Clinical manifestations

Presentation and course

Hypomelanosis of Ito is a multisystem disorder in which most organs of the body may show anomalies in addition to the skin. The most frequent alterations are found in the musculoskeletal and central nervous systems.

The main features that define hypomelanosis of Ito are the cutaneous anomalies.

In many instances, patients present with skin hypopigmentation following the lines of Blaschko without any other associated anomaly (38; 51). The frequency of cutaneous or extracutaneous abnormalities in published articles and reviews may reflect the detail of the investigation in the series or the population studied. For example Metzker and colleagues did not find extracutaneous involvement in an analysis of 30 children with hypomelanosis of Ito (36). Nehal and colleagues and Ruggieri and Pavone recorded low frequencies of extracutaneous abnormalities (30%) whereas Ruiz-Maldonado and colleagues reported nearly 100%, Pascual-Castroviejo and colleagues 94%, Glover and colleagues 79%, and Zvulunov and Esterly 75% (43; Grover et al 1989; 55; 71; 38; 51).

Skin manifestations. The pigmentary lesions in hypomelanosis of Ito are either recognizable at birth or become visible during early childhood. Unilateral or bilateral areas of hypopigmentation with irregular borders characterize the typical phenotype with lesions arranged in whorls, patches, or linear patterns along the lines of the Blaschko (26; 27).

This system of lines (Blaschko lines) forms streaks displaying a v-shape or fountain-like pattern over the face and spine and s-shaped or whorled patterns over the anterior and lateral aspects of the trunk, and a linear arrangement over the extremities with a characteristic sharp midline cutoff (06).

The lines of Blaschko are always associated with mosaicism (26; 07). Pigmentary anomalies associated with human mosaicism may show several patterns of distribution in the skin: (1) type 1, typically following the lines of Blaschko (either narrow band, type 1a, or broad band, type 1b); (2) type 2, checkerboard pattern; (3) type 3, phylloid pattern; (4) type 4, patchy pattern without midline separation (26); and (5) type 5, spiral pattern (51; 45). Accordingly, other types of cutaneous pigmentary patterns, such as the zosteriform or dermatome or plaque-like arrangement, have likewise been observed in hypomelanosis of Ito. All of these cutaneous changes are associated with mosaicism, but not all are hypopigmented zones, and not all correspond to hypomelanosis of Ito skin patterns other than those following Blaschko lines.

The hypopigmented zones in hypomelanosis of Ito can be seen in any part of the body: head, face, neck, trunk, or extremities (they also have been observed in the iris) (58; 55; 44).

Areas of hyperpigmentation following the lines of Blaschko may also be seen as a counterpart to areas of hypopigmentation. In many patients, determination that the lighter areas of skin were hypopigmented rather than the darker areas hyperpigmented has been arbitrary (62). Areas of hypomelanosis are more easily detected in ethnic groups with increased skin pigmentation, such as Asians, Hispanics, or Africans. Inspection with a Wood (ultraviolet) lamp could help distinguish hypochromic zones, especially in Caucasians with fair skin (58). The extent of the hypopigmented cutaneous lesion does not always correlate either with the severity of neurologic disease or with the neuroimaging or histological findings (54). It is a necessary prerequisite that hypopigmented skin is not preceded by vesicular or verrucous stages because cutaneous lesions in the stage IV of incontinentia pigmenti are indistinguishable from those of hypomelanosis of Ito (26; 27).

Sweat glands and fingernails also may be abnormal (43; 55). Hypohidrosis corresponds to hypopigmented areas, which may represent a pathological cell line. This feature, however, has been found in about one third of patients with hypomelanosis of Ito (33). Absence of sweating with absence of glands in a skin biopsy has been reported, and this may be an argument in favor of the heterogeneity of hypomelanosis of Ito.

Other types of cutaneous lesions associated with hypomelanosis of Ito include café-au-lait spots, nevus marmorata, angiomatous nevi, nevus of Ota, and slate gray spots.

