NCBI Bookshelf. Incontinentia pigmenti IP is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system; it occurs primarily in females and on occasion in males. Characteristic skin lesions evolve through four stages:. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed.

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NCBI Bookshelf. Incontinentia pigmenti IP is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system; it occurs primarily in females and on occasion in males. Characteristic skin lesions evolve through four stages:. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed.

Neovascularization of the retina, present in some individuals, predisposes to retinal detachment. Neurologic findings including seizures, intellectual disability, and developmental delays are occasionally seen.

The diagnosis of IP is established in a proband with at least one major criterion characteristic skin lesion. Identification of a heterozygous IKBKG pathogenic variant in a female proband or a hemizygous IKBKG pathogenic variant in a male proband confirms the diagnosis if clinical features are inconclusive.

Prevention of secondary complications: Standard measures to reduce the risk of skin infection; evaluate for retinal detachment if vision decreases, strabismus appears, or head trauma occurs. Surveillance: Eye examination: monthly until age four months, then every three months from age four months to one year, every six months from age one to three years, and annually after age three years.

Assessment of neurologic function at routine visits with pediatrician, pediatric neurologist, or developmental pediatrician; routine evaluation by a pedodontist or dentist. Evaluation of relatives at risk: Identification of affected relatives by physical examination and retinal examination so that screening ophthalmology examinations can be performed.

IP is inherited in an X-linked manner. A male with somatic and germline mosaicism may transmit the IKBKG pathogenic variant to daughters females who inherit the pathogenic variant will be affected ; an affected male would not transmit an IKBKG pathogenic variant to sons.

Prenatal testing for pregnancies at increased risk is possible if the familial pathogenic variant has been identified. Incontinentia pigmenti IP should be suspected in individuals with characteristic clinical findings of the skin, teeth, hair, nails, eyes, and CNS, and family history as detailed below.

Note: Though the lesions classically occur in the indicated stages, more than one type of lesion may be present at any time. The locations of the lesions can vary from stage to stage. Note: 1 The presence of minor criteria supports the clinical diagnosis. The diagnosis of IP is established in a proband if at least one of the major criteria is present.

If clinical features are inconclusive, the diagnosis of IP can be established by identification on molecular genetic testing of one of the following:. The most efficacious molecular genetic testing approach is single- gene testing. Single- gene testing.

Targeted analysis for the common For more information on pseudogenes, click here. Note: In affected males, somatic mosaicism can result in failure to detect an IKBKG loss-of-function pathogenic variant. For this reason, molecular genetic testing of a tissue sample e. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

View in own window. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Three of 18 males with IP with somatic mosaicism for the common Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. Fusco et al [] reported a male with IP with somatic mosaicism for the c. Chang et al [] reported a male with the pathogenic variant c. Although no evidence of additional loci causing IP has been reported, there remain 4.

For them locus heterogeneity cannot be excluded [ Fusco et al ]. Skin biopsy for histopathology can be considered in affected individuals in whom an IKBKG pathogenic variant is not identified on molecular genetic testing. Incontinentia pigmenti IP is a disorder of the skin and its appendages, eye, and central nervous system CNS that occurs primarily in females and on occasion in males. The largest cohort of individuals with IP in whom the clinical and molecular diagnosis has been confirmed is reported in Fusco et al [].

See Figure 1 , Figure 2 , Figure 3 , and Figure 4. IP manifests in stages that evolve sequentially. The onset and duration of each stage vary among individuals, and not all individuals experience all four stages. The skin abnormalities that define each stage occur along lines of embryonic and fetal skin development known as Blaschko's lines see Figure 3. Blaschko's lines correspond with cell migration or growth pathways that are established during embryogenesis.

Like dermatomes, they are linear on the limbs and circumferential on the trunk. Unlike dermatomes, Blaschko's lines do not correspond to innervation patterns or spinal cord levels.

IP in an affected female; stage I: the blistering stage. Note that the blisters are not necessarily linear. IP in an affected female; stage II: the verrucous "warty" stage. The lesions do not necessarily arise in the same place as those of stage I. Alopecia may occur on the scalp and also on the trunk and extremities. Patchy alopecia of the scalp may correspond to areas of scarring left from blistering in stage I, but may also occur in individuals who have had no stage I or II lesions on the scalp.

