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Incontinentia Pigmenti

Bloch-Sulzberger Syndrome

, MD, FAAP, FACMG and , PhD.

Author Information
, MD, FAAP, FACMG
Tesserae Genetics
Texas Department of State Health Services
Birth Defect Epidemiology and Surveillance Branch
Texas Center for Birth Defects Research and Prevention
Dallas, Texas
, PhD
Department of Molecular and Human Genetics
Institute of Genetics and Biophysics
National Research Council
Naples, Italy

Initial Posting: ; Last Update: October 28, 2010.

Summary

Disease characteristics. Incontinentia pigmenti (IP) is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system. Characteristic skin lesions evolve through four stages: I. blistering (birth to age ~4 months); II. a wart-like rash (for several months); III. swirling macular hyperpigmentation (age ~6 months into adulthood); and IV. linear hypopigmentation. 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 cognitive delays/intellectual disability are occasionally seen.

Diagnosis/testing. The diagnosis of IP is based on clinical findings and molecular genetic testing of IKBKG (previously NEMO), the only gene known to be associated with IP. A deletion that removes exons 4 through 10 of IKBKG is present in about 80% of affected individuals.

Management. Treatment of manifestations: Standard management of blisters and skin infections; cryotherapy and laser photocoagulation of retinal neovascularization to reduce risk of retinal detachment; standard management of retinal detachment; neurologic assessment for microcephaly, seizures, spasticity, or focal deficits; brain MRI for functional neurologic abnormalities and/or retinal neovascularization; dental care by a pedodontist; dental implants in childhood as needed; care by a speech pathologist and/or pediatric nutritionist if dental abnormalities interfere with chewing and/or speech; developmental programs and special education as needed for developmental delay.

Prevention of secondary complications: 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: Identify young affected relatives by physical examination and retinal examination so that routine eye examinations can be performed on those found to have IP.

Other: Topical and systemic steroids have no effect on the early stages of the rash.

Genetic counseling. IP is inherited in an X-linked manner. IP is an embryonic lethal in many males. Affected surviving males have been found with 47,XXY karyotype or somatic mosaicism for the common IKBKG deletion. A female with IP may have inherited the IKBKG mutation from the mother or have a de novo mutation. Parents may either be clinically affected or be unaffected but have germline mosaicism. Affected women have a 50% chance of transmitting the mutant IKBKG allele at conception; however, male conceptuses with a loss-of-function mutation of IKBKG miscarry. Thus, the expected ratio among liveborn children is approximately 33% unaffected females, 33% affected females, and 33% unaffected males. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family has been identified.

Diagnosis

Clinical Diagnosis

No strict diagnostic criteria for incontinentia pigmenti (IP) exist. Establishing the diagnosis relies on detection of the characteristic clinical findings of the skin, teeth, hair, and nails.

The clinical diagnosis of IP can be made if at least one of the major criteria is present.

The presence of minor criteria supports the clinical diagnosis; the complete absence of minor criteria should raise doubt regarding the diagnosis [Landy & Donnai 1993].

Family history consistent with X-linked inheritance or a history of multiple miscarriages also supports the diagnosis.

Major criteria (skin lesions that occur in stages from infancy to adulthood)

  • Erythema followed by blisters (vesicles) anywhere on the body except the face, usually in a linear distribution. The blisters clear within weeks and may be replaced by a new crop. Erythema occurs in stage I (first weeks of life to age four months)
  • Hyperpigmented streaks and whorls that respect Blaschko's lines, occurring mainly on the trunk and fading in adolescence; stage III (age four months to 16 years)
  • Pale, hairless, atrophic linear streaks or patches; stage IV (adolescence through adulthood)

Minor criteria

  • Teeth. Hypodontia or anodontia (partial or complete absence of teeth), microdontia (small teeth), abnormally shaped teeth
  • Hair. Alopecia, woolly hair (lusterless, wiry, coarse)
  • Nails. Mild ridging or pitting; onychogryposis (hypertrophied, curved nails)
  • Retina. Peripheral neovascularization

Testing

Peripheral blood. Leukocytosis with up to 65% eosinophils may occur, particularly in stages I and II. The cause of the leukocytosis is unknown.

Skin biopsy

  • Affected females. Histologic examination of a skin biopsy to confirm the diagnosis in a female is now rarely needed given the widespread availability and sensitivity of molecular genetic testing (see Molecular Genetic Testing). Nonetheless, skin biopsy to evaluate for eosinophilic infiltration and/or extracellular melanin granules may be helpful in confirming the diagnosis in a female with borderline or questionable findings in whom molecular genetic testing has not identified a disease-causing mutation.
  • Affected males. In affected males, somatic mosaicism can make detection of IKBKG loss-of-function mutation problematic. For this reason, molecular genetic testing of a tissue sample, such as skin from an affected/involved site, may be needed if no mutation is identified by molecular genetic testing of a blood sample. The detection frequency of somatic mosaicism for a loss-of-function IKBKG mutation may vary among tissues.

