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 chromosomal abnormality. Although polygenic disorders ...

. PKS is due to the presence of an extra and abnormal

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

termed a

small supernumerary marker chromosome A small supernumerary marker chromosome (sSMC) is an abnormal extra chromosome. It contains copies of parts of one or more normal chromosomes and like normal chromosomes is located in the cell's nucleus, is replicated and distributed into each d ...

(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. 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 tissue, and persists ...

. 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 to ...

. 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, also known as a congenital disorder, 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 ...

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, also known as a congenital disorder, 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 ca ...

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 o ...

of the brain, and/or spot calcifications in the brain's

lateral sulcus In neuroanatomy, the lateral sulcus (also called Sylvian fissure, after Franciscus Sylvius, or lateral fissure) is one of the most prominent features of the human brain. The lateral sulcus is a deep fissure in each hemisphere that separates the ...

; deafness and/or blindness; autonomic nervous system dysfunctions such as

anhidrosis Hypohidrosis is a disorder in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyp''er''hidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidrosi ...

hypohidrosis Hypohidrosis is a disorder in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyp''er''hidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidrosi ...

, and/or episodic spells of hyperventilation interspersed with breath-holding; symptoms of spinal cord malformations; profound or less commonly mild to severe intellectual disability;

epileptic seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

; 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 * Hiatal ...

s; marked muscle weakness;

supernumerary nipples A supernumerary nipple is an additional instance of nipple occurring in mammals, including humans. They are often mistaken for moles. Studies variously report the prevalence of supernumerary nipples as approximately 1 in 18 and 1 in 40. https:/ ...

; abnormal facial features such as

frontal bossing Skull bossing is a descriptive term in medical physical examination indicating a protuberance of the skull, most often in the frontal bones of the forehead ("frontal bossing"). Although prominence of the skull bones may be normal, skull bossing m ...

, high frontal hairline, balding around the

temple A temple (from the Latin ) is a building reserved for spiritual rituals and activities such as prayer and sacrifice. Religions which erect temples include Christianity (whose temples are typically called churches), Hinduism (whose temples ...

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 as ...

, small and flat nose, full cheeks, long

philtrum The philtrum ( la, philtrum from Ancient Greek ''phíltron,'' 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 tubercl ...

, 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 the bow of Cupid, the Roman god of erotic love. The peaks of the bow coincide with the philtral columns giving a prominent bow appearance to the ...

-shaped upper lip,

micrognathia Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorm ...

(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 () or alveolar bone is the thickened ridge of bone that contains the tooth sockets on the jaw bones (in humans, the maxilla and the mandible). The structures are covered by gums as part of the oral cavity. The synonymous t ...

and/or gums, delayed teeth eruption, and/or missing or double teeth; patchy skin

depigmentation Depigmentation is the lightening of the skin or loss of pigment. Depigmentation of the skin can be caused by a number of local and systemic conditions. The pigment loss can be partial (injury to the skin) or complete (caused by vitiligo). It can be ...

s; skeletal anomalies such as limb shortening,

lymphedema Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns interstitial fl ...

, increased soft tissues in the extremities, short/broad palms and/or fingers, and/or

clinodactyly Clinodactyly is a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger"). It is a fairly common iso ...

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

. 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 Inhibitor of growth protein 4 is a protein that in humans is encoded by the ''ING4'' gene. Function The protein encoded by this gene is similar to ING1, a tumor suppressor protein that can interact with TP53, inhibit cell growth, and induce a ...

CHD4 Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the ''CHD4'' gene. Function The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling ...

'', 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.e. a failure of its

homologous chromosomes A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...

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 dup ...

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 that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

, placenta chorionic villi, cells isolated from the amniotic fluid, fibroblasts isolated from the fetus's

umbilical cord In 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 is physiologi ...

, 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 which is 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. Su ...

, contain polyhydramnios (excess amniotic fluid 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 membranes that hold a developing embryo (and later fetus) until s ...

s), and have

rhizomelic Rhizomelia refers to either a disproportion of the length of the proximal limb, such as the shortened limbs of achondroplasia, or some other disorder of the hip or shoulder. According to Stedman's medical dictionary "rhizomelic" means "relating to ...

limbs (shortening of the proximal part of the limbs). Less commonly, the imaging evidences

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 from a mothers blood is extracted and screened for the presence of specific chromosome abnormalities such as those associated with the

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...

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 comp ...

(also termed trisomy 13), and

Edwards syndrome Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features inc ...

(also termed trisomy 18). (Small amounts of a fetus's DNA escapes through the

placenta The placenta 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 the physically separate mate ...

to circulate in the mothers blood.) A

genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any vari ...

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 Pregnancy options counseling is a form of counseling that provides information and support regarding pregnancy. Women seeking pregnancy options counseling are typically doing so in the case of an unplanned or unintended pregnancy. Limited access to ...

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, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions about the pati ...

and various

radiography Radiography is an 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 radiography ("diagnostic" and "therapeu ...

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

, 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

, 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 pair. It detects copy number changes at the molecular level, ...

(i.e. MLPA) or

microarray-based comparative genomic hybridization Comparative genomic hybridization (CGH) is a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The ai ...

(i.e. array CGH). Because of mosaicism, testing an individual's circulating blood lymphocytes only rarely detects (i.e. gives mostly false negative results) in true PKS cases.

References

External links

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