The first case of cholestasis usually improves spontaneously during preschool and early school age and returns at various intervals of two to six months. [ 5 ]  The severity of the disease varies in these patients, with some even experiencing complete liver failure. In these cases, liver transplantation is necessary. [ 5 ] [ 9 ]  Untreated cholestasis is accompanied by  jaundice ,  itching , malabsorption of fat and fat-soluble vitamins. This can lead to  skeletal  abnormalities and a higher susceptibility to bleeding. [ 5 ]  In early childhood and adolescence, lymphedema most often develops in all patients' lower limbs, but the upper limbs or chest are no exception. [ 5 ] [ 9 ]  Untreated lymphedema can cause chronic tissue damage. [ 5 ]


A biochemical analysis revealed a significant increase of  bilirubin  concentration in patients in the first months of life, with a later decrease. Around the age of 3 or 4, the value was optimized to normal limits. [ 10 ]


In patients aged 10–20 years, serum concentrations of bilirubin, bile acids and transaminases ( alanine aminotransferase ,  aspartate aminotransferase ) reached normal or almost optimal values. [ 10 ] [ 11 ]


Patients without observed liver cirrhosis compared to the control group had elevated levels of ALP ( alkaline phosphatase ) and GGT ( gamma-glutamyl transferase ). There was no significant difference in serum bile acid concentrations between patients and control group. However, test patients had lower values for total protein,  CRP ,  albumin  and  creatinine . Moreover, the value for  fibrinogen  was higher in patients with Aagenaes syndrome. [ 10 ]


There was only a slight increase in  mean cell hemoglobin  (MCH) in terms of  erythrocyte ,  leukocyte  and  platelet  counts. Serum albumin concentrations decreased with age, but not in the control group. [ 10 ]


Although no cure for this disease has been found, improvements in the course of the disease have been significantly seen after the administration of nutritional and vitamin supplements, especially in children. It is stated that if there is no remission by about 12 to 18 months of childhood, liver transplantation is necessary at a later age. [ 5 ] [ 10 ]


Neonatal cholestasis  lasted no more than one year in some patients or lasted until the age of 6/7 years in some cases. In recent decades, cholestatic episodes have lasted a shorter time than before 1970. There has also been a decline in  rickets , growth retardation, and  neuropathy  over time. The reasons for this are improved nutritional habits, vitamin and cholestyramine supplementation. Nevertheless, it is not yet possible to prevent serious liver disease. [ 10 ]


The first reported cases of Aagenaes syndrome were described in a study in 1968 from the southwest of  Norway . [ 12 ] [ 13 ]  Four out of five children born before 1939 died of  bleeding  in the first weeks of life.  Vitamin K  was introduced this year, after the birth of another four children after 1939. When these children received one dose of this vitamin, three of them died at the age of 5–9 months. The confirmed cause of death in one or two children in this group was bleeding. The remaining seven children, born in 1935 and in 1942–1966, who were part of a study published in 1968, were alive at the time. [ 12 ]


Aarskog–Scott syndrome  ( AAS ) is a rare disease  inherited  as X-linked and characterized by  short stature , facial abnormalities, skeletal and genital anomalies. [ 2 ]  This condition mainly affects males, although females may have mild features of the syndrome. [ 3 ] [ 4 ]


People with Aarskog–Scott syndrome often have distinctive facial features, such as widely spaced eyes ( hypertelorism ), a small nose, a long area between the nose and mouth ( philtrum ), and a  widow's peak  hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers ( brachydactyly ), curved pinky fingers (fifth finger  clinodactyly ), webbing of the skin between some fingers (cutaneous  syndactyly ), and a single crease across the palm. Other abnormalities in people with Aarskog–Scott syndrome include heart defects and a split in the upper lip ( cleft lip ) with or without an opening in the roof of the mouth ( cleft palate ). [ 3 ]


Most males with Aarskog–Scott syndrome have a  shawl scrotum , in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes ( cryptorchidism ) or a soft out-pouching around the belly-button ( umbilical hernia ) or in the lower abdomen ( inguinal hernia ). [ 3 ]


The intellectual development of people with Aarskog–Scott syndrome varies widely. Some may have mild learning and behavior problems, while others have normal intelligence. In rare cases, severe intellectual disability has been reported. [ 3 ]


Mutations in the FGD1 gene are the only known genetic cause of Aarskog-Scott syndrome. The FGD1 gene provides instructions for making a protein that turns on (activates) another protein called Cdc42, which transmits signals that are important for various aspects of development before and after birth. [ 3 ]


Mutations in the FGD1 gene lead to the production of an abnormally functioning protein. These mutations disrupt Cdc42 signaling, leading to the wide variety of abnormalities that occur in people with Aarskog-Scott syndrome. [ 3 ]


Only about 20 percent of people with this disorder have identifiable mutations in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals is unknown. [ 3 ]


Genetic testing  may be available for mutations in the FGDY1 gene.  Genetic counseling  is indicated for individuals or families who may carry this condition, as there are overlapping features with  fetal alcohol syndrome . [ 5 ] [ 4 ]


Other examinations or tests can help with diagnosis. These can include:


Similar to all genetic diseases Aarskog–Scott syndrome cannot be cured, although numerous treatments exist to increase the quality of life. [ 6 ]


Surgery  may be required to correct some of the anomalies, and  orthodontic  treatment may be used to correct some of the facial abnormalities. Trials of  growth hormone  have been effective to treat short stature in this disorder. [ 7 ]


Some people may have some mental slowness, but children with this condition often have good social skills. Some males may have problems with fertility. [ 4 ]


The syndrome is named for  Dagfinn Aarskog , a Norwegian pediatrician and human geneticist who first described it in 1970, [ 8 ]  and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971. [ 9 ]


Achondrogenesis  is a number of disorders that are the most severe form of  congenital   chondrodysplasia  (malformation of  bones  and  cartilage ). These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of their serious health problems, infants with achondrogenesis are usually born  prematurely , are  stillborn , or die shortly after birth from respiratory failure. Some infants, however, have lived for a while with intensive medical support.


Researchers have described at least three forms of achondrogenesis, designated as Achondrogenesis type 1A,  achondrogenesis type 1B  and  achondrogenesis type 2 . These types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause. Other types of achondrogenesis may exist, but they have not been characterized or their cause is unknown.


Achondrogenesis type 1A is caused by a defect in the microtubules of the  Golgi apparatus . In mice, a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210), resulted in defects similar to the human disease. When their DNA was sequenced, human patients with achondrogenesis type 1A also had loss-of-function mutations in GMAP-210. GMAP-210 moves proteins from the endoplasmic reticulum to the Golgi apparatus. Because of the defect, GMAP-210 is not able to move the proteins, and they remain in the endoplasmic reticulum, which swells up. The loss of Golgi apparatus function affects some cells, such as those responsible for forming bone and cartilage, more than others. [ 1 ]


Achondrogenesis type 1B is caused by a similar mutation in SLC26A2, which encodes a sulfate transporter.


Achondrogenesis, type 2 is one of several skeletal disorders caused by mutations in the  COL2A1  gene. Achondrogenesis, type 2 and  hypochondrogenesis  (a similar skeletal disorder) together affect 1 in 40,000 to 60,000 births.


This article incorporates public domain text from  The U.S. National Library of Medicine


Achondrogenesis type 1B  is a severe  autosomal recessive  skeletal disorder, invariably fatal in the perinatal period. [ 1 ]  It is distinguished by its elongated, spherical midsection, small chest, and exceedingly short limbs. The feet can turn inward and upward ( clubfeet ), and the fingers and toes are little. Babies affected often have a soft out-pouching at the groin (an  inguinal hernia ) or around the belly button (an  umbilical hernia ). [ 2 ]


Achondrogenesis type 1B (ACG1B), one of the most serious forms of  chondrodysplasia , is a perinatal-lethal condition in which a person dies either during pregnancy or soon after birth. It is uncertain what mechanism causes perinatal death. Shortly after birth,  respiratory failure  results in the death of a live-born neonate. [ 1 ]


Breech births  are common in fetuses with ACG1B.  Polyhydramnios  can lead to pregnancy issues, such as maternal respiratory difficulties and preterm labor. [ 1 ]


Since their skeletons are so small, infants with ACG1B appear  hydropic  and have a lot of soft tissue. The neck is short and has thicker soft tissue, while the face is flat. The limbs are severely shortened, with  brachydactyly  (short, stubby fingers and toes) and inturning of the foot and toes ( talipes equinovarus ). The abdomen protrudes, and the thorax is thin.  Inguinal  or  umbilical hernias  are commonly seen. [ 1 ]


Achondrogenesis type 1B is the most severe of several skeletal abnormalities induced by mutations in the  SLC26A2  gene. Instructions for producing a protein necessary for appropriate cartilage formation and bone conversion are provided by this gene. Because mutations in the  SLC26A2  gene alter the structure of growing cartilage, improper bone formation occurs, leading to the skeletal issues typical with achondrogenesis type 1B. [ 2 ]


Because achondrogenesis type 1B is inherited in an autosomal recessive manner, each cell's two copies of the  SLC26A2  gene are mutated. A person with an autosomal recessive disorder typically has parents who each carry one copy of the defective gene but do not exhibit the condition's symptoms. [ 2 ]


Molecular  genetic testing  can identify biallelic pathogenic (or potentially pathogenic) mutations in  SLC26A2  and/or the distinctive clinical and radiographic features in a proband that support the diagnosis of ACG1B. [ 1 ]


Achondrogenesis, type 2  is an uncommon  skeletal dysplasia  that is autosomal dominant and occurs at a frequency of approximately 0.2 per 100,000 births. [ 1 ]  Also known by the name  Langer-Saldino achondrogenesis , it is one of the fatal short-limbed dwarfisms linked to structural mutations in  type II collagen . [ 2 ]


Typically, achondrogenesis type II manifests in the perinatal period as  short stature ,  edema /hydropic look, narrow chest with  pulmonary hypoplasia , severely short limbs ( micromelia ), and extraskeletal characteristics (e.g., flat midface,  Pierre Robin sequence ). Most of these babies are  stillborn , delivered before their due date, or pass away from  cardiorespiratory failure  soon after delivery, meaning that they do not live to term. [ 3 ]


The characteristic features of achondrogenesis type 2 are short arms and legs, a tiny chest with short ribs,  lung hypoplasia , a small chin, a prominent forehead, and an enlarged abdomen that may also include  hydrops , and  polyhydramnios . [ 4 ]


Mutations in the  COL2A1  gene can cause a number of skeletal abnormalities, including achondrogenesis type 2. Instructions for producing a protein that produces  type II collagen  are provided by this gene.  Type II collagen  molecule assembly is disrupted by mutations in the  COL2A1  gene, impairing the normal development of bones and other connective tissues. [ 5 ]


Because achromogenesis type 2 is caused by a mutated gene that only needs one copy in each cell, it is regarded as an autosomal dominant disorder. [ 5 ]


Achondroplasia  is a  genetic disorder  with an autosomal dominant pattern of inheritance whose primary feature is  dwarfism . [ 3 ]  It is the most common cause of dwarfism [ 4 ]  and affects about 1 in 27,500 people. [ 3 ]  In those with the condition, the  arms and legs are short , while the  torso  is typically of normal length. [ 3 ]  Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. [ 3 ]  Other features can include an  enlarged head  with  prominent forehead (frontal bossing) [ 3 ]  and underdevelopment of the midface (midface hypoplasia). [ 6 ]  Complications can include  sleep apnea  or recurrent  ear infections . [ 3 ]  Achondroplasia includes the extremely rare  short-limb skeletal dysplasia with severe combined immunodeficiency .


