Due to the protein (albumin) losses many patients have reduced muscle tone and may experience delays in certain physical milestones such as sitting, crawling and walking. Similarly many patients experience growth delays due to protein loss. Delays vary from mild to significant but most patients experience growth spurts once they receive their transplanted kidney. Physical therapy may be useful for the child to strengthen muscle tone. Children who have a history of stroke from thrombotic complications can have neurologic delays. [ 1 ]


Undiagnosed cases are often fatal in the first year due to blood clots, infections or other complications. [ citation needed ]


Congenital rubella syndrome  (CRS) occurs when a human  fetus  is infected with the  rubella virus  (German measles) via maternal-fetal transmission and develops  birth defects . [ 1 ]  The most common congenital defects affect the ophthalmologic, cardiac, auditory, and neurologic systems. [ 2 ]


Rubella infection in pregnancy can result in various outcomes ranging from asymptomatic infection to  congenital defects  to  miscarriage  and fetal death. [ 3 ] [ 4 ]  If infection occurs 0–11 weeks after conception, the infant has a 90% risk of being affected. [ 1 ]  If the infection occurs 12–20 weeks after conception, the risk is 20%. Infants are not generally affected if rubella is contracted during the third trimester. [ 3 ]  Diagnosis of congenital rubella syndrome is made through a series of clinical and laboratory findings and management is based on the infant's clinical presentation. Maintaining  rubella  outbreak control via vaccination is essential in preventing congenital rubella infection and congenital rubella syndrome. [ 3 ]


Congenital rubella syndrome was discovered in 1941 by Australian  Norman McAlister Gregg . [ 5 ]


The classic triad for congenital rubella syndrome is: [ 8 ]


Other manifestations of CRS may include:


Children who have been exposed to rubella in the womb should also be watched closely as they age for any indication of:


Diagnosis of congenital rubella syndrome is made based on clinical findings and laboratory criteria. [ 3 ]  Laboratory criteria includes at least one of the following:


Clinical definition is characterized by findings in the following categories:


A patient is classified into the following cases depending on their clinical and laboratory findings: [ 3 ]


Vaccinating the majority of the population is effective at preventing congenital rubella syndrome. [ 25 ]  With the introduction of the rubella vaccine in 1969, the number of cases of rubella in the United States has decreased 99%, from 57,686 cases in 1969 to 271 cases in 1999. [ 3 ]  For women who plan to become pregnant, the  MMR (measles mumps, rubella) vaccination  is highly recommended, at least 28 days prior to conception. [ 17 ]  The vaccine should not be given to women who are already pregnant as it contains live viral particles. [ 17 ]  Other preventative actions can include the screening and vaccinations of high-risk personnel, such as medical and child care professions. [ 26 ]


Infants with birth defects suspected to be caused by congenital rubella infection should be investigated thoroughly. Confirmed cases should be reported to the local or state health department to assess control of the virus and isolation of the infant should be maintained. [ 27 ]


Infants with known rubella exposure during pregnancy or those with a confirmed or suspected infection should receive close follow-up and supportive care. There are no medications or antivirals that will shorten the clinical course of the virus. [ 4 ]  Only those with  immunity  to rubella should have contact with infected infants, as they can shed viral particles in their respiratory secretions though 1 year of age (unless they test with repeated negative viral cultures at age 3 months). [ 3 ]  Many infants can be born with multiple birth defects that require multidisciplinary management and interventions based on clinical manifestations. Often these infants will require extended period or life-long follow up with medical specialists. Early diagnosis of congenital rubella syndrome is important for planning future medical care and educational placement. [ 19 ]


Many infants with CRS may be born with  sensorineural deafness  and thus should undergo a newborn hearing evaluation. Hearing loss may not be apparent at birth and thus requires close auditory follow up. Infants with confirmed hearing impairment may require hearing aids and may benefit from an early intervention program. [ 4 ]


Eye abnormalities including cataracts, infantile glaucoma and retinopathy are common in infants born with CRS. [ 27 ]  Infants should undergo eye examinations after birth and during early childhood. Those with congenital eye defects require care from a pediatric ophthalmologist for specialized care and follow up. [ 4 ]


Congenital cardiac anomalies including  pulmonary artery stenosis  and  patent ductus arteriosus  can be seen in infants with CRS. Infants should undergo cardiac evaluation soon after birth and those with confirmed cardiac lesions will require specialized care with a pediatric cardiologist for any interventions and follow-up care. [ 4 ]


Constriction ring syndrome  ( CRS ) is a  congenital disorder  with unknown cause. Because of the unknown cause there are many different, and sometimes incorrect, names. It is a malformation due to intrauterine bands or rings that produce deep grooves in (most commonly  distal ) extremities such as fingers and toes. In rare cases the constriction ring can form around other parts of the  fetus  and cause amputation or even  intrauterine death . The anatomy  proximal  to the site of constriction (or amputation) is developmentally normal. [ 2 ] [ 3 ] [ 4 ]
CRS can be associated with other malformations, with  club foot  being most common. [ 5 ] [ 6 ] [ 7 ]
The precise configuration of the bands, lymphedema, and character of the amputations are not predictable and vary with each individual patient. Also, more than one extremity is usually affected, and it is rare for only one ring to present as an isolated malformation with no other manifestation of this syndrome. [ 2 ] [ 3 ] [ 8 ] [ 9 ]


The constriction of appendages by amniotic bands may result in: [ citation needed ]


There are three different theories to the cause of the constriction ring syndrome.


The first is the intrinsic theory, which was proposed by Streeter in 1930. This theory implicates an anomaly in  germ plasm  resulting in the defects. [ 10 ]  This theory is reinforced by the clinical presentation of the constriction rings with other internal  visceral  and systematic anomalies. [ 10 ]  Because of these other anomalies, the names  constriction ring syndrome ,  constriction band syndrome , and  Streeter bands  are given to this defect/disease. This is sometimes attributed to  vascular disruption  shared between  cleft palate  and other forms of cleft defects occurring together with ABS; this co-occurrence suggests an intrinsic defect of the blood circulation. [ citation needed ]


The second theory postulates the involvement of an intrauterine disruption during  pregnancy  followed by a cascade of events involving  amniotic  rupture. When spontaneous rupture of the amnion occurs early in the second trimester, the separation of amnion from  chorion  produces many small, thin strands that can become entangled within digits and toes. [ 10 ] [ 11 ]  Later, as the fetus grows but the bands do not, the bands become constricting. This constriction reduces blood circulation, and hence causes congenital abnormalities. In some cases a complete "natural"  amputation  of one or more digits or limbs may occur before birth or the digits or limbs may be necrotic (dead) and require surgical amputation following birth. The names  amniotic band syndrome  (ABS),  amniotic disruption complex , and  amniochorionic mesoblastic fibrous strings  are based on this theory.


The third theory postulates the involvement of intrauterine trauma. Intrauterine trauma could be something like amniocentesis, or something like a  fetal surgery . An intrauterine trauma could result in hemorrhage leading to acrosyndactyly. One study also showed the presence of bands as confirmed by sonography after fetal surgery. [ 10 ] [ 12 ]


Because of these different theories, there are many names for this syndrome. For a long time people believed the second theory about the amniotic rupture and strands. In the research cases not every child had a real (amniotic) strand. This could mean that there has to be another explanation for the development of these anomalies.


Diagnosis of constriction ring syndrome can be confirmed with an  ultrasonography . The clinical manifestations can be extremely variable. It could be a single or multiple manifestation. This can be confirmed at the end of the first trimester or at the beginning of the second trimester. [ 13 ]  However, not every patient will be diagnosed at that moment; most will be diagnosed at birth. [ citation needed ]


Individual strands are small and hard to see on ultrasound, so bands are detected indirectly because of the constrictions and swelling upon limbs or digits. Misdiagnosis is also common, so if there are any signs of amniotic bands, further detailed ultrasound tests should be done to assess the severity. 3D ultrasound and MRI can be used for more detailed and accurate diagnosis of bands and the resulting damage/danger to the fetus.


Decreased fetal movement could be a sign of a serious problem which may include ABS. It is rare but possible for the membrane to become wrapped around the placenta or the neck of the baby in the womb causing strangulation and death.


There is a strong relationship between ABS and  clubfoot  (also called talipes). 31.5% of clubfoot cases can be correlated with ABS, with 20% occurring  bilaterally . Other abnormalities found with ABS include:  clubhands ,  cleft lip , and/or  cleft palate , and  hemangioma .


The differential diagnosis includes: [ citation needed ]


ADAM Complex ; CRS is sometimes mislabeled as ADAM complex. ADAM is an abbreviation for  amniotic deformity,  adhesions   mutilations . CRS is the malformation due to a constriction ring around mostly a limb. ADAM complex is the association of limb defects (caused by constriction rings) and certain craniofacial  clefts [ 8 ] [ 14 ] [ 15 ]


" Adams–Oliver syndrome  is often mislabeled as CRS and consists of  cutis aplasia  of the scalp in which a longitudinal defect can vary in size and can often be associated with full-thickness skullcap loss. The distal digital or toe  hypoplasia - aplasia  is often confused with CRS. Constriction rings with or without  edema  are not present. The digital or toe hypoplasia-aplasia usually contains diminutive nails or nail folds". [ 8 ]


The constriction ring syndrome is a complex collection of asymmetric congenital anomalies, in which no two cases are exactly alike. [ 16 ]  This is why a classification is difficult to make.


The most widely used classification system was proposed by Patterson. This classification system is based on the severity of the syndrome and is useful because, the different types require different treatments. Other clinicians have amended this scheme by separating the depth of the ring into mild, moderate, severe, and amputation [ 3 ] [ 17 ] [ 18 ]  and by further defining the presence or absence of lymphedema or soft tissue loss distal to the ring. [ 4 ]  Expanding over subdivision in depth of the clefts for every classification is not necessary because the principles of treatment and technique for correction are the same. [ 8 ]


There are four categories:


Patterson divided the constriction ring associated with acrosyndactyly into three types:


There are simple constriction rings which are strands most commonly around the distal extremities as fingers and toes. In general, the thumb is not likely to be affected by a constriction ring because the fetus typically holds the thumb in tight adduction flexion, making entanglement with strands less likely. [ 2 ]  These malformations need to be surgically removed which must be executed in different stages and can done by different techniques (see also treatment).


