Incontinentia pigmenti achromians is another term used for this syndrome; however, because no true incontinentia pigmenti (melanin absent in the epidermis and present in the dermis) exists in the skin specimens, HI syndrome has become the preferred name.

In 1992, Ruiz-Maldonado and associates established some diagnostic criteria for HI syndrome. Nonetheless, Ruiz-Maldonado et al's criteria link the diagnosis to the presence of systemic nondermatological (eg, CNS, skeletal) or chromosomal abnormalities. These criteria exclude cases with only dermatological manifestations. Cases with skin manifestations suggestive of HI with and without systemic alterations have been described in the same family, showing that the HI syndrome can have a variable degree of systemic involvement. Studies that do not use systemic manifestations as diagnostic criteria for HI found that approximately 30-74% of cases with typical HI skin lesions do not have nondermatological pathology.

In spite of recent advances, the genetic substrate for HI syndrome is far from homogenous and not completely understood. A wide range of chromosomal abnormalities may be observed, including balanced X autosome translocations, supernumerary X chromosome ring fragment, ring chromosome 10, mosaic triploidy, mosaic trisomies (8, 13, 14, 18, 22), mosaic translocations, and mosaic deletions. Autosomal deletions and duplications may involve chromosomes 7, 12, 13, 14, 15, and 18. The pattern of chromosomal aberrations and the polymorphic nature of this disease have led some to believe that HI syndrome is a descriptive term rather than a true syndrome.

A familial form of HI syndrome exists; however, less than 3% of the patients have a family history of HI-type skin lesions. Although HI syndrome is most commonly a de novo occurrence, familial cases appear to be transmitted by an autosomal dominant trait. A family history of seizures or epilepsy is recorded in approximately 10% of the patients, but the phenotypic expression is variable so pigmentary changes may be the only clue to its genetic basis.

Frequency:

• Internationally: To date, very few epidemiological data on this syndrome exist. It appears to be the third most common neurocutaneous disease, second only to neurofibromatosis and tuberous sclerosis. In a pediatric neurology service in Spain, 1 out of 600-700 patients referred was diagnosed with HI syndrome. It is diagnosed in 1 out of every 7805 general pediatric outpatient visits, 1 out of every 790 pediatric dermatology clinic visits, and 1 out of every 2983 children in a general pediatric service. Approximately three fourths of the patients with the typical skin lesions have systemic manifestations.

Sex: Male-to-female ratios are variable. In earlier series, the male-to-female ratio was reported to be 1:2.5, but, in larger and more recent series, the male-to-female ratio was 1:1.2. The severity of systemic manifestations appears to be similar in both sexes.

History:

• HI may involve many organs. Several manifestations can be elicited by history, such as seizures and mental retardation. For the sake of better understanding of the subject, data from the history and physical examination are fused into a discussion of the signs and symptoms of the involvement by each organ system. The dermatological alterations are discussed first, followed by the description of systemic involvement.

Physical:

• Skin and neurological examinations are crucial for diagnosis; a thorough examination is extremely important.

• Dermatological manifestations

• Hypochromic lesions in distinctive patterns (eg, whirls, patches, streaks) characterize this syndrome; they often resemble whirled marble. The lesions may be unilateral (46%) or bilateral, and they usually show a midline cutoff.
• Patients with HI and hemimegalencephaly often have unilateral skin lesions. They are contralateral to the side of brain malformation and may show a zigzag pattern of lines. The hypochromic lesions are visualized readily in patients with pigmented skin, such as blacks, Asians, Spaniards, and Hispanic persons (eg, Mexicans). In children with fair skin, the use of a Wood lamp (ultraviolet light) is helpful in demonstrating these hypochromic lesions, which occur in the trunk, legs, arms, and face. They are more prominent in the ventral surface of the trunk and flexor surface of the limbs. The lesions are located on both the torso and the extremities in 59% of the cases, on just the torso in 23%, and exclusively on the extremities in 6%. Some authors advocate stricter criteria for diagnosis, requiring cutaneous involvement of 2 or more segments for diagnosis of HI.
• Skin lesions usually appear during the first year of life (70%) and may be noticeable at birth (54%). Rare cases are documented in which the lesions are not visible until mid childhood.

