Recent studies have shown higher rates of heterotaxy syndrome among  Hispanic  infants of  Mexican  descent, as well as female infants of non-Hispanic black and white mothers. Additional studies must be done to clarify the mechanisms behind  racial disparities  in heterotaxy syndrome. [ 28 ]  Individuals of Asian descent show a higher prevalence of heterotaxy syndrome in general than members of the  Western world . [ 29 ]


The National Birth Defects Prevention study (October 2014) attempted to link clinical presentations of situs ambiguus to  demographics  in an  epidemiological  study. [ 30 ]  This proved a difficult task due to the vast differences in presentation of this disorder. However, the authors are hopeful that finding a link can help inform clinical decision-making, predictive analyses, and future outcomes. [ citation needed ]


Situs inversus  (also called  situs transversus  or  oppositus ) is a  congenital condition  in which the major  visceral organs  are reversed or  mirrored  from their normal positions. The normal arrangement of internal organs is known as  situs solitus . Although cardiac problems are more common, many people with  situs inversus  have no medical symptoms or complications resulting from the condition, and until the advent of modern medicine, it was usually undiagnosed.


Situs inversus  is found in about 0.01% of the population, or about 1 person in 10,000. In the most common situation,  situs inversus totalis , it involves complete transposition (right to left reversal) of all of the  viscera . The heart is not in its usual position in the left chest, but is on the right, a condition known as  dextrocardia  ( lit.   ' right-hearted ' ). Because the relationship between the organs is not changed, most people with  situs inversus  have no associated medical symptoms or complications. [ 1 ]


An uncommon form of  situs inversus  is  isolated levocardia , in which the position of the heart is not mirrored alongside the other organs. Isolated levocardia carries a risk of heart defects, and so patients with the condition may require surgery to correct them.


In rarer cases such as  situs ambiguus  or heterotaxy,  situs  cannot be determined. In these patients, the liver may be midline, the spleen absent or multiple, and the bowel malrotated. Often, structures are duplicated or absent altogether. This is more likely to cause medical problems than  situs inversus totalis . [ 2 ]


In the absence of congenital heart defects, individuals with  situs inversus  are homeostatically normal, and can live standard healthy lives, without any complications related to their medical condition. There is a 5–10% prevalence of  congenital heart disease  in individuals with  situs inversus totalis , most commonly  transposition of the great vessels . The incidence of congenital heart disease is 95% in  situs inversus  with  levocardia . [ citation needed ]


Many people with  situs inversus totalis  are unaware of their unusual anatomy until they seek medical attention for an unrelated condition, such as a  rib fracture  or a bout of  appendicitis . The condition may also be discovered during the administration of certain medicines or during tests such as a  barium meal  or  enema . [ 3 ]  The reversal of the organs may then lead to some confusion, as many signs and symptoms will be on the atypical side. For example, if an individual with  situs inversus  develops  appendicitis , they will present to the physician with lower left abdominal pain, since that is where their appendix lies. [ note 1 ]  Thus, in the event of a medical problem, the knowledge that the individual has  situs inversus  can expedite diagnosis. People with this rare condition should inform their  doctors  before an examination, so the doctor can redirect their search for  heart sounds  and other  signs . Wearing a  medical identification tag  can help inform health care providers in the event the person is unable to communicate. [ citation needed ]


Situs inversus  also complicates  organ transplantation  operations as donor organs will more likely come from  situs solitus  (normal) donors. As hearts and livers are  chiral , geometric problems arise placing an organ into a cavity shaped in the mirror image. For example, a person who requires a heart transplant needs all their  great vessels  reattached to the donor heart. However, the orientation of these vessels in a person with  situs inversus  is reversed, necessitating steps so that the blood vessels join properly.


Situs inversus  is generally an  autosomal recessive   genetic  condition, although it can be  X-linked  or found in identical  "mirror image" twins . [ 4 ]


About 25% of individuals with  situs inversus  have an underlying condition known as  primary ciliary dyskinesia  (PCD). PCD is a dysfunction of the  cilia  that occurs during early  embryonic development . Normally functioning cilia determine the position of the internal organs during early development, and so embryos with PCD have a 50% chance of developing  situs inversus . If they do, they are said to have  Kartagener syndrome , characterized by the  triad  of  situs inversus , chronic  sinusitis , and  bronchiectasis . Cilia are also responsible for  clearing mucus  from the lung, and the dysfunction causes increased susceptibility to lung infections. Kartagener syndrome can also manifest with male infertility as functional cilia are required for proper sperm flagella function. [ citation needed ]


A marked increase in cases was observed several months after the lifting of the  zero-COVID-19 policy in China , which coincided with a rise in  SARS-CoV-2  infections. This rare clinical evidence suggests a possible link between  infection during pregnancy  and the development of situs inversus in the fetus, specifically during gestational weeks 4–6, the critical period for organ positioning. [ 5 ]


The condition affects all major structures within the  thorax  and  abdomen . Generally, the organs are simply transposed through the  sagittal plane . The heart is located on the right side of the thorax, the  stomach  and  spleen  on the right side of the abdomen and the  liver  and  gall bladder  on the left side. The heart's normal right atrium occurs on the left, and the left atrium is on the right. The lung anatomy is reversed and the left lung has three lobes while the right lung has two lobes. The intestines and other internal structures are also reversed from the normal, and the  blood vessels ,  nerves , and  lymphatics  are also transposed.


If the heart is swapped to the right side of the thorax, it is known as " situs inversus  with  dextrocardia " or " situs inversus totalis ". If the heart remains on the normal left side of the thorax, a much rarer condition (1 in 2,000,000 of the general population), it is known as " situs inversus  with  levocardia " or " situs inversus incompletus ".


Situs inversus  of the optic disc may occur unilaterally or bilaterally, associated with reduced  binocularity  and  stereoacuity  resembling  monofixation syndrome . It is characterized by emergence of the retinal vessels in an anomalous direction (from the nasal rather than the temporal aspect) with dysversion (tilt) of the optic disc. [ 6 ]


Situs inversus  does not appear to significantly affect rates of  handedness . Based on a 2004 study documenting  situs inversus  in individuals with  primary ciliary dyskinesia , the proportion of right-handedness among those with situs inversus did not differ significantly from that of those with  situs solitus . [ 7 ]  A more recent 2023 study failed to find statistically significant differences in cognition, albeit left-handedness was significantly more common at 26% compared to the 10.6% of general  population. [ 8 ]


Diagnosis of  situs inversus  can be made using  imaging techniques  such as  x-ray ,  ultrasound ,  CT scan , and  magnetic resonance imaging  (MRI). [ 9 ]


Any potential treatment would involve a complete and highly invasive surgical rearrangement of the internal viscera of the patient. Such a procedure is unnecessary, given that  situs inversus  rarely causes any additional symptoms. No treatment, medical or surgical, is prescribed for  situs inversus  individuals, with medical professionals instead treating any other symptoms the patient may have with awareness of the unique anatomy of the patient. [ citation needed ]


Situs inversus  is rare, affecting 0.01% of the population. [ 10 ] [ 11 ]


Dextrocardia  (the  heart  being located on the right side of the  thorax ) was seen and drawn by  Leonardo da Vinci , [ citation needed ]  and then recognised by  Marco Aurelio Severino  in 1643.  Situs inversus  was first described more than a century later by  Matthew Baillie . [ 2 ]


The term  situs inversus  is a short form of the  Latin  phrase  situs inversus viscerum , meaning "inverted position of the internal organs".


Notable individuals with documented cases of situs inversus include:


Smith–Fineman–Myers syndrome  (SFMS1) is a  congenital disorder  that causes  birth defects . This syndrome was named after Richard D. Smith, Robert M. Fineman and Gart G. Myers who discovered it around 1980. [ 3 ]


SFMS affects the skeletal and nervous system. This syndrome's external signs would be an unusual facial appearance with their heads being slightly smaller than average, a  narrow face  (clinically known as  dolichocephaly ), a large mouth with a drooping lower lip that is held open, protruding upper jaw, widely spaced upper front teeth, an underdeveloped chin,  cleft palate  and exotropied-slanted eyes with drooping eyelids.


Males who have SFMS have short stature and a thin body build. The skin is lightly pigmented with multiple freckles. They may have  scoliosis  and chest abnormalities.


Affected boys have reduced muscle tone as infants-young children. X-rays sometimes show that their bones are underdeveloped and show characteristics of the bones of younger children. Boys under the age of 10 usually have reduced muscle tone but later, patients with SFMS over the age of 10 have increased muscle tone and reflexes that cause spasticity. Their hands are short with unusual palm creases with short, shaped fingers and foot abnormalities, such as are shortened and  fused toes .


They have spleen agenesis (absence of the  spleen ) and the genitals may also show undescended testes ranging from mild to severe that leads to female gender assignment.


People who have SFMS have severe  intellectual disability  (formerly known as mental retardation). They are restless on occasion, have behavioral problems, seizures and  severe delay in language development . They are self-absorbed with reduced ability to socialize with others around them. They also have  psychomotor retardation  which is the slowing-down of thoughts and a reduction of physical movements. They have cortical atrophy (also known as degeneration) of the brain's outer layer, although it is usually found in older affected people. [ 4 ]


SFMS  is an X-linked disease by  chromosome  Xq13. X-linked diseases map to the human  X chromosome  because this syndrome is an X chromosome linked females who have two chromosomes are not affected but because males only have one X chromosome, they are more likely to be affected and show the full clinical symptoms. This disease only requires one copy of the abnormal X-linked gene to display the syndrome. Since females have two X chromosomes, the effect of one X chromosome is  recessive  and the second chromosome masks the affected chromosome. [ 5 ]


Affected fathers can never pass this X-linked disease to their sons but affected fathers can pass the X-linked gene to their daughters who has a 50% chance to pass this disease-causing gene to each of her children. Since females who  inherit  this gene do not show symptoms, they are called  carriers . Each of the female's carrier's son has a 50% chance to display the symptoms but none of the female carrier's daughters would display any symptoms. [ 4 ]


Some patients with SFMS have been founded to have a  mutation  of the gene in the  ATRX  on the X chromosome, also known as the  Xq13 location .  ATRX  is a gene disease that is associated with other forms of X-linked mental retardation like  Alpha-thalassemia/mental retardation syndrome ,  Carpenter syndrome ,  Juberg-Marsidi syndrome , and  spastic paraplegia . It is possible that patients with SFMS have   Alpha-thalassemia/mental retardation syndrome  without the affected  hemoglobin H  that leads to  Alphathalassemia/ mental retardation syndrome  in the traditionally recognized disease. [ 5 ]


The assessment for Smith-Finemen-Myers syndrome like any other mental retardation includes a detailed family history and physical exam that tests the mentality of the patient. The patient also gets a brain and skeletal imaging though CT scans or x-rays. They also does a chromosome study and certain other genetic biochemical tests to help figure out any other causes for the mental retardation.