Molecular Genetic Testing

Gene. IKBKG (previously NEMO) is the only gene known to be associated with IP.

Clinical testing

  • Targeted mutation analysis. Approximately 65% (500/770) of affected females have an approximately 11.7-kb deletion (c.399-?_1260+?del) that removes exons 4 through 10 of IKBKG [Fusco et al 2008 and references therein].
  • Sequence analysis. In addition to the common 11.7-kb deletion, other small intragenic IKBKG mutations have been found in persons with IP (in the study by Fusco et al [2008], 8.6% of females;16/166). Small intragenic substitutions, deletions, and duplications are scattered throughout the IKBKG gene; however, there is a cluster of recurrent mutations in exon 10, which is extremely GC rich [Fusco et al 2008]. Exon 10 intragenic deletions and duplications that involve the mononucleotide tract of seven cytosines have also been reported [Aradhya et al 2001b, Fusco et al 2008].
  • X-chromosome inactivation studies. Females with IP have skewed X-chromosome inactivation in which the X chromosome with the mutant IKBKG allele is preferentially inactivated [Parrish et al 1996].

    Note: In individuals with IP, skewed X-chromosome inactivation has been demonstrated only in blood specimens; X-chromosome inactivation patterns in other tissues have not been studied.

Table 1. Summary of Molecular Genetic Testing Used in IP

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected Males Affected Females
IKBKGTargeted mutation analysis ~11.7-kb common deletion3/18 (16%) 2 ~65% 3
Sequence analysis 4, 5Sequence variants 6 Unknown (1167insC) 7 ~8.6% 3

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Three of 18 males with IP with somatic mosaicism for the common 11.7kb deletion [Fusco et al 2007]

3. Fusco et al [2008]

4. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in females.

5. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in males; confirmation may require targeted mutation analysis for the common deletion or additional testing by deletion/duplication analysis.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

7. Chang et al [2008] reported a male with the mutation c.1167dupC (also known as 1167insC); he is the only male known to have both HED-ID (hypohidrotic ectodermal dysplasia and immunodeficiency) and the skin findings of IP.

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • Because non-random X-chromosome inactivation is not unique to IP, results of X-chromosome inactivation studies are supportive only and need to be interpreted in the context of clinical findings and/or family history.
  • Failure to identify an IKBKG mutation does not rule out the diagnosis of IP.

Testing Strategy

To confirm/establish the diagnosis in a male or female proband

  • To make a presumptive diagnosis, clinical evaluation including the history of skin abnormalities; detailed family history
  • For supportive findings, evaluation for eosinophilia
  • To confirm the diagnosis, molecular genetic testing:
    • Targeted mutation analysis to identify the common 11.7-kb IKBKG deletion
    • Complete IKBKG sequencing in individuals who meet diagnostic criteria but do not have the common deletion
    • In affected individuals in whom a IKBKG mutation is not identified by the above methods:
      • Females. The following investigations could be pursued in either order:

        1. X-chromosome inactivation studies in leukocytes. Note: Although skewing of X-chromosome inactivation suggests involvement of an X-linked gene, it is not specific for IP.

        2. Skin biopsy of an affected area for histologic examination and/or molecular testing of IKBKG
      • Males. Molecular genetic testing of a second tissue (e.g., skin from an involved site) for evidence of somatic mosaicism for the common IKBKG deletion

The following additional studies should be considered in males with IP:

  • A karyotype to look for evidence of 47,XXY, estimated to be present in approximately 7% of males with IP [Pacheco et al 2006]
  • Interphase fluorescence in situ hybridization (FISH) studies using X and Y chromosome-specific probes to look for evidence of 46,XY/47,XXY mosaicism

Testing for at-risk female relatives who may have few or no clinical findings of IP requires:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Incontinentia pigmenti (IP) is a disorder of the skin, eye, and central nervous system (CNS) that occurs primarily in females and on occasion in males. Affected females have an erythematous, vesicular rash that appears at birth or soon thereafter. The rash evolves over time, becoming verrucous and pigmented, and then atrophic. Adults have areas of linear hypopigmentation. Other manifestations include alopecia, hypodontia/misshapen teeth, leukocytosis with eosinophilia, vascular abnormalities of the retina, and other eye findings. Occasionally, skeletal anomalies, seizures, and intellectual disability are observed.

