The terms pigmentary mosaicism or patterned dyspigmentation describe a spectrum of clinical findings that range from localized areas of dyspigmentation with no systemic findings to widespread dyspigmentation with associated neurologic, musculoskeletal, and cardiac abnormalities, and other sequelae that can lead to early demise. Given this wide spectrum, these patients must be approached with caution, but with the understanding that most who have localized pigmentary anomalies, such as segmental pigmentary disorder (SegPD) seem to have no systemic manifestations. These patients can be approached in many different ways, but generally children with more widespread dyspigmentation, and any with associated abnormalities or not meeting neurodevelopmental milestones, should be evaluated closely. Children with any red flags warrant subspecialty referral, and all children deserve close clinical follow-up with their primary care physician to ensure they meet all of their developmental milestones. Fortunately, parents can be reassured that most children with SegPD, and many with more widespread patterned pigmentation, are otherwise healthy.
Patterned pigmentation describes a phenotype in which the skin has lighter or darker shades in a particular pattern. The skin pigmentation can either be isolated or signal an underlying disorder with systemic manifestations. The most commonly recognized patterns of cutaneous pigmentation are those following lines of Blaschko (which can be thin or broad), checkerboard pattern, and phyloid or leaf pattern ( Fig. 1 ). Blaschko’s lines mark the embryonic migration of ectodermal cells, with both melanocytes and keratinocytes arising from the ectoderm. Blaschko’s lines are more wavy and whorled than the straight bands of dermatomes, which follow the distribution of cutaneous sensory nerves. Pigmentary demarcation lines can often be seen vertically oriented on the upper anterior arms and lower abdomen in dark-skinned patients, and are normal physiologic patterns that do not signify a disorder.
If a genetic error leads to a distinct set of cells that has a darker or lighter phenotype, Blaschko’s lines become visible as a line of darker or lighter pigmentation along that cell and its progeny’s migration path. The term pigmentary mosaicism is often used to describe these patterns. In some situations, the genetic error resulting in dyspigmentation may also result in abnormalities that are not isolated to the skin. This term implies two separate cell lines in the same person. Whether mosaicism is the cause of the patterned pigmentation in all patients is unknown. Pigmentary mosaicism may manifest as areas of hypopigmentation or hyperpigmentation in an individual; however, the areas that represent the “baseline” skin color may be difficult to distinguish from the areas of dyspigmentation in an individual with extensive pigment mosaicism ( Fig. 2 ).
Hypomelanosis of Ito (HI) and linear and whorled nevoid hypermelanosis (LWNH) are syndromes that are classically described as being associated with pigmentary mosaicism. Not all patients with patterned pigmentation have extensive involvement. Hogeling and Frieden recently described a subset of patients with block-like and unilateral hypo- or hyperpigmentation (similar to the checkerboard or phyloid patterns described by Happle ) who rarely have associated anomalies, using the term segmental pigmentary disorder (SegPD) to describe the condition. This term was originally described by Metzker and colleagues.
Paller proposed that the earlier in development a genetic error occurs, the more tissues it is likely to affect. Therefore, the more widespread a pigmentary anomaly is, the more likely it is associated with underlying systemic abnormalities. Unfortunately, the terminology is confusing because the genotype–phenotype correlations and exact pathophysiology are still being investigated, but attempting to separate patients with very low risk for systemic anomalies (SegPD) will help avoid unnecessary workup.
Mechanisms of mosaicism
The most readily recognized pattern of mosaicism in humans is the programmed inactivation that occurs of one X chromosome in women with XX karyotype (lyonization). This ability to inactivate aberrant or potentially dangerous genetic material on one X chromosome essentially allows women to pick the best genetic material. This selection confers protection from life-threatening genetic conditions carried on the X chromosome, which are often lethal in men who are forced to use their only copy of the X chromosome (eg, incontinentia pigmenti).
Happle originally suggested that abnormalities within lines of Blaschko resulted from lyonization within these cells and their progeny as they migrated. Probably many different types of genetic aberrations can lead to pigmentary mosaicism. Some patients with patterned hyperpigmentation or hypopigmentation (LWNH) phenotype and HI phenotype) have been described with a balanced translocation of an autosomal chromosome to an X chromosome, and disruption of Xp11 was described in earlier case series of patients with HI.
More recently Taibjee and colleagues proposed that X;autosome translocations lead to preferential inactivation of the normal X chromosome to preserve the autosomal gene expression because the genetic information from the autosomal chromosome is deemed more essential and allowed to remain active. To learn more about the relationship between pigmentary mosaicisms and the genes involved in pigmentation, these investigators created a database of cytogenetic abnormalities reported in cases of pigmentary mosaicism (including reported cases of HI and LWNH). They noted that cytogenetic abnormalities overlapping with one or more genes involved in pigmentation were found in 88% of cases. Abnormalities in karyotype can be detected in 30% to 60% of patients with HI or LWNH. However, this relatively high percentage likely represents a reporting bias, because cases that have no karyotype abnormality may be underreported.
