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Incontinentia Pigmenti

Synonym: Bloch-Sulzberger Syndrome

, MD, FAAP, FACMG and , PhD.

Author Information
, MD, FAAP, FACMG
Division of Genetics and Metabolism
Department of Pediatrics
University of Texas Southwestern Medical Center
Dallas, Texas
, PhD
Department of Molecular and Human Genetics
Institute of Genetics and Biophysics
National Research Council
Naples, Italy

Initial Posting: ; Last Update: February 12, 2015.

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.

Wart-like rash (for several months)

III.

Swirling macular hyperpigmentation (age ~6 months into adulthood)

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 and learning 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 approximately 65% 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; standard measures to reduce the risk of skin infection.

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 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 to limit early-stage rashes have been prescribed. Their efficacy has not been documented.

Genetic counseling.

IP is inherited in an X-linked manner. About 65% of affected individuals have IP as a result of de novo mutation. 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 pathogenic variant 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 pathogenic variant in the family has been identified.

Diagnosis

Suggestive Findings

Diagnosis of incontinentia pigmenti (IP) should be suspected in individuals with characteristic clinical findings of the skin, teeth, hair, nails, eyes, CNS, and family history as detailed below [Landy & Donnai 1993, Minić et al 2014].

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 24 months; most prominent <6 months of age)
  • Verrucous lesions that respect Blaschko’s lines, occurring mainly on the limbs; stage II (first weeks of life to 24 months)
  • Hyperpigmented streaks and whorls that respect Blaschko's lines, occurring mainly on the trunk and fading in adolescence; stage III (age 4 months to 16 years, rarely persisting into adulthood)
  • Pale, hairless, atrophic linear streaks or patches; stage IV (adolescence through adulthood)

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.

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
  • Family history consistent with X-linked inheritance or a history of multiple miscarriages

Note:

*

Minić et al [2014] have suggested that CNS, palate, and nipple/breast anomalies be added to the minor diagnostic criteria.

Note: 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].

Establishing the Diagnosis

The diagnosis of IP is established in a proband with the identification of a heterozygous pathogenic variant of IKBKG (previously NEMO). (see Table 1).

Molecular testing approaches can include:

In affected individuals in whom an IKBKG pathogenic variant is not identified by the above methods, skin biopsy can be considered.

  • 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 Table 1). 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 pathogenic variant.
  • 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 pathogenic variant 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.

Table 1.

Summary of Molecular Genetic Testing Used in IP

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
MalesFemales
IKBKGTargeted mutation analysis for ~11.7-kb common deletion
(c.399-?_1260+?del)
3/18 (16%) 2 ~65% 3
Sequence analysis 4Unknown 5, 6 ~8.6% 3, 7
Deletion / duplication analysis 8None reported~4% 9
Unknown 10NA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this 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 detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

6.

Chang et al [2008] reported a male with the pathogenic variant 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 (see Genetically Related Disorders).

7.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

8.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9.

Quantitative PCR analysis of IKBKG locus to evaluate partial copy number loss or copy number gain along the locus revealed pathogenic variants due to aberrant recombination in the locus producing deletions involving IKBKG, the IKBKG pseudogene, and eventually the neighboring gene G6PD [Fusco et al 2012, Conte et al 2014].

10.

Although no evidence of additional loci causing IP has been reported, there remain 4.7% of individuals with IP who have no mutation in the IKBKG locus assigned. For them locus heterogeneity cannot be excluded [Fusco et al 2014].

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Fusco et al 2013] (full text).

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.

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]; more 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, although some may have been reported more than once. Also, many reports do not include molecular confirmation. The largest cohort of patients with IP in whom the clinical and molecular diagnosis has been confirmed is reported in Fusco et al [2014].

Skin. 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.

Figure 1. . IP in an affected female; stage I: the blistering stage.

Figure 1.

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

Figure 2. . IP in an affected female; stage II: the verrucous (“warty”) stage.

Figure 2.