The diagnosis of SFMS is based on visible and measurable symptoms. Until 2000, SFMS was not known to be associated with any particular gene. As of 2001, scientists do not yet know if other genes are involved in this rare disease. Generic analysis of the ATRX gene may prove to be helpful in diagnosis of SFMS. [ 6 ]


Treatments are usually based on the individuals symptoms that are displayed. The seizures are controlled with  anticonvulsant  medication. For the behavior problems, the doctors prescribe a few medications and behavioral modification routines that involve therapists and other types of therapy. Even if mental retardation is severe, it does not seem to shorten the lifespan of the patient or to get worse with age.


On September 15, 1991 in  Sydney, Australia , the  Prince of Wales Children's Hospital , reported on two brothers with a distinct facial appearance, severe mental retardation, short stature,  cryptorchidism  (undescended testicle),  asplenia  in one (absent spleen), dramatic failure to thrive, early  hypotonia , and later hypertonia, all suggestive of the Smith–Fineman–Myers syndrome. All five of the reported cases have been males, suggesting  X-linked  inheritance. [ 7 ]


On September 23, 1998 at the Hospital Injury Research and Rehabilitation at the University of São Paulo in Bauru, Brazil report on two boys,  monozygotic  twins born to normal and non consanguineous parents, presenting with an unusual facial appearance, cortical  atrophy ,  dolichocephaly , short stature,  cleft palate ,  micrognathia , prominent upper central incisors, bilateral Sidney line, minor foot deformities, unstableness in walking, early hypotonia,  hyperreflexia ,  hyperactivity ,  psychomotor retardation , and severe delay in language development. These symptoms resemble those previously described in the Smith–Fineman–Myers syndrome. [ 8 ]


Snyder–Robinson syndrome  ( SRS ) is an extremely rare  inherited   genetic disorder [ 1 ]  characterized by muscular and skeletal abnormalities, varying degrees of  intellectual disability , seizures, [ 2 ]  and slow development. [ 3 ]


SRS is caused by a mutated  SMS  gene  at  chromosome  Xp21.3-p22.12, which carries instructions for producing the  enzyme   spermine synthase . [ 4 ]  Spermine synthase in turn helps the body produce  spermine , a  polyamine  critical to cell processes such as  cell division , tissue repair, and  apoptosis . [ 5 ]  The resulting shortage of spermine in cells causes problems with development and brain function, though the exact mechanism is not understood.


The syndrome has also been referred to as  Snyder–Robinson X-linked mental retardation syndrome  ( MRXSSR ) and  spermine synthase deficiency . SRS exclusively affects males. [ 1 ]  Only about ten families currently have a child with SRS, and 50 people have been diagnosed worldwide since 1969. [ 6 ]


Snyder–Robinson usually is noticeable in infants, causing  hypotonia  and declining muscle tone with age.  Seizures  can occur in childhood, and children are especially susceptible to  broken bones . [ 3 ]


During early childhood, SRS causes mild to profound intellectual disability; speech difficulties; problems with walking;  osteoporosis ;  marfanoid habitus ; and  scoliosis ,  kyphosis , or both ( kyphoscoliosis ). Distinctive facial features include a  cleft palate ,  facial asymmetry , and a prominent lower lip. Kidney problems may also occur, such as  nephrocalcinosis  and renal  cysts . [ citation needed ]


Other symptoms that frequently appear in patients with Snyder-Robinson syndrome include  arachnodactyly , decreased muscle mass, disproportionately tall stature, long and  narrow face , nasal speech, slender toe, and thick lower lip  vermilion . [ 7 ]


SRS is a  recessive   X-linked  condition. [ 8 ]  There are no known female cases, as both copies of the  X chromosome  would need to be mutated. [ citation needed ]


When SRS is suspected, doctors will order a molecular genetic test to confirm a mutation in the  SMS  gene—specifically a " hemizygous   loss-of-function ... pathogenic variant". However, there are currently no formal criteria for a diagnosis. [ 3 ]


Individuals with Snyder–Robinson may be assisted by  occupational therapy ,  physical  or  speech therapy . Anti-seizure medications such as  carbamazepine ,  phenobarbital , and  clobazam  can be used to manage seizures [ 2 ] —the medication used often is influenced by the type of seizure. Bone density can be determined via a  DXA  scan and may be improved with  calcium  supplements. [ 3 ]


In 2014, several parents of individuals with SRS founded the Snyder–Robinson Foundation, a  501(c)(3)   non-profit  based in the US. [ 9 ] [ 6 ]  It is a member of the  National Organization for Rare Disorders . [ 10 ]


SRS was first reported in a 1969 paper published in  Clinical Pediatrics  by Russell D. Snyder [ 11 ]  and Arthur Robinson, who described the syndrome as "recessive sex-linked mental retardation in the absence of other recognizable abnormalities". [ 12 ]


Spondyloepimetaphyseal dysplasia  is a genetic condition affecting the bones. [ 1 ]


Types include:


Spondyloepimetaphyseal dysplasia, Strudwick type  is an inherited disorder of  bone  growth that results in  dwarfism , characteristic skeletal abnormalities, and problems with  vision . [ 1 ]  The name of the condition indicates that it affects the bones of the  spine  (spondylo-) and two regions near the ends of bones ( epiphyses  and  metaphyses ). This type was named after the first reported patient with the disorder. [ 2 ]  Spondyloepimetaphyseal dysplasia, Strudwick type is a subtype of  type II collagenopathies . [ 3 ]


The signs and symptoms of this condition at birth are very similar to those of  spondyloepiphyseal dysplasia congenita , a related skeletal disorder. Beginning in childhood, the two conditions can be distinguished in  X-ray  images by changes in areas near the ends of bones (metaphyses). [ 4 ]


People with this condition are short-statured from birth, with a very short trunk and shortened limbs. Their hands and feet, however, are usually average-sized. Curvature of the spine ( scoliosis  and lumbar lordosis) may be severe and can cause problems with breathing. Changes in the spinal bones ( vertebrae ) in the neck may also increase the risk of  spinal cord  damage. Other skeletal signs include flattened vertebrae ( platyspondyly ), severe protrusion of the breastbone ( pectus carinatum ), a  hip  joint deformity in which the upper leg bones turn inward ( coxa vara ), and a foot deformity known as  clubfoot . [ citation needed ]


Affected individuals have mild and variable changes in their facial features. The  cheekbones  close to the nose may appear flattened. Some infants are born with an opening in the roof of the mouth, which is called a  cleft palate . Severe nearsightedness (high  myopia ) and detachment of the  retina  (the part of the eye that detects light and color) are also common. [ citation needed ]


This condition is one of a spectrum of skeletal disorders caused by mutations in the  COL2A1  gene. The protein made by this gene forms type II  collagen , a molecule found mostly in  cartilage  and in the clear gel that fills the eyeball (the  vitreous ). Type II collagen is essential for the normal development of bones and other  connective tissues . Mutations in the  COL2A1  gene interfere with the assembly of type II collagen molecules, which prevents bones from developing properly and causes the signs and symptoms of this condition. [ citation needed ]


This condition is inherited in an  autosomal dominant  pattern, which means one copy of the altered gene is sufficient to cause the disorder. [ 5 ]


Spondyloperipheral dysplasia  is an  autosomal   dominant [ 1 ]  disorder of  bone  growth. The condition is characterized by flattened bones of the  spine  ( platyspondyly ) and unusually short fingers and toes ( brachydactyly ). Some affected individuals also have other skeletal abnormalities, short stature, nearsightedness ( myopia ), hearing loss, and  mental retardation . Spondyloperipheral dysplasia is a subtype of  collagenopathy, types II and XI .


Spondyloperipheral dysplasia is one of a spectrum of skeletal disorders caused by mutations in the  COL2A1   gene , located on  chromosome   12q13.11-q13.2 . [ 2 ]  The protein made by this gene forms type II  collagen , a molecule found mostly in  cartilage  and in the clear gel that fills the  vitreous humour  (the eyeball). Type II collagen is essential for the normal development of bones and other connective tissues (the tissues that form the body's supportive framework). [ citation needed ]


Mutations in the  COL2A1  gene interfere with the assembly of type II collagen molecules. The protein made by the altered  COL2A1  gene cannot be used to make type II collagen, resulting in a reduced amount of this type of collagen in the body. Instead of forming collagen molecules, the abnormal protein builds up in cartilage cells ( chondrocytes ). These changes disrupt the normal development of bones, leading to the signs and symptoms of spondyloperipheral dysplasia. [ citation needed ]


The disorder is believed to be inherited in an autosomal dominant manner. [ 1 ]  This indicates that the defective gene responsible for the disorder is located on an  autosome  (chromosome 12 is an autosome), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.


This article incorporates public domain text from  Spondyloperipheral dysplasia  at  NLM  Genetics Home Reference


Status marmoratus  is a congenital condition due to maldevelopment of the  corpus striatum  associated with  choreoathetosis , in which the striate nuclei have a marble-like appearance caused by altered  myelination  in the  putamen ,  caudate , and  thalamus  (there are bilateral hyperdensities restricted to the thalamus). This results from acute total  asphyxia  in the  basal nucleus  of full-term infants. It is associated with athetoid cerebral palsy and spastic quadriplegia. [ 1 ] [ 2 ]


Strophosomia  is a severe form of congenital ventral fissure, all abdominal and thoracic viscera being free in the uterus.


It is an extreme case of  celosomia .


It is a very rare  dysmorphic feature  in humans. [ 1 ]


The condition occurs regularly in  calves  and  lambs . The spine is flexed 180° so that the caudal region is near the neck, in so-called  Schizosoma reflexum . [ 2 ]


During the  obstetrical operations , the viscera are reached first, but the four limbs fold backwards may be barely accessible.


Cesarian section  is often required in  cows .  Fetotomy  can resolve the condition in  ewes .


This  veterinary medicine –related article is a  stub . You can help Wikipedia by  expanding it .


