This suggests that the term "Burnside–Butler syndrome" should be used with caution, if at all. In the context of low penetrance for a very common variant, it is not surprising that the features that have been attributed to the deletion are highly variable and inconsistent. No consistent set of features has been described that would meet the usual criteria for naming a syndrome, and the use of the term is likely to cause confusion. [ citation needed ]


Arterial calcification due to CD73 deficiency  or  Calcification of joints and arteries  is a rare genetic disorder affecting adults. [ 1 ]


This condition is characterised by calcification of the peripheral arteries. [ 2 ]


This condition is caused by mutations in the 5'-Nucleotidase Ecto ( NT5E ) gene. [ 3 ]


Medical evaluation and genetic test are used to ascertain Arterial calcification due to CD73 deficiency [ 4 ]


This a rare disorder, up to 2020 less than 20 individuals have been reported to have the condition [ 5 ]


This condition was first described in 2011. [ 6 ]


CAMFAK syndrome  (or  CAMAK syndrome ) is an  acronym  used to describe a rare inherited  neurologic  disease, characterized by peripheral and central  demyelination  of nerves, similar to that seen in  Cockayne syndrome . [ 1 ]  The name "CAMFAK" comes from the first letters of the characteristic findings of the disease:   ca taracts ,  m icrocephaly ,  fa ilure to thrive , and  k yphoscoliosis . [ 2 ]   The disease may occur with or without failure to thrive and  arthrogryposis .


Low birth weight and a bird-like face may be the first signs.  Severe intellectual deficit and death within the first decade are typical.


CAMFAK syndrome is inherited in an autosomal recessive manner. [ 2 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.


Camptodactyly  is a  medical condition  that causes one or more  digits  ( fingers  or  toes ) to be permanently bent. It involves fixed  flexion   deformity  of the proximal  interphalangeal joints .


Camptodactyly can be caused by a  genetic disorder . In that case, it is an  autosomal dominant  trait that is known for its incomplete genetic  expressivity . This means that when a person has the genes for it, the condition may appear in both hands, one, or neither. A linkage scan proposed that the chromosomal locus of camptodactyly was 3q11.2-q13.12. [ 6 ]


The specific cause of camptodactyly remains unknown, but there are a few deficiencies that lead to the condition. A deficient  lumbrical muscle  controlling the flexion of the fingers, and abnormalities of the flexor and extensor tendons. [ 7 ]


A number of  congenital   syndromes  may also cause camptodactyly:


The pattern of inheritance is determined by the phenotypic expression of a gene—which is called  expressivity . [ 11 ]  Camptodactyly can be passed on through generations in various levels of phenotypic expression, which include both or only one hand. This means that the genetic expressivity is incomplete. It can be inherited from either parent.


In most of its cases, camptodactyly occurs sporadically, but it has been found in several studies that it is inherited as an autosomal dominant condition. [ 6 ]


If a contracture is less than 30 degrees, it may not interfere with normal functioning. [ 7 ]  The common treatment is splinting and occupational therapy. [ 12 ]  Surgery is the last option for most cases as the result may not be satisfactory. [ 13 ]


The name is derived from the  ancient Greek  words καμπτός,  kamptos  ( bent ) and δάκτυλος,  daktylos  ( finger ).


Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature  ( CANDLE )  syndrome  is an  autosomal recessive  disorder that presents itself via various autoinflammatory responses throughout the body, multiple types of  skin lesions , and recurrent long-term  fever  symptoms. [ 1 ]  The current known cause for the disorder is a mutation in the  PSMB8  gene or mutations in other closely related genes. [ 1 ]  The syndrome was first named and classified in March 2010 after four patients were reviewed with similar symptoms. [ 2 ]  There have been approximately 30 cases reported in the scientific literature as of 2015. [ 3 ]


The symptoms of CANDLE syndrome can manifest themselves in a variety of different ways and combinations related to skin disorders, internal inflammatory responses, and fever-based conditions. The types of outwardly visible conditions involve  facies  not matching other known disorders,  contracture  of the joints, and skin lesions appearing across any part of the body. The multiple inflammatory developments include nonspecific  lymphadenopathy ,  hepatosplenomegaly , and  autoimmune hemolytic anemia . Other possible conditions are  hypertriglyceridemia  and  lipodystrophy . [ 1 ]


Other novel mutations resulting in the syndrome have also involved the manifestation of other conditions, such as  Sweet's syndrome  and  pericarditis . [ 4 ]  Another case in 2015 showcased previously undescribed dental symptoms, such as  microdontia  and  osteopenia  of the jaw, along with a general case of  diabetes mellitus . [ 3 ]


The most common known cause of the syndrome are mutations in the  Proteasome Subunit, Beta Type, 8 (PSMB8) gene that codes for  proteasomes  that in turn break down other proteins. This occurs specifically when a mutation causes the  homozygous  recessive form to emerge. The mutated gene results in proteins not being degraded and  oxidative  proteins building up in cellular tissues, eventually leading to  apoptosis , especially in muscle and fat cells. [ 3 ]


A study conducted by Brehm et al. in November 2015 discovered additional mutations that can cause CANDLE syndrome, including  PSMA3  (encodes α7),  PSMB4  (encodes β7),  PSMB9  (encodes β1i), and the  proteasome maturation protein  (POMP), with 8 mutations in total between them. An additional unknown mutation type in the original PSMB8 gene was also noted. [ 5 ]


Unlike other autoinflammatory disorders, patients with CANDLE do not respond to  IL-1  inhibition treatment in order to stop the autoinflammatory response altogether. This suggests that the condition also involves  IFN  dysregulation. [ 5 ]


The category that CANDLE syndrome is a part of, along with related disorders, falls under the banner of  proteasome-associated autoinflammatory syndromes  (PRAAS). The first one to be described was by Nakajo at  Tohoku University  in 1939, where he collected symptoms including skin lesions,  clubbing  of the fingers, and various thickening of heart walls. He termed the collective symptoms  Nakajo-Nishimura syndrome  (NKJO). Further symptoms were added onto the overall condition from work by Nishimura, with the overall symptoms being similar to CANDLE syndrome. [ 3 ] [ 6 ]  A related syndrome was described by Garg et al. in 2010 and titled Joint contractures, Muscular Atrophy, Microcytic anemia, and Panniculitis-induced Lipodystrophy (JMP) syndrome. [ 3 ] [ 7 ]


The primary differences between the syndromes is the lack of fever in JMP syndrome and the lack of seizures in NKJO syndrome, both of which are present in CANDLE syndrome. [ 3 ]  Though it has been proposed by Wang et al. that the different syndromes are actually just clinical  phenotypic variations  of the same syndrome based around different mutations of the PSMB8 gene. [ 8 ]


Cat-eye syndrome  (CES) or  Schmid–Fraccaro syndrome  is a rare condition caused by an abnormal extra  chromosome , i.e. a  small supernumerary marker chromosome . [ 2 ]  This chromosome consists of the entire short arm and a small section of the long arm of  chromosome 22 . In consequence, individuals with the cat-eye syndrome have three ( trisomic ) or four ( tetrasomic ) copies of the genetic material contained in the abnormal chromosome instead of the normal two copies. [ 3 ]  The prognosis for patients with CES varies depending on the severity of the condition and their associated signs and symptoms, especially when  heart or kidney abnormalities are seen. [ 4 ]


The term "cat eye" syndrome was coined because of the particular appearance of the vertical colobomas in the eyes of some patients, but over half of the CES patients in the literature do not present with this trait. [ 6 ]


The small supernumerary marker chromosome (sSMC) in CES usually arises spontaneously. It may be hereditary and parents may be mosaic for the marker chromosome, but show no  phenotypic   symptoms  of the  syndrome . [ 7 ]  This sSMC may be small, large, or ring-shaped, and typically includes  2 Mb , i.e. 2 million DNA  base pairs , termed the CES critical region, located on its q arm(s) between its  band  11 and terminus (area notated as 22pter→q11)(also see  small supernumerary marker chromosomes in cat eye syndrome ). [ 2 ] [ 8 ]  This area contains the  CECR1 ,  SLC25A18 , and  ATP6V1E1  genes which are strong  candidate genes  for causing or promoting at least some of the birth defects in CES. [ 9 ]


An ultrasound exam may be used by a doctor to detect a birth defect that might be CES before a baby is born. An ultrasound creates an image of the fetus using sound waves. It might uncover specific CES-specific flaws. A follow-up test, like an amniocentesis, may be ordered by the doctor if they see these characteristics on an ultrasound. The doctor collects an amniotic fluid sample for analysis during amniocentesis. Extra chromosomal material from chromosome 22q11 helps doctors identify CES. The diagnosis can be verified through  genetic testing . These tests could consist of:


The healthcare provider will likely order more testing when CES is identified to look for any potential extra problems, like heart or kidney disorders. These tests may include: [ medical citation needed ]


The abnormalities common to CES were first cataloged in 1899, [ 10 ]  and described in association with a small marker chromosome in 1965. [ 11 ]  Early reports of CES discuss the possibility of chromosome 13 involvement. Now, CES is considered to be present with the chromosome 22 trisomy findings. [ 12 ]


Caudal duplication , (or caudal duplication syndrome) is a rare  congenital disorder  in which various structures of the caudal region,  embryonic cloaca , and  neural tube  exhibit a spectrum of abnormalities such as duplication and malformations. [ 2 ]  The exact causes of the condition is unknown, [ 2 ]  though there are several theories implicating abnormal embryological development as a cause for the condition. [ 3 ]  Diagnosis is often made during prenatal development of the second trimester through anomaly scans or immediately after birth. [ 4 ]  However, rare cases of adulthood diagnosis has also been observed. Treatment is often required to correct such abnormalities according to the range of symptoms present, [ 4 ]  whilst treatment options vary from conservative expectant management to resection of caudal tissue to restore normal function or appearance. [ 5 ]  As a rare congenital disorder, the prevalence at birth is less than 1 per 100,000  [ 3 ]  with less than 100 cases reported worldwide. [ 6 ]


The term "caudal duplication syndrome" has been coined since 1993 [ 2 ]  to describe caudal abnormalities and conditions. However, there has been recent debate into the appropriateness of the term being "caudal split syndrome" instead of caudal duplication due to the "splitting" nature of the abnormalities, rather than "duplication". [ 5 ]


The condition’s symptoms vary greatly due to the diverse spectrum of gastrointestinal (GI), urogenital (genitourinary, GU), spinal, and limb anomalies possible. [ 7 ]  Common forms include anorectal malformation and duplication of the external genitalia, [ 7 ]  while less common forms may include incomplete duplication of the lower spine and spinal cord, ( diastematomyelia )  [ 8 ]  and partial fusion to complete duplication of the uterus, vagina, colon, and bladder. [ 9 ]


Malformations of the spine are indicated to cause varying levels of neurological impairment. [ 8 ]  Although the level of neurological impairment is dependent upon the severity and type of spinal abnormality, most reported cases of spinal cord duplication exhibit severe neurological impairment, [ 8 ]  though cases of mild or absent neurological impairment has also been observed. [ 8 ]


