|X-linked dominant inheritance works differently depending upon whether the mother (left image) or father (right image) is the carrier of a gene that causes a disease or disorder.|
Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disorder that affects the skin, hair, teeth, nails and central nervous system. It is named from its appearance under a microscope. It is also known as Bloch–Siemens syndrome, Bloch–Sulzberger disease, Bloch–Sulzberger syndrome, melanoblastosis cutis and nevus pigmentosus systematicus.
The disease is characterized by skin abnormalities that begin in childhood, usually a blistering rash which heals, followed by the development of harder skin growths. The skin may develop grey or brown patches which fade with time. Other symptoms can include hair loss, dental abnormalities, eye abnormalities that can lead to vision loss and lined or pitted fingernails and toenails. Associated problems can include delayed development, intellectual disability, seizures and other neurological problems. Most males with the disease do not survive to childbirth.
Incontinentia pigmenti is caused by a mutation in the IKBKG gene, which encodes the NEMO protein, which serves to protect cells against TNF-alpha-induced apoptosis. A lack of IKBKG therefore makes cells more prone to apoptosis.
There is no specific treatment; individual conditions must be managed by specialists.
The skin lesions evolve through characteristic stages:
- blistering (from birth to about four months of age),
- a wart-like rash (for several months),
- swirling macular hyperpigmentation (from about six months of age into adulthood), followed by
- linear hypopigmentation.
Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays/mental retardation are occasionally seen.
Discolored skin is caused by excessive deposits of melanin (normal skin pigment). Most newborns with IP will develop discolored skin within the first two weeks. The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines. The discoloration sometimes fades with age.
Neurological problems can include: cerebral atrophy, the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex. About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, mental retardation, and seizures. They are also likely to have visual problems, which can include: crossed eyes, cataracts, and severe visual loss. Dental problems are common, and include missing or peg-shaped teeth - patients with IP often keep milk teeth into adult life.
Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary nipples.
Skeletal and structural anomalies can occur in approximately 14% of patients, including:
- Somatic asymmetry,
- Spina bifida,
- Acheiria (congenital absence of the hands - note: other limbs may be affected),
- Ear anomalies,
- Extra ribs,
- Skull deformities,
- Primary pulmonary hypertension,
- Cardiopulmonary failure
IP is inherited in an X-linked dominant manner. IP is lethal in most, but not all, males. A female with IP may have inherited the IKBKG mutation from either parent or have a new gene mutation. Parents may either be clinically affected or have germline mosaicism. Affected women have a 50% risk of transmitting the mutant IKBKG allele at conception; however, most affected male conceptuses miscarry. Thus, the effective ratio for liveborn children from a mother carrying the mutation is 33% unaffected females, 33% affected females, and 33% unaffected males. Genetic counseling, prenatal testing, and preimplantation genetic diagnosis is available.
IP is caused by mutations in a gene called NEMO (NF-κB essential modulator).
The diagnosis of IP is established by clinical findings and occasionally by corroborative skin biopsy. Molecular genetic testing of the NEMO IKBKG gene (chromosomal locus Xq28) reveals disease-causing mutations in about 80% of probands. Such testing is available clinically.
In addition, females with IP have skewed X-chromosome inactivation; testing for this can be used to support the diagnosis.
Many people in the past were misdiagnosed with a second type of IP, formerly known as IP1. This has now been given its own name - 'Hypomelanosis of Ito' (incontinentia pigmenti achromians). This has a slightly different presentation: swirls or streaks of hypopigmentation and depigmentation. It is not inherited and does not involve skin stages 1 or 2. Some 33–50% of patients have multisystem involvement — eye, skeletal, and neurological abnormalities. Its chromosomal locus is at Xp11, rather than Xq28.
There does not yet exist a specific treatment for IP. Treatment can only address the individual symptoms.
- List of cutaneous conditions
- List of radiographic findings associated with cutaneous conditions
- List of dental abnormalities associated with cutaneous conditions
- Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.[page needed]
- Sulzberger, Marion B (1928). "Über eine bisher nicht beschriebene congenitale Pigmentanomalie" [About a previously udescribed congenital pigment anomaly]. Archiv für Dermatologie und Syphilis (in German). 154: 19–32. doi:10.1007/bf01828398.
- Pettigrew, Rachel; Kuo, Hung-Chih; Scriven, Paul; Rowell, Paula; Pal, Kalyani; Handyside, Alan; Braude, Peter; Ogilvie, Caroline Mackie (2000). "A pregnancy following PGD for X-linked autosomal dominant Incontinentia Pigmenti (Bloch-Sulzberger syndrome): Case Report". Human Reproduction. 15 (12): 2650–2. doi:10.1093/humrep/15.12.2650. PMID 11098039.
- "Incontinentia pigmenti. DermNet NZ".
- The International Incontinentia Pigmenti (IP) Consortium; Smahi, Asmae; Courtois, G; Vabres, P; Yamaoka, S; Heuertz, S; Munnich, A; Israël, A; Heiss, Nina S; Klauck, S. M; Kioschis, P; Wiemann, S; Poustka, A; Esposito, Teresa; Bardaro, T; Gianfrancesco, F; Ciccodicola, A; d'Urso, M; Woffendin, Hayley; Jakins, T; Donnai, D; Stewart, H; Kenwrick, S. J; Aradhya, Swaroop; Yamagata, T; Levy, M; Lewis, R. A; Nelson, D. L (2000). "Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti". Nature. 405 (6785): 466–72. Bibcode:2000Natur.405..466T. doi:10.1038/35013114. PMID 10839543.
- "Incontinentia pigmenti". Medline Plus. Retrieved 26 December 2017.
- Bloch-Sulzberger pigment dermatosis (Bruno Bloch) at Who Named It?
- Bloch, B. (1926). "Eigentümliche, bisher nicht beschriebene Pigmentaffektion (incontinentia pigmenti)" [Peculiar, as yet unexplained pigment affection (incontinentia pigmenti)]. Schweizerische medizinische Wochenschrift (in German). Basel. 56: 404–5.