Pediatric Hypomelanosis of Ito

Ito first introduced the syndrome 1951.[4] In 1967, Hamada et al confirmed the association between the skin lesions and systemic abnormalities, including mental retardation.[5] Finally, Pascual-Castroviejo et al delineated the full spectrum of associated neurological abnormalities in a systematic study of the largest series published.[6]

Incontinentia pigmenti (IP) achromians is another term for this syndrome; however, because no true IP (melanin absent in the epidermis and present in the dermis) is present in the skin specimens, hypomelanosis of Ito syndrome has become the preferred name.

In 1992, Ruiz-Maldonado and associates established some diagnostic criteria for hypomelanosis of Ito syndrome.[7] Nonetheless, Ruiz-Maldonado et al's criteria link the diagnosis to the presence of systemic nondermatological (eg, CNS, skeletal) or chromosomal abnormalities. These criteria exclude patients with only dermatological manifestations. Patients with skin manifestations suggestive of hypomelanosis of Ito with and without systemic alterations have been described in the same family, demonstrating that hypomelanosis of Ito syndrome’s systemic involvement can vary. Studies that do not include systemic manifestations as diagnostic criteria for hypomelanosis of Ito reported that approximately 30-74% of patients with typical hypomelanosis of Ito skin lesions do not have nondermatological pathology.

A karyotype analysis survey was performed on 115 patients and revealed chromosomal anomalies in 60 (52%).[8] Many patients have a chromosomal mosaic pattern, often leading to the generation of 2 cell lineages, which produce patterns of hypopigmented and hyperpigmented skin. X-chromosome alterations are not unusual in hypomelanosis of Ito syndrome, and recent evidence points to X-chromosome inactivation, activation, and mosaicism as the main causes of these different patterns of cell behavior in the skin.

The nevus of Ito, like Nevus of Ota, is a hyperpigmentary dermal melanocytosis developing as a consequence of disturbances or failures during migration of melanocytes from the neural crest towards the epidermis.[9]

Perhaps this can also be found in other tissues, such as the fundus (tessellated or radial pigmentation of the fundi), iris (hypopigmentation), and the brain (areas with abnormal cell morphology and neuroblast migration side by side with normal patterns). Karyotyping the blood cells may not be diagnostic; a skin biopsy for fibroblasts may be necessary to detect the hypomelanosis of Ito–related chromosomal anomalies.

Despite recent advances, the genetic substrate for hypomelanosis of Ito syndrome is far from homogenous and is not completely understood. A wide range of chromosomal abnormalities may be observed, including balanced X-autosome translocations, supernumerary X-chromosome ring fragment, ring chromosome 10, mosaic triploidy, mosaic trisomies (8, 13, 14, 18, 22), mosaic translocations, and mosaic deletions. Autosomal deletions and duplications may involve chromosomes 7, 12, 13, 14, 15, and 18. The pattern of chromosomal aberrations and the polymorphic nature of this disease have led some to believe that hypomelanosis of Ito syndrome is a descriptive term rather than a true syndrome.

A familial form of hypomelanosis of Ito syndrome is noted; however, less than 3% of the patients have a family history of hypomelanosis of Ito–type skin lesions. Although hypomelanosis of Ito syndrome is most commonly a de novo occurrence, familial cases appear to be transmitted as an autosomal dominant trait. In one family, a 16% trisomy 2 mosaicism was identified.[10]

Approximately 10% of the patients report a family history of seizures or epilepsy, but the phenotypic expression varies; therefore, pigmentary changes may be the only clue to the genetic basis. A cutaneous ultrastructural study that shows abnormal nerve termination in close proximity to basal keratinocytes, degenerated melanocytes, premelanosomes, and Langerhans cells has suggested that this finding may be important in the pathogenesis of hypomelanosis of Ito.[11]

Several chromosomal abnormalities have been reported in hypomelanosis of Ito (see Pathophysiology), but the etiology remains elusive.

To date, epidemiological data on this syndrome are limited. It appears to be the third most common neurocutaneous disease, second only to neurofibromatosis and tuberous sclerosis. In a pediatric neurology service in Spain, 1 in 600-700 patients referred was diagnosed with hypomelanosis of Ito syndrome. It is diagnosed in 1 of every 7805 general pediatric outpatient visits, 1 of every 790 pediatric dermatology clinic visits, and 1 of every 2983 children in a general pediatric service.[6] Approximately three fourths of the patients with typical skin lesions have systemic manifestations.

Sex

Male-to-female ratios vary. In earlier series, the male-to-female ratio was reported to be 1:2.5. However, in larger and more recent series, the male-to-female ratio was 1:1.2. The severity of systemic manifestations appears to be similar in both sexes.

Age

Data in relation to age of diagnosis are usually reported in regard to the skin manifestations of hypomelanosis of Ito syndrome. Typical skin lesions are initially demonstrated during the first year of life in as many as 70% of patients; they are noticeable at birth in 54% of patients. Rarely, lesions are not visible until mid childhood.

Prognosis depends on the patient’s manifestations and complications of the disease. About three fourths of patients with typical hypomelanosis of Ito skin lesions have systemic manifestations of the disease.

