eMedicine Specialties > Pediatrics: General Medicine > Dermatology

Hypomelanosis of Ito

Author: Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Coauthor(s): Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Contributor Information and Disclosures

Updated: Sep 29, 2008

Introduction

Background

Hypomelanosis of Ito (HI) syndrome is characterized by the presence of whirled hypochromic skin lesions often associated with systemic manifestations. Ito first introduced the syndrome 1951.¹ In 1967, Hamada et al confirmed the association between the skin lesions and systemic abnormalities, including mental retardation.² Finally, Pascual-Castroviejo et al delineated the full spectrum of associated neurological abnormalities in a systematic study of the largest series published.³

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, HI syndrome has become the preferred name.

In 1992, Ruiz-Maldonado and associates established some diagnostic criteria for HI syndrome.⁴ 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 HI with and without systemic alterations have been described in the same family, demonstrating that HI syndrome’s systemic involvement can vary. Studies that do not include systemic manifestations as diagnostic criteria for HI reported that approximately 30-74% of patients with typical HI skin lesions do not have nondermatological pathology.

Pathophysiology

Despite recent advances, the genetic substrate for HI 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 HI syndrome is a descriptive term rather than a true syndrome.

A familial form of HI syndrome exists; however, less than 3% of the patients have a family history of HI-type skin lesions. Although HI syndrome is most commonly a de novo occurrence, familial cases appear to be transmitted as an autosomal dominant trait. 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 HI.⁶

Frequency

International

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 HI 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.³ 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 HI 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.

Clinical

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

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 HI and hemimegalencephaly often have unilateral skin lesions. They are contralateral to the side of brain malformation and may show a zigzag pattern of lines. 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. 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 HI.
  • 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, HI 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 HI may be present at birth but are frequently more obvious later in infancy or early childhood.
  • Hypohidrosis of hypopigmented skin can be detected in HI 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 HI. 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 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.
• Neurological manifestations
  • Neurological involvement is found in 76% of patients during the first decade of life. Mental retardation and seizures are the most common presenting symptoms.
  • 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.⁷ 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 HI 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 HI. 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 HI.
  • 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.
  • Cataracts and retinal detachment may produce vision loss.
  • 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.⁸  
  • 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
  • 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
  • Hypospadias
  • Micropenis
  • Single kidney
  • Urethral duplication
  • Cryptorchidism
  • Precocious puberty
  • Gynecomastia
  • Asymmetrical breasts
  • Nephritis
• Other types of abnormalities
  • Hepatomegaly
  • Segmental dilation of the colon
  • Diaphragmatic, umbilical, and inguinal hernia
• HI 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.⁹  
• Malignant and benign tumors are associated with HI. 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 HI are often associated with chromosomal anomalies.

Causes

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

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• Hypomelanosis of Ito (Dermatology)
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