IP in an affected female; stage II: the verrucous (“warty”) stage. The lesions to not necessarily arise in the same place as those of stage I.

Figure 3.

Figure 3.

IP in an affected female with stage III "rash"

Figure 4.

Figure 4.

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 girl age five years who was already manifesting the stage IV rash [Darné & 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 (see Figure 2). 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 3). 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 can persist into adulthood. The hyperpigmentation usually begins to fade in the teens and early twenties (see Figure 4). 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.

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. Seizures, intellectual disability, and other CNS abnormalities have been reported in approximately 30% of individuals with IP [Minić et al 2014]. The actual incidence of neurocognitive disability is unclear because mildly affected cases without neurocognitive problems may not come to medical attention [Phan et al 2005]. Neurocognitive disability is more common in simplex than in familial cases, presumably because mildly affected family members are identified [Landy & Donnai 1993]. Males with IP are more likely than females to have neurologic abnormalities. In general, neurologic abnormalities in patients with IP appear to be associated with underlying CNS vasculopathy [Meuwissen & Mancini 2012].

  • Seizures. Seizures in IP range from a single episode in a lifetime to chronic epilepsy. The type of seizure varies because the stroke etiology may involve any part of the cerebrum. In the review of well-documented patients with IP who have neurocognitive disability, Meuwissen and Mancini [2012] note that in the cases where seizure type was reported, focal clonic seizures were the most frequently observed type. Of all affected persons with neurocognitive problems, about 25% experience one or more seizures (i.e., ~7% of all patients diagnosed with iP). The vast majority of seizures manifest within the first year of life (32 of 35 patients with seizures where onset was reported). Fourteen of 25 patients in whom recurrence was reported experienced only one seizure [Meuwissen & Mancini 2012].
  • 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 males, co-occurrence of a 47,XXY karyotype may complicate the intellectual phenotype of IP.

    Pizzamiglio et al [2014] reported a group of ten individuals with IP who were underwent cognitive assessment. Seven of the ten had deficits in calculation/arithmetic reasoning and reading but not writing skills. This evaluation makes it possible to place “learning disabilities” among the manifestations of IP.
  • Brain anomaly. Primary brain anomalies are rare. The following have been seen in individual patients: agenesis of the corpus callosum with an occipital encephalocele [Demirel et al 2009]; polymicrogyria [Godambe et al 2005]; and gray matter heterotopias [Mangano & Barbagallo 1993]

    Evidence that IKBKG pathogenic variants 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]. Neurovascular abnormalities are most common in the first year of life with only a handful of patients reported after that, and only three after age four years [Meuwissen & Mancini 2012].

    Periventricular leukomalacia is documented in 27 of 43 MRIs in patients with IP who have neurocognitive disabilities, especially seizures, and subcortical white matter changes were also seen commonly. Some patients have subsequent cystic changes. Myelination delays and ventricular dilation have also been reported [Meuwissen & Mancini 2012].
  • Spastic paresis. The frequency of this finding is unknown. It is difficult to interpret older literature findings. As with other neurologic abnormalities in IP, the risk and severity of spastic paresis appears to be related to CNS vasculopathy.

Ophthalmologic. Individuals with IP are at increased risk (20%-77%) for ophthalmologic abnormalties.

  • Retinal hypervascularization is most common. When untreated, this leads to retinal detachment. The greatest risk for retinal detachment is in infancy and childhood; it almost never occurs after age six years. The changes are visible on indirect ophthalmoscopy through a dilated pupil.
  • Other eye findings include: strabismus, cataracts, optic atrophy, retinal pigmentary abnormalities, and microphthalmia [Meuwissen & Mancini 2012, Fusco et al 2014].

Other

  • Leukocytosis with up to 65% eosinophils may occur, particularly in stages I and II. The cause of the leukocytosis is unknown. Eosinophilia is not consistently associated with any clinical manifestations and typically resolves spontaneously.
  • Primary pulmonary hypertension was seen in three girls who 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).