Achondroplasia is caused by a mutation in the  fibroblast growth factor receptor 3  ( FGFR3 )  gene  that results in its  protein  being  overactive . [ 3 ]  Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). [ 7 ]  The disorder has an  autosomal dominant  mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. [ 8 ]  About 80% of cases occur in children of parents without the disease, and result from a new ( de novo , or sporadic) mutation, which most commonly originates as a spontaneous change during  spermatogenesis . [ 5 ]  The rest are inherited from a parent with the condition. [ 3 ]  The risk of a new mutation increases with the  age of the father . [ 4 ]  In families with two affected parents, children who inherit both affected genes typically  die before birth or in early infancy  from breathing difficulties. [ 3 ]  The condition is generally diagnosed based on the clinical features but may be confirmed by  genetic testing . [ 5 ]  Mutations in FGFR3 also cause achondroplasia related conditions including hypochondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), a rare disorder of bone growth characterized by skeletal, brain, and skin abnormalities resulting in severe  short-limb skeletal dysplasia with severe combined immunodeficiency . [ 9 ]


Treatments include small molecule therapy with a C-natriuretic peptide analog ( vosoritide ), approved to improve growth velocity in children with achondroplasia based on results in Phase 3 human trials, although its long-term effects are unknown. [ 10 ]   Growth hormone therapy  may also be used. [ 5 ]  Efforts to treat or prevent complications such as  obesity ,  hydrocephalus ,  obstructive sleep apnea ,  middle ear infections  or  spinal stenosis  may be required. [ 5 ]   Support groups  support people with achondroplasia, including the  Little People of America (LPA)  and  Growing Stronger . Nonprofit physician organizations also exist to disseminate information about treatment and management options, including development of  patient resources .


Children with achondroplasia often have less muscle tone; because of this it is common for them to have delayed walking and motor skills. It is also common for children to have bowed legs, scoliosis, lordosis, arthritis, issues with joint flexibility, breathing problems, ear infections, and crowded teeth. [ 12 ]  These issues can be treated with surgery, braces, or physical therapy. [ citation needed ]


Hydrocephalus is a severe effect associated with achondroplasia in children. This condition occurs when cerebrospinal fluid is not able to flow in and out of the skull because of how the spine narrows. [ 13 ]  This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability. [ 14 ]  A  shunt surgery  is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done. [ 15 ]


Adults with achondroplasia often face issues with obesity and sleep apnea. It is also typical for adults to experience numbness or tingling in their legs because of nerve compression. [ citation needed ]


Some research has found that adults with achondroplasia may also experience  psychosocial  complications, usually associated with short stature. [ 7 ] [ 16 ]


Pregnancy in women with achondroplasia is considered higher risk. Women with achondroplasia generally have their babies delivered through C-sections to prevent complications that could occur with a natural birth. [ 17 ]  Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. [ 18 ]


Achondroplasia is caused by a mutation in  fibroblast growth factor receptor 3  ( FGFR3 ) gene. [ 19 ]  This gene encodes a protein called fibroblast growth factor receptor 3, which contributes to the production of collagen and other structural components in tissues and bones. [ 20 ]  When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height. [ 21 ]


In normal development,  FGFR3  has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active, and this leads to severely shortened bones. This is an example of a  gain of function  mutation. The effect is  genetically dominant , with one variant of the  FGFR3  gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal ( recessive lethal ) before or shortly after birth. This occurs due to respiratory failure from an underdeveloped ribcage. [ 3 ]  People with achondroplasia are often born to parents that do not have the condition due to  spontaneous mutation . [ 22 ]


Where achondroplasia is inherited, its pattern is autosomal dominant. In couples where one partner has achondroplasia there is a 50% chance of passing the disorder on to their child every pregnancy. In situations where both parents have achondroplasia there is a 50% chance the child will have achondroplasia, 25% chance the child will not, and a 25% chance that the child will inherit the gene from both parents resulting in  double  dominance  and leading to lethal bone  dysplasia . [ 23 ]


Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during  spermatogenesis ; it has been theorized that sperm carrying the mutation in FGFR3 have a selective advantage over sperm with normal FGFR3. [ 4 ]  The frequency of mutations in sperm leading to achondroplasia increases in proportion to paternal age, as well as in proportion to exposure to  ionizing radiation . [ 24 ]  The occurrence rate of achondroplasia in the children of fathers over 50 years of age is 1 in 1,875, compared to 1 in 15,000 in the general population. [ 25 ]  Research by  urologist  Harry Fisch of the Male Reproductive Center at  Columbia Presbyterian Hospital  in 2013 indicated that in humans this defect may be exclusively inherited from the father and becomes increasingly probable with paternal age, specifically males reproducing after 35. [ 26 ]


There are two other syndromes with a genetic basis similar to achondroplasia:  hypochondroplasia  and  thanatophoric dysplasia .


Achondroplasia can be detected before birth by  prenatal   ultrasound , although signs are often subtle and not apparent before the 24th week of pregnancy. [ 27 ]  A DNA test can be performed before birth to detect  homozygosity , wherein two copies of the mutant gene are inherited, a lethal condition leading to  stillbirths . Postnatal diagnosis of achondroplasia is typically uncomplicated, involving an assessment of physical and radiographic features. [ 28 ]   Clinical features include megalocephaly, short limbs, prominent forehead,  thoracolumbar  kyphosis and mid-face hypoplasia. [ 29 ]  Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. [ 29 ]  The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction. [ citation needed ]


A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow  foramen magnum , and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed  spinal canal . The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. [ 30 ] [ 31 ]  The tubular bones are short and thick with  metaphyseal  cupping and flaring and irregular growth plates. [ 30 ]   Fibular  overgrowth is present. The hand is broad with short  metacarpals  and  phalanges , and a trident configuration. The ribs are short with cupped anterior ends. [ 30 ]  If the  radiographic  features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often " double jointed ". The diagnosis can be made by fetal  ultrasound  by progressive discordance between the short  femur  length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended. [ citation needed ]


Another common characteristic of the syndrome is thoracolumbar  gibbus  in infancy. [ 32 ]


There is no known cure for achondroplasia even though the cause of the mutation in the growth factor receptor has been found. Although used by those without achondroplasia to aid in growth,  human growth hormone  does not help people with achondroplasia, which involves a different hormonal pathway. Usually, the best results appear within the first and second year of therapy. [ 33 ]  After the second year of growth hormone therapy, beneficial bone growth decreases, [ 34 ]  so the therapy is not a satisfactory long-term treatment. [ 33 ]  As of December 2020, the treatment of achondroplasia with human growth hormone was approved only in Japan. [ 35 ]


A small-molecule drug  vosoritide  is used to improve growth velocity in children with achondroplasia, [ 10 ]  although its long-term effects are unknown. Vosoritide inhibits the activity of  FGFR3 . [ 36 ]  It has been gradually made available in different countries starting from 2021.


Limb-lengthening  will increase the length of the legs and arms of someone with achondroplasia, [ 37 ]   but little medical consensus exists regarding this practice. The age of surgery can vary from early childhood to adulthood. [ 38 ]


Research has also shown that introducing parents of children with achondroplasia to support and advocacy groups at the time of diagnosis can improve outcomes. [ 39 ]  Several patient advocacy groups exist to support people with achondroplasia and their families. [ 40 ]   Resources  are available to support patients and their caregivers with information that they can distribute to their physicians, who may not be familiar with the unique medical requirements of managing achondroplasia. Physician-oriented best practice guidelines are also available to guide physicians managing the spinal disorders, [ 41 ]  foramen magnum stenosis, [ 6 ]  craniofacial implications, [ 42 ]  pregnancy, [ 43 ]  and peri-operative [ 44 ]  needs of people with achondroplasia.


Homozygous achondroplasia is invariably considered terminal even with aggressive treatment.


Achondroplasia is one of several congenital conditions with similar presentations, such as  osteogenesis imperfecta ,  multiple epiphyseal dysplasia  tarda,  achondrogenesis ,  osteopetrosis , and  thanatophoric dysplasia . This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births. [ 45 ]  Another study at the same time found a rate of 1 per 10,000. [ 45 ]  A 2020 review and meta-analysis estimated a worldwide prevalence of 4.6 per 100,000. [ 46 ]


In addition to physical challenges, individuals with achondroplasia may also experience psychological challenges such as fear or negative perception of individuals with achondroplasia. Gollust et al. have indicated that adults with achondroplasia tend to have lower self-esteem, annual income, educational attainment, and overall quality of life (QOL) when compared to their unaffected siblings. [ 47 ]  Interestingly, the Golust study revealed that the subjects were as likely to cite disadvantages relating to social barriers as those relating to health issues and functioning. [ citation needed ]


On the other hand, other investigators, such as Ancona, state that for many individuals in immediate environments that have natural acceptance of the condition from the beginning, their main challenge lies in adapting to a world designed for those without the condition. However, when society rejects the condition from the start and associates it with destructive anxiety, it significantly damages the individual's self-image and leads to their social exclusion. Thus, the author hypothesizes, an accepting environment is crucial to prevent significant suffering for individuals with achondroplasia and to ensure the best outcomes for corrective interventions, rather than perpetuating rejection. [ 48 ]


Similarly, a study conducted in Japan by Nishimura and Hanaki found that children with achondroplasia faced challenges related to their short stature, but there was no indication of psychosocial maladjustment. They hypothesized that focusing on coping strategies and self-efficacy may play a crucial role in promoting psychological well-being among children with achondroplasia. [ 49 ]


Social support and peer connections can be important for individuals with achondroplasia. Support groups, online communities, and advocacy organizations can provide a sense of belonging and can help individuals with achondroplasia connect with others who understand their experiences. Additionally, these communities can serve as a resource for information and support for both individuals with achondroplasia and their families. In the  United States , The Little People of America (LPA) is a national organization that provides support, resources, and advocacy for individuals with dwarfism, including achondroplasia. [ 50 ]


Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the  dachshund ,  basset hound ,  corgi  and  bulldog  breeds. [ 51 ] [ 52 ] [ 53 ]  Data from whole genome association studies in short-limbed dogs reveal a strong association of this trait with a retro-gene coding for fibroblast growth factor 4 ( FGF4 ). [ 54 ]  Therefore, it seems unlikely that dogs and humans are achondroplastic for the same reasons. However, histological studies in some achondroplastic dog breeds have shown altered cell patterns in cartilage that are very similar to those observed in humans exhibiting achondroplasia. [ 55 ]


A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. The dwarfism was inherited dominant in the offspring from this litter. The piglets were born phenotypically normal but became more and more symptomatic as they reached maturity. [ 56 ]  This involved a mutation of the protein  collagen, type X, alpha 1 , encoded by the COL10A1 gene.  In humans a similar mutation (G595E) has been associated with  Schmid metaphyseal chondrodysplasia  (SMCD), a relatively mild skeletal disorder that is also associated with dwarfism. [ citation needed ]


The now extinct  Ancon sheep  was created by humans through the selective breeding of common domestic sheep with achondroplasia. The average-sized torso combined with the relatively smaller legs produced by achondroplasia was valued for making affected sheep less likely to escape without affecting the amount of wool or meat each sheep produced. [ 57 ]


EDAR  ( EDAR hypohidrotic ectodermal dysplasia )


Achondroplasia in children  is the most common form of  dwarfism ; it accounts for about 70% of all cases of dwarfism. [ 1 ]   Achondroplasia  falls into the category of “disproportionate dwarfism”. It is linked to a mutation in the fibroblast growth factor receptor-3. More than 250,000 people in the world are diagnosed with achondroplasia. Achondroplasia diagnosis occurs somewhere between one in every 10,000 and one in every 30,000 live births. [ 2 ]


Some symptoms of achondroplasia are short stature, a long and narrow trunk, shortening of the proximal segments of limbs, large head, mid-face  hypoplasia , and joint hyperextension, among others. Achondroplasia is defined by central nervous system defects as well as the prior physical symptoms. Average height for an adult man or woman diagnosed with achondroplasia is about 120 centimeters (47.2 inches), although technically a maximum of 148 centimeters (58.2 inches) is also considered achondroplastic. [ 3 ]  Achondroplastic people typically have a long trunk and smaller upper legs and upper arms. Achondroplastic people of normal intelligence are able to lead independent and productive lives.


Because achondroplastic children have different genes, their growth cycle should be expected to differ from that of a non-achondroplastic child. It is very typical for an achondroplastic child to snore because of their smaller than average size airways. [ 3 ]  There is no data that unfailingly states respiratory problems. Even though achondroplastic children have reduced lung volumes, this does not seem to result in respiratory problems. [ 4 ]


Typical for achondroplastic children, as well, is sweating more than is average for children. Achondroplastic children’s diets should be watched very closely because it is easy for children to become obese when they are young. Their diets should be restricted to smaller portions than that of a child who is not diagnosed with achondroplasia.  Gastroesophageal reflux  is more common in achondroplastic children as well and should be treated and watched very closely if it furthers already heightened respiratory problems. Most infants diagnosed with achondroplasia will develop  thoracolumbar  kyphosis, which will need to be treated delicately so they can develop good posture with much care. If not watched properly or treated carefully, thoracolumbar kyphosis can help lead to  spinal stenosis . [ 3 ]


A child may be diagnosed with achondroplasia as early as the fetal stages of pregnancy. Most cases are first identified as early as 26 weeks in the gestational period. 85% of children born with achondroplasia are born of parents who are average height who are not themselves achondroplastic. However, 75% of all cases are the result of  de novo , or entirely new, genetic mutations. If both parents are diagnosed with achondroplasia, however, there is a higher chance of life-threatening problems. [ 3 ]


For an achondroplastic child to develop better, activities such as biking or swimming should be included in their daily schedule. Such activities may help with strength in the limbs and posture and will help to avert the problems of thoracolumbar kyphosis and spinal stenosis. Other activities, like gymnastics or rough sports should be avoided because they will help with the deteriorating of their back support and posture. Achondroplastic children should also be worked with daily on their verbal skills, so as to help them overcome the speech impairments they may likely encounter. [ 3 ]


Achondroplastic births are completely sporadic and the chances of having another child who is also achondroplastic is not more likely than for anyone else - having an achondroplastic child is entirely situational. [ 5 ]


Acrodysostosis   is a rare  congenital malformation  syndrome which involves shortening of the interphalangeal  joints  of the  hands  and  feet ,  intellectual disability  in approximately 90% of affected children, and peculiar  facies . Other common  abnormalities  include short head (as measured front to back), small broad upturned  nose  with flat  nasal bridge ,  protruding jaw , increased  bone age ,  intrauterine growth retardation ,  juvenile arthritis  and  short stature . Further  abnormalities  of the  skin ,  genitals ,  teeth , and  skeleton  may occur. [ 4 ] [ 5 ]


Other common abnormalities include short head (as measured front to back), small broad upturned  nose  with flat  nasal bridge ,  protruding jaw , increased  bone age ,  intrauterine growth retardation ,  juvenile arthritis  and  short stature . Further  abnormalities  of the  skin ,  genitals ,  teeth , and  skeleton  may occur. [ 6 ] [ 7 ]


Acrodysostosis presents with a wide spectrum of clinical manifestations. The following is a list of conditions and complications associated with acrodysostosis.
 [ 8 ]


Acrodysostosis is believed to be caused by mutations in the PRKAR1A gene (type 1) or the PDE4D gene (type 2). It has been suggested that the condition might be  genetically  related i.e. in an  autosomal dominant  mode of  transmission . Both males and females are affected. The disorder has been associated with the  older age of parents  at the time of  conception .


A  PRKAR1A   mutation  has been identified in acrodysostosis with  hormone  resistance. [ 9 ]


There are currently no approved treatments or standardised treatment guidelines for acrodysostosis. [ 10 ]  Management of acrodysostosis typically focuses on addressing specific symptoms that occur in each individual and may include surgery, physical therapy and special education.


A number of transgenic mouse models have been generated that harbour genetic mutations within genes linked to the condition in humans. These mouse models exhibit phenotypes similar to that observed in Acrodysostosis in humans. [ 11 ]


The actress  Olivia Colman  partnered with the charity  Acrodysostosis Support and Research  to raise awareness for the disease. She participated in a promotional video campaign in December 2020.


In  medicine ,  agenesis  ( / eɪ ˈ dʒ ɛ n ə s ə s / [ 1 ] ) refers to the failure of an  organ  to develop during  embryonic  growth and development due to the absence of primordial tissue. Many forms of agenesis are referred to by individual names, depending on the organ affected:


Eye agenesis  is a medical condition in which people are born with no  eyes .


Ear agenesis  is a medical condition in which people are born without  ears .


Because the middle and inner ears are necessary for hearing, people with complete agenesis of the ears are totally  deaf . Minor agenesis that affects only the visible parts of the outer ear, which may be called  microtia , typically produces cosmetic concerns and perhaps hearing impairment if the opening to the ear canal is blocked, but not deafness.


Allogeneic processed thymus tissue , sold under the brand name  Rethymic , is a  thymus  tissue  medical therapy  used for the treatment of children with  congenital athymia . [ 4 ]  It takes six months or longer to reconstitute the immune function in treated people. [ 4 ]


The most common adverse reactions include  high blood pressure ,  cytokine release syndrome ,  low blood magnesium levels ,  rash ,  low platelets , and  graft versus host disease . [ 4 ]


It was approved for medical use in the United States in October 2021. [ 4 ] [ 5 ] [ 6 ]  Allogeneic processed thymus tissue is the first thymus tissue product approved by the U.S.  Food and Drug Administration  (FDA). [ 4 ]


Allogeneic processed thymus tissue is composed of human  allogeneic  (donor-derived) thymus tissue that is processed and cultured, and then implanted into people to help reconstitute immunity (improve immune function) in people who are athymic. [ 4 ] [ 7 ]  Dosing is patient customized, determined by the surface area of the allogeneic processed thymus tissue slices and the body surface area of the patient. [ 4 ]


Allogeneic processed thymus tissue is  indicated  for immune reconstitution in children with congenital athymia. [ 2 ] [ 6 ]


The safety and efficacy of allogeneic processed thymus tissue were established in clinical studies that included 105 participants, with ages from one month to 16 years, who each received a single administration of allogeneic processed thymus tissue, from 1993 to 2020. [ 4 ]  Allogeneic processed thymus tissue improved survival of people with congenital athymia, and most people treated with this product survived at least two years. [ 4 ]


The U.S.  Food and Drug Administration  (FDA) granted the application for allogeneic processed thymus tissue a rare pediatric disease voucher and granted approval of Rethymic to Enzyvant Therapeutics, Inc. [ 4 ]


This article incorporates  public domain material  from the  United States Department of Health and Human Services


Amyoplasia  is a condition characterized by a generalized lack in the newborn of muscular development and growth, with  contracture  and deformity that affect at least two joints. [ 1 ]  It is the most common form of  arthrogryposis . [ 2 ]


It is characterized by the four limbs being involved, and by the replacement of  skeletal muscle  by dense fibrous and adipose tissue. [ 3 ]  Studies involving amyoplasia have revealed similar findings of the muscle tissue due to various causes including that seen in  sacral agenesis  and  amyotrophic lateral sclerosis . So amyoplasia may also include an intermediate common pathway, rather than the primary cause of the contractors.


Amyoplasia results when a fetus is unable to move sufficiently in the womb. Mothers of children with the disorder often report that their baby was abnormally still during the pregnancy. The lack of movement in utero (also known as fetal akinesia) allows extra connective tissue to form around the joints and, therefore, the joints become fixed. This extra  connective tissue  replaces muscle tissue, leading to weakness and giving a wasting appearance to the muscles. Additionally, due to the lack of fetal movement, the tendons that connect the muscles to bone are not able to stretch to their normal length and this contributes to the lack of joint mobility as well. [ medical citation needed ]


There is no single factor that is consistently found in the prenatal history of individuals affected with amyoplasia and, in some cases, there is no known cause of the disorder.


Amyoplasia is a sporadic condition that occurs due to lack of  fetal movement  in the womb. There is no specific gene that is known to cause the disorder. It is thought to be multifactorial, meaning that numerous genes and  environmental factors  play a role in its development. The recurrence risk is minimal for siblings or children of affected individuals. There have been no reports of recurrent cases of amyoplasia in a family. [ 1 ]


The fetal  akinesia  in amyoplasia is thought to be caused by various maternal and fetal abnormalities. In some cases, the mother's  uterus  does not allow for adequate fetal movement because of a lack of  amniotic fluid , known as  oligohydramnios , or an abnormal shape to the uterus, called a  bicornuate uterus .


