Hypomelanosis of Ito

Etiology

HOI is not an inherited disorder but typically results from sporadic postzygotic mutations during early embryonic development. These mutations lead to chromosomal mosaicism, in which 2 distinct cell populations emerge, 1 with a normal genetic makeup and the other with chromosomal abnormalities or gene mutations.[5] This mosaicism in pigment-producing neural crest-derived cells causes the characteristic features associated with HOI.[6] While chromosomal mosaicism is most commonly somatic, leading to different cell lines with varying cell numbers, recent research has also identified monogenic postzygotic mutations, such as those in the  MTOR (OMIM 601231), RHOA (OMIM 165390), USP9X (OMIM 300072), TFE3 (OMIM 314310), KCNQ5 (OMIM 607357), and PHF6 (OMIM 300414) genes associated with pigmentary mosaicism in some cases.[7][8][9]

Epidemiology

HOI is an uncommon neurocutaneous disorder, and the exact prevalence is unknown.[10] Results from a study at a Spanish hospital reveal an incidence of 1 in 8000 to 10,000 outpatient pediatric patients and 1 in 800 pediatric patients presenting to the dermatology clinic.[11] An additional study in Catania, Italy, estimates the prevalence as 1 case per 7540 births and 1 case per 82,000 inhabitants in the general population.[12]

Initial research indicated HOI was more common in women than men; however, more recent research suggests that both sexes are affected at similar rates.[13] Additionally, HOI affects patients of all ethnic backgrounds equally. Cutaneous symptoms are generally evident at or shortly after birth, and neurological symptoms typically become evident during infancy, though mild symptoms may have a delayed onset.

The exact incidence of affected patients with extracutaneous manifestations is unknown. Initial reports from pediatric neurology centers suggested that between 80% and 90% of affected patients experienced neurological anomalies. However, this data is not supported by reports from pediatric dermatology clinics, which report an incidence between 15% and 30%.[3][14] Some experts believe this percentage is likely lower since individuals without extensive cutaneous involvement are less likely to seek treatment.

Pathophysiology

HOI arises from chromosomal mosaicism, in which 2 or more genetically distinct cell lines exist within the same individual. This mosaicism typically results from postzygotic mutations that occur during early embryonic development. The affected cell lines exhibit genetic abnormalities that involve pigmentation genes, resulting in impaired melanin production in specific areas of the skin. As these genetically altered cells spread along the lines of Blaschko, the embryonic developmental lines, they give rise to the characteristic whorled and linear patterns of hypopigmentation.

These hypopigmented areas correspond to the regions populated by the abnormal cell lines. These genetically distinct cells can also migrate to different body parts, including the nervous and musculoskeletal systems, resulting in the associated anomalies encountered in patients with HOI. Because the disorder can affect cells derived from neural crest cells, including those in the brain and skin, affected patients can experience associated neurologic, musculoskeletal, renal, cardiovascular, ocular, genitourinary, and developmental abnormalities.

Histopathology

Histopathology of affected skin in HIO reveals a reduced number of melanocytes and smaller, less numerous melanosomes within the basal layer of the epidermis, accompanied by a selective decrease in eumelanin.[15] The absence of pigmentary incontinence, defined as abnormal melanin deposition in the dermis, supports the non-inflammatory nature of the condition and helps exclude other inflammatory disorders involving damage to the basal layer. Depigmented areas demonstrate an increased number of epidermal Langerhans cells. Special stains, such as Fontana-Masson, and immunohistochemical stains, including SRY-related HMG-box 10 (SOX10), microphthalmia-associated transcription factor (MITF), and Melan-A (MART-1), can be used to confirm reduced melanocytic activity.

History and Physical

The clinical presentation of HOI is quite variable. Pigmentary changes appear as sharply demarcated streaks or swirls of hypopigmentation anywhere on the body and characteristically involve more than 2 body segments. Distribution may be unilateral or bilateral and either localized or extensive, usually sparing the palms and soles. Individuals with scalp involvement may exhibit patterned changes in hair color, alopecia, and hair with trichorrhexis or a white-grayish color.[12] Rare findings are hypohidrosis or streaks of linear hypertrichosis. The skin findings are present at birth but may not become apparent until the first few months or after initial sun exposure.[16] Minor associated cutaneous manifestations include café-au-lait spots, morphea, ichthyosis, nevus of Ota, congenital dermal melanocytosis, soft fibroma, pilomatrixoma, and atopic dermatitis.[16] 

Nervous system manifestations include microcephaly, cognitive and motor delays, seizures, ataxia, hyperkinesia, sensorineural hearing loss, cortical visual impairment, and hypotonia. Intellectual disabilities and behavioral disturbances are the most common neurological findings, with seizures following as the second.[17] Seizures associated with HOI commonly begin within the first year of life.

Common musculoskeletal findings include short stature; hemihypertrophy or hemihypotrophy of a portion or entire side of the body; scoliosis; pectus carinatum or excavatum; and digital anomalies such as clinodactyly, polydactyly, syndactyly, brachydactyly, and foot deformities including pes cavus.[18] Congenital heart disease is rare, but cases of abdominal aortic hypoplasia and atrial and ventricular septal defects have been reported.[19][20][21][22] Recent case reports describing carotid artery aneurysms in patients with HOI highlight the need for further research to explore a potential association between the 2 conditions.[20] Oral manifestations include defective dental implantation, partial anodontia, dental hypoplasia or dysplasia, conical teeth, and defective enamel. Additional reported anomalies are precocious puberty and genitourinary abnormalities. 