Though patients often present a diverse variety of symptoms, a case was observed in which a female adult with duplication of the colon, rectum, anus, urinary bladder, urethra, uterus, cervix, vagina, and external genitalia exhibited no detrimental effects. [ 4 ]  This suggests that rarely seen cases of complete duplication of the urogenital and gastrointestinal tract are often  asymptomatic . [ 10 ]


As patients often present a multitude of differing symptoms within the caudal region, each patient exhibits a unique, characterised symptom which may or may not be cosmetically or physiologically detrimental to the individual. [ 2 ]


The exact cause of the condition is unknown. [ 2 ]  Although various theories indicate incomplete separation of monozygotic twins as an etiological factor, [ 3 ]  abnormal adherence between the  ectoderm  and  endoderm  during  gastrulation , [ 7 ]  polytopic primary developmental field defects, [ 11 ]   somatic  and  germ line mutations  in  developmental genes , [ 3 ]  and damage to the caudal cell mass and posterior gut have also been linked to cause structural anomalies in the caudal region. [ 7 ]


It is speculated that the condition is related to the  HOX gene , [ 3 ]  namely HOX10 and HOX11. Normally coding for the mammalian appendicular and axial skeleton, misexpression of the genetic factors could lead to abnormal proliferation of the caudal  mesenchyme . [ 3 ]


Embryology is suggested to have an intimate association with the development of caudal duplication syndrome. [ 2 ]  At day 15 after fertilisation, the  notochord  grows from the  primitive knot , in which it invaginates and forms the notochord canal within. [ 2 ]  Progressively, on day 20, the ventral wall of the notochord dissolves, while communications are formed between the amniotic and yolk sac. [ 2 ]  One such connection is the Kovalevsky’s canal. From the 23rd to 25th day of gestation, the spinal cord develops except for its distal-most aspect where the notochord and neural tube are joined to form the caudal cell mass. [ 2 ]  The canal of Kovalevsky crosses the caudal cell mass, while endoderm located anteriorly to the cell mass develops into the  hindgut , various insults towards the cell mass and hindgut during the stage of development may lead to the development of caudal anomalies, one of which is caudal duplication syndrome. [ 2 ]


The incomplete regression of Kovalevsky’s canal may also lead to formations of fibrous bands joining the hindgut to the  spinal canal , [ 5 ]  possibly leading to the onset of diastemetaomyelia. [ 4 ]  These bands may divide the notochord, developing into duplications of the lower spine and spinal cord, the adjacent mesoderm is also divided, resulting in duplicates of GI and GU tracts. [ 4 ]  Subsequently, the duplications can also lead to the presence of a range of anomalies including  dorsal enteric fistulas , enteric cysts,  spina bifida , malformed or duplicated colon, bladder, sacrum, and lower spinal cord. [ 2 ] [ 12 ]


Moreover, a midline pelvic mass defect during gestation could be an obstacle to caudal migration of paramesonephric structures ( Müllerian duct ), which could lead to duplication of the genital tract. [ 2 ]  Whilst failures of migration or fusion of those structures is one of the more prevalent embryological theories for duplication of lower genitourinary organs such as the bladder. [ 2 ]  Intestinal duplications extending into the rectum or anus is often rare. [ 2 ] [ 6 ]  However, if the caudal cell mass is divided early, duplications of the distal bowel may still occur. [ 2 ]


In gastrointestinal abnormalities, a mechanism known as “caudal twinning” [ 3 ]   is proposed in which during the 23rd to 25th day of gestation, the intestinal tract is filled by rapid proliferation of endothelial cells, as the gut increases in size, vacuoles appear within the cell masses to constitute a single lumen. [ 2 ] [ 4 ]  However, in abnormal cases where a vacuole is pinched off, a second lumen is created. [ 4 ]  The second lumen is then proposed to magnify in size in proportion to the growth of the colon, effectively duplicating all caudal structures distal from the point of separation. [ 2 ] [ 10 ]


The condition can often be seen as malformations that can be diagnosed by a prenatal anomaly scan in the second trimester, while progressively detailed examinations can be conducted after the first day of life of the baby. [ 3 ]  If an abnormality is detected early on, psychological and surgical preparation may be required to resort to a  cesarean section  to prevent obstructed labour, in which medical paediatric and surgical care soon follows after delivery. [ 13 ] [ 14 ] [ 15 ]


Diagnosis during adulthood is extremely rare [ 2 ]  in cases where abnormalities are  asymptomatic  or are not visible upon physical inspection upon prenatal or birth inspections. [ 6 ]  Similarly to paediatric and prenatal diagnosis, an adulthood diagnosis can be made through various imaging modalities [ 4 ]  such as computed tomography (CT) scans to explicitly define the range of symptoms present in caudal duplication. [ 13 ]


Dipygus deformity is a severe and extreme type of caudal duplication that occurs at the caudal end of the body axis, where it duplicates completely. [ 16 ]


The rare, complex syndrome includes a wide spectrum of malformations ranging from partial or isolated to complete duplication of caudal organs in GI, GU, and neural systems. [ 13 ]  The syndrome may cause functional impairments such as an  imperforate anus  and hernia which may lead to death due to shock and organ failure and require prompt surgical intervention, [ 17 ]  but most presented symptoms are not life-threatening and duplicated organs are in fact functional in many cases. [ 2 ] [ 6 ]  For instance, patients with genital duplication are mostly expected to have normal menstruation, sexual intercourse, and even pregnancy, [ 18 ]  although their self-esteem and quality of life may be influenced. [ 5 ]  Since the clinical presentation of each patient and its complexity vary greatly, the management which usually includes surgery are carefully planned and individualised based on the extent of duplication and functionality of the involved organs. [ 4 ]


An extensive medical work-up is required primarily before prognosis to understand the anatomy of patients and to decide appropriate treatment. Imaging modalities such as  echocardiography ,  conventional X-ray ,  magnetic resonance imaging  (MRI),  ultrasonography ,  barium enema ,  computed tomography  (CT) scan, and  voiding cystourethrography  (VCU) can be used to examine anomalies in detail. [ 3 ] [ 4 ] [ 13 ]   Exploratory laparotomy  can also be conducted when needed. [ 7 ]  In most cases, surgical approach is utilised to excise or fuse the duplicated organs; [ 3 ] [ 7 ] [ 19 ]  however, surgical intervention is not a compulsory procedure for patients that do not exhibit functional deterioration and symptoms. [ 4 ]  Based on the work-up results, a multidisciplinary team consisting of a (paediatric) surgeon, a urologist, and a neurosurgeon plans individualised, staged correction. [ 20 ]


If a prenatal or after birth diagnosis is made, medical paediatric and surgery care are organised soon after delivery. [ 15 ]  Adults with the syndrome, however, usually do not require surgical treatment unless accompanied by symptoms or psychological issues. [ 4 ] [ 6 ]  Reconstructive surgeries are performed to resolve the issue of functional impairments such as obstruction of colon, anatomic anomalies that hinder movement or cause infertility, and to improve cosmetic appearances in the case of genital duplication. [ 4 ]


Treatments for colonic duplication varies from conservative management for asymptomatic cases to excision of duplicated colon to avoid potential issues such as colon structure and obstruction. [ 4 ] [ 7 ]  Resection is possible when each duplicated colon has a complete blood supply. If the duplicated colons share a wall, a septotomy can be performed to create a small hole to connect two colons. [ 4 ] [ 7 ]  In cases where rectum is also duplicated, either the rectums should be converted into one reservoir through septotomy followed by anorectoplasty or the duplicated colon and rectum should be removed and colostomies should be constructed. [ 4 ]  For patients with poor prognosis for bowel control, a  Malone procedure  can be utilised during the colostomy. [ 4 ]  Alternatively, in cases of renal duplication, the  Mitrofanoff procedure  is performed instead. [ 4 ]


Duplication of genital tract that does not involve functional impairment does not require surgical intervention; however, plastic surgery can be carried out to improve patients’ self-esteem and social status. [ 19 ]  For duplication of female genital tract, the septum between duplicated organs such as vagina, cervix, and vulva are resected to combine two duplicated organs into one or one duplicated organ could be detached and excised. [ 19 ]  For male patients, one duplicated genitalia can be removed, and duplicated scrotum and testis can be either combined or excised. [ 15 ]  The external genitalia of both male and female can be reconstructed by midline apposition of tissues. [ 19 ]  For duplication of urinary tract, bladders can be combined to form a single larger bladder without altering the duplicated ureters. [ 19 ]


In cases of spine duplication,  prophylactic  surgery can be done to remove one duplicated spine, although it depends on the severity of duplication. [ 21 ]  In cases of malformation of the neural cord such as  myelomeningocele  and tethered cord which accompanies severe symptoms, preserving neurological function is the utmost importance by closing myelomeningocele and detethering the neural cord. [ 4 ]  This is a highly complex procedure that requires extreme caution not to injure the rectum in which case can cause a cerebrospinal fluid infection. [ 4 ]  For duplication of lower limb which not only hinders patients’ gait but also is highly visible and may affect patients’ self-esteem, excision of the supernumerary, non-functional pair of limb is often carried out. [ 15 ]


Due to the spectrum of symptoms present within caudal duplication, there is no uniform surgical treatment in relieving symptoms. [ 20 ]  The type and severity of surgical intervention is often dependent upon the type and complexity of symptoms presented. [ 20 ]  Thus, the primary goal of surgical treatment for the syndrome is to relieve symptoms, not to restore normal anatomy, and hence, potentially life-threatening malformations are addressed first and often followed by other anatomic or aesthetic reconstructions in later stages. [ 4 ] [ 6 ]  After the medical treatment, the patients are periodically monitored. [ 19 ] [ 15 ]


Caudal duplication syndrome is a rare condition with only less than 100 patients in literature worldwide as of 2014 with only 2 patients diagnosed in adulthood. [ 6 ]  The prevalence of the syndrome is less than one per 100,000 births. [ 5 ]  The sex ratio of male to female patients is about 1:2, with no familial or racial predisposition being found. [ 20 ]


The first systematic review for caudal duplication symptoms was done and the term "caudal duplication syndrome" was first proposed in 1993. [ 2 ]  The term was coined to describe rare anomalies associated with complete or partial duplication of caudal structures resulted from insults during embryogenesis to distinguish symptoms of spinal duplication syndrome which only involves spinal duplicity, only when there is associated complete or partial duplicity of vascular structures and/or organs such as bladder and distal gastrointestinal tract the term caudal duplication syndrome can be used. [ 12 ]


However, recently in 2013, it was suggested that “duplication” is a misnomer based on an analysis of two cases and literature review in which researchers found “hemi” organs was “split” not duplicated, proposing caudal “split” syndrome may be a more appropriate title. [ 5 ]


Caudal regression syndrome , or  sacral agenesis  (or  hypoplasia  of the  sacrum ), is a rare birth defect. It is a  congenital disorder  in which the  fetal development  of the lower  spine —the  caudal  partition of the spine—is abnormal. [ 1 ]  It occurs at a rate of approximately one per 60,000 live births. [ 2 ]


Some babies are born with very small differences compared to typical development, and others have significant changes. Most grow up to be otherwise typical adults who have difficulty with walking and incontinence.