The CRS involves strands which obstruct the  lymphatic vessels  and thus causing fluid retention, distal of the affected extremity. This utters itself with swollen parts distal of the constriction.


In this form there is a complex form of  syndactyly  named acrosyndactyly, the fingers (or toes) were initially separated but due to the constriction they are formed back together. Sometimes multiple fingers can be involved. The distal fusion between digits or toes never initially involves a skeletal coalition. [ 8 ]  The digits are usually hypoplastic if multiple digits are involved. When the constriction cuts off the blood supply to the fingers, the fingers can form a peak with the most palmar digit being the index finger. Normal  neurovascular bundles  are not present in the distal parts. [ 8 ]  Hands with fused fingers need to be released in phases to preserve the distal blood supply.


One of the most severe consequence of constriction strains is probably intrauterine amputations, this is where the constriction goes as deep as the bone and cuts off the blood supply of the proximal extremity. The result will be that the developing toe or finger will become  ischemic  and fall off. Because the result is a transverse amputation that cuts off the vascular supply to the developing extremity, [ 2 ]  the actual constriction ring is not seen. [ 8 ]
This can result in different outcomes:


In extremely rare cases a strain can form around the  umbilical cord  and cut off the blood supply to the fetus which will result in intrauterine death.


The percentage of associated anomalies varies from 40% to as high as 80% [ 16 ] [ 17 ] [ 19 ]
Constriction ring deformities are as common on the lower extremity as on the upper, almost all of these involve the  musculoskeletal system , with clubbed feet being the most common in up to 30% of reported cases. [ 7 ] [ 12 ] [ 17 ] [ 20 ]
Large reported series reveal an incidence between 5% and 15% of craniofacial malformations with  clefting of the lip or palate . [ 14 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ]


Amniotic band syndrome is considered an accidental event and it does not appear to be genetic or hereditary, so the likelihood of it occurring in another pregnancy is remote. The cause of amnion tearing is unknown and as such there are no known preventative measures. [ citation needed ]


Surgical correction is recommended when a constriction ring results in a limb contour deformity, with or without  lymphedema . [ 27 ]


At the beginning of the surgery a  tourniquet  will be applied to the limb. A tourniquet compresses and controls local arterial and venous circulation for about two hours. The constriction band must be dissected very carefully to avoid damaging the underlying neurovasculature. When the constriction band is excised, there will be a direct closure. This allows the fatty tissue to naturally reposition itself under the skin. [ 28 ]


"With complete circumferential constriction bands, it is recommended that a two-stage correction approach be used. At the first operation, one-half of the circumference is excised and the other one-half can be excised after three to six months. This will avoid any problems to the distal circulation in the limb, which may already be compromised.  Lymphedema , when present, will significantly improve within a few weeks of the first surgery." [ 28 ]


For the direct closure of the defect after dissecting a constriction band there are two techniques:


In rare cases, if diagnosed in utero, fetal surgery may be considered to save a limb that is in danger of amputation or other deformity. This operation has been successfully performed on fetuses as young as 22 weeks. [ 29 ]   Monash Medical Centre  in Melbourne, Australia, as well as multiple facilities in the United States, have performed successful amniotic band release surgery.


Treatment usually occurs after birth and where plastic and reconstructive surgery is considered to treat the resulting deformity. [ 30 ]  Plastic surgery ranges from simple to complex depending on the extent of the deformity. Physical and occupational therapy may be needed long-term. [ citation needed ]


Prosthetics may help some people with ABS to live more functional lives. The price and complexity of these prosthetics vary dramatically, but advances in  3-D printing  have helped to increase the availability of artificial fingers while reducing their cost of production. [ 31 ]


The  prognosis  depends on the location and severity of the constricting bands. Every case is different and multiple bands may be entangled around the fetus.


Bands which wrap around fingers and toes can result in  syndactyly  or  amputations  of the digits. In other instances, bands can wrap around limbs causing restriction of movement resulting in clubbed feet. In more severe cases, the bands can constrict the limb causing decreased blood supply and amputation. Amniotic bands can also sometimes attach to the face or neck causing deformities such as cleft lip and palate. If the bands become wrapped around the head or umbilical cord it can be life-threatening for the fetus.


The number of cases of  miscarriage  that can be attributed to ABS is unknown, although it has been reported that it may be the cause of 178 in 10,000 miscarriages. Up to 50% of cases have other congenital anomalies including cleft lip, cleft palate, and clubfoot deformity. Hand and finger anomalies occur in up to 80%.


The reported  incidence  of constriction ring syndrome varies from 1/1200 and 1/15,000 live births. [ 19 ]  The  prevalence  is equal in male and female. [ 12 ]


Fetomaternal factors like  prematurity , maternal illness,  low birth weight , and maternal drug exposure are predisposing factors for the constriction ring syndrome. [ 12 ]


No positive relationship between CRS and genetic inheritance has been reported. [ 8 ]


Notable people living with ABS include:


Crandall syndrome  is a very rare  congenital  disorder characterised by progressive  sensorineural hearing loss , hair loss associated with  pili torti , and  hypogonadism  demonstrated through low levels of  luteinising hormone  and  growth hormone . It is thought to be an autosomal recessive disorder closely related to  Björnstad syndrome  which presents similarly but without hypogonadism. [ 1 ]


The condition was first reported by B. F. Crandall in 1973. [ 2 ]


This article about an endocrine, nutritional, or metabolic disease is a  stub . You can help Wikipedia by  expanding it .


The  Crane–Heise syndrome  is a very rare and lethal  birth defect  without a known cause. It was first described in a 1981 publication, and its main signs are facial malformations, lack of bone mineralization, and musculoskeletal anomalies. [ 1 ]


According to a 2011 publication that summarizes the nine known cases, the leading symptoms are:


The clustering of the cases suggests an autosomal recessive disorder (see  genetical dominance ). In the  aminopterin-syndrome sine aminopterin syndrome  (ASSAS), a poorly mineralized calvarium is present, too, but many other tell-tale symptoms of Crane–Heise are lacking. A similar disease is  cleidocranial dysplasia , but this is an autosomal dominant disease caused by mutations in the  RUNX2  gene – and such mutations have not been found in Crane–Heise cases.  Chromosomal abnormalities  are also absent in the Crane–Heise syndrome. [ 2 ]


As the cause is still unknown, the only diagnostic is ultrasound, which can detect a lack of skull mineralization by the 10th week of pregnancy. [ 2 ]


Craniopagus parasiticus  is an extremely rare type of  parasitic twinning  occurring in about 4 to 6 of 10,000,000 births. [ 1 ]  In craniopagus parasiticus, a parasitic twin head with an undeveloped body is attached to the head of a developed twin. Fewer than a dozen cases of this type of  conjoined twin  have been documented in literature.


The exact development of craniopagus parasiticus is not well known. However, it is known that the underdeveloped twin is a  parasitic twin . Parasitic twins are known to occur  in utero  when  monozygotic twins  start to develop as an embryo, but the embryo fails to completely split. When this happens, one embryo will dominate development, while the other's development is severely altered. The key difference between a parasitic twin and  conjoined twins  is that in parasitic twins, one twin, the  parasite , stops development during  gestation , whereas the other twin, the autosite, develops completely. [ citation needed ]


In normal  monozygotic twin  development, one egg is fertilized by a single  sperm . The egg will then completely split into two, normally at the two-cell stage. If the egg splits in the early  blastocyst  stage, two inner cell masses will be present, eventually leading to the twins sharing the same  chorion  and  placenta , but with separate  amnions . However, the egg can split into two, but still have one blastocyst. This will lead to one  inner cell mass  and one blastocyst. Then, as the twins develop, they will share the same placenta, chorion, and amnion. [ 2 ]  This is thought to be the most likely reason why conjoined twins occur, [ 2 ]  and could possibly play a role in the development of craniopagus parasiticus. [ citation needed ]


One hypothesis is that craniopagus parasiticus starts with the development of two fetuses from a single zygote that fail to separate at the head region around the second week of gestation. [ 1 ]  Another is that it occurs later in development, around the fourth week of gestation, at which time the two embryos fuse together near the anterior open neuropore. [ 1 ]


A third hypothesis is that there is joining of the somatic and placental vascular system of the twins, as well as a degeneration of the umbilical cord of the parasitic twin. This suggests that craniopagus parasiticus develops due to the lack of blood supply to one of the twins. [ 3 ]


In addition to craniopagus parasiticus, a few other conditions involve a child's, or animal's, birth with two heads or faces.


Dicephalic parapagus  is a condition where two heads are side by side on a single torso, with varying degrees of twinning of organs and structures within the torso. [ 4 ]


Diprosopus  occurs when a single body and neck are present, but there is a duplication of the structures of the face. This is different from craniopagus parasiticus in that there is only one head, although there is a duplication of the  craniofacial  features. Diprosopus can range from having two fully formed faces to just a duplication of the nose or eyes. [ citation needed ]  Cats with the condition are referred to as ' Janus cats '. A cat named  Frankenlouie  was a famous example noted by the  Guinness Book of World Records  in 2012 for being the longest surviving Janus cat.


