History
Hypomelanosis of Ito (HI) syndrome may involve many organs. Several manifestations, such as seizures and mental retardation, can be elicited in the history. For the sake of better understanding the subject, data from the history and physical examination are fused into a discussion of the signs and symptoms of each organ system’s involvement. The dermatological alterations are discussed first, followed by the description of systemic involvement.
Physical Examination
Skin and neurological examinations are crucial for diagnosis; a thorough examination is extremely important.
Dermatological manifestations
Hypochromic lesions in distinctive patterns (eg, whirls, patches, streaks) characterize this syndrome; they often resemble whirled marble. The lesions may be unilateral (46%) or bilateral, and usually show a midline cutoff.
Patients with hypomelanosis of Ito and hemimegalencephaly often have unilateral skin lesions. They are contralateral to the side of brain malformation and may show a zigzag pattern of lines. One with hypomelanosis of Ito and hemimegalencephaly was described with trisomy 21. [12] The hypochromic lesions are readily visualized in patients with pigmented skin, such as blacks, Asians, Spaniards, and Hispanic persons (eg, Mexicans). In children with fair skin, the use of a Wood lamp (ultraviolet light) is helpful in demonstrating these hypochromic lesions, which develop on the trunk, legs, arms, and face. [13]
They are more prominent in the ventral surface of the trunk and flexor surface of the limbs. The lesions are located on both the torso and the extremities in 59% of patients, on just the torso in 23% of patients, and exclusively on the extremities in 6% of patients. Some advocate stricter criteria for diagnosis, requiring cutaneous involvement of 2 or more segments for a diagnosis of hypomelanosis of Ito.
Skin lesions usually appear during the first year of life (70%) and may be noticeable at birth (54%). Lesions are not visible until mid childhood in rare cases.
Hypopigmented or depigmented lesions may appear in swirls or patches with irregular borders. They tend to run parallel to one another, following the lines of Blaschko; however, hypomelanosis of Ito is not the only syndrome associated with pigmentary anomalies along the lines of Blaschko. In 22% of the patients, lesions are patchy (square or rounded) rather than linear.
In linear or whorled nevoid hypermelanosis and nevus depigmentosus, lesions also follow these lines. The lines of Blaschko are relatively consistent and distinct from dermatomal lines. They represent orderly migration of mesodermal and ectodermal precursors during embryogenesis, occurring after X inactivation or activation. Genetic alterations (see Pathophysiology) or other problems that perturb morula cells and their daughter cells generate the swirl pattern of hypopigmentation along the lines of Blaschko. The color changes observed in skin lesions of hypomelanosis of Ito may be present at birth but are frequently more obvious later in infancy or early childhood.
Hypohidrosis of hypopigmented skin can be detected in hypomelanosis of Ito by application of iodine and starch in the skin, followed by a subcutaneous injection of pilocarpine hydrochloride.
Nonspecific skin lesions are reported in 20-40% of individuals with hypomelanosis of Ito. These lesions are most frequently café-au-lait spots, but the following lesions have also been described:
-
Persistent mongolian blue spots
-
Nevus of Ota: Nevus of Ota has been described in a patient with nevus of Ito and meningeal melanocytosis. [9]
-
Nevus marmoratus and angiomatous nevi
-
Soft fibroma
-
Pilomatrixoma
-
Aplasia cutis
-
Atopic dermatitis
Hair abnormalities include the following:
-
Slow growth
-
Diffuse alopecia
-
Trichorrhexis
-
Widow’s peak
-
Generalized hirsutism
-
Facial hypertrichosis
-
Coarse and curly hair
-
Low hairline (7% of patients)
-
Appearance of a zone of alopecia or white hair in the scalp (may precede hypopigmented lesions)
Fingernails may show some alterations, especially ungual hypoplasia.
Abnormal sweat glands are reported.
Hypomelanosis of Ito may rarely been seen in association with the Sturge-Weber syndrome. [14]
Neurological manifestations
Psychomotor retardation and cognitive deficits are salient findings. [1] Neurological involvement is found in 76% of patients during the first decade of life. Mental retardation and seizures are the most common presenting symptoms. It may become first evident with neurologic signs, [15] including adult-onset dementia. [16] A brain MRI may show marked enlarged perivascular Virchow-Robin spaces. [17]
In one series of 19 patients, 10 displayed neurological symptoms before cutaneous symptoms arose; however, the proportion of patients with neurological involvement is clearly biased. [18] The pattern of referral is as high as 84% in a pediatric neurology clinic–generated series but somewhat lower in a dermatologist-generated series. When systemic involvement was used as a key diagnostic criterion, as many as 90% of the patients were found to have neurological involvement. Approximately 50% of the patients presented with seizures, although a lower frequency (37%) was reported in the pediatric dermatology clinic–based series. Generalized tonic-clonic seizures were most common (25%), whereas partial seizures were noted in 12% of patients, infantile spasms were reported in 8%, and myoclonic seizures were observed in 4%. Patients with Lennox-Gastaut syndrome have been reported.
Seizure control was achieved in 40-70% of patients. Some patients with partial seizures had very localized dysplastic lesions on neuroimaging that showed the typical localized, almost continuous, spike activity using electroencephalography (EEG).
Approximately one half to two thirds of patients have mental retardation (ie, intelligence quotient [IQ] < 70). Chromosomal anomalies do not appear to increase the risk of mental retardation. Approximately 40% of patients with hypomelanosis of Ito have an IQ of less than 50, and fewer than one fourth have an IQ of more than 85.
Autistic behavior has been found in approximately 11% of patients with hypomelanosis of Ito. It may be associated with infantile spasms and other severe seizures. Similarly, the presence of mental retardation is linked with seizures (65%). Although the causal association of seizures and mental retardation or autism is attractive and present outside of HI, a common mechanism for both can be easily demonstrated (eg, patients with neuroblast migration and neuronal dysplasias).
