Incontinentia pigmenti: Description, Causes and Risk Factors:
Incontinentia pigmenti is an inherited disorder of skin pigmentation that is also associated with abnormalities of the teeth, skeletal system, eyes, and central nervous system (CNS). It is one of a group of gene-linked diseases known as neurocutaneous disorders.
In most cases, incontinentia pigmenti is caused by mutations in a gene called NEMO (NF-kappa-B essential modulator). The gene is also known as IKKgamma or IKBKG, which is its "official" gene name. It is involved in a cellular process known as "signal transduction" where signals from outside the cell are transmitted to the nucleus of the cell to alter gene expression.
The NEMO gene is of less than average size, spanning about 23 thousand base pairs. The NEMO gene produces a protein that is essential for cells, and defects in it result in Incontinentia pigmenti. Males with cannot survive without a functioning NEMO gene, and thus die in utero. In females, some cells have a normal functioning NEMO gene (from the normal X chromosome) while other cells have a defective NEMO gene. Currently, it is thought that the symptoms of incontinentia pigmenti in females result from cells with a defective NEMO gene in the affected tissue. Now that the gene has been found, this view can be tested. The normal function of NEMO is to allow cells to respond to outside signals, such as growth factors. In about 85% of families, the mutation in the NEMO gene that results in incontinentia pigmenti is identical, even though the families are unrelated. A portion of the NEMO gene is duplicated, and these duplicated parts can result in deletions that disrupt the NEMO gene's function. This is unusual in human genetic disorders (most of the time, the mutations are different in different families). The presence of a frequent mutation, however, allows for easier testing (see the testing page).
Males are more severely affected than females. Discolored skin is caused by excessive deposits of melanin (normal skin pigment). Most newborns with incontinentia pigmenti will develop discolored skin within the first two weeks.
Cutaneous findings are the most common manifestation of IP and usually represent the presenting signs. They are divided into four overlapping stages: (1) vesiculobullous, which favors the extremities during the first few months of life (but occasionally recurs during childhood in association with a febrile illness); (2) verrucous, which favors the distal extremities in patients one to six months of age (and sometimes adolescents); (3) hyperpigmented, which favors the trunk and intertriginous sites from three months of age through adolescence; and (4) hypopigmented/atrophic, which affects the calves in adolescents and adults. Stage 1 often features peripheral blood leukocytosis and eosinophilia as well as lesional eosinphilic spongiosis, and necrotic keratinocytes are prominent in stages 1 and 2. IP was named for the incontinent pigment that characterizes the gray-brown streaks of stage 3. Scarring alopecia (often swirled at the vertex) and nail dystrophy also can occur.
The extracutaneous manifestations of IP, which are less frequent than are the skin findings, are more likely to cause morbidity. Approximately one-third of patients have ocular involvement, which is characterized by retinal vascular abnormalities that can lead to visual loss during the first year of life. Infants with IP should be referred to a pediatric ophthalmologist for evaluation and close follow-up. CNS abnormalities also occur in one-third of IP patients and can include seizures, developmental delay, and spastic paresis. Neurodevelopmental status should be monitored, and a pediatric neurologist consulted if problems arise. Lastly, dental anomalies, such as delayed eruption, hypodontia and conical teeth affect 50-75 percent of patients, and early dental intervention can help to optimize outcomes
The pigmentation usually involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines. The discoloration fades with age. Neurological problems include loss of brain tissue (known as cerebral atrophy), the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex. About 20% of children with incontinentia pigmenti will have slow motor development, muscle weakness in one or both sides of the body, mental retardation, and seizures. They are also likely to have visual problems, including crossed eyes, cataracts, and severe visual loss. Dental problems are also common, including missing or peg-shaped teeth. A related disorder, incontinentia pigmenti achromians, features skin patterns of light, unpigmented swirls and streaks that are the reverse of Incontinentia pigmenti. Associated neurological problems are similar.
No incidence or prevalence data are available on incontinentia pigmenti in the US population. Incontinentia pigmenti is an uncommon disease. Up until 1987, only 700 cases had been reported in the literature. The disease is probably underreported because many mild or uncomplicated cases are likely unrecognized.
Infants with IP are born with streaky, blistering areas. When the areas heal, they turn into rough bumps. Eventually, these bumps go away, but leave behind darkened skin, called hyperpigmentation. After several years, the skin returns to normal. In some adults, there may be areas of lighter colored skin (hypopigmentation).
IP is associated with central nervous system problems, including:
Persons with IP may also have abnormal teeth, hair loss, and visual problems.
The doctor will perform a physical exam, look at the eyes, and test muscle movement.There may be unusual patterns and blisters on the skin, as well as bone abnormalities. An eye exam may reveal cataracts, strabismus (crossed eyes), or other problems.
When acute inflammatory skin changes are present, eosinophilia (?80%) may be seen in the peripheral blood. Evidence of neutrophil dysfunction (defects in chemotaxis), lymphocyte dysfunction (decreased proliferation in response to mitogen stimulation), and altered immunologic reactivity has been reported in some patients. Quantitative immunoglobulin levels and lymphocyte subpopulation counts are normal.
Head CT scanning and brain MRI may demonstrate cerebral edema, hydrocephalus, structural brain abnormalities, cerebral infarctions, and hypointense areas or hypoattenuation.
Magnetic resonance spectroscopy and angiography have demonstrated reduced cerebral blood flow and elevated cerebrospinal fluid lactate levels, consistent with cerebral ischemia secondary to cerebrovascular occlusive events.
Single-photon emission CT scanning may show decreased cerebral blood flow.
EEG is helpful for localizing CNS lesions and epileptogenic foci in patients with seizures.
Karyotype analysis is recommended in male infants with incontinentia pigmenti in order to detect Klinefelter syndrome (XXY syndrome).
Genetic testing for NEMO/IKK -gamma mutations is available.
Treatment is not usually required for the cutaneous lesions, although use of topical tacrolimus and topical corticosteroids has been reported to hasten the resolution of the inflammatory stage. The vesicles of the inflammatory stage should be left intact, and the skin should be monitored for the development of secondary bacterial infections. Emollients and topical antibiotics may be used as needed.
Oral hygiene and regular dental care is necessary, and dental restoration may be indicated.
Seizures should be treated with anticonvulsants. Additionally, routine neurodevelopmental assessments should be made, with referral to occupational and physical therapists as warranted.
Frequent ophthalmologic evaluations are required, especially during the first year of life, in order to diagnose and treat potential ophthalmologic complications. Abnormal retinal fibrovascular proliferation can be treated with xenon laser photocoagulation or cryosurgery. Retinal detachments may be treated using vitreoretinal surgery.
Consultation with the following specialists may be needed:
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
- General dentists.