Few individuals survive until birth. For those who do, the only treatment available is to surgically remove the parasitic twin. Of the two documented attempts, however, one child died within hours and neither reached their second birthday. [ citation needed ]  The problem with surgical intervention is that the arterial supplies of the head are so intertwined that it is very hard to control the bleeding, but it has been suggested that cutting off the parasitic twin's arterial supply might improve the odds of the developed twin's survival. [ 5 ]


There have been at least eighty reported cases of craniopagus parasiticus. Only ten cases of craniopagus have been documented in medical research literature. [ 6 ]


Only four cases have been documented by modern medicine to have survived birth: [ 6 ]


In the past, the use of terminology when describing  parasitic twins  has been somewhat inconsistent. By definition, a parasitic twin is joined to another twin in a certain anatomical location or position on the developed twin's body. The underdeveloped twin is termed the  parasite , and the developed twin is termed the autosite. The autosite can have some abnormalities, as well. For the most part, however, they have developed enough that they can live on their own. [ 13 ]


Crossed beak , also known as  cross beak  and  scissor beak , is a  congenital deformity  in birds, particularly  poultry , where the upper and lower parts of the  beak  do not align properly. This condition results in the beak crossing or growing in a way that prevents the bird from closing its beak properly. As a result, affected birds may have difficulty eating and performing other essential activities.


Crossed beak is a deformity characterized by a misalignment of the upper and lower beak, with one or both beaks exhibiting lateral deviation from the head's longitudinal axis. [ 1 ]


The upper beak frequently exhibits horizontal bending at its base, alongside the affected  mandible , and the skull, particularly the nasals and orbits, shows asymmetry. [ 1 ]


Several factors, including incubation temperatures and variations,  hereditary  elements, developmental mishaps, bone morphogenetic protein 4, and management practices, have been identified as potential associations with or causes of crossed beak.


In a 1966 study focused on non-hereditary factors associated with crossed beak, it was identified that fluctuations in incubator temperature, stemming from electrical disruptions, emerged as a primary cause. [ 2 ]


Recent studies have identified potential candidate genes for beak deformity in domestic chickens, with several belonging to the  keratin  family. In a breeding trial involving  Appenzeller Barthuhn  chickens, believed to have a high genetic predisposition for crossed beak, mating affected parent stock led to a notably higher proportion of offspring with deformed beaks compared to mating unaffected parents. Specifically, mating affected parents resulted in 13 (15.7%) offspring with crossed beak and 67 (80.7%) with normal beaks. Conversely, mating unaffected parents yielded 3 (2.9%) offspring with crossed beak and 95 (93.1%) with normal beaks. These findings suggest a potential hereditary link to beak deformations although the genetic basis of this condition remains unclear. [ 3 ]  A 2019 study on Huiyang bearded chickens revealed a correlation between the levels of bone morphogenetic protein 4 (BMP4) expression in craniofacial bones and the presence of crossed beak deformities. BMP4 expression was highest in severe cases of crossed beak. [ 4 ]


In 1949, Frederick Bruce Hutt documented non-hereditary beak deformities linked to unilateral  microphthalmia  or  anophthalmia  in chick embryos. He observed that most crossed beak cases stemming from these conditions often go unnoticed, as affected chicks typically don't survive the later stages of incubation. Hutt suggested that the abnormality likely arises due to developmental accidents, possibly influenced by unfavorable environmental factors. [ 5 ]  A 1961 study involving 12 hens and 5 cocks with unilateral microphthalmia or anophthalmia was conducted to investigate the heredity of the associated cross beak deformity. All the offspring produced in the experiment exhibited normal beaks, leading to the conclusion that this specific type of cross beak is not inherited. [ 6 ]


Crossed beak has been reported in at least 12 chicken strains worldwide, including commercial strains like  leghorn  (Landauer, 1938) and  Rhode Island Red  (Landauer, 1956), as well as native breeds like the  Appenzeller Barthuhn ,  Schweizer  (Joller et al., 2018),  Chinese silk chicken  (Bai et al., 2014, 2016), Beijing-You (Bai et al., 2018a), and Huiyang bearded chicken (Hong et al., 2019), with frequencies ranged from 0.2 to 7.4%. The deformity is present in around 30% of 114 Chinese native chicken strains. [ 1 ]


In a 2019 study conducted by Aidin Azizpour on congenital anomalies, 1,796,863  broiler  chicks were evaluated. Of these, 56,031 chicks exhibited congenital anomalies, with crossed beak detected in approximately 27.43% of those affected. [ 7 ]


The occurrence of crossed beak appears to show no distinction between male and female offspring. [ 1 ]


Crossed beak in birds lead to decreased feed consumption, hindered growth, subpar production performance, and reduced survival rates. The abnormality poses both economic and animal welfare challenges within the poultry sector. [ 1 ]


Cyclopia  (named after the Greek mythology characters  cyclopes ), also known as  alobar holoprosencephaly , is the most extreme form of  holoprosencephaly  and is a  congenital disorder  (birth defect) characterized by the failure of the embryonic  prosencephalon  to properly divide the  orbits  of the eye into two cavities. Its incidence is 1 in 16,000 in born animals and 1 in 200 in  miscarried fetuses . [ 1 ] [ 2 ]


Typically, the nose is either missing or not functional. This deformity (called  proboscis ) forms above the center eye and is characteristic of a form of cyclopia called rhinencephaly or rhinocephaly. [ 3 ]  Most such embryos are either naturally  miscarried  or are  stillborn  upon  delivery .


Although cyclopia is rare, several cyclopic human babies are preserved in medical museums (e.g. The  Vrolik Museum , Amsterdam, Trivandrum Medical College). [ 4 ]


Some extreme cases of cyclopia have been documented in farm animals (horses, sheep, pigs, goats, and sometimes chickens). In such cases, the nose and mouth fail to form, or the nose grows from the roof of the mouth, obstructing airflow and resulting in suffocation shortly after birth. [ 5 ]


Genetic defects or toxins can misdirect the embryonic forebrain-dividing process. [ 6 ]  One highly  teratogenic  alkaloid toxin that can cause cyclopia is  cyclopamine  or 2-deoxyjervine, found in the plant  Veratrum californicum  (also known as corn lily or false hellebore). Grazing animals are most likely to ingest this plant and induce cyclopia in offspring. People sometimes accidentally ingest false hellebore while pregnant thinking it is  hellebore , which has been suggested as a "natural" treatment for  vomiting ,  cramps , and poor circulation – three conditions which may be present in the early stages of pregnancy. [ 7 ]  Cyclopia occurs  when  certain proteins are inappropriately expressed , [ 8 ]  causing the brain to stay whole, rather than developing two distinct hemispheres. This leads to the fetus having one  optic lobe  and one  olfactory lobe , resulting in the eye and nose malformations of cyclopia. [ 9 ]


The  Sonic hedgehog protein  (SHH) is the gene regulator involved in the separation of the single eye field into two bilateral fields. [ 10 ]
Although not proven, it is thought that SHH emitted from the prechordal plate suppresses  Pax6 , which causes the eye field to divide into two. If the SHH gene is mutated, the result is cyclopia, a single eye in the center of the face (Gilbert, 2000).


First , That it had no sign of any  Nose  in the usual place, nor had it any, in any other place of the Head, unless the double Bagg CC that grew out of the midst of the forehead, were some rudiment of it.  Next , That the  two Eyes  were united into one  Double Eye  which was placed just in the middle of the Brow. [ 11 ]


The  Islamic State  used photos of babies born with cyclopia in its recruitment campaign. ISIS claimed the photos depicted  Masih ad-Dajjal , who according to the Hadith, would have only one eye. Mainstream Islamic scholars consider the prophecy as referring to a one-eyed man, not a cyclops. [ 26 ]  One infant whose image was circulated in 2014 was claimed to be  Israeli , but was actually  Bolivian  and from 2008. The baby girl from India born in 2006 (see notable cases above) also had her image used. [ 27 ]


Media related to  Cyclopia (medicine)  at Wikimedia Commons


A  cystic hygroma  is a form of  lymphatic malformation . It is an abnormal growth that usually appears on a baby's neck or head. It consists of one or more  cysts  and tends to grow larger over time. The disorder usually develops while the fetus is still in the uterus, but can also appear after birth.


Also known as  cystic lymphangioma  and  macrocystic lymphatic malformation , the growth is often a  congenital   lymphatic   lesion  of many small cavities (multiloculated) that can arise anywhere, but is classically found in the left  posterior triangle  of the  neck  and armpits. The malformation contains large  cyst -like cavities containing  lymph , a watery fluid that circulates throughout the  lymphatic system . Microscopically, cystic hygroma consists of multiple  locules  filled with lymph. Deep locules are quite big, but they decrease in size towards the surface.


Cystic hygromas are  benign , but can be  disfiguring . It is a condition which usually affects children; very rarely it can be present in adulthood. [ 2 ]


Currently, the medical field prefers to use the term  lymphatic malformation , because the term cystic hygroma means water tumor. [ 3 ]  Lymphatic malformation is more commonly used now because it is a  sponge -like collection of abnormal growth that contains clear lymphatic fluid. The fluid collects within the cysts or channels, usually in the soft tissue. Cystic hygromas occur when the  lymphatic vessels  that make up the lymphatic system are not formed properly. The two types of lymphatic malformations are macrocystic  (large cysts) and microcystic (small cysts) lymphatic malformations. A person may have only one kind of the malformation or can have a mixture of both macro- and microcysts.


Cystic hygroma can be associated with a  nuchal   lymphangioma  or a  fetal hydrops . [ 4 ]  Additionally, it can be associated with  Down syndrome ,  Turner syndrome , [ 5 ]  or  Noonan syndrome . If it is diagnosed in the third trimester, then chances of association with Down syndrome are increased, but if diagnosed in the second trimester, then it is associated with Turner syndrome.


A lethal version [ 6 ]  of this condition exists, known as  Cowchock–Wapner–Kurtz syndrome , that, in addition to cystic hygroma, includes  cleft palate  and  lymphedema , a condition of localized  edema  and tissue swelling caused by a compromised lymphatic system. [ 7 ]


Cystic hygromas are increasingly diagnosed by  prenatal   ultrasonography . A common sign is a neck growth. It may be found at birth, or discovered later in an infant after an  upper respiratory tract infection . [ 8 ]  Cystic hygromas can grow very large and may affect breathing and swallowing. Some symptoms may include a mass or lump in the mouth, neck, cheek, or tongue. It feels like a large, fluid-filled sac. In addition, cystic hygromas can be found in other body parts, such as the arms, chest, legs, groin, and buttocks. Cystic hygromas are also often seen in Turner's syndrome, although a patient who does not have the syndrome can present with this condition.


