Incontinentia Pigmenti

[Bloch-Sulzberger Syndrome]

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.

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. The need for skin biopsy has diminished with the advent of molecular genetic testing with a high mutation detection frequency. Skin biopsy may be helpful in borderline or questionable cases.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

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

Clinical testing

• Deletion/duplication analysis. Approximately 80% of probands have a deletion that removes exons 4 through 10 of the IKBKG gene [Smahi et al 2000].

• Sequence analysis. In addition to the common deletion mutation, other IKBKG mutations have been found in persons with IP. None of these other mutations has been found in a significant fraction of affected individuals. Data are currently insufficient to determine a detection rate for such cases.

• X-chromosome inactivation studies. Females with IP have skewed X-chromosome inactivation in which the X chromosome with the mutant allele is preferentially inactivated [Parrish et al 1996].

  • Because non-random X-chromosome inactivation is not unique to IP, the results of X-chromosome inactivation studies are supportive only and need to be used in the context of clinical findings and/or family history.

  • In individuals with IP, skewed X-chromosome inactivation has been demonstrated only in blood; X-chromosome inactivation patterns in other tissues have not been studied. (For laboratories offering X-chromosome inactivation studies, see .)

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in IP

Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Deletion/duplication analysis	Deletion of exons 4-10 of IKBKG (NEMO)	~80%	Clinical
Sequence analysis	IKBKG sequence variations	Unknown

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Failure to identify an IKBKG mutation does not rule out the diagnosis of IP.

Testing Strategy

Establishing 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:

  • Deletion/duplication analysis to identify the common IKBKG deletion

  • Complete IKBKG sequencing in individuals who meet diagnostic criteria but do not have the common deletion

  • X-chromosome inactivation studies to look for evidence of skewing if an IKBKG mutation cannot be identified

The following should be considered in males with IP:

• A karyotype to look for evidence of 47,XXY

• Interphase fluorescence in situ hybridization (FISH) studies using X and Y chromosome-specific probes to look for evidence of 46,XY/47,XXY mosaicism

Note: Histologic examination of a skin biopsy is not necessary to make the diagnosis.

Carrier testing for at-risk female relatives requires prior identification of the disease-causing mutation in the family member. X-chromosome inactivation studies to look for evidence of skewing can be helpful if an IKBKG mutation cannot be identified.

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

Genetically Related (Allelic) Disorders

Other phenotypes associated with mutations in the IKBKG gene are X-linked hypohydrotic ectodermal dysplasia and immunodeficiency (HED-ID) and HED-ID with osteopetrosis and lymphedema (OL-HED-ID) [Zonana et al 2000, Döffinger et al 2001]. HED-ID and OL-HED-ID occur in males and are caused by single-base mutations within the IKBKG gene that result in impaired, but not absent, NF-KB signaling. HED-ID and OL-HED-ID are distinct from the X-linked form of hypohydrotic ectodermal dysplasia caused by mutation or deletion of the EDA gene (see Hypohydrotic Ectodermal Dysplasia).

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 mental retardation are observed.

Recent reports of more than 300 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]; the recent reports rely on standardized diagnostic criteria and are thus less likely than older reports to include persons with alternate diagnoses.

Figure 1. IP in an affected female; Stage I, the blistering (more...)

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 with Stage III (more...)

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

Figure 3. An adult with reticulated pigmentation patterns (more...)

Figure 3. An adult with reticulated pigmentation patterns

Figures 1

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• 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.

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, mental retardation, 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 (one 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 9% had severe disabilities such as mental retardation 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 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.

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 ophthalmoloscopy 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 abnormalties, suggesting that abnormalities of retinal vascularization may be a marker for other neurologic abnormalities.

• In 40 individuals (38 female, two 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%.

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 mental retardation 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 et al 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; however, 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.

• Mutations that produce a milder form of the condition, such as duplication of a 7-cytosine tract of exon 10 [Aradhya et al 2001b, Kenwrick et al 2001]

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 a problem; conception of an unaffected fetus should result in normal pregnancy and delivery.