This condition exists in a variety of forms, ranging from partial absence of the  tail bone  regions of the spine to absence of the lower vertebrae, pelvis and parts of the thoracic and/or lumbar areas of the spine. In some cases, where only a small part of the spine is absent, there may be no outward sign of the condition. In cases where more substantial areas of the spine are absent, there may be fused, webbed or smaller lower extremities and paralysis. Bowel and bladder control is usually affected. [ citation needed ]


The condition arises from some factor or set of factors present during approximately the 3rd week to 7th week of fetal development. Formation of the sacrum/lower back and corresponding nervous system is usually nearing completion by the 4th week of development. Due to abnormal gastrulation, the mesoderm migration is disturbed. This disturbance results in symptoms varying from minor lesions of the lower vertebrae to more severe symptoms such as complete fusion of the lower limbs. While the exact cause is unknown, it has been speculated that the condition has a combination of environmental and genetic causes, and that various types of the condition may have differing causes. [ citation needed ]


Sacral agenesis syndrome (a type of caudal regression syndrome involving agenesis of the  lumbar spine , sacrum, and  coccyx , and hypoplasia of the lower extremities) is a well-established congenital anomaly associated with maternal  diabetes  mellitus. [ 3 ] [ 4 ]  Other causes are presumably involved, as demonstrated by the rare overall incidence of caudal regression syndrome (1:60,000) compared to diabetes; however, the condition does have a greatly increased incidence among infants born to mothers with diabetes, estimated at 1 in 350 newborns of mothers with diabetes. [ 2 ]


The dominant inherited sacral agenesis (also referred to as  Currarino syndrome ) is very often correlated with a  mutation  in the Hb9 (also called HlxB9) gene (shown by Sally Ann Lynch, 1995, Nature Genetics). [ citation needed ]


It was previously thought to be related to  sirenomelia  ("Mermaid syndrome") but has now been determined not to be related to this condition. [ 5 ]


There are four levels (or types) of malformation. The least severe indicates partial deformation (unilateral) of the sacrum. The second level indicates a bilateral (uniform) deformation. The most severe types involve a total absence of the sacrum. [ citation needed ]


Depending on the type of sacral agenesis, bowel or urinary bladder deficiencies may be present. A permanent  colostomy  may be necessary in the case of  imperforate anus . Incontinence may also require some type of continence control system (e.g., self-catheterization) to be utilized. The condition often impacts the formation of the knees, legs or feet that is sometimes addressed through surgery. For some with tightly webbed, bent knees or knees that are fused straight, disarticulation surgery at the knee may be a viable option to maximize mobility options. [ citation needed ]


Before more comprehensive medical treatment was available, full amputation of the legs at the hip was often performed. More recently, the amputation (actually a disarticulation because no cutting of the bone is involved) is done at the knee for those who have bent knee positions and webbing between thigh and calf to enable more ease of mobility and better seating. Some children with knee disarticulation use prosthetic legs to walk. Prosthetics for children without substantial hip and  trunk  control is usually abandoned in favor of faster and easier wheelchair mobility as the child's weight and age increase. Children may walk on their hands and generally are able to climb and move about to accomplish whatever they need and want to accomplish. Children more mildly affected may have normal gait and no need for assistive devices for walking. Others may walk with bracing or crutches. [ citation needed ]


There is typically no cognitive impairment associated with this disability. Adults with this disability live independently, attend college, and have careers in various fields. In 2012,  Spencer West , a man with sacral agenesis and both legs amputated, climbed  Mount Kilimanjaro  using only his hands. [ 6 ]  In 2021, athlete  Zion Clark  broke the Guinness World Record 20 m running on hands. [ 7 ]


Char syndrome  is an  autosomal dominant   congenital disease  caused by mutations in  TFAP2B gene  which affects the development of the bones of the face as well as the heart and limbs. [ 2 ] [ 3 ]  During  embryo development , TFAP2B regulates the production of the protein AP-2β, a  transcription factor  that is active in the  neural crest  and helps regulate genes that control  cell division  and  apoptosis . [ 4 ]  There are at least 10 mutations of this gene that have been identified in people presenting Char syndrome, [ 5 ] [ 6 ]  which alters specific regions of the gene preventing production of the transcription factor and disrupting normal development of embryo structures. People with this condition present a very distinct facial appearance with flattened cheek bones, flat and broad tip nose, shortened distance between the nose and upper lip, triangular-shaped mouth with tick lips and strabismus. It is also characterized by a  patent ductus arteriosus , which is the failure to close the ductus that connects the  aorta  and  pulmonary artery  during pre-birth life and may cause many symptoms including breathing issues and heart failure. Abnormalities of hand and finger development have also been reported in people with this condition, including short or absent fifth finger. Other abnormal findings include supernumerary nipples. [ 7 ]  These conditions often affect multiple members of a family and there are no reports of non-genetic factors that might be related with incidence of this syndrome. It was first described by Florence Char in 1978. [ 8 ]


Chromosome No. 1 Syndrome  is a genetic defect observed in  embryos  of newts from the  genus   Triturus . Approximately half of the eggs laid fail to develop, as their growth halts at a certain stage, leading to the death of the embryos. Surviving embryos always possess two distinct forms of chromosome 1, differing in length. However, having two short forms or two long forms invariably results in embryo death.


This phenomenon is explained by a past  chromosomal translocation  between what were once identical chromosomes in pair 1, or by these chromosomes historically functioning as sex chromosomes.


Newt development, as described by Manuela D'Amen's team using the  Triturus carnifex  complex as a model, starts with the  division  of the egg. This is followed by the  gastrulation  phase, which then leads to the  formation of the nervous system . [ 1 ]  Subsequently, the process progresses through two stages of  organogenesis . The first is known as the tailbud stage, while the second is the larval period. Alternatively, the development can be divided into 42 stages. [ 1 ]  Up to stages 21–22, the development of embryos across different newt species follows a similar pattern. However, differences become apparent during the tailbud and larval stages. [ 1 ]


Approximately one-quarter of  T. carnifex  eggs fail to reach the  blastula  stage and do not hatch. [ 1 ]


It has been observed that about half (from 38% to 62%) of  Triturus carnifex  larvae stop growing at the end of the tailbud stage (stages 26–30), resulting in their death. [ 1 ]  A similar effect was noted by Stanley Sessions and others in the  northern crested  and  marbled  newts, with the latter experiencing this earlier than the two species mentioned before. This phenomenon also occurs in  Triturus dobrogicus  and  Triturus karelinii . [ 2 ]  The death happens after several days of development. [ 3 ]  No such developmental disruptions are observed in other newt species. [ 2 ]  D'Amen's team showed that this process in  T. carnifex  is independent of both temperature and water  pH . [ 1 ]


Embryos that stop developing do not form a homogeneous group, but instead consist of two distinct  phenotypes , which occur with similar frequency. One of them, until the point of developmental arrest, is morphologically indistinguishable from normally developing embryos, [ 2 ]  up until stages 25–27, after which the growth rate slows down. This type is referred to as phenotype A [ 1 ]  or ST (slim-tailed). [ 2 ]


The second phenotype shows abnormalities even during the transition from  gastrula  to  neurula . It is characterized by a protruding  yolk plug [ 2 ]  and delayed head development, [ 1 ]  including the eyes, gills, mouth, and balance organ. [ 2 ]  Dorsal swelling appears, first observed by D'Amen. [ 1 ]  The tail region becomes swollen, and the  notochord  may be disrupted. [ 2 ]  D'Amen named this phenotype B, [ 1 ]  while Sessions' team called it FT (fat-tailed). [ 2 ]


These groups also differ in the quality of the flexion response. It proceeds normally in ST of the northern crested newts and  T. carnifex , but it does not occur in ST of marbled newts or in FT forms of these species. [ 2 ]


A common feature of both phenotypes is abnormal tail rounding development. [ 1 ]  In both groups, heart development is disrupted: although it appears morphologically normal, it sometimes does not beat at all, and in other cases, it beats weakly. The abnormalities are more pronounced in FT individuals. [ 2 ]  Additionally, after developmental arrest, regardless of the phenotype, the larvae survive for several more days. During this time, their bodies undergo slight changes. However, cells die, and tissues degenerate. Blisters form, some of which burst. The surrounding egg membrane loses its transparency and integrity, eventually releasing the embryo. [ 1 ]


The developmental disorder described is related to features of  chromosome 1 , the longest chromosome in the newt  karyotype , [ 1 ]  which has a characteristic large region of  heterochromatin  on its long arm containing ribosomal and satellite DNA. [ 2 ]  In the genus  Triturus , this chromosome shows heteromorphism, visible through  Giemsa staining  or in the case of  lampbrush chromosomes . There are two distinct forms of chromosome 1, [ 1 ]  named 1A and 1B, and this difference affects the long arm of the chromosome. The variation is most strongly expressed in the marbled newt. [ 1 ]  Callan and Lloyd first observed and described it in 1960 in the northern crested newt and later in the marbled newt. It was not found in the  alpine newt  ( Ichthyosaura alpestris ). [ 3 ]


Chromosome 1B is identified by two dark C-bands in the distal region of the lighter  euchromatin  at the end of the chromosome, visible in Giemsa staining. [ 2 ]  Chromosome 1A does not carry the characteristic bands of 1B, and if similar bands appear, they are located differently. [ 2 ]


In the past, in the  most recent common ancestor  of  Triturus , a  chromosomal translocation  occurred between the two chromosomes of the first pair during  mitosis  in the  germline cells . A portion of one chromosome was transferred to its  homolog , and vice versa. As a result, two chromosomes were formed, with part of the genetic material being  deleted  and part  duplicated . [ 2 ]  Chromosome 1A has a large duplication of regions labeled 6–8, accompanied by a small deletion of region 3. In contrast, chromosome 1B has a large deletion of regions 6–8 with a duplication of a small region 3 (such deletions in a  monozygotic  state would be lethal). In the form of lampbrush chromosomes, they create a different number of loops. [ 2 ]  The differences between chromosomes 1A and 1B are primarily in the described heterochromatin region, and are more pronounced in the marble newt (23%, while in  T. karelinii  it is 7%), which is linked to the earlier developmental arrest in this species. Furthermore, the pair of chromosomes with a larger deletion (1B1B) is associated with a more disturbed FT phenotype. [ 2 ]


The differences between the forms are linked to the inability to form  chiasmata  between the chromosomes. [ 1 ]  1A and 1B do not pair during the  chromosomal crossover . This allowed for the accumulation of additional changes in the examined heterochromatin region. As a result, this chromosome grew, making it the largest in the  Triturus  karyotype, although it contains roughly the same amount of euchromatin as the small chromosomes of the newts. [ 2 ]