Scalp and hair. Scalp alterations mainly include changes in hair color, diffuse alopecia, and hair with trichorrhexis and white-grayish color (44; 51). Some patients show alopecia in areas of the scalp until 3 to 5 years of age, at which time trichorrhexis and grey-white hair may appear (43; 44). Patients with hair anomalies (mostly color changes) may show an increased frequency of systemic anomalies (including macrocephaly, hemicranial or hemifacial hypertrophy, ocular, nasal, or oral abnormalities, cerebral malformations, asymmetry of the trunk or extremities, and others) than patients without hair changes. Hypochromic hair may appear as areas of patches, streaks, or extending over the entire scalp, associated with achromic or hypochromic skin. Focal hypertrichosis of the genital area without signs of precocious puberty has been observed. In addition, multifocal hypertrichosis and hirsutism have also been reported (35).

Eye manifestations. Ocular alterations are rarely reported, and they are not specifically related to hypomelanosis of Ito. These include strabismus, nystagmus, dacryostenosis, hypertelorism, ptosis, symblepharon, nonclosure of the upper lid, myopia, amblyopia, iridal heterochromia, scleral melanosis, cataracts, striated patchy hypopigmented fundi, atrophy of the choroid, corneal opacity, micro-ophthalmia, macro-ophthalmia, optic nerve hypoplasia, and retinal degeneration (32; 58; 43; 55; 54; 51; 45).

Oral manifestations. Oral anomalies are of a wide variety and consist of defective dental implantation, partial anodontia, dental hypoplasia or dysplasia, conical teeth, and defective enamel (44). Hamartomatous cuspids protruding from the dental crowns of permanent teeth might be histologically reminiscent of odontoma. Bifid uvula and submucosal cleft palate are other unusual anomalies.

Musculoskeletal manifestations. Musculoskeletal disturbances are usually observed in more severe phenotypes (43; 55; 44). Skeletal defects include short stature and asymmetry with hemihypertrophy or hemihypotrophy of a part or of an entire side of the body (51; 45), scoliosis, thoracic deformities (pectus carinatum or excavatum), various finger and toe anomalies (clinodactyly, polydactyly, syndactyly, brachydactyly), and foot deformities (pes cavus, talipes equiinovarus) (32; 43; 44; 51; 64).

Hypertrophic or hypotrophic areas are usually seen on the same side as the hypomelanotic skin. Unilateral hypertrophy, also referred to as hemi-overgrowth, occurs in 7% of patients and is associated with a higher prevalence of extracutaneous manifestations (47). Bilateral hypertrophy is found in some cases with generalized hypomelanotic skin. The patients usually show coarse facies and macrocephaly (58, 43; 58, 44). All these defects are likely related to the age-dependent effect of the genetic mosaic abnormality (51; 51).

Nervous system manifestations. Anomalies of the CNS may include microcephaly or macrocephaly, cognitive and motor retardation, seizures, ataxia, hyperkinesias, and hypotonia (32; 43; 55; 54; 44; 51). They represent the most severe complications of hypomelanosis of Ito and there is a consistent discrepancy between the reported prevalence figures; by literature review, the incidence of associated neurologic disease was as high as 100% (28), 94% (43), or 80% (24), or as low as 61% (50), 50% (23), 40% (41), or 30% (38; 51).

Cognitive and behavioral problems. These are the most frequent neurologic problems in individuals with hypomelanosis of Ito. An IQ below 70 has been reported in 30% (38; 51), 57% (44), and 70% (55) of cases, likely depending on ascertainment bias in tertiary referral centers (51). Patients with mental retardation have been reported to exhibit autism spectrum disorders (43; 21; 01; 55; 70), but again the highest prevalence figures for autism in hypomelanosis of Ito (8% to 10%) are likely due to a bias toward child neuropsychiatry referrals (01; 70). Most patients with mental retardation, autism spectrum disorders, or both previously suffered infantile spasms or severe seizures (Pascual-Castroviejo 1989; 55; 44). The association of mental retardation with seizures is seen in 65% of cases (55; 54; 44).