There may also be a  myogenic  cause to the fetal akinesia, meaning that fetal muscles do not develop properly due to a muscle disease (for example, a congenital  muscular dystrophy ). Similarly, connective tissue tendon and skeletal defects may contribute to the fetal akinesia and be the primary cause of amyoplasia. Additionally, malformations may occur in the central nervous system and/or spinal cord that can lead to a lack of fetal movement in utero. This  neurogenic  cause is often accompanied by a wide range of other conditions. Other causes of fetal akinesia may include a maternal fever during pregnancy or a virus.


It is the most common form of arthrogryposis multiplex congenita (AMC), where multiple joint contractures are present at birth. Arthrogryposis is derived from the Greek word meaning "with crooking of joints."  It occurs in about one out of every 3,000 live births. There are more than 150 types of AMC. Amyoplasia accounts for 40% of AMC cases. [ citation needed ]


Children with amyoplasia often suffer from internally rotated shoulders, extended elbows, ulnar flexed wrists. The type of displacement of the hips and knees is more variable, and they often have  club feet . [ citation needed ]


About 10% of children with amyoplasia have evidence of vascular compromise including  Intestinal atresia ,  abdominal wall defects , and  gastroschisis . [ citation needed ]


Surgery may be necessary to address the congenital deformities frequently occurring in conjunction with arthrogryposis. Surgery on feet, knees, hips, elbows and wrists may also be useful if more range of motion is needed after therapy has achieved maximum results. In some cases,  tendon transfers  can improve function. Congenital deformities of the feet, hips and spine may require surgical correction at or about one year of age. [ 4 ]


Overall prognosis for children with amyoplasia is good. Intensive therapies throughout a child's developing years include  physical therapy ,  occupational therapy  and multiple orthopedic procedures. Most children require therapy for years, but almost 2/3 are eventually able to walk, with or without braces, and attend school. [ citation needed ]


Anorectal anomalies  are congenital malformations of the  anus  and  rectum . [ 1 ]  One anal anomaly,  imperforate anus  has an estimated incidence of 1 in 5000 births. [ 2 ] [ 3 ]  It affects boys and girls with similar frequency. [ 4 ]


Examples of anorectal anomalies include: [ citation needed ]


This article about a  disease , disorder, or medical condition is a  stub . You can help Wikipedia by  expanding it .


Arachnoid cysts  are  cerebrospinal fluid  covered by  arachnoidal cells  and  collagen [ 1 ]  that may develop between the surface of the  brain  and the cranial base or on the  arachnoid membrane , one of the three  meningeal layers  that cover the brain and the  spinal cord . [ 2 ]  Primary arachnoid cysts are a  congenital disorder  whereas secondary arachnoid cysts are the result of head injury or trauma. [ 3 ]  Most cases of primary cysts begin during infancy; however, onset may be delayed until adolescence. [ 2 ]


Patients with arachnoid cysts may never show symptoms, even in some cases where the cyst is large. Therefore, while the presence of symptoms may provoke further clinical investigation, symptoms independent of further data cannot—and should not—be interpreted as evidence of a cyst's existence, size, location, or potential functional impact on the patient. [ citation needed ]


Symptoms vary by the size and location of the cyst(s), though small cysts usually have no symptoms and are discovered only incidentally. [ 2 ]  On the other hand, a number of symptoms may result from large cysts:


The exact cause of arachnoid cysts is not known. Researchers believe that most cases of arachnoid cysts are developmental malformations that arise from the unexplained splitting or tearing of the arachnoid membrane. [ citation needed ]


In some cases, arachnoid cysts occurring in the middle fossa are accompanied by underdevelopment ( hypoplasia ) or compression of the  temporal lobe . The exact role that temporal lobe abnormalities play in the development of  middle fossa  arachnoid cysts is unknown. [ citation needed ]


There are some cases where hereditary disorders have been connected with arachnoid cysts. [ 18 ]


Some complications of arachnoid cysts can occur when a cyst is damaged because of minor  head trauma . [ 19 ]   Trauma can cause the fluid within a cyst to leak into other areas (e.g.,  subarachnoid space ). Blood vessels on the surface of a cyst may tear and bleed into the cyst (intracystic  hemorrhage ), increasing its size. If a blood vessel bleeds on the outside of a cyst, a collection of blood ( hematoma ) may result. In the cases of intracystic hemorrhage and hematoma, the individual may have symptoms of increased pressure within the cranium and signs of compression of nearby nerve (neural) tissue. [ citation needed ]


Some scientists debate whether arachnoid cysts are a true congenite condition or if this should be separated from secondary cysts. [ 20 ]  A recent study shows differences in communication between the arachnoid cyst and the subarachnoid space by  CT cisternography . [ 21 ]  A comparison of arachnoid cyst fluid and CSF in a series of patients show differences in chemical composition. [ 22 ]


Arachnoid cysts can also occur secondary to other disorders such as  Marfan syndrome ,  arachnoiditis , or  agenesis of the corpus callosum . [ citation needed ]


Diagnosis is principally by  MRI .  Frequently, arachnoid cysts are incidental findings on MRI scans performed for other clinical reasons.  In practice, diagnosis of symptomatic arachnoid cysts requires symptoms to be present, and many with the disorder never develop symptoms. [ citation needed ]


Additional clinical assessment tools that can be useful in evaluating a patient with arachnoid cysts include the  mini-mental state examination  (MMSE), a brief questionnaire-based test used to assess  cognition . [ 9 ]


Arachnoid cysts can be found on the brain or on the  spine .  Intracranial arachnoid cysts usually occur adjacent to the arachnoidal cistern. [ 23 ]   Spinal arachnoid cysts may be extradural, intradural, or perineural and tend to present with signs and symptoms indicative of a  radiculopathy . [ 23 ]


Arachnoid cysts may also be classified as primary (congenital) or secondary (acquired) and have been reported in humans, cats, and dogs. [ 24 ]


Arachnoid cysts can be relatively  asymptomatic  or present with  insidious  symptoms; for this reason, diagnosis is often delayed. [ citation needed ]


Most arachnoid cysts are asymptomatic and do not require treatment. Treatment may be necessary when symptomatic. [ 2 ]   A variety of procedures may be used to decompress (remove pressure from) the cyst.


Most arachnoid cysts are asymptomatic, and do not require treatment.  Where complications are present, leaving arachnoid cysts untreated may cause permanent severe neurological damage due to the progressive expansion of the cyst(s) or  hemorrhage  (bleeding). [ 2 ]  However, with treatment most individuals with symptomatic arachnoid cysts do well. [ citation needed ]


More specific prognoses are listed below:


Arachnoid cysts are seen in up to 1.1% of the population [ 34 ] [ 35 ]  with a gender distribution of 2:1 male:female. [ 36 ]   Only 20% of these have symptoms, usually from secondary  hydrocephalus . [ 34 ]


A study that looked at 2,536 healthy young males found a prevalence of 1.7% (95%  CI  1.2 to 2.3%). Only a small percentage of the detected abnormalities require urgent medical attention. [ 37 ]


Creutzfeldt–Jakob disease


Archibald's sign  (also known as  Archibald's metacarpal sign ) refers to a feature in the hand characterized by a shortening of the fourth or/and fifth metacarpals when the fist is clenched. [ 1 ] [ 2 ] [ 3 ]


The causes of Archibald's sign are not known; however, it has been discovered that it occurs more often in populations with certain disorders. Archibald's sign appears to be more common in individuals who have  Turners syndrome . It also seems to be more commonly found in  pseudohypoparathyroidism  of Albright's hereditary osteodystrophy,  brachydactyly ,  acrodysostosis , and occasionally with  homocystinuria . [ 4 ]


This  medical sign  article is a  stub . You can help Wikipedia by  expanding it .


Asplenia with cardiovascular anomalies , also known as  Ivemark syndrome  and  right atrial isomerism , [ 1 ]  is an example of a  heterotaxy syndrome . These uncommon  congenital disorders  are characterized by defects in the heart, spleen and paired organs such as the lungs and kidneys. Another name is "asplenia-cardiovascular defect-heterotaxy". [ 2 ]


Right atrial isomerism is named for its discoverer, Swedish pathologist  Biörn Ivemark . [ 3 ]


In right atrial isomerism, both atria of the heart are morphological right atria leading to associated abnormalities in the pulmonary venous system. In addition, individuals with right atrial isomerism develop  asplenia , a midline liver, malrotation of the small intestine and the presence of two morphologic right lungs. Individuals with left atrial isomerism, by comparison, have two morphologic left atria,  polysplenia , intestinal malrotation and two morphologic left lungs. [ 4 ]


The cause of heterotaxy is unknown. [ 5 ]


The  Ivemark Syndrome Association , which is based in  Dorset , [ 1 ]  is one of the organisations dedicated to helping patients and funding research.


Atransferrinemia  is an  autosomal   recessive   metabolic disorder  in which there is an absence of  transferrin , a  plasma   protein  that transports  iron  through the  blood . [ 2 ] [ 4 ]
Atransferrinemia is characterized by  anemia  and  hemosiderosis  in the  heart  and  liver . The iron damage to the heart can lead to  heart failure . The anemia is typically  microcytic  and hypochromic (the  red blood cells  are abnormally small and pale). Atransferrinemia was first described in 1961 and is extremely rare, with only ten documented cases worldwide. [ 5 ]


The presentation of this disorder entails  anemia , arthritis, hepatic anomalies, and recurrent  infections  are clinical signs of the disease. [ 1 ]  Iron overload occurs mainly in the liver, heart,  pancreas ,  thyroid , and  kidney . [ 6 ]


In terms of genetics of atransferrinemia researchers have identified  mutations  in the TF gene as a probable cause of this genetic disorder in affected people. [ 2 ]


Transferrin is a serum transport protein that transports iron to the  reticuloendothelial system  for utilization and  erythropoiesis , since there is no transferrin in atransferrinemia, serum free iron cannot reach reticuloendothelial cells and there is microcytic anemia. [ 7 ] [ 8 ] [ 9 ]


The diagnosis of atransferrinemia is done via the following means to ascertain if an individual has the condition: [ 2 ]


There are two forms of this condition that causes an absence of transferrin in the affected individual: [ 10 ]


The treatment of atransferrinemia is apotransferrin. The missing protein without iron. Iron treatment is detrimental as it does not correct the anemia and is a cause of secondary hemochromatosis. [ 3 ]


Autosomal dominant GTP cyclohydrolase I deficiency  (AD-GTPCHD) is a disease caused by dysfunction of  GTP cyclohydrolase I , an enzyme that plays an important role in the synthesis of  tetrahydrobiopterin , and, as a consequence, of  dopamine . This condition is one of the six known causes of  tetrahydrobiopterin deficiency [ 2 ]  and is the most frequently-reported cause of  dopa-responsive dystonia . [ 1 ]


In more than half the cases, the clinical picture is dominated by postural or action-induced  dystonia  of one or both lower limbs manifesting as gait difficulties. [ 2 ]  Dystonia gradually worsens during the day and becomes less pronounced after a period of rest. [ 2 ]  The fluctuating pattern is highly typical of this disease, especially in the first 30 years, after which this diurnal variation becomes less prominent. [ 2 ]


The typical age at onset is during the first decade of life, although an onset in the second decade of life is also common, and in rare cases the disease may present itself in the first 12–18 months of life. [ 2 ]


Autosomal dominant GTP cyclohydrolase I deficiency is caused by mutations in the GCH1 gene that encodes for the enzyme GTP Cyclohydrolase I. [ 3 ]


Diagnosis is complicated because, unlike the majority of  BH 4  deficiencies , AD-GTPCHD does not present with  hyperphenylalaninemia , and is therefore missed during newborn screening. [ 2 ]  Furthermore, unlike the majority of BH 4  deficiencies, this condition does not have a specific pterin pattern. [ 2 ]  Thus, according to data gathered by the year 2021, the average delay of diagnosis ranged from 8 [ 1 ]  to 10 [ 2 ]  years.