• Hypopigmented or depigmented lesions may appear in swirls or patches with irregular borders. They tend to run parallel to one another following the lines of Blaschko; however, HI is not the only syndrome showing pigmentary anomalies along the lines of Blaschko. In 22% of the patients, lesions are patchy (square or rounded) rather than linear.
• In linear or whorled nevoid hypermelanosis and nevus depigmentosus, lesions also follow these lines. The lines of Blaschko are relatively consistent and distinct from dermatomal lines. They represent orderly migration of mesodermal and ectodermal precursors during embryogenesis, occurring after X inactivation or activation. Genetic alterations (see above) or other problems perturbing the cells of the morula and their daughter cells generate the swirl pattern of hypopigmentation along the lines of Blaschko. The color changes observed in skin lesions of HI may be present at birth but are frequently more obvious later in infancy or early childhood.
• Hypohidrosis of hypopigmented skin can be detected in HI by application of iodine and starch in the skin, followed by a subcutaneous injection of pilocarpine hydrochloride.
• Nonspecific skin lesions are reported in 20-40% of HI cases. These lesions most frequently are café-au-lait spots, but the following also have been described:
  • Persistent mongolian blue spots
  • Nevus of Ota
  • Nevus marmoratus and angiomatous nevi
  • Soft fibroma
  • Pilomatrixoma
  • Aplasia cutis
  • Atopic dermatitis
• Hair abnormalities include the following
  • Slow growth
  • Diffuse alopecia
  • Trichorrhexis
  • Widows peak
  • Generalized hirsutism
  • Facial hypertrichosis
  • Coarse and curly hair
  • Low hairline (noted in 7% of patients)
  • Appearance of a zone of alopecia, or white hair in the scalp (may precede hypopigmented lesions)
• Fingernails may show some alterations, especially ungual hypoplasia.
• Abnormal sweat glands are reported.

• Neurological manifestations

• Neurological involvement is found in 76% of patients during the first decade of life. Mental retardation and seizures are the most common presenting symptoms. In one series of 19 patients, 10 noted neurological symptoms before the cutaneous signs arose; however, the proportion of patients with neurological involvement clearly is biased. The pattern of referral is as high as 84% in a pediatric neurology clinic–generated series but somewhat lower in a dermatologist-generated series. When systemic involvement was used as a key diagnostic criterion, up to 90% of the patients were found to have neurological involvement. Approximately 50% of the patients presented with seizures; although, a lower frequency (37%) was reported in the pediatric dermatology clinic–based series. Generalized tonic-clonic seizures were most common (25%), whereas partial cases were 12%, infantile spasms were 8%, and myoclonic were 4%. Occasionally, cases of Lennox-Gastaut syndrome have been reported.
• Seizure control was achieved in 40-70% of seizures. Some patients with partial seizures had very localized dysplastic lesions on neuroimaging that, on electroencephalogram (EEG), showed the typical localized almost continuous spike activity.
• Mental retardation (ie, intelligence quotient [IQ] <70) is noted in approximately one half to two thirds of the patients. Chromosomal anomalies do not appear to increase the risk of mental retardation. In fact, approximately 40% of patients with HI have an IQ less than 50, and fewer than one fourth have an IQ higher than 85.
• Autistic behavior has been found in approximately 11% of HI patients. It may be associated with infantile spasms and other severe seizures. Similarly, the presence of mental retardation is linked with seizures (65%). Even though the causal association of seizures and mental retardation or autism is attractive and present outside of HI, a common mechanism for both can be demonstrated easily (eg, patients with neuroblast migration and neuronal dysplasias).
• HI is occasionally associated with hemimegalencephaly; however, more focal dysplastic lesions also are observed. Motor development delay is present in approximately one fourth of patients. Hypotonia also is a common finding, which is usually accompanied by pes and genu valgus.
• Somatic hemihypertrophy, macrocephaly, and microcephaly also may be present (see below).
• Brain tumors are described in association with HI, including medulloblastoma and choroid plexus papilloma.
• Other neurological problems include ataxic gait, sensory neuropathy, chronic distal spinal muscular atrophy, torticollis, auditory conduction defect, hyperactivity, and spina bifida occulta.
• Visual field defects may be present in patients with occipital lesions, but some of these could represent sporadic associations.
• Neuropathological studies demonstrate polymicrogyria, disarray of cortical lamination, heterotopic neurons in the white matter, and giant cells.

• Ophthalmologic abnormalities

• Approximately one fifth of patients present with ocular abnormalities.
• Retinal pigment abnormalities are described as tessellated fundus, radial hypopigmented streaks, or geographic areas of hypopigmentation. Unilateral heterochromic iris with hypopigmentation of the cornea also is described.
• Cataracts and retinal detachment may produce loss of vision.
• Other ophthalmologic changes include myopia, hyperopia, astigmatism, megalocornea, opaque corneas, scleral melanosis, strabismus, slow pupillary response, pupillary atrophy or irregularity, nonclosure of the upper eyelid, ptosis, symblepharon, optic atrophy, choroidal atrophy, microphthalmia, macrophthalmia, epicanthal folds, dacryostenosis, and nystagmus.
• Perform a slit lamp examination in patients with ophthalmologic abnormalities.

