OVERVIEW: What every practitioner needs to know

Are you sure your patient has hypomelanosis of Ito? What are the typical findings for this disease?

Hypomelanois of Ito (HI), also known as pigmentary mosaicism of the Ito type (and formerly known as incontinentia pigmenti [IP]achromians and IP type 1) is a disorder that primarily involves the skin and nervous system.

The unifying sign of HI is unilateral or bilateral irregular hypopigmented areas on the skin that are typically described as whorls, streaks, and patches and generally, but not exclusively, follow the lines of Blaschko. These findings are typically evident at birth (~50% of cases) but can also manifest later in infancy.

The pattern of abnormal pigmentation is usually readily apparent in darker skinned individuals but may be missed initially in those with lighter skin. In these children, hypopigmented areas can frequently be made more evident with ultraviolet light. Care should be taken to distinguish HI from other disorders that may share similar cutaneous manifestations.

Continue Reading

HI is not a distinct entity but rather the characteristic cutaneous findings that result from an underlying genetic mosaicism or chimerism that is also responsible for the other manifestations seen in HI.

HI has broad clinical and overlapping phenotypes, which makes specifying and quantifying the various abnormalities difficult. This is further complicated by uncertain or unconfirmed diagnoses in many of the case series in the literature.

Central nervous system (CNS) involvement in HI is common, but estimates range widely from 33% to almost 95%. The most common CNS complication is developmental delay and mental retardation. Closely associated with the cognitive deficits are seizures of various types, including myoclonic seizures, partial seizures, tonic-clonic seizures, as well as infantile spasms, or West syndrome.

Other CNS abnormalities seen in HI include white and gray matter changes on magnetic resonance imaging (MRI) and pathologic specimens consistent with neuronal migration disorders. Also described are macrocephaly, megancephaly, hemimegancephaly, as well as all manner of craniofacial abnormalities.

Other associated non-CNS findings by organ system are listed below, in no particular order:

Musculoskeletal abnormalities such as short stature, joint contractures, limb asymmetry, scoliosis, and disorders of digit formation

Ocular manifestations, including abnormalities of the retina, optic nerve, iris, lens and also disorders of ocular movements and alignment such as nystagmus and strabismus

Various abnormalities of the hair, nails and teeth

Abnormalities of the cardiac and urogenital systems, as well as some association with various malignancies; there does not appear to be an increased incidence of dermatologic neoplasms in HI

What other disease/condition shares some of these symptoms?

HI is frequently confused with IP and was previously called IP type 1. Like HI, IP is also characterized by pigmentary abnormalities, with swirling patterns seen in infancy; it also affects multiple organ systems such as the CNS, eyes, and teeth. However the skin findings in IP usually begin as an inflammatory disease that presents with a vesiculopustular eruption in the first few weeks of life and progresses to a verrucal stage, followed by a hyperpigmented and atrophic phase.

The hyperpigmentation seen in IP will decrease and can disappear by adolescence, whereas the skin coloration in HI is relatively static and is not preceded by inflammatory skin changes.

IP is overwhelmingly a disease of female patients, since the vast majority of male patients with IP die in utero. However there are dozens of documented cases of boys born with IP whose disease course matches that of girls.

Dental abnormalities are a key feature of IP, which may help distinguish IP from HI when the preceding inflammatory lesions cannot be confirmed. Up to 80% of patients with IP will have abnormal dentition, such as absence of the full set of teeth, supernumerary teeth, and pegged or conically shaped teeth.

HI can be difficult to distinguish from IP if a history of vesicles or verrucal lesions is not present. Confirming a diagnosis of IP may require skin biopsies to demonstrate inflammatory or postinflammatory skin changes. Genetic testing can also confirm the diagnosis of IP. (See above section on IP for more information.)

Other disorders that can be confused with HI because of abnormal pigmentation include X-linked dominant chondrodysplasia punctata, Naegeli-Franceschetti-Jadassohn syndrome, dermatopathia pigmentosa reticularis, and linear and whorled nevoid hypermelanosis.

What caused this disease to develop at this time?

HI is a congenital disorder. It is not known what influences the timing of the skin manifestations. HI is essentially a sporadic genetic disorder, with no currently known risk factors due to race, family history, geography, or environmental exposures. (See the discussion below on genetics.)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of HI is based on clinical signs. In some patients the diagnosis can be supported by demonstrating chromosomal alterations or mosaicism with a karyotype of peripheral blood. However blood can frequently be normal, and thus a karyotype of skin melanocytes from both normal and affected areas can confirm the diagnosis.

Would imaging studies be helpful? If so, which ones?

Screening imaging studies in HI such as brain MRI are not necessary and should be obtained only if needed to address particular symptoms. This is particularly true with studies requiring ionizing radiation in infants and young children. The presence of seizures, developmental delay, or focal neurologic findings should be evaluated with an MRI of the brain. If there are lower motor neuron findings or mixed upper and lower motor neuron findings, MRI of the spine can also be considered.

If you are able to confirm that the patient has hypomelanosis of Ito, what treatment should be initiated?

There is no cure for HI, and there is no particular treatment that is specific to HI because of the diverse presentation and clinical course of patients with HI. Treatment or therapies should be directed at individual complaints or manifestations of disease in each patient.

Seizures should be evaluated and treated with conventional pharmacotherapy based on seizure phenotype, as there is not yet any evidence that any one drug or class of drugs is more effective than others for seizures in children with HI. If seizures are not easily controlled with medication, patients should be referred to an epilepsy center for determination of whether surgical resection of an epileptic focus would be beneficial.

Children with HI who have developmental delay, difficulty with vision, mobility issues, or musculoskeletal abnormalities should be referred to appropriate specialists for evaluation and treatment.

There are no particular treatments or precautions for the cutaneous findings.

What are the adverse effects associated with each treatment option?

These effects vary depending on the various complications of the disease and the treatment used.

What are the possible outcomes of this disease?

Children with HI can have widely different potential outcomes because of the diverse chromosomal backgrounds that can lead to HI. The prognosis of HI does not appear to be related to the severity or prominence of the cutaneous markings.

What causes this disease and how frequent is it?

Patients with HI are presumed to have a chromosomal somatic mosaicism or chimerism, which can be identified in about half of patients. This results in cells in one individual having more than one genotype. In the case of HI, the abnormal pigmentation is evidence of the two genotypes present in skin cells resulting in two sets of coloration.

The most commonly identified mosaicism in HI involves Xp11 (which was previously classified as a subtype of IP). However, mosaicism of any kind can lead to the cutaneous findings seen in HI, including partial trisomies (i.e., partial XXX or partial trisomy 18).

The incidence of HI is estimated to be about 1/8000 children and about 1/800 children referred to pediatric dermatologists or pediatric neurologists. This makes HI the third most common neurocutaneous disorder, behind neurofibromatosis type 1 and tuberous sclerosis.

What is the evidence?

Thomas, IT, Frias, JL, Cantu, ES. “Association of pigmentary anomalies with chromosomal and genetic mosaicism and chimerism”. Am J Hum Genet. vol. 45. 1989. pp. 193-205. (A list of eight patients with HI briefly discuss their presentation and their discovered chromosomal anomalies, illustrating the diverse genetic alterations that can lead to similar clinical manifestations.)

Assogba, K, Ferlazzo, E, Striano, P. “Heterogeneous seizure manifestations in hypomelanosis of Ito: report of four new cases and review of the literature”. Neurol Sci. vol. 31. 2010. pp. 9-16. (Case reports of four patients with seizures and HI, illustrating the range of seizure phenotypes that can occur in HI.)