Segmental pigmentary disorder
Hypopigmentation
Hypopigmented areas of SegPD are also commonly named nevoid hypomelanosis or segmental nevus depigmentosus . Localized hypopigmentation must be differentiated from ash leaf macules and confetti hypopigmentation associated with tuberous sclerosis (TS). Hypopigmented patches seen in TS are often smooth-bordered and oval-shaped (ash leaf macules) or small individual macules that do not follow a blaschkoid pattern. Hypopigmentation SegPD with hypopigmentation can also be differentiated from disorders such as vitiligo, which lead to depigmented areas that appear more starkly white and highlight distinctly with a Wood’s lamp examination.
Hyperpigmentation
SegPD that is hyperpigmented is often called nevoid hypermelanosis or segmental café au lait . Large areas of hyperpigmented can be associated with McCune-Albright syndrome (polyostotic fibrous dysplasia with endocrinopathies such as precocious puberty). Large isolated café au lait macules associated with segmental neurofibromatosis tend to be more of a large oval or rectangular shape instead of the wavy and streaky blaschkoid pigmentation of nevoid hypermelanosis (see Fig. 2 ).
Segmental pigmentary disorder
Hypopigmentation
Hypopigmented areas of SegPD are also commonly named nevoid hypomelanosis or segmental nevus depigmentosus . Localized hypopigmentation must be differentiated from ash leaf macules and confetti hypopigmentation associated with tuberous sclerosis (TS). Hypopigmented patches seen in TS are often smooth-bordered and oval-shaped (ash leaf macules) or small individual macules that do not follow a blaschkoid pattern. Hypopigmentation SegPD with hypopigmentation can also be differentiated from disorders such as vitiligo, which lead to depigmented areas that appear more starkly white and highlight distinctly with a Wood’s lamp examination.
Hyperpigmentation
SegPD that is hyperpigmented is often called nevoid hypermelanosis or segmental café au lait . Large areas of hyperpigmented can be associated with McCune-Albright syndrome (polyostotic fibrous dysplasia with endocrinopathies such as precocious puberty). Large isolated café au lait macules associated with segmental neurofibromatosis tend to be more of a large oval or rectangular shape instead of the wavy and streaky blaschkoid pigmentation of nevoid hypermelanosis (see Fig. 2 ).
Syndromes associated with patterned pigmentation
Hypomelanosis of Ito
HI is characterized by linear and whorled hypopigmented streaks in the skin. HI is most commonly associated with neurologic abnormalities, such as seizures, delayed neurologic development, and macrocephaly, and abnormalities in the ocular, cardiac, and musculoskeletal systems are described in some cases. Currently many experts feel that the diagnosis of HI should be reserved for individuals who have the characteristic patterned hypopigmentation and neurologic abnormalities, and should not be given to those who only have the skin manifestations. However, earlier case reports do not always distinguish between these groups.
HI was originally described as incontinentia pigmenti achromians because the final stage of incontinentia pigmenti (IP) resembles the streaky hypopigmentation of HI, but HI lacks the preceding vesicular and verrucous stages (described later). The term IP achromians should be abandoned because it can be confused with true IP.
The streaks in HI are typically present at birth but may be difficult to notice in very–fair-skinned children until their skin melanizes. HI does not represent a single genetic/chromosomal disorder, but is a cutaneous phenotype and has been associated with many different genetic abnormalities, including chromosomal translocations, insertions, aneuploidy, and microdeletions, often leading to chromosomal mosaicism. A genetic abnormality is not always found.
The variability in the clinical presentation is likely from the large number of distinct genetic abnormalities that can lead to the same clinical phenotype of streaky hypopigmentation. Although neurologic abnormalities such as seizures, developmental delay, and macrocephaly are most common, the list of associated underlying abnormalities, including musculoskeletal, cardiac, and ophthalmologic, is long. Some of the more common associations are summarized in Table 1 . Approximately 30% to 90% of children (depending on the study) may have extracutaneous manifestations ; however, this is likely an overestimate because children who only have skin changes may never seek medical attention and are often not reported. It is also likely that the more widespread the skin pigmentary anomaly is the more likely systemic manifestations are present, perhaps because more of the ectodermal cells have the genetic defect. Although the number of associations can seem overwhelming, this is likely because of the large variability in genetic abnormalities, and therefore any one child is unlikely to have all of the manifestations described.