Evaluation

The diagnosis of HOI is clinical. A careful examination with a wood lamp can enhance hypopigmentation and help confirm the diagnosis.[23] Affected individuals should undergo a thorough physical examination and a corresponding evaluation based on the examination findings. Computed tomography and magnetic resonance imaging may be necessary in patients with neurologic findings. Likewise, an electroencephalogram is necessary for patients with seizures and electromyography for patients with hypotonia. While typically unnecessary in the evaluation of HOI, children with seizures, hypotonia, or cognitive and developmental delays may undergo a variety of laboratory tests to evaluate for underlying causes. Clinicians must closely monitor children's neurodevelopmental progress to ensure optimal growth and development. 

Genetic analysis is not typically necessary. However, karyotyping of peripheral blood lymphocytes or genetic analysis of lesional skin fibroblasts may help provide a more accurate diagnosis in patients with extracutaneous manifestations. Karyotyping of peripheral blood lymphocytes reveals mosaic chromosomal abnormalities in up to 33% of affected patients, with genetic analysis of skin fibroblast lesions revealing chromosomal abnormalities in an additional 25%.[24] 

Some experts recommend using the term HOI exclusively for patients with extracutaneous manifestations and linear nevoid hypopigmentation for patients with findings limited to the skin. Though not universally adopted, given the broad clinical variability and overlap with other mosaic pigmentary disorders, Ruiz-Maldonado et al proposed diagnostic criteria for HOI to aid in clinical recognition.[19]

Major Criteria

• Non-hereditary hypopigmented streaks or patches following the lines of Blaschko, involving 2 or more body segments, and appearing at birth or within the first months of life
• Presence of neurological or musculoskeletal abnormalities

Minor criteria:

• Documented chromosomal anomalies indicative of mosaicism
• Two or more congenital anomalies not involving the nervous or musculoskeletal systems

The diagnosis is supported by the presence of both major criteria, or 1 major and 1 minor, or 2 minor criteria.

Treatment / Management

Management of HOI is primarily symptomatic, focusing on the specific clinical manifestations present in each patient. The cutaneous findings typically do not require medical treatment; however, cosmetic camouflage may be helpful for individuals with aesthetic concerns. Sometimes, the hypopigmented areas may fade over time, with partial or complete resolution observed in adolescence or adulthood. Early intervention is critical for addressing developmental or cognitive delays, and anticonvulsant therapy is typically necessary for seizure management. Ongoing follow-up is essential to monitor for emerging complications. Clinicians should offer genetic counseling and referrals to appropriate specialists to ensure comprehensive care.[25]

Differential Diagnosis

The potential differential diagnoses for HOI include the following:

• The fourth stage of incontinentia pigmenti
• Piebaldism
• Teitz syndrome
• Waardenburg disease
• Segmental vitiligo
• Lichen striatus
• Linear and whorled nevoid hypermelanosis
• Linear leukoderma
• Nevus depigmentus
• Pigmentary demarcation lines
• Vitiligo
• Epidermal nevus
• Nevus comedonicus
• Extragenital lichen sclerosus
• Focal dermal hypoplasia
• Menkes syndrome
• Darier disease
• Congenital X-linked dominant chondrodysplasia punctata type 2 [26]

Prognosis

The prognosis of HOI is highly variable and closely linked to the extent of extracutaneous involvement, particularly central nervous system abnormalities. Individuals with isolated cutaneous findings and no systemic involvement have an excellent prognosis, with a normal life expectancy and cognitive development.[27] The presence of developmental delays, intellectual disabilities, along with seizures, which often require long-term antiepileptic therapy, can have a significant effect.

Complications

Given the large variety of phenotypes associated with HOI, the potential complications are numerous and correlate with individual extracutaneous manifestations. People with seizures face a range of psychosocial and medical challenges that impact their quality of life. They often experience a loss of independence, underemployment, reduced social status, limited leisure activities, decreased physical activity, and higher rates of substance use compared to the general population. Mental health conditions, particularly depression and anxiety, are common and should be routinely screened for during long-term follow-up. Cognitive impairment is frequently present at diagnosis and may worsen over time due to factors such as seizure burden, treatment side effects, underlying neurological conditions, and coexisting depression or anxiety. Additionally, individuals with seizures are more prone to seizure-related injuries like falls, fractures, and drowning and face a significantly higher risk of premature death, with the leading causes including sudden unexpected death in epilepsy, status epilepticus, accidental injuries, and suicide.

Adults with intellectual disabilities experience healthcare disparities, leading to worse health outcomes. Because of the increased incidence of limited mobility or inactive lifestyles, patients are at higher risk for obesity, osteoporosis, hyperlipidemia, diabetes, and cardiovascular disease. Additionally, they experience increased rates of depression and anxiety, social isolation, and are at greater risk of abuse.[28]

Associated dental anomalies place patients at risk for cavities and gum disease, difficulties with chewing and malnutrition, and premature tooth loss. Those who develop retinal hypopigmentation, the most common ocular anomaly, as well as dacryostenosis, strabismus, astigmatism, nystagmus, ptosis, hypertelorism, and cataracts, can struggle with blurred vision, night blindness, recurrent eye infections, diplopia, poor depth perception, and dizziness. 

Genitourinary complications due to having only a single kidney, cystic kidney disease, micropenis, cryptorchidism, and urethral duplication are diminished renal function, sexual dysfunction, urinary tract infections, urinary tract obstruction, incontinence, and infertility. Complications due to abdominal aortic hypoplasia and arteriovenous malformations in the brain include hypertension, reduced lower extremity perfusion, mesenteric ischemia, renal ischemia, growth restriction, stroke, intracerebral hemorrhage, seizures, aneurysm formation, hydrocephalus, and death. Additional cardiovascular complications are right ventricular hypertrophy, heart failure, arrhythmias, and an increased risk of endocarditis.