Recent reports of more than 700 females and 60 males with IP support and expand previous descriptions of the disease [Hadj-Rabia et al 2003, Phan et al 2005, Ardelean & Pope 2006, Kim et al 2006, Pacheco et al 2006, Badgwell et al 2007, Fusco et al 2007, Fusco et al 2008]; the recent reports rely on standardized diagnostic criteria and are thus less likely than older reports to include persons with alternate diagnoses. To date, as many as 1200 persons with IP have been reported; however, it is not clear if the same individual has been reported more than once. Also, many reports do not include molecular confirmation.

Skin. See Figures 1, 2, and 3. 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 2). 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.

Figure 1

Figure

Figure 1. IP in an affected female; stage I, the blistering stage. Note that the blisters are not necessarily linear.

Figure 2

Figure

Figure 2. IP in an affected female with stage III "rash"

Figure 3

Figure

Figure 3. An adult with reticulated pigmentation patterns

  • Stage I – The bullous stage is characterized by blister-like bullous eruptions (Figure 1) that are linear on the extremities and/or circumferential on the trunk. The eruptions can be erythematous and may appear infectious. Stage I manifests within the first six to eight weeks and can be present at birth. The stage I rash generally disappears by age 18 months, although a vesicobullous eruption was reported in a five-year-old girl who was already manifesting the stage IV rash [Darne & Carmichael 2007].
  • Stage II – The verrucous stage is characterized by a hypertrophic, wart-like rash that is linear on the extremities and/or circumferential on the trunk. This stage manifests within the first few months of life. It can occasionally be present at birth but typically arises as stage I begins to resolve. Stage II usually lasts for a few months, but it can last for years. Stage II can also include the appearance of dystrophic nails and abnormalities of tooth eruption.
  • Stage III – The hyperpigmentation stage is characterized by macular, slate grey, or brown hyperpigmentation that occurs in a "marble cake" or swirled pattern along Blaschko's lines, usually circumferential on the trunk and linear on the extremities (see Figure 2). The hyperpigmentation stage is the most characteristic stage for IP. Not all women have extensive hyperpigmentation; it can be quite limited. The most frequently involved areas are the groin and axilla. The entire skin surface may need to be examined to find characteristic patterns. Hyperpigmentation begins between age six months and one year, usually as stage II begins to resolve. It is NOT present at birth. Stage III persists into adulthood. The hyperpigmentation usually begins to fade in the teens and early twenties (see Figure 3). The pigmentation changes can be linear, swirled, or reticulated. A woman in her thirties or later may show no skin changes associated with IP.
  • Stage IV – The atretic stage is characterized by linear hypopigmentation and alopecia, particularly noticeable on the extremities and, when it happens, on the scalp. Phan et al [2005] noted stage IV lesions on the calves of 92% of 53 individuals. The definition of stage IV remains open. There may not be true hypopigmentation, but rather a loss of hair and epidermal glands. As with the first three stages, the pattern follows Blaschko's lines. Stage IV does not occur in all individuals. When present, it arises after the hyperpigmentation fades.

Hair. 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." Areas of alopecia may be very small, unnoticed by the affected individual and difficult to find, particularly when covered by other scalp hair. Sparse eyelashes and eyebrows are also reported.

Breast. Abnormalities of mammary tissue ranging from aplasia of the breast to supernumerary nipples are variably present. Badgwell et al [2007] reported supernumerary nipples, athelia, or nipple asymmetry in 11% of individuals in their series, while abnormalities of breast tissue were not reported in three other large series of affected females [Hadj-Rabia et al 2003, Phan et al 2005, Kim et al 2006]; two of the latter reports, however, focused on prepubescent children.

Teeth. Abnormalities include hypodontia (too few teeth), microdontia (small teeth), abnormally shaped teeth (e.g., conical teeth or accessory cusps), delayed eruption, or impaction. Enamel and tooth strength are normal. Wu et al [2005] noted a longer crown, shorter root, and "tulip shape" of the permanent maxillary central incisors in two persons. Three persons were noted to have a high palate [Minic et al 2006].

Nails. Nails can be dystrophic (i.e., lined, pitted, or brittle). These changes often resemble fungal infections of the nails. Dystrophic nails are most commonly associated with stage II. The nail changes may be transient, but a single, chronic, longitudinal ridge in the nail was present in 28% of persons in one study [Phan et al 2005].

Central nervous system. Historically, seizures, intellectual disability, and other CNS abnormalities have been reported in as many as 30% of individuals with IP; however, in cases reported prior to availability of genetic testing, it is difficult to know if IP was the appropriate diagnosis. The true prevalence of CNS abnormalities is lower in more recent cohorts. Males with IP are more likely than females to have neurologic abnormalities.

