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org/rare-diseases/hypomelanosis-of-ito

NORD gratefully acknowledges Raymond E. Boissy, PhD, Professor of Dermatology & Cell Biology,
Department of Dermatology, University of Cincinnati College of Medicine, for assistance in the
preparation of this report.

Synonyms of Hypomelanosis of Ito

HMI
incontinenti pigmenti achromians
pigmentary dysplasia
pigmentary mosaicism
IPA
ITO
Ito Hypomelanosis

General Discussion
Hypomelanosis of Ito is a rare condition characterized by distinctive skin changes, in
which areas of the body lack skin color (hypopigmentation). These skin changes may
present as patches, streaks or spiral-shaped (whorled) areas. In many affected
individuals, additional symptoms affecting areas outside of the skin also occur. There are
a wide variety of symptoms potentially associated with hypomelanosis of Ito.
Neurological findings such as seizures and developmental delays and musculoskeletal
symptoms such as abnormal curvature of the spine (scoliosis) are commonly associated
with this condition. Because of the neurological and skin symptoms, hypomelanosis of
Ito may be referred to as a "neurocutaneous" syndrome. However, in many patients the
condition arises from genetic irregularities that are present in some cells of the body, but
not in others (mosaicism). Some researchers believe that hypomelanosis of Ito does not
represent a distinct disorder but rather a symptom common to a group of disorders
involving genetic mosaicism.

Signs & Symptoms

The most distinctive finding associated with hypomelanosis of Ito is characteristic skin
changes. Most affected individuals develop areas that lack skin color (hypopigmentation).
Any area of the body may be involved although the scalp, palms and soles are rarely
affected. Skin changes may occur as patches, streaks or spiral-shaped (whorled) areas of
discoloration and may affect one side of the body (unilateral) or both sides (bilateral).
Affected areas of skin are usually normal otherwise. The skin lesions usually appear

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during the first year of life and remain unchanged through childhood, but may fade or
darken in adulthood. Skin lesions are not associated with inflammation or a
premalignant (verrucous) condition.

In some cases of hypomelanosis of Ito, additional non-cutaneous features may occur. It

is important to note that the specific symptoms that occur vary greatly from person to
person and affected children will not have all the symptoms discussed below. Because
children with the characteristic skin changes of hypomelanosis of Ito and no associated
abnormalities may go unreported, determining the actually frequency of associated
findings is difficult. The number of affected individuals with additional symptoms has
been estimated to be anywhere from 30-90 percent.

Neurological findings may occur in some cases including seizures that occur during
infancy and are often resistant to therapy, some degree of cognitive impairment, and
delays in attaining milestones that require the coordination of muscular and mental
activity (psychomotor impairment). In some cases, one side of the brain may be larger
than the other (hemimegalencephaly).

Less often, some individuals have crossed eyes (strabismus), eyes that a spaced apart
wider than normal (hypertelorism), cleft palate, cleft lip, and dental anomalies such as
missing teeth (anodontia). Loss of hair usually in a patchy pattern (alopecia) may also
occur. Some infants may have microcephaly, a condition that indicates that the head
circumference is smaller than would be expected for age and sex; others may have
macrocephaly, which indicates that head circumference is larger than would normally be
expected.

A variety of skeletal abnormalities have occurred in individuals with hypomelanosis of Ito

including abnormal side-to-side curvature of the spine (scoliosis), disproportionate
length of the legs (limb length discrepancy), and abnormal fixation or “locking” of the
pinky in a bent position (clinodactyly). Diminished muscle tone (hypotonia) may also
occur.

Additional symptoms that may affect individuals with hypomelanosis of Ito include
additional eye abnormalities, deafness, overgrowth of one side of the body
(hemihypertrophy), heart (cardiac) abnormalities, kidney (renal) malformations, and
abnormalities of the genitourinary tract, which contains the reproductive organs and
urinary system.

Causes
The exact cause of hypomelanosis of Ito is unknown. Many cases are associated with
genetic mosaicism and sporadic gene mutations. Genetic mosaicism is the term for
individuals who have two distinct cell lines in the body that developed because of a gene
mutation that occurred during embryonic development. The two cell lines have
differences involving the chromosomes (chromosomal mosaicism).

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Chromosomes, which are present in the nucleus of human cells, carry the genetic
information for each individual. Human body cells normally have 46 chromosomes. Pairs
of human chromosomes are numbered from 1 through 22 and the sex chromosomes
are designated X and Y. Males have one X and one Y chromosome and females have two
X chromosomes. Each chromosome has a short arm designated “p” and a long arm
designated “q”. Chromosomes are further sub-divided into many bands that are
numbered. The numbered bands specify the location of the thousands of genes that are
present on each chromosome.