Genomic structural variation  is the variation in structure of an organism's  chromosome , such as deletions, duplications,  copy-number variants , insertions,  inversions  and  translocations . Originally, a structure variation affects a sequence length about 1kb to 3Mb, which is larger than  SNPs  and smaller than  chromosome abnormality  (though the definitions have some overlap). [ 1 ]  However, the operational range of structural variants has widened to include events > 50bp. [ 2 ]  Some structural variants are associated with  genetic diseases , however most are not. [ 3 ] [ 4 ]  Approximately 13% of the human genome is defined as structurally variant in the normal population, and there are at least 240 genes that exist as  homozygous  deletion  polymorphisms  in human populations, suggesting these genes are dispensable in humans. [ 4 ]  While humans carry a median of 3.6 Mbp in SNPs (compared to a reference genome), a median of 8.9 Mbp is affected by structural variation which thus causes most genetic differences between humans in terms of raw sequence data. [ 4 ]


Microscopic means that it can be detected with  optical microscopes , such as  aneuploidies ,  marker chromosome , gross rearrangements and variation in chromosome size. [ 5 ] [ 6 ]  The frequency in human population is thought to be underestimated due to the fact that some of these are not actually easy to identify. These structural abnormalities exist in 1 of every 375 live births by putative information. [ 7 ]


Sub-microscopic structural variants are much harder to detect owing to their small size. The first study in 2004 that used  DNA microarrays  could detect tens of genetic  loci  that exhibited  copy number variation ,  deletions  and  duplications , greater than 100  kilobases  in the human genome. [ 8 ]  However, by 2015 whole genome sequencing studies could detect around 5,000 of structural variants as small as 100  base pairs  encompassing approximately 20  megabases  in each individual genome. [ 3 ] [ 4 ]  These structural variants include deletions, tandem duplications,  inversions ,  mobile element insertions . The mutation rate is also much higher than microscopic structural variants, estimated by two studies at 16% and 20% respectively, both of which are probably underestimates due to the challenges of accurately detecting structural variants. [ 3 ] [ 9 ]  It has also been shown that the generation of spontaneous structural variants significantly increases the likelihood of generating further spontaneous  single nucleotide variants  or  indels  within 100  kilobases  of the structural variation event. [ 3 ]


Copy-number variation (CNV) is a large category of structural variation, which includes  insertions ,  deletions  and  duplications . In recent studies, copy-number variations are tested on people who do not have genetic diseases, using methods that are used for quantitative SNP genotyping. Results show that 28% of the suspected regions in the individuals actually do contain copy number variations. [ 10 ] [ 11 ]  Also, CNVs in human genome affect more nucleotides than  Single Nucleotide Polymorphism  (SNP).
It is also noteworthy that many of CNVs are not in coding regions. Because CNVs are usually caused by  unequal recombination , widespread similar sequences such as  LINEs  and  SINEs  may be a common mechanism of CNV creation. [ 12 ] [ 13 ]


There are several inversions known which are related to human disease. For instance, recurrent 400kb inversion in factor VIII gene is a common cause of  haemophilia A , [ 14 ]  and smaller inversions affecting  idunorate 2-sulphatase  (IDS) will cause  Hunter syndrome . [ 15 ]  More examples include  Angelman syndrome  and  Sotos syndrome . However, recent research shows that one person can have 56 putative inversions, thus the non-disease inversions are more common than previously supposed. Also in this study it's indicated that inversion breakpoints are commonly associated with segmental duplications. [ 16 ]  One 900 kb inversion in the  chromosome 17  is under  positive selection  and are predicted to increase its frequency in European population. [ 17 ]


More complex structural variants can occur include a combination of the above in a single event. [ 3 ]  The most common type of complex structural variation are non-tandem duplications, where sequence is duplicated and inserted in inverted or direct orientation into another part of the genome. [ 3 ]  Other classes of complex structural variant include deletion-inversion-deletions, duplication-inversion-duplications, and tandem duplications with nested deletions. [ 3 ]
There are also  cryptic translocations  and  segmental uniparental disomy  (UPD). There are increasing reports of these variations, but are more difficult to detect than traditional variations because these variants are balanced and array-based or  PCR -based methods are not able to locate them. [ 18 ]


Some  genetic diseases  are suspected to be caused by structural variations, but the relation is not very certain. It is not plausible to divide these variants into two classes as "normal" or "disease", because the actual output of the same variant will also vary. Also, a few of the variants are actually positively selected for (mentioned above).
A series of studies have shown that gene disrupting  spontaneous  ( de novo ) CNVs disrupt genes approximately four times more frequently in autism than in controls and contribute to approximately 5–10% of cases. [ 3 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ]  Inherited variants also contribute to around 5–10% of cases of autism. [ 3 ]


Structural variations also have its function in population genetics. Different frequency of a same variation can be used as a genetic mark to infer relationship between populations in different areas. A complete comparison between human and chimpanzee structural variation also suggested that some of these may be fixed in one species because of its adaptative function. [ 23 ]  There are also deletions related to resistance against  malaria  and  AIDS . [ 24 ] [ 25 ]  Also, some highly variable segments are thought to be caused by balancing selection, but there are also studies against this hypothesis. [ 26 ]


Some of genome browsers and  bioinformatic  databases have a list of structural variations in human genome with an emphasis on CNVs, and can show them in the genome browsing page, for example,  UCSC Genome Browser . [ 27 ]  Under the page viewing a part of the genome, there are "Common Cell CNVs" and "Structural Var" which can be enabled.
On NCBI, there is a special page  [ 28 ]  for structural variation. In that system, both "inner" and "outer" coordinates are shown; they are both not actual breakpoints, but surmised minimal and maximum range of sequence affected by the structural variation. The types are classified as insertion, loss, gain, inversion, LOH, everted, transchr and UPD. [ citation needed ]


New methods have been developed to analyze human genetic structural variation at high resolutions. The methods used to test the genome are in either a specific targeted way or in a genome wide manner.  For Genome wide tests, array-based comparative genome hybridization approaches bring the best genome wide scans to find new copy number variants. [ 30 ]  These techniques use DNA fragments that are labeled from a genome of interest and are hybridized, with another genome labeled differently, to arrays spotted with cloned DNA fragments. This reveals copy number differences between two genomes. [ 30 ]


For targeted genome examinations, the best assays for checking specific areas of the genome are primarily PCR based. The best established of the PCR based methods is real time quantitative polymerase chain reaction (qPCR). [ 30 ]  A different approach is to specifically check certain areas that surround known segmental duplications since they are usually areas of copy number variation. [ 30 ]  An SNP genotyping method that offers independent fluorescence intensities for two alleles can be used to target the nucleotides in between two copies of a segmental duplication. [ 30 ]  From this, an increase in intensity from one of the alleles compared to the other can be observed.


With the development of  next-generation sequencing  (NGS) technology, four classes of strategies for the detection of structural variants with NGS data have been reported, with each being based on patterns that are diagnostic of different classes of SV. [ 31 ] [ 29 ] [ 32 ] [ 33 ]


Tay–Sachs disease  is a  genetic disorder  that results in the destruction of nerve cells in the  brain  and  spinal cord . [ 1 ]  The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. [ 1 ]  This is then followed by  seizures ,  hearing loss , and  inability to move , with death usually occurring by the age of three to five. [ 3 ] [ 1 ]  Less commonly, the disease may occur later in childhood, adolescence, or adulthood (juvenile or late-onset). [ 1 ]  These forms tend to be less severe, [ 1 ]  but the juvenile form typically results in death by age 15. [ 4 ]


Tay–Sachs disease is caused by a  genetic mutation  in the  HEXA  gene on  chromosome 15 , which codes a  subunit  of the  hexosaminidase   enzyme  known as hexosaminidase A. [ 1 ]  It is inherited in an  autosomal recessive  manner. [ 1 ]  The mutation disrupts the activity of the enzyme, which results in the build-up of the molecule  GM2 ganglioside  within cells, leading to toxicity. [ 1 ]  Diagnosis may be supported by measuring the blood hexosaminidase A level or  genetic testing . [ 2 ]  Tay–Sachs disease is a type of  GM2 gangliosidosis  and  sphingolipidosis . [ 5 ]


The treatment of Tay–Sachs disease is  supportive  in nature. [ 2 ]  This may involve multiple specialities as well as psychosocial support for the family. [ 2 ]  The disease is rare in the general population. [ 1 ]  In  Ashkenazi Jews ,  French Canadians  of southeastern  Quebec , the  Old Order Amish  of  Pennsylvania , and the  Cajuns  of southern  Louisiana , the condition is more common. [ 2 ] [ 1 ]  Approximately 1 in 3,600 Ashkenazi Jews at birth are affected. [ 2 ]


The disease is named after British ophthalmologist  Waren Tay , who in 1881 first described a symptomatic red spot on the  retina  of the eye; and American neurologist  Bernard Sachs , who described in 1887 the  cellular  changes and noted an increased rate of disease in Ashkenazi Jews. [ 6 ]  Carriers of a single Tay–Sachs  allele  are typically normal. [ 2 ]  It has been hypothesized that being a carrier may confer protection from  tuberculosis , explaining the persistence of the allele in certain populations. [ 7 ]  Researchers are looking at  gene therapy  or  enzyme replacement therapy  as possible treatments. [ 2 ]


Tay–Sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimuli, known as the "startle response". There may also be listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset age of  neurological   symptoms . [ 8 ] [ 9 ]


Infants  with Tay–Sachs disease appear to develop normally for the first six months after  birth . Then, as  neurons  become distended with GM2 gangliosides, a relentless  deterioration  of mental and physical abilities begins. The child may become  blind ,  deaf , unable to  swallow ,  atrophied , and  paralytic . Death usually occurs before the age of four. [ 8 ]


Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease experience  cognitive  and  motor skill  deterioration,  dysarthria ,  dysphagia ,  ataxia , and  spasticity . [ 10 ]  Death usually occurs between the ages of five and fifteen years. [ 4 ]


A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of  gait  and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in  adolescence  or early  adulthood  – include  speech  and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a  schizophrenia -like  psychosis . [ 11 ]  Late-onset Tay–Sachs patients may become fully  wheelchair -bound. [ 12 ]


Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such as  Friedreich's ataxia . [ 13 ]


Tay–Sachs disease is an  autosomal recessive  genetic disorder, meaning that when both parents are  carriers , there is a 25% risk of giving birth to an affected child with each pregnancy. The affected child would have received a mutated copy of the gene from each parent. [ 8 ]  If a child received a normal copy from one parent and a mutated copy from the other, it is a  carrier . [ medical citation needed ]