According to a consensus guideline on BH 4  deficiency published in 2020, if the presence of AD-GTPCHD is suspected, a genetic assessment should be carried out to look for mutations of the  GTPCH1  gene. [ 2 ]  Genetic assessment requires specialized methods able to detect  deletions , because in a significant number of patients with AD-GTPCHD no sequence alterations were found. [ 2 ]  Furthermore,  cerebrospinal fluid  analysis of biogenic amines and pterins (Figure 1) should be performed to gain additional clues. [ 2 ]


If neither of the first-line tests described above (CSF, genetic tests) are available, a phenylalanine loading test could be performed, which could provide a clue by revealing an increased phenylalanine/tyrosine ratio. [ 2 ]


In children whose symptoms are suggestive of  dopa-responsive dystonia  but for whom neither genetic nor biochemical assessment are available,  L-dopa  could be briefly prescribed as a trial to see if the patient's condition improves. [ 2 ]  In case of improvement, the patient would be suspected to have autosomal dominant GTP cyclohydrolase I deficiency, but would still have to undergo genetic and biochemical testing to distinguish their condition from other diseases. [ 2 ]


Patients are prescribed  L-dopa  in conjunction with a  DC inhibitor  such as  carbidopa  or benserazide. [ 2 ]  If symptoms persist,  dopamine agonists  such as  pramipexole ,  bromocriptine , or cabergoline could be considered as a second line of treatment. [ 2 ]   Anticholinergic drugs  or  COMT inhibitors  could be considered as a third line of treatment. [ 2 ]


As of 2020, there was a lack of precise data on the prevalence and incidence of the disease. [ 2 ]  One estimate, produced in 2017, puts the prevalence at 2.96 persons in a million people. [ 2 ]


Autosomal recessive GTP cyclohydrolase I deficiency  (AR-GTPCHD) is a disorder associated with the deficient operation of the enzyme  GTP cyclohydrolase I . The condition leads to insufficient production of the cofactor  tetrahydrobiopterin  necessary for the proper synthesis of  dopamine  and  serotonin  and for maintenance of adequate levels of  phenylalanine . As of 2020, autosomal recessive GTP cyclohydrolase I deficiency was one of the six known causes of  tetrahydrobiopterin deficiency . [ 1 ]  It is also considered part of the spectrum of  dopa-responsive dystonias . [ 2 ]


Patients may present with developmental delay, axial hypotonia, delayed development of speech, or dysarthria. [ 1 ]  The list of possible motor disturbances includes dystonia,  oculogyric crises ,  parkinsonism /hypokinesia. Patients may have a number of psychiatric symptoms. [ 1 ]


Biochemically, patients present with  hyperphenylalaninemia , and usually have decreased levels of  biopterin  and  neopterin  in urine and in dry blood spots. [ 1 ]


According to a consensus guideline published in 2020, patients may be put on a phenylalanine-restricted diet to help bring down their elevated phenylalanine levels. [ 1 ]   To the same effect, and to normalise their production of neurotransmitters, they may be prescribed  sapropterin , an artificially produced analogue of  tetrahydrobiopterin . [ 1 ]   Another first-line drug in this disease is  L-DOPA . Prescription of  5-hydroxytryptophan  is also possible. [ 1 ]


Prolonged therapy with large doses of L-DOPA may lead to the development of  cerebral folate deficiency , therefore patients with decreased concentrations of  5-MTHF  in their  cerebrospinal fluid  may be prescribed  folinic acid , which efficiently penetrates the blood-cerebrospinal fluid barrier and helps restore the folate status. [ 1 ]


Ayazi syndrome  (or  Chromosome 21 Xq21 deletion syndrome ) [ 1 ]  is a  syndrome  characterized by  choroideremia , congenital  deafness  and  obesity .


The presentation for this condition is as follows: [ citation needed ]


Ayazi syndrome's inheritance pattern is described as  x-linked recessive . Genes known to be deleted are CHM and POU3F4, both located on the  Xq21 locus . [ 1 ]


This  genetic disorder  article is a  stub . You can help Wikipedia by  expanding it .


Bangstad syndrome  is a severe, inherited  congenital disorder  associated with abnormalities of the  cell membrane .


It was characterized in 1989 by H. J. Bangstad. [ 1 ]


Presenting at birth, [ 2 ]  features of the disorder include moderately severe  IUGR ,  microcephaly ,  craniosynostosis , moderately severe post-uterine growth retardation, deafness, deep-set eyes,  cryptorchidism ,  truncal obesity  and  acanthosis nigricans , small teeth,  prognathism , dislocated radial heads without generalized skeletal dysplasia, however, tall vertebrae, moderate mental retardation,  hypothyroidism ,  insulin resistance ,  hypoparathyroidism . [ 3 ]


Thyroid-stimulating hormone ,  parathyroid hormone ,  luteinizing hormone ,  follicle-stimulating hormone ,  adrenocorticotropic hormone ,  glucagon , and  insulin  levels in the blood are usually elevated. [ 3 ]


Barakat syndrome  is a  rare disease  characterized by  hypoparathyroidism ,  sensorineural deafness  and  renal disease , and hence also known as  HDR syndrome . It is an autosomal dominant condition with  incomplete penetrance  and  variable expressivity [ 2 ]  that was first described by  Amin J. Barakat  et al. in 1977. [ 3 ]


It is a genetic developmental disorder [ 4 ]  with clinical diversity characterized by  hypoparathyroidism ,  sensorineural deafness  and  renal disease . [ 5 ]  Sensorineural deafness typically presents in childhood or adolescence. Affected people usually present with  hypocalcaemia ,  tetany , or afebrile convulsions at any age. [ 1 ]  Hearing loss is usually bilateral and may range from mild to profound impairment. Renal disease includes  nephrotic syndrome ,  cystic kidney ,  renal dysplasia ,  hypoplasia  or  aplasia , pelvicalyceal deformity,  vesicoureteral reflux , chronic kidney disease,  hematuria ,  proteinuria  and renal scarring. [ citation needed ]


Other reported features include:  intellectual disability ,  polycystic ovaries , particular distinct facial characteristics,  ischaemic stroke  and  retinitis pigmentosa . [ 5 ]


Barakat syndrome is a rare condition inherited as  autosomal dominant  trait. [ 5 ] [ 6 ]


The defect in the majority of cases has mapped to  chromosome 10p  (Gene Map Locus: 10pter-p13 or 10p14-p15.1).  Haploinsufficiency  (deletions) of zinc-finger transcription factor GATA3 or mutations in the  GATA3   gene [ 7 ]  appear to be the underlying cause of this syndrome. It causes the failure in the specification of prosensory domain and subsequently leads to increased cell death in the cochlear duct thus causing deafness. [ 8 ]


Since the spectrum of phenotypic variation in affected people is quite large, Barakat syndrome probably arises as a low penetrance haploinsufficient disorder in which their genetic background plays a major role in the severity of the disease. [ 9 ] [ 2 ]


A thorough diagnosis should be performed on every affected individual, and siblings should be studied for deafness, parathyroid and renal disease. The syndrome should be considered in infants who have been diagnosed  prenatally  with a  chromosome 10p  defect, and those who have been diagnosed with well defined  phenotypes  of urinary tract abnormalities. [ citation needed ]


Management consists of treating the clinical abnormalities at the time of presentation and includes genetic counselling, correcting calcium, treating hearing problems, monitoring kidney function and close monitoring of cysts of the kidney. [ 1 ] [ 5 ]


Prognosis  depends on the severity of the kidney disease. Life expectancy is unaffected if the disease is mild. [ 1 ]


The frequency is unknown, but the disease is considered to be very rare. [ 10 ]  Both male and females have been noted to be affected by hypoparathyroidism, sensorineural deafness, and renal disease. [ 1 ]   However, specific symptoms and severity can vary. Around 65% of people with Barakat syndrome have hypoparathyroidism, sensorineural deafness and kidney disease together. [ 5 ]  As of 2023, the global medical literature has documented 180 reported cases. [ 11 ]


Bartter syndrome  ( BS ) is a rare inherited disease characterised by a defect in the  thick ascending limb  of the  loop of Henle , which results in low potassium levels ( hypokalemia ), [ 2 ]  increased blood pH ( alkalosis ), and normal to  low blood pressure . There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder,  Gitelman syndrome , is milder than both subtypes of Bartter syndrome. [ citation needed ]


In 90% of cases,  neonatal Bartter syndrome  is seen between 24 and 30 weeks of gestation with excess  amniotic fluid  ( polyhydramnios ). After birth, the infant is seen to urinate and drink excessively ( polyuria , and  polydipsia , respectively). Life-threatening dehydration may result if the infant does not receive adequate fluids. About 85% of infants dispose of excess amounts of calcium in the urine ( hypercalciuria ) and kidneys ( nephrocalcinosis ), which may lead to  kidney stones . In rare occasions, the infant may progress to  kidney failure . [ 3 ]


Patients with  classic Bartter syndrome  may have symptoms in the first two years of life, but they are usually diagnosed at school age or later. Like infants with the neonatal subtype, patients with classic Bartter syndrome also have polyuria, polydipsia, and a tendency to dehydration, but normal or just slightly increased urinary calcium excretion without the tendency to develop kidney stones. These patients also have vomiting and growth retardation. Kidney function is also normal if the disease is treated, [ 4 ]  but occasionally patients proceed to end-stage kidney failure.
Bartter syndrome consists of  low levels of potassium in the blood , alkalosis, normal to low blood pressures, and elevated plasma renin and aldosterone. Numerous causes of this syndrome probably exist. Diagnostic pointers include high urinary potassium and chloride despite low serum values, increased plasma renin,  hyperplasia  of the  juxtaglomerular apparatus  on  kidney biopsy , and careful exclusion of diuretic abuse. Excess production of  prostaglandins  by the kidneys is often found. Magnesium wasting may also occur. Homozygous patients experience severe hypercalciuria and nephrocalcinosis. [ 5 ]