Epilepsy. This is the second most frequent neurologic manifestation of hypomelanosis of Ito. Seizures may occur in 11% (38) to about 50% (43; 44) of cases. Seizures commonly appear early, within the first year of life and are mostly associated with cognitive deficits. Seizures can be refractory but are controlled with antiepileptic drugs in 70% (44). Epilepsy surgery can be successful in the carefully chosen candidate with medication-refractory epilepsy (48; 34). Seizure semiology is heterogeneous; of those patients with epilepsy, about 50% manifest as generalized tonic-clonic seizures, 25% as partial seizures, 15% as infantile spasms, and 8% as myoclonic seizures (44; 03; 46). There is no consistent EEG pattern in hypomelanosis of Ito. The EEG can yield normal results or show a wide range of abnormalities, with both focal and generalized epileptiform discharges (17; 39; 46).

Other neurologic manifestations. Speech delay in hypomelanosis of Ito has been occasionally reported with higher scores on performance IQ (mean PIQ = 90) than verbal IQ (mean VIQ = 73), delays in the production of speech sound and in communication milestones, and specific expressive language disabilities (70; 54). Other neurologic alterations found in isolated cases include muscular hypotonia, ataxia, neurosensorial deafness, and cortical visual impairment (51; 59).

Imaging findings. There are no constant findings in hypomelanosis of Ito, as expected. Most hypomelanosis of Ito cases (and likely almost all cases with no clinical neurologic signs or symptoms) display normal neuroimaging studies (04; 14) or only show enlarged perivascular spaces (54) to include the possibility of unilateral enlarged perivascular spaces (65). In the remainder, abnormalities may be grouped into white matter alterations and structural malformations (14). Nonprogressive white matter abnormalities on MRI (thought to be pathologically related to dilated Virchow-Robin spaces or altered/delayed myelination) may appear as early as a few months of age, and on T2-weighted and FLAIR sequences show multifocal, symmetric, high-signal foci in the periventricular and subcortical white matter, particularly in the centrum semiovale.

CT shows the same features as multiple low-density areas in the deep white matter of the hemispheres or as diffuse low density in the white matter (when a large number of lesions are present) (14). White matter lesions are static over time (18) and show no correlation between the extent of the lesions and the patient age (54). The most frequent structural anomalies are cerebellar hypoplasia or atrophy, focal cerebral atrophy or generalized cerebral atrophy, cerebral dysplasias, or other migrational abnormalities rarely associated with hemimegalencephaly. Other anomalies include gray matter heterotopia, blurred gray/white matter junction, agyria, polymicrogyria, porencephaly, and periventricular cysts (51; 04; 14; 45). Rare cases have also been reported of hypomelanosis of Ito with Sturge-Weber syndrome-like unilateral leptomeningeal angiomatoses (19; 10).

Other system anomalies. These can include congenital cardiac disease (43; 55; 44), renal disease including single kidney or ureteral duplication, focal segmental glomerulosclerosis with end-stage renal disease, or glomerulocystic kidney disease (20; 66), and genitourinary anomalies including cryptorchidism, micropenis, or macrogenitosomia (43; 55; 44). Asymmetric breast development (30; 44), gynecomastia in either boys or prepubertal girls (43), and precocious puberty (42) have all been reported. Hypomelanosis of Ito occasionally is associated with vascular anomalies such as moyamoya disease (13), carotid artery aneurysms (11), aortic malformations (67), intracranial arteriovenous malformation, or intestinal lymphangiectasia. Finally, lung involvement with segmental pulmonary hypoplasia has also been reported (05).

Hypomelanosis of Ito and tumors. A limited number of hypomelanosis of Ito cases are occasionally associated with tumors, including cystic teratoma in association with diploic epidermoid cyst, complex mature sacrococcygeal dysembryoma tumor, choroid plexus papilloma, and dental hamartomatous tumor (complex composite odontome-like). Rarely, malignancies such as acute lymphoblastic leukemia, medulloblastoma, neuroblastoma, and retinoblastoma have been reported (52; 16).