Tay–Sachs results from  mutations  in the  HEXA   gene  on  chromosome 15 , which encodes the alpha-subunit of  beta-N-acetylhexosaminidase A , a  lysosomal   enzyme . By 2000, more than 100 different mutations had been identified in the human  HEXA  gene. [ 14 ]  These mutations have included single base insertions and deletions,  splice phase mutations ,  missense mutations , and other more complex patterns. Each of these mutations alters the  gene's protein product  (i.e., the enzyme), sometimes severely inhibiting its function. [ 15 ]  In recent years, population studies and pedigree analysis  have shown  how such mutations arise and spread within small  founder populations . [ 16 ] [ 17 ]  Initial research focused on several such founder populations:


In the 1960s and early 1970s, when the  biochemical  basis of Tay–Sachs disease was first becoming known, no mutations had been  sequenced  directly for genetic diseases. Researchers of that era did not yet know how common  polymorphisms  would prove to be. The "Jewish Fur Trader Hypothesis", with its implication that a single mutation must have spread from one population into another, reflected the knowledge at the time. [ 22 ]  Subsequent research, however, has proven that a large variety of different  HEXA  mutations can cause the disease. Because Tay–Sachs was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of  compound heterozygosity  has been demonstrated. [ 23 ]


Compound heterozygosity ultimately explains the disease's variability, including the late-onset forms. The disease can potentially result from the inheritance of two unrelated mutations in the  HEXA  gene, one from each parent. Classic infantile Tay–Sachs disease results when a child has inherited mutations from both parents that completely stop the  biodegradation  of  gangliosides . Late onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically be heterozygotes, with two differing  HEXA  mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least one  HEXA  copy that still enables some level of hexosaminidase A activity, a later onset disease form occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote. [ 24 ]


Heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity but manifest no disease symptoms. This phenomenon is called dominance; the biochemical reason for  wild-type  alleles' dominance over nonfunctional mutant alleles in  inborn errors of metabolism  comes from how  enzymes  function. Enzymes are  protein   catalysts  for chemical reactions; as catalysts, they speed up reactions without being used up in the process, so only small enzyme quantities are required to carry out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so will manifest the abnormal  phenotype  (i.e. will develop full-blown disease). A normal:mutated heterozygote (heterozygous individual, also known as a 'carrier') has at least half of the normal enzyme activity level, due to the expression of the wild-type allele. This level is normally enough to enable normal functioning and thus prevent phenotypic expression (i.e. a normal:mutated carrier will not become ill). [ 25 ]


Tay–Sachs disease is caused by insufficient activity of the enzyme  hexosaminidase A . Hexosaminidase A is a vital  hydrolytic enzyme , found in the  lysosomes , that breaks down  sphingolipids . When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks down  fatty acid  derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. Patients with and carriers of Tay–Sachs can be identified by a simple  blood test  that measures hexosaminidase A activity. [ 8 ]


The  hydrolysis  of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; the third is a small  glycolipid  transport protein, the GM2 activator protein ( GM2A ), which acts as a substrate-specific  cofactor  for the enzyme. Deficiency in any one of these proteins leads to ganglioside storage, primarily in the  lysosomes  of  neurons . Tay–Sachs disease (along with  AB-variant GM2-gangliosidosis  and  Sandhoff disease ) occurs because a mutation inherited from both parents deactivates or inhibits this process. Most Tay–Sachs mutations probably do not directly affect protein functional elements (e.g., the  active site ). Instead, they cause incorrect  folding  (disrupting function) or disable intracellular transport. [ 26 ]


In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset, the initial testing involves an  enzyme assay  to measure the activity of hexosaminidase in  serum ,  fibroblasts , or  leukocytes . Total hexosaminidase enzyme activity is decreased in individuals with Tay–Sachs as is the percentage of hexosaminidase A. After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued. [ 27 ]  All patients with infantile onset Tay–Sachs disease have a "cherry red"  macula  in the  retina , easily observable by a physician using an  ophthalmoscope . [ 8 ] [ 28 ]  This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. The  choroidal  circulation is showing through "red" in this  foveal  region where all  retinal ganglion cells  are pushed aside to increase  visual acuity . Thus, this cherry-red spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic analysis of the retinal neurons shows they are distended from excess ganglioside storage. [ 29 ]  Unlike other lysosomal storage diseases (e.g.,  Gaucher disease ,  Niemann–Pick disease , and  Sandhoff disease ),  hepatosplenomegaly  (liver and spleen enlargement) is not seen in Tay–Sachs. [ 30 ]


Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:


As of 2010 there was no treatment that addressed the cause of Tay–Sachs disease or could slow its progression; people receive  supportive care  to ease the symptoms and extend life by reducing the chance of contracting infections. [ 36 ]  Infants are given feeding tubes when they can no longer swallow. [ 37 ]  In late-onset Tay–Sachs, medication (e.g.,  lithium  for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g.,  tricyclic antidepressants ,  phenothiazines ,  haloperidol , and  risperidone ) are associated with significant adverse effects. [ 24 ] [ 38 ]


As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4. Children with the juvenile form are likely to die between the ages 5–15, while the lifespans of those with the adult form will probably not be affected. [ 36 ]


Ashkenazi Jews  have a high incidence of Tay–Sachs and other  lipid storage diseases . In the  United States , about 1 in 27 to 1 in 30  Ashkenazi Jews  is a recessive carrier. The disease  incidence  is about 1 in every 3,500 newborn among Ashkenazi Jews. [ 39 ]   French Canadians  and the  Cajun  community of  Louisiana  have an occurrence similar to the Ashkenazi Jews.  Irish Americans  have a 1 in 50 chance of being a carrier. [ 40 ]  In the general population, the incidence of carriers as  heterozygotes  is about 1 in 300. [ 9 ]  The incidence is approximately 1 in 320,000 newborns in the general population in the United States. [ 41 ]


Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:


Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. Studies of Tay–Sachs mutations using new molecular techniques such as  linkage disequilibrium  and  coalescence  analysis have brought an emerging consensus among researchers supporting the founder effect theory. [ 43 ] [ 45 ] [ 46 ]


Waren Tay  and  Bernard Sachs  were two physicians. They described the disease's progression and provided  differential diagnostic  criteria to distinguish it from other neurological disorders with similar symptoms. [ 6 ]


Both Tay and Sachs reported their first cases among Ashkenazi Jewish families. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member. [ 47 ]  By 1884, he had seen three cases in a single family. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to other New York Neurological Society members. [ 48 ] [ 49 ]


Sachs, who recognized that the disease had a familial basis, proposed that the disease should be called  amaurotic familial idiocy . However, its genetic basis was still poorly understood. Although  Gregor Mendel  had published his article on the genetics of peas in 1865, Mendel's paper was largely forgotten for more than a generation – not rediscovered by other scientists until 1899. Thus, the Mendelian model for explaining Tay–Sachs was unavailable to scientists and doctors of the time. The first edition of the  Jewish Encyclopedia , published in 12 volumes between 1901 and 1906, described what was then known about the disease: [ 50 ]


It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases has been observed in the United States—over thirty in number. It was at first thought that this was an exclusively Jewish disease because most of the cases at first reported were between Russian and Polish Jews; but recently there have been reported cases occurring in non-Jewish children. The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities; and marasmus, associated with symmetrical changes in the macula lutea. On investigation of the reported cases, they found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease. No preventive measures have as yet been discovered, and no treatment has been of benefit, all the cases having terminated fatally.


Jewish immigration to the United States  peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in  Eastern Europe ; this was also a period of  nativism  (hostility to immigrants) in the United States. Opponents of immigration often questioned whether immigrants from southern and eastern Europe could be assimilated into American society. Reports of Tay–Sachs disease contributed to a perception among nativists that Jews were an inferior race. [ 49 ]


In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs disease was caused by an enzyme defect; they also proved that Tay–Sachs patients could be diagnosed by an assay of hexosaminidase A activity. [ 51 ]  The further development of enzyme assays demonstrated that levels of hexosaminidases A and B could be measured in patients and carriers, allowing the reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis. [ 35 ] [ 52 ]  By the end of 1979, researchers had identified three variant forms of  GM2 gangliosidosis , including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing. [ 53 ]


Since carrier testing for Tay–Sachs began in 1971, millions of Ashkenazi Jews have been screened as carriers. Jewish communities embraced the cause of genetic screening from the 1970s on. The success with Tay–Sachs disease has led  Israel  to become the first country that offers free genetic screening and  counseling  for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel. [ 54 ]


Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was an  enzyme assay  test (prior to  polymerase chain reaction  testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of a  selective process . A continuing controversy is whether  heterozygotes  (carriers) have or had a selective advantage. The presence of four different  lysosomal storage disorders  in the  Ashkenazi Jewish  population suggests a past selective advantage for heterozygous carriers of these conditions." [ 45 ]


This controversy among researchers has reflected various debates among geneticists at large: [ 55 ]


Enzyme replacement therapy  techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay–Sachs as well. The goal would be to replace the nonfunctional enzyme, a process similar to  insulin  injections for  diabetes . However, in previous studies, the  HEXA  enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that forms the  blood–brain barrier  in humans. [ citation needed ]


Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into the  cerebrospinal fluid  (CSF) which bathes the brain. However, intracerebral neurons seem unable to take up this physically large  molecule  efficiently even when it is directly by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective so far. [ 57 ]


Tay–Sachs disease exists in  Jacob sheep . [ 58 ]  The biochemical mechanism for this disease in the Jacob sheep is virtually identical to that in humans, wherein diminished activity of hexosaminidase A results in increased concentrations of GM2 ganglioside in the affected animal. [ 59 ]  Sequencing of the  HEXA  gene  cDNA  of affected Jacobs sheep reveal an identical number of  nucleotides  and  exons  as in the human  HEXA  gene, and 86% nucleotide sequence  identity . [ 58 ]  A missense mutation (G444R) [ 60 ]  was found in the  HEXA  cDNA of the affected sheep. This mutation is a single nucleotide change at the end of exon 11, resulting in that exon's deletion (before translation) via  splicing . The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy  clinical trials , which may prove useful for disease treatment in humans. [ 58 ]


Other experimental methods being researched involve  substrate reduction therapy , which attempts to use alternative enzymes to increase the brain's catabolism of GM2 gangliosides to a point where residual degradative activity is sufficient to prevent substrate accumulation. [ 61 ] [ 62 ]  One experiment has demonstrated that using the enzyme  sialidase  allows the genetic defect to be effectively bypassed, and as a consequence, GM2 gangliosides are metabolized so that their levels become almost inconsequential. If a safe pharmacological treatment can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – then this new form of therapy could essentially cure the disease. [ 63 ]