Lymphatic malformations may be detected in the human fetus by ultrasound if they are of sufficient size. Detection of a cystic malformation may prompt further investigation, such as  amniocentesis , to evaluate for genetic abnormalities in the fetus. Lymphatic malformations may be discovered postnatally or in older children/adults, and most commonly present as a mass or as an  incidental finding  during  medical imaging .


Verification of the diagnosis may require more testing, as multiple cystic masses can arise in children. [ 9 ]  Imaging, such as ultrasound or MRI, may provide more information as to the size and extent of the lesion.


A baby with a prenatally diagnosed cystic hygroma should be delivered in a major medical center equipped to deal with neonatal complications, such as a  neonatal intensive care unit . An  obstetrician  usually decides the method of delivery. If the cystic hygroma is large, a  cesarean section  may be performed. After birth, infants with a persistent cystic hygroma must be monitored for airway obstruction. A thin needle may be used to reduce the volume of the cystic hygroma to prevent facial deformities and airway obstruction. Close observation of the baby by a  neonatologist  after birth is recommended. If resolution of the cystic hygroma does not occur before birth, a  pediatric surgeon  should be consulted. [ 10 ]


Cystic hygromas that develop in the third trimester, after 30 weeks' gestation, or in the  postnatal period  are usually not associated with  chromosome abnormalities . A chance exists of recurrence after  surgical  removal of the cystic hygroma. The chance depends on the extent of the cystic hygroma and whether its wall was completely removed. [ 10 ]


Treatments for removal of cystic hygroma are surgery or  sclerosing agents , which include:


D-glycerate dehydrogenase deficiency  (or 3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD) is a rare  autosomal  metabolic disease where the young patient is unable to produce an enzyme necessary to convert  3-phosphoglycerate  into  3-phosphohydroxypyruvate , which is the only way for humans to synthesize  serine . This disorder is called  Neu–Laxova syndrome  in neonates.


Homozygous  or  compound heterozygous mutations  in 3- phosphoglycerate dehydrogenase  (PHGDH) cause Neu-Laxova syndrome [ 2 ] [ 3 ]  and phosphoglycerate dehydrogenase deficiency. [ 4 ]


3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the  committed step  in the phosphorylated pathway of  L-serine  biosynthesis. It is also essential in  cysteine  and  glycine  synthesis, which lie further downstream. [ 5 ]  This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants. [ 6 ] [ 7 ]


Treatment typically involves oral supplementation of serine and glycine. [ 8 ] [ 9 ]


The  Denis Browne bar , also known as the  Denis Browne splint  or  foot abduction orthosis , is a medical device used in the treatment of  club foot . The device is named after  Sir Denis Browne  (1892-1967), an Australian-born surgeon at  Great Ormond Street Hospital  in London who was considered the father of  pediatric surgery  in the United Kingdom. [ 1 ]  Browne first described the device in 1934. [ 2 ]  The bar may be used as part of the  Ponseti method , a series of nonsurgical techniques to address club foot. [ citation needed ]


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


This article about  orthopedic surgery  is a  stub . You can help Wikipedia by  expanding it .


This article related to  medical equipment  is a  stub . You can help Wikipedia by  expanding it .


Diprosopus  ( Greek :  διπρόσωπος , "two-faced", from  δι- ,  di- , "two" and  πρόσωπον ,  prósopon  [neuter], "face", "person"; with  Latin  ending), also known as  craniofacial duplication  (cranio- from Greek  κρανίον , "skull", the other parts Latin), is an extremely rare  congenital disorder  whereby parts (accessories) or all of the face are duplicated on the head. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


Although classically considered conjoined twinning (which it resembles), diprosopus is not normally due to the fusion or incomplete separation of two embryos. It is the result of abnormal activity by the protein  SHH (sonic hedgehog) . [ 7 ] [ 8 ] [ 9 ]  (The name of this protein was inspired by the  Sonic the Hedgehog  video game character and is part of an idiosyncratic naming tradition in molecular biology research.) [ 10 ] [ 11 ]


SHH and its corresponding genes have been found to play an important role in signaling craniofacial patterning during embryonic development. Among other things, SHH governs the width of facial features. In excess it leads to widening of facial features and to duplication of facial structures. [ 7 ]  The greater the widening, the more structures are duplicated, often in a mirror image form. This has been demonstrated in the laboratory by introducing pellets of the SHH protein into chicken embryos, resulting in chickens with duplicate beaks. Inadequate amounts of that protein lead to opposite conditions such as  cyclopia  where facial features are insufficiently developed. [ 12 ]


Healthy brain development is also dependent on the signaling function of SHH. [ 13 ]  During embryonic development, SHH directs embryonic cells to organize in specific areas that later become specialized neural tissues, thus controlling the size and shape of brain structures.


Diprosopus often occurs in combination with other  congenital disorders , particularly  anencephaly ,  neural tube defect  and  cardiac malformations . [ 14 ]  When present, the brain may show abnormalities ranging from partial to complete duplication of brain structures, and/or underdevelopment of brain tissues. [ 15 ] [ 16 ]


Most human infants with diprosopus are stillborn. Known instances of humans with diprosopus surviving for longer than minutes to hours past birth are very rare; only a few are recorded. In 2002 and 2003, two living male infants with partial diprosopus were described in the medical literature in separate case reports. [ 17 ] [ 18 ]  One infant was born with duplication of the nose and the cerebral frontal lobes, two widely spaced eyes, a small, underdeveloped central eye socket, and a large, asymmetric mouth. The other infant was born with duplication of the upper and lower jaw, two tongues arising from the same base,  cleft palate , a slightly divided tip of the nose, and two widely spaced eyes, as well as absence of the  corpus callosum , duplication of the pituitary gland and stalk, and abnormalities in the midbrain. Because they were born with a milder, partial form of diprosopus, both infants were considered candidates for surgical correction of their abnormal facial features.


In January 1775, a  Spanish  family gave birth to a girl with diprosopus. She had 3 eyes (one a combination of 2), 2 noses, 2 mouths, and 3 chins. The child was taken on tour from village to village, and gained much attention in Spain and neighboring countries. Her case is mentioned in Nicolas-François and Geneviève Regnault's  Les écarts de la nature , published that year. [ 19 ]   Her full lifespan is unknown, but is mentioned to still be alive in French publications as late as 1777.


Tres Johnson was born on September 29, 2004, in Missouri, to Brandy and Joshua Johnson. He has a large cleft, two separate nostrils, and a head with an unusual shape. He also has cognitive delays and suffers from seizures. He was not expected to live more than a few hours, but he defied the odds and celebrated his 18th birthday in 2022.


Tres has undergone several surgeries to repair his cleft and reduce his seizures. He takes medication to control his epilepsy and attends a special school. He enjoys playing video games, listening to music, and spending time with his family and friends. He has a Facebook page [ 20 ]  and an Instagram account where he shares his journey with diprosopus and epilepsy.


Lali Singh (10 March – 10 May 2008) [ 2 ]  was born to Sushma and Vinod Singh in  Saini, Sunpura Sohanpur  village, near  Delhi ; the birth was delayed by  dystocia  caused by her large head, and her birth in a hospital was facilitated by her mother receiving an  episiotomy . She was one of the very few infants with diprosopus to survive well past birth, and may have been the only known living individual with complete facial duplication. Her facial features included two pairs of eyes, two noses, and two mouths (but only one pair of ears). She was seen as the reincarnation of the goddess  Durga , who is sometimes depicted with many limbs and eyes.


Sushma and Vinod Singh declined an offer from local doctors to evaluate their daughter through  CT  or  MRI  scanning. Without diagnostic imaging, it was not possible to know the full extent to which the child's condition might have affected her brain and other vital structures in her head and neck. Thus, any estimation of her ability to thrive or even survive could be only speculative, though Lali's family described her as functioning normally. It is also unknown whether neurosurgeons or craniofacial surgeons, if consulted, would have had feasible solutions to offer with respect to corrective surgery. A local doctor told reporters that the baby should be considered a healthy child who currently was living a normal life, a previously unknown occurrence among sufferers of the disorder. [ 21 ]


Lali's two middle eyes suffered from  corneal opacity  due to abnormal anatomy of the facial muscles, which prevented her from properly closing those eyes; initially, this was wrongly blamed on  camera flashes .


A cleft palate caused difficulty in her feeding under village conditions. A poor diet of bottle-fed sugar solution and diluted milk, allowed to drip down her throat, as she could not suck properly due to her cleft palate, weakened her condition, and vomiting and infection ensued. Admission to hospital was delayed by discussion (including taking her back home from hospital) among her  extended family  and her village's  headman . Finally, her parents, alarmed at her illness and  dehydration , defied her other relatives and took her back to hospital, where under proper medical treatment including  antibiotic  and a  saline drip  she started to improve, stopped vomiting, started drinking milk and defecating normally. However, six hours later, at two months old to the day, she died of a  heart attack . [ 22 ]  She was buried in her village, as is usual in Hinduism with children who die very young. Later a  temple  was built at the village in her memory. [ citation needed ]


Faith Daisy and Hope Alice Howie (8 May – 27 May 2014) were born in  Sydney ,  Australia , to parents Simon Howie and Renee Young. Faith and Hope shared one body and skull, but had complete duplication of the facial features, as well as duplication of the brain; both brains joined to one brain stem. Young and Howie had learned at nineteen weeks gestation of their children's condition, but opted not to terminate the pregnancy. The children were born six weeks prematurely and appeared to be doing well, able to breathe unaided several days after their birth, and they were observed to sleep and cry at different times. [ 23 ]  They died nineteen days following their birth due to unknown causes, although some sources [ which? ]  indicated that the girls died following an operation for unknown reasons. [ citation needed ]


Janus, a goat with two faces on one body, survived from April 5 to May 5, 2020 in  Wittenberg, Wisconsin . [ 24 ]
Few two-faced animals have survived due to associated  internal organ  abnormalities and brain abnormalities. One of the most famous was  Ditto , a pig. [ 25 ]  Ditto was raised to adulthood, but died of  pneumonia  caused by food inhalation when breathing through one muzzle while eating with the other.