Therefore, if, as postulated by Sessions, the translocation occurred in the early mitosis of germline cells, the defect was passed on to numerous  gametes  produced by this individual. [ 2 ]  Crossing with a normal individual resulted in the creation of hybrids containing chromosome 1 and either 1A or 1B. They must have survived. By crossing among themselves, they would produce offspring in which, for the first time, individuals with 1A1A, 1A1B, and 1B1B combinations would appear. [ 2 ]


In all adult individuals, heteromorphism of this chromosome is present; they always have chromosomes 1A1B, indicating that the existence of two forms is a necessary condition for development. The presence of both chromosomes is essential because they contain different elements of the original chromosome 1. [ 2 ]


All homomorphic embryos of  Triturus  regarding the short or long form of chromosome 1 die. [ 4 ]  The two groups of embryos with developmental arrest described above have either two short or two long copies of chromosome 1. [ 2 ]  It turns out that embryos with the 1B1B genotype have more defects (FT form), [ 1 ]  while 1A1A forms the ST population. [ 2 ]


The hypothesis of Sessions is supported by the viability of  Triturus  hybrids with related newt species, whose gametes supply missing chromosome regions to the zygotes. [ 2 ]   Triploid  hybrids of the marble and northern crested newts (such crosses also occur in nature, but in this case, individuals are formed as if from crosses of newts of the same species) also survive and thrive. This confirms that the cause of developmental arrest is not the presence of excess genetic material, but its deficiency. [ 2 ]


A similar disorder has been observed in  axolotl  mutants (c and p). By analogy with the axolotl mutation p, it is suggested that the disorder causing developmental arrest in newts may be due to abnormal development of the  endoderm . Its improper distribution in FT may be related to faulty closure of the  blastopore  and defective  epiboly . [ 2 ]  The first factor particularly affects the endoderm of the yolk sac, which then interacts abnormally with adjacent cells, causing swelling in the tail area. However, epiboly in ST proceeds normally, and the disorders in the  central nervous system  in both groups indicate broader abnormalities not limited to the endoderm. [ 2 ]


Wallace proposed that chromosome pair 1 was associated with  sex-determination system , creating a system of 1A1A/1A1B (comparable to the  XX/XY system  in humans). Individuals with the 1B1B genotype would be lethal. This idea was rejected because adult newts of both sexes have the 1A1B genotype. It was also unclear how a homogametic 1A1A sex chromosome would transform into a lethal form. [ 3 ]  It has since been excluded that chromosome 1 is currently involved in sex determination; in newts, a different chromosome pair (number 4) is responsible for sex determination. [ 2 ]  However, Christine Grossen's team proposes a different solution: they argue that the presence of non-pairing  autosomes  is not possible, and thus pair 1 must have served as  sex chromosomes  in the past, with pair 4 later taking over this role. They note that non-pairing regions and significant size differences between chromosomes are typical of sex chromosomes. To avoid the difficulties in Wallace's model, Grossen had to create a completely different one. [ 3 ]


They proposed that the function of the mammalian Y chromosome was originally carried by both 1A and 1B. They justified this by pointing out that non-recombining Y chromosomes naturally accumulate mutations, and that different  haplotypes  of Y occur in different populations. They further noted that in some species, YY individuals can be viable, suggesting recessive mutations accumulated in each haplotype. Finally, they mentioned the role of temperature in sex determination in some vertebrates. Higher temperatures masculinize the northern crested newt, while lower temperatures feminize it. [ 3 ]  Based on these facts, Grossen proposes the following scenario: in the original population, there were 2 haplotypes, labeled Y A  and Y B , each carrying different recessive lethal mutations. Then, due to climatic changes or an expansion of their range northward, the populations were exposed to cooler temperatures, which promoted the development of more females, including those with genotypes XY A  and XY B . These females would mate with males of the same genotype. Crosses between XY A  and XY B  would produce, among others, the genotypes Y A Y A  and Y B Y B . Both chromosomes would carry the same lethal mutation, leading to embryo death. [ 3 ]  In contrast, in the Y A Y B  system, the chromosomes would carry different recessive lethal mutations. Such an organism would develop normally. However, the fact that females were more frequent in such a population would reinforce the selection for mutations favoring masculinization. This mutation could have appeared on chromosome 4, forming a new pair of sex chromosomes. [ 3 ]


This trait has been recognized as one of the  synapomorphies  of the genus  Triturus  in its new understanding, [ 4 ]  referring to the  phylogenetic  line of the northern crested newt. This includes the species  Triturus carnifex ,  Triturus karelinii ,  Triturus dobrogicus ,  Triturus marmoratus , and  Triturus pygmaeus . [ 1 ]  Previously, these species were classified under the subgenus  Neotriton  within the genus  Triturus . It included the group of northern crested newts and the group of marbled newts. The presence of the same genetic defect is considered evidence of their close relationship – they together form a single  monophyletic  developmental line. This view has been supported by electrophoresis studies. [ 2 ]


This situation suggests that in the past, the ancestor of modern newts, which are affected by the defect, underwent unequal genetic material exchange between the two copies of chromosome 1. This line diverged between 12 and 10 million years ago. Sessions emphasizes its significant role in the evolution of the genus  Triturus  in its old understanding. A line was formed in which half of the offspring were unable to develop. Despite this, the genetic defect somehow became established, despite competition from other newts. [ 2 ]  This would lead to a decrease in  fitness , expressed for 1A by the formula 1-p and for 1B by 1-q, where p and q represent frequencies in the gametes. [ 3 ]  For this to happen, the defect must have arisen in a population with a small  effective size , where  heterozygotes  predominated. It could not be eliminated by intra-species selection because the defect affected all reproducing individuals equally. Perhaps the harmful effect of half of the eggs dying was balanced by the larger size of  Triturus  compared to other newts, which was associated with a higher number of eggs produced. In the marbled newt line, additional mutations occurred, expanding the heterochromatin area. [ 2 ]  Then, 10.4 million years ago, the  T. karelinii  line separated.  T. carnifex  and  T. macedonicus  diverged 9.3 million years ago, and the northern crested newt and  T. dobrogicus  diverged 8.8 million years ago. [ 5 ]


Cleft lip and/or palate  is a congenital abnormality that is seen frequently around the world. On average, about 1 in every 500-750 live births result in a cleft (Hardin-Jones, Karnell, & Peterson-Falzone, 2001). Furthermore, in the U.S., the  prevalence  for cleft lip with or without cleft palate (CL +/- P) is 2.2 to 11.7 per 10,000 births. Cleft palate alone (CP) results in a prevalence rate of 5.5 to 6.6 per 10,000 births (Forrester & Merz, 2004). Cleft of the lip, palate, or both is one of the most common congenital abnormalities and has a birth prevalence rate ranging from 1/1000 to 2.69/1000 amongst different parts of the world (McLeod, Saeed, & Arana- Urioste, 2004).


A look into the prevalence rates of different cultures in the U.S. when compared to country of origin begins with  Africans  and  African Americans . One per 2500 African Americans are born with a cleft (Suleiman, Hamzah, Abusalab, & Samaan, 2005). African Americans have a lower prevalence rate of CL +/- P when compared to Caucasians. A prevalence rate of 0.61 per 1,000 and 1.05 per 1,000 live births respectively was reported by Croen, Shaw, Wasserman and Tolarova (1998). In  Malawi  there is a reported low prevalence rate for cleft lip and/or palate, 0.7 per 1,000 live births (Chisi, Igbibi, & Msamati, 2000). Suleiman et al. (2005) found that the prevalence rate of clefting among a group of Sudanese hospital new-borns in the city of Khartoum is 0.9 per 1,000 live births.


Mestizo Americans are people of mixed European and Native American origins from  Mexico ,  Central America  and  South America , and the  Caribbean  (Meyerson, 1990). The prevalence of Mestizo Americans is lower than that of Caucasians and  Native Americans , yet it is still higher than African Americans (Croen et al., 1998). Mestizo have a prevalence of clefting of 9.7 per 10,000 live births (Kirby, Petrini & Alter, 2000). In Sucre,  Bolivia  the prevalence rate of CL +/- P is 1.23 per 1,000 live births (McLeod et al., 2004).


Al Omari & Al-Omari (2004) reported that no study exists that has specifically looked at clefting among  Jordanians  prior to their investigation. Al Omari et al. (2004) examined the prevalence of clefting over an eleven-year period in Jordan and found an overall rate of 1.39 per 1,000 live births for CL +/- P. This was found to be similar with the prior studies that have examined clefting in other  Arab  populations. A further study by Aqrabawi HE (2008) stated that the total number of liveborn infants was 25 440, 60 of whom (2.4/1000) had facial clefts: 20 (33%) with cleft lip, 15 (25%) with cleft palate and 25 (42%) with both


Hawaii  is a U.S. state which has an extremely diverse population consisting of 73% people of  Asian  and  Pacific Islander  descent. Forrester & Merz (2004) found that the prevalence rates of CL +/- P per 10,000 live births in Hawaii were: 10 in Caucasians, 16 in people of Far East Asian descent, 11 in people of Pacific Islander descent, and 14.5 in people of  Filipino  descent.


When looking at the countries of origin, a higher rate was seen for Asians, specifically in  Pakistan , with the prevalence rate being 1.91 per 1,000 live births (Elahi, Jackson, Elahi, Khan, Mubarak, Tariq, & Mitra, 2004). Similarly, C. Oh, S. Kim, W. Kim, & J. Kim (2002) found a similar prevalence rate of 1.81 per 1,000 births in the  Republic of Korea . Valid prevalence rates in the native countries of the  Philippines  and Pacific Islands could not be reported.