In many individuals with hypomelanosis of Ito, certain cells have the normal 46
chromosomes (one cell line) while others cells do not have the normal 46 chromosomes
(second cell line). This second cell line may contain various abnormalities affecting the
chromosomes such as a mutation in a specific gene, or the presence of an extra material
on a chromosome (trisomy), loss of a portion of chromosome (monosomy), or a
chromosomal translocation. Translocations occur when portions of certain
chromosomes break off and are rearranged, resulting in shifting of genetic material and
an altered set of chromosomes in the immediate daughter cells and their subsequent
progeny cells. Specific chromosomal abnormalities have been identified in certain cases
of hypomelanosis of Ito including ones affecting chromosome 9q33, chromosome 15q11-
q13, chromosome Xp11 and Xp21.2. Chromosomal abnormalities have been identified in
approximately 60 percent of cases of hypomelanosis of Ito and have included up to 64
distinct cytogenetic (chromosomal) abnormalities.

The chromosomal abnormalities affecting hypomelanosis of Ito occur after fertilization,

often for unknown reasons (spontaneously). The disorder is not inherited. The specific
gene(s) involved in the development of hypomelanosis of Ito have not been identified.

Affected Populations
In earlier reports, hypomelanosis of Ito affected women more often than men by a ratio
of 2.5:1. More recent, larger studies suggest that the difference may not be as large. The
incidence of hypomelanosis of Ito is estimated to be 1 in 8,000-10,000 people in the
general population. The symptoms usually become apparent during the first or second
year of life. Hypomelanosis of Ito was first described in the medical literature in 1952.

Related Disorders
Symptoms of the following disorders can be similar to those of hypomelanosis of Ito.
Comparisons may be useful for a differential diagnosis.

Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin,
hair, teeth, and central nervous system. It is inherited as an X-linked dominant trait. IP is
characterized by four stages, some of which may overlap. The first stage may be present
at birth or appear in early infancy and consists of redness or inflammation of the skin.
This irritation includes the scalp as well as the extremities and can last from a few weeks
to several months. In the second stage, blisters develop into a raised, wart-like
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appearance with lesions that look like pustules. The extremities are involved almost
exclusively in this stage, which may last for several months but rarely as long as a year. In
the third phase, the skin darkens in a swirled pattern sometimes described as a “marble
cake” appearance. The fourth stage is called the “atrophic” stage. Pale, hairless patches
appear among adolescent and adult patients. The skin changes may fade later in life.
(For more information on this disorder, choose “incontinentia pigmenti” as your search
term in the Rare Disease Database.)

Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent

shortly after birth. The disorder can cause a wide range of potential signs and symptoms
and is associated with the formation of benign (non-cancerous) tumors in various organ
systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently
affected. These tumors are often referred to as hamartomas. Hamartoma is a general
term for a tumor or tumor-like growth that is made up of cells normally found in the area
of the body where the hamartoma forms. Hamartomas are not malignant; they do not
metastasize and spread to other areas of the body. However, these abnormal growths
can grow larger and can damage the affected organ system. The number, size, and
specific location of these abnormal growths in individuals with tuberous sclerosis can
vary widely and consequently the severity of the disorder can vary widely as well.
Tuberous sclerosis results from alterations (mutations) in a gene or genes that may
occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal
dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no
family history of the disease. Mutations of at least two different genes are known to
cause tuberous sclerosis, the TSC1 gene or the TSC2 gene. (For more information on this
disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)

Vitiligo is a dermatological condition characterized by the appearance of white patches

of skin on different parts of the body as a result of the destruction of the cells that make
pigment (melanocytes). Hypopigmented lesions are not present at birth in vitiligo but
develop later in life. This may vary from one or two white spots on the skin to large areas
of depigmentation. Vitiligo is not contagious. It seems to occur more often among people
who have certain autoimmune diseases. For some people, although not for everyone, the
depigmentation is progressive

Diagnosis
A diagnosis of hypomelanosis of Ito is made based upon a thorough clinical evaluation, a
detailed patient history, identification of characteristic findings and a variety of
specialized tests such as the finding of chromosomal mosaicism in fibroblasts (the major
cell type of the lower layer of the skin) or keratinocytes (the major cell of the outer layer
of the skin [epidermis]) obtained from an area of affected (hypopigmented) skin.
Computed tomography (CT) scans or magnetic resonance imaging (MRI) may be able to
detect structural abnormalities of the brain if neurological abnormalities are present.

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During CT scanning, a computer and x-rays are used to create a film showing cross-
sectional images of certain tissue structures. An MRI uses a magnetic field and radio
waves to produce cross-sectional images of particular organs, tissues and structures.

Standard Therapies
Treatment

The treatment of hypomelanosis of Ito is directed toward the specific symptoms that are
apparent in each individual. Treatment may require the coordinated efforts of a team of
specialists. Pediatricians, dermatologists, neurologists, specialists who diagnose and
treat skeletal disorders (orthopedists), dental specialists, specialists who diagnose and
treat eye disorders (ophthalmologists), surgeons and other healthcare providers may
need to systematically and comprehensively plan an affect child’s treatment.

The characteristic skin abnormality (hypopigmentation) of hypomelanosis of Ito tends to

darken or fade without treatment. Some individuals may use cosmetics to hide or darken
these areas. Antiseizure medications (anticonvulsants) may be used to treat infants and
children with seizures, but are ineffective in some cases. Surgical techniques to treat
seizures may be necessary for some affected individuals.

