528 528 In 1952, Ito reported a female patient with a widespread, symmetric pattern of depigmented whorls and streaks, naming it incontinentia pigmenti achromians, because the distribution of the depigmented lesions is the negative image of the hyper- pigmented streaks of incontinentia pigment. Hypomelanosis of Ito (HI) is a relatively common disorder with a frequency of 1 in 8000–10,000 patients in a general pediatric hospital and 1 in 1000 patients in a pediatric neurology service.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Sporadic occurrence in nearly all cases with no affected sibs or parents
i. Result of a de novo postzygotic mutation ii. Mutation can only survive in a mosaic state b. Only a few cases with possible genetic inheritance
reported
i. X-linked dominant inheritance ii. Autosomal dominant
iii. Autosomal recessive 2. Pathogenesis
a. Chromosome abnormalities (52%)
i. Mosaicism leading to generation of two cell lin- eages producing patterns of hypopigmented and hyperpigmented skin
ii. Balanced X/autosome translocations
iii. Supernumerary X chromosome/ring fragment iv. Ring chromosomes (10, 14, 22)
v. Mosaic triploidy
vi. Mosaic trisomies (8, 13, 14, 18, 22) vii. Mosaic translocations
viii. Mosaic deletions
ix. Autosomal deletions and duplications involving chromosomes 7, 12, 13, 14, 15, and 18
b. X chromosome abnormalities i. Inactivation
ii. Activation iii. Mosaicism
3. A descriptive term rather than a true syndrome
a. Suggested by the pattern of chromosomal aberrations and the polymorphic nature of the disease
b. A term used for a phenotype
i. Presence of linear streaks lighter than the patient’s background skin color, extending around the trunk and down the long axes of the extremities, roughly following the lines of Blaschko
ii. Association with systemic findings
CLINICAL FEATURES
1. Cutaneous symptoms a. Onset
i. Recognizable at birth (54%) ii. Visible during childhood (70%)
b. No signs of inflammation or verrucous changes char- acteristically seen in incontinentia pigmenti
c. Hypopigmented lesions i. Typical phenotype
a) Cutaneous pattern: essentially the reverse of the third stage of incontinentia pigmenti b) Bilateral or unilateral whirls, patches, and
streaks corresponding to the lines of Blaschko, often showing a midline cutoff
c) Eruption not preceded by any inflammatory lesions (unlike incontinentia pigmenti) ii. Unilateral skin lesions contralateral to the side of
brain malformation in patients with HI and hemimegalencephaly
iii. Wood lamp useful in demonstrating hypopig- mented lesions in persons with fair skin
iv. Atypical phenotype: checkerboard pattern, zos- teriform, dermatomal, or plaquelike arrangement d. Nonspecific skin lesions (20–40%)
i. Café-au-lait spots
ii. Persistent mongolian blue spots iii. Nevus of Ota
iv. Nevus marmoratus and angiomatous nevi v. Soft fibroma
vi. Pilomatrixoma vii. Aplasia cutis viii. Atopic dermatitis 2. Hair/nail/sweat gland anomalies
a. Focal hypertrichosis b. Slow growth c. Diffuse alopecia d. Coarse, curly hair e. Trichorrhexis
f. Widows peak
g. Generalized hirsutism h. Facial hypertrichosis
i. Low hairline j. Ungual hypoplasia
k. Hypohidrosis corresponding to hypopigmented areas 3. Associated extracutaneous anomalies (75%)
a. CNS anomalies
i. Mental retardation (50–75%) ii. Seizures (50%)
iii. Autistic behavior (11%) iv. Microcephaly
v. Hypotonia vi. Hyperkinesia vii. Ataxia viii. Deafness
ix. Hemimegalencephaly
Hypomelanosis of Ito
HYPOMELANOSIS OF ITO 529
x. Brain tumors (medulloblastoma, choroid plexus papilloma)
b. Ophthalmological abnormalities (20%) i. Microphthalmia
ii. Ptosis
iii. Nonclosure of the upper lid iv. Symblepharon
v. Dacryostenosis vi. Strabismus vii. Nystagmus viii. Myopia
ix. Hyperopia x. Astigmatism xi. Amblyopia xii. Megalocornea xiii. Corneal opacification