Clitoridectomy  or  clitorectomy  is the  surgical  removal, reduction, or partial removal of the  clitoris . [ 1 ]  It is rarely used as a therapeutic medical procedure, such as when  cancer  has developed in or spread to the clitoris. Commonly, non-medical removal of the clitoris is performed during  female genital mutilation . [ 2 ]


A clitoridectomy is often done to remove  malignancy  or  necrosis  of the clitoris. This is sometimes done along with a radical complete  vulvectomy . Surgery may also become necessary due to therapeutic  radiation treatments  to the pelvic area. [ 3 ]


Removal of the clitoris may be due to malignancy or trauma. [ 3 ] [ 4 ]


Female infants born with a  46,XX  genotype but have a clitoris size affected by  congenital adrenal hyperplasia  and are treated surgically with  vaginoplasty  that often reduces the size of the clitoris without its total removal. The atypical size of the clitoris is due to an endocrine imbalance in utero. [ 1 ] [ 5 ]  Other reasons for the surgery include issues involving  microphallism  and those who have  Müllerian agenesis . Treatments on children raise human rights concerns. [ 6 ]


Clitoridectomy surgical techniques are used to remove an invasive malignancy that extends to the clitoris. Standard surgical procedures are followed in these cases. This includes evaluation and  biopsy . Other factors that will affect the technique selected are age, other existing medical conditions, and obesity. Other considerations are the probability of extended hospital care and the development of infection at the surgical site. [ 3 ]


The surgery proceeds with the use of  general anesthesia , and prior to the vulvectomy/clitoridectomy an inguinal  lymphadenectomy  is first done. The extent of the surgical site extends 1 to 2 cm (0.39 to 0.79 in) beyond the boundaries of malignancy. Superficial  lymph nodes  may also need to be removed. If the malignancy is present in any  muscles  in the region, then the affected muscle tissue is also removed. In some cases, the surgeon is able to preserve the clitoris despite extensive malignancy. The cancerous tissue is removed and the incision is closed. [ 3 ]


Post-operative care may employ the use of suction drainage to allow the deeper tissues to heal toward the surface. Follow-up after surgery includes the stripping of the drainage device to prevent blockage. A typical hospital stay can last up to two weeks. The site of the surgery is left unbandaged to allow for frequent examination. [ 3 ]


Complications can include the development of  lymphedema ; not removing the saphenous vein during the surgery can help prevent this. In some instances, the buildup of fluid can be reduced through methods such as foot elevation,  diuretic  medication, and wearing  compression stockings . [ 3 ]


In a clitoridectomy for infants with a  clitoromegaly , the clitoris is often reduced instead of removed. The surgeon cuts the shaft of the elongated phallus and sews the  glans  and preserved nerves back onto the stump. In a less common surgery called clitoral recession, the surgeon hides the clitoral shaft under a fold of skin so only the glans remains visible. [ 7 ]


While much  feminist  scholarship has described clitoridectomy as a practice aimed at controlling women's sexuality, the historic emergence of the practice in ancient European and Middle Eastern cultures may also have derived from ideas about what a normal female genitalia should look like and the policing of boundaries between the sexes. [ 8 ]


In the seventeenth century, anatomists remained divided on whether a clitoris was a normal female organ, with some arguing that it was an abnormality in female development and, if large enough to be visible, it should always be removed at birth. [ 9 ]  In the 19th century, a clitoridectomy was thought by some to curb  female masturbation ; until the late 19th century, masturbation  was thought by many  to be unhealthy or immoral. [ 10 ]   Isaac Baker Brown  (1812–1873), an English gynaecologist who was president of the  Medical Society of London   believed that the "unnatural irritation" of the clitoris caused  epilepsy ,  hysteria , and  mania , and he worked "to remove [it] whenever he had the opportunity of doing so", according to his obituary in the  Medical Times and Gazette .  Peter Lewis Allen  writes that Brown's views caused outrage, and he died penniless after being expelled from the  Obstetrical Society . [ 11 ]


Occasionally, in American and English medicine of the nineteenth century,  circumcision  was done as a cure for insanity. Some believed that  mental and emotional disorders  were related to female reproductive organs and that removing the clitoris would cure the neurosis. This treatment was discontinued in 1867. [ 12 ]


Aesthetics  may determine clitoral norms. A lack of ambiguity of the genitalia is seen as necessary in the  assignment of a sex  to infants and therefore whether a child's genitalia is normal, but what is considered ambiguous or normal can vary from person to person. [ 13 ]


Sexual behavior is another reason for clitoridectomies. Author Sarah Rodriguez stated that the history of medical textbooks has indirectly created accepted ideas about the female body. Medical and gynecological textbooks are also at fault in the way that the clitoris is described in comparison to a male's  penis . The importance and originality of a female's clitoris is underscored because it is seen as "a less significant organ, since anatomy texts compared the penis and the clitoris in only one direction." Rodriguez said that a male's penis created the framework of the sexual organ. [ 14 ]


Not all historical examples of clitoral surgeries should be assumed to be clitoridectomy (removal of the clitoris). In the nineteen thirties, the French psychoanalyst  Marie Bonaparte  studied African clitoral surgical practices and showed that these often involved removal of the clitoral hood, not the clitoris. She also had a surgery done to her own clitoris by the Viennese surgeon Dr Halban, which entailed cutting the  suspensory ligament of the clitoris  to permit it to sit closer to her vaginal opening. These sorts of clitoral surgeries, contrary to reducing women's sexual pleasure, actually appear aimed at making coitus more pleasurable for women, though it is unclear if that is ever their actual outcome. [ 15 ]


Clitoridectomies are the most common form of female genital mutilation. The  World Health Organization  (WHO) estimates that clitoridectomies have been performed on 200 million girls and women that are currently alive. The regions that most clitoridectomies take place are Asia, the Middle East and west, north and east Africa. The practice also exists in migrants originating from these regions. Most of the surgeries are for cultural or religious reasons. [ 16 ]


Clitoridectomy of people with conditions such as  congenital adrenal hyperplasia  that cause a clitoromegaly is controversial when it takes place during childhood or under duress. Many women who were exposed to such treatment have reported loss of physical sensation in the affected area, and loss of  autonomy . [ 17 ] [ 18 ]  In recent years, multiple human rights institutions have criticized early surgical management of such characteristics. [ 19 ] [ 20 ] [ 21 ]


In 2013, it was disclosed in a medical journal that four unnamed elite female athletes from developing countries were subjected to gonadectomies and partial clitoridectomies after  testosterone testing  revealed that they had an  intersex  variation or disorder of sex development. [ 22 ] [ 23 ]  In April 2016, the  United Nations Special Rapporteur  on health, Dainius Pūras, condemned this treatment as a form of genital mutilation "in the absence of symptoms or health issues warranting those procedures." [ 24 ]


Congenital afibrinogenemia  is a rare, genetically inherited blood  fibrinogen disorder  in which the  blood  does not clot normally due to the lack of  fibrinogen , a blood  protein  necessary for  coagulation . [ 1 ]  This disorder is  autosomal recessive , meaning that two unaffected parents can have a child with the disorder. [ 2 ]  The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding. [ 3 ]


As this is a disorder that is present in an individual from birth, there are no warning signs to look for. The first symptom usually seen is  hemorrhage  from the umbilical cord that is difficult to stop. [ 2 ]


Other symptoms include: [ 4 ]


A missense or nonsense mutation to the genes that code for the fibrinogen protein are affected. Usually the mutation leads to an early stop in the production of the protein. [ 3 ]  Due to the problem being genetically based, there is no way to prevent the disease. Individuals can get  genetic testing  done to see if they are a carrier of the trait, and if so may choose to complete genetic counseling to better understand the disorder and help manage family planning. Parents can choose to do prenatal genetic testing for the disorder to determine if their child will have the disease. [ 6 ]


Individuals with the disorder have a mutation to their fibrinogen gene that prevents the formation of the protein. [ 3 ]  In normal conditions, fibrinogen is converted to  fibrin  when it is cleaved by the enzyme  thrombin  in the blood. The newly formed fibrin forms a fiber-rich network that helps trap red blood cells to start the coagulation process and form a clot. [ 7 ]


When a problem of fibrinogen is suspected, the following tests can be ordered:


Blood fibrinogen levels of less than 0.1 g/L and prolonged bleeding test times are indicators of an individual having afibrinogenemia. [ 2 ]


A suspicion of congenital afibrinogenemia may appear on a  platelet aggregation function  test.


The most common treatment is fibrinogen replacement therapy, including  cryoprecipitate ,  blood plasma , and fibrinogen concentration transfusions to help with bleeding episodes or prior to surgery. [ 11 ]  Although some thrombotic complications have been reported following replacement therapy, transfusions of fibrinogen concentrate are widely considered to be the most beneficial.  Fibrinogen concentrate is pure, contains a known quantity of fibrinogen, is virally inactivated, and is transfused in small amounts. [ 12 ]  There is a lower chance of allergic reaction in response to transfusion. Alternatively, cryoprecipitate contains other coagulation factors, factors VIII, XIII, and von Willebrand factor. [ 12 ]  There are no known cures or forms of holistic care to date. Most complications arise from the symptoms of the disorder. [ 5 ]


As there is not much data out on the life expectancy of an individual with afibrinogenemia, it is difficult to determine the average lifespan. However, the leading cause of death thus far is linked to CNS hemorrhage and postoperative bleeding. [ 5 ]


It was first described in 1920 by German doctors, Fritz Rabe and Eugene Salomon, studying a bleeding disorder presenting itself in a child from birth. [ 13 ]  This disorder may also be simply called afibrinogenemia or familial afibrinogenemia. [ 4 ]  About 1 in 1 million individuals are diagnosed with the disease; typically at birth. [ 14 ]  Both males and females seem to be affected equally, [ 2 ]  but it has a higher occurrence in regions where  consanguinity  is prevalent. [ 4 ]


Currently research is based in pharmacological treatments. [ 15 ]  A case from 2015 was seen in which congenital afibrinogenemia was resolved in a patient after receiving a liver transplant. [ 16 ]


Congenital athymia  is an extremely rare disorder marked by the absence of the  thymus  at birth. [ 1 ]   T cell  maturation and selection depend on the  thymus , and newborns born without a  thymus  experience severe  immunodeficiency . [ 2 ]  A significant  T cell deficiency , recurrent infections, susceptibility to  opportunistic infections , and a tendency to develop autologous  graft-versus-host disease  (GVHD) or, in the case of complete  DiGeorge syndrome , a "atypical" phenotype are characteristics of congenital athymia. [ 3 ] [ 4 ]


Congenital athymia's clinical symptoms are directly related to the thymus's absence and its incapacity to generate  T cells  with the necessary immune capabilities. An increased vulnerability to bacterial, viral, and fungal infections results from  T-cell   immunodeficiency . [ 1 ]


These patients have an especially high incidence of  pneumonias .  M. bovis  and the  respiratory syncytial virus  have been linked to additional cases of severe  pulmonary infections . This group is also prone to  gastrointestinal infections , such as those caused by the  rotavirus ,  norovirus ,  enterovirus ,  M. bovis , and  C. difficile  viruses.  Diarrhea ,  malabsorption , and  failure to thrive  can result from these infections. Although gastrointestinal and lung infections are the most frequently reported infection types, congenital athymia patients can present with a wide range of other infection types. There have been reports of infections of the head, ears, nose, and throat, including  meningitis ,  sinusitis ,  mastoiditis , and  thrush , as well as infections of the  urinary tract  caused by  K. pnuemoniae ,  E. faecium , and  echovirus . [ 5 ] [ 6 ] [ 7 ]


T cells  may expand extrathymic oligoclonally in congenital athymia. These cells can infiltrate organs and result in autologous  graft-versus-host disease , but they confer little to no protective  immunity . Individuals who have an expansion of oligoclonal  T cells  usually have an  eczematous  rash and accompanying  lymphadenopathy .  T cell  infiltration can result in  enteropathy  and  transaminitis  in the  gastrointestinal tract . [ 8 ]


Congenital athymia patients also have other autoimmune-mediated manifestations, such as  autoimmune thyroiditis ,  hypothyroidism , and Coombs-positive  hemolytic anemia . [ 7 ] [ 6 ] [ 5 ]