Another metabolic therapy under investigation for Tay–Sachs disease uses  miglustat . [ 64 ]  This drug is a reversible  inhibitor  of the enzyme  glucosylceramide synthase , which catalyzes the first step in synthesizing glucose-based  glycosphingolipids  like GM2 ganglioside. [ 65 ]


As Tay–Sachs disease is a deficiency of β-hexosaminidase A, deterioration of affected individuals could be slowed or stopped through the use of a substance that increases its activity. However, since in infantile Tay–Sachs disease there is no β-hexosaminidase A, the treatment would be ineffective, but for people affected by Late-Onset Tay–Sachs disease, β-hexosaminidase A is present, so the treatment may be effective. The drug  pyrimethamine  has been shown to increase activity of β-hexosaminidase A. [ 66 ]  However, the increased levels of β-hexosaminidase A still fall far short of the desired "10% of normal HEXA", above which the phenotypic symptoms begin to disappear. [ 66 ]


This is a highly invasive procedure which involves destroying the patient's blood system with chemotherapy and administering  cord blood . Of five people who had received the treatment as of 2008, two were still alive after five years and they still had a great deal of health problems. [ 67 ]


Critics point to the procedure's harsh nature—and the fact that it is unapproved. Other significant issues involve the difficulty in crossing the  blood–brain barrier , as well as the great expense, as each unit of cord blood costs $25,000, and adult recipients need many units. [ 68 ]


On 10 February 2022, the first ever gene therapy was announced, it uses an  adeno-associated virus (AAV)  to deliver the correct instruction for the  HEXA  gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related  adverse events . [ 69 ] [ 70 ] [ 71 ]


A  teratoma  is a  tumor  made up of several types of  tissue , such as  hair ,  muscle ,  teeth , or  bone . [ 4 ]  Teratomata typically form in the  tailbone  (where it is known as a  sacrococcygeal teratoma ),  ovary , or  testicle . [ 4 ]


Symptoms may be minimal if the tumor is small. [ 2 ]  A testicular teratoma may present as a painless lump. [ 1 ]  Complications may include  ovarian torsion ,  testicular torsion , or  hydrops fetalis . [ 1 ] [ 2 ] [ 3 ]


They are a type of  germ cell tumor  (a tumor that begins in the cells that give rise to  sperm  or  eggs ). [ 4 ] [ 8 ]  They are divided into two types: mature and immature. [ 4 ]  Mature teratomas include  dermoid cysts  and are generally  benign . [ 8 ]  Immature teratomas may be  cancerous . [ 4 ] [ 9 ]  Most ovarian teratomas are mature. [ 10 ]  In adults, testicular teratomas are generally cancerous. [ 11 ]  Definitive diagnosis is based on a  tissue biopsy . [ 2 ]


Treatment of coccyx, testicular, and ovarian teratomas is generally by surgery. [ 5 ] [ 6 ] [ 12 ]  Testicular and immature ovarian teratomas are also frequently treated with  chemotherapy . [ 6 ] [ 10 ]


Teratomas occur in the coccyx in about one in 30,000 newborns, making them one of the most common tumors in this age group. [ 5 ] [ 7 ]  Females are affected more often than males. [ 5 ]  Ovarian teratomas represent about a quarter of  ovarian tumors  and are typically noticed during middle age. [ 10 ]  Testicular teratomas represent almost half of  testicular cancers . [ 13 ]  They can occur in both children and adults. [ 14 ]  The term comes from the Greek word for "monster" [ 15 ]  plus the "-oma" suffix used for tumors.


Teratomas can cause an autoimmune illness called  Anti-NMDA receptor encephalitis . In this condition, the teratomas may contain B cells with NMDA-receptor specificities. [ 16 ]


After teratoma removal surgery,  a risk exists of regrowth in place, or in nearby organs. [ 17 ]


A mature teratoma is a grade 0 teratoma.  They are highly variable in form and histology, and may be solid, cystic, or a combination of the two.  A mature teratoma often contains several different types of tissue such as  skin ,  muscle , and  bone .  Skin may surround a cyst and grow abundant  hair   (see:  § Dermoid cyst ) .  Mature teratomas generally are benign, with 0.17–2% of mature cystic teratomas becoming malignant. [ 18 ]


Immature teratoma is the malignant counterpart of the mature teratoma and contains immature tissues which typically show  primitive or embryonal   neuroectodermal  histopathology. Immature teratoma has one of the lowest rates of  somatic mutation  of any tumor type and results from one of five mechanisms of  meiotic failure . [ 19 ]


Gliomatosis peritoneii, which presents as a deposition of mature glial cells in the peritoneum, is almost exclusively seen in conjunction with cases of ovarian teratoma. Through genetic studies of exome sequence, it was found that gliomatosis is genetically identical to the parent ovarian tumor and developed from cells that disseminate from the ovarian teratoma. [ 19 ]


A  dermoid cyst  is a mature cystic teratoma containing hair (sometimes very abundant) and other structures characteristic of normal skin and other tissues derived from the  ectoderm . The term is most often applied to teratoma on the skull sutures and in the ovaries of females. [ citation needed ]


Fetus  in fetu  and fetiform teratoma are rare forms of mature teratomas that include one or more components resembling a malformed fetus.  Both forms may contain or appear to contain complete organ systems, even major body parts, such as a torso or limbs.  Fetus  in fetu  differs from fetiform teratoma in having an apparent  spine  and  bilateral symmetry . [ 20 ]


Most authorities agree that fetiform teratomas are highly developed mature teratomas;  the natural history of fetus  in fetu  is controversial. [ 20 ]  It has been noted that fetiform teratoma is reported more often (by gynecologists) in ovarian teratomas, and fetus  in fetu  is reported more often (by general surgeons) in retroperitoneal teratomas.  Fetus  in fetu  has often been interpreted as a  fetus  growing within its  twin .  As such, this interpretation assumes a special complication of  twinning , one of several grouped under the term  parasitic twin .  In many cases, the fetus  in fetu  is reported to occupy a fluid-filled cyst within a mature teratoma. [ 21 ] [ 22 ] [ 23 ] [ 24 ]   Cysts within mature teratomas may have partially-developed organ systems: reports include cases of partial  cranial bones ,  long bones  and a rudimentary, beating heart. [ 25 ] [ 26 ]


Regardless of whether fetus  in fetu  and fetiform teratoma are one entity or two, they are distinct from and not to be confused with  ectopic pregnancy .


A struma ovarii (also known as  goitre  of the ovary or ovarian goiter) is a rare form of mature teratoma that contains mostly  thyroid  tissue. [ 27 ]


Epignathus is a rare teratoma originating in the oropharyngeal area that occurs  in utero . It presents with a mass protruding from the mouth at birth. Untreated, breathing is impossible. An  EXIT procedure  is the recommended initial treatment.


Teratomas may be found in babies, children, and adults. Teratomas of embryonal origin are most often found in babies at birth, in young children, and, since the advent of  ultrasound imaging , in fetuses.


The most diagnosed fetal teratomas are  sacrococcygeal teratoma  (Altman types I, II, and III) and cervical (neck) teratoma.  Because these teratomas project from the fetal body into the surrounding  amniotic fluid , they can be seen during routine prenatal ultrasound exams.  Teratomas within the fetal body are less easily seen with ultrasound;  for these, MRI of the pregnant uterus is more informative. [ 28 ] [ 29 ]


Teratomas are not dangerous for the fetus unless either a  mass effect  occurs or a large amount of blood flows through the tumor (known as vascular steal). The mass effect frequently consists of obstruction of normal passage of fluids from surrounding organs.  The vascular steal can place a strain on the growing heart of the fetus, even resulting in heart failure, thus must be monitored by fetal  echocardiography .


Teratomas belong to a class of tumors known as  nonseminomatous   germ cell tumor .  All tumors of this class are the result of abnormal development of  pluripotent  cells:  germ cells  and  embryonal cells . Teratomas of embryonic origin are  congenital ; teratomas of germ cell origin may or may not be congenital. The kind of pluripotent cell appears to be unimportant, apart from constraining the location of the teratoma in the body.


Teratomas derived from germ cells occur in the  testicle  and  ovaries . Teratomas derived from embryonic cells usually occur on the subject's midline: in the brain, elsewhere in the  skull , in the nose, in the tongue, under the tongue, and in the  neck  (cervical teratoma),  mediastinum ,  retroperitoneum , and attached to the  coccyx .  Teratomas may also occur elsewhere: very rarely in solid organs (most notably the heart and liver) and hollow organs (such as the stomach and bladder), and more commonly on the  skull sutures .


Teratoma rarely include more complicated body parts such as  teeth ,  brain matter , [ 30 ]   eyes , [ 31 ] [ 32 ]  or  torso . [ 33 ]


Concerning the origin of teratomas,  numerous hypotheses exist. [ 20 ]   These hypotheses are not to be confused with the unrelated hypothesis that fetus  in fetu  (see below) is not a teratoma at all, but rather a  parasitic twin .


Teratomas are thought to originate  in utero , so can be considered  congenital  tumors. Many teratomas are not diagnosed until much later in childhood or in adulthood. Large tumors are more likely to be diagnosed early on. Sacrococcygeal and cervical teratomas are often detected by prenatal  ultrasound . Additional diagnostic methods may include prenatal  magnetic resonance imaging . In rare circumstances, the tumor is so large that the fetus may be damaged or die. In the case of large sacrococcygeal teratomas, a significant portion of the fetus'  blood flow  is redirected toward the teratoma (a phenomenon called  steal syndrome ), causing  heart failure , or  hydrops , of the fetus. In certain cases,  fetal surgery  may be indicated.


Beyond the newborn period, symptoms of a teratoma depend on its location and organ of origin. Ovarian teratomas often present with abdominal or  pelvic pain , caused by  torsion  of the ovary or irritation of its ligaments. A recently discovered condition where ovarian teratomas cause encephalitis associated with antibodies against the  N-methyl-D-aspartate  receptor antibody (NMDAR) - often referred to as " anti-NMDA receptor encephalitis ", was identified as a serious complication. Patients develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. [ 34 ]  Testicular teratomas present as a palpable mass in the testis;  mediastinal  teratomas often cause compression of the lungs or the airways and may present with  chest pain  and/or respiratory symptoms.


Some teratomas contain  yolk sac  elements, which secrete  alpha-fetoprotein . Its detection may help to confirm the diagnosis and is often used as a marker for recurrence or treatment efficacy, but is rarely the method of initial diagnosis. (Maternal serum  alpha-fetoprotein  is a useful  screening test  for other fetal conditions, including  Down syndrome ,  spina bifida , and  abdominal wall  defects such as  gastroschisis .)