CNS findings were described in four retrospective studies:

  • In 47 children, Hadj-Rabia et al [2003] found severe neurologic abnormalities in 7.5%.
  • In 53 individuals, Phan et al [2005] noted seizures in 11 (23%) of the 47 on whom history was available, and intellectual deficit in four (who also had eye abnormalities). Of note, seizures and intellectual deficit were found only in probands; all relatives with IP ascertained through family history were neurologically normal.
  • In 38 females, Kim et al [2006] identified seven (18%) with seizures (1 with infantile spasms), four with cerebral palsy, and one with both. Additionally, one had leukomalacia.
  • In 198 individuals with IP, Badgwell et al [2007] reported CNS involvement in 28%; only nine percent had severe disabilities such as intellectual disability and/or significant motor impairment. One third had minor and transient CNS abnormalities such as uncomplicated neonatal seizure. The remaining individuals had mild developmental delay or unilateral hemiparesis.
  • In 60 individuals with IP, Fusco et al [2004] reported CNS involvement (i.e. seizures, spastic paresis, motor and intellectual disability, and microcephaly) in 13%.

In a prospective study of 12 individuals who had an MRI at diagnosis and again as indicated by their clinical course, Pascual-Castroviejo et al [2006] determined that:

  • The five girls who had functional neurologic abnormalities also had brain abnormalities. The lesions were present at birth, did not correspond to a vascular watershed, and did not progress. The authors noted a direct correlation between the brain lesions, stage I scalp lesions, and ocular abnormalities.
  • The seven who were functionally normal had no brain abnormalities.

Triki et al [1992] and Wolf et al [2005] reported neonates with an encephalitis-like presentation and impressive cortical necrosis. One child had apnea on the second day of life associated with MRI changes. Repeat MRI in that child at age five months showed cystic lesions, atrophic basal ganglia, and no progress in myelination. Abe et al [2010] reported a child who presented at age two months with seizures and encephalopathy; brain MRI was abnormal.

Retina. Individuals with IP have an increased risk of retinal detachment. The greatest risk for retinal detachment is in infancy and childhood; it almost never occurs after age six years. Retinal detachment is preceded by neovascularization in the peripheral retina, which is often followed by exudation and/or fibrosis. These changes are visible on indirect ophthalmoscopy through a dilated pupil.

In a study of 30 affected individuals, 77% had some ophthalmologic manifestation of IP, including 43% with vision-threatening problems [Holmstrom & Thoren 2000]. Serious findings included retinal detachment, phthisis bulbi, retinal ridges, severe myopia, optic atrophy, and strabismus. Less serious findings were retinal pigment epithelial (RPE) defects and corneal opacities. The study suggests a higher incidence of eye problems than previously reported.

Ophthalmologic findings were described in four retrospective studies:

  • In 47 children, Hadj-Rabia et al [2003] found ocular abnormalities in 20%; the problems were severe in 8%.
  • In 53 individuals, Phan et al [2005] determined that the four with intellectual deficit also had ocular abnormalities, suggesting that abnormalities of retinal vascularization may be a marker for other neurologic abnormalities.
  • In 40 individuals (38 female, 2 male), Kim et al [2006] found retinopathy in ten (25%) and strabismus or other ocular problems in seven (17.5%) additional individuals.
  • In 198 individuals, Badgwell et al [2007] reported eye abnormalities in 20%.
  • In 60 individuals, Fusco et al [2004] reported eye abnormalities (i.e., strabismus, cataracts, optic atrophy, retinal vascular or pigmentary abnormalities, and microphthalmia) in 22%.

Pascual-Castroviejo et al [2006] noted eye abnormalities only in those individuals who also had structural brain lesions.

Intellect. The majority of individuals with IP, both male and female, are intellectually normal [Hadj-Rabia et al 2003, Phan et al 2005, Kim et al 2006]. The incidence of intellectual disability or developmental delays in males who meet the IP diagnostic criteria is approximately 25%-35% in those studies that clearly report such findings [Scheuerle 1998, Ardelean & Pope 2006, Fusco et al 2007]. In both males and females, ocular abnormalities leading to significant vision problems may secondarily affect psychomotor development. In males, co-occurrence of a 47,XXY karyotype may complicate the intellectual phenotype of IP.

Other. Eosinophilia is not consistently associated with any clinical manifestations and typically resolves spontaneously.

Three girls with significant primary pulmonary hypertension did not have other cardiovascular defects [Triki et al 1992, Godambe et al 2005, Hayes et al 2005]. All had brain lesions and one had transverse terminal acromelia of the right hand. All three died of complications of pulmonary hypertension. The suggested mechanism is microvascular abnormalities in the lungs (autopsy was declined in two and the lung findings are not reported in the third).