Bartter syndrome is caused by mutations of genes encoding proteins that transport ions across renal cells in the  thick ascending limb  of the nephron also called as the ascending loop of Henle. [ 4 ]  Specifically, mutations directly or indirectly involving the  Na-K-2Cl cotransporter  are key. The Na-K-2Cl cotransporter is involved in electroneutral transport of one sodium, one potassium, and two chloride ions across the apical membrane of the tubule. The basolateral  calcium-sensing receptor  has the ability to downregulate the activity of this transporter upon activation. Once transported into the tubule cells, sodium ions are actively transported across the basolateral membrane by  Na + /K + -ATPases , and chloride ions pass by facilitated diffusion through basolateral chloride channels. Potassium, however, is able to diffuse back into the tubule lumen through apical potassium channels, returning a net positive charge to the lumen and establishing a positive voltage between the lumen and interstitial space. This charge gradient is obligatory for the paracellular reabsorption of both calcium and magnesium ions. [ citation needed ]


Proper function of all of these transporters is necessary for normal ion reabsorption along the thick ascending limb, and loss of any component can result in functional inactivation of the system as a whole and lead to the presentation of Bartter syndrome. Loss of function of this reabsorption system results in decreased sodium, potassium, and chloride reabsorption in the thick ascending limb, as well as abolishment of the lumen-positive voltage, resulting in decreased calcium and magnesium reabsorption. Loss of reabsorption of sodium here also has the undesired effect of abolishing the hypertonicity of the renal medulla, severely impairing the ability to reabsorb water later in the distal nephron and  collecting duct system , leading to significant diuresis and the potential for volume depletion. Finally, increased sodium load to the distal nephron elicits compensatory reabsorption mechanisms, albeit at the expense of potassium by excretion by principal cells and resulting  hypokalemia . This increased potassium excretion is partially compensated by α-intercalated cells at the expense of hydrogen ions, leading to  metabolic alkalosis . [ citation needed ]


Bartter and Gitelman syndromes can be divided into different subtypes based on the genes involved: [ 6 ]


People with Bartter syndrome present symptoms that are identical to those of patients who are on  loop diuretics  like  furosemide , given that the loop diuretics target the exact transport protein that is defective in the syndrome (at least for type 1 Bartter syndrome). The other subtypes of the syndrome involve mutations in other transporters that result in functional loss of the target transporter. Patients often admit to a personal preference for salty foods. [ 9 ]


The clinical findings characteristic of Bartter syndrome is hypokalemia, metabolic alkalosis, and normal to low blood pressure. These findings may also be caused by other conditions, which may cause confusion. When diagnosing a Bartter's syndrome, the following conditions must be ruled out as possible causes of the symptomatology: [ citation needed ]


Patients with Bartter syndrome may also have elevated  renin  and  aldosterone  levels. [ 10 ]


Prenatal Bartter syndrome can be associated with  polyhydramnios . [ 11 ]


However, Bartter syndrome is also characterized by high renin, high aldosterone, hypercalciuria, and an abnormal Na + -K + -2Cl −  transporter in the thick ascending limb of the loop of Henle, whereas Gitelman syndrome causes hypocalciuria and is due to an abnormal thiazide-sensitive transporter in the distal segment. [ 13 ]


Pseudo-Bartter's syndrome  is a syndrome of similar presentation as Bartter syndrome but without any of its characteristic genetic defects. Pseudo-Bartter's syndrome has been seen in  cystic fibrosis , [ 14 ]  as well as in excessive use of  laxatives . [ 15 ]


Medically supervised sodium, chloride and potassium supplementation is necessary, and  spironolactone  can be also used to reduce potassium loss. [ 2 ]  Free and unqualified access to water is necessary to prevent dehydration, as patients maintain an appropriate thirst response. In severe cases where supplementation alone cannot maintain biochemical homeostasis,  nonsteroidal anti-inflammatory drugs  (NSAIDs) can be used to reduce glomerular filtration and can be very useful, although may cause gastric irritation and should be administered alongside stomach acid suppression therapies.  Angiotensin-converting enzyme (ACE) inhibitors  can also be used to reduce glomerular filtration rate. In young babies and children, a low threshold to check serum electrolytes during periods of illness compromising fluid intake is necessary. [ 16 ]


Surveillance renal ultrasound should be employed to monitor for the development of nephrocalcinosis, a common complication which further augments urinary concentrating difficulty. [ 17 ]


The limited prognostic information available suggests that early diagnosis and appropriate treatment of infants and young children with classic Bartter Syndrome may improve growth and perhaps intellectual development. On the other hand, sustained hypokalemia and hyperreninemia can cause progressive  tubulointerstitial nephritis , resulting in  end-stage kidney disease  (kidney failure). With early treatment of the electrolyte imbalances, the prognosis for patients with classic Bartter Syndrome is good. [ citation needed ]


The condition is named after Dr.  Frederic Bartter , who, along with Dr. Pacita Pronove, first described it in 1960 and in more patients in 1962. [ 10 ] [ 18 ] [ 19 ] [ 20 ]


Benjamin syndrome  is a type of multiple  congenital anomaly / intellectual disability  (MCA/MR) syndrome. It is characterized by  hypochromic anemia  with  intellectual disability  and various  craniofacial  and other anomalies. [ 1 ]  It can also include  heart murmur ,  dental caries  and  splenic   tumors . [ 2 ]


It was first described in the medical literature in 1911. [ 3 ]  Symptoms include  megalocephaly , external  ear  deformities,  dental caries ,  micromelia ,  hypoplastic  bone deformities,  hypogonadism ,  hypochromic anemia  with occasional  tumors , and  intellectual disability . [ 4 ]


Bhaskar–Jagannathan syndrome  is an extremely rare genetic disorder and there is a limited amount of information related to it. Similar or related medical conditions are  arachnodactyly ,  aminoaciduria ,  congenital   cataracts ,  cerebellar ataxia , and delayed  developmental milestones .


Bhaskar–Jagannathan has symptoms such as long fingers, thin fingers, poor balance, incoordination, high levels of amino acids in urine, cataracts during infancy, and ataxia. Ataxia, which is a neurological sign and symptom made up of gross incoordination of muscle movements and is a specific clinical manifestation [ citation needed ]


There are three different ways to diagnose Bhaskar–Jagannathan.  This disorder may be diagnosed by a urine test, a blood test, and an  X-ray  of the eyes or other body parts. [ citation needed ]


Treatment for this rare genetic disorder can be  physical therapy , there have been  antibiotics  found to be effective, and surgery has been found to be another solution.


[ 1 ]
 [ 2 ]


Boomerang dysplasia  is a lethal form of  osteochondrodysplasia [ 1 ]  known for a characteristic  congenital  feature in which  bones  of the  arms  and  legs  are malformed into the shape of a  boomerang . [ 2 ]  Death usually occurs in early infancy due to complications arising from overwhelming systemic  bone   malformations . [ 1 ]


Osteochondrodysplasias are skeletal disorders that cause malformations of both bone and  cartilage .


Prenatal and neonatal diagnosis of boomerang dysplasia includes several prominent features found in other osteochondrodysplasias, though the "boomerang" malformation seen in the  long bones  is the delineating factor. [ 2 ]


Featured symptoms of boomerang dysplasia include:  dwarfism [ 3 ]  (a lethal type of  infantile  dwarfism caused by systemic  bone deformities ), [ 4 ]   underossification  (lack of bone formation) in the  limbs ,  spine  and  ilium  ( pelvis ); [ 1 ]  proliferation of multinucleated giant-cell  chondrocytes  (cells that produce  cartilage  and play a role in skeletal development - chondrocytes of this type are rarely found in osteochondrodysplasias), [ 5 ]   brachydactyly  (shortened fingers) and  micromelia  (undersized, shortened bones). [ 2 ]


The characteristic "boomerang" malformation presents intermittently among random absences of long bones throughout the skeleton, in affected individuals. [ 3 ] [ 6 ]  For example, one individual may have an absent  radius  and  fibula , with the "boomerang" formation found in both  ulnas  and  tibias . [ 6 ]  Another patient may present "boomerang"  femora , and an absent  tibia . [ 3 ]


Mutations in the  Filamin B ( FLNB )  gene cause boomerang dysplasia. [ 1 ]  FLNB is a  cytoplasmic   protein  that regulates intracellular communication and signalling by cross-linking the protein  actin  to allow direct communication between the  cell membrane  and  cytoskeletal network , to control and guide proper skeletal development. [ 7 ]  Disruptions in this pathway, caused by FLNB  mutations , result in the bone and cartilage abnormalities associated with boomerang dysplasia. [ citation needed ]


Chondrocytes , which also have a role in bone development, are susceptible to these disruptions and either fail to undergo  ossification , or ossify incorrectly. [ 1 ] [ 7 ]


FLNB mutations are involved in a spectrum of  lethal bone dysplasias . One such disorder,  atelosteogenesis type I , is very similar to boomerang dysplasia, and several symptoms of both often overlap. [ 8 ] [ 9 ]


Early journal reports of boomerang dysplasia suggested  X-linked   recessive   inheritance , based on observation and family history. [ 3 ]  It was later discovered, however, that the disorder is actually caused by a  sporadic  genetic  mutation  fitting an  autosomal   dominant  genetic profile. [ 8 ]


Autosomal dominant inheritance indicates that the defective gene responsible for a disorder is located on an  autosome , and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder. [ 10 ]


Boomerang dysplasia, although an autosomal dominant disorder, [ 8 ]  is  not  inherited because those afflicted do not live beyond infancy. [ 1 ]  They cannot pass the gene to the next generation. [ citation needed ]


Ankyrin :  Long QT syndrome 4


Bosch–Boonstra–Schaaf optic atrophy syndrome  is a rare autosomally inherited condition characterised by developmental delay, intellectual disability and decreased visual acuity. [ 2 ] [ 3 ] [ 4 ]


All patients described have suffered from developmental delay, intellectual disability (intelligence quotient range 48–74) and decreased visual acuity. Ocular abnormalities include small discs, pale discs, disc excavation,  strabismus  and latent  nystagmus .


Other features of this condition are somewhat variable and include:


This condition is caused by mutations in the  NR2F1  gene. This gene is located on the long arm of  chromosome 5  (5q15) and encodes a  protein  that acts as a nuclear receptor and transcriptional regulator. The syndrome is inherited in an autosomal dominant fashion. [ citation needed ]


There is no curative treatment known at present for his condition. Management is supportive. [ citation needed ]


This condition is considered to be rare with fewer than 50 cases described in the modern literature.