• Musculoskeletal abnormalities

• Musculoskeletal abnormalities are rather common. Hemihypertrophy is found in one fifth of patients, usually ipsilaterally to hypomelanotic lesions.
• Arm and leg length discrepancy and scoliosis are reported.
• Fingers may be abnormal, showing atrophy, syndactyly, polydactyly, clinodactyly, or bifid thumb
• Other limb anomalies include luxatio coxae (caused by hypoplastic femoral heads) and genu valgus.

• Head and face anomalies

• Facial malformations include hypertelorism, coarse facies, cleft lip and palate, bifid uvula, and nose and ear anomalies.
• Macrocephaly is present in 3-23% of patients, often associated with coarse facies.
• In a study by Pascual-Castroviejo et al, microcephaly was described in 8% of patients.
• Delayed fontanelle closure and asymmetry of the head can be present.

• Dental problems include imperfect implantation of the teeth, partial anodontia and dental dysplasia, defective enamel, and hamartomatous cuspids.

• Cardiac anomalies

• Ventricular septum defect
• Atrial septum defect
• Pulmonary artery stenosis
• Tetralogy of Fallot
• Incomplete right bundle branch block and cardiomegaly of unknown etiology (occasionally noted)

• Genital and reproductive organ anomalies

• Hypospadias
• Micropenis
• Single kidney
• Urethral duplication
• Cryptorchidism
• Precocious puberty
• Gynecomastia
• Asymmetrical breasts
• Nephritis

• Other types of abnormalities
  Hepatomegaly
  Segmental dilation of the colon
  Diaphragmatic, umbilical, and inguinal hernia

• Malignant and benign tumors are found in association with HI. One patient study reported a mature cystic teratoma present in the posterior mediastinum and a diploic epidermoid cyst of the parietal bone. Brain tumors may be present (see above); however, the benign tumors observed in HI often are associated with chromosomal anomalies.

Causes:

Tuberous sclerosis

Many other skin pigmentary abnormalities may be associated with systemic and neurological abnormalities. In tuberous sclerosis, the lesions are either round or in the shape of an ash leaf and do not follow the lines of Blaschko.

Linear and whorled nevoid hypermelanosis

These conditions are characterized by brown pigmentation and hypopigmentation in streaks and whorls, which follow the lines of Blaschko. Because it is difficult to determine whether the darker skin color or the lighter one is normal, Sybert supports that the differentiation of dermatological features of linear and whorled nevoid hypermelanosis from the ones of HI are virtually impossible. In linear and whorled nevoid hypermelanosis, the lesions appear in infancy and gradually spread though the body. This feature is not helpful in the differentiation from HI, in which skin lesions are present at birth in more than half the cases. Linear and whorled nevoid hypermelanosis are not associated with systemic abnormalities in contrast with HI.

Nevus depigmentosus

Nevus depigmentosus is characterized by hypochromic lesions in streaks and whorls, which also follow the lines of Blaschko. The hypochromic lesions tend to be circumscribed, and they are present at birth changing little thereafter.
Systemic abnormalities are rare in nevus depigmentosus.

Incontinentia pigmenti

Incontinentia pigmenti (IP) is a condition seen mostly in girls; thus, X-linked dominant transmission is postulated. Similar to what is observed in HI, patients frequently have systemic involvement, including CNS manifestations. In IP, cutaneous lesions undergo 3 stages, which may be overlapping.

The first phase is characterized by vesiculobullous lesions in a linear array (but no dermatomal distribution), which are present from birth or in the first 2 weeks of life in 90% of the cases. Vesicles are proximal in the limbs, located in flexor surfaces, and contain eosinophils. This first phase may last days to months. Between the second and sixth week of life, the vesicles become pustular, verrucous, or keratotic, marking the second phase. In this phase, the lesions tend to be more prominent distally and dorsally in the limbs.
The second phase usually lasts for months, during which hypopigmentation and skin atrophy develop.

During the third phase, hyperpigmentation of lesions is observed peaking from 12-26 weeks of life. The dermatological appearance is one of streaks, whorls, macules, and flecks. The color of the lesions is chocolate-brown or tan. Some patients are born with lesions already in the third phase. This phenomenon is thought to be caused by in utero onset of the inflammatory process.

The term incontinentia pigmenti is used because melanin is not observed in the epidermis but is present in the dermis, as if it had leaked or dropped into the deeper layer of the skin; thus, the epidermis is incontinent of melanin. This incontinence of melanin is not observed in the skin of patients with HI. Alopecia may be observed in one third of patients with IP. Neuropathologically, patients with IP may show neuroblast migration disturbances, such as polymicrogyria. Inflammatory and destructive alterations often accompany IP lesions, which is a pattern often missing in HI. The reader is referred to Rosman, 1987, for a review of the clinical picture of incontinentia pigmenti.