As many as three fourths of patients have neurological symptoms in the first decade of life. Cognitive deficit is defined as an IQ of less than 70. Association of mental retardation and seizures suggests hypomelanosis of Ito, although the cause-effect link is difficult to prove, except in the intractable cases.

Patients with chromosomal anomalies are at risk for tumors.

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.

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:

• Ventricular septum defect

• Atrial septum defect

• 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:

• Hypospadias

• Micropenis

• Single kidney

• Urethral duplication

• Cryptorchidism

• Precocious puberty: Patients with hypomelanosis of Ito may also have sexual precocity.[20] Sexual precocity is a possible associated symptom.

• Gynecomastia

• Asymmetrical breasts

• Nephritis

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.

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]

Neuroradiological abnormalities are reported in at least one third of the patients. Because many of the lesions are dysplastic or neuroblastic migration abnormalities, MRI is more useful than CT scanning.

Increase in the T2 signal of white matter is one of the most common findings. White matter abnormalities are somewhat predictive of a poor neurological outcome.

Neuroblast migration includes heterotopia, pachygyria, and polymicrogyria. Heterotopia may be observed at the level of the basal ganglia or as a periventricular band. Some of the dysplastic lesions may be localized, and hemimegalencephaly is also visualized.

Cerebral atrophy can be unilateral or generalized. Cases of cerebral hemiatrophy and porencephaly are often associated with a history of perinatal hypoxia or low birth weight.

Other rare imaging associations include the following:

• Noncommunicating hydrocephalus

• Megacisterna magna

• Arteriovenous malformation

• Cerebellar hypoplasia (hemispheres and vermis)

• Brainstem hypoplasia

• Brain tumors: MRI rarely reveals brain tumors; thus, patients occasionally have abnormal MRI findings but are neurologically healthy.

Brain imaging in patients with hypomelanosis of Ito (HI) and medically refractory epilepsy: The area that generates seizures (zone of ictal onset) should be found using a prolonged video-EEG, single-photon emission computed tomography (SPECT) or positron emission tomography (PET), and high-resolution MRI. If resective epilepsy surgery is a serious consideration after the preliminary tests are done (video-EEG, SPECT or PET) and the zone of ictal onset could not be determined, the patient may need to undergo invasive EEG monitoring with subdural grids or strips.

Other imaging tests

Musculoskeletal abnormalities often require radiography for proper quantification. A CT scan of the chest may be necessary when mediastinal tumors are investigated.

Abdominal ultrasonography may be required for diagnosis of genitourinary anomalies such as single kidney and urethral duplication.

Dihydroxyphenylalanine (DOPA) staining of the skin may reveal decreased size and number of melanosomes in hypopigmented areas. The melanocytes may be smaller and fewer, and their dendrites are short and sparse. Melanin incontinence (ie, melanin is absent in the epidermis but present in the deeper dermis) is not observed in patients with hypomelanosis of Ito. Histopathological alterations are not always typical; normal histology findings have been described in some cases. Neuropathological studies demonstrate polymicrogyria, disarray of cortical lamination, and heterotopic neurons in the white matter and giant cells.

Ultrastructural cutaneous studies may reveal normal-appearing basal and malpighian keratinocytes but a lack of melanosomes in the malpighian cells.[11] Melanosomes are dramatically reduced in the basal keratinocytes and appear small, single, or clustered and surrounded by a membrane. Melanocytic degeneration may be evident, and dendritic melanocytes contain various stages of nonmelanized premelanosome (stage II), partially melanized premelanosome (stage III), and, rarely, stage IV melanosomes. Unmyelinated axons of nerve-containing melanosomes may be seen at the dermoepidermal junction. Abnormal nerve termination has been observed in close relationship with basal keratinocytes, degenerated melanocytes, premelanosomes, and Langerhans cells.

Approximately 30% of patients with seizures do not respond to anticonvulsant medications. In these patients, conduct an appropriate evaluation to verify if they are good candidates for resective epilepsy surgery or vagal nerve stimulation.

The patient may have large lesions and require a hemispherectomy for the treatment of their refractory epilepsy; however, in other cases, the removal of a more focal lesion may stop the seizures.

Cataracts and retinal detachment may produce loss of vision and can be successfully treated with surgery.

In patients with craniofacial malformation, such as cleft lip and palate, repair is done in the same fashion as in patients without hypomelanosis of Ito.

Consultation with an orthopedic specialist is indicated for patients with skeletal abnormalities.

Suggest consultation with an ophthalmologist for patients with ophthalmologic abnormalities.

Consultation with a nephrologist is recommended for patients with renal abnormalities.

Suggest a consultation with an endocrinologist for patients with associated abnormalities.

Patients with hypomelanosis of Ito who were initially seen by a dermatologist may benefit from a consultation with a neurologist; conversely, patients initially referred to a neurologist may benefit from a consultation with a dermatologist and geneticist. Always offer the patient and parents the option of a consultation with a geneticist.

Refer patients who have seizures that are not completely controlled by anticonvulsant medications to an appropriate tertiary center with a comprehensive epilepsy program for proper evaluation (video-EEG, single-photon emission computed tomography [SPECT] or positron emission tomography [PET], high-resolution MRI).