Because of the role of IKBKG in regulating inflammation and immune response, mutations in the gene may interfere with either or both of these processes. In males with IP, immune dysregulation appears to be a significant feature of the phenotype. There are case reports of females with IP who have immune deficiency. Those who do not may be protected by skewed X-chromosome inactivation. Because syndrome delineation is fluid, it could be argued that the females with immune regulation abnormalities may not have IP.

Males with IP. Although IP has been identified as a "male-lethal" disease, more than 60 males who meet diagnostic criteria for IP have been reported. Survival in a male is mediated through one of three mechanisms:

  • 47,XXY karyotype, estimated to be present in 7% of males with IP [Pacheco et al 2006]
  • Somatic mosaicism
    • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [Franco et al 2006]. The affected child did not have a demonstrable IKBKG mutation.
    • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism.
    • Eighteen males showed the characteristic clinical features and, when examined, histologic skin defects. Six also had neurologic, ophthalmologic, and/or dental manifestations [Fusco et al 2007].
  • Mutations 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 2008]. Only one male has been reported with HED-ID and also clinical findings of IP in association with the 1167insC IKBKG variant [Chang et al 2008].

Life expectancy. For persons without significant neonatal or infantile complications, life expectancy is considered to be normal.

Reproductive fitness. Women with IP have a higher than usual risk of 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 seem to be impaired; conception of an unaffected fetus would be expected to result in an uncomplicated pregnancy and delivery.

Pathophysiology. Evidence that IKBKG mutations may cause abnormalities in microvasculature supports the theory that CNS dysfunction is secondary to vascular problems that result in transient ischemic attacks or full-blown hemorrhagic strokes [Fiorillo et al 2003, Hennel et al 2003, Shah et al 2003]. However, other studies fail to show a relationship between brain abnormalities and vascular patterns.

The protein encoded by IKBKG functions in an immune system pathway. It thus follows that immunodeficiency could be part of the IP phenotype. To date, however, immune system abnormalities in IP have not been well studied or established. It seems that the absence of immune system abnormalities in females with IP would most likely be the result of skewed X-chromosome inactivation in blood cells.

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 1996], although mouse models suggest that liver failure plays a role [Rudolph et al 2000].

Genotype-Phenotype Correlations

Small IKBKG gene mutations, mainly in exon 10 (including missense, single base insertion/deletion causing frameshift, and nonsense mutations), are associated with a milder IP phenotype in females and a lower risk of miscarriage of male fetuses. Indeed, most of these variants allow survival of males with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) and HED-ID with osteopetrosis and lymphedema (OL-HED-ID) (see Genetically Related Disorders). These mutations result in impaired but not absent NF-kappaB signaling [Fusco et al 2008].

Penetrance

Incontinentia pigmenti has high penetrance. Most persons with IP appear to express the phenotype within a few months of age.

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 so that an affected adult woman may not have clinically evident diagnostic findings on physical examination.

Nomenclature

Some individuals with structural abnormalities of the X chromosome manifest swirled hyperpigmentation even though their X-chromosome abnormalities do not involve the IKBKG locus (Xq28). This observation led to the designation of a separate condition, incontinentia pigmenti type I (IP type I), with a suggested locus at Xp11. 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 1998].

The clinical manifestations of individuals with structural abnormalities of the X chromosome that overlap with IP are more likely caused by X-chromosome inactivation resulting from physical disruption of the X chromosome itself (deletion, translocation) than by mutation of a specific gene.

Prevalence

The prevalence of IP is unknown. IP is referred to as "rare" or "uncommon." Approximately 900-1200 affected individuals have been reported in the medical literature to date. It is unknown whether each case reported represents a unique individual because of the number of large retrospective studies. Since the discovery of IKBKG as the gene in which mutation is causative, about 700 females have had confirmatory molecular genetic testing.

Differential Diagnosis

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 2005].

The differential diagnosis for the skin manifestations of IP varies by stage. Because a child with IP may have an infectious comorbidity, findings consistent with an infectious disease should be evaluated accordingly, regardless of the presence of IP.

  • Stage I – blistering stage. The following need to be considered [Wagner 1997]: congenital herpes simplex, varicella, staphylococcal or streptococcal bullous impetigo, and (in severe cases) epidermolysis bullosa (see Dystrophic Epidermolysis Bullosa, Epidermolysis Bullosa Simplex). The infectious conditions are typically associated with other signs of inflammation including fever and symptoms of systemic toxicity. Scrapings and cultures of the lesions are diagnostic for the infectious diseases. Blistering lesions that appear after light trauma are characteristic of epidermolysis bullosa. Diagnosis is established by analysis of a skin biopsy, transmission electron microscopy or immunofluorescent antibody/antigen mapping, and molecular genetic testing.
  • Stage II – verrucous stage. The findings are not likely to be confused with other conditions, although a mild case of IP may resemble simple warts or molluscum contagiosum. When the lesions are numerous and appear in the appropriate pattern, they are more likely to be IP than either warts or molluscum contagiosum. Differentiating single IP lesions from warts can be difficult without a biopsy.
  • Stage III – hyperpigmented stage. The differential diagnosis includes any condition that leads to irregular areas of skin pigmentation or other anomalies along the lines of Blaschko [Nehal et al 1996].