Alopecia occurs in areas of skin hypopigmentation as part of stage IV skin changes. Scalp hair may be thin or sparse in early childhood. Hair may also be lusterless, wiry, and coarse, often at the vertex in a "woolly-hair nevus. Sparse eyelashes and eyebrows are also reported. Abnormalities include hypodontia too few teeth , microdontia small teeth , abnormally shaped teeth e.

Enamel and tooth strength are normal. Nails can be dystrophic i. These changes often resemble fungal infections of the nails. Dystrophic nails are most commonly associated with stage II. Central nervous system. The actual incidence of neurocognitive disability is unclear because mildly affected individuals without neurocognitive problems may not come to medical attention [ Phan et al ].

Neurocognitive disability is more common in simplex than in familial cases, presumably because mildly affected family members are identified. Males with IP are more likely than females to have neurologic abnormalities. The recognized frequency of breast abnormalities may be limited because reports tend to focus on prepubertal children.

Males with IP. Although IP has been identified as a "male-lethal" disease, there are well-documented affected males.

There are a few individual case reports published each year and intermittent reviews of the literature. The reasoning behind male lethality in IP is that male conceptuses that inherit an X chromosome with a mutated IKBKG gene lack the normal protein necessary for viability.

The precise mechanism of male lethality is unknown [ Hatchwell ], although mouse models suggest that liver failure plays a role [ Rudolph et al ].

Pathogenic variants that produce a milder form of the condition are always associated with immunodeficiency, known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency HED-ID , in males [ Fusco et al ]. Life expectancy. For persons without significant neonatal or infantile complications, life expectancy is considered to be normal. Reproductive fitness. Women with IP are at increased risk for pregnancy loss, presumably related to low viability of male fetuses.

It is common for women with IP to experience multiple miscarriages, often around the third or fourth month of gestation. Fertility does not otherwise appear to be impaired; conception of an unaffected fetus would be expected to result in an uncomplicated pregnancy and delivery. A group of pathogenic variants mainly located in exon 10 that result in impaired but not absent NF-kappaB signaling [ Fusco et al ] are associated with a milder IP phenotype in females and a lower risk of miscarriage of male fetuses.

Incontinentia pigmenti has high penetrance. Most persons with IP appear to express the phenotype within a few months after birth. Expressivity, however, is highly variable. In addition, the skin findings can resolve over time and may be indistinguishable from other skin conditions with age. Furthermore, the dental, hair, and nail abnormalities can be managed cosmetically such that an affected adult woman may not have clinically evident diagnostic findings on physical examination.

Some individuals with structural abnormalities of the X chromosome manifest swirled hyperpigmentation even though their X-chromosome abnormalities do not involve the IKBKG locus Xq This observation led to the designation of a separate condition, incontinentia pigmenti type I IP type I , with a suggested locus at Xp Detailed research failed to document consistent linkage to Xp11 or a consistent phenotype. Thus, the designation "IP type I" is thought to be incorrect [ Happle ].

The number of reported females and males continues to grow, especially with further delineation of the underlying molecular mechanisms. Public health birth defect surveillance systems put the birth prevalence of IP at 0. The female:male ratio is [Orphanet Report Series ]. Orphanet recently estimated prevalence at birth of 1.

They are caused primarily by missense variants although in-frame deletions, frameshifts, and splicing and other pathogenic variants are known within IKBKG that result in impaired, but not absent, nuclear factor-kappaB NF-kappaB signaling. A diagnosis other than incontinentia pigmenti IP should be considered when an individual has skeletal involvement other than secondary to neurologic deficit , gross neurologic deficit, severe alopecia, atypical hyperpigmentation, or gross hypopigmentation.

Body segment asymmetry is not usually associated with IP; however, one individual with IP and transverse terminal upper acromelia has been reported [ Hayes et al ].


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Incontinentia pigmenti

Incontinentia pigmenti is a condition that can affect many body systems, particularly the skin. This condition occurs much more often in females than in males. Incontinentia pigmenti is characterized by skin abnormalities that evolve throughout childhood and young adulthood. Many affected infants have a blistering rash at birth and in early infancy, which heals and is followed by the development of wart-like skin growths. In early childhood, the skin develops grey or brown patches hyperpigmentation that occur in a swirled pattern. These patches fade with time, and adults with incontinentia pigmenti usually have lines of unusually light-colored skin hypopigmentation on their arms and legs.

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