xiv. Cataracts
xv. Iridal heterochromia xvi. Scleral melanosis xvii. Heterochromia of the iris xviii. Optic atrophy
xix. Striated patchy hypopigmented fundi xx. Retinal detachment
c. Dental abnormalities
i. Defective dental implantation ii. Conical teeth
iii. Partial anodontia
iv. Dental dysplasia/hypoplasia v. Defective enamel
vi. Hamartomatous dental cusps d. Skeletal defects
i. Short stature
ii. Facial and limb asymmetry (hemihypertrophy) iii. Pectus carinatum or excavatum
iv. Scoliosis v. Syndactyly vi. Polydactyly vii. Brachydactyly viii. Clinodactyly e. Congenital heart defect
i. Tetralogy of Fallot ii. Pulmonary stenosis iii. Ventricular septal defect
iv. Atrial septal defect
v. Incomplete right bundle branch block vi. Cardiomegaly of unknown etiology f. Abdomen/gastrointestinal anomalies
i. Diastasis recti ii. Hepatomegaly
iii. Segmental dilation of the colon
iv. Diaphragmatic, umbilical, and inguinal hernias g. Genitourinary anomalies
i. Hypospadias ii. Micropenis iii. Single kidney
iv. Urethral duplication v. Cryptorchidism vi. Precocious puberty vii. Gynecomastia viii. Asymmetrical breasts
ix. Nephritis
4. Diagnostic criteria (Ruiz-Maldonado et al., 1992) a. Sine qua non criterion: congenital or early acquired
nonhereditary cutaneous hypopigmentation in linear streaks or patches involving more than two body segments
b. Major criterion
i. One or more nervous system anomalies ii. One or more musculoskeletal anomalies c. Minor criterion
i. Two or more congenital malformations other than nervous system or musculoskeletal anomalies ii. Chromosomal anomalies
d. Definitive diagnosis: sine qua non criterion plus one or more major criteria or two or more minor criteria e. Presumptive diagnosis: sine qua non criterion alone
or in association with one minor criterion
DIAGNOSTIC INVESTIGATIONS
1. Cytogenetic investigation
a. Peripheral blood karyotyping indicated especially when systemic manifestations are present
b. Fibroblast karyotyping by sampling the dark and light skin for demonstrating mosaicism or chromosomal abnormalities
c. Presence of a wide variety of karyotypic abnormalities 2. Histopathology
a. Decreased numbers of melanocytes
b. Decreased numbers and size of pigmented melanosomes c. Neuropathological features
i. Polymicrogyria
ii. Disarray of cortical lamination
iii. Heterotopic neurons in the white matter iv. Giant cells
3. CT and MRI of the brain
a. White matter abnormalities somewhat predictive of a poor neurological outcome
b. Neuroblast migration i. Heterotopia ii. Pachygyria iii. Polymicrogyria
c. Localized or generalized cerebral atrophy d. Cerebral hemiatrophy
e. Hemimegalencephaly f. Other rare anomalies
i. Noncommunicating hydrocephalus ii. Megacisterna magna
iii. Arteriovenous malformation
iv. Cerebellar hypoplasia (hemispheres and vermis) v. Brainstem hypoplasia
vi. Brain tumors
4. Radiography for musculoskeletal anomalies 5. EEG for seizures
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless a parent shows chromosomal abnormalities
b. Patient’s offspring:
i. Not increased unless the patient has chromosomal abnormalities
530 HYPOMELANOSIS OF ITO
ii. Guarded counseling in women with a phenotype similar to HI who have nonmosaic balanced X;
autosome translocations
2. Prenatal diagnosis: undetermined for affected mother who has a specific type of chromosome abnormality 3. Management
a. Early intervention programs including physical, occu- pational, and speech therapies
b. Special education c. Seizure control
d. Surgical treatment of cataracts and retinal detachment
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HYPOMELANOSIS OF ITO 531
Fig. 1. Two children with hypomelanosis of Ito showing hypopigmented skin lesions in a characteristic distribution of whirls and streaks on the trunk and limbs. The first patient has 49,XXXXY.
