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Last updated: 6/15/2023
Years published: 1988, 1990, 1999, 2003, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Michelle Yanik, NORD Editorial Intern from the University of Notre Dame, and Angela Scheuerle, MD, Department of Pediatrics, Division of Genetics and Metabolism University of Texas, Southwestern Medical Center, for assistance in the preparation of this report.
Summary
Incontinentia pigmenti (IP) is a genetic ectodermal dysplasia affecting the skin, hair, teeth, microvasculature and central nervous system. Progressive skin changes occur in four stages, the first of which appear in early infancy or can be present at birth. IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene.
Introduction
IP was named based on the appearance of the skin under the microscope during the later stages of the condition.
Skin
Skin changes are the most characteristic and common features in IP. They are described in four stages. In all the stages, the lesions appear in lines on the arms and legs or a swirled pattern on the trunk. They can be on the face and scalp. They do not always occur in order, may occur at the same time and the later stages may be permanent once they appear.
1) The first stage of IP may be present at birth or appear during early infancy. This phase consists of redness or inflammation of the skin (erythema), blisters and boils, most often affecting the extremities and the scalp. It can fade and come back again and again, commonly when there is an illness with fever. These recurrences may happen for years, even into adulthood.
2) The second stage may overlap the first and may be present at birth. During this phase, the blisters develop a raised, wart-like (verrucous) appearance, and the lesions look like warts. There can be thick crusts or scabs with healing and areas of darkened skin (increased pigmentation). The extremities are involved almost exclusively in this stage. These recurrences may happen for years.
3) The third stage may be present at birth in a small number of affected individuals, but usually appears between the ages of 6 and 12 months. In this phase, the skin is darkened (hyperpigmented). On the trunk, the dark skin occurs in a swirled pattern and is sometimes described as a โmarble cakeโ appearance. Hyperpigmentation does not necessarily appear where the stage 1 and 2 rashes happen. The heavy pigmentation may fade over time, though it is permanent in many patients.
4) The โatrophic stageโ is called the fourth stage, but there are suggestions that it may be present, but not obvious, at birth. These skin changes are pale or hypopigmented and hairless. There may be a diminished number of sweat glands.
Teeth
Between 50 to 75 percent of individuals with IP have dental abnormalities. These abnormalities include a delay in the eruption of primary teeth; abnormal shape (contour) of teeth, giving them a peg-like or cone-shaped appearance; or the congenital absence of both primary and secondary teeth (anodontia); or small teeth (microdontia).
Nails
Some individuals with IP have ridged, pitted, thickened (onychogryposis), or missing nails on the hands and/or feet. In some patients, painful growths may develop under the nail. These changes can be permanent.
Hair
Approximately 50 percent of individuals with IP have abnormal bald patches on the scalp (alopecia). This may happen where the stage one and two lesions have left scars or as part of a congenital skin dysplasia. The hair may be coarse, wiry, hard to comb, and/or lusterless.
Eyes
Nearly one-third of individuals have eye (ocular) abnormalities. The most serious, but least frequent, is a congenitally small, abnormal eye. In any patient there can be an abnormality in the growth of blood vessels in the membrane lining the eyes (retina). If it is going to occur, it typically happens before the age of five. This problem may be treated if detected early. If left untreated, it may cause retinal detachment leading to permanent visual impairment or total blindness.
Nervous System
Most individuals with IP will have no involvement of the nervous system and normal intellectual development. Severe neurologic complications can occur because of IP, the most serious of which is congenital or neonatal strokes. Some affected individuals may experience episodes of uncontrolled electrical disturbances in the brain (seizures). About 30 percent of children with IP will have slow motor development, muscle weakness in one or both sides of the body, intellectual disability and/or seizures. Severe problems are unusual and may be most associated with early strokes.
Other
Abnormalities in the development of the breast, ranging from extra nipples to complete absence of the breast, are sometimes seen in individuals with IP. Whether this is more common than in the general population has not been studied.
There are anecdotal reports of heat intolerance or lack of normal sweating in people with IP, but this has not been formally studied.
IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene (formerly called NEMO). IKBKG codes for a protein that helps regulate other proteins that help protect cells from self-destruction in response to specific triggers.
X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the abnormality causing a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive pregnancy. Affected males who survive may have an IKBKG gene mutation with relatively mild effects, an IKBKG mutation in only some of the bodyโs cells (mosaicism), or an extra copy of the X chromosome in each cell.
IP affects all racial and ethnic groups. As of 2014 there were more than 2000 female with IP reported in the scientific literature and this number, along with reports of affected males, continues to rise. Current estimates from public health and analytical systems put the birth prevalence at 0.6-2.1/1,000,000. Orphanet reports an estimated birth prevalence of 1.2/100,000 in the European Union which is likely more accurate. The female:male ratio is 20:1.