Additional treatment is symptomatic and supportive and consultation with proper

specialists may be necessary. For example, consultation with an orthopedist may be
necessary to treat scoliosis.

Services that may be beneficial to some children with hypomelanosis of Ito include
special remedial education and other medical, social, and/or vocational services. Genetic
counseling may be of benefit for affected individuals and their families.

Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All
studies receiving U.S. Government funding, and some supported by private industry, are
posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in
Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

For information about clinical trials conducted in Europe, contact:

https://www.clincialtrialsregister.eu/

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NORD Member Organizations
National Foundation for Ectodermal Dysplasias
6 Executive Drive
Suite 2
Fairview Hights, IL 62208 USA
Phone: (618) 566-2020
Email: info@nfed.org
Website: http://www.nfed.org

Other Organizations
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/
HITS (UK) Family Support Network
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Torquay
Devon, TQ2 7JQ United Kingdom
Phone: 4401803401018
Email: tgrant@hitsuk.freeserve.co.uk
Website: http://www.e-fervour.com/hits
March of Dimes
1550 Crystal Dr, Suite 1300
Arlington, VA 22202 USA
Phone: (888) 663-4637
Website: http://www.marchofdimes.org
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675 USA
Phone: (301) 495-4484
Toll-free: (877) 226-4267
Email: NIAMSinfo@mail.nih.gov
Website: http://www.niams.nih.gov/
The Arc
1825 K Street NW, Suite 1200
Washington, DC 20006
Phone: (202) 534-3700
Toll-free: (800) 433-5255
Email: info@thearc.org
Website: http://www.thearc.org
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References
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Pigmentary System. Blackwell Publishing, Oxford, UK. 2006.

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Elsevier Saunders. Philadelphia, PA; 2005:389.

Spitz JL. Genodermatoses. 2nd ed. Lippincott Williams & Wilkins. Philadelphia, PA;
2005:70-71.

Lewis RA. Hypomelanosis of Ito. NORD Guide to Rare Disorders. Lippincott Williams &
Wilkins. Philadelphia, PA. 2003:119.

Champion RH, Burton JL, Ebling FJG. Eds. Textbook of Dermatology. 5th ed. Blackwell
Scientific Publications. London, UK; 1992:1607.

JOURNAL ARTICLES
Assogba K, Ferlazzo E, Striano P, et al. Heterogeneous seizure manifestations in
Hypomelanosis of Ito: report of four new cases and review of the literature. Neurol Sci.
2010;31:9-16.

Gatter N, Hoppe B, Nutzenadel F, Waldherr R, Querfeld U. A cutaneous disease with

multisystem involvement: hypomelanosis of Ito may be associated with proteinuria, focal
segmental glomerulosclerosis and end-stage renal disease. Nephrol Dial Transplant.
2007;22:1796-1798.

Quigg M, Rust RS, Miller JQ. Clinical findings of the phakomatoses: hypomelanosis of Ito.
Neurology 2006;66:45.

Garcia Muret MP, Puig L, Allard C, Alomar A. Hypomelanosis of Ito with Sturge-Weber-like
leptomeningeal angiomatosis. Pediatr Dermatol. 2002;19:536-540.

Coward RJ, Risdon RA, Bingham C, Hattersley AT, Woolf AS. Kidney disease in
hypomelanosis of Ito. Nephrol Dial Transplant. 2001;1267-69.

Happle R. Incontinentia pigmenti versus hypomelanosis of Ito: the whys and wherefores
of a confusing issue. (Letter) Am J Med Genet. 1998;79:64-65.

Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al. Hypomelanosis of Ito. A study

of 76 infantile cases. Brain Dev.1998:20:36-43.

Fryburg JS, Lin KY, Matsumoto J. Abnormal head MRI in a neurologically normal boy with
hypomelanosis of Ito. Am J Med Genet. 1996;66:200-03.

Sybert VP. Hypomelanosis of Ito: a description, not a diagnosis. J Invest Dermatol.

1994;103(5Suppl):141S-143S.
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Ruiz-Maldonado R, Toussaint S, Tomayo L, et al. Hypomelanosis of Ito: diagnostic criteria
and report of 41 cases. Pediatr Dermatol.1992;9:1-10.

Donnai D, Read AP, McKeown C, et al. Hypomelanosis of Ito: a manifestation of

mosaicism or chimerism. J Med Genet. 1988;25:809-18.

FROM THE INTERNET

Janniger CK, Sotero de Menezes M. Hypomelanosis of Ito. Medscape. Last Update June
24, 2016. Available at: http://www.emedicine.com/PED/topic1123.htm Accessed January
12, 2017.

Ratz J, Gross N. Hypomelanosis of Ito. Medscape. Last Update April 18, 2016. Available at:
http://www.emedicine.com/DERM/topic186.htm Accessed January 12, 2017.

Years Published
1993, 1996, 2002, 2010, 2017
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