Findings
Hypomelanosis of Ito (HI) is a rare neurocutaneous disorder characterized by hypopigmented skin lesions distributed along Blaschko’s lines, predominantly over the trunk and limbs [1]. Neurological manifestations such as cognitive impairment, seizures, and developmental delays occur in approximately 30%-90% of affected individuals [2]. We describe two cases of HI with associated brain abnormalities, in which the lesions appear to result from disrupted neuronal migration. Notably, magnetic resonance imaging (MRI) in these cases revealed hemimegalencephaly, white matter changes, and nodular lesions suggestive of intracranial melanosis. These findings led us to hypothesize that melanin may migrate into the brain along pathways similar to those of neurons, reflecting their common embryologic origin.
Our first case involved a 9-year-old boy with underlying intellectual disability who presented with drug-resistant epilepsy, with seizure onset at 6 months of age. He had been treated with multiple antiseizure medications, including oxcarbazepine, levetiracetam, clobazam, and valproate, achieving reasonable seizure control on his current regimen. Neurological examination revealed right-sided hemiparesis with increased muscle tone, exaggerated deep tendon reflexes, and weakness on the right side of the body. Cranial nerve and sensory examinations were normal, and no cerebellar signs were observed. Cutaneous examination revealed multiple hypopigmented macular patches distributed over the face, neck, torso, and thighs (Fig. 1A-C), prompting a clinical suspicion of HI. MRI of the brain demonstrated hemimegalencephaly involving the left cerebral hemisphere with diffuse white matter abnormalities. Multiple nodular lesions were also observed within the abnormal white matter of the left hemisphere—T2-hypointense and T1-hyperintense—suggesting possible hamartomatous intracranial melanosis (Fig. 1D-I). Despite strong radiologic and clinical suspicion of melanin deposition within the brain parenchyma, histologic confirmation was not possible because the patient’s caregivers declined consent for an invasive brain biopsy.
Our second case involved a 7-year-old female child with an underlying intellectual disability who presented with left focal seizures beginning at 7 months of age. During a routine follow-up visit, her guardian noticed patchy white discoloration of the skin on the right side of the face and neck, for which clotrimazole ointment had been prescribed by a dermatologist under the impression of tinea versicolor. The skin changes were not associated with systemic symptoms, rashes, or pruritus. There was no family history of developmental delay, seizures, or similar dermatologic findings. Notably, the child had a history of ostium secundum atrial septal defect, which had closed spontaneously; she had been followed annually by cardiology and was eventually discharged from care.
On examination, the child appeared well developed and well nourished, without dysmorphic features or other findings suggestive of neurocutaneous syndromes. Skin examination revealed well-defined macular hypopigmentation over the right side of the face and neck (Fig. 2A), without erythema, scaling, or pruritus. Neurological examination revealed normal cranial nerve function, age-appropriate gait, normal strength and tone, intact sensation, and symmetrical deep tendon reflexes. Cardiac and respiratory evaluations were unremarkable. Neuroimaging with axial T2-weighted MRI demonstrated gyral thickening and hyperintensity in the juxtacortical white matter of the right medial occipital lobe, consistent with cortical malformation and possible gliosis. Susceptibility-weighted imaging (SWI) revealed multiple blooming foci in the same region, suggestive of possible intracranial melanin deposition (Fig. 2B-D). Although a biopsy was recommended for definitive diagnosis, the caregivers declined consent. The patient’s focal seizures were effectively managed with oxcarbazepine and clobazam.
HI, first described by Ito [1] in 1952, is a neurocutaneous disorder characterized by hypopigmented streaks, whorls, or patches distributed along Blaschko’s lines, most commonly on the trunk and limbs. It occurs in approximately 1 in 8,500 to 1 in 10,000 individuals and is the third most prevalent neurocutaneous disorder after neurofibromatosis type 1 and tuberous sclerosis [3,4]. Lesions typically appear at birth or in early infancy, are noninflammatory, and may fade with age [5]. The key entity to distinguish in the differential diagnosis is incontinentia pigmenti, which also follows Blaschko’s lines but includes inflammatory skin stages and is associated with an X-linked mutation, unlike HI [6].