The diagnosis of IP is based on clinical evaluation, detailed patient history, and molecular genetic testing for mutations in the IKBKG gene. IKBKG is the only gene known to be associated with IP and 65% of patients have a specific deletion within the gene. Another 20% or so have mutations found by gene sequencing. IKBKG is appropriately studied using Sanger sequencing. Next generation sequencing (NGS) such as is found in multi-gene testing panels or exome sequencing will not identify IKBKG variants. There is a related pseudogene very similar to IKBKG (has sequence homology) that interferes with NGS testing technology.
A skin biopsy to confirm the diagnosis in a female may be diagnostic but can be considered a secondary or follow-up test given the widespread availability and sensitivity of molecular genetic testing. Skin biopsy 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.
Clinical Testing and Work-Up
It is very important for babies born with IP to have an eye examination by a pediatric ophthalmologist. This should be done 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. The eye problems associated with IP can be severe but may be effectively managed if recognized early.
The following evaluations may be done to determine the severity of disease in those affected with IP: Physical examination with particular emphasis on the skin, hair, nails, and neurologic system: electroencephalography (EEG) and brain magnetic resonance imaging (MRI) or angiography (MRA) if seizures, other neurologic abnormalities, or retinal abnormalities are present and developmental screening.
Because IP can be very mild, even in infancy, an affected female may not know that she has it. It is important that a full evaluation of the mother be done by a geneticist, dermatologist or other physician after the birth of a child with IP.
Treatment
Skin abnormalities characteristic of IP may disappear by adolescence or adulthood without any treatment. The Stage 1 and 2 lesions may recur with routine febrile illness well into adulthood. There are no directed treatments for these skin lesions. Topical steroids are not effective. The lesions and surrounding skin should be kept clean, and irritation minimized to avoid secondary infection.
Neurological symptoms such as seizures, muscle spasms, or paralysis may be controlled with various drugs and/or medical devices. Developmental delays and/or intellectual disabilities should be managed as needed with targeted therapies and school assistance.
Cryotherapy and laser photocoagulation may be used to treat affected individuals with retinal neovascularization that predisposes to retinal detachment.
Dental abnormalities can often be treated effectively by dentists who may provide implants in childhood as needed. If dental abnormalities interfere with chewing and/or speech, assistance from a speech pathologist and/or pediatric nutritionist may be necessary.
Hair problems may require the attention of a dermatologist, although they are usually not severe.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about Incontinentia Pigmenti:
United States:
Angela Scheuerle, MD
University of Texas, Southwestern Medical Center
Department of Pediatrics
Division of Genetics and Metabolism
5323 Harry Hines Blvd.
Dallas TX 75390
Phone: 214-456-2357
Fax: 214-456-2567
[email protected]
Europe (based in Italy):
Information and links to resources may be found here: https://www.igb.cnr.it/ipgb/index.php/patient-advocacy-groups/
TEXTBOOKS
Carey JC, Battaglia A, Viskochil D, Cassidy SB ed. Cassidy and Allansonโs Management of Genetic Syndromes, 4th ed. West Sussex, UK: Wiley; 2021: 505-514
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrisonโs Principles of Internal Medicine. 18th edNew York, NY: McGraw-Hill; 2011.
Ruggieri M, Pascual-Castroviejo I, Di Rocco C, eds. Neurocutaneous Disorders: Phakomatoses & Hamartoneoplastic Syndromes. New York, NY: Springer; 2007: 363.
Kanski JJ, ed. Clinical Ophthalmology. 4th ed Woburn, MA: Butterworth-Heinemann; 1999: 342.
Adams RD, Victor M, Ropper AA, eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Inc.; 1997:1002.
Jones KL, Jones MC, Del Campo M, ed. Smithโs Recognizable Patterns of Human Malformation. 8th ed. Philadelphia, PA: Elsevier 2021.
Sybert VP. Genetic Skin Disorders. Oxford UK: Oxford University Press. 2017
JOURNAL ARTICLES
Fusco F, Paciolla M, Conte MI, Pescatore A, Esposito E, Mirabelli P, Lioi MB, Ursini MV. Incontinentia pigmenti: report on data from 2000 to 2013. Orphanet J Rare Dis. 2014;9:93.
Courtois G, Smahi A. NF-kappaB-related genetic diseases. Cell Death Differ. 2006;13:843โ51.
Goldberg MF. Macular vasculopathy and its evolution in incontinentia pigmenti. Ophthalmic Genet. 1998;19(3):141-8.Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev. 2006;16(3):282-8.
Dรถffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001;27:277โ85.
INTERNET
Scheuerle AE, Ursini MV. Incontinentia Pigmenti. 1999 Jun 8 [Updated 2017 Dec 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1472/ Accessed June 14, 2023.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Incontinentia Pigmenti; IP. Entry No: 308300. Last Edited: 04/20/2022. Available at: https://omim.org/entry/308300 Accessed June 14. 2023
Incontinentia Pigmenti. Genetics Home Reference. Reviewed March 13, 2023. https://ghr.nlm.nih.gov/condition/incontinentia-pigmenti. Accessed June 14, 2023.
Incontinentia Pigmenti Genetic Biobank: https://www.igb.cnr.it/ipgb/ Accessed June 14, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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