This condition was first described in 2014. [ 2 ]


Bowen–Conradi syndrome  is a disease in humans that can affect children. [ 2 ]  The disease is due to an  autosomal recessive  abnormality of the  EMG1   gene , which plays a role in  small ribosomal subunit  (SSU) assembly. [ 1 ] [ 3 ]  The preponderance of diagnoses has been in North American  Hutterite  children, but BWCNS can affect other population groups. [ 2 ] [ 4 ]


BWCNS is a  ribosomopathy . [ 1 ] [ 5 ]  A D86G  mutation  of  EMG1  destroys an  EcoRV  restriction  endonuclease  site in the most highly conserved region of the protein. [ 3 ]


Skeletal  dysmorphology  is seen [ 2 ] [ 4 ]  and severe prenatal and postnatal growth failure usually leads to death by one year of age. [ 6 ]


Brugada syndrome  ( BrS ) is a  genetic disorder  in which the electrical activity of the  heart  is abnormal due to  channelopathy . [ 2 ]  It increases the risk of  abnormal heart rhythms  and  sudden cardiac death . [ 2 ]  Those affected may have episodes of  syncope . [ 2 ]  The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. [ 1 ] [ 5 ]  They may be triggered by a  fever . [ 1 ] [ 5 ]


About a quarter of those with Brugada syndrome have a family member who also has the condition. [ 2 ]  Some cases may be due to a new genetic  mutation  or certain medications. [ 1 ]  The most commonly involved  gene  is  SCN5A  which encodes the cardiac  sodium channel . [ 6 ]  Diagnosis is typically by  electrocardiogram  (ECG), however, the abnormalities may not be consistently present. [ 2 ]  Medications such as  ajmaline  may be used to reveal the ECG changes. [ 2 ]  Similar ECG patterns may be seen in certain  electrolyte disturbances [ 7 ]  or when the  blood supply to the heart has been reduced . [ 8 ]


There is no cure for Brugada syndrome. [ 3 ]  Those at higher risk of sudden cardiac death may be treated using an  implantable cardioverter defibrillator  (ICD). [ 4 ]  In those without symptoms the risk of death is much lower, and how to treat this group is less clear. [ 3 ] [ 9 ]   Isoproterenol  may be used in the short term for those who have frequent life-threatening abnormal heart rhythms, while  quinidine  may be used longer term. [ 3 ] [ 10 ]  Testing people's family members may be recommended. [ 3 ]


The condition affects between 1 and 30 per 10,000 people. [ 2 ]  It is more common in males than females and in those of Asian descent. [ 1 ] [ 2 ]  The onset of symptoms is usually in adulthood. [ 2 ]  It was first described by Andrea Nava and Bortolo Martini, in Padova, in 1989; [ 11 ]  it is named after Pedro and Josep Brugada, two Spanish cardiologists, who described the condition in 1992. [ 3 ] [ 12 ]  Chen first described the genetic abnormality of SCN5A channels. [ 13 ]


Although many of those with Brugada syndrome do not have any symptoms, Brugada syndrome may cause fainting or sudden cardiac death due to serious abnormal heart rhythms, such as  ventricular fibrillation  or  polymorphic ventricular tachycardia . [ 9 ]   Blackouts may be caused by brief abnormal heart rhythms that revert to a normal rhythm spontaneously.  If a dangerous heart rhythm does not stop by itself and is left untreated, the person may have a fatal cardiac arrest. However, blackouts can occur in those with Brugada syndrome despite a normal heart rhythm, because of a sudden drop in blood pressure, known as  vasovagal syncope . [ 2 ]


The abnormal heart rhythms seen in Brugada syndrome often occur at rest, after a heavy meal, and even during sleep. [ 5 ]  These situations are linked to periods when the  vagus nerve  is activated, referred to as periods of high  vagal tone . Abnormal heart rhythms may also occur during  fever  and after excessive alcohol use.  Sodium-channel-blocking  medications, commonly used to treat cardiac arrhythmia, may also worsen the tendency to abnormal heart rhythms in patients with Brugada syndrome and should be avoided. [ 14 ] [ 15 ]


The individual  heart muscle cells  communicate with each other with electrical signals that are disrupted in those with Brugada syndrome. As a  genetic condition , the syndrome is ultimately caused by changes to a person's  DNA , known as  genetic mutations . The first mutations described in association with Brugada syndrome were in a  gene  responsible for a protein or  ion channel  that controls the flow of  sodium ions  through the  cell membrane  of  heart muscle cells  – the  cardiac sodium channel . Many of the genetic mutations that have subsequently been described in association with Brugada syndrome influence the sodium current in some way, or affect other ionic currents. [ 8 ]


A long list of factors that can generate a Brugada ECG pattern have been described, including certain medications, electrolyte disturbances such as a  decrease in the levels of potassium in the blood , and a  reduction in blood supply  to key areas of the heart, specifically the  right ventricular outflow tract . [ 8 ]  Drugs that have been implicated include  antiarrhythmic  medications such as  flecainide ,  verapamil  and  propranolol , antidepressants such as  amitryptiline , and drugs that enhance vagal tone such as  acetylcholine . The ECG pattern can also be seen following excessive use of  alcohol  or  cocaine . [ 8 ]


Brugada syndrome is inherited in an  autosomal dominant  manner, meaning that only one copy of the defective gene is needed to produce the syndrome. However, a person diagnosed with the condition may be the first in their family to have Brugada syndrome if it has arisen as a new mutation. [ 5 ]   The gene in which mutations are most commonly found in Brugada syndrome, known as  SCN5A , is responsible for the cardiac sodium channel. Mutations in SCN5A associated with Brugada syndrome generally cause the flow of sodium ions to decrease.  However, only 20% of cases of Brugada syndrome are associated with mutations in  SCN5A , as in the majority of patients with Brugada syndrome genetic testing is unable to identify the genetic mutation responsible. [ 5 ]  Over 290 mutations in the  SCN5A  gene have been discovered to date, each altering sodium channel function in subtly different ways. [ 16 ]   This variation partially explains the differences in severity of the condition between different persons, ranging from a highly dangerous condition causing death at a young age to a benign condition that may not cause any problems at all.  However, the genetics of Brugada syndrome are complex, and it is likely that the condition results from the interactions of many genes.  Because of these complex interactions, some members of a family who carry a particular mutation may show evidence of Brugada syndrome while other carrying the same mutation may not, referred to as variable  penetrance . [ 17 ]  Mutations in the SCN5A gene seem to have a prognostic value. [ 18 ] [ 19 ] [ 20 ]


Several other genes have been identified in association with Brugada syndrome. Some are responsible for other proteins that form part of the  sodium channel , known as sodium channel β subunits ( SCN1B ,  SCN2B ,  SCN3B ) while others form different types of sodium channel ( SCN10A ). Some genes encode ion channels that carry calcium or potassium ions ( CACNA1C ,  CACNB2 ,  KCND3 ,  KCNE3 ,  KCNJ8 , KCNT1), [ 21 ]  while others generate proteins that interact with ion channels. ( GPD1L ,  PKP2 , MOG1,  FGF12 ). Another gene associated with this condition is  RRAD . [ 22 ]  The genes associated with Brugada syndrome and their description include:


Some mutations associated with Brugada syndrome can also cause other heart conditions.  Those who show more than one cardiac conditions at the same time caused by a single mutation are described as having an ' overlap syndrome '.  An example of an overlap syndrome is Brugada and  long QT syndrome  (LQT3) caused by a mutation in SCN5A that reduces the peak sodium current but simultaneously leaves a persistent current leak. [ 8 ]  Brugada syndrome has been described as overlapping with  arrhythmogenic right ventricular cardiomyopathy  (ARVC) caused by a mutation in the PKP2 gene, causing a Brugada ECG pattern but structural changes in the heart characteristic of ARVC. [ 27 ]  Another example of an overlap syndrome would be Brugada syndrome and  major aortopulmonary collateral arteries  (MAPCAs) caused by a mutation in  KCNT1  that leads to an abnormal  gain-of-function  in potassium channels of  neurons  and  cardiomyocytes . [ 28 ] [ 29 ]


The abnormal heart rhythms seen in those with Brugada syndrome are typically dangerous arrhythmias such as ventricular fibrillation or polymorphic ventricular tachycardia, but those with BrS are also more likely to experience rapid heart rates due to less dangerous arrhythmias such as  AV nodal re-entrant tachycardia [ 30 ]  and abnormally slow heart rhythms such as  sinus node dysfunction . [ 31 ]  There are several mechanisms by which the genetic mutations causing this condition might produce these arrhythmias. [ 32 ]


Some argue that the main reason these arrhythmias arise is due to abnormally slow electrical conduction in areas of the heart, specifically the  right ventricle .  The genetic variants associated with BrS support the concept as SCN5A, the gene most commonly associated with the condition, along with SCN10A, SCN1B, SCN2B and SCN3B, all directly affect the sodium current  I Na . The sodium current is a major contributor to the characteristic flow of electrical charge across the membrane of heart muscle cells that occurs with each heartbeat known as the  action potential .   I Na  causes the initial rapid upstroke of the action potential (phase 0), and decreasing the early peak current, as occurs in BrS-associated genetic variants, leads to slowing of the electrical conduction through the heart muscle. [ 8 ]  This slow conduction allows 'short circuits' to form, blocking the waves of electrical activity in some areas while allowing the waves to pass in others in a phenomenon known as wavebreak.  Given the right circumstances, this wavebreak can allow the waves of electricity to perform a U-turn within the muscle, travelling in the reverse direction before beginning to rapidly circle around a point, referred to as re-entry, and causing an abnormal heart rhythm. [ 8 ]  Those who support this view (known as the depolarisation hypothesis) argue that conduction slowing may explain why arrhythmias in those with Brugada syndrome tend to occur in middle age, when other factors such as scarring or fibrosis that accompany old age have exacerbated the tendency to conduction slowing caused by the genetic mutation. [ 32 ]


Others suggest that the main cause of arrhythmias is a difference in the electrical properties between the inside ( endocardium ) and outside ( epicardium ) of the heart (known as the repolarisation hypothesis). [ 8 ]  The shape of the action potential differs between the epicardium and the endocardium. The action potential in cells from the epicardium shows a prominent notch after the initial spike due to a transient outward current. This notch is far less evident in cells from the endocardium, and the difference between the endocardium and epicardium are most clearly seen in the right ventricle. In those with Brugada syndrome, these differences are increased, creating a brief period within each cardiac cycle when current flows from the endocardium to the epicardium creating the characteristic ECG pattern.  The differences in electrical properties between the epi- and endocardium are described as a 'transmural dispersion of repolarisation" which if large enough can lead to electrical impulses becoming blocked in some regions but not others.  Once again, this wavebreak can allow the waves of electricity which usually travel in only one direction to instead begin circling around a point as a re-entrant circuit, causing an arrhythmia. [ 8 ]