Cats with the condition are known as ' Janus  cats', after the Roman god. [ 26 ]  In July 2006, a six-year-old male Janus cat called " Frank and Louie " from  Millbury, Massachusetts , USA, received publicity. In their case, only one  esophagus  (and possibly only one  trachea ) were functional; this aided survival. In September 2011, when Frank and Louie were twelve years old, it was announced that they would appear in the 2012 Guinness Book of World Records as the longest-surviving Janus cat on record. [ 27 ]  In 2014, Frank and Louie died at the age of fifteen. [ 28 ]


Dopamine-responsive dystonia  ( DRD ) also known as  Segawa syndrome  ( SS ), is a  genetic   movement disorder  which usually manifests itself during early childhood at around ages 5–8 years (variable start age).


Characteristic symptoms are increased muscle tone ( dystonia , such as  clubfoot ) and  Parkinsonian features , typically absent in the morning or after rest but worsening during the day and with exertion. Children with dopamine-responsive dystonia are often misdiagnosed as having  cerebral palsy . The disorder responds well to treatment with  levodopa .


The disease typically starts in one limb, typically one leg. Progressive dystonia results in clubfoot and tiptoe walking. The symptoms can spread to all four limbs around age 18, after which progression slows and eventually symptoms reach a plateau. There can be regression in  developmental milestones  (both motor and mental skills) and  failure to thrive  in the absence of treatment.


In addition, dopamine-responsive dystonia  is typically characterized by signs of parkinsonism that may be relatively subtle. Such signs may include slowness of movement (bradykinesia), tremors, stiffness and resistance to movement (rigidity), balance difficulties, and postural instability. Approximately 25 percent also have abnormally exaggerated reflex responses (hyperreflexia), particularly in the legs. These symptoms can result in a presentation similar to that of  Parkinson's disease .


Many patients experience improvement with sleep, are relatively free of symptoms in the morning, and develop increasingly severe symptoms as the day progresses (i.e., diurnal fluctuation). Accordingly, this disorder has sometimes been referred to as "progressive hereditary dystonia with diurnal fluctuations"(Segawa, 2000). Yet some people with dopamine-responsive dystonia  do not experience such diurnal fluctuations, causing many researchers to prefer other disease terms.


Autosomal dominant  and  autosomal recessive  forms of the disease have been reported.  Mutations  in five  genes  have been shown to cause dopamine-responsive dystonia. These mutations, according to a review published in 2021, are associated with the following conditions: [ 1 ]


The precursor of the  neurotransmitter   dopamine ,  L-dopa , is synthesised from  tyrosine  by the  enzyme   tyrosine hydroxylase  and utilises  tetrahydrobiopterin  (BH4) as a  cofactor . A mutation in the gene  GCH1 , which encodes the enzyme  GTP cyclohydrolase I , disrupts the production of BH4, decreasing dopamine levels (hypodopaminergia). This autosomal-dominant condition is the most frequent cause of dopamine-responsive dystonia. [ 1 ]  Mutations in the gene for  tyrosine hydroxylase  may lead to tyrosine hydroxylase deficiency, a rare form of dopamine-responsive dystonia inherited in an autosomal recessive manner. [ 2 ]  The activity of dopaminergic neurons in the  nigrostriatal pathway  normally peaks during the morning and also decreases with age until after age 20, which explains why the symptoms worsen during the course of the day and with increasing age until the third decade of life. [ 3 ]


Due to the condition's rarity, it is frequently misdiagnosed, often as cerebral palsy. This results in patients often living their entire childhood with the condition untreated.


The diagnosis of dopamine-responsive dystonia can be made from a typical history, a trial of dopamine medications, and  genetic testing . Not all patients show mutations in the GCH1 gene ( GTP cyclohydrolase I ), which makes genetic testing imperfect.


Sometimes a lumbar puncture is performed to measure concentrations of  biopterin  and  neopterin , which can help determine the exact form of dopamine-responsive movement disorder: early onset parkinsonism (reduced biopterin and normal neopterin), GTP cyclohydrolase I deficiency (both decreased) and tyrosine hydroxylase deficiency (both normal).


In approximately half of cases, a  phenylalanine  loading test can be used to show decreased conversion from the  amino acid  phenylalanine to tyrosine. This process uses BH4 as a cofactor.


During a sleep study ( polysomnography ), decreased twitching may be noticed during  REM sleep .


An  MRI scan  of the brain can be used to look for conditions that can mimic dopamine-responsive dystonia (for example, metal deposition in the basal ganglia can indicate  Wilson's disease  or  pantothenate kinase-associated neurodegeneration ).  Nuclear imaging  of the brain using  positron emission tomography  (PET scan) shows a normal radiolabelled dopamine uptake in dopamine-responsive dystonia, contrary to the decreased uptake in Parkinson's disease.


Other  differential diagnoses  include metabolic disorders (such as  GM2 gangliosidosis ,  phenylketonuria ,  hypothyroidism ,  Leigh disease )  primarily dystonic juvenile parkinsonism ,  autosomal recessive early onset parkinsonism with diurnal fluctuation ,  early onset idiopathic parkinsonism ,  focal dystonias ,  dystonia musculorum deformans  and  dyspeptic dystonia with hiatal hernia .


In those with dopamine-responsive dystonia, symptoms typically dramatically improve with low-dose administration of  levodopa , which is a biochemically significant metabolite of the amino acid  phenylalanine , as well as a biological precursor of the  catecholamine   dopamine , a neurotransmitter. (Neurotransmitters are naturally produced molecules that may be sequestered following the propagation of an action potential down a nerve towards the axon terminal, which in turn may cross the synaptic junction between neurons, enabling neurons to communicate in a variety of ways.) Low-dose L-dopa usually results in near-complete or total reversal of all associated symptoms for these patients. In addition, the effectiveness of such therapy is typically long term, without the complications that often occur for those with Parkinson's disease who undergo L-dopa treatment. Thus, most experts indicate that this disorder is most appropriately known as dopa-responsive dystonia.


No data are available on mortality associated with dopamine-responsive dystonia, but patients surviving beyond the fifth decade with treatment have been reported. However, in severe, early autosomal recessive forms of the disease, patients have been known to pass away during childhood. Girls seem to be somewhat more commonly affected. The disease less commonly begins during puberty or after age 20, and very rarely, cases in older adults have been reported.


Due to commonly being misdiagnosed, it is common for the disease to remain untreated. When left untreated, patients often need Achilles' tendon surgery by the age of 21. They will also struggle with walking, an ability that will degrade throughout the day.  Power napping  can provide temporary relief in untreated patients. It also impairs development into adulthood, reduces balance, and reduces calf muscle development. Socially, it can result in depression, lack of social skills, and inability to find employment.


This condition is very rare, only affecting one in two million people. It is more common in females than in males. There are several hundred cases in the United States, 25 known cases in the United Kingdom, and less than that in Australia and New Zealand.


Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial  International Working Group on Neurotransmitter Related Disorders . [ 4 ]


The disease is named after Dr. Masaya Segawa, who provided an early clinical description in 1976. [ 5 ]


Duane syndrome  is a congenital rare type of  strabismus  most commonly characterized by the inability of the  eye  to move outward. The syndrome was first described by ophthalmologists  Jakob Stilling  (1887) and Siegmund Türk (1896), and subsequently named after  Alexander Duane , who discussed the disorder in more detail in 1905. [ 2 ]


Other names for this condition include: Duane's retraction syndrome, eye retraction syndrome, retraction syndrome, congenital retraction syndrome and Stilling-Türk-Duane syndrome. [ 3 ]


The characteristic features of the syndrome are:


While usually isolated to the eye abnormalities, Duane syndrome can be associated with other problems including cervical spine abnormalities  Klippel–Feil syndrome ,  Goldenhar syndrome ,  heterochromia , and congenital deafness. [ 5 ]


Duane syndrome is most probably a miswiring of the  eye muscles , causing some eye muscles to contract when they shouldn't and other eye muscles not to contract when they should. [ 3 ]  Alexandrakis and Saunders found that in most cases the abducens nucleus and nerve are absent or hypoplastic, and the lateral rectus muscle is innervated by a branch of the oculomotor nerve. [ 6 ]  This view is supported by the earlier work of Hotchkiss et al. who reported on the autopsy findings of two patients with Duane's syndrome. In both cases the  sixth cranial nerve  nucleus and nerve was absent, and the lateral rectus muscle was innervated by the inferior division of the third  oculomotor nerve . This misdirection of nerve fibres results in opposing muscles being innervated by the same nerve. Thus, on attempted abduction, stimulation of the lateral rectus via the oculomotor nerve will be accompanied by stimulation of the opposing medial rectus via the same nerve; a muscle which works to adduct the eye. Thus, co-contraction of the muscles takes place, limiting the amount of movement achievable and also resulting in retraction of the eye into the socket. They also noticed mechanical factors and considered them secondary to loss of innervation: During corrective surgery fibrous attachments have been found connecting the horizontal recti and the orbital walls and fibrosis of the lateral rectus has been confirmed by biopsy. This fibrosis can result in the lateral rectus being 'tight' and acting as a tether or leash. Co-contraction of the medial and lateral recti allows the globe to slip up or down under the tight lateral rectus producing the up and down shoots characteristic of the condition. [ 7 ]


There are two known genetic associations with Duane Syndrome. In some families the condition is associated with variants in the  Chimerin 1  gene [ 8 ]  and in others it is associated with variants in the  Transcription factor MafB  gene. [ 9 ]


Duane's syndrome has three variants:


Brown(1950) has classified Duane's syndrome according to the characteristics of the limitation of movement-


The first type is more common and accounts for 85% of the cases. [ 5 ] [ 10 ]


In the clinical setting, the principal difficulties in differential diagnosis arise as a consequence of the very early age at which patients with this condition first present. The clinician must be persistent in examining abduction and adduction, and in looking for any associated palpebral fissure changes or head postures, when attempting to determine whether what often presents as a common childhood squint (note-"squint" is a British term for two eyes not looking in the same direction [ 11 ] ) is in fact Duane syndrome. Fissure changes, and the other associated characteristics of Duane's such as up or down shoots and globe retraction, are also vital when deciding whether any abduction limitation is the result of Duane's and not a consequence of VI or abducens cranial nerve palsy.


