Incontinentia pigmenti | |
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Other names | Bloch–Siemens syndrome, Bloch–Sulzberger disease, Bloch–Sulzberger syndrome, nelanoblastosis cutis, nevus pigmentosus systematicus [1] |
This condition is inherited in an X-linked dominant manner. | |
Specialty | Medical genetics |
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. [1]
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. [2]
The skin lesions evolve through characteristic stages:[ citation needed ]
Alopecia, dental anomalies, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays or intellectual disability are occasionally seen.[ citation needed ]
The 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.[ citation needed ]
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, intellectual disability, and seizures. They are also likely to have visual problems, which can include: crossed eyes, cataracts, retinal detachment, and severe visual loss. Dental problems are also common, and can include hypodontia, abnormally shaped teeth, and delayed tooth eruption. [3]
Breast anomalies can occur in 1% of patients and can include hypoplasia or supernumerary nipples.
Skeletal and structural anomalies can occur in approximately 14% of patients, including:[ citation needed ]
IP is inherited in an X-linked dominant manner. [4] [5] 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.[ citation needed ]
In females, the cells expressing the mutated IKBKG gene due to lyonization selectively die around the time of birth, so the X-inactivation is extremely skewed. [6]
IP is caused by mutations in a gene called NEMO (NF-κB essential modulator).[ citation needed ]
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.[ citation needed ]
There does not yet exist a specific treatment for IP. Treatment can only address the individual symptoms. [7]
This disorder was first reported by Swiss dermatologist Bruno Bloch in 1926 and American dermatologist Marion Sulzberger in 1928. [8] [9] [2]
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.
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Heřmanský–Pudlák syndrome is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism, bleeding problems due to a platelet abnormality, and storage of an abnormal fat-protein compound. It is thought to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.
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Ectrodactyly–ectodermal dysplasia–cleft syndrome, or EEC, and also referred to as EEC syndrome and split hand–split foot–ectodermal dysplasia–cleft syndrome is a rare form of ectodermal dysplasia, an autosomal dominant disorder inherited as a genetic trait. EEC is characterized by the triad of ectrodactyly, ectodermal dysplasia, and facial clefts. Other features noted in association with EEC include vesicoureteral reflux, recurrent urinary tract infections, obstruction of the nasolacrimal duct, decreased pigmentation of the hair and skin, missing or abnormal teeth, enamel hypoplasia, absent punctae in the lower eyelids, photophobia, occasional cognitive impairment and kidney anomalies, and conductive hearing loss.
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