Regardless of location in the body, a teratoma is classified according to a  cancer staging  system.  This indicates whether  chemotherapy  or  radiation therapy  may be needed in addition to surgery.  Teratomas commonly are classified using the  Gonzalez-Crussi [ 20 ]  grading system: 0 or mature ( benign ); 1 or immature, probably benign; 2 or immature, possibly  malignant  (cancerous); and 3 or frankly malignant. If frankly malignant, the tumor is a cancer for which additional cancer staging applies. [ citation needed ]


Teratomas are also classified by their content; a solid teratoma contains only tissues (perhaps including more complex structures); a cystic teratoma contains only pockets of fluid or semifluid such as  cerebrospinal fluid ,  sebum , or fat; a mixed teratoma contains both solid and cystic parts. Cystic teratomas usually are grade 0 and, conversely, grade 0 teratomas usually are cystic.


Grades 0, 1, and 2 pure teratomas have the potential to become malignant (grade 3), and malignant pure teratomas have the potential to  metastasize .  These rare forms of teratoma with malignant transformation may contain elements of somatic (not germ cell) malignancy such as  leukemia ,  carcinoma , or  sarcoma . [ 35 ]
A teratoma may contain elements of other germ cell tumors, in which case it is not a pure teratoma, but rather is a mixed  germ cell tumor  and is malignant.  In infants and young children, these elements usually are  endodermal sinus tumor , followed by  choriocarcinoma .  Finally, a teratoma can be pure and not malignant yet highly aggressive;  this is exemplified by growing teratoma syndrome, in which chemotherapy eliminates the malignant elements of a mixed tumor, leaving pure teratoma, which paradoxically begins to grow very rapidly. [ 36 ]


A "benign" grade 0 (mature) teratoma nonetheless has a risk of malignancy.  Recurrence with malignant  endodermal sinus tumor  has been reported in cases of formerly benign mature teratoma, [ 37 ] [ 38 ]  even in fetiform teratoma and fetus in fetu. [ 39 ] [ 40 ]   Squamous cell carcinoma  has been found in a mature cystic teratoma at the time of initial surgery. [ 41 ]  A grade 1 immature teratoma that appears to be benign (e.g., because AFP is not elevated) has a much higher risk of malignancy, and requires adequate follow-up. [ 42 ] [ 43 ] [ 44 ] [ 45 ]
This grade of teratoma also may be difficult to diagnose correctly.  It can be confused with other small round cell neoplasms such as neuroblastoma, small cell carcinoma of hypercalcemic type, primitive neuroectodermal tumor, Wilm's tumor, desmoplastic small round cell tumor, and non-Hodgkin  lymphoma . [ 46 ]


A teratoma with malignant transformation  is a very rare form of teratoma that may contain elements of somatic malignant tumors such as leukemia, carcinoma, or sarcoma. [ 35 ]  Of 641 children with pure teratoma, nine developed TMT: [ 47 ]  five carcinoma, two  glioma , and two embryonal carcinoma (here, these last are classified among germ cell tumors).


Extraspinal  ependymoma , usually considered to be a glioma (a type of nongerm cell tumor), may be an unusual form of mature teratoma. [ 48 ]


The treatment of choice is complete surgical removal ( i.e.,  complete resection). [ 49 ] [ 50 ]  Teratomas are normally well-encapsulated and noninvasive of surrounding tissues, hence they are relatively easy to resect from surrounding tissues. Exceptions include teratomas in the brain, and very large, complex teratomas that have pushed into and become interlaced with adjacent muscles and other structures.


Prevention of recurrence does not require  en bloc  resection of surrounding tissues.


For malignant teratomas, usually, surgery is followed by chemotherapy.


Teratomas that are in surgically inaccessible locations, or are very complex, or are likely to be malignant (due to late discovery and/or treatment) sometimes are treated first with chemotherapy.  [ citation needed ]


Although often described as benign, a teratoma does have malignant potential.  A UK study of 351 infants and children diagnosed with "benign" teratoma reported 227 with MT, 124 with IT.  Five years after surgery, event-free survival was 92.2% and 85.9%, respectively, and overall survival was 99% and 95.1%. [ 51 ]   A similar study in Italy reported on 183 infants and children diagnosed with teratoma.  At 10 years after surgery, event-free and overall survival were 90.4% and 98%, respectively. [ 52 ]


Depending on which tissue(s) it contains, a teratoma may secrete a variety of chemicals with systemic effects. Some teratomas secrete the "pregnancy hormone"  human chorionic gonadotropin  (βhCG), which can be used in clinical practice to monitor the successful treatment or relapse in patients with a known HCG-secreting teratoma. This hormone is not recommended as a diagnostic marker, because most teratomas do not secrete it. Some teratomas secrete  thyroxine , in some cases to such a degree that it can lead to clinical  hyperthyroidism  in the patient. Of special concern is the secretion of  alpha-fetoprotein  (AFP); under some circumstances, AFP can be used as a diagnostic marker specific for the presence of  yolk sac  cells within the teratoma.  These cells can develop into a frankly malignant tumor known as  yolk sac tumor  or  endodermal sinus tumor .


Adequate follow-up requires close observation, involving repeated physical examination, scanning (ultrasound, MRI, or CT), and measurement of AFP and/or βhCG. [ 53 ] [ 54 ]


Embryonal teratomas most commonly occur in the sacrococcygeal region;  sacrococcygeal teratoma  is the single most common tumor found in newborn humans.


Of teratomas on the skull sutures, about 50% are found in or adjacent to the  orbit . [ 56 ]  Limbal dermoid is a  choristoma , not a teratoma.


Teratoma qualifies as a  rare disease , but is not extremely rare.  Sacrococcygeal teratoma alone is diagnosed at birth in one out of 40,000 humans.  Given the current human population and birth rate, this equals five per day or 1800 per year.  Add to that number sacrococcygeal teratomas diagnosed later in life, and teratomas in other locales, and the  incidence  approaches 10,000 new diagnoses of teratoma per year. [ citation needed ]


Ovarian teratomas have been reported in  mares , [ 57 ]
 mountain lions , [ 58 ] [ 59 ]  and canines. [ 60 ]  Teratomas also occur, rarely, in other species. [ 61 ]


Pluripotent stem cells including human induced pluripotent stem cells have a unique property of being able to generate teratomas when injected in rodents in the research laboratory. [ 62 ]  The roots of this observation has been attributed to  Leroy Stevens  of the  Jackson Laboratory . [ 63 ]  In 1970, Stevens noticed that the cell populations that gave rise to teratomas were very similar to the cells of very early embryos.
For this reason, the so-called "teratoma assay" is one of the gold-standard validation assays for pluripotent stem cells. [ 64 ]  Because differentiated human pluripotent stem cells are being developed as the basis for numerous regenerative medicine therapies, there is concern that residual undifferentiated stem cells could lead to teratoma formation in injected patients, and researchers are working to develop methods to address this concern. [ 65 ]


New research has looked at utilizing the human teratoma in chimeric animal studies as a promising platform for modeling multi-lineage human development, pan-tissue functional genetic screening, and tissue engineering. [ 66 ]


This article incorporates  public domain material  from  Dictionary of Cancer Terms .  U.S. National Cancer Institute .


Tetra-amelia syndrome  ( tetra-  +  amelia ), also called  autosomal recessive tetraamelia , [ 1 ]  is an extremely rare  autosomal   recessive [ 2 ]   congenital disorder  characterized by the absence of all four limbs. Other areas of the body are also affected by malformations, such as the face, skull, reproductive organs, anus, lungs and pelvis. [ 1 ]  The disorder can be caused by  recessive  mutations in the  WNT3  or  RSPO2  genes. [ 2 ] [ 3 ]


Tetra-amelia syndrome is characterized by the complete absence of all four limbs. The syndrome causes severe malformations of various parts of the body, including the face and head, heart, nervous system, skeleton, and genitalia. [ 1 ]  In many cases, the lungs are underdeveloped, which makes breathing difficult or impossible. Because children with tetra-amelia syndrome have such serious medical problems, most are stillborn or die shortly after birth.


Researchers have found loss-of-function  mutations  in the  WNT3  or the  RSPO2  genes in people with tetra-amelia syndrome from several  consanguineous  families. These two gene encode proteins belonging to the  WNT  pathway which plays critical roles during development.


The protein produced from the WNT3 and RSPO2 genes are involved in the formation of the limbs and other body systems during embryonic development. Mutations in the WNT3 or RSPO2 genes prevent cells from producing functional WNT3 and RSPO2 proteins, which disrupts normal limb formation and leads to the other serious birth defects associated with tetra-amelia syndrome.


According to a 2018 study by  Bruno Reversade , the loss of  RSPO2 , unlike WNT3, also prevents formation of the lungs causing a lethal syndrome of tetra-amelia. [ 3 ]


In most of the families reported so far, tetra-amelia syndrome appears to have an  autosomal  recessive pattern of inheritance. [ 1 ] [ 2 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.


Tetra-amelia syndrome has been reported in only a few families worldwide.
According to a 2011 study by Bermejo-Sanchez,  amelia  – that is, the lacking of one or more limbs – occurs in roughly 1 out of every 71,000 pregnancies. [ 1 ]


Thumb hypoplasia  is a spectrum of congenital abnormalities of the  thumb  varying from small defects to complete absence of the thumb. [ 1 ]  It can be isolated, when only the thumb is affected, and in 60% of the cases [ 2 ]  it is associated with radial dysplasia [ 1 ]  (or radial club, radius dysplasia, longitudinal radial deficiency). Radial dysplasia is the condition in which the forearm bone and the soft tissues on the thumb side are underdeveloped or absent. [ 3 ]


In an embryo the upper extremities develop from week four of the gestation. [ 1 ]  During the fifth to eighth week the thumb will further develop. [ 4 ]  In this period something goes wrong with the growth of the thumb but the exact cause of thumb hypoplasia is unknown. [ 1 ]
One out of every 100,000 live births shows thumb hypoplasia. [ 2 ]  In more than 50% of the cases both hands are affected, otherwise mainly the right hand is affected. [ 1 ] [ 2 ]


About 86% of the children with hypoplastic thumb have associated abnormalities. [ 1 ] [ 2 ]  Embryological hand development occurs simultaneously with growth and development of the cardiovascular, neurologic and hematopoietic systems. [ 2 ]  Thumb hypoplasia has been described in 30 syndromes wherein those abnormalities have been seen. A syndrome is a combination of three or more abnormalities. Examples of syndromes with an hypoplastic thumb are  Holt–Oram syndrome ,  VACTERL association [ 1 ]  and thrombocytopenia absent radius ( TAR syndrome ). [ 2 ]