HI may also present with various subtle cutaneous manifestations in approximately 40% of cases, including café-au-lait macules, mottled skin (cutis marmorata), vascular nevi, localized scleroderma, ichthyosis, nevus of Ota, abnormal sweating, Mongolian spots, fibromas, pilomatrixomas, and signs of atopic dermatitis [7]. Hair and scalp abnormalities are also documented, including alopecia, hypertrichosis, hair depigmentation, and nail dystrophy [2].
Approximately three-fourths of HI cases exhibit multisystem involvement, particularly affecting the neurological, ocular, musculoskeletal, cardiac, and renal systems, supporting its classification as a neurocutaneous syndrome [8]. The most frequent central nervous system (CNS) manifestations are intellectual disability and seizures, with additional findings such as autism, cortical malformations (including hemimegalencephaly and pachygyria), heterotopias, corpus callosum hypoplasia, cerebral or brainstem atrophy, hamartomas, and periventricular cysts [9,10]. White matter lesions, usually appearing in infancy [11], often correlate with the severity of cognitive delay and seizure activity, although some exceptions exist [7].
Common seizure types include generalized tonic-clonic, complex partial, myoclonic seizures, and infantile spasms [10,12]. While some generalized seizures respond well to pharmacotherapy, many patients develop drug-resistant focal seizures requiring nonpharmacologic interventions [7]. Both of our cases exhibited focal seizures: one was refractory to multiple antiseizure medications, while the other achieved good control with oxcarbazepine and clobazam.
MRI findings in HI typically include extensive white matter abnormalities, such as cystic changes or disordered myelination, often involving more than half of the periventricular and subcortical regions [10], hemispheric asymmetry such as hemimegalencephaly [13] or hemiatrophy, cerebellar, cerebral, or brainstem atrophy, gray matter heterotopia (double cortex syndrome), porencephaly, and poor differentiation of gray-white matter [14].
In both cases presented here, brain MRI revealed abnormal signal intensities indicative of underlying cortical and white matter pathology consistent with HI. Notably, imaging in both children raised the possibility of intracranial melanin deposition, a rare but increasingly recognized association with HI.
In the first case, MRI demonstrated hemimegalencephaly of the left cerebral hemisphere with widespread white matter signal abnormalities. Within these areas, multiple nodular lesions were identified that were T2-hypointense and T1-hyperintense. This characteristic signal pattern of melanin-containing lesions suggested hamartomatous intracranial melanosis (Fig. 1E and F). In the second case, MRI revealed gyral thickening and hyperintense signal in the juxtacortical white matter of the right medial occipital lobe on T2-weighted images, consistent with focal cortical dysplasia (FCD). Additionally, SWI demonstrated multiple blooming foci in the same region. Blooming on SWI typically indicates the presence of paramagnetic substances such as blood, calcification, or melanin, again supporting the suspicion of intracranial melanin deposition (Fig. 2D).
In both of our reported cases, there was no clinical evidence suggesting trauma or vascular insult as the underlying etiology. Although differentiating the MRI signal characteristics of melanin from those of hemorrhage with complete certainty remains challenging, the observed T1 hyperintense and T2 hypointense signal patterns are highly suggestive of intracranial melanin deposition. It is important to acknowledge that the absence of histopathological confirmation represents a limitation of our hypothesis. Nevertheless, alternative possibilities are less likely, as the T1 hyperintense lesions did not show suppression on fat-saturated sequences, thereby excluding lipid-rich content. Calcification was also ruled out on SWI, which did not reveal phase patterns consistent with calcific deposits. Moreover, demyelinating lesions are typically T1 hypointense and T2 hyperintense, opposite to our findings, further supporting the likelihood of melanin involvement [15].
Additionally, FCD and heterotopia were excluded based on their imaging characteristics: FCD typically presents with variable cortical thickening and a transmantle sign [16], while heterotopia demonstrates signal intensity identical to normal gray matter across all sequences [17]. In contrast, our cases showed distinct, noncongruent signal patterns, suggesting that classic cortical malformations are unlikely and instead pointing toward melanin deposition.
