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 (61). 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 in distinguishing hypochromic zones, especially in Caucasians with fair skin (57). 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 (53). 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 (25; 26).
Sweat glands and fingernails also may be abnormal (42; 54). 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 (32). 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 (43; 50). 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 (42; 43). 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 has also been reported (34).
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 (31; 57; 42; 54; 53; 50; 44).
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 (43). 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 (42; 54; 43). Skeletal defects include short stature, asymmetry with hemihypertrophy or hemihypotrophy of a part or of an entire side of the body (50; 44), scoliosis, thoracic deformities (pectus carinatum or excavatum), various finger and toe anomalies (clinodactyly, polydactyly, syndactyly, brachydactyly), and foot deformities (pes cavus, talipes equiinovarus) (31; 42; 43; 50; 63).
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 (46). Bilateral hypertrophy is found in some cases with generalized hypomelanotic skin. The patients usually show coarse facies and macrocephaly (57, 42; 57, 43). All these defects are likely related to the age-dependent effect of the genetic mosaic abnormality (50; 50).
Nervous system manifestations. Anomalies of the CNS may include microcephaly or macrocephaly, cognitive and motor retardation, seizures, ataxia, hyperkinesias, and hypotonia (31; 42; 54; 53; 43; 50). 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% (27), 94% (42), or 80% (23), or as low as 61% (49), 50% (22), 40% (40), or 30% (37; 50).
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% (37; 50), 57% (43), and 70% (54) of cases, likely depending to ascertainment bias in tertiary referral centers (50). Patients with mental retardation have been reported to exhibit autism spectrum disorders (42; 20; 01; 54; 69), 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; 69). Most patients with mental retardation, autism spectrum disorders, or both previously suffered infantile spasms or severe seizures (54; 43). The association of mental retardation with seizures is seen in 65% of cases (54; 53; 43).
Epilepsy. This is the second most frequent neurologic manifestation of hypomelanosis of Ito. Seizures may occur in 11% (37) to about 50% (42; 43) 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% (43). Epilepsy surgery can be successful in the carefully chosen candidate with medication-refractory epilepsy (47; 33). 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 (43; 03; 45). 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 (16; 38; 45).
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 (69; 53). Other neurologic alterations found in isolated cases include muscular hypotonia, ataxia, neurosensorial deafness, and cortical visual impairment (50; 58).
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; 13) or only show enlarged perivascular spaces (53) to include the possibility of unilateral enlarged perivascular spaces (64). In the remainder, abnormalities may be grouped into white matter alterations and structural malformations (13). Nonprogressive white matter abnormalities on MRI (thought to be pathologically related to dilated Virchow-Robin spaces and/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) (13). White matter lesions are static over time (17) and show no correlation between the extent of the lesions and the patient age (53). 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 (50; 04; 13; 44). Rare cases have also been reported of hypomelanosis of Ito with Sturge-Weber syndrome-like unilateral leptomeningeal angiomatoses (18; 10).
Other system anomalies. These can include congenital cardiac disease (42; 54; 43), renal disease including single kidney or ureteral duplication, focal segmental glomerulosclerosis with end-stage renal disease, or glomerulocystic kidney disease (19; 65), and genitourinary anomalies including cryptorchidism, micropenis, or macrogenitosomia (42; 54; 43). Asymmetric breast development (29; 43), gynecomastia in either boys or prepubertal girls (42), and precocious puberty (41) have all been reported. Hypomelanosis of Ito occasionally is associated with vascular anomalies such as moyamoya disease (12), aortic malformations (66), 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 (51; 15).
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 (42; 53), especially because of disordered neuronal migration (16). 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 (43; 50). Autistic spectrum disorders, even rarely, must be taken into consideration. Musculoskeletal and other systemic abnormalities are congenital and, thus, are not progressive.