Acquired Duane's syndrome is a rare event occurring after peripheral nerve palsy. [ 12 ]


The majority of patients remain symptom free and able to maintain binocularity with only a slight face turn.  Amblyopia  is uncommon and, where present, rarely dense. This can be treated with occlusion, and any refractive error can also be corrected.


Duane syndrome cannot be cured, as the "missing"  cranial nerve  cannot be replaced, and traditionally there has been no expectation that surgery will result in any increase in the range of eye movement. Surgical intervention, therefore, has only been recommended where the patient is unable to maintain binocularity, where they are experiencing symptoms, or where they are forced to adopt a cosmetically unsightly or uncomfortable head posture in order to maintain binocularity. The aims of surgery are to place the eye in a more central position and, thus, place the field of binocularity more centrally also, and to overcome or reduce the need for the adoption of an abnormal head posture. Occasionally, surgery is not needed during childhood, but becomes appropriate later in life, as head position changes (presumably due to progressive muscle  contracture ). [ citation needed ]


Surgical approaches include:


Most patients are diagnosed by the age of 10 years and Duane's is more common in girls (60 percent of the cases) than boys (40 percent of the cases). A French study reports that this syndrome accounts for 1.9% of the population of strabismic patients, 53.5% of patients are female, is unilateral in 78% of cases, and the left eye (71.9%) is affected more frequently than the right. [ 15 ]  Around 10–20% of cases are  familial ; these are more likely to be bilateral than non-familial Duane syndrome. Duane syndrome has no particular race predilection. [ citation needed ]


Dyskeratosis congenita  ( DKC ), also known as  Zinsser-Engman-Cole syndrome , is a rare progressive  congenital disorder  with a highly variable  phenotype . [ 3 ]  The entity was classically defined by the triad of abnormal skin pigmentation, nail  dystrophy , and  leukoplakia  of the oral  mucosa , and  myelodysplastic syndrome  (MDS) or  acute myeloid leukemia  (AML), but these components do not always occur. [ 3 ]  DKC is characterized by short  telomeres . The disease initially can affect the  skin , but a major consequence is progressive  bone marrow  failure which occurs in over 80%, causing early mortality. [ 3 ]


DKC can be characterized by cutaneous pigmentation, premature graying,  dystrophy  of the  nails ,  leukoplakia  of the oral mucosa, continuous lacrimation due to  atresia  of the  lacrimal ducts , often  thrombocytopenia ,  anemia ,  testicular atrophy  in the male carriers, and predisposition to  cancer . [ 4 ] [ 5 ]   Also, liver abnormalities are associated with this syndrome, Nodular Regenerative Hypoplasia of the liver, although rare, it is one of many manifestations of liver disorders short telomeres can cause. [ 6 ]


It is thought  [ 7 ]  that without functional telomerase, chromosomes will likely be attached together at their ends through the  non-homologous end joining  pathway. If this proves to be a common enough occurrence, malignancy even without telomerase present is possible. Myelodysplastic Syndrome is associated with this syndrome usually presenting as a Hypoplastic Bone Marrow that can resemble Aplastic Anemia, but can be differentiated with >10% dysplasia in affected cell lines, sometimes not possible though because of the Hypoplastic marrow reducing blood cells to be observed, genetic clones are usually not present more often than not with Hypoplastic Myelodysplastic Disorder associated with Dyskeratosis Congenita.


Of the components of the telomerase RNA component (TERC), one of key importance is the  box H/ACA  domain.  This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The  mammalian  H/ACA  ribonucleoprotein  contains four  protein  subunits: dyskerin, Gar1, Nop10, and Nhp2.   Mutations  in Nop10, [ 8 ]  Nhp2 [ 9 ]  and dyskerin1 [ 10 ]  have all been shown to lead to DKC-like symptoms.


The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the  X chromosome  in the gene DKC1. [ 7 ] [ 10 ]  This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin.  Of the five mutations described by Heiss and colleagues in  Nature Genetics , [ 10 ]  four were single nucleotide polymorphisms all resulting in the change of highly  conserved amino acids .  One case was an in-frame deletion resulting in the loss of a  leucine   residue , also conserved in mammals. In three of the cases, the specific amino acids affected ( phenylalanine ,  proline ,  glycine ) are found in the same  locus  in humans as they are in yeast ( S. Cerevisiae ) and the  brown rat  ( R. Norvegicus ). [ 10 ]   This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the  post-transcriptional   pseudouridylation  of specific  uridines  found in non-coding RNAs, such as  ribosomal RNA  (rRNA).  Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA. [ 7 ]   In humans, this role can be attributed to dyskerin. [ 10 ]   Thus, the X-linked form of this disease may result in specific issues related to dysfunctional RNA and perhaps a graver phenotype.  Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. [ 11 ]  This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.  [ 12 ]


3 genes: TERC, TERT, TINF2
The evidence supporting the importance of the H/ACA domain in human telomerase is abundant.  At least one study [ 13 ]  has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA.  Nonetheless, mutations that directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. [ 7 ]  In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on  chromosome 3  which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance.  Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease. [ 14 ]


6 genes:
The true  phenotype  of DKC individuals may depend upon which protein has incurred a mutation.  One documented autosomal recessive mutation [ 8 ]  in a family that carries DKC has been found in NOP10.  Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the NOP10 sequence.  This mutation, on  chromosome 15 , results in an  amino acid  change from  arginine  to  tryptophan .   Homozygous recessive  individuals show the symptoms of dyskeratosis congenita in full.  As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length.  Furthermore, heterozygotes, those who have one normal  allele  and one coding for the disease, also show relatively shortened telomeres.  The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation.  With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described. [ 8 ]


NHP2 mutations are similar in characterization to NOP10.  These mutations are also autosomal recessive with three specific  single-nucleotide polymorphisms  being recognized which result in dyskeratosis congenita.  Also, like NOP10, individuals with these NHP2 mutations have a reduction in the amount of  telomerase RNA component  (TERC) present in the cell.  Again, it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres.  Those homozygous recessive for mutations in NHP2 do show shorter telomeres when compared with age-matched normal individuals. [ 9 ]


Dyskeratosis congenita is a disorder of poor  telomere  maintenance [ 7 ]  mainly due to a number of  gene   mutations  that give rise to abnormal ribosome function, termed  ribosomopathy . Specifically, the disease is related to one or more mutations which directly or indirectly affect the  vertebrate   telomerase RNA component  (TERC).  [ 15 ]


Telomerase is a  reverse transcriptase  which maintains a specific repeat sequence of  DNA , the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal  end-shortening  that occurs during normal  DNA replication . [ 16 ]  This end-shortening is the result of the eukaryotic  DNA polymerases  having no mechanism for synthesizing the final  nucleotides  present on the end of the "lagging strand" of double stranded DNA.  DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'→3' direction.  Given that DNA has two strands that are complementary, one strand must be 5'→3' while the other is 3'→5'.  This inability to synthesize in the 3'→5' directionality is compensated with the use of  Okazaki fragments , short pieces of DNA that are synthesized 5'→3' from the 3'→5' as the replication fork moves. As DNA polymerase requires  RNA primers  for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized.  When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed.  Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases. [ 16 ] [ 17 ]


Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. [ 7 ] [ 8 ] [ 10 ]   With TERC levels down, telomere maintenance during development suffers accordingly.  In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer). [ 11 ]  Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.  [ 18 ]


A study shows that proliferative defects in DC skin  keratinocytes  are corrected by expression of the  telomerase reverse transcriptase , TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 of the  telomerase RNA component , TERC. [ 19 ]


Since the disease has a wide variety of symptoms due to involvement of multiple systems of the body, diagnostic testing depends on the clinical findings in each individual patient.  Commonly used tests include a complete blood count (CBC), bone marrow examination, leukocyte telomere length test (e.g. Flow FISH), pulmonary function test, and  genetic testing . [ 20 ] [ 21 ]


The mainstay of treatment in dyskeratosis congenita is  hematopoietic stem cell transplantation , best outcome with sibling donor. Short term therapy in initial stages is with anabolic steroids [oxymetholone, danazol] or with erythropoietin-like hormones or with granulocyte-colony stimulating factor [filgrastim) all these therapies are directed to cope with effects of bone marrow failure which manifests as low red and white blood cell counts. These medications help to increase the blood components and make up for the deficiencies caused due to bone marrow failure. Dyskeratosis Congenita in regards to stem cell transplantation have to be very carefully treated with low intensity radiation/chemo to avoid potentially catastrophic effects of Host versus graft disease and toxicity to other organs affected by short telomeres which makes them very sensitive to any radiation especially the lungs, and liver.  [ 22 ]


DC is associated with shorter life expectancy, but many live to at least age 60. [ 23 ]
Main cause of mortality in these patients are related to bone marrow failure. Nearly 80% of the patients of dyskeratosis congenita develop bone marrow failure. [ 24 ]


Recent research has used  induced pluripotent stem cells  to study disease mechanisms in humans, and discovered that the reprogramming of somatic cells restores telomere elongation in dyskeratosis congenita (DKC) cells despite the genetic lesions that affect telomerase. The reprogrammed DKC cells were able to overcome a critical limitation in  TERC  levels and restored function (telomere maintenance and self-renewal). Therapeutically, methods aimed at increasing TERC expression could prove beneficial in DKC. [ 25 ]


An  ectopic pancreas  is an  anatomical  abnormality in which  pancreatic  tissue has grown outside its normal location ( ectopia ) and without  vascular  or other anatomical connections to the pancreas. [ 2 ]  It is a  disease  which is  congenital [ 2 ]  and is also known as heterotopic, accessory, or aberrant pancreas. [ 3 ]


Often, heterotopic pancreas is  asymptomatic . When present,  symptoms  may include  abdominal pain  and distension. [ 1 ]  Heterotopic pancreas is commonly recognized as an  incidental finding  on imaging studies performed for an unrelated reason.