Congenital athymia is linked to a number of  genetic disorders , congenital syndromes, and environmental variables. Genetic abnormalities that are either (1) specific to thymic development or (2) related to the development of the midline region as a whole can cause congenital athymia. [ 1 ]


Congenital athymia is linked to multiple environmental etiologies. Affected fetal thymus size and other congenital anomalies like  renal agenesis  and  butterfly vertebrae  are linked to  diabetic embryopathy . [ 9 ]  It has been shown that babies of diabetic mothers have thymic aplasia. [ 10 ]   Retinoic acid  exposure during fetal development is also linked to phenotypes associated with  DiGeorge syndrome , such as hypoplasia and thymic developmental abnormalities such as aplasia and ectopia. [ 11 ]


The most well-known gene associated with thymic development is Forkhead Box N1 ( FOXN1 ). As a member of the transcription factor family known as the forkhead box gene family,  FOXN1  plays a role in the growth and differentiation of skin  epithelial cells  as well as the development, differentiation, and maintenance of  thymic epithelial cells  during embryonic and postnatal life. [ 12 ] [ 13 ] [ 14 ]


The  transcription factors  known as the paired box family, which control tissue differentiation, includes Paired Box 1 ( PAX1 ). [ 15 ]  Numerous studies have reported on patients with autosomal recessive  otofaciocervical syndrome  type 2 (OTFCS2) and mutations in  PAX1 . Because of altered thymus development, OTFCS2 is associated with a syndromic form of  SCID . [ 16 ] [ 17 ]


The two most common genetic syndromes linked to thymus development defects are  22q11.2 deletion syndrome  and  CHARGE syndrome . Patients with these syndromes exhibit a variety of symptoms because the genes  TBX1  and  CHD7 , associated with these disorders, play a role in the development of the entire midline region. [ 1 ]  Additional genes that may be involved in healthy thymus development are  FOXI3  and  TBX2 . [ 18 ] [ 19 ]


In October 2021, the thymus tissue product  Rethymic  was approved by U.S.  Food and Drug Administration  (FDA) as a  medical therapy  for the treatment of children with congenital athymia. [ 20 ]  It takes six months or longer to reconstitute the immune function in treated children. [ 20 ]


Congenital fiber type disproportion  ( CFTD ) is an inherited form of  myopathy  with small  type 1 muscle fibers  that may occur in a number of  neurological disorders . [ 3 ]   It has a relatively good outcome and follows a stable course. [ 4 ]   While the exact genetics is unclear, there is an association with mutations in the genes  TPM3 ,  ACTA1  and  SELENON . [ 5 ]   It is a rare condition. [ 6 ]


Congenital fiber-type disproportion can cause  contractures  as well as  lordosis  or  scoliosis . Approximately 30% of people with this disorder have mild to severe  respiratory issues  due to  weakness  of breathing muscles. Some people with these breathing issues need noninvasive  mechanical ventilation  at night and on occasion during the day. Due to throat muscle weakness, approximately 30% of those affected have  difficulty swallowing .  Dilated cardiomyopathy  is a rare complication of this condition. [ 2 ]


Other symptoms include congenital nonprogressive  hypotonia  and  weakness ,  kyphoscoliosis ,  high-arched palate ,  dislocated hips ,  short stature , and feet deformities. [ 1 ]


A positive family history has been reported in approximately 40% of cases, however, the inheritance pattern remains unknown. Both  autosomal recessive  and  autosomal dominant  inheritance patterns have been proposed. [ 7 ]  Some CFTD children appear to "grow out" of their  hypotonia  and  weakness  during childhood, and this can often be accompanied by a normalization of type 1 fiber size. [ 3 ]


According to the current literature, patients are most likely to carry mutations in  TPM3 ,  RYR1 ,  ACTA1 , and possibly  TPM2  and  SEPN1  in that order. Nearly every patient with known genetic causes have at least 40% fiber size disproportion. [ 8 ]   TPM3  mutation is the most prevalent cause of CFTD reported so far. [ 5 ]


To be diagnosed with CFTD, the main diagnostic abnormality must be a disproportion in fiber sizes, and the diagnosis is only appropriate after every other type of  congenital myopathy  has been ruled out. Before CFTD is diagnosed, a number of other  neuromuscular  (and systemic) disorders must be taken into account and ruled out as possible causes of mild cases of fiber size disproportion (FSD). These factors make CFTD a diagnosis of exclusion. [ 8 ]


A consistent difference in size between type 1 fibers, which are small in comparison to type 2 fibers, and type 2 fibers on  muscle biopsy  is the defining feature of CFTD, but only when it is the primary diagnostic abnormality. [ 8 ]  The best threshold for the degree of fiber size disproportion required to diagnose CFTD is still being debated, but it is generally agreed that it should be greater than 12%. [ 5 ]


Similar to other types of  congenital myopathy , there is currently no known treatment that can strengthen muscles or stop the natural progression of  muscle weakness . Nonetheless, much can be done to help people with CFTD maintain their health and well-being. [ 8 ]


Patients who experience nocturnal  hypoventilation  in childhood or adulthood nearly always react favorably to noninvasive nocturnal ventilation. [ 5 ]


To ensure proper nutrition, some patients with severe  dysphagia  and generalized  weakness  need to be fed through a  gastrostomy tube . [ 9 ]


Patients will occasionally develop severe  scoliosis  that requires surgical correction, most commonly in connection with mutations in  RYR1  and  TPM3 . [ 5 ]


Patients with CFTD may develop  contractures  of the  Achilles tendons  as a result of  RYR1  and  TPM3  mutations; in these cases, surgical tendon lengthening may be necessary.  Physiotherapy  to maintain ankle and other joint range of motion is frequently beneficial. [ 8 ]


Brooke coined the term congenital fiber type disproportion (CFTD) in 1971 to describe children whose  biopsies  revealed an abnormal size disparity between type 1 and type 2 fibers in the absence of any other obvious histologic abnormalities. [ 1 ]


Congenital hypofibrinogenemia  is a rare disorder in which one of the three genes responsible for producing  fibrinogen , a critical  blood clotting factor , is unable to make a functional fibrinogen  glycoprotein  because of an inherited  mutation . In consequence, liver cells, the normal site of fibrinogen production, make small amounts of this critical  coagulation  protein, blood levels of fibrinogen are low, and individuals with the disorder may develop a  coagulopathy , i.e. a  diathesis  or propensity to experience episodes of abnormal bleeding. However, individuals with congenital hypofibrinogenemia may also have episodes of abnormal blood clot formation, i.e.  thrombosis . This seemingly paradoxical propensity to develop thrombosis in a disorder causing a decrease in a critical protein for blood clotting may be due to the function of  fibrin  (the split product of fibrinogen that is the basis for forming blood clots) to promote the  lysis  or disintegration of blood clots. Lower levels of fibrin may reduce the lysis of early fibrin strand depositions and thereby allow these depositions to develop into clots. [ 1 ]


Congenital hypofibrinogenemia must be distinguished from:  a)   congenital afibrinogenemia , a rare disorder in which blood fibrinogen levels are either exceedingly low or undetectable due to mutations in both fibrinogen genes;  b)   congenital hypodysfibrinogenemia , a rare disorder in which one or more genetic mutations cause low levels of blood fibrinogen, at least some of which is dysfunctional and thereby contributes to excessive bleeding; and  c)  acquired hypofibrinogenemia, a non-hereditary disorder in which blood fibrinogen levels are low because of e.g. severe liver disease or because of excessive fibrinogen consumption resulting from, e.g.  disseminated intravascular coagulation . [ 1 ] [ 2 ]


Certain gene mutations causing congenital hypofibrinogenemia disrupt the ability of liver cells to secrete fibrinogen. In these instances, the un-mutated gene maintains blood fibrinogen at reduce levels but the mutated gene produces a fibrinogen that accumulates in liver cells sometimes to such extents that it becomes toxic. In the latter cases, liver disease may ensue in a syndrome termed  fibrinogen storage disease. [ 3 ]


Individuals with congenital hypofibringenemia often lack any symptoms are detected by routine lab testing of fibrinogen or when tested for it because close relatives have symptomatic hypofibrinogenemia. Indeed, studies indicate that, among family members with the identical congenital hypofibrinogenemia mutation, some never exhibit symptoms and those that are symptomatic develop symptoms only as adults. [ 1 ]


Individuals with this disorder are usually less symptomatic than patients with other  fibrinogen disorders  because their fibrinogen levels are generally sufficient to prevent spontaneous bleeding. Those with particularly low blood fibrinogen levels (<0.5 gram/liter) may develop serious bleeding spontaneously and many with the disorder do so following trauma or surgery. Depending on their fibrinogen levels, women with the disorder may also bleed excessively during delivery and the  postpartum  period; in rare cases, they may have an increased risk of suffering  miscarriages . [ 1 ] [ 4 ] [ 5 ]  Individuals with the disorder also experience thrombotic events which may include blockage of large arteries in relatively young patients who have high levels of  cardiovascular risk factors . The thrombi which form in these individuals are unstable, tend to  embolize , and may therefore lead to thromboembolic events such as  pulmonary embolism . Both bleeding and thrombotic events can occur at separate times or even concurrently in the same individual with the disorder. [ 1 ]


All individuals with mutations causing fibrinogen storage disease have low blood fibrinogen levels but usually lack severe bleeding episodes, thrombotic episodes or liver disease. Individuals that do have fibrinogen storage disease often come to attention either because they have close relatives with the disease, are found to be hypofibrinogenemic during routing testing, or exhibit clinical (e.g.  jaundice ) or laboratory (e.g. elevated blood levels of liver enzymes) evidence of liver disease. Unlike other forms of congenital hypofibrinogenemia, a relatively high percentage of individuals with fibrinogen storage disease have been diagnosed in children of very young age. [ 3 ] [ 6 ] [ 7 ]


Fibrinogen is made and secreted into the blood by liver  hepatocytes . The final secreted protein is composed of two  trimers  each of which is composed of three polypeptide chains,  Aα  (also termed α) encoded by the  FGA  gene,  Bβ  (also termed β) encoded by the  FGB  gene, and γ encoded by the  FGG  gene. All three genes are located on the long or "p" arm of human chromosome 4 (at  positions  4q31.3, 4q31.3, and 4q32.1, respectively). [ 8 ] [ 9 ]  The genes are ordered  FGB, FGA,  and  FGG  and are  transcribed  into  messenger RNA  in tight synchrony. [ 6 ]  The messenger RNAs associate with the  endoplasmic reticulum ,  translated  into polypeptides, and enter the endoplasmic reticulum where they assembled together. The assembled protein is passes to the  Golgi apparatus  where it is  glycosylated ,  hydroxylated ,  sulfated , and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood. Congenital hypofibrinogenemia results from inherited mutations in one of the three fibrinogen chains that results in the disruption of fibrinogen synthesis, assembly, stability, processing through the endoplasmic reticulum-Golgi apparatus pathway, and/or secretion into the blood. [ 3 ] [ 6 ] [ 10 ]


