Continuing Education Activity

Hypomelanosis of Ito (HI), or pigmentary mosaicism, was previously named incontinentia pigmenti achromians. The disease is currently named hypomelanosis of Ito to distinguish this condition from incontinentia pigmenti. HI was first described by Ito in 1952. Hypomelanosis of Ito represents the third most frequent neurocutaneous disease, after neurofibromatosis type 1 and tuberous sclerosis. This activity explains when this condition should be considered on a differential diagnosis, articulates how to properly evaluate for this condition, and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Review the pathophysiology of hypomelanosis of Ito.
• Describe the presentation of a patient with hypomelanosis of Ito.
• Summarize the differentials to consider for hypomelanosis of Ito.
• Outline the importance of enhancing care coordination among the interprofessional team to ensure proper evaluation and management of hypomelanosis of Ito.

Introduction

Hypomelanosis of Ito (HI), or pigmentary mosaicism, was previously named incontinentia pigmenti achromians. The disease is currently named hypomelanosis of Ito to distinguish this condition from incontinentia pigmenti. HI was first described by Ito in 1952. [1] Hypomelanosis of Ito represents the third most frequent neurocutaneous disease, after neurofibromatosis type 1 and tuberous sclerosis. It is characterized by linear nevoid hypopigmentation along the lines of Blashko located on the limbs and the trunk.  This cutaneous pattern appears at birth or in early childhood and usually becomes evident in infancy. The phenotype of HI would be the result of a mosaic dermal abnormality of monogenic or chromosomal origin.  HI is a rare neurocutaneous disease with multisystemic involvement. The most common defects involve the central nervous and musculoskeletal systems. Hypomelanosis of Ito is currently a descriptive rather than definitive diagnosis. Blaschkoid or mosaic hypomelanosis is a better descriptive term.

Etiology

The etiology of hypomelanosis of Ito remains mysterious. The familial occurrence was described as suggesting an underlying chromosomal abnormality. Several models of inheritance have been proposed: X-linked, autosomal-dominant, and recessive gene transmission. However, to date, there is no evidence for genetic transmission. Most cases are sporadic. Chromosomal mosaicism and chromosomal translocations were reported. [2] 

Epidemiology

HI is an uncommon congenital condition. Its prevalence is unknown. The prevalence estimated in Catania, Italy is about 1 case per 7540 births. The prevalence among the general population is about 1 case per 82000 inhabitants. In Spain, there was 1 case per 8000-10000 new patients admitted to a pediatric hospital. [3] Its incidence is estimated between 1/10 000 and 1/8 500. [4] It is the third most frequent neurocutaneous disorder. Both sexes are affected, but it is more common in women than in men with a female to male ratio:  2.5:1. There is no racial bias for HI, but lesions are more easily diagnosed in darker skin. The injuries are present at birth or less commonly during early childhood in 25% of cases.

Pathophysiology

HI is related to pigmentary mosaicism. The different pigmented skin areas correspond to the distribution of the two different cell lines with different pigment potential in single individuals. It is characterized by a clone of skin cells with a reduced capacity for melanin production. Chromosomal aberrations have been detected in a cytogenetic analysis in peripheral blood lymphocytes and skin fibroblasts. Chromosomal aberrations affect the locations of genes involved in pigmentation. Extracutaneous manifestations might be caused by the presence of different genetic defects. Hence it seems that HI is associated with a variety of chromosomal anomalies rather than a single gene disease.

Histopathology

Histopathology in affected skin shows a reduction of the number of melanocytes and a decreased number and size of melanosomes in the epidermal basal layer with a selective decrease in eumelanin without pigmentary incontinence. There is no extracellular melanin in the dermis and no evidence of inflammation. Depigmented areas contain increased numbers of epidermal Langerhans cells. Special stains such as Fontana-Masson and immunostains such as SOX 10, MIFT, or Melan A can confirm the decreased activity of melanocytes.