Finally, these imaging findings are consistent with previously published cases. For example, a reported case of neurocutaneous melanosis demonstrated MRI findings similar to ours—T1 hyperintense and T2 hypointense brain foci—though histopathological confirmation was lacking [18]. In contrast, biopsy-proven cases of metastatic melanoma have revealed MRI signal characteristics that align with our observations, lending further support to our interpretation of intracranial melanin deposition [19].
These findings suggest a potential pathophysiological link between HI and intracranial melanosis, likely arising from the shared embryologic origin of melanocytes and neurons (Fig. 3). We propose that melanin may enter the cerebral parenchyma via neuronal migratory pathways during development, a hypothesis supported by the parallel distribution of cortical abnormalities and cutaneous lesions along Blaschko’s lines. Both the cutaneous hypopigmentation and neuroimaging changes appear to stem from somatic mosaicism with defective neuronal migration affecting ectoderm-derived tissues [20].
Recent advances in melanocyte biology reinforce this proposed connection between melanocytes and neurons, as both originate from neural crest cells and share migratory patterns, signaling pathways (endothelins, FGFs, neurotrophins, p53), and receptors such as p75NTR, which play critical roles in neuronal survival and degeneration. Like neurons, melanocytes form dendritic processes, respond to neurotrophic stimuli, and interact with beta-amyloid via p75NTR, undergoing apoptosis similar to neuronal degeneration (Fig. 3) [21]. These parallels suggest that melanocytes may follow neuronal migratory routes and deposit pigment within the brain, explaining intracranial melanin observed on imaging and supporting a shared developmental mechanism underlying CNS involvement in HI.
Ophthalmic manifestations occur in approximately 25% of HI cases and include strabismus, nystagmus, refractive errors, ptosis, hypertelorism, heterochromia, microphthalmia, dacryostenosis, coloboma, cataract, amblyopia, and posterior segment changes such as optic atrophy, pigmentary retinopathy, and retinal detachment [3]. Musculoskeletal anomalies are also frequent, including limb asymmetry, short stature, kyphoscoliosis, clinodactyly, polydactyly, syndactyly, hemihypertrophy, and hypotonia [10], often accompanying CNS abnormalities as major extracutaneous features. Less commonly (<10%), congenital heart defects such as tetralogy of Fallot, atrial septal defect, and ventricular septal defect have been reported [11].
The diagnosis of HI remains primarily clinical and is supported by Wood’s lamp examination of hypopigmented lesions [22]. It is widely considered a cutaneous marker of chromosomal mosaicism, though genetic abnormalities may not always be detectable. Patients presenting with linear hypopigmentation along Blaschko’s lines require comprehensive systemic evaluation, including neuroimaging, electroencephalogram for seizure assessment, and skeletal radiography [23]. Diagnostic criteria include major features such as nonhereditary linear hypopigmentation with neurological or musculoskeletal involvement, while minor criteria encompass chromosomal abnormalities and multiple congenital defects unrelated to the nervous or musculoskeletal systems. A diagnosis is established with one major or two minor criteria [2]. Management is primarily supportive, focusing on seizure control, educational and rehabilitative interventions, periodic follow-up, and genetic counseling, while cutaneous lesions typically require only cosmetic management [2].
To the best of our knowledge, we present one of the first probable cases of intracranial melanin accumulation in patients with HI, supported by characteristic MRI signal features and the developmental parallels between melanocytes and neurons. Given their common neural crest origin and shared migratory pathways during embryogenesis, it is plausible that melanocytes may aberrantly migrate into cerebral parenchyma (Fig. 3). While imaging findings strongly support this hypothesis, histopathological confirmation was not possible due to the absence of tissue sampling, and no previous studies have provided such evidence. This underscores the need for further neuropathological and developmental research to clarify the association between pigmentary disorders and CNS abnormalities.
Written consent was obtained from the patient's guardian to publish.
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