    The most commonly confused diagnosis is hypomelanosis of Ito, which can demonstrate the same "swirled" pigmentation pattern [Happle 1998]. The most significant difference is that in individuals with IP the hyperpigmented areas are abnormal, whereas in hypomelanosis of Ito hypopigmentation is typical but patches of hyperpigmentation can also be observed. Hypomelanosis of Ito is often the result of chromosomal mosaicism. Individuals with chromosomal mosaicism often have intellectual disability and congenital malformations, including brain anomalies. Reports of individuals with hypomelanosis of Ito having IP may account for the higher incidence of intellectual disability and CNS anomalies reported in individuals with IP than in those identified in large series [Scheuerle, unpublished]. Individuals with findings suggestive of hypomelanosis of Ito warrant evaluation for chromosomal mosaicism by a blood karyotype, and if that is normal, by skin fibroblast karyotype [Nehal et al 1996].
  • Stage IV – atretic stage. The atretic skin areas can resemble scarring, vitiligo (with localized alopecia), or any other condition demonstrating hypopigmentation and localized alopecia. Differentiation is based largely on medical history. Vitiligo is progressive and the hypopigmented areas can be surrounded by areas of hyperpigmentation. Vitiligo is not preceded by the other stages of IP or accompanied by non-cutaneous manifestations. Piebaldism, an autosomal dominant form of hypopigmentation in which manifestations are limited to the skin, is most often present at birth and does not progress.

The differential diagnosis of other manifestations of IP includes the following disorders:

  • Naegeli syndrome, a rare autosomal dominant disorder affecting the skin and skin derivatives, resembles IP, but also includes hyperhidrosis and punctate hyperkeratosis of the palms and soles. Unlike IP, Naegeli syndrome does not evolve through different stages of skin involvement. Naegeli syndrome is extremely rare; an individual with linear, wart-like lesions is more likely to have IP.
  • Retinal neovascularization is observed in retinopathy of prematurity and familial exudative vitreoretinopathy, which can be inherited in an X-linked recessive manner as part of the Norrie disease spectrum (see NDP-Related Retinopathies) or in an autosomal dominant manner (see Autosomal Dominant Familial Exudative Vitreoretinopathy). Skin findings are not present in these disorders.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with incontinentia pigmenti (IP), the following evaluations are recommended:

  • Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the presence and extent of manifestations
  • Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal neovascularization
  • EEG and MRI if seizures, other neurologic abnormalities, or retinal hypervascularization are present [Wolf et al 2005, Pascual-Castroviejo et al 2006]
  • Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is consistent with a stroke-like pattern
  • Developmental screening, with further evaluation if significant delays are identified

Treatment of Manifestations

Treatment includes the following:

  • Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g., medications, oatmeal baths) to relieve discomfort
  • Treatment of infections as for any other cellulitis
  • For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation [Wong et al 2004]
  • Standard treatment for retinal detachment
  • Referral to a pediatric neurologist for evaluation if microcephaly, seizures, spasticity, or focal deficits are present
  • Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization [Wolf et al 2005, Pascual-Castroviejo et al 2006]
  • Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental problems (see Hypohidrotic Ectodermal Dysplasia).
  • Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth interferes with chewing and/or speech development
  • Appropriate developmental stimulation and special education as indicated for developmental delay

Prevention of Secondary Complications

Management in the newborn period is aimed at reducing the risk of infection of blisters using standard medical management: not rupturing sealed blisters, keeping the areas clean while they are healing, and careful monitoring for excessive inflammation and signs of systemic involvement.

The parents should be instructed about the possibility of retinal detachment particularly in children younger than age seven years; any apparent changes in vision or any evidence of acquired strabismus should be evaluated promptly. Head trauma may precipitate retinal detachment; therefore, any evaluation for head trauma should include a thorough eye examination.

Surveillance

No schedule for eye examinations has been established, but the following has been suggested [Holmstrom & Thoren 2000]:

  • Monthly until age three to four months
  • Every three months between ages four months and one year
  • Every six months between ages one and three years
  • Annually after age three years

Neurologic function should be assessed at routine visits with a pediatrician, pediatric neurologist, or developmental pediatrician.

Ongoing evaluation by a pedodontist or dentist is appropriate.