The reproductive fitness of males with IP is not known. A few affected men have fathered children, but the incidence of miscarriage in their partners has not been documented.

Histopathology. The most characteristic finding on light microscopic examination of a skin biopsy obtained from an abnormal area of skin in the hyperpigmented stage of the disorder (stage III) is the presence of free melanin granules in the dermis, or "incontinence of pigment," leading to the name incontinentia pigmenti; however, free melanin granules in the dermis can be present in other conditions [Delaporte et al 1996, Machado-Pinto et al 1996, Scheuerle 1998].

In the bullous stage (stage I), infiltration of eosinophils into the epidermis and vacuolization of the dermis and epidermis can be seen by light microscopy, althoughf these findings are not specific to IP. When mutated, IKBKG may activate eotaxin, an eosinophil cytokine, causing abnormally high migration of eosinophils into the skin and vascular endothelial cells [Jean-Baptiste et al 2002].

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 immune malfunction could be part of the IP phenotype. To date the existence of immune system abnormalities in IP has not been well-studied or established.

The reasoning behind male lethality in IP is that if a male inherits the X chromosome with the mutated IKBKG gene, the normal protein necessary for viability is not present, and thus the male embryo or fetus does not survive. The precise mechanism of male lethality is unknown [Hatchwell 1996], although mouse models suggest that liver failure in fetuses contributes to their demise [Rudolph et al 2000].

Genotype-Phenotype Correlations

Duplications of a 7-cytosine tract of exon 10 are associated with survival of males and a milder phenotype in females [Aradhya et al 2001b].

HED-ID and OL-HED-ID are caused by single-base mutations within the IKBKG gene (see Genetically Related Disorders). These mutations result in impaired but not absent NF-KB signaling.

Penetrance

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

Anticipation

Anticipation has not been reported.

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, 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), rather 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 literature. It is unknown whether each case reported represents a unique individual because of the number of large retrospective studies.

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 Hypohydrotic 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 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 asssessed at routine visits with a pediatrician, pediatric neurologist, or developmental pediatrician.

Ongoing evaluation by a pedodontist or dentist is appropriate.

Testing 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, but there is no evidence that it affects the course of the rash.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 a new gene mutation or may have inherited the IKBKG mutation from either her mother or her father [Scheuerle 1998].

• Inheritance of the familial form is most likely from the mother.

• When IP occurs as the result of a de novo mutation, the mutation usually occurs in the IKBKG gene inherited from the father [Smahi et al 2000]. Clinical evaluation of both parents is warranted.

• If the mother meets the diagnostic criteria for IP or if she has another affected relative, she will have an IKBKG gene mutation.

• If the disease-causing IKBKG gene mutation has been identified in the proband, molecular genetic testing of a parent 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 found to be affected, the risk to sibs of inheriting the mutant IKBKG allele at conception is 50%; however, most male conceptuses with the mutant IKBKG allele miscarry. Thus, at delivery the expected ratio among offspring is approximately 33% unaffected females, 33% affected females, and 33% unaffected males.

• If neither parent has IP and/or an 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:

  • A de novo mutation in a sib

  • Germline mosaicism in a parent

• Theoretically, germline mosaicism can occur in either parent of a female with IP, but it has only been demonstrated in a father.

Figure 4. Genotype of conceptuses compared with genotype (more...)

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

Figure 4

• 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 the mutant IKBKG allele miscarry. Thus, at delivery the expected ratio among offspring is approximately 33% unaffected females, 33% affected females, and 33% unaffected males.

• Affected males. A male with IP transmits the IKBKG mutation to all of his daughters and none of his sons.

Other family members of a proband. If a parent of the proband is found to have 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 available on a clinical basis if the mutation has been identified in the family. X-chromosome inactivation studies to look for evidence of skewing can be helpful if an IKBKG mutation cannot be identified in the proband.

Related Genetic Counseling Issues

See Management, Testing 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 or at risk.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 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 results in a milder phenotype than with point mutations, and thus a likely lower risk for miscarriage. (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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Acknowledgments

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

Revision History

• 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