History and Physical

The clinical presentation is very variable. HI lesions suggest the ‘negative image’ seen in incontinentia pigmenti. It is characterized by hypopigmented macules following the lines of Blashko, arranged in sharply demarcated whorls, streaks, and patches. The lines of Blashko represent migratory pathways for fetal epidermal cell migration. The hypopigmentation can be unilateral or bilateral, located or diffuse, sparing the palms, soles, and mucous membranes. The pattern of lines involves the trunk, the limbs, and more rarely the head.  Hypopigmentation may become more apparent in the first few months or after the first exposure to the sun, by increasing the contrast with healthy skin. It may fade within adulthood, rarely in childhood. [5] The areas of leukoderma are hypomelanotic rather than amelanotic. Minor cutaneous manifestations include café-au-lait spots, morphea, ichthyosis nevus of Ota, Mongolian blue spots, soft fibroma, pilomatrixoma, and atopic dermatitis. [5] 

Extracutaneous findings are found in 75 % of cases. Neurological manifestations are seen in 90 % of cases. In addition to musculoskeletal symptoms which are found in 70 % of cases, ophthalmologic manifestations are present in 25 %, and 10 % have cardiac defects. Scalp alteration including changes in hair color, alopecia, and hair with trichorrhexia and white-grayish color may be found. [4] However, other extracutaneous manifestations are less common including genitourinary, endocrine, and oro-dental abnormalities.

Evaluation

The diagnosis of hypomelanosis of Ito is clinical. When the disease is suspected, a careful examination with Wood’s lamp can enhance the hypopigmentation and help to confirm the diagnosis. [6] Besides any patient with hypopigmentation along the lines of Blashko should be evaluated for neurological, musculoskeletal, cardiac, genitourinary, and ophthalmological abnormalities although computed tomography (CT) and magnetic resonance imaging (MRI) should be performed only in cases of neurologic symptoms. Skeletal radiography should be completed in all cases. In the case of patients with seizure disorders, electromyography (EEG) should be performed.

Diagnostic criteria have been established for HI:[7]

Major criteria:

• Non-hereditary cutaneous hypopigmented linear streaks or patches involving more than two body segments, appearing at birth or in the first months
• One or more neurological or musculoskeletal manifestations.

Minor criteria

• Chromosomal anomalies
• Two or more congenital malformation, excluding nervous and musculoskeletal systems.

The diagnosis is retained with one major or minor criterion or two minor standards.

Treatment / Management

Treatment of hypomelanosis of Ito is symptom directed, targeting the specific clinical manifestations. Skin lesions do not require special treatment. Camouflage make-up may be employed for cosmetic concerns. Special education and anticonvulsants are often necessary. Close patient follow-up is needed to monitor for complications. Genetic counseling should be part of the management scheme.

Differential Diagnosis

• Systematized nevus depigmentosus
• The fourth stage of incontinentia pigmenti
• Piebaldism
• Teitz syndrome
• Waardenburg disease
• Segmental vitiligo

Prognosis

The cutaneous findings are of good prognosis. The overall prognosis depends on the severity of the associated abnormalities. Death is rare.

Complications

Complications may occur as a result of associated abnormalities. Malignant transformation of the affected skin is exceptional.

• Neurological manifestations encompass seizures in 50% to 75%, psychomotor delay in 30 % to 75 %, hemimegaloencephaly, macrocephaly, microcephaly, autism, ataxia, cerebral hypoplasia, agenesis of the corpus callosum, and psychiatric symptoms including autism.
• Musculoskeletal symptoms include hemihypertrophy, asymmetric limbs, finger abnormalities, hypotonia, scoliosis, short stature, and chest wall deformity.
• Cardiac symptoms may include tetralogy of Fallot, septal defects, and pulmonary stenosis.
• Ophthalmological manifestations include retinal hypopigmentation which is the most common complication, dacryostenosis, strabismus, astigmatism, nystagmus, ptosis, hypertelorism, and cataracts.
• Genitourinary: single kidney, cystic kidney disease, micropenis, cryptorchidism, and urethral duplication
• Endocrine: precocious puberty
• Oro-dental anomalies: dental dysplasia, hypoplasia, tooth malformations, and anodontia
• Vascular: abdominal aortic hypoplasia, and brain arteriovenous malformations.

Enhancing Healthcare Team Outcomes

The diagnosis and the treatment of HI are interprofessional including dermatologists, neurologists, pediatricians, orthopedic surgeons, ophthalmologists, dentists, and geneticists. Since the treatment of skin lesions is not necessary and has an excellent prognosis, the focus must be on the management of noncutaneous abnormalities with regular follow-up by a dermatologist and specialty-trained dermatology nurse providing coordination of care. [Level V]