Prognosis and complications

Approximately one third (or fewer) of patients with hypomelanosis of Ito and related disorders (depending on the reported series) have psychomotor delay in infancy and present with cognitive or behavioral deficits later in childhood. Approximately the same percentage presents some type of seizure. Seizures in these disorders may be refractory (43; 54), especially because of disordered neuronal migration (17). However, control of seizures in 70% of patients with hypomelanosis of Ito has been reported in series of Pascual-Castroviejo and colleagues and Ruggieri and Pavone (44; 51). Autistic spectrum disorders, even rarely, must be taken into consideration. Musculoskeletal and other systemic abnormalities are congenital and, thus, are not progressive.

Biological basis

Etiology and pathogenesis

Mendelian transmission. There have been a number of single case reports claiming familial occurrence and supporting single gene inheritance (12; 51; 51; 45).

Two families were reported with a mother and her daughter and one family with a brother and sister affected by hypomelanosis of Ito (02; 68; 51). Members of the same family having hypomelanosis of Ito have been mentioned in other series (44). Paradominant inheritance has been claimed to be a possible mechanism in these families as well as in some non-Mendelian recurrences of hypomelanosis of Ito phenotypes running in families (27).

There have been reports on daughters from mothers with balanced X-autosome translocations with breakpoint above the juxtacentromeric X region with phenotypes overlapping with hypomelanosis of Ito (29).

Chromosome studies. The recognition of a variety of chromosomal mosaicisms (to include associations with trisomies such as trisomy 2 and 21) (22; 40), and ring chromosomes, such as ring chromosome 20 (08), as the pathogenic basis of many cases of hypomelanosis of Ito was a clue to explain the protean clinical manifestations of this condition and their often asymmetrical expression (61; 12; 51; 51). The primary question addressed is how such disparate genotypes could produce the common cutaneous phenotype of patchy pigmentation. By cross-comparing karyotype abnormalities in hypomelanosis of Ito and in cases with demonstrated pigmentary mosaicism with 76 pigmentary and candidate pigmentary gene loci, either in humans or animals, Taibjee and colleagues showed extensive (88%) overlaps between cytogenetic abnormalities and one or more pigmentary genes as well as significant (74%) overlaps between pigmentary genes and one or more karyotype abnormalities supporting the hypothesis that the pigmentary phenotype could arise through karyotype abnormalities specifically disrupting either expression or function of pigmentary genes (63; 45).

In hypomelanosis of Ito the pigmentary phenotype could arise through karyotype abnormalities specifically disrupting either expression or function of pigmentary genes. Likely mechanisms to explain the disruption are (63; 45): (1) parallel comigration of genetically different but not necessarily abnormal cell clones; (2) X-chromosome functional disomy; (3) “spreading” of X inactivation to autosomes; (4) transposons (transposable elements of retroviral origin) regulating gene activation and silencing and modulating the activity of pigmentary genes; (5) genetic imprinting; and (6) phenotype reversion. None of these, however, has so far been demonstrated as the likely mechanism to explain hypomelanosis of Ito. The various processes controlled by the (disrupted) pigmentary genes are: (1) melanoblast migration from the neural crest in fetal life; (2) melanocytes function including synthesis, transport, and degradation of melanosomes; and (3) physiology of the surrounding melanocytes milieu that include keratinocytes, intercellular matrix, growth factors, etc. It is unknown, however, at which level the process is disrupted. Sarnat and Flores-Sarnat hypothesized that the lines of Blaschko and hypomelanotic whorls and patches may represent a disorder of neural crest migration and terminal differentiation of melanocytes (56).

In addition, rare mosaic single-gene anomalies have been reported to include mosaic-activating mTOR (mechanistic target of rapamycin) pathogenic variants, identified within both brain and skin biopsies. The clinical spectrum of mTOR-related hypomelanosis of Ito can include patients with features of macrocephaly, hemimegalencephaly, intellectual disability, and epilepsy (09).

Epidemiology

For hypomelanosis of Ito a frequency of one in every 7805 general pediatric outpatients, one in every 790 general pediatric dermatology outpatients, one in every 2983 general pediatric inpatients, and one in every 63 pediatric dermatology inpatients was reported by Ruiz-Maldonado and colleagues. A prevalence of about one per 600 to 700 new patients referred to a pediatric neurology service at a large National Children's Hospital was reported by Pascual-Castroviejo (43; 55).