Evaluation of Relatives at Risk

Physical examination including examination of the retina should be performed on young at-risk relatives to identify those who are affected so that routine eye examinations can be performed on those found to have IP.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Topical and systemic steroids have been prescribed in an attempt to limit the stage I and II rashes. Case reports have described the use of various topical therapies [Kaya et al 2009, Jessup et al 2009]; however, no controlled clinical trials of topical therapies for IP have been conducted.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Incontinentia pigmenti (IP) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • When the mother of an affected female is also affected, the risk to sibs of inheriting the mutant IKBKG allele at conception is 50%; however, most male conceptuses with loss-of-function mutation of IKBKG miscarry. Thus, at delivery the expected ratio among offspring is approximately 33% unaffected females, 33% affected females, and 33% unaffected males.
  • When a mother with IP has an IKBKG mutation that has reduced, but not absent, activity, male conceptuses may survive and manifest EDA-ID at birth. Note: A mother with IP and the common 11.7-kb deletion (which abolishes activity) is not at increased risk of having a liveborn child with EDA-ID.
  • If neither parent has IP or an IP-related IKBKG mutation, the risk to the sibs of a proband of having IP is less than 1%. Two possibilities account for the small increased risk:
  • Germline mosaicism can occur in either parent of a female with IP. De novo mutation in IKBKG is common: 59 of 91 females (65%) with IP and the common 11.7-kb deletion had a de novo mutation [Fusco et al 2009].

Offspring of a proband (see Figure 4)

Figure 4

Figure

Figure 4. Genotype of conceptuses compared with genotype of liveborn children

  • Affected females
    • The risk to the offspring of females with IP must take into consideration the presumed lethality to affected males during gestation (Figure 4).
    • At conception, the risk that the mutant IKBKG allele will be transmitted is 50%; however, most male conceptuses with a loss-of-function mutation of IKBKG miscarry. Thus, at delivery the expected ratio among offspring is approximately 33% unaffected females, 33% affected females, and 33% unaffected males.
    • When a mother with IP has an IKBKG mutation that has reduced, but not absent, activity, male conceptuses may survive and manifest EDA-ID at birth. Note: A mother with IP and the common 11.7-kb deletion (which abolishes activity) is not at increased risk of having a liveborn child with EDA-ID.
  • Affected males. To date, all males with IP have had somatic mosaicism for the IKBKG mutation. Because the mosaicism does not include the germline, IP transmission from an affected male to his daughter(s) does not occur.

Other family members of a proband. If a parent of the proband has a disease-causing mutation, his or her family members may be at risk of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family.

X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an IKBKG mutation that cannot be identified in the proband.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

As with many other genetic conditions, diagnosis of IP in a newborn may result in evaluation and diagnosis of the mother or other family members who were previously unaware of the presence of a genetic disorder in the family. The diagnosis of IP in a newborn can be difficult for the mother and her relatives because of implications for their health and because of a sense of "responsibility" for illness in their offspring. Efforts should be made to anticipate these issues.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an IKBKG mutation, or are at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Because the prognosis for affected females differs from that for affected males, the fetal karyotype must be determined for accurate genetic counseling. In addition, the disease-causing allele of an affected family member must be identified before prenatal testing can be performed:

  • If the fetal karyotype is 46,XX, parents should be informed that 50% of fetuses are likely to be affected with IP.
  • If the fetal karyotype is 46,XY, counseling should include discussion of the increased risk of miscarriage of affected males after the first trimester.
  • If the fetal karyotype is 47,XXY, counseling should include a discussion of the more severe IP phenotype in males and of Klinefelter syndrome.

Note: (1) The exon 10 duplication and point mutations which result in a milder phenotype are likely to have a lower risk for miscarriage (see Genotype-Phenotype Correlations). (2) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Incontinentia Pigmenti International Foundation (IPIF)
    30 East 72nd Street
    New York NY 10021
    Phone: 212-452-1231
    Fax: 212-452-1406
    Email: ipif@ipif.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Incontinentia Pigmenti: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Incontinentia Pigmenti (View All in OMIM)

300248INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE OF, GAMMA; IKBKG
308300INCONTINENTIA PIGMENTI; IP

Molecular Genetic Pathogenesis

The genomic organization around IKBKG is complex. Within IKBKG are two 870-bp direct repeats termed MER67B; one is in intron 3 and the second is downstream of IKBKG. A recombination between the MER67B regions results in a deletion of exons 4 through 10 of IKBKG. This is the 11.7-kb deletion that is common in individuals with IP (Table 2). Rearrangements between other complex repeated elements in the region account for normal (non-pathologic) allelic variants which are recurrent among the control population (1%-2% estimated frequency).

Normal allelic variants. The functional IKBKG gene is 22 kb away from an IKBKB pseudogene (IKBKGP1 or Delta-NEMO). The gene and pseudogene are arranged in an inverted fashion.