Ectopic pancreatic tissue may occur anywhere in the  abdominal  cavity, though more than 90 percent are found in the  stomach ,  duodenum , or  jejunum . [ 1 ]  Rarely, pancreatic heterotopic tissue may be found in the  colon ,  spleen  or  liver . [ 1 ]


The  diagnosis  of ectopic pancreas can be challenging. Confirmation of the diagnosis requires tissue sampling, via  biopsy  or  surgical resection .


If no symptoms are present, then  treatment  is not necessary. When symptoms are present, treatment consists of  surgical  resection. [ 1 ]


The  incidence  of heterotopic pancreas is relatively low. [ 1 ]


This article related to  pathology  is a  stub . You can help Wikipedia by  expanding it .


Ehlers–Danlos syndromes  ( EDS ) are a group of 13  genetic   connective-tissue disorders . [ 7 ]  Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. [ 1 ]  These may be noticed at birth or in early childhood. [ 3 ]  Complications may include  aortic dissection ,  joint dislocations ,  scoliosis ,  chronic pain , or early  osteoarthritis . [ 1 ] [ 4 ]  The current classification was last updated in 2017, when a number of rarer forms of EDS were added. [ 1 ] [ 8 ]


EDS occurs due to mutations in one or more particular genes—there are 19 genes that can contribute to the condition. [ 1 ]  The specific gene affected determines the type of EDS, though the genetic causes of hypermobile Ehlers–Danlos syndrome (hEDS) are still unknown. [ 1 ] [ 9 ]  Some cases result from a new variation occurring during early development, while others are inherited in an  autosomal dominant  or  recessive  manner. [ 1 ]  Typically, these variations result in defects in the structure or processing of the protein  collagen  or  tenascin . [ 1 ]


Diagnosis is often based on symptoms and confirmed by  genetic testing  or  skin biopsy , particularly with hEDS, but people may initially be misdiagnosed with  hypochondriasis ,  depression , or  myalgic encephalomyelitis/chronic fatigue syndrome . [ 4 ]  Genetic testing can be used to confirm all other types of EDS. [ 9 ]


A cure is not yet known, [ 6 ]  and treatment is  supportive  in nature. [ 4 ]   Physical therapy  and bracing may help strengthen muscles and support joints. [ 4 ]  Several medications can help alleviate symptoms of EDS such as pain and blood pressure drugs, which reduce joint pain and complications caused by blood vessel weakness. [ 10 ]  Some forms of EDS result in a normal  life expectancy , but those that affect  blood vessels  generally decrease it. [ 6 ]  All forms of EDS can result in fatal outcomes for some patients. [ 11 ] [ 12 ] [ 13 ]


While hEDS affects at least one in 5,000 people globally, [ 1 ] [ 14 ]  other types occur at lower frequencies. [ 11 ] [ 8 ]  The prognosis depends on the specific disorder. [ 4 ]  Excess mobility was first described by  Hippocrates  in 400 BC. [ 15 ]  The syndromes are named after two physicians,  Edvard Ehlers  and  Henri-Alexandre Danlos , who described them at the turn of the 20th century. [ 16 ]


In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria. [ 5 ]  According to the  Ehlers–Danlos Society , the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those that affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect  glycosaminoglycan  biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS. [ 17 ]


Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint  subluxations  (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle or bone pain. [ 5 ]  It affects the skin less than other forms. It has no available genetic test. [ 18 ]  hEDS is the most common of the 19 types of connective tissue disorders. Since no genetic test exists, providers have to diagnose hEDS based on what they know about the condition and the patient's physical attributes. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing. [ 19 ]


Pregnant individuals who have hEDS are at an increased risk for complications. Some possible complications are pre-labor rupture of membranes, a drop in blood pressure with anesthesia, precipitated birth (very fast, active labor), malposition of the fetus, and increased bleeding. Individuals with hEDS may run the risk of falling,  postpartum depression  (more than the general population), and slow healing from the birthing process. [ 20 ]


The Medical University of South Carolina discovered a gene variant common with hEDS patients. [ 21 ]


While 12 of the 13 subtypes of EDS have genetic variations that can be tested for by  genetic testing , there is no known genetic cause of hEDS. Recently, several labs and research initiatives have been attempting to uncover a potential hEDS gene. In 2018, the  Ehlers–Danlos Society  began the Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study. [ 22 ]  The ongoing study has screened over 1,000 people who have been diagnosed with hEDS by the 2017 criteria to evaluate their genome for a common mutation. To date, 200 people with hEDS have had  whole genome sequencing , and 500 have had whole  exome  sequencing; this study aims to increase those numbers significantly. [ citation needed ]


Promising outcomes of this increased screening have been reported by the Norris Lab, led by Russell Norris, in the Department of Regenerative Medicine and Cell Biology at  Medical University of South Carolina . [ 23 ]  Using  CRISPR  Cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene" [ 24 ]  for hEDS. This finding, and a greater understanding of cardiac complications associated with the majority of EDS subtypes, has led to the development of multiple druggable pathways involved in  aortic  and  mitral valve  diseases. While this candidate gene has not been publicly identified, the Norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible hEDS genes. A mutation in  COL3A1 [ 25 ]  in a single family with autosomal dominant hEDS phenotype was found to cause reduced collagen secretion and an over-modification of collagen. In 35 families, copy number alterations in  TPSAB1 , [ 26 ]  encoding alpha-tryptase, were associated with increased basal serum  tryptase  levels, associated with  autonomic dysfunction ,  gastrointestinal disorders , allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with hEDS phenotype.


Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is  DZIP1 , which regulates cardiac valve development in mammals through a  CBY1 -beta-catenin mechanism. Mutations at this gene affect the  beta-catenin  cascade involved in development, causing malformation of the extracellular matrix, resulting in loss of collagen. A lack of collagen here is consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the  PDGF  signaling pathway, which is involved in growth factor ligands and receptor isoforms. [ 27 ]  Mutations in this pathway affect the ability to localize  cilia  in various cell types, including cardiac cells. With the resulting  ciliopathies , structures such as the  cardiac outflow tract ,  heart tube  assembly, and cardiac fusion are limited and/or damaged. [ citation needed ]


Classical EDS is characterized by extremely elastic skin that is fragile and bruises easily and hypermobility of the joints. Molluscoid pseudotumors (calcified  hematomas  that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) are also often seen. A side complication of the hyperelasticity presented in many EDS cases makes wounds closing on their own more difficult. [ 28 ]  Sometimes, motor development is delayed and  hypotonia  occurs. [ 5 ]  The variation causing this type of EDS is in the genes  COL5A2 ,  COL5A1 ,  and less frequently  COL1A1 . It involves the skin more than hEDS. [ 28 ]  In classical EDS, large variation in symptom presentation is seen. Because of this variance, EDS has often been underdiagnosed. [ 29 ]  Without genetic testing, healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones, as well as by neurological assessment. [ 30 ]


A good way to begin the diagnostic process is by reviewing a person's family history. EDS is an autosomal dominant condition, so is often inherited from parents. [ 28 ]  Genetic testing remains the most reliable way to diagnose EDS. [ 31 ]  No cure for type 1 EDS has been found, but a course of non-weight-bearing exercise can help with muscular tension, which can help correct some EDS symptoms. Anti-inflammatory drugs and lifestyle changes can help with joint pain. Lifestyle choices should also be made with children who have EDS to try to prevent wounds to the skin. Protective garments can help with this. In a wound, deep stitches are often used and left in place for longer than normal. [ 28 ]


Vascular EDS (formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features, including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes. [ 32 ]  Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include  club foot , tendon and/or muscle rupture,  acrogeria  (premature aging of the skin of the hands and feet), early-onset  varicose veins ,  pneumothorax  (collapse of a lung), the recession of the gums, and a decreased amount of fat under the skin. [ 5 ]  It can be caused by the variations in the  COL3A1  gene. [ 32 ]  Rarely,  COL1A1  variations can also cause it. [ 8 ]


Kyphoscoliosis EDS (formerly categorized as type 6) is associated with severe  hypotonia  at birth, delayed motor development, progressive  scoliosis  (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and  osteopenia  (low bone density). Other common features include a " marfanoid  habitus" characterized by long, slender fingers ( arachnodactyly ), unusually long limbs, and a sunken chest ( pectus excavatum ) or protruding chest ( pectus carinatum ). [ 5 ]  It can be caused by variations in the gene  PLOD1 , or rarely, in the  FKBP14  gene. [ 33 ]


Arthrochalasia EDS (formerly categorized as types 7A and B) is characterized by severe joint hypermobility and congenital  hip dislocation . Other common features include fragile, elastic skin with easy bruising,  hypotonia ,  kyphoscoliosis  ( kyphosis  and  scoliosis ), and mild  osteopenia . [ 5 ]   Type-I collagen  is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Variations in the genes   COL1A1  and  COL1A2   cause it. [ 34 ]


Dermatosparaxis EDS (formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Variations in the  ADAMTS2  gene cause it. It is extremely rare, with around 11 cases reported worldwide. [ 35 ]


Brittle-cornea syndrome is characterized by the progressive thinning of the  cornea , early-onset progressive  keratoglobus  or keratoconus, nearsightedness, hearing loss, and blue  sclerae . [ 5 ] [ 36 ]  Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often. [ 37 ]  It has two types. Type 1 occurs due to variations in the  ZNF469  gene. Type 2 is due to variations in the  PRDM5  gene. [ 36 ]


Classical-like EDS is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous  ecchymoses  (discolorations of the skin resulting from bleeding underneath). [ 5 ]  It can be caused by variations in the  TNXB  gene. [ 8 ]


