation in this area compared with the patient's unaffected skin. (See "Congenital and inherited hyperpigmentation disorders", section on 'Neurofibromatosis type 1-like syndrome (Legius syndrome)' and "Congenital and inherited hyperpigmentation disorders", section on 'Neurofibromatosis type 1'.)

●Large/giant café-au-lait macule – CALMs tend to be oval or round in shape without midline demarcation; their borders are sharply defined, without fading at the lateral margin [8].

●Becker nevus – Becker nevus presents as a hyperpigmented patch that typically breaks up into smaller macules at its periphery and may have associated hypertrichosis (picture 13). It favors the upper lateral trunk and can either be congenital or appear around the time of puberty. Skin biopsy shows subtle features of a smooth muscle hamartoma. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Becker nevus'.)

●Speckled lentiginous nevus (nevus spilus) – Macular and/or papular "speckles" representing lentigines and melanocytic nevi of various types (including Spitz nevi in some patients) progressively develop on a hyperpigmented background patch, which may be large and block-like (picture 14). (See "Congenital melanocytic nevi", section on 'Speckled lentiginous nevus'.)

Chimerism — An individual composed of two genetically distinct original cell lines (eg, by fertilization of one egg by two sperm or fusion of two zygotes) may display an admixture of lighter and darker skin pigmentation. This often has a checkerboard configuration with sharp midline demarcation, but patterns range from almost perfect rectangles to narrow bands to ill-defined, mottled patches [9].

Pigmentary demarcation lines — These bilateral, symmetric physiologic lines of demarcation between the ventral and relatively hyperpigmented dorsal surfaces are most evident in individuals with darkly pigmented skin and should not be confused with pigmentary mosaicism. (See "Congenital and inherited hyperpigmentation disorders", section on 'Pigmentary demarcation lines'.)

The five major forms on the trunk and extremities are:

●Type A (most common) – Vertical line on the anterolateral upper arm, sometimes extending to the chest (picture 15)

●Type B – Curved line on the posteromedial thigh, sometimes extending to the ankle (picture 16)

●Type C – Vertical or curved hypopigmented band on the mid chest resulting from two parallel pigmentary demarcation lines

●Type D – Vertical line along the spine

●Type E – Hypopigmented macules/patches on the chest from mid clavicle to areola

MANAGEMENT AND FOLLOW-UP — Management of pigmentary mosaicism is directed at extracutaneous manifestations when present. The abnormal skin pigmentation does not typically respond well to treatments, although some fading of linear nevoid hyperpigmentation has been reported with the use of Q-switched lasers [39].

Long-term follow-up with the child's pediatrician is important to monitor growth and development over time. Any suspected extracutaneous abnormalities that arise should be properly investigated and managed by the appropriate specialist.

PROGNOSIS — The prognosis for most individuals with pigmentary mosaicism without extracutaneous findings is excellent. Although the pigmentary alteration is usually persistent, fading of hyperpigmented lesions has been reported [7,40].

In patients with extracutaneous findings, the clinical course and prognosis vary, based upon the type and extent of the underlying abnormalities.

SUMMARY AND RECOMMENDATIONS

●Definition – Pigmentary mosaicism refers to patterned hypo- or hyperpigmentation that results from a clone of skin cells with altered ability to produce melanin. A wide variety of underlying mosaic cytogenetic abnormalities have been identified. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical patterns – The three major clinical patterns of pigmentary mosaicism are:

•Linear nevoid hypo-/hyperpigmentation, with streaks and swirls following Blaschko lines (picture 1A-B)

•Segmental pigmentation disorder, showing segmental or "checkerboard" distribution, often with midline demarcation on the anterior trunk (picture 3)

•Phylloid pattern, usually phylloid hypomelanosis due to mosaic trisomy 13q (picture 4) (see 'Clinical manifestations' above)

●Extracutaneous manifestations – A small minority (≤15 percent) of individuals with linear nevoid hypo-/hyperpigmentation have associated extracutaneous findings, most often neurodevelopmental abnormalities that become apparent during infancy. The term "hypomelanosis of Ito" should be reserved for this subgroup of patients. (See 'Extracutaneous manifestations' above.)

●Diagnosis – The diagnosis of pigmentary mosaicism is usually clinical, based on the pattern and distribution of hypo- and hyperpigmentation. Genetic analysis should be considered in children with extracutaneous abnormalities. (See 'Diagnosis' above.)

●Management – The management of pigmentary mosaicism involves a thorough history and physical examination to assess for extracutaneous involvement, with further evaluation directed by any abnormal findings. The abnormal skin pigmentation does not typically respond well to treatment. Long-term follow-up with the child's pediatrician is important to monitor growth and development over time. (See 'Management and follow-up' above.)