Pallister–Killian Syndrome
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The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe
genetic disorder 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 chromosome abnormality. Although polygenic disorders ...
. PKS is due to the presence of an extra and abnormal
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and
neoplasms A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
. The sSMC in PKS consists of multiple copies of the short (i.e. "p") arm of
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12's are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related
birth defects A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart. PKS was first described by Philip Pallister in 1977 and further researched by Maria Teschler-Nicola and Wolfgang Killian in 1981.


Presentation

Individuals with PKS present prenatally or at birth with multiple
birth defect A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
s. These defects include:
brain atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...
, agenesis of the corpus callosum,
polymicrogyria Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri ( microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region of ...
of the brain, and/or spot calcifications in the brain's
lateral sulcus The lateral sulcus (or lateral fissure, also called Sylvian fissure, after Franciscus Sylvius) is the most prominent sulcus (neuroanatomy), sulcus of each cerebral hemisphere in the human brain. The lateral sulcus (neuroanatomy), sulcus is a deep ...
; deafness and/or blindness;
autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...
dysfunctions such as anhidrosis,
hypohidrosis Hypohidrosis is a medical condition in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyperhidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidr ...
, and/or episodic spells of
hyperventilation Hyperventilation is irregular breathing that occurs when the rate or tidal volume of breathing eliminates more carbon dioxide than the body can produce. This leads to hypocapnia, a reduced concentration of carbon dioxide dissolved in the blo ...
interspersed with breath-holding; symptoms of spinal cord malformations; profound or less commonly mild to severe intellectual disability;
epileptic seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
; heart and/or anal defects;
diaphragmatic hernia Diaphragmatic hernia is a defect or hole in the diaphragm that allows the abdominal contents to move into the chest cavity. Treatment is usually surgical. Types * Congenital diaphragmatic hernia ** Morgagni's hernia ** Bochdalek hernia * Hi ...
s; marked muscle weakness; supernumerary nipples; abnormal facial features such as frontal bossing, high frontal hairline, balding around the
temple A temple (from the Latin ) is a place of worship, a building used for spiritual rituals and activities such as prayer and sacrifice. By convention, the specially built places of worship of some religions are commonly called "temples" in Engli ...
and frontal areas, sparse eyebrows and lashes,
hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...
, small and flat nose, full cheeks, long
philtrum The philtrum (, from Ancient Greek , lit. 'love charm') or medial cleft is a vertical indentation in the middle area of the upper lip, common to therian mammals, extending in humans from the nasal septum to the tubercle of the upper lip. Toget ...
, large mouth with downturned corners, thin
cupid's bow The Cupid's bow is a facial feature where the double curve of a human upper lip is said to resemble a recurve bow of the sort used in ancient Greece or Rome. The name is taken from Cupid, the bow-wielding Roman god of erotic love equivalent to ...
-shaped upper lip, micrognathia (i.e. undersized jaw), disformed ears that are low-set, thick eyebrows, and/or prominent lips and chin; abnormal oral/dental features such as enlarged tongue, overgrowth of the
alveolar ridge The alveolar process () is the portion of bone containing the tooth sockets on the jaw bones (in humans, the maxilla and the mandible). The alveolar process is covered by gums within the mouth, terminating roughly along the line of the mandib ...
and/or gums, delayed teeth eruption, and/or missing or double teeth; patchy skin depigmentations; skeletal anomalies such as limb shortening,
lymphedema Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized edema, swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns inters ...
, increased soft tissues in the extremities, short/broad palms and/or fingers, and/or clinodactyly of the fifth fingers or toes; excessive prenatal and birth weights followed by postnatal declines in growth rates; delayed closure of the anterior fontanel; and/or delayed puberty in males but not females.


Causes

PKS is caused by an sSMC that consists of two copies or, less commonly, four copies of the genetic material in the p arm of
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
. Recent studies in two individuals with PKS found their sSMCs consisted specifically of genetic material located in a stretch of chromosome 12 's p arm starting at its band 11 and running to its end. This area, called the PKS critical region, contains three genes, '' ING4,
CHD4 Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the ''CHD4'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleo ...
'', and '' MFAP5'' (also termed the ''MAGP2'' gene), which are candidates for contributing to the development of the syndrome. One suggested mechanism for the development of the sSMC in PKS involves three sequential events: 1) chromosome 12 suffers a
nondisjunction Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I ...
, i.e. a failure of its
homologous chromosomes Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same locus (genetics), loci, where they provide points along e ...
or
sister chromatids A sister chromatid refers to the identical copies ( chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the du ...
to separate properly during the second meiosis cell division that forms maternal eggs; 2) while most of the eggs with this nondisjunction die, a rare egg with the nondisjunction acquires a second structural aberration, isochromosome formation, that results in the creation of an extra chromosome consisting of copies of two or four p arms but no q arms of chromosome 12, i.e. the sSMC; and 3) the sSMC-containing egg, after being fertilized by a genetically normal sperm, develops into an offspring containing copies of this sSMC in some but not all cells, tissues, and/or organs consequently have some but not all of the defects associated with PKS. This mechanism applies only to female parents who are by far the most common originators of the sSMC in PKS. The mechanism explaining the few cases in which male parents form a sperm containing this sSMC has not yet been clearly formulated.