There are >25 fibrinogen mutations that have been associated with hypofibrinogenemia. The following Table lists examples of those mutations which cause hypofibrinogenemia that is not associated with liver injury. The Table gives:  a)  each mutated protein's trivial name;  b)  the gene mutated (i.e.  FGA, FGB,  or  FGG ), its mutation site (i.e. numbered nucleotide in the gene beginning with the initial nucleotide base at the (start codon) of  genomic DNA  (as indicated by the "g." notation), and name of the nucleotides (i.e.  C ,  T ,  A ,  G ) at these sites before>after the mutation; and  c)  the name of the altered fibrinogen peptide (Aα, Bβ, or λ), the numbered position(s) of the amino acid changed by the mutation in the circulating peptide of the mutated fibrinogen, and the identity of the amino acids before-after the mutation using  standard three letter abbreviations . [ 3 ]  In the Table, fs indicates a mutation that causes a  Translational frameshift  and consequently a premature  stop codon  (designated by "X") mutation and translation of a shortened fibrinogen chain, del is a deletion, and ins is an insertion. [ citation needed ]


As of 2016, there have been six mutations discovered to be associated with the accumulation of the mutated fibrinogen in the endoplasmic reticulum and consequential development of liver injury that may lead to  liver cirrhosis , i.e. fibrinogen storage disease. Other fibrinogen mutations have also led to their accumulation in the endoplasmic reticulum but have not been associated with liver injury perhaps because these fibrinogens are less toxic to the liver than those that cause liver injury. The following Table lists these 6 mutations. Note that all of these 6 mutations occur in the  FGG  gene, that all the mutations are  missense mutations  except for the deletion mutation of fibrinogen Anger, and that the Table reports the gene mutation site as found in  cloned  (as notated by "c.") rather than genomic DNA. Fibrinogen Aguadilla is the most common mutation known to cause fibrinogen storage disease. [ 1 ] [ 3 ] [ 7 ]  The abbreviations in this Table are defined in the previous Table.


The diagnosis of hypofibrinogenemia is indicated in individuals who have low levels (<1.5 gram/liter) of plasma fibrinogen as determined by both immunological (e.g.  immunoelectrophoresis  and (i.e. able to be clotted) methods. The ratio of immunological to functional fibrinogen masses should be ~1.0 as assayed with  partial thromboplastin time ,  activated partial thromboplastin time ,  thrombin time , and  reptilase time  tests. [ 8 ]  These tests are used to distinguish hypofibrinogenemia from hypodysfibrinogenemia, a typically more severe disorder in which plasma fibrinogen levels are low and this fibrinogen includes at least in part dysfunctional fibrinogen. Immunological/functional fibrinogen ratios for the plasma of individuals with hypodysfibrinogenemia for all the cited tests are usually <0.7. Where available, further analyses are recommended; these include analyses of the fibrinogen genes and protein chains for mutations and specialized studies of individuals in vitro induced blood clots for stability and susceptibility to lyses. [ 11 ]


The diagnosis of fibrin storage disease requires liver biopsy and the finding of immunologically detectable fibrinogen  inclusion bodies  in hepatocytes. [ 3 ]


Recommended treatment of asymptomatic congenital hypofibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as indicated by the personal history of the affected individual and family members. Where possible, determination of the exact mutation causing the disorder and the propensity of this mutation type to develop these complications may be helpful. [ 11 ]  Individuals with fibrinogen levels >1.0 gram/liter typically do not develop bleeding or thrombosis episodes. Individuals with fibrinogen levels of 0.5-1.0 grams/liter require  fibrinogen supplementation preferably with a plasma-derived fibrinogen concentrate to maintain fibrinogen levels of >1 gram/liter prior to major surgery. Individuals with fibrinogen levels of <0.5 gram/liter require fibrinogen supplementation to maintain fibrinogen levels of  a)  >1 to 2 gram/liter at the end of pregnancy and during the postpartum period;  b)  > 1 gram/liter prior to major surgery;  c)  > 0.5 to 1 gram/liter during the first two trimesters of pregnancy; and  d)  >0.5 gram/liter prior to minor surgery.  Tranexamic acid  may be used in place of fibrinogen supplementation as prophylactic treatment prior to minor surgery and to treat minor bleeding episodes. [ 11 ]


Individuals with hypofibrinogenemia who have a history of excessive bleeding should be treated at a center specialized in treating  hemophilia  and avoid all  medications  that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or, if unavailable infusion of  fresh frozen plasma  and/or  cryoprecipitate  (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. [ 11 ]


Individuals with hypofibrinogenemia who experience episodic thrombosis should also be treated at a center specialized in treating  hemophilia . Standard recommendations for these individuals are that they use  antithrombotic  agents and be instructed on antithrombotic behavioral methods in high risk situations (e.g. long car rides and air flights). Acute venous thrombosis episodes should be treated with  low molecular weight heparin  for a time that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended. [ 11 ]


There are too few cases of fibrinogen storage disease to establish optimal treatments for the liver diseases. Management of the disorder has been based on general recommendations for patients with  liver disease , particularly  Alpha 1 antitrypsin deficiency -associated liver disease. In the latter disease,  autophagy , the pathway that cells use to dispose of dysfunctional or excessively stored components including proteins, has been targeted using autophagy-enhancing drugs, e.g.  carbamazepine ,  vitamin E , and  ursodeoxycholic acid . These drugs have been tested in individual patients with fibrin storage disease with some success in reducing evidence of liver injure, i.e. reduction in blood liver enzyme levels. These and other autophagy-enhancing drugs are suggested to be further studied in fibrinogen storage disease. [ 3 ]


Congenital iodine deficiency syndrome  ( CIDS ), also called  cretinism , [ 2 ]  is a medical condition present at birth marked by impaired physical and mental development, due to insufficient  thyroid hormone production  ( hypothyroidism ) often caused by insufficient dietary  iodine  during pregnancy. It is one cause of underactive thyroid function at birth, called  congenital hypothyroidism . [ 3 ]  If untreated, it results in impairment of both physical and mental development. Symptoms may include:  goiter , poor length growth in infants, reduced adult stature, thickened skin, hair loss, enlarged tongue, a protruding abdomen, delayed  bone maturation  and  puberty  in children,  mental deterioration ,  neurological impairment , impeded  ovulation , and  infertility  in adults. [ 4 ]


In developed countries,  thyroid function testing  of newborns has assured that in those affected, treatment with the synthetic thyroid hormone  thyroxine  is begun promptly. This screening and treatment successfully  cures the disease . [ 5 ]


Iodine deficiency causes gradual enlargement of the thyroid gland, referred to as a goiter. Poor length growth is apparent as early as the first year of life. Adult stature without treatment ranges from 100 to 160 cm (3 ft 3 in to 5 ft 3 in), depending on severity, sex, and other genetic factors. Other signs include thickened skin, hair loss, enlarged tongue, and a protruding abdomen. [ 6 ]  In children,  bone maturation  and  puberty  are severely delayed. In adults,  ovulation  is impeded and  infertility  is common. [ 7 ] [ 8 ]


Mental deterioration is common. Neurological impairment may be mild, with reduced  muscle tone  and  motor coordination , or so severe that the person cannot stand or walk. Cognitive impairment may also range from mild to so severe that the person is  nonverbal  and dependent on others for basic care. Thought and reflexes are slower. [ 9 ] [ 10 ]


Around the world, the most common cause of congenital iodine deficiency syndrome (endemic cretinism) [ 1 ]  is dietary  iodine deficiency .


Iodine  is an essential trace element, necessary for the synthesis of thyroid hormones. Iodine deficiency is the most common preventable cause of neonatal and childhood brain damage worldwide. [ 11 ]  Although iodine is found in many foods, it is not universally present in all soils in adequate amounts. Most iodine, in iodide form, is in the oceans, where the iodide ions are reduced to elemental iodine, which then enters the atmosphere and falls to earth in rain, introducing iodine to soils. Soil deficient in iodine is most common inland, in mountainous areas, and in areas of frequent flooding. It can also occur in coastal regions, where iodine might have been removed from the soil by glaciation, as well as leaching by snow, water and heavy rainfall. [ 12 ]  Plants and animals grown in iodine-deficient soils are correspondingly deficient. Populations living in those areas without outside food sources are most at risk of iodine deficiency diseases. [ 13 ]


Dwarfism may also be caused by malnutrition or other hormonal deficiencies, such as insufficient growth hormone secretion,  hypopituitarism , decreased secretion of  growth hormone-releasing hormone , deficient  growth hormone receptor  activity and downstream causes, such as  insulin-like growth factor 1  (IGF-1) deficiency. [ 14 ]


There are public health campaigns in many countries which involve iodine administration. As of December 2019, 122 countries have mandatory iodine food fortification programs. [ 15 ]


Congenital iodine deficiency has been almost eliminated in developed countries through iodine supplementation of food and by  newborn screening  using a blood test for thyroid function. [ 5 ]


Treatment consists of lifelong administration of  thyroxine  (T4). Thyroxine must be dosed as tablets only, even to newborns, as the liquid oral suspensions and compounded forms cannot be depended on for reliable dosing. For infants, the T4 tablets are generally crushed and mixed with breast milk, formula milk or water.  If the medication is mixed with formulas containing iron or soya products, larger doses may be required, as these substances may alter the absorption of thyroid hormone from the gut. [ 16 ]   Monitoring TSH blood levels every 2–3 weeks during the first months of life is recommended to ensure that affected infants are at the high end of normal range. [ 17 ]


A  goiter  is the most specific clinical marker of either the direct or indirect insufficient intake of iodine in the human body. There is evidence of goiter, and its medical treatment with iodine-rich algae and burnt sponges, in Chinese, Egyptian, and Roman ancient medical texts. In 1848, King  Carlo Alberto  of  Sardinia  commissioned the first epidemiological study of congenital iodine deficiency syndrome, in northern  Savoy  where it was frequent. In past centuries, the well reported social diseases prevalent among the poorer social classes and farmers, caused by dietary and agricultural monocultures, were:  pellagra ,  rickets ,  beriberi ,  scurvy  in long-term sailors, and the  endemic goiter  caused by iodine deficiency. However, this disease was less mentioned in medical books because it was erroneously considered to be an aesthetic rather than a clinical disorder. [ 18 ]


Congenital iodine-deficiency syndrome was especially common in areas of southern Europe around the Alps and was often described by ancient Roman writers and depicted by artists. The earliest Alpine mountain climbers sometimes came upon whole villages affected by it. [ 19 ]  The prevalence of the condition was described from a medical perspective by several travellers and physicians in the late 18th and early 19th centuries. [ 20 ]   At that time the cause was not known and it was often attributed to "stagnant air" in mountain valleys or "bad water". The proportion of people affected varied markedly throughout southern Europe and even within very small areas; it might be common in one valley and not another. The number of severely affected persons was always a minority, and most persons were only affected to the extent of having a goitre and some degree of reduced cognition and growth. The majority of such cases were still socially functional in their pastoral villages. [ 21 ]