HI is occasionally associated with hemimegalencephaly; however, more focal dysplastic lesions are also observed. Approximately one fourth of patients have a motor development delay. Hypotonia, which is usually accompanied by pes and genu valgus, is also a common finding.
Somatic hemihypertrophy, macrocephaly, and microcephaly may also be present (see below).
Brain tumors, including medulloblastoma and choroid plexus papilloma, are associated with hypomelanosis of Ito.
Other neurological problems include ataxic gait, sensory neuropathy, chronic distal spinal muscular atrophy, torticollis, auditory conduction defect, hyperactivity, and spina bifida occulta.
Patients with occipital lesions may have visual field defects but could represent sporadic associations.
Neuropathological studies demonstrate polymicrogyria, disarray of cortical lamination, heterotopic neurons in the white matter, and giant cells.
Ophthalmologic abnormalities
Approximately one fifth of patients present with ocular abnormalities.
Retinal pigment abnormalities are described as tessellated fundus, radial hypopigmented streaks, or geographic areas of hypopigmentation. Unilateral heterochromic iris with hypopigmentation of the cornea has also been described.
Other ophthalmologic changes include myopia, hyperopia, astigmatism, megalocornea, opaque corneas, scleral melanosis, strabismus, slow pupillary response, pupillary atrophy or irregularity, nonclosure of the upper eyelid, ptosis, symblepharon, optic atrophy, choroidal atrophy, microphthalmia, macrophthalmia, epicanthal folds, dacryostenosis, and nystagmus.
Musculoskeletal abnormalities
Musculoskeletal abnormalities are common. One fifth of patients have hemihypertrophy, usually ipsilateral-to-hypomelanotic lesions.
Arm and leg length discrepancy and scoliosis are reported.
Fingers may be abnormal, showing atrophy, syndactyly, polydactyly, clinodactyly, or bifid thumb.
Other limb anomalies include luxatio coxae (caused by hypoplastic femoral heads) and genu valgus.
Head and face anomalies
Facial malformations include hypertelorism, coarse facies, cleft lip and palate, bifid uvula, and nose and ear anomalies.
Macrocephaly, often associated with coarse facies, develops in 3-23% of patients.
In a study by Pascual-Castroviejo et al, microcephaly was described in 8% of patients. [19]
Delayed fontanelle closure and asymmetry of the head can be present.
Dental problems include imperfect teeth implantation, partial anodontia and dental dysplasia, defective enamel, and hamartomatous cuspids.
Cardiac anomalies
Cardiac manifestations may include the following:
-
Pulmonary artery stenosis
-
Tetralogy of Fallot
-
Incomplete right bundle branch block and cardiomegaly of unknown etiology (occasionally noted)
Genital and reproductive organ anomalies
These may include the following:
-
Single kidney
-
Urethral duplication
-
Precocious puberty: Patients with hypomelanosis of Ito may also have sexual precocity. [20] Sexual precocity is a possible associated symptom.
-
Gynecomastia
-
Asymmetrical breasts
Other types of abnormalities
Others may include the following:
-
Hepatomegaly
-
Segmental dilation of the colon
-
Diaphragmatic, umbilical, and inguinal hernia
-
Linear leukoplakia [15]
-
Partial or total body hemiovergrowth [21]
Hypomelanosis of Ito is considered a cutaneous disease with multisystem involvement. It may be associated with the above findings and may also be associated with proteinuria, focal segmental glomerulosclerosis and end-stage renal disease. [22]
Malignant and benign tumors are associated with hypomelanosis of Ito. One patient study reported a mature cystic teratoma in the posterior mediastinum and a diploic epidermoid cyst of the parietal bone. Brain tumors may be present (see above); however, the benign tumors in patients with hypomelanosis of Ito are often associated with chromosomal anomalies.
Complications
Seizures are due directly to cerebral malformations. Patients with seizures, especially those with infantile spasms, are at risk for mental retardation and autistic behavior. Careful screening and follow-up with cognitive testing are suggested. Because seizures are often difficult to control using anticonvulsant medications, patients who have intractable partial seizures with secondary generalization or infantile spasms are at risk for neurocognitive deterioration; therefore, a workup should be completed at an epilepsy center.
Because of the possibility of ophthalmologic complications or manifestations, refer the patient to an ophthalmologist (see Consultations).
Similarly, patients with the following urologic (cryptorchidism), endocrinic, and renal complications need specialized follow-up:
-
Hypospadias
-
Micropenis
-
Single kidney
-
Urethral duplication
-
Precocious puberty
-
Gynecomastia
-
Asymmetrical breasts
-
Nephritis
Various benign and malignant tumors may complicate the course of hypomelanosis of Ito because their manifestations may be protean. Remain attentive for any change in clinical status and consider the possibility of a tumor. Similarly, any significant and unexplained change in neurological status should raise suspicion for a brain tumor; therefore, consider MRI in these cases. [13]
Craniofacial malformations, such as cleft lip and palate, may significantly affect the well-being of patients by interfering with their feeding and speech. The management of these complications requires consultation with a team of craniofacial specialists, including a plastic surgeon, craniofacial surgeon, or both and a speech therapy specialist.
Many of the dental malformations (eg, dental dysplasia, defective enamel, hamartomatous cuspids) seen in patients with hypomelanosis of Ito may lead to secondary dental problems, which, in turn, may lead to increased decay. These require careful attention by a dentist.
Hypomelanosis of Ito may be associated with other extracutaneous manifestations, including skeletal ones, such as club foot. [23]
-
Hypomelanosis of Ito on the torso.