Males with IP. Although IP has been identified as a "male-lethal" disease, there are well-documented male cases. A large review of male cases was published in 1998 [Scheuerle 1998]. Since then, an examination of the literature reveals a multitude of reports of affected males originating from all over the world. Fusco et al [2007] reported eighteen males with characteristic clinical features and, when examined, histologic skin defects. Six also had neurologic, ophthalmologic, and/or dental manifestations.

Survival in a male is mediated through one of two mechanisms:

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].

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 2008]. Only one male has been reported with HED-ID and also clinical findings of IP in association with the c.1167dupC 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 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.

Genotype-Phenotype Correlations

Pathogenic sequence variants in IKBKG, 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 pathogenic variants 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 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.

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].

Prevalence

As of 2010, about 1000 female IP cases had been reported. The literature of both female and male cases 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 0.6 – 0.7/1,000,000 [Orphanet, Texas Birth Defects Registry, unpublished data]. The female:male ratio is 20:1 [Orphanet].

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 (OMIM 300337), 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 (OMIM 172800), 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 (OMIM 161000), 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. Pathogenic variants in KRT14 cause Naegeli syndrome.
  • 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation for diagnosis, treatment plan, testing, and family counseling
  • Involvement of a pediatric dermatologist for diagnosis, and for management of significantly involved cases
  • 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. Significant skin involvement may benefit from dermatology management.
  • 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 [Holmström & 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

It is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures (routine eye examinations).

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, physical examination, including examination of the skin, teeth, hair, nails, retina and CNS, can be used to clarify the disease status of at-risk relatives.

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

Pregnancy Management

Overall pregnancy health and management usually does not vary from normal. The risk of spontaneous abortion is higher than population rates, but management of pregnancy loss is done in the standard manner. For women with retinal problems, delivery management to minimize or eliminate labor should be considered to avoid retinal detachment.

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.

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

  • A female with IP may have inherited the IKBKG pathogenic variant from her mother or may have de novo mutation.
  • When IP occurs as the result of de novo mutation, the mutation occurs more frequently in the IKBKG allele inherited from the father [Smahi et al 2000, Fusco et al 2004].
  • De novo mutation in IKBKG is common: 59 (65%) of 91 females with IP and the common 11.7-kb deletion had de novo mutation [Fusco et al 2009].
  • If the mother meets the diagnostic criteria for IP or if she has an affected first-degree relative, she has a pathogenic variant in IKBKG.
  • If the pathogenic variant in IKBKG has been identified in the proband:
    • Molecular genetic testing of a parent and relatives with clinical findings is warranted.
    • If neither parent has clinical findings, molecular genetic testing of the mother is warranted because of the widely variable expressivity of the phenotype. Adult women may be unaware of mild findings present during their own childhood and may, as adults, have no easily discernable physical findings.

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 pathogenic variant that results in reduced (though not absent) protein activity, male conceptuses may survive and manifest ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID) at birth. Note: A mother with IP and the common 11.7-kb deletion (resulting in the complete absence of protein activity) is not at increased risk of having a liveborn child with EDA-ID.
  • If neither parent has IP or an IP-related IKBKG pathogenic variant, the risk to the sibs of a proband of having IP is lower than 1%. Two possibilities account for the small increased risk:
  • Germline mosaicism can occur in either parent of a female with IP.

Offspring of a proband (see Figure 5)

Figure 5.

Figure 5.

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 5).
    • At conception, the risk that the IKBKG pathogenic variant 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 pathogenic variant that results in reduced (though not absent) protein activity, male conceptuses may survive and manifest EDA-ID at birth. Note: A mother with IP and the common 11.7-kb deletion (resulting in the complete absence of protein 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 pathogenic variant. Because the mosaicism does not include the germline, IP transmission from an affected male to his female offspring does not occur.

Other family members of a proband. If a parent of the proband has an IKBKG pathogenic variant, his or her family members may be at risk of being affected.