More mildly affected areas of Europe and North America in the 19th century were referred to as "goitre belts". The degree of iodine deficiency was milder and manifested primarily as thyroid enlargement rather than severe mental and physical impairment. In Switzerland, for example, where soil does not contain a large amount of iodine, cases of congenital iodine deficiency syndrome were very abundant and even considered genetically caused. As the variety of food sources dramatically increased in Europe and North America and the populations became less completely dependent on locally grown food, the prevalence of endemic goitre diminished. This is supported by a 1979 WHO publication which concluded that "changes in the origin of food supplies may account for the otherwise unexplained disappearance of endemic goitre from a number of localities during the past 50 years". [ 22 ]


The early 20th century saw the discovery of the relationships of neurological impairment with hypothyroidism due to iodine deficiency. Both have been largely eliminated in the developed world. [ 23 ]


The term  cretin  was originally used to describe a person affected by this condition, but, as with words such as  spastic  and  lunatic , it underwent  pejoration  and is now considered derogatory and inappropriate. [ 24 ]   Cretin  became a medical term in the 18th century, from an  Occitan  and an  Alpine   French  expression, prevalent in a region where persons with such a condition were especially common (see below); it saw wide medical use in the 19th and early 20th centuries, and was a "tick box" category on Victorian-era census forms in the UK. The term spread more widely in popular English as a markedly derogatory term for a person who behaves stupidly. Because of its pejorative connotations in popular speech, current usage among health care professionals has abandoned the noun "cretin" referring to a person. The noun  cretinism , referring to the condition, still occurs in medical literature and textbooks but its use is waning. [ citation needed ]


The etymology of  cretin  is uncertain. Several hypotheses exist. The most common derivation provided in English dictionaries is from the Alpine French dialect pronunciation of the word  Chrétien  ("(a)  Christian "), which was a greeting there. According to the  Oxford English Dictionary , the translation of the French term into "human creature" implies that the label "Christian" is a reminder of the humanity of the affected, in contrast to brute beasts. [ 25 ]  Other sources suggest that  Christian  describes the person's "Christ-like" inability to sin, stemming, in such cases, from an incapacity to distinguish right from wrong. [ 26 ] [ 27 ]


Other speculative etymologies have been offered:


Media related to  Congenital iodine deficiency syndrome  at Wikimedia Commons


Congenital malaria  was first reported in 1876, it is an extremely rare condition which occurs due to transplacental transmission of maternal infection. [ 1 ] [ 2 ]  Maternal  prophylactic treatments  of malaria can be important when talking about the risk of congenital malaria, as the absences of these treatments can increase the chance for a fetus to contract the disease. [ 3 ]  A positive cord or  peripheral blood smear  for malaria in a 24 hour to 7 day old newborn defines congenital malaria. [ 3 ]  This disease can persist past 7 days old, but after this mark it is then regarded as neonatal malaria rather than congenital. [ 4 ]


Maternal malaria is when a woman contracts malaria while pregnant. There is an increased risk of infection and severe malaria in women who are pregnant compared to women who are not. [ 5 ]  The depression of  cell-mediated immunity  is thought to be the cause of the increased risk of severity. [ 5 ]  The effects of malaria on pregnancy aren't the same risks as congenital malaria, the risks for maternal malaria include low birth weight, spontaneous abortion, congenital infection, stillbirth, preterm delivery, and maternal death. [ 5 ]


With maternal malaria, prophylactic treatments of malaria may reduce the risk of congenital malaria. [ 3 ]  It's recommended that pregnant women travelling to endemic regions start prophylactic treatments and the continue them after returning, which will help with reducing the risk of placental transmission. [ 5 ] [ 3 ]


The most common clinical features include fever,  anemia , and  splenomegaly . More rare clinical features include  hepatomegaly ,  jaundice , feeding issues, diarrhea, drowsiness or restlessness, and  cyanosis . [ 6 ]  Clinical features can commence anywhere from 10 days to 30 days after birth. [ 6 ]  This is due to the protective effect of transplacentally transmitted antibodies, a naturally low iron level, and fetal hemoglobin. [ 4 ] [ 1 ]  There's a chance that due to a delay in and non-specific presentation of symptoms from congenital malaria, it may be widely under-reported. [ 4 ]


Prevalence of congenital malaria has been wide debated over, and that might be because of the lack of a clear definition of the disease. [ 3 ]  The prevalence can range anywhere from 0% to 46%, but  PCR testing  and blood smears among other testing routes aren't the standard of care in endemic regions. [ 3 ]


The treatment of malaria varies between regions as the different species of Plasmodium require different medications. [ 5 ]  Treatment with  chloroquine  has been a success for some cases of  P. vivax , but there has been an increased report of chloroquine resistance. [ 6 ]  In these cases, and cases of  P. falciparum  and  P. ovale , a treatment plan of  sulfadoxine-pyrimethamine ,  artesunate , or a  quinine  and  clindamycin  was tried with good results. [ 6 ]


The first reported case of congenital malaria was reported in 1876. [ 2 ]  After this, more reported cases of congenital malaria were found and studied in Central Africa as far back as the 1920s and 1930s. [ 7 ]  Many reports before the 1970s had said that congenital malaria was a rare event with maternal malaria infections. [ 6 ]  But with the development of more testing methods for congenital malaria there's been a higher reported prevalence in some areas. [ 3 ]


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Congenital nephrotic syndrome  is a rare  kidney disease  which manifests in infants during the first 3 months of life, and is characterized by high levels of  protein  in the  urine  ( proteinuria ), low levels of protein in the blood, and swelling. [ 1 ]  This disease is primarily caused by genetic mutations which result in damage to components of the  glomerular  filtration barrier and allow for leakage of plasma proteins into the urinary space. [ 2 ]


Urine protein loss leads to total body swelling (generalized  edema ) and abdominal distension in the first several weeks to months of life. [ 1 ]  Fluid retention may lead to cough (from  pulmonary edema ),  ascites , and widened cranial sutures and  fontanelles . [ 1 ]  High urine protein loss can lead to foamy appearance of urine. Infants may be born prematurely with low birth weight, and have  meconium  stained amniotic fluid or a large placenta. [ 1 ] [ 3 ]


[ 1 ] [ 3 ]


Mutations in the following five genes account for greater than 80% of the genetic causes of congenital nephrotic syndrome: [ 1 ]


An examination reveals massive fluid retention and generalized  swelling . Abnormal sounds are heard when listening to the  heart  and lungs with a  stethoscope .  Blood pressure  may be high. The patient may have signs of  malnutrition . [ citation needed ]


A  urinalysis  reveals large amounts of protein and sometimes small amounts of blood in the urine. [ 4 ]  Kidney function may be normal in the first weeks or months of life. [ 3 ]  Laboratory studies show low serum levels of protein (albumin) and immunoglobulins, and elevated levels of triglycerides and cholesterol. [ 1 ]  Blood work may also show thyroid and vitamin D deficiency. [ 1 ]  Kidneys on ultrasound imaging may appear enlarged and brighter (hyperechoic). [ 4 ]  The disorder can be screened during  pregnancy  by finding elevated levels of  alpha-fetoprotein  on a routine sampling of  amniotic fluid . [ 3 ]


Indication for kidney biopsy remains unclear as histologic findings do no reveal the cause of congenital nephrotic syndrome, but findings may help in developing treatment strategies. [ 1 ] [ 2 ]  Findings on light microscopy can vary from  minimal change nephropathy  to  focal segmental glomerulosclerosis  or diffuse mesangial sclerosis. [ 3 ] [ 4 ]  Electron microscopy shows podocyte disruption (loss of  podocyte foot processes  or slit diaphragm). [ 3 ] [ 4 ]


Genetic analysis and infectious workup are needed to determine the precise cause of congenital nephrotic syndrome. [ 1 ]  Understanding the underlying cause can assist in disease management, prognosis, and genetic counseling. [ 1 ]


Genetic forms of nephrotic syndrome are typically resistant to steroid and other  immunosuppressive  treatment. [ 4 ]  Goals of therapy are to control urinary protein loss and swelling, provide good nutrition to allow the child to grow, and prevent complications. [ 1 ]  Early and aggressive treatment is required to control the disorder.


Patients with severe urine protein loss require albumin infusions help replace protein loss and  diuretic  medications help rid the body of excess fluid. [ 3 ]  For patients with mild to moderate urine protein losses,  ACE  inhibitor medications (like  Captopril  and others) and non-steroidal  anti-inflammatory drugs  (like  indomethacin ) are used to slow the spilling of  protein  (albumin) in the urine. [ 3 ] [ 4 ]  Removal of the  kidneys  (one at the time or both) can decrease protein loss and limit the number of albumin infusions needed. [ 1 ] [ 4 ]  Infants with  WT1  mutations will undergo bilateral kidney removal to prevent development of Wilms' tumor. [ 4 ]


Antibiotics may be needed to control infections. Immunizations are recommended after kidney removal but prior to transplantation. [ 3 ]  Patients may also take iron supplements, potassium chloride, thyroxine and other vitamins to replenish what minerals the kidneys have leaked out. Anticoagulants (such as  aspirin ,  dipyridamole , and  warfarin ) are used to prevent clot formation. [ 2 ] [ 3 ]


Dietary modifications may include the restriction of  sodium  and use of  dietary supplements  as appropriate for the nature and extent of  malnutrition . Fluids may be restricted to help control swelling. Children with this disease require diets high in calories and protein, and many patients require a feeding tube (nasogastric tube or gastrostomy tube (g-tube)) for medication and/or feeds. [ 3 ]  Some patients develop oral aversions and will use the tube for all feeds. Other patients eat well and only use the tube for medicine or supplemental feeds. The tube is also useful for patients needing to drink large amounts of fluids around the time of transplant. [ citation needed ]


While infants with infectious causes of congenital nephrotic syndrome may improve with antibiotics or antiviral medications, those with genetic causes progress to end-stage renal disease and require  dialysis , and ultimately a  kidney transplant . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


Congenital nephrotic syndrome can be successfully controlled with early diagnosis and aggressive treatment including albumin infusions, nephrectomy, and medications. Affected children have rapid decline in kidney function resulting in end-stage renal disease within the first years of life, and require treatment with dialysis and kidney transplantation. [ 1 ] [ 4 ]  Most children live fairly normal life post-transplant but will spend significant time hospitalised pre-transplant and have numerous surgeries to facilitate treatment. Kidney transplantation outcomes for children with congenital nephrotic syndrome are similar to those of other patient groups. [ 1 ] [ 2 ]  Nephrotic syndrome typically does not reoccur following kidney transplantation, however recurrences have been seen in children with  NPHS1  mutations who develop anti-nephrin antibodies. [ 1 ] [ 3 ] [ 4 ]