A further factor promoting arrhythmias in Brugada syndrome is changes to the structure of the heart. [ 32 ]  Whilst the heart of those with Brugada syndrome may look normal, scarring or fibrosis is often seen in particular regions of the heart, specifically the right ventricular outflow tract.  As Brugada syndrome can be caused by mutation in many different genes, it is possible that different mechanisms may be responsible for the arrhythmias seen in different patients. [ 32 ]


Brugada syndrome is diagnosed by identifying characteristic patterns on an  electrocardiogram . [ 14 ]  The pattern seen on the ECG includes  ST elevation  in leads V 1 -V 3  with a  right bundle branch block  (RBBB) appearance. There may be evidence of a slowing of electrical conduction within the heart, as shown by a prolonged  PR interval . These patterns may be present all the time, but may appear only in response to particular drugs (see below), when the person has a  fever , during exercise, or as a result of other triggers. The ECG pattern may become more obvious by performing an ECG in which some of the electrodes are placed in different positions from usual, specifically by placing leads V 1  and V 2  higher up the chest wall in the 1st or 2nd intercostal spaces. [ 33 ]


Three forms of the Brugada ECG pattern have historically been described, [ 34 ]  although the Type 3 pattern is frequently merged with the Type 2 pattern in contemporary practice. [ 35 ]


According to current recommendations, only a Type 1 ECG pattern, occurring either spontaneously or in response to medication, can be used to confirm the diagnosis of Brugada syndrome as Type 2 and 3 patterns are not infrequently seen in persons without the disease. [ 9 ]


Some medications, particularly antiarrhythmic drugs that block the cardiac sodium current  I Na,  can reveal a Type 1 Brugada pattern in susceptible people.  These drugs can be used to help make a diagnosis in those suspected of having Brugada syndrome (e.g. survivors of an unexplained cardiac arrest, family members of a person with Brugada syndrome) but in whom a diagnostic ECG pattern has not been seen. [ 2 ]   In these cases, sodium current blocking medications can be given in a controlled environment. [ 33 ]  The most commonly used drugs for this purpose are  ajmaline , flecainide, and  procainamide , with some suggestions indicating that ajmaline may be the most effective. [ 36 ]  Precaution must be taken in giving these medications as there is a small risk of causing abnormal heart rhythms. [ 33 ]


Genetic testing  can be helpful to identify patients with Brugada syndrome, most commonly in family members of a person with Brugada syndrome, but sometimes performed in a person who has died suddenly and unexpectedly. [ 5 ]  However, interpretation of the results of genetic testing is challenging.  In family members who all carry a particular genetic variant associated with Brugada syndrome, some family members may show evidence of Brugada syndrome on their ECGs while others may not. [ 5 ]   This means that carrying a genetic mutation associated with Brugada syndrome does not necessarily imply that a person is truly affected by the condition.  To further complicate matters, many frequently occurring variations in the SCN5A gene do not cause any problems, and therefore genetic variants are sometimes identified in persons with Brugada syndrome that are not truly causing the disease. [ 37 ]


Invasive  electrophysiological studies , in which wires are passed through a vein to stimulate and record electrical signals from the heart, can sometimes be used to assess the risk of a person with Brugada syndrome experiencing dangerous abnormal heart rhythms. [ 38 ]   Risk stratification is also sometimes performed using a  signal averaged ECG . [ 5 ]   Ambulatory ECG monitoring , including implantation of a  loop recorder , is sometimes used to assess whether dizziness or faints in a person with Brugada syndrome are due to abnormal heart rhythms or other causes such as vasovagal syncope. [ 39 ]


The main aim when treating people with Brugada syndrome is to reduce the risk of sudden death due to serious  abnormal heart rhythms  such as ventricular fibrillation or polymorphic ventricular tachycardia. [ 40 ]  While some with this condition are at high risk of serious heart rhythm disturbances, others are at much lower risk, meaning that some may require more intensive treatment than others. [ 9 ]   In addition to treating the person who has Brugada syndrome, it is often important to investigate members of their immediate family to see if they too carry the condition. [ 9 ]


The first line of treatment, suitable for all people with Brugada syndrome regardless of their risk of arrhythmias, is lifestyle advice. [ 9 ]  People should be advised to recognise and avoid things that may increase the risk of serious arrhythmias.  These include avoiding excessive alcohol consumption, avoiding certain medications, [ 14 ]  and treating fever promptly with  paracetamol . [ 9 ]  Although the abnormal heart rhythms seen in Brugada syndrome are generally more likely to occur at rest or even during sleep, some people with Brugada syndrome experience arrhythmias during strenuous exercise.  Some physicians may therefore advise people with Brugada syndrome that while gentle exercise is helpful, very strenuous exercise should be avoided. [ 41 ] [ 42 ]


In people felt to be at higher risk of sudden cardiac death, an  implantable cardioverter-defibrillator  (ICD) may be recommended. [ 9 ]   These small devices implanted under the skin continuously monitor the heart rhythm.  If the device detects a potentially life-threatening arrhythmia it can give the heart a small electric shock, stunning the heart back into a normal rhythm. [ 43 ]  An ICD can also function as a  pacemaker , preventing abnormally slow heart rates that can also occur in people with Brugada syndrome.


Implanting an ICD is a relatively low-risk procedure and is frequently performed as a day case under  local anaesthetic . [ 43 ]  However, complications such as infection, bleeding or unnecessary shocks can occur, which can sometimes be serious. [ 44 ]  Because of the small risk associated with implanting an ICD, as well as the cost of the devices, ICDs are not recommended for all people with Brugada syndrome but are instead reserved for people deemed at higher risk of sudden cardiac death. [ 9 ]


Quinidine  is an antiarrhythmic drug that may reduce the chance of serious abnormal heart rhythms occurring in some people with Brugada syndrome. [ 10 ] [ 45 ]  It is most frequently used in people with Brugada syndrome who have an ICD and have experienced several episodes of life-threatening arrhythmias, but may also be used in people at high risk of arrhythmias but in whom an ICD is not appropriate. [ 9 ]


Isoprenaline , a drug that has similarities with  adrenaline , can be used in an emergency for people with Brugada syndrome who are having frequent repeated life-threatening arrhythmias, known as an "electrical storm". [ 9 ]  This drug must be given as a continuous infusion into a vein and therefore is not suitable for long-term use.


A further treatment option for people with Brugada syndrome is  radiofrequency catheter ablation . [ 46 ]  In this procedure, wires are passed through a vein in the leg into the heart, or through a small hole underneath the  sternum .  These wires are used to find the area of the heart responsible for initiating the arrhythmias.  The tip of one of these wires is used to make a series of tiny burns, intentionally damaging the area of abnormal heart muscle that has been causing the problem.  Current recommendations suggest that this treatment should be reserved for those with Brugada syndrome who have had repeated shocks from an ICD. [ 9 ]


Between 1 and 30 per 10,000 people are affected by Brugada syndrome. [ 1 ] [ 2 ]  Although those affected are born with the condition, symptoms typically only begin in adulthood. While the rare cases seen in childhood are equally likely to be male or female, in adulthood symptoms occur more frequently in males than females, potentially due to the higher testosterone levels found in men. [ 2 ] [ 47 ]


Brugada syndrome is more common in people of  Asian  descent and is the most common cause of sudden death in young males without known underlying cardiac disease in  Thailand  and  Laos . [ 2 ] [ 48 ]  In these countries Brugada syndrome is likely to be responsible for many cases of sudden unexpected nocturnal death syndrome (SUNDS). Local names vary – in the  Philippines  the condition has been known as  Bangungut  meaning "a scream followed by sudden death during sleep", [ 48 ]  while in Thailand it was known as  Lai Tai , and in  Japan   Pokkuri . [ 49 ] [ 50 ]    Type 1 Brugada ECG patterns are seen more frequently in Asian populations (0–0.36%) than those in Europe (0–0.25%) and the United States (0.03%). Similarly, Type 2 and Type 3 ECG patterns are more prevalent in Asia (0.12–2.23%) than in Europe (0.0–0.6%) or the United States (0.02%). [ 51 ]


Brugada syndrome is named after the Spanish cardiologists Josep and Pedro Brugada who described the condition in 1992, [ 12 ]  although the association between the characteristic ECG pattern and sudden cardiac death had been reported in 1989. [ 11 ]   Brugada syndrome was described as a cause for the sudden unexplained cardiac death syndrome seen in Thai men in 1997. [ 50 ]  The first genetic mutations affecting the SCN5A gene associated with the syndrome were identified by their brother Ramon Brugada in 1998, [ 13 ]  with many more mutations affecting at least 19 genes subsequently identified by others. [ 16 ]  Studies in the 2000s led to competing theories surrounding the mechanisms by which abnormal heart rhythms were generated. [ 52 ]   Research into Brugada syndrome is ongoing, identifying new genetic variants, exploring mechanisms of arrhythmias, and searching for better treatments. [ 52 ]


Burnside–Butler syndrome  is a name that has been applied to the effects of  microdeletion  of  DNA  sequences involving four neurodevelopmental genes ( TUBGCP5 ,  CYFIP1 ,  NIPA1 , and  NIPA2 ). [ 1 ]   Varying  developmental  and  psychiatric disorders  have been attributed to the microdeletion; however, the great majority of people with the deletion do not have any clinical features associated with it. More studies are needed to delineate the range of  clinical presentation . [ 2 ] [ 3 ]


The 15q11.2 BP1–BP2 microdeletion (Burnside–Butler syndrome) was the most common  cytogenetic  abnormality found in a recent study using ultra-high resolution  chromosomal microarray analysis  optimized for  neurodevelopmental disorders  of 10,351 consecutive patients presenting for  genetic laboratory testing  who had  autism spectrum  disorders (ASD). [ 4 ]  It may represent an under-recognized contributor to the global prevalence of ASD, which is a common clinical manifestation of many rare  genetic disorders , many of which can be identified by chromosome microarray analysis. The 15q11.2 BP1-BP2 microdeletion was reported to account for 9% of the top 85 genetic findings associated with neurodevelopmental disorders followed by the proximal 16p11.2 deletion syndrome (5%). [ 4 ]  However, the very high frequency of the deletion in unaffected population controls suggests that there is considerable ascertainment bias and that most people who have a neurodevelopmental condition and the deletion are likely to have an alternate cause for their symptoms. In a large population-based study, [ 5 ]   1 in 292 people in the general population had this deletion. While the deletion was over-represented in cases vs controls (1 in 126 cases had the deletion) suggesting that it likely does contribute to neurodevelopmental problems in some individuals, the penetrance is likely to be very low. To understand this point, it is important to remember that affected individuals make up only  a small proportion of the population. Assuming that 1% have intellectual disability, for example, this would imply penetrance of ~1.3% for the deletion - i.e. 98.7% of people with the deletion would have no symptoms as a result. [ citation needed ]