Diagnosis


Prenatal diagnosis

PKS is commonly diagnosed by detecting its causative sSMC as defined by identifying the overexpression of its genetic material. This method has detected the sSMC and therefore diagnosed a fetus as having PKS based on genomic analyses of fetal skin
fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...
, placenta
chorionic villi Chorionic villi are Wiktionary:villus, villi that sprout from the chorion to provide maximal contact area with maternal blood. They are an essential element in pregnancy from a histology, histomorphologic perspective, and are, by definition, a pr ...
, cells isolated from the
amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
, fibroblasts isolated from the fetus's
umbilical cord In Placentalia, placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord i ...
, and cells isolated from the fetus's umbilical cord blood. PKS can also be diagnose using fetal ultasound imaging methods. Ultrasound imaging in PKS commonly find fetuses that are too large for their
gestational age In obstetrics, gestational age is a measure of the age of a pregnancy taken from the beginning of the woman's last menstrual period (LMP), or the corresponding age of the gestation as estimated by a more accurate method, if available. Such metho ...
, contain
polyhydramnios Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in about 1% of pregnancies. It is typically diagnosed when the amniotic fluid index (AFI) is greater than 24 cm. There are two clini ...
(excess
amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
in their
amniotic sac The amniotic sac, also called the bag of waters or the membranes, is the sac in which the embryo and later fetus develops in amniotes. It is a thin but tough transparent pair of biological membrane, membranes that hold a developing embryo (and l ...
s), and have rhizomelic limbs (shortening of the proximal part of the limbs). Less commonly, the imaging evidences
diaphragmatic hernia Diaphragmatic hernia is a defect or hole in the diaphragm that allows the abdominal contents to move into the chest cavity. Treatment is usually surgical. Types * Congenital diaphragmatic hernia ** Morgagni's hernia ** Bochdalek hernia * Hi ...
s and/or various other major PKS structural malformations. In most cases, however, the ultrasound findings are not diagnostic of PKS. Furthermore, ultrasound diagnoses is best applied in the second or third pregnancy trimester when structural anomalies are more clearly defined and detectable. Because the prenatal diagnosis of PKS using the methods just cited is difficult, often indecisive, and/or best employed later in a woman's pregnancy, prenatal cell-free DNA screening (cfDNA screening), also known as noninvasive prenatal screening, has been used to diagnose PKS. This method can diagnose PKS in 10 week and older fetuses. In cfDNA screening,
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
from a mothers blood is extracted and screened for the presence of specific chromosome abnormalities such as those associated with the Down syndrome,
Patau syndrome Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. The extra genetic material disrupts normal development, causing multiple and co ...
(also termed trisomy 13), and
Edwards syndrome Edwards may refer to: People * Edwards (surname), an English surname * Edwards family, a prominent family from Chile * Edwards Barham (1937–2014), American politician * Edwards Davis (1873–1936), American actor, producer, and playwright * Edwa ...
(also termed trisomy 18). (Small amounts of a fetus's DNA escapes through the
placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
to circulate in the mothers blood.) A
genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different individuals to see if any variant is associated with a trait. GWA s ...
done in China used genome-wide cfDNA analyses to diagnose various chromosome-related disorders including PKS. The study scanned the DNA in the blood of 29,007 pregnant women and found three cases with abnormal amount of DNA originating from the entire p-arm of chromosome 12. All three cases were confirmed to have a fetus with PKS. Two of these cases were missed by chromosomal microarray analysis of the placenta and chorionic villi. However, the study did not define the rate of false negative cases, i.e. negative results in women actually carrying a fetus with PKS. While further studies are required, this method may turn out to be a critically useful addition for the prenatal detection of PKS, particularly during early pregnancies for the purpose of pregnancy options counseling.


Postnatal diagnosis

The postnatal diagnosis of PKS is strongly suggested or indicated in most cases based on finding the key defects of PKS in an individual on
physical examination In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a Disease, medical condition. It generally consists of a series of ...
and various
radiography Radiography is an imaging technology, imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical ("diagnostic" radiog ...
,
ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...
, and related methods. However, some individuals with this syndrome do not have a sufficient number of these defects or have a set of defects that are also compatible with other birth defect disorders such as Fryns syndrome, trisomy 12p, and Sifrim-Hitz-Weiss syndrome (also termed CHD4 Neurodevelopmental Disorder). The diagnosis can be confirmed in these cases as well as in all cases of PKS by detecting its sSMC using special methods. This sSMC has been successfully detected (>90% of confirmed cases) in the DNA extracted by a buccal swab taken from the inside of an individual's cheek or the DNA extracted form an individual's cultured skin
fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...
, i.e. fibroblasts from a skin biopsy grown in a laboratory for at least several days. The sSMC in these tissues or cells is identified by
multiplex ligation-dependent probe amplification Multiplex ligation-dependent probe amplification (MLPA) is a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer (molecular biology), primer pair. It detects copy number cha ...
(i.e. MLPA) or microarray-based comparative genomic hybridization (i.e. array CGH). Because of mosaicism, testing an individual's circulating blood
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
only rarely detects (i.e. gives mostly false negative rate) in true PKS cases.


See also

*
List of cutaneous conditions Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the Human body, body and composed of Human skin, skin, hair, Nail (anatomy), nails, and related muscle and glands. The major function o ...


References


External links

{{DEFAULTSORT:Pallister-Killian syndrome Chromosomal abnormalities Rare syndromes Disturbances of human pigmentation Diseases named after discoverers