Spondylodysplastic EDS is characterized by short stature (progressive in childhood), muscle  hypotonia  (ranging from severe congenital to mild later-onset), and bowing of limbs. [ 5 ]  It can be caused by variations in both copies of the  B4GALT7  gene. Other cases can be caused by variations in the  B3GALT6  gene. People with variations in this gene can have  kyphoscoliosis , tapered fingers,  osteoporosis ,  aortic aneurysms , and problems with the lungs. Other cases can be caused by the  SLC39A13  gene. Those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility. [ 38 ]


Musculocontractural EDS is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or  talipes equinovarus  ( clubfoot ), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling. [ 5 ]  It can be caused by variations in the  CHST14  gene. Some other cases can be caused by variations in the  DSE  gene. [ 39 ]


As of 2021, 48 individuals have been reported to have mcEDS-CHST14, while 8 individuals have mcEDS-DSE. [ 40 ]


Bethlem myopathy 2 , formally known as Myopathic EDS (mEDS), is characterized by three major criteria: congenital muscle  hypotonia  and/or  muscle atrophy  that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands). [ 5 ]  Four minor criteria may also contribute to a diagnosis of mEDS. This disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern. [ 17 ]  Molecular testing must be completed to verify that mutations in the  COL12A1  gene are present; if not, other collagen-type myopathies should be considered. [ 17 ]


Periodontal EDS (pEDS) is an autosomal-dominant disorder [ 17 ]  characterized by four major criteria of severe and intractable  periodontitis  of early-onset (childhood or adolescence), lack of attached  gingiva , pretibial plaques, and family history of a first-degree relative who meets clinical criteria. [ 5 ]  Eight minor criteria may also contribute to the diagnosis of pEDS. Molecular testing may reveal mutations in  C1R  or  C1S  genes affecting the  C1r  protein. [ 17 ]


Cardiac-valvular EDS (cvEDS) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints). [ 5 ]  Four minor criteria may aid in the diagnosis of cvEDS. [ 17 ]  cvEDS is an autosomal recessive disorder, inherited through variation in both  alleles  of the gene  COL1A2 . [ 41 ]


This group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. However, as connective tissue is found throughout the body, EDS may result in an array of unexpected impacts with any degree of severity, and the condition is not limited to joints, skin, and blood vessels. [ 42 ]  Effects may range from mildly loose joints to life-threatening  cardiovascular  complications. [ 43 ]  Due to the diversity of subtypes within the EDS family, symptoms may vary widely between individuals diagnosed with EDS. [ 44 ]


Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to  sprain ,  dislocation ,  subluxation , and  hyperextension . [ 4 ] [ 16 ]  As a result of frequent tissue injury, there can be an early onset of advanced  osteoarthritis , [ 45 ]  chronic degenerative joint disease, [ 45 ]   swan-neck deformity  of the fingers, [ 46 ]  and  Boutonniere deformity  of the fingers. Tendon and ligament laxity offer minuscule protection from tearing in muscles and tendons, but these problems still persist. [ 47 ]


Deformities of the spine, such as  scoliosis  (curvature of the spine),  kyphosis  (a thoracic hump),  tethered spinal cord syndrome ,  craniocervical instability  (CCI), and atlantoaxial instability may also be present. [ 48 ] [ 49 ]   Osteoporosis  and osteopenia are also associated with EDS and symptomatic joint hypermobility [ 50 ] [ 51 ]


There can also be  myalgia  (muscle pain) and  arthralgia  (joint pain), [ 52 ]  which may be severe and disabling.  Trendelenburg's sign  is often seen, which means that when standing on one leg, the pelvis drops on the other side. [ 53 ]   Osgood–Schlatter disease , a painful lump on the knee, is common as well. [ 54 ]  In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs. [ 55 ]


The weak connective tissue causes abnormal skin. This may present as stretchy or in other types simply be velvet soft. In all types, some increased fragility occurs, but the degree varies depending on the underlying subtype. The skin may tear and bruise easily, and may heal with abnormal atrophic scars; [ 45 ]  atrophic scars that look like cigarette paper are a sign seen including in those whose skin might appear otherwise normal. [ 1 ] [ 16 ] [ 28 ]  In some subtypes, though not the hypermobile subtype, redundant skin folds occur, especially on the eyelids. Redundant skin folds are areas of excess skin lying in folds. [ 45 ] [ 56 ]


Other skin symptoms include molluscoid pseudotumors, [ 57 ]  especially on pressure points,  petechiae , [ 58 ]  subcutaneous spheroids, [ 57 ]   livedo reticularis ;  piezogenic papules  are less common. [ 59 ]  In vascular EDS, skin can also be thin and translucent. In dermatosparaxis EDS, the skin is extremely fragile and saggy. [ 1 ]


Weakened connective tissues can lead to  pelvic organ prolapse  in female patients with Ehlers–Danlos syndrome. [ 67 ]  Patients may also experience voiding difficulties, frequent  urinary tract infections , and incontinence due to structural abnormalities. [ 68 ]   Pelvic girdle pain  is also frequently reported. [ 69 ]


Menorrhagia ,  dysmenorrhea , and  dyspareunia  are common symptoms associated with Ehlers–Danlos syndrome [ 70 ]  and are often mistaken for endometriosis. [ 70 ]  Excessive menstrual bleeding can sometimes be attributed to inappropriate platelet aggregation, but faulty collagen leads to weakened capillary walls which increase the likelihood of hemorrhage. [ 71 ]


In cases of pregnancy, patients with Ehlers–Danlos syndrome are more likely to experience complications during  parturition . [ 71 ]   Post-partum hemorrhage  and maternal injury such as sporadic pelvic displacement,  hip dislocation , torn and stretched ligaments, and skin tearing can all be linked to altered structure of connective tissues. [ 72 ]


Research suggests a correlation between connective tissue disorders such as Ehlers–Danlos syndrome and both structural and functional problems within the gastrointestinal tract. [ 73 ]


High incidences of coexisting inflammatory disorders suggest a correlation between connective tissue disorders and the development of such aforementioned conditions.  Inflammatory bowel diseases  such as  Crohn's disease ,  ulcerative colitis [ 74 ]  and  celiac disease [ 75 ]  are more common in EDS patients when compared to control groups. Of note, patients who are already diagnosed with an inflammatory bowel disorder are not necessarily likely to develop symptoms of a connective tissue disorder, as the two have separate but not totally confounding etiologies. [ 76 ]   Eosinophilic esophagitis , an inflammatory condition characterized by allergic-type reactions to various foods and chemicals and extensive esophageal remodeling, is eight times more likely in patients with connective tissue disorders when compared to patients without. [ 77 ]


Functionally, small bowel dysmotility,  delayed gastric emptying  and delayed colonic transit are commonly related to EDS. [ 78 ] [ 79 ]  These changes in transit speeds within the gastrointestinal system can cause a host of symptoms, including but not limited to abdominal pain,  bloating ,  nausea , reflux symptoms,  vomiting ,  constipation , and  diarrhea . [ 80 ]


Some studies also suggest problems with the  liver , which is in large part responsible for  bilirubin  conjugation. Although research in this area is sparse, patients with joint hypermobility were found to have higher rates of indirect  hyperbilirubinemia  than control groups. [ 81 ]


Structurally, changes within the musculature in the intestine such as increased elastin, can lead to increased frequency of herniation. [ 73 ]  Laxity of the phreno-esophageal and gastro-hepatic ligaments can lead to  hiatal hernia , [ 82 ] [ 83 ]  which in turn can lead to commonly reported symptoms such as  acid reflux , abdominal pain, early  satiety , and bloating. Internal organ prolapses and intestinal  intussusceptions  occur with greater frequency in patients with weakened connective tissues. [ 84 ]


Although neurogastroenterological manifestations in connective tissue disorders are common, their root cause is not yet known. [ 83 ]  Splanchnic circulation,  small fiber neuropathy  and altered vascular compliance have all been named as potential contributors to gastrointestinal complaints, [ 85 ]  particularly for patients who have a known, comorbid autonomic condition.


Chronic headaches are common in patients with Ehlers–Danlos syndrome, whether related to  dysautonomia , [ 86 ]   TMJ , muscle tension, or  craniocervical instability . Craniocervical instability is caused by trauma(s) to the head and neck areas such as concussion and whiplash. Ligaments in the neck are unable to heal properly, so the neck structure cannot support the skull, which can then sink into the brain stem, blocking the flow of cerebrospinal fluid, which in turn causes autonomic dysfunction. [ 87 ] [ 49 ]


Arnold–Chiari malformation [ 88 ]  is also more frequently found in patients with EDS because of the instability at the juncture between skull and spine. This causes herniation of the posterior fossa below the  foramen magnum . [ 89 ]  Increased pressure created by the malformation can lead to a flattened  pituitary gland , hormone changes, sudden severe headaches,  ataxia , and poor  proprioception . [ 90 ]


Ophthalmological manifestations include  nearsightedness , retinal tearing and  retinal detachment ,  keratoconus , blue sclera, dry eye,  Sjogren's syndrome , lens subluxation, angioid streaks,  epicanthal folds ,  strabismus , corneal scarring, brittle cornea syndrome,  cataracts ,  carotid-cavernous sinus fistulas , and  macular degeneration . [ 91 ]


Otological complications may also occur.  Hearing loss  is common, both conductive and sensorineural, and is most often bilateral. [ 92 ]   Otosclerosis  and instability of the bones in the inner ear may also contribute to hearing loss. [ 93 ]


Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDS have been mischaracterized as child abuse. [ 105 ]  The pain may also be misdiagnosed as a behavior disorder or  Munchausen by proxy . [ 106 ]


The pain associated with EDS ranges from mild to debilitating. [ 107 ]


Every type of EDS except the hypermobile type (which affects the vast majority of people with EDS) can be positively tied to specific genetic variation [ citation needed ] .


Variations  in these genes can cause EDS: [ 8 ]


Variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. [ 1 ]  Inheritance patterns depend on the specific syndrome.


Most forms of EDS are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected. It can also be an individual ( de novo  or "sporadic")  variation . Sporadic variations occur without any inheritance. [ 108 ]