In general there are five types of thumb hypoplasia, originally described by Muller in 1937 and improved by Blauth, Buck-Gramcko and Manske. [ 1 ]


-  Type I : the thumb is small, normal components are present but undersized. [ 3 ]  Two muscles of the thumb, the  abductor pollicis brevis  and  opponens pollicis , are not fully developed. [ 2 ] [ 3 ]  This type requires no surgical treatment in most cases. [ 1 ] [ 5 ]


-  Type II  is characterized by a tight web space between the thumb and index finger which restricts movement, [ 5 ]  poor  thenar  muscles and an unstable middle joint of the thumb  metacarpophalangeal joint . [ 3 ]  This unstable thumb is best treated with reconstruction of the mentioned structures. [ 1 ]


-  Type III  thumbs are subclassified into two subtypes by Manske. Both involve a less developed first metacarpal and a nearly absent thenar musculature. [ 2 ]  Type III-A has a fairly stable  carpometacarpal joint  and type III-B does not. [ 1 ] [ 2 ] [ 3 ]  The function of the thumb is poor. [ 2 ]  Children with type III are the most difficult patients to treat because there is not one specific treatment for the hypoplastic thumb. The limit between  pollicization  and reconstruction varies. Some surgeons have said that type IIIA is amenable to reconstruction and not type IIIB. Others say type IIIA is not suitable for reconstruction too. [ 4 ]  Based on the diagnosis the doctor has to decide what is needed to be done to obtain a more functional thumb, i.e. reconstruction or pollicization. In this group careful attention should be paid to anomalous tendons coming from the forearm (extrinsic muscles, like an aberrant long thumb flexor –  flexor pollicis longus ). [ 3 ] [ 4 ] [ 5 ]


-  Type IV  is called a pouce flottant, floating thumb. [ 1 ] [ 2 ] [ 3 ] [ 5 ]  This thumb has a  neurovascular bundle  which connects it to the skin of the hand. [ 1 ] [ 3 ] [ 5 ]  There's no evidence of thenar muscles and rarely functioning tendons. [ 4 ] [ 5 ]  It has a few rudimentary bones. [ 4 ] [ 5 ]  Children with type IV are difficult to reconstruct. [ 1 ] [ 4 ]  This type is nearly always treated with an index finger pollicization to improve hand function. [ 1 ] [ 5 ]


-  Type V  is no thumb at all [ 2 ] [ 3 ]  and requires pollicization. [ 1 ] [ 5 ]


The cause is unknown, and likely related to genetic abnormalities. Children with Fanconi anemia can sometimes display hypoplasia of the thumb. [ citation needed ]


Three main points in diagnosing thumb hypoplasia are: width of the first web space, instability of the involved joints and function of the thumb. [ 5 ]  Thorough  physical examination  together with anatomic verification at operation reveals all the anomalies. [ 1 ] [ 5 ]  An X-ray of the hand and thumb in two directions is always mandatory. [ 5 ]  When the pediatrician thinks the condition is associated with some kind of syndrome other tests will be done. [ 1 ]  More subtle manifestations of types I and II may not be recognized, especially when more obvious manifestations of longitudinal radial deficiency in the opposite extremity are present. Therefore, a careful examination of both hands is important. [ 3 ]


When it comes to treatment it is important to differentiate a thumb that needs stability, more web width and function, or a thumb that needs to be replaced by the index finger. [ 4 ]  Severe thumb hypoplasia is best treated by pollicization of the index finger. [ 3 ] [ 5 ]  Less severe thumb hypoplasia can be reconstructed by first web space release, ligament reconstruction and muscle or tendon transfer. [ 3 ] [ 5 ]


It has been recommended that pollicization is performed before 12 months, but a long-term study of pollicizations performed between the age of 9 months and 16 years showed no differences in function related to age at operation. [ 3 ]


It is important to know that every reconstruction of the thumb never gives a normal thumb, because there is always a decline of function. [ 4 ]  When a child has a good index finger, wrist and fore-arm the maximum strength of the thumb will be 50% after surgery in comparison with a normal thumb. [ 3 ] [ 4 ]  The less developed the index finger, wrist and fore-arm is, the less strength the reconstructed thumb will have after surgery. [ 3 ] [ 4 ]


TORCH syndrome  is a cluster of symptoms caused by  congenital infection  with  toxoplasmosis ,  rubella ,  cytomegalovirus ,  herpes simplex , and other organisms including  syphilis ,  parvovirus , and  Varicella zoster . [ 1 ]   Zika virus  is considered the most recent member of TORCH infections. [ 2 ]


TORCH  is an acronym for (T)oxoplasmosis, (O)ther Agents, (R)ubella, (C)ytomegalovirus, and (H)erpes Simplex. [ 3 ]


Though caused by different infections, the signs and symptoms of TORCH syndrome are consistent. They include  hepatosplenomegaly  (enlargement of the  liver  and  spleen ), fever, lethargy, difficulty feeding,  anemia ,  petechiae ,  purpurae ,  jaundice , and  chorioretinitis . The specific infection may cause additional symptoms. [ 1 ]


TORCH syndrome may develop before birth, causing stillbirth, in the neonatal period, or later in life. [ 4 ]


TORCH syndrome is caused by in-utero infection with one of the TORCH agents, disrupting  fetal development . [ 1 ]


Presence of IgM is diagnostic and persistence of IgG beyond 6–9 months is diagnostic. [ citation needed ]


TORCH syndrome can be prevented by treating an infected pregnant woman, thereby preventing the infection from affecting the fetus. [ 4 ]


The treatment of TORCH syndrome is mainly supportive and depends on the symptoms present; medication is an option for herpes and cytomegalovirus infections. [ 1 ]


Developing countries are more severely affected by TORCH syndrome than developed countries. [ 4 ]


Toxocara malayasiensis  is a species of feline roundworm, a  parasite  which infects the intestine of cats. Feline roundworms are passed in the fecal matter of cats, and can be transmitted to humans, causing  toxocariasis , a potentially serious disease. [ 1 ]


This  Chromadorea  nematode (or roundworm-) related article is a  stub . You can help Wikipedia by  expanding it .


Transient myeloproliferative disease  ( TMD ) occurs in a significant percentage of individuals born with the  congenital   genetic disorder ,  Down syndrome . It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops  in utero , is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop  acute megakaryoblastic leukemia  at some time during the 5 years following its resolution. TMD is a life-threatening,  precancerous condition  in fetuses [ 1 ]  as well as infants in their first few months of life. [ 2 ]


Transient myeloproliferative disease involves the excessive proliferation of non-malignant  megakaryoblasts . Megakaryoblasts are hematological  precursor cells  which mature to  megakaryocytes . Megakaryocytes release  platelets  into the  bloodstream . Platelets are critical for normal  blood clotting . [ 3 ]  In consequence of this mutation, megkaryoblasts fail to mature properly, accumulate in multiple organs, may damage these organs, and may become  cancerous . The diseases also causes a reduction in the maturation of  erythroblasts  to circulating  red blood cells  and, consequently, mild  anemia . [ 4 ]


Most individuals with TMD have clinical evidence of damage to various organs, particularly the liver, due to megakaryoblast infiltration, the accumulation of fluid in various tissue compartments, a  bleeding tendency  due to low levels of circulating platelets (i.e.  thrombocytopenia ), anemia due to reduced production of red blood cells, and/or other signs or symptoms of the disorder. [ 5 ]  However, some individuals with transient myeloproliferative disease have a presumably small clone of rapidly proliferating megakaryoblasts with inactivating  GATA1  mutations but no other signs or symptoms of the disease. This form of TMD is termed silent transient abnormal myelopoiesis (i.e. silent TAM). Silent TAM is of clinical significance because it, like symptomatic TMD, may progress to an acute megakaryoblastic leukemia. This progression occurs in ~10% of TMD cases at some time during the 4-5 following birth and is due to the acquisition by the rapidly proliferating megakaryoblast clones of oncogenic mutations in other genes. [ 2 ]


Chemotherapeutic  regimens are used to treat individuals with TMD but only those who have life-threatening complications of the disease. It is not known if these regimens have an impact on the development of acute megakaryoblastic leukemia. Currently, it is recommended that individuals with TMD be followed medically for signs, symptoms, or laboratory evidence of its progression to this malignant disease with the notion that its early treatment may be of clinical benefit. [ 2 ]


Transient myeloproliferative disease develops and may be of concern in fetuses. Features in a review of 39 reported fetal cases include: reduced platelet production often accompanied by significantly reduced levels of circulating platelets; reduced red blood cell production sometimes accompanied by mild anemia; increased levels of circulating megakaryoblasts and  white blood cells ; grossly enlarged liver and liver dysfunction due to an excessive accumulation of platelet precursor cells; enlarged spleen presumed due mostly to the  portal hypertension  accompanying liver disease with  extramedullary hematopoiesis  possibly contributing to the enlargement; accumulation of excessive fluid in bodily compartments such as the  pericardial ,  pleural ,  abdominal  spaces;   hydrops fetalis , i.e. the accumulation of excessive fluid in two or more bodily compartments; cardiomegaly and other cardiac abnormalities resulting form  atrial septal defects , small  ventricular septal defects , and/or, possibly, accumulation of megakaryocytes and secondary cardiac fibrosis. [ 1 ]   Hydrops fetalis , when accompanied by liver dysfunction, is a particularly poor prognostic combination in TMD. [ 6 ]


Clinical features in a review of 3 studies reporting on a total of 329 cases of symptomatic TMD include:  premature birth  (33-47%); enlarged liver (55-62%); evidence of liver dysfunction (13-63%); enlarged spleen (36-44%); heart disease (47-71%); gastrointestinal abnormalities (1-25%); and fluid accumulations in lung, heart, and/or abdomen (16-21%). In other studies; 5% of cases were associated with a  vesiculopapular eruption ; 3-6% of cases were associated with kidney failure or insufficiency presumed due mostly to complications of cardiac and/or liver dysfunction; rare cases of lung dysfunction due primarily to its compression by a massively enlarged liver and/or fluid accumulations in the pleural space; [ 2 ]  and rare cases of asymptomatic megakaryoblastic infiltration and secondary fibrosis in the pancreas. [ 5 ]  Other reports find decreased levels circulating platelets in 50% of cases, abnormal blood clotting in 10-25% of cases, anemia in 5-10%, and increased levels of circulating white blood cells in 50% of cases. The incidence of all these features except for low levels of blood platelets are appreciably higher in TMD than in Down syndrome individuals that lack inactivating  GATA1  mutations. [ 2 ]  There are also uncommon instances of stillbirths and infant death within 24 hours of delivery. [ 1 ]


