Incontinentia pigmenti (IP) is a rare

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. ...

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

that affects the skin, hair, teeth, nails and central nervous system. It is named from its appearance under a microscope. The disease is characterized by skin abnormalities that begin in childhood, usually a blistering rash which heals, followed by the development of harder skin growths. The skin may develop grey or brown patches which fade with time. Other symptoms can include hair loss, dental abnormalities, eye abnormalities that can lead to vision loss and lined or pitted fingernails and toenails. Associated problems can include delayed development, intellectual disability, seizures and other neurological problems. Most males with the disease do not survive to childbirth. Incontinentia pigmenti is caused by a mutation in the ''

IKBKG NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the ''IKBKG'' gene. NEMO is a subunit of the IκB kinase complex that activates NF-κ ...

'' gene, which encodes the NEMO protein, which serves to protect cells against

TNF-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

-induced

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. A lack of IKBKG therefore makes cells more prone to apoptosis. There is no specific treatment; individual conditions must be managed by specialists.

Presentation

The

skin lesion A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this s ...

s evolve through characteristic stages: #

blister A blister is a small pocket of body fluid (lymph, serum, plasma, blood, or pus) within the upper layers of the skin, usually caused by forceful rubbing (friction), burning, freezing, chemical exposure or infection. Most blisters are filled wi ...

ing (from birth to about four months of age), # a

wart Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...

-like rash (for several months), # swirling macular

hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

(from about six months of age into adulthood), followed by # linear

hypopigmentation Hypopigmentation is characterized specifically as an area of skin becoming lighter than the baseline skin color, but not completely devoid of pigment. This is not to be confused with depigmentation, which is characterized as the absence of all pi ...

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...

, dental anomalies, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to

retinal detachment Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...

in early childhood. Cognitive delays or

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

are occasionally seen. The discolored skin is caused by excessive deposits of

melanin Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...

(normal skin

pigment A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...

). Most newborns with IP will develop discolored skin within the first two weeks. The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines. The discoloration sometimes fades with age. Neurological problems can include

cerebral atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...

, the formation of small cavities in the central white matter of the brain, and the loss of

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

in the

cerebellar cortex The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...

. About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, intellectual disability, and seizures. They are also likely to have visual problems, which can include:

crossed eyes Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

, and severe visual loss. Dental problems are also common, and can include

hypodontia Hypodontia is defined as the developmental absence of one or more teeth excluding the third molars. It is one of the most common dental anomalies, and can have a negative impact on function, and also appearance. It rarely occurs in primary teet ...

, abnormally shaped teeth, and delayed

tooth eruption Tooth eruption is a process in tooth development in which the teeth enter the mouth and become visible. It is currently believed that the periodontal ligament plays an important role in tooth eruption. The first human teeth to appear, the decidu ...

. Breast anomalies can occur in 1% of patients and can include

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.supernumerary nipples. Skeletal and structural anomalies can occur in approximately 14% of patients, including: * Somatic asymmetry *

Hemivertebrae Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condi ...

Scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

Spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, me ...

Syndactyly Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, ''syn'' 'together' and δάκ� ...

* Acheiria (

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

absence of the hands—note: other limbs may be affected) * Ear anomalies * Extra ribs * Skull deformities

Genetics

IP is inherited in an X-linked dominant manner. IP is lethal in most, but not all, males. A female with IP may have inherited the IKBKG mutation from either parent or have a new gene mutation. Parents may either be clinically affected or have germline

mosaicism Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...

. Affected women have a 50% risk of transmitting the mutant IKBKG allele at conception; however, most affected male conceptuses miscarry. Thus, the effective ratio for liveborn children from a mother carrying the mutation is 33% unaffected females, 33% affected females, and 33% unaffected males.

Genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...

, prenatal testing, and

preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal ...

is available. In females, the cells expressing the mutated IKBKG gene due to

lyonization X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...

selectively die around the time of birth, so the X-inactivation is extremely

skewed In probability theory and statistics, skewness is a measure of the asymmetry of the probability distribution of a real-valued random variable about its mean. The skewness value can be positive, zero, negative, or undefined. For a unimoda ...

. IP is caused by mutations in a gene called NEMO (

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

essential modulator).

Diagnosis

The diagnosis of IP is established by clinical findings and occasionally by corroborative skin biopsy. Molecular genetic testing of the NEMO

gene (chromosomal locus Xq28) reveals disease-causing mutations in about 80% of probands. Such testing is available clinically. In addition, females with IP have skewed X-chromosome inactivation; testing for this can be used to support the diagnosis. Many people in the past were misdiagnosed with a second type of IP, formerly known as IP1. This has now been given its own name: 'Hypomelanosis of Ito' ( incontinentia pigmenti achromians). This has a slightly different presentation: swirls or streaks of hypopigmentation and depigmentation. It is ''not'' inherited and does not involve skin stages 1 or 2. Some 33–50% of patients have multisystem involvement—eye, skeletal, and neurological abnormalities. Its chromosomal locus is at Xp11, rather than Xq28.

Treatment

There does not yet exist a specific treatment for IP. Treatment can only address the individual symptoms.

History

This disorder was first reported by Swiss dermatologist Bruno Bloch in 1926 and American dermatologist

Marion Sulzberger Marion Baldur Sulzberger (12 May 1895 - 23 November 1983) was an American dermatologist known for major contributions in his discipline. In 1928, 2 years after the Swiss dermatologist Bruno Bloch, he published a paperSulzberger MB. Ueber eine bish ...

in 1928.

References

External links

GeneReview/NIH/UW entry on Incontinentia Pigmenti
{{DEFAULTSORT:Incontinentia Pigmenti Eosinophilic cutaneous conditions X-linked dominant disorders Enzyme defects Syndromes affecting the nervous system Rare diseases