IKBKGP1 contains only exons 3-10 [Aradhya et al 2001a]. Recently, 10% to 12% of parents of individuals with IP were found to have two non-pathologic variants. One was the 11.7-kb deletion of exons 4-10 in the IKBKG pseudogene (IKBKGP1). The second was a duplication of MER67B that replicates the exon 4-10 region downstream of the normal IKBKG gene (termed MER67Bdup). Both variants were rare normal allelic variants in a control population [Fusco et al 2009]. These data suggest that the IP locus undergoes recombination producing recurrent variants that could be ‘‘at risk’’ of generating de novo in offspring the 11.7-kb pathologic deletion.

Pathologic allelic variants. The most common mutation in individuals with IP is an 11.7-kb deletion of exons 4 through 10 of IKBKG (see Molecular Genetic Pathogenesis).

Smaller mutations in IKBKG (mostly in exon 10) that have reduced but not absent activity have been reported [Zonana et al 2000, Aradhya et al 2001b, Döffinger et al 2001, Fusco et al 2008]. These mutations lead to milder disease in females and support survival of males who have hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) and HED-ID with osteopetrosis and lymphedema (OL-HED-ID) (Genotype-Phenotype Correlations). For more information, see Table A.

Table 2. Selected IKBKG Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.399-?_1260+?del
(common 11.7-kb deletion)
NM_003639​.3
NP_003630​.1
p.Glu390Argfs*5p.Glu390Argfs*5

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The 2.8-kb IKBKG cDNA encodes a 419-amino acid protein that is acidic and rich in glutamic acid and glutamine residues (each 13%), and contains a leucine zipper motif at amino acids 315-342 [Yamaoka et al 1998]. The IKK proteins — alpha, beta, and gamma — form a complex. The nuclear factor-kappaB (NF-kappaB ) essential modulator protein encoded by IKBKG is commonly known as IKK-gamma. The 419-amino acid IKK-gamma protein (NP_003630.1) is composed of a zinc finger domain and a leucine zipper motif. IKK-gamma forms dimers and trimers and interacts with IKK-beta and IKK-alpha [Rothwarf et al 1998, Li et al 1999, Hayden & Ghosh 2008].

The NF-kappaB essential modulator protein (IKK-gamma) is produced beginning in early embryogenesis and is expressed ubiquitously [Aradhya et al 2001c]. The normal product, in complex, activates NF-kappaB, which protects against the apoptosis induced by tumor necrosis factor alpha, among many other functions.

Abnormal gene product. Because abnormal or absent NF-kappaB essential modulator (IKK-gamma) results in the inability to form the normal complex with IKK-alpha and IKK-beta, cells from individuals with IP lack normal NF-kappaB activation. Activated NF-kappaB protects against apoptosis; thus, IP cells are highly sensitive to proapoptotic signals and die easily [Smahi et al 2000]. The common 11.7-kb deletion results in a lack of NF-kappaB activation which in turn results in extreme susceptibility to apoptosis, thus explaining the embryonic death in males and extremely skewed X-chromosome inactivation in females with IP [Smahi et al 2000, Courtois & Smahi 2006]. Two IKBKG mutations associated with severe IP studied at molecular levels revealed that impaired NF-kappaB activation in response to diverse external stimuli is the cause of the disease [Sebban-Benin et al 2007, Gautheron et al 2010].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Courtois G. The NF-kappaB signaling pathway in human genetic diseases. Cell Mol Life Sci. 2005;62:1682–91. [PubMed: 15924263]
  2. Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev. 2006;16:282–8. [PubMed: 16647846]
  3. Uzel G. The range of defects associated with nuclear factor kappaB essential modulator. Curr Opin Allergy Clin Immunol. 2005;5:513–8. [PubMed: 16264331]

Chapter Notes

Author History

David L Nelson, PhD; Baylor College of Medicine (1996-2010)
Angela Scheuerle, MD, FAAP, FACMG (1996-present)
Matilde Valeria Ursini, PhD (2010-present)

Acknowledgments

Dr. Scheuerle's research included above was done at Baylor College of Medicine in the laboratory of Dr. David Nelson.

Dr. Ursini’s work was supported by the TELETHON grant GGP08125.

Revision History

  • 28 October 2010 (me) Comprehensive update posted live
  • 28 January 2008 (cd/as) Revision: Risk to Family Members, Parents of a proband
  • 4 October 2007 (me) Comprehensive update posted to live Web site
  • 31 March 2005 (me) Comprehensive update posted to live Web site
  • 27 March 2003 (me) Comprehensive update posted to live Web site
  • 19 December 2000 (me) Comprehensive update posted to live Web site
  • 8 June 1999 (pb) Review posted to live Web site
  • 22 December 1998 (as) Original submission
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