Silent TAM lacks almost all of the clinical features of TMD, i.e. newborns with this disease exhibit no signs or symptoms that differ from those found in Down syndrome individuals who lack inactivating  GATA1  mutations. Silent TAM nonetheless carries the threat of progressing to AMKL with an incidence similar to that occurring in TMD. [ 2 ]


Down syndrome is caused be the presence of an extra  chromosome 21  (i.e.  trisomy 21 ) due to a failure in normal chromosomal pairing or premature unpairing during the  cell division  of  meiosis  in  egg  or sperm cells. In these cases, virtually all cells in Down syndrome individuals bear an extra chromosome 21. However, there are other genetic changes that may either cause Down syndrome or cause an individual without Down syndrome to bear disease susceptibilities of the syndrome. These genetic changes include:  a)   genetic mosaicism  in which some body cells bear a normal chromosome complement while others bear an extra chromosome 21;  b)  a part of chromosome 21 is located on another chromosome due to a  Robertsonian translocation ;  c)  partial trisomy 21 in which only part of chromosome 21 is duplicated;  d)  an  isochromosome  in which chromosome 21 contains two long but no short arms; and  e)  key genes on chromosome 21 are duplicated on this or other chromosomes. [ 7 ]  These genetic changes do occur in rare cases of individuals who  do not have Down syndrome but nonetheless develop transient myeloproliferative disease [ 8 ]  due to the presence of extra copies of key genes normally found on chromosome 21  genes caused by mosaic, Robertsonian translocation, partial trisomy 21, isochromosome formation, or duplication. [ 5 ]


Down syndrome by itself (i.e. in the absence of  GATA1  gene mutations) is a cause for numerous hematological abnormalities which are similar to those seen in TMD. These Down syndrome-related abnormalities include increased numbers of  stem cell  precursors to platelets and red blood cells, impaired maturation of these precursors to platelets and red blood cells, thrombocytopenia, abnormal bleeding, anemia,  leukocytosis , and serious liver damage. Since TMD is restricted to individuals with Down syndrome or otherwise have an excess of key chromosome 21 genes, it is suggested that certain chromosome 21 genes that are in triplicate and cause these hematological disorders in Down syndrome are essential for the development of  GATA1  inactivating mutations and thereby TMD. These genes include  ERG , a potentially cancer-causing  oncogene  that codes for a transcription factor;  DYRK1A , which codes for a  protein kinase  type of  enzyme  involved in promoting cellular proliferation; and  RUNX1 , which codes for a transcription factor that regulates the maturation of hematological stem cells and, when mutated, is involved in the development of various myeloid neoplasms. [ 2 ]  It is hypothesized that trisomy 21 induces genome instability and stress, contributing to the development of somatic mutations associated with progression to leukemia. [ 9 ]


The human  GATA1  gene is located on the short (i.e. "p") arm of the  X chromosome [ 10 ]  at position 11.23. [ 11 ]  It is 7.74  kilobases  in length, consists of 6  exons , and codes for a full length protein, GATA1, of 414  amino acids  ( atomic mass =50 kilodaltons) and a shorter protein, GATA1-S (also termed GATA1s). GATA1-S lacks the first 83 amino acids of GATA1 and consists of 331 amino acids (atomic mass = 40 kilodaltons). [ 12 ]  GATA1 and GATA1-S are  transcription factors , i.e.  nuclear proteins  that regulate the expression of genes. [ 10 ]  The genes targeted by these two transcription factors help control the maturation of megakaryoblasts and  promegakaryocytes  to platelet-forming megakaryocytes [ 12 ]  and the maturation of  erythroblasts  to red blood cells. [ 13 ]  GATA1-S is less active than GATA1 in controlling most of these genes including those that stimulate megakaryoblast maturation but appears more effective than GATA1 in stimulating megakaryoblast proliferation. [ 12 ]  Outside of the Down syndrome (or a triplication in key chromosome 21 genes),  GATA1  inactivating mutations cause or contribute to various non-malignant  X-linked   bleeding  and anemic disorders that are due to failures in the maturation of precursor cells to platelets and red blood cells. [ 4 ]


The  GATA1  mutations in Down syndrome cause TMD. They occur in exon 2 or 3 of the gene and are truncating mutations that result in the gene's exclusive formation of GATA1-S, i.e. the gene makes no GATA1. [ 12 ]  Some 20% of individuals with Down syndrome bear one truncating mutation although some may bear up to 5 different truncating mutations and therefore have 5 different  GATA1  mutant clones. These mutations occur in utero and can be detected in fetuses of 21 weeks  gestational age . In the absence of GATA1, the GATA1-S transcription factor increases the proliferation but not maturation of megakaryoblasts [ 4 ]  and is insufficient to support the normal maturation of red blood cell precursors. [ 14 ]  Consequently, fetuses [ 1 ]  and, during their first few months of live, infants [ 2 ]  with these mutations exhibit extensive accumulations of immature megakaryoblasts in fetal blood-forming organs (particularly liver and bone marrow) and decreases in circulating platelet counts; they may also exhibit modest reductions in circulating red blood cells; and they may exhibit severe injuries in various organs. In ~80% of individuals, hematological changes resolve completely within ~3 months although organ injuries, particularly those to the liver, may take months or even years to fully resolve. During this resolution period,  GATA1  mutations become undetectable. However, the original mutations are again detected in the acute megakaryoblastic leukemia cells indicating that the  GATA1  mutations causing TMD decrease to undetectable levels as TMD resolves but, at least in cases that progress to AMKL, persist in a tiny clone of megakaryoblasts that evolve into the malignant cells of AMKL. In most cases, this evolution occurs over 1–5 years but in ~20% of cases the in utero [ 1 ]  or postnatal disease [ 3 ]  is severe, prolonged, and/or fatal or progresses to AMKL without exhibiting a resolution phase. [ citation needed ]


The  GATA1  gene also regulates the maturation of  eosinophils  and  dendritic cells . Its impact on the former cell type may underlie the increase in circulating blood eosinophils in TMD. [ 13 ]


TMD may be followed within weeks to ~5 years by a subtype of  myeloid leukemia , acute megakaryoblastic leukemia. AMKL is extremely rare in adults. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without  Down syndrome . The disease in Down syndrome occurs in ~10% of individuals who previously had TMD. [ 15 ]  During the interval between TMD and the onset of AMKL, individuals accumulate multiple  somatic mutations  in cells that bear an inactivating GATA1 mutation plus trisomy 21 (or the presence of extra chromosome 21 genes involved in the development of TMD). These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the  GATAT1  mutation in the presence of trisomy 21 (or the presence of extra chromosome 21 genes involved in the development of TMD) and to be responsible for progression of the transient disorder to AMKL. The mutations occur in one or more genes including:  TP53 ,  FLT3 ,  ERG ,  DYRK1A ,  CHAF1B ,  HLCS ,  RUNX1 , MIR125B2  (which is the gene for  microRNA  MiR125B2 CTCF , [ 3 ]   STAG2 ,  RAD21 ,  SMC3 ,  SMC1A ,  NIPBL ,  SUZ12 ,  PRC2 ,  JAK1 ,  JAK2 ,  JAK3 ,  MPL ,  KRAS ,  NRAS , and  SH2B3 . [ 15 ]


The development and progression of TMD result from collaborations between various genes:  1)  during fetal development, an immature megakaryoblast which has extra copies of key genes located on chromosome 21 (e.g.  ERG, DYKR1A , and/or  RUNX1 ) acquires an inactivating mutation in  GATA1  that causes it to make only GATA1-S;  2)  this cell(s) grows into a genetically identical group, i.e. a clone, of non-malignant megakaryoblasts which proliferate excessively, fail to mature normally, and over-populate fetal blood-forming organisms, particularly the liver and bone marrow, thereby establishing TMD;  3)  most cells in this clone are still genetically programmed to die during the ensuing fetal and early postnatal period thereby resolving TMD;  4)  some cells in this  GATA1 -mutant clone escape the death program although their numbers are too low for detection by current methods;  5)  in ~10% of TMD cases, the surviving cells from the  GATA1  mutant clone undergo an  evolution to cancer , i.e. they acquire mutations in other genes (see preceding section) which causes at least one of them to be malignant, immortal, and rapidly proliferating thereby founding a clone of megakaryoblasts that have the original  GATA1  mutation, extra chromosome 21 genes, and one or more one of the newly acquired  oncogenic  gene mutations; and  6)  the cells in this malignant clone infiltrate, accumulate in, and injure various organs and tissues thereby establishing AMKL. [ 2 ] [ 7 ]  These stages in the development and progression of TMD may involve up to 5 different  GATA1  gene mutations in different megakaryoblasts and therefore result in the evolution of up to 5 different  GATA1 -mutant clones, at least one of which may found the malignant clone involved in AMKL. [ 4 ]


The severity of transient myeloproliferative disease appears to depend on the size of the  GATA1  mutant clone. It is likely, for example, that the lack of clinical features in silent TAM is a reflection of the small size of its mutant  GATA1  clone. [ 2 ]


The liver of TMD-individuals accumulate abnormally high numbers of platelet and -to a lesser extent- red blood cell precursors. The liver, it is suggested, may be the primary site for excessive proliferation of the  GATA1  mutant clone(s) of platelet precursor cells, primarily megakaryobllasts and the accumulation of these precursor cells along to red blood cell precursor cells appears to be an important cause of the liver enlargement and dysfunction occurring in TMD. [ 15 ]


TMD is associated with  fibrosis  (i.e. replacement of normal tissue with fibrous tissue) in the liver. This fibrosis may be severe and even life-threatening. [ 16 ]  Based primarily on mouse [ 17 ]  and isolated human cell studies, [ 18 ]  this myelofibrosis is thought to result from the excessive accumulation of mutant  GATA1 -bearing platelet precursor cells in these organs: the precursor cells make and release abnormally large amounts of cytokines ( platelet-derived growth factor ;  transforming growth factor beta 1 ) which stimulate tissue  stromal cells  to become fiber-secreting  fibroblasts .


ML-DS (Myeloid leukemia in Down syndrome) features mutations in the cohesin complex, including  RAD21 ,  STAG1 ,  SMC3 ,  SMC1A , and the associated factor  NIPBL  in over half of cases, whereas these mutations are rare in TAM (transient abnormal myelopoiesis).  Notably, cohesin mutations alter chromatin accessibility at  ERG ,  RUNX1 , and  GATA transcription factor  motifs. [ 19 ]