The calculated incidence and prevalence data in the area of Catania, Italy (800,000 inhabitants with approximately 13,000 births per year) were one in 7540 births (0.013%) and one in 82,000 individuals in the general population (0.0012%) (51).

The female:male ratio is 1:1 (55; 44).

Prevention

Affected adults should be reassured that the risk of the same condition in their offspring is low. Peripheral blood karyotyping is warranted, however, in the affected child and his or her parents before considering further pregnancies. Paradominant inheritance is a remote but possible mechanism.

Because of the reports on families with balanced X-autosome translocations with breakpoint above the juxtacentromeric X region whose phenotypes overlapped with hypomelanosis of Ito (29; 51), one should consider an “unfortunate” X inactivation resulting in a severe hypomelanosis of Ito phenotype. Conversely, reassurance can be given to a phenotypically normal mother with a balanced X-autosome translocation having a male offspring with the same translocation that her son would be phenotypically normal, although male infertility would be expected (29; 51).

Differential diagnosis

Confusing conditions

Hypomelanosis of Ito presents many similarities with other diseases with hypopigmented spots on the skin. These diseases are incontinentia pigmenti of Bloch and Sulzberger (OMIM #308300), tuberous sclerosis (OMIM #191100), vitiligo, and skin fungal infections.

Identical to hypomelanosis of Ito, incontinentia pigmenti shows the streaky pigmentary changes and the frequent occurrence of extracutaneous abnormalities. Hypomelanosis of Ito also differs from classical incontinentia pigmenti in the absence of preceding inflammatory or verrucous lesions and the occurrence of a much wider spectrum of associated abnormalities. Furthermore, hypomelanosis of Ito occurs as a sporadic trait (51; 63), whereas incontinentia pigmenti is X-linked and now known to be due to mutations of the IKBKG (NEMO) gene (60). Incontinentia pigmenti is also characterized by affecting almost only females and by a dynamic course of distinct cutaneous lesions that appear successively soon after birth, which include: (1) linear dermatitis with vesicles and erythema, (2) linear verrucous anomalies, (3) hyperpigmented streaks, and (4) hypochromic or achromic lesions similar to those of hypomelanosis of Ito. In contrast to incontinentia pigmenti, the hypopigmentation in patients with hypomelanosis of Ito is either recognized at birth, during the neonatal period, or in early childhood and remains unchanged for many years or for the entire life.

Cutaneous lesions in tuberous sclerosis present as multiple independent spots, irregularly bordered, and frequently have the characteristic ash-leaf configuration. In addition, brain MRIs in tuberous sclerosis have specific characteristics (ie, cortical-subcortical tubers, subependymal nodules, radial white matter abnormalities, calcifications, and more rarely subependymal cell astrocytoma).

Vitiligo is a straightforward diagnosis for dermatologists.

Skin fungal lesions are local problems of the skin that do not involve the CNS and can disappear after a variable period of time, whereas cutaneous lesions of hypomelanosis of Ito do not disappear. Wood lamp examination and superficial skin biopsies could help the differential diagnosis.

Misdiagnosis of hypomelanosis of Ito. In the absence of a recognized diagnosis, the label of hypomelanosis of Ito has often been used for individuals having diffuse or patchy, generalized or limited, linear or spotty skin dyspigmentation or hypopigmentation in many patchy or streaky configurations. This has caused great confusion and has expanded the phenotype of hypomelanosis of Ito, melting under the same rubric several conditions of different etiologies solely because of the presence of hypopigmented skin lesions. Often, in such cases, the presumptive diagnosis of a child having CNS or musculoskeletal abnormalities associated with cutaneous anomalies has been based only on a single or a pair of pigmentary skin lesions that could ultimately have been merely a presenting symptom of other diseases (51; 51). Notably, in the London Dysmorphology Database, there are more than 70 different syndromes (including hypomelanosis of Ito) under the same entry, “patchy depigmentation of skin” (69). Thus, we would favor the use of the term hypomelanosis of Ito (and related disorders) only in cases with “overt” and “widely distributed” pigmentary abnormalities, with or without associated extracutaneous manifestations.