Lab Studies:
 

• Chromosomal analysis

• Blood karyotype is indicated, especially when systemic abnormalities are present.

• Fibroblast karyotyping by sampling the dark and light skin can demonstrate mosaicism, but this is not mandatory for the diagnosis.

Imaging Studies:

• Neuroradiological abnormalities are registered in at least one third of the patients. Because of the nature of the lesions, many being dysplastic or neuroblastic migration abnormalities (see below), MRI is more valuable than computerized tomography.

• One of the most common findings is an increase in the T2 signal of white matter. White matter abnormalities are somewhat predictive of a poor neurological outcome. Neuroblast migration includes heterotopia, pachygyria, and polymicrogyria. Heterotopia may be observed at the level of the basal ganglia or as a periventricular band. Some of the dysplastic lesions may be quite localized, and hemimegalencephaly also is visualized.

• Cerebral atrophy is documented, which can be unilateral or generalized. Cases of cerebral hemiatrophy and porencephaly often are associated with a history of perinatal hypoxia or low birth weight.

• Other rare imaging associations include the following:

• Noncommunicating hydrocephalus
• Megacisterna magna
• Arteriovenous malformation
• Cerebellar hypoplasia (hemispheres and vermis)
• Brainstem hypoplasia
• Brain tumors: MRI rarely demonstrates brain tumors; thus, patients occasionally may have abnormal MRI findings but be neurologically normal.

• Brain imaging in patients with HI and medically refractory epilepsy: The area of generating seizures (zone of ictal onset) should be found with a prolonged video-EEG, single-photon emission computed tomography (SPECT) or positron emission tomography (PET), and high-resolution MRI. If resective epilepsy surgery is still a serious consideration after the preliminary tests are done (video-EEG, SPECT or PET) and the zone of ictal onset could not be determined, the patient may need invasive EEG monitoring with subdural grids or strips.

• Other imaging tests

• Musculoskeletal abnormalities often require radiograph examination for proper quantification. A CT scan of the chest may be necessary when investigating mediastinal tumors.

• Abdominal ultrasound may be required for diagnosis of genitourinary anomalies such as single kidney and urethral duplication.

Other Tests:

• In patients with seizures, an EEG is indicated to show focal discharges and slowing.

• Most patients with cardiac anomalies require an ECG.

Procedures:

• Biopsies of affected and nonaffected skin sometimes are indicated.

• In select patients with cardiac anomalies, cardiac catheterization is recommended for proper diagnosis.

Histologic Findings: DOPA staining of the skin may show decreased size and number of melanosomes in hypopigmented areas. The melanocytes may be smaller and fewer, and their dendrites are short and sparse. Melanin incontinence (ie, absence of melanin in the epidermis but present in deeper dermis) is not observed in HI. Histopathological alterations are not always typical, and normal histology is described in some cases. Neuropathological studies demonstrate polymicrogyria, disarray of cortical lamination, and heterotopic neurons in the white matter and giant cells.

Medical Care:

• No specific treatment is available for HI.

• Suggest consultation with an ophthalmologist for patients with ophthalmologic abnormalities.

• A nephrology consultation is recommended for patients with renal abnormalities.

• Suggest a consultation with an endocrinologist for patients with associated abnormalities.

• Patients with HI who were seen initially by a dermatologist may benefit from a neurological consultation; conversely, patients initially referred to a neurologist may benefit from a dermatological and genetics consultation. Always offer the patient and parents the option of genetic consultation.

• Refer patients who have seizures that are not completely controlled by anticonvulsant medications to an appropriate tertiary center with a comprehensive epilepsy program for proper evaluation (video-EEG, SPECT or PET, high-resolution MRI).

Diet:

• No dietary restrictions are indicated.

• Occasionally, patients with seizures who are unresponsive to anticonvulsant medication may benefit from using a high-fat low-carbohydrate diet (ie, the ketogenic diet).

Activity:

• No restriction in activity is recommended.

Deterrence/Prevention:

• No known method of prevention exists except for rare cases of familial HI. Because familial HI is autosomal dominant, genetic counseling is indicated as a way of preventing new cases in the same family. Nonetheless, most cases are a de novo occurrence.

Complications:

• Complications are almost indistinguishable from the manifestations of the disease.

• Seizures are a direct consequence of the cerebral malformations. Patients with seizures, especially those with infantile spasms, are at risk for mental retardation and autistic behavior. Screening carefully and following with cognitive testing is suggested. Because seizures often are difficult to control with anticonvulsant medications, patients who have intractable partial seizures with secondary generalization or infantile spasms are at risk for neurocognitive deterioration; therefore, workup should be completed at an epilepsy center.