X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an IKBKG pathogenic variant 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 pathogenic variant, 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the IKBKG pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Because the prognosis for affected females differs from that for affected males, the fetal karyotype must be determined for accurate genetic counseling.

  • 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 a discussion of Klinefelter syndrome.

Note: The exon 10 duplication and single nucleotide variants which result in a milder phenotype are likely to be at lower risk for miscarriage (see Genotype-Phenotype Correlations).

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the IKBKG pathogenic variant 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 ASSociazione Italiana (I.P.ASS.I.) – Onlus
    Via Altair, 5
    00012 Guidonia Montecelio
    Italy
    Phone: 393332089513
    Email: presidenza@incontinentiapigmenti.it
  • Incontinentia Pigmenti France
    69370 Saint Didier au Mont D'Or
    Lyon
    France
    Phone: 33(0)478 35 96 32
    Email: christel.monnet69@orange.fr
  • 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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
IKBKGXq28NF-kappa-B essential modulatorIKBKG @ LOVDIKBKG

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 (previously known as NEMO) are two 870-bp direct repeats termed MER67B; one is in intron 3 and the second is downstream of IKBKG (Figure 6). Recombination between the MER67B direct repeats results in 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 benign allelic variants, which are recurrent among the control population (1%-2% estimated frequency) (Figure 6).

Figure 6. . Recurrent and non-recurrent rearrangements in IP locus.

Figure 6.

Recurrent and non-recurrent rearrangements in IP locus. The inverted repeats are depicted on the top line by the two large regions outlined by inverted boxes and containing both MER67B repeats (red arrows). The location of real-time PCR amplicons assayed (more...)

Gene structure. IKBKG (previously known as NEMO) has multiple transcript variants encoding different isoforms. The transcript variant NM_003639.3 has ten exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

IKBKG has a highly similar pseudogene, designated IKBKGP1 (also known as NEMOP) (Figure 6), located in an adjacent region of the X chromosome. IKBKGP1 is a partial pseudogene with sequences highly similar to those in exons 3-10 of the functional gene.

The functional IKBKG (NEMO) is 22 kb distant from the pseudogene IKBKGP1 (NEMOP); they are arranged in an inverted fashion.

Benign allelic variants. In a study by Fusco et al [2009] 10%-12% of parents of individuals with IP were found to have two benign variants. One was the 11.7-kb deletion of exons 4-10 in the IKBKG pseudogene (IKBKGP1) (Figure 6, upper green chromosome schematic). The second was a duplication of MER67B (lower green chromosome schematic) 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.

Pathogenic allelic variants. The recurrent pathogenic variant in individuals with IP is an 11.7-kb deletion of exons 4 through 10 of IKBKG (Figure 6, red chromosome schematic) (see Molecular Genetic Pathogenesis). Figure 6 also depicts some of the non-recurrent deletions that cause IP.

Small intragenic substitutions, deletions, and duplications are scattered throughout IKBKG; 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 2001a, Fusco et al 2008].

Smaller pathogenic variants in IKBKG (mostly in exon 10) that result in protein with reduced but not absent activity have been reported [Zonana et al 2000, Aradhya et al 2001a, Döffinger et al 2001, Fusco et al 2008]. These pathogenic variants 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 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.399-?_1260+?del
(common 11.7-kb deletion)
NM_003639​.3
NP_003630​.1
c.1167dupCp.Glu390ArgfsTer5

Note on variant classification: Variants listed in the table have been provided by the authors. 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.

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 2001b]. 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 pathogenic variants 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].

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Suggested Reading

  1. Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev. 2006;16:282–8. [PubMed: 16647846]
  2. Senegas A, Gautheron J, Maurin AG, Courtois G. IKK-related genetic diseases: probing NF-kB functions in humans and other matters. Cell Mol Life Sci. 2014 Nov 29 Epub ahead of print. [PubMed: 25432706]
  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

  • 12 February 2015 (me) Comprehensive update posted live
  • 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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