Linear and whorled nevoid hypermelanosis. Linear and whorled nevoid hypermelanosis is a sporadic disorder characterized by (49): (1) asymmetrically distributed linear and whorled hyperpigmentation following Blaschko lines as well as reticulated hyperpigmentation; (2) coexistence (in some cases) of hyper- and hypopigmented lesions in the same patient; (3) skin lesions noted at birth or within the first 2 years of life; (4) no preceding inflammatory event or palpable lesion; (5) gradual increase (spread) of involvement during the first 2 years of life and subsequent stabilization or gradual fading; (6) sparing of mucous membranes, palms, and soles; (7) sporadic male and female (equal) incidence; (8) increased pigmentation of the basal layer and prominence or vacuolation of melanocytes, with no pigment incontinence or dermal melanophages on histological examination; and (9), in approximately 30% of cases (07; 38), associated systemic anomalies consisting in atrial septal defects, dextrocardia, mild hypereosinophilia, cerebral palsy, psychomotor delay, seizures, and deafness.

Under the term linear and whorled nevoid hypermelanosis two different clinical presentations may be included corresponding to the same spectrum: (1) the classical generalized pattern with onset within the first 2 weeks of life; and (2) unilateral cases involving only one quadrant of the body, with a later onset at about the second decade of life.

Phylloid hypomelanosis. The so-called phylloid hypomelanosis (previously regarded as a hypomelanosis of Ito-related disorder) appears to be constantly associated to trisomy 13 mosaicism (57) and, therefore, is ruled out on a cytogenetic basis.

Diagnostic workup

Patients who exhibit pigmentary anomalies (hypopigmentation or depigmentation or hyperpigmentation) along the lines of Blaschko, in a patchy or linear distribution, unilaterally or bilaterally, should be fully evaluated for structural systemic abnormalities. Laboratory or imaging tests, including EEG and neuroimaging, should be only oriented by the abnormal findings on clinical examination. Karyotyping of peripheral blood, and if this is normal, skin fibroblasts or better keratinocytes or melanocytes obtained from biopsies taken from affected and unaffected areas, should be performed in affected individuals to support the diagnosis.

Histopathology. Regarding follow-up controls, each case should be examined individually and further evaluated to the extent that the history, careful clinical examination, and investigations dictate more frequent re-evaluations in children with unusual symptoms or complications requiring special care. Parents should be reassured that serious complications, if present, are congenital and, thus, typically evident clinically early in infancy. The chance occurrence of a tumor in an affected patient should be almost the same as in the general population.

The routine or screening use of brain MRI does not improve hypomelanosis of Ito prognosis because the majority of CNS abnormalities are either unspecific or not treatable and overall do not predict a poor outcome. Conversely, a full brain MRI study is warranted if and when seizures ensue because some patients could have underlying neuronal migration anomalies.

Management

No special treatment is indicated for the skin lesions, and no precaution has to be taken regarding sun exposure or cream applications. Malignant transformation was never recorded in the skin lesions in the largest series so far reported, including ours. No data are available in the literature about pregnant mothers with pigmentary mosaicism who suffered complications or about children of affected mothers who suffered complications during gestation or delivery.

Convulsive episodes should be treated similarly to seizures of other etiologies. Motor disturbances may be minimized with good physiotherapy and orthopedic care.

Mental retardation is approached educationally, and special vocational training should be appropriate to each patient's individual capabilities.

Ocular, oral, urogenital, and other disturbances must receive appropriate individual treatment.

Although the identification of mTOR-related hypomelanosis of Ito brings up the theoretical possibility of beneficial treatment with mTOR inhibitors, no data are available (09).

Special considerations

Pregnancy

Affected adults should be reassured that the risk of the same condition in their offspring is low. Peripheral blood karyotyping is warranted, however, in the affected child and in his or her parents before considering further pregnancies. The risk for a pregnant woman affected by hypomelanosis of Ito is related to the complications or systemic manifestations of the disorder.

Anesthesia

Special precautions are needed as in other individuals affected by genetic conditions associated with systemic complications and are related to the underlying abnormalities (eg